Conditions: Hereditary Angioedema (HAE)
Keywords: DX-2930(SHP643) Dyax Hereditary Angioedema
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 212
Healthy volunteers: no

Brief summary:
This study is an open-label, long term safety and efficacy study to evaluate DX-2930 in preventing acute angioedema attacks in participants with Type I and Type II HAE.

Detailed description:

Arms:
arm 1: Participants who rollover from the DX-2930-03 study will receive 300 milligram (mg) DX-2930 subcutaneous injection at Day 0 followed by second dose following the first HAE attack and then once in every 2 weeks until the end of the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days is required between subsequent administrations. arm 2: Participants who were not participants in DX-2930-03 will receive 300 milligram (mg) DX-2930 subcutaneous injection once in every 2 weeks until the end of the treatment period (up to 924 days).

Interventions: intervention 1: DX-2930 intervention 2: DX-2930
Intervention descriptions: intervention 1: Participants who rollover from the DX-2930-03 study will receive 300 milligram (mg) DX-2930 subcutaneous injection at Day 0 followed by second dose following the first HAE attack and then once in every 2 weeks until the end of the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days is required between subsequent administrations. intervention 2: Participants who were not participants in DX-2930-03 will receive 300 milligram (mg) DX-2930 subcutaneous injection once in every 2 weeks until the end of the treatment period (up to 924 days).

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT02741596 
 
Study Title:  
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long- 
Term Safety and Efficacy of DX-2930 for Prevention Against Acute 
Attacks of Hereditary Angioedema (HAE) 
 
 
Study Number:  
DX-2930-04 
 
 
Protocol Version and Date:  
 
Original Protocol: 14 December 2015 
Amendment 1.0: 27 June 2016 
Amendment 2.0: 20 January 2017 
Amendment 3.0: 29 June 2017 


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Clinical Trial Protocol: DX-2930-04
Study Title:
HELP Study ExtensionTM: An Open-Label Study to Evaluate the 
Long-Term Safety and Efficacy of DX-2930 for Prevention Against 
Acute Attacks of Hereditary Angioedema (HAE)
Study Number:
DX-2930-04
Study Phase:
Phase 3 
Product Name:
DX-2930
IND Number:
116647
EudraCT Number:
2015-005255-27
Indication:
Prevention of angioedema attacks in patients with HAE
Investigators:
Multicenter
Sponsor:
Dyax Corp.
55 Network Drive, Burlington, MA 01803 USA
Sponsor Contact:
, Clinical Development
55 Network Drive, Burlington, MA 01803 USA
Phone: 
Medical Monitor US 
and Canada:
, M.D.
Rho, Inc.
6330 Quadrangle Drive, Chapel Hill, NC 27517 USA
Phone: 
Medical Monitor 
Europe and Jordan:
, M.D.
Voisin Consulting
3, rue des Longs Prés
92100 Boulogne, France
Phone: 
Date:
Original Protocol
14 December 2015 
Confidentiality Statement
This document is the property of Dyax Corp. The information in this document contains trade secrets and 
commercial information that are privileged or confidential and may not be disclosed without the express written 
permission of Dyax unless required by federal or state law or regulations. Any person to whom the information 
is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential.


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PROTOCOL SIGNATURE PAGE
Study Title:
HELP Study ExtensionTM: An Open-Label Study to Evaluate the 
Long-Term Safety and Efficacy of DX-2930 for Prevention Against 
Acute Attacks of Hereditary Angioedema (HAE)
Study Number:
DX-2930-04
Final Date:
14 December 2015
This clinical study protocol was subject to critical review and has been approved by the 
Sponsor. The signature of the Sponsor representative indicates that the Sponsor will comply 
with all Sponsor obligations detailed in applicable regulations and guidelines and will ensure 
the Investigator is informed of all relevant information that becomes available.
Signed:
Date:
, Clinical Development
55 Network Drive, Burlington, MA 01803
I have read the foregoing protocol and agree that it contains all necessary details for carrying 
out this study.  I will conduct the study in compliance with the Declaration of Helsinki, Good 
Clinical Practice (GCP), and all applicable regulatory requirements and guidelines as 
outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study.  I will discuss this material with 
them to ensure they are fully informed regarding the drug and the conduct of the study.
I will use only the informed consent form approved by Dyax Corp. and my Institutional 
Review Board (IRB), Research Ethics Board (REB) or Ethics Committee (EC) and will 
fulfill all responsibilities for submitting pertinent information to the IRB/REB/EC 
responsible for this study.
I further agree that Dyax Corp. or their designees shall have access to any source documents 
from which eCRF information may have been generated.
By signing this protocol, I agree to adhere to the instructions and procedures described in it 
and thereby to adhere to the principles of GCP to which it conforms.
Signed:
Date:
Investigator
Address: 


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SYNOPSIS
Sponsor:
Dyax Corp.
Name of Finished Product:
DX-2930 Drug Product (DP)
Name of Active Ingredient:
DX-2930 is a recombinant, Chinese hamster ovary (CHO) cell-expressed, fully human 
immunoglobulin G subclass 1 (IgG1), kappa light chain, monoclonal antibody.
Names of Inactive Ingredients:
Sodium phosphate dibasic dihydrate, citric acid monohydrate, L-histidine, sodium chloride, 
and Polysorbate 80
Study Title:
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-Term Safety and 
Efficacy of DX-2930 for Prevention Against Acute Attacks of Hereditary Angioedema 
(HAE)
Study Number:
DX-2930-04
Study Phase: Phase 3
Study Location:
Approximately 60 study sites planned across the United States, Italy, United Kingdom, 
Germany, Canada and Jordan
Primary Objective:
To evaluate the long-term safety of repeated subcutaneous administrations of DX-2930
Secondary Objectives:
•
To evaluate the long-term efficacy of DX-2930 in preventing HAE attacks
•
To characterize the outer bounds of dosing frequency for DX-2930
Tertiary Objectives:
•
To assess the immunogenicity of chronically administered DX-2930
•
To evaluate the effect of DX-2930 upon quality of life (QOL) assessments
•
To evaluate Pharmacodynamic (PD) and Pharmacokinetic (PK) data following open-label 
DX-2930 dosing


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Study Design:
This study is an open-label, long term safety and efficacy study to evaluate DX-2930 in 
preventing acute angioedema attacks in patients with Type I and Type II HAE. There are two 
types of subjects who will be enrolled into this study:
1. Subjects who rollover from the DX-2930-03 study
2. Subjects who were not participants in DX-2930-03.
Roll-over Subjects:
Rollover subjects are subjects who complete the double-blind treatment period at Day 182 of 
the DX-2930-03 study and consent to enter DX-2930-04.  Subjects who discontinue from 
DX-2930-03 after enrollment are not eligible to enroll in DX-2930-04.  Willing subjects must 
sign informed consent for DX-2930-04 no later than the DX-2930-03 Day 182 treatment 
period study visit.  
The first DX-2930-04 visit for rollover subjects (Day 0) will occur on the same day as the 
DX-2930-03 Day 182 study visit. Rollover subjects will complete all DX-2930-03 final study 
assessments at which time they will be discharged from that study. No assessments 
conducted between the DX-2930-03 Day 182 study visit and the first DX-2930-04 visit 
(Day 0) will be duplicated. Results of the final DX-2930-03 assessments will be used as the 
pre-dose results for Day 0 Dose 1 of DX-2930-04.
Subjects who are eligible to roll over into DX-2930-04 but elect not to may not enroll in 
DX-2930-04 at a later time.
All subjects, caregivers, Investigators and site personnel will remain blinded to the 
DX-2930-03 treatment assignment until the conclusion of the DX-2930-04 study.
Non-rollover subjects:
Up to 50 subjects who were not participants in the DX-2930-03 study will be permitted to 
enroll if they meet the eligibility requirements. Subjects who screen fail out of DX-2930-03 
for not meeting the minimum attack requirements during the run-in period must wait until 
enrollment for the double-blind study has ended before they can screen for DX-2930-04. The 
Sponsor may ease this restriction based on the enrollment rate observed in DX-2930-03.
Screening Period:
There is no screening period for rollover subjects.
Non-rollover subjects must provide informed consent and have screening assessments 
completed within 4 weeks prior to their first open-label dose.  Screened non-rollover subjects 
who are on long-term prophylactic (LTP) therapy for HAE are required to undergo a 
minimum 2 week washout period prior to the start of the treatment period.  This LTP 
washout is permitted as long as the Investigator determines that doing so would not place the 
subject at any undue safety risk and the subject is at least 18 years of age.  The Investigator 
must confirm the subject has successfully completed the 2 week washout period and have no 
ongoing adverse events related to the washout before they can receive their first open-label 


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dose.
Treatment Period:
Rollover Subjects: Following informed consent and pre-dose assessments, rollover subjects 
will receive a single open-label dose of 300 mg DX-2930 administered subcutaneously (SC).    
Subjects will not receive any additional DX-2930 doses until their first reported HAE attack.  
The duration of time between the first open-label dose and first reported HAE attack will 
vary by rollover subject.  All rollover subjects must adhere to the Study Activities Schedule, 
for the entire duration of the study.  However, until a rollover subject reports their first HAE 
attack, only scheduled study visits where the following tests and assessments are performed 
must be conducted at the investigative site: pregnancy testing, clinical laboratory testing, 
physical examination, 12-Lead ECG, QOL, PK, PD and anti-drug antibody sample 
collection.  All other scheduled study visits may be conducted via site check-in calls to 
collect information on adverse events, concomitant therapy, and HAE attack data.  Refer to 
the Appendix 1 Study Activities Schedule.
Once a rollover subject reports their first HAE attack they will present to the investigative 
site for their second open-label dose of DX-2930 as quickly as subject and site schedules 
allow.  If the second dose is to be administered within the accepted ±4 day window around a
scheduled study visit, this treatment visit will represent that scheduled visit unless that 
scheduled visit has already occurred.  
For example, if the second dose is to be administered on Day 52, all of the tests and 
assessments scheduled for the Day 56 visit will be conducted.  This Day 52 visit to 
receive the second dose will count as the Day 56 visit. 
As another example, if the second dose is to be administered on Day 46, the subject can 
have this study visit count as their Day 42 visit if they have not already attended the Day 
42 visit. If they have already attended the Day 42 visit, then this Day 46 visit will be 
considered an acceptable, extra study visit.
In the scenario that the second dose is to be administered outside of the accepted ±4 day 
window around a scheduled visit, this visit will not replace any scheduled visit and will thus 
represent an acceptable, extra study visit. 
For example, if the second dose is to be administered on Day 63, this visit will represent 
an acceptable, extra study visit.  
Regardless of the study day, at the visit in which the second open-label dose of DX-2930 is 
administered, the subject will undergo pre-dose assessments for vital signs, physical 
examination, clinical laboratory testing, PK, PD, and anti-drug antibody. Vital signs will be 
obtained at 1 hour post-dosing. As with all study visits, information will be collected on 
adverse events, concomitant therapy, and HAE attack data. 
Subsequent doses after dose 2 require a minimum of 10 days and maximum of 18 days 
between administrations, and should fall within the accepted ±4 day window around study 


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visits.
For example, if the second dose is to be administered on Day 37, the third dose should be 
administered between Day 52 and Day 55, which would ensure both a dosing interval 
within 10 to 18 days from the second dose and a visit within the ±4 day window around 
the Day 56 study visit.  The fourth dose should then be administered between Day 66 and 
Day 73, which would ensure both a dosing interval within 10 to 18 days from the third 
dose and a visit within the ±4 day window around the Day 70 study visit.
Regardless of when a subject’s first HAE attack occurs, there will be a minimum of 10 days 
between their first open-label dose and their second open-label dose. Following their second 
dose, rollover subjects will continue to receive repeated SC administrations of open-label 
300 mg DX-2930 every 2 weeks for the remaining duration of the treatment period. The 
treatment period will last 26 weeks from the date of the first open-label dose. The number of 
doses administered during this period will vary by subject based on the date of each subject’s 
second dose, but will not exceed 13 doses. The Day 168 study visit is the last visit at which a
dose may be administered. 
Non-rollover Subjects: Once all screening assessments have been completed, eligibility 
confirmed and LTP washout completed (if applicable), non-rollover subjects will arrive at 
the study site and, following pre-dose assessments, receive an open-label dose of 300 mg 
DX-2930 administered SC.  Non-rollover subjects will continue to receive SC 
administrations of open-label 300 mg DX-2930 every 2 weeks throughout the duration of the 
treatment period.  A total of 13 doses will be administered with the last dose administered at 
the Day 168 study visit.
Follow-up Period:
After completion of the 26-week treatment period, all subjects will undergo safety 
evaluations during an 8-week follow-up period unless rolling over into another ongoing 
DX-2930 clinical study or access program that permits such a rollover.
Modifications to Open-Label Dosing:
If, at any time, an important dose-related safety signal is identified either from this study or 
DX-2930-03, the Sponsor may decide to switch the enrolled subjects who have not yet 
completed the treatment period, and any subsequent subjects, to receive a different open-
label DX-2930 dose and/or frequency.
In addition, based on the results of the DX-2930-03 study, the Sponsor may switch to a 
different dose and/or frequency. 
Study Population:
The study is expected to enroll subjects from the DX-2930-03 study, as well as up to 50 
additional subjects who were not enrolled in DX-2930-03. The total enrollment is expected to 
be approximately 150 HAE Type I or II subjects. Subjects will be 12 years of age or older 
who experience at least 1 attack per 12 weeks. HAE diagnosis will be confirmed through 
documented clinical history and diagnostic testing conducted either during screening or 
during prior participation in study DX-2930-02 or DX-2930-03.  The study will aim to enroll 


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at least 10 subjects who are 12 to 17 years of age, inclusive of subjects 12 to 17 years old 
who roll over from the DX-2930-03 study.
Criteria for Inclusion:
Subjects must meet the following criteria to be enrolled in this study:
1. Male and female HAE subjects who are 12 years of age or older at the time of screening. 
2. Documented diagnosis of HAE (Type I or II)  based on all of the following:

Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria).

Diagnostic testing results obtained during screening (or a prior DX-2930 study) 
that confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level < 40% of 
the normal level. Subjects with functional C1-INH level 40-50% of the normal 
level may be enrolled if they also have a C4 level below the normal range.  
Subjects may be retested if results are incongruent with clinical history or 
believed by the Investigator to be confounded by recent LTP use. 

At least one of the following: Age at reported onset of first angioedema symptoms 
≤ 30 years, a family history consistent with HAE Type I or II, or C1q within 
normal range.
3. A historical baseline HAE attack rate of at least 1 attack per 12 weeks
4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, 
understand, and sign an informed consent form. Subjects age 12 to 17, whose caregiver 
has provided informed consent, are willing and able to read, understand and sign an 
assent form.
5. Males and females who are fertile and sexually active must adhere to contraception 
requirements for the duration of the study as follows:

Females of childbearing potential must agree to be abstinent or else use any two of 
the following medically acceptable forms of contraception from the screening period 
through 30 days after the final study visit: progestin-only oral contraceptive, condom 
with or without spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or 
intra-uterine device (IUD, all types). A female whose male partner has had a 
vasectomy must agree to use one additional form of medically acceptable 
contraception.

Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal 
for at least 12 months do not require contraception during the study.

Males, including males who are surgically sterile (post vasectomy), with female 
partners of childbearing potential must agree to be abstinent or else use a medically 
acceptable form of contraception from the screening period through 60 days after the 
final study visit.


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Criteria for Exclusion:
Subjects who meet any of the following criteria will be excluded from the study:
1. Discontinued from DX-2930-03 after enrollment for any reason.
2. If rolling over from DX-2930-03, presence of important safety concerns that would 
preclude participation in this study.
3. Concomitant diagnosis of another form of chronic, recurrent angioedema such as 
acquired angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), 
idiopathic angioedema, or recurrent angioedema associated with urticaria. 
4. Dosing with an investigational drug (not including DX-2930) or exposure to an 
investigational device within 4 weeks prior to screening.
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systemic absorption (such as oral contraceptives or hormonal 
replacement therapy) within 4 weeks prior to screening.
6. Use of long-term prophylactic therapy for HAE (C1-INH, attenuated androgens, or anti-
fibrinolytics) within 2 weeks prior to the start of the treatment period (Day 0).
7. Use of short-term prophylaxis for HAE by non-rollover subjects within 7 days prior to 
the start of the treatment period (Day 0).  Short-term prophylaxis is defined as C1-INH, 
attenuated androgens, or anti-fibrinolytics used to avoid angioedema complications from 
medically indicated procedures.
8. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) 
> 3x upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of 
normal, or total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a 
result of Gilbert’s Syndrome).
9. Pregnancy or breastfeeding.
10. Subject has any condition that, in the opinion of the Investigator or Sponsor, may 
compromise their safety or compliance, preclude successful conduct of the study, or 
interfere with interpretation of the results (e.g., history of substance abuse or dependence, 
a significant pre-existing illness or other major comorbidity that the Investigator 
considers may confound the interpretation of study results).
Test Product; Dose; and Mode of Administration:
DX-2930 is a sterile, preservative-free solution for injection, pH 6.0. The active ingredient, 
DX-2930, is formulated using the following compendial components:  30 mM sodium 
phosphate dibasic dihydrate, 19.6 mM citric acid, 50 mM histidine, 90 mM sodium chloride, 
0.01% Polysorbate 80. Each open-label vial contains a nominal concentration of 150 mg 
DX-2930 active ingredient in 1 mL solution.
For each 300 mg dose of DX-2930, each subject will receive a total of 2 mL, which will be 
administered in a single 2 mL SC injection. The injection will be given in the upper arm, 
thigh or abdomen.
Duration of Treatment:
All subjects will receive open-label DX-2930 during a 26-week treatment period. The 
number of doses that rollover subjects receive during this period will vary by subject but will 
not exceed 13 doses. The last dose of open-label DX-2930 administered to these subjects 


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may be given at the Day 168 study visit. Non-rollover subjects will receive 300 mg DX-2930 
every 2 weeks for a total of 13 doses, with the first dose administered on Day 0 and the final 
dose administered at the Day 168 study visit.
There will be a ±4-day window around each study visit. There will be a minimum of 10 days 
between any two doses. Excluding the interval between the first and second open-label doses 
for rollover subjects, there will be a maximum of 18 days between any two doses. Subjects 
will be monitored at the study site through 1 hour post-dose.
Duration of Study for Individual Subjects:
Following informed consent, subjects will either rollover from DX-2930-03 or undergo 
screening assessments (non-rollover subjects). Screening assessments for non-rollover 
subjects must occur within 4 weeks prior to the first open-label dose. Eligible subjects will be 
enrolled and undergo a 26-week treatment period. At the conclusion of the 26-week 
treatment period, subjects will be followed for an additional 8 weeks unless rolling over into 
another ongoing DX-2930 clinical study or access program that permits such a rollover.
Prohibited Concomitant Treatments:
Use of the following treatments will not be permitted during the study:
•
Long-term prophylaxis for HAE (e.g., use of C1-INH for long-term prophylaxis, 
attenuated androgens, or anti-fibrinolytics).
•
Angiotensin-converting enzyme (ACE) inhibitors.
•
Estrogen-containing medications with systemic absorption (such as oral contraceptives or 
hormonal replacement therapy).
•
Androgens (e.g., stanozolol, danazol, oxandrolone, methyltestosterone, testosterone).
•
Any other investigational drug or device.
The use of short-term prophylactic treatment for HAE will be permitted if medically 
indicated.  Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-
fibrinolytics used to avoid angioedema complications from medically indicated procedures.
Management of Acute Attacks:
Acute HAE attacks during the study are to be managed in accord with the Investigator’s 
usual care of their patients, including use of acute attack therapies that the Investigator 
deems as medically appropriate. Use of C1-INH will be permitted as an acute attack therapy 
but not as a long-term prophylactic therapy.
Safety Assessments:
Safety assessments will include the following:
•
Adverse events (AEs), including serious adverse events (SAEs) and adverse events of 
special interest (AESI). SAEs and AESI will be reported to the Sponsor within 24 hours 
of becoming aware of the event.
•
Vital signs, including sitting or supine blood pressure (BP), heart rate (HR), body 
temperature, and respiratory rate (RR)
•
Physical examination


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•
Clinical laboratory testing (hematology, serum chemistry, coagulation and urinalysis)
•
12-Lead electrocardiogram (ECG)
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Hypersensitivity reactions and events of disordered coagulation will be considered AESI.
Pharmacokinetic (PK) Assessments:
Blood samples will be collected for the measurement of plasma DX-2930 concentrations.
Pharmacodynamic (PD) Assessments:
Blood samples will be collected to evaluate the pharmacodynamic effects of DX-2930 
through biomarker assays.
Immunogenicity Assessments:
Blood samples will be collected to assay for the presence of anti-drug antibodies, including 
evaluation of neutralizing antibodies (if any confirmed positive anti-drug antibodies are 
detected).
C1-INH, C1q and C4 Assessments:
Samples will be obtained for C1-INH, C4, and C1q assays at screening for non-rollover 
subject eligibility assessment.
Quality of Life Assessments:
Quality of life (QOL) assessments will be conducted using the EQ5D, SF-36 and the 
Angioedema Quality of Life Questionnaire (AEQoL).
Collection of HAE Attack Data:
The collection, reporting and assessment of attacks in this study will be done in accordance 
with the HAE Attack Assessment and Reporting Procedures (HAARP). Refer to Appendix 4.  
Site personnel will be trained on HAARP prior to screening and enrolling subjects at their 
site.
Site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide.  The 
patient (and caregiver) will confirm their understanding of what is required of them for 
reporting attacks to the site.
At screening, HAE attack history will be collected for non-rollover subjects. Information 
collected will include any prior history of laryngeal attacks, attack frequency, average 
severity, predominant attack location(s), average duration, acute attack therapy use and 
history of long-term prophylaxis.
During the study, subjects (or caregivers) will be instructed to notify and report details to the 
study site within 72 hours of the onset of an attack. This includes the first attack experienced 
by rollover subjects following their first open-label dose.  In the situation that a subject is 
incapacitated following an attack, this information can be provided to the site by a family 
member or other individual with detailed knowledge of the event. If desired by the subject, 
memory aids may be provided to assist in tracking any HAE attacks experienced. 


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Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack:

Date and time symptoms of an attack were first experienced

Description of symptoms experienced, including location(s)

Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits

Any medications used to treat the attack

If the attack resolved, date and time the subject was no longer experiencing symptoms
Site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP.
Site personnel will contact rollover subjects approximately every 7 days following the first 
dose of open-label DX-2930 to solicit for any HAE attacks not already reported.  Site check-
ins will continue until the subject has received their second open-label dose.
During each study visit, site personnel will solicit for any new HAE attack information that 
was not already provided to the site.
In this study, HAE attacks will be captured as AEs. All AEs, regardless of seriousness, 
severity, or causal relationship to DX-2930, will be recorded on the AE page of the 
eCRF. Any AE reported to the site meeting criteria for a serious adverse event must be 
reported to the Sponsor using the SAE Reporting Form in the EDC system within 24 hours of 
becoming aware of the event. For all serious adverse events that are reported as HAE 
attacks, the Principal Investigator or physician designee will review the event within 24 hours 
of initial notification and, in accordance with HAARP, evaluate if it represented a confirmed 
HAE attack. For all non-serious AEs that are reported as HAE attacks, the Principal 
Investigator or physician designee will review the event within 3 days of initial notification 
and, in accordance with HAARP, evaluate if it represented a confirmed HAE attack. If 
necessary for the evaluation, the Investigator or designee may contact the subject to receive 
additional information. Any subject-reported attack not confirmed by the Investigator or 
physician designee must have an alternate AE diagnosis recorded.  All subject-reported and 
Investigator/ physician designee-confirmed HAE attacks will be recorded in the eCRF. 
Emergency department visits for HAE attacks and HAE attacks resulting in hospital 
admissions will be captured.
To be confirmed as an attack, the event must have symptoms or signs consistent with an 
attack in at least one of the following locations: 
•
Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region


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•
Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea
•
Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx
Despite the presence of these symptoms, the investigator or physician designee may still 
clinically determine that the event did not represent an attack if there are features that 
strongly refute such a diagnosis. For example, the reported event is accompanied by 
symptoms that are not consistent with an HAE attack (e.g., urticaria), the reported event 
persists well beyond the typical time course of an HAE attack (e.g., greater than 7 days), or 
there is a likely alternate etiology for the event (e.g., the subject’s abdominal symptoms are 
attributable to a viral gastroenteritis outbreak in the household). 
To be counted as a unique attack distinct from the previous attack, the new symptoms must 
occur at least 24 hours after resolution of the prior attack’s symptoms.
Study Stopping Rules:
Safety data, including SAEs and AESI, will be monitored regularly throughout the duration 
of the study. If any potential safety signal is identified as a result of monitoring in this study, 
or from any safety findings from the DX-2930-03 study, the Sponsor may take actions as 
deemed appropriate, including suspending further dosing, while the potential risk is 
evaluated and a course of action has been determined.
Individual Stopping Rules:
Dosing for any individual subject will be discontinued if the subject experiences a 
DX-2930-related SAE (or a DX-2930-related, clinically significant non-serious AE) that, in 
the assessment of the Investigator, warrants discontinuation from further dosing for that 
subject’s well-being. The Investigator has the ability to contact and consult with the Medical 
Monitor on such matters. Subjects will continue to be followed through the completion of all 
scheduled non-dosing visits, unless they request to be discontinued from the study.
Criteria for Evaluation:
Safety Measures:
•
AEs including SAEs and AESI
•
Clinical Laboratory testing (hematology, clinical chemistry, coagulation and urinalysis)
•
Vitals signs including blood pressure, heart rate, oral body temperature and respiratory 
rate
•
Physical Examination
•
12-lead ECG
Efficacy Endpoints:
•
Time to first HAE attack for rollover subjects (based upon time from first open label 
study dose until first HAE attack)
•
Mean rate of HAE attacks for all subjects (14 days post-second dose to Day 182 for 
rollover subjects; Day 14 to Day 182 for non-rollover subjects)


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•
Mean rate of acute therapy usage for all subjects (14 days post-second dose to Day 182 
for rollover subjects; Day 14 to Day 182 for non-rollover subjects)
•
Mean rate of moderate or severe attacks for all subjects (14 days post-second dose to 
Day 182 for rollover subjects; Day 14 to Day 182 for non-rollover subjects)
•
Mean rate of high-morbidity attacks for all subjects (14 days post-second dose to 
Day 182 for rollover subjects; Day 14 to Day 182 for non-rollover subjects); a high-
morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation 
< 24 hours), hemodynamically significant (systolic blood pressure < 90, requires IV 
hydration, or associated with syncope or near-syncope) or laryngeal.
Additional Measures:
•
Anti-drug antibody development
•
Pharmacokinetics (PK) 
•
Pharmacodynamic (PD) effects
•
Quality of Life Assessments
Analysis Populations:
The analysis population will be based on subjects who receive at least one dose of DX-2930 
after entering the study.
Sample Size Determination:
No formal sample size calculation was performed.  The sample size is not based on any 
statistical considerations.  This study is designed to evaluate the safety and efficacy of open-
label treatment with DX-2930 in subjects who participated in DX-2930-03 and individuals 
who were not otherwise able to participate in DX-2930-03.
Statistical Methodology:  
The distribution of time from first open-label dose to first HAE attack will be determined for 
rollover subjects. The estimation will be based on a standard Cox proportional hazards model 
where several baseline covariates will be tested including baseline attack rate prior to 
entering DX-2930-03, the treatment arm in DX-2930-03, the time since the last dose given in 
DX-2930-03, the time since the last HAE attack, and the rate of attacks during DX-2930-03. 
The distribution of time to first attack will be adjusted for any significant baseline (p < 0.05) 
covariates, and by examining the distribution separately by the treatment arm the patient was 
in during DX-2930-03. In this survival analysis, one observation (time to first attack) per 
subject will be generated.
For other efficacy endpoints, mean event rates will be assessed for all subjects (14 days post-
second dose to Day 182 for rollover subjects; Day 14 to Day 182 for non-rollover subjects).
In addition, for rollover subjects, the mean change from the documented values in 
DX-2930-03 at baseline (last measurement prior to randomization into DX-2930-03) and 
entry (last measurement in DX-2930-03 prior to enrollment into DX-2930-04) will be 
compared to the values assessed at DX-2930-04 time points from 14 days after the second 


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dose in DX-2930-04 through Day 182 (i.e., 2 weeks after the final scheduled dose on 
Day 168). Changes will be calculated and presented as descriptive statistics for each 
DX-2930-03 treatment group (300 mg DX-2930 every 2 weeks, 300 mg DX-2930 every 4 
weeks, 150 mg DX-2930 every 4 weeks). For each time period, graphs will be constructed 
for mean changes in efficacy variables from baseline. Time periods will be defined as 
relative time from the DX-2930-03 baseline for those who participated.
For non-rollover subjects, efficacy variables will be presented as descriptive statistics only.
For disposition, demographic and safety analyses, subjects will be represented in the 
reporting as follows:

Subjects who received 26 weeks of 300 mg DX-2930 every 2 weeks in DX-2930-03 
and up to 26 weeks of DX-2930 treatment in DX-2930-04.

Subjects who received 26 weeks of 300 mg DX-2930 every 4 weeks in DX-2930-03 
and up to 26 weeks of DX-2930 treatment in DX-2930-04.

Subjects who received 26 weeks of 150 mg DX-2930 every 4 weeks in DX-2930-03 
and up to 26 weeks of DX-2930 treatment in DX-2930-04.

Subjects who received 26 weeks of placebo in DX-2930-03 and up to 26 weeks of 
DX-2930 treatment in DX-2930-04.

Subjects who received up to 26 weeks of DX-2930 treatment in DX-2930-04.
Data from the start of DX-2930 treatment through the final treatment period study visit (up to 
52 weeks for subjects whose treatment with DX-2930 was initiated in DX-2930-03) will be 
combined for safety evaluation of the overall DX-2930 exposure.
Safety Analysis:
All Subjects:
Safety measures include AEs, concomitant medications, clinical laboratory tests, vital signs 
(blood pressure, heart rate, respiratory rate, and body temperature), physical examination 
findings, and ECGs.
Treatment-emergent AEs (TEAEs) are defined as AEs with onset at the time of or following 
the start of treatment with DX-2930, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. The number and percentage of subjects with TEAEs will be displayed by body 
system and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Summaries in terms of severity and relationship to DX-2930 will also be 
provided. SAEs will be summarized separately in a similar fashion. Patient listings of AEs 
causing discontinuation of DX-2930 treatment, AEs resulting in death, SAEs and AESI will 
be produced.


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AESI will be analyzed according to primary System Organ Classes (SOCs) and Preferred 
Terms (PTs) determined by the search of relevant Standardized MedDRA Queries (SMQs). 
Summary tables with SOCs and PTs, from the SMQ searches, will be generated 
presenting the number and percentage of subjects by AE, severity, seriousness, and 
relationship to study medication.
Usage of concomitant medications (other than rescue medications) will be summarized 
descriptively.
Actual values and change from Day 0 in vital signs and clinical laboratory tests will be 
summarized with descriptive statistics at each assessment obtained. For all laboratory tests, a 
shift table will be produced summarizing changes from normal to abnormal and vice-versa.
The number and percentage of subjects with normal, abnormal-not clinically significant, and 
abnormal-clinically significant ECG findings will be displayed. Other safety parameters, 
such as subject withdrawals will be summarized.
Rollover Subjects: Adverse events that started during subject participation in DX-2930-03 
and were ongoing at the time of first open-label dose in DX-2930-04 will not be counted as 
an AE in DX-2930-04 unless that event has worsened in severity or frequency following the 
first open-label dose.  Adverse events that started during subject participation in DX-2930-03 
and resolved following the first open-label dose in DX-2930-04 and then subsequently 
reappeared in DX-2930-04 will be counted as a new TEAE in DX-2930-04.
The incidence of AEs in DX-2930-04 from each DX-2930-03 treatment group (300 mg 
DX-2930 every 2 weeks vs. 300 mg DX-2930 every 4 weeks vs. 150mg DX-2930 every 4 
weeks vs placebo) as well as evaluation of overall AEs in the combined group of all rollover 
subjects will be assessed.  Changes from baseline (last measurement prior to the first dose of 
DX-2930 received, regardless of if it occurred in DX-2930-03 or DX-2930-04) to the 
DX-2930-04 time points for physical examination results, vital sign parameters, and clinical 
laboratory parameters will be summarized by DX-2930-03 treatment group and for the 
combined group of all rollover subjects.
Non-rollover Subjects: Adverse events will be captured from the time of informed consent 
through the final study visit.  Adverse event tabular summaries will be based on all 
treatment-emergent AEs
Date of Original Protocol:  14 December 2015


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Final: 14 December 2015
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Study Activities Schedule 
Study Activities Schedule
Screening 
Visit1
Treatment Period
± 4 days for each visit 
Follow-up Period2
± 4 days for each 
visit
Tests and 
Assessments
Visit 1
Dose 1
Day 0
Site 
Check
-in3
Visit 2 
Dose 24
Day 14
Visit 3 
Dose 3
Day 28
Visit 4 
Dose 4
Day 42
Visit 5 
Dose 5
Day 56
Visit 6
Dose 6
Day 70
Visit 7 
Dose 7
Day 84
Visit 8 
Dose 8
Day 98
Visit 9
Dose 9
Day 112
Visit 10 
Dose 10
Day 126
Visit 11 
Dose 11
Day 140
Visit 12
Dose 12
Day 154
Visit 13 
Dose 13
Day168
Visit 14
Day 182
Visit 15
Day 2105
Visit 16
Day 238
Informed Consent6
X
Eligibility Review
X
X
Long-term 
prophylactic 
therapy washout7
X
DX-2930 
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
Demographic and 
Medical History
X
C1-INH, C1q and 
C4 Testing8
X
Pregnancy Test9 
(females)
X
X
X
X
X
Vital Signs10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examination11
X
X
X
X
X
X
X
Clinical 
Laboratory 
Testing12
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
Concomitant 
Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HAE Attack Data13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Assessments14
X
X
X
X


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Study Activities Schedule
Screening 
Visit1
Treatment Period
± 4 days for each visit 
Follow-up Period2
± 4 days for each 
visit
Tests and 
Assessments
Visit 1
Dose 1
Day 0
Site 
Check
-in3
Visit 2 
Dose 24
Day 14
Visit 3 
Dose 3
Day 28
Visit 4 
Dose 4
Day 42
Visit 5 
Dose 5
Day 56
Visit 6
Dose 6
Day 70
Visit 7 
Dose 7
Day 84
Visit 8 
Dose 8
Day 98
Visit 9
Dose 9
Day 112
Visit 10 
Dose 10
Day 126
Visit 11 
Dose 11
Day 140
Visit 12
Dose 12
Day 154
Visit 13 
Dose 13
Day168
Visit 14
Day 182
Visit 15
Day 2105
Visit 16
Day 238
PK Blood 
Sampling15
X
X
X
X
PD Sample 
Collection15
X
X
X
X
Plasma Anti-Drug 
Antibody Testing15
X
X
X
X
Discharge from 
Study16
X
ECG = Electrocardiogram; PK = Pharmacokinetic; PD = Pharmacodynamic
1. Screening visit is for non-rollover subjects only.  Screening visit can occur up to 28 days prior to first open-label dose.
2. The Follow-up Period is not required for subjects who choose to roll over into an ongoing DX-2930 clinical study or access program that permits such a rollover.
3. Site personnel will contact rollover subjects approximately every 7 days following the first dose of open-label DX-2930 to solicit for any HAE attacks not already reported.  Site 
check-in with rollover subjects will continue until the subject receives their second open label dose.
4. For rollover subjects, the timing of Dose 2 for will vary by subject based on when their first HAE attack occurs following Dose 1.  Following the first reported attack, subjects 
will begin receiving regular SC administrations of 300 mg DX-2930 every 2 weeks.  A minimum of 10 days between the first and second open-label doses is required. If the 
second dose is to be administered within the accepted ±4 day window around a scheduled study visit, this treatment visit will represent that scheduled visit unless that scheduled 
visit has already occurred. If that scheduled visit has already occurred, or if the second dose is to be administered outside of the accepted ± 4 day window around a scheduled 
visit, this visit will not replace any scheduled visit and will thus represent an acceptable, extra study visit. Regardless, at the visit in which the second open-label dose of DX-
2930 is administered, the subject will undergo pre-dose assessments for vital signs, physical examination, clinical laboratory testing, PK, PD, and anti-drug antibody. Vital signs 
will be obtained at 1 hour post-dosing. As with all study visits, information will be collected on adverse events, concomitant therapy, and HAE attack data. 
5. The Day 210 Visit is a site check-in for all rollover and non-rollover subjects.
6. Rollover subjects will provide consent no later than the Day 182 DX-2930-03 study visit.
7. Non-rollover subjects who are on long-term prophylactic (LTP) therapy for HAE are required to undergo a minimum 2 week washout period prior to the start of the treatment 
period.
8. Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment unless already collected as part of protocol DX-2930-02 or DX-2930-03.  
9. The pregnancy test will only be conducted in females of childbearing potential.  Tests performed on Day 0 must be urine-based to confirm eligibility prior to first dose.  Tests 
performed at screening, Day 98, Day 182, and Day 238 can be serum or urine-based.
10.There is a ± 15 minute window for all vital signs. Vital signs will be obtained prior to dosing and 1 hour after dosing.
11.Height and weight will be collected at the Screening visit only. Physical examinations will be conducted for all rollover and non-rollover subjects according to the study 
activities schedule.  In addition to the physical examinations specified in the study activities schedule, an additional physical examination will be conducted for these subjects 
prior to dosing on the day of their second open-label dose, at whatever study visit that occurs.


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12.Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis. Clinical laboratory testing will be conducted for all rollover and non-
rollover subjects according to the study activities schedule.  In addition to the testing specified in the study activities schedule, additional testing will be conducted for rollover 
subjects prior to dosing on the day of their second open-label dose, at whatever study visit that occurs.
13.Historical attack information will be collected at screening. During the study subjects (or caregivers) are instructed to report details of the attack to the study site within 72 hours 
of the onset of the attack. During study visits, site personnel will solicit for any new HAE attack information that was not given through prior subject contact with the site.
14.Quality of life data will be obtained using the EQ5D, SF-36 and Angioedema Quality of Life Questionnaire (AE-QoL).
15.PK, PD and Anti-drug Antibody PD samples will be drawn for all rollover and non-rollover subjects according to the study activities schedule.  In addition to the samples 
specified in the study activities schedule, an additional PK, PD and Anti-drug Antibody sample will be drawn for rollover subjects prior to dosing on the day of their second 
open-label dose, at whatever study visit that occurs.
16.Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures as Day 182 at their final study visit.


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Clinical Trial Protocol: DX-2930-04
Final: 14 December 2015
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE ...........................................................................................2
SYNOPSIS.................................................................................................................................3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................24
1
INTRODUCTION ...........................................................................................................27
1.1
DX-2930 ................................................................................................................27
1.2
Hereditary Angioedema.........................................................................................27
1.3
Therapeutic Rationale for DX-2930 ......................................................................27
1.4
Safety Rationale for DX-2930 ...............................................................................28
1.5
DX-2930 Non-Clinical Pharmacology and Toxicology........................................28
1.6
DX-2930 Clinical Data ..........................................................................................29
1.6.1
Single-Ascending Dose Study in Healthy Subjects (DX-2930-01).............29
1.6.2
Multiple-Ascending Dose Study in HAE Patients (DX-2930-02)...............29
1.7
Rationale for Open-Label Extension Study DX-2930-04......................................31
2
STUDY OBJECTIVES....................................................................................................32
2.1
Primary Objective..................................................................................................32
2.2
Secondary Objectives.............................................................................................32
2.3
Tertiary Objectives.................................................................................................32
3
INVESTIGATIONAL PLAN..........................................................................................33
3.1
Overall Study Design and Plan..............................................................................33
3.1.1
Overview......................................................................................................33
3.1.2
Stopping Rules.............................................................................................36
3.1.2.1
Study Level Stopping Rules...............................................................36
3.1.2.2
Individual Stopping Rules..................................................................37
3.1.3
Follow-up for Subjects Meeting Stopping Criteria......................................37
3.2
Rationale for Open-Label Extension Dose Selection ............................................37
3.3
Individual Subject Dosing and Follow-Up ............................................................37
3.4
Study Duration for Individual Subjects .................................................................38
4
STUDY POPULATION SELECTION ...........................................................................39
4.1
Study Population....................................................................................................39
4.2
Inclusion Criteria ...................................................................................................39
4.3
Exclusion Criteria ..................................................................................................40
5
STUDY TREATMENT(S)..............................................................................................42
5.1
Description of Treatment(s)...................................................................................42
5.2
Dosing and Follow-Up Scheme.............................................................................42
5.3
Method of Identifying Subjects .............................................................................42
5.4
Prior and Concomitant Therapy.............................................................................43


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5.4.1
Allowed Therapies.......................................................................................43
5.4.2
Excluded Concomitant Therapies................................................................43
5.5
Restrictions ............................................................................................................43
5.5.1
Medical Interventions ..................................................................................43
5.5.2
Fluid and Food Intake..................................................................................44
5.5.3
Activity ........................................................................................................44
5.6
Treatment Compliance...........................................................................................44
5.7
Packaging and Labeling.........................................................................................44
5.8
Storage and Accountability....................................................................................44
5.9
Investigational Medicinal Product Retention at Study Site...................................44
6
STUDY PROCEDURES .................................................................................................45
6.1
Informed Consent...................................................................................................45
6.2
Eligibility Review..................................................................................................45
6.3
Demographics and Medical History ......................................................................45
6.4
HAE Attack Information Collection......................................................................45
6.5
Vital Signs..............................................................................................................47
6.6
Physical Examination.............................................................................................47
6.7
Electrocardiography (ECG) ...................................................................................48
6.8
Clinical Laboratory Tests.......................................................................................48
6.8.1
Laboratory Parameters.................................................................................48
6.8.1.1
Hematology........................................................................................49
6.8.1.2
Coagulation........................................................................................49
6.8.1.3
Chemistry...........................................................................................49
6.8.1.4
Urinalysis ...........................................................................................50
6.8.1.5
Pregnancy Test...................................................................................50
6.8.1.6
C1-INH Functional Assay..................................................................50
6.8.1.7
C4 Assay............................................................................................50
6.8.1.8
C1q Assay..........................................................................................50
6.8.1.9
PK Sample Collection........................................................................51
6.8.1.10
PD Sample Collection........................................................................51
6.8.1.11
Plasma Anti-Drug Antibody Testing .................................................51
6.8.2
Sample Collection, Storage, and Shipping ..................................................51
6.9
Pharmacokinetic Assessments ...............................................................................51
6.10
Pharmacodynamic Assessments ............................................................................51
6.11
Plasma Anti-Drug Antibody Testing .....................................................................51
6.12
Prior and Concomitant Therapy.............................................................................51
6.13
Investigational Medicinal Product Treatment........................................................52
6.14
Quality of Life Assessments..................................................................................52
6.15
Adverse Event Reporting.......................................................................................52
6.15.1
Definitions....................................................................................................52


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6.15.1.1
Adverse Event....................................................................................52
6.15.1.2
Serious Adverse Event.......................................................................53
6.15.1.3
Overdose ............................................................................................53
6.15.1.4
Planned Hospitalization .....................................................................53
6.15.1.5
Treatment-Emergent Adverse Events (TEAE) ..................................53
6.15.1.6
Adverse Events of Special Interest (AESI)........................................54
6.15.2
Monitoring ...................................................................................................54
6.15.2.1
Monitoring of Adverse Events...........................................................54
6.15.2.2
Monitoring of Safety Laboratory Assessments..................................55
6.15.3
Assessment of Adverse Events....................................................................55
6.15.3.1
Assessment of Severity......................................................................55
6.15.3.2
Assessment of Causality ....................................................................56
6.15.3.3
Assessment of Clinical Significance..................................................56
6.15.4
Clinical Laboratory Adverse Events............................................................57
6.15.5
Reporting Investigator Safety Observations to the Sponsor........................57
6.15.5.1
Reporting Non-serious Adverse Events.............................................57
6.15.5.2
Reporting Pregnancies .......................................................................57
6.15.5.3
Safety Observations Requiring Expedited Reporting by the 
Investigator to Dyax...........................................................................58
6.15.5.4
Expedited Reporting by the Sponsor to a Regulatory Health 
Authority............................................................................................58
6.15.5.5
Safety Contact Information................................................................59
6.15.5.6
Safety Notifications by the Sponsor to the Investigator ....................59
6.16
Subject Withdrawal................................................................................................59
6.17
Appropriateness of Measurements.........................................................................60
7
STUDY ACTIVITIES .....................................................................................................61
7.1
Screening Visit (Up to Day −28) For Non-Rollover Subjects...............................61
7.2
Start of Treatment Period: Visit 1, Dose 1 (Day 0) ...............................................61
7.3
Interval between Dose 1 and Dose 2 for Rollover Subjects ..................................62
7.4
Dose 2 of DX-2930 for Rollover Subjects.............................................................63
7.5
Visit 2 (Day 14 ±4 days); Dose 2 of DX-2930 for Non-Rollover Subjects...........64
7.6
Continuation of Treatment Period: Visits 3 and 4 (Days 28 and 42, All 
±4 Days).................................................................................................................65
7.7
Continuation of Treatment Period: Visit 5 (Day 56 ±4 Days)...............................65
7.8
Continuation of Treatment Period: Visits 6 and 7 (Days 70 and 84, All 
±4 Days).................................................................................................................66
7.9
Continuation of Treatment Period: Visit 8 (Day 98 ±4 Days)...............................66
7.10
Continuation of Treatment Period: Visits 9 and 10 (Days 112 and 126, All 
±4 Days).................................................................................................................67
7.11
Continuation of Treatment Period: Visit 11 (Day 140 ±4 Days)...........................67
7.12
Continuation of Treatment Period: Visits 12 and 13 (Days 154 and 168 All 
±4 Days).................................................................................................................68


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7.13
Completion of Treatment Period: Visit 14 (Day 182 ±4 Days).............................69
7.14
Follow-up Period: Visit 15 (Day 210 ±4 Days).....................................................69
7.15
Final Follow-up Visit: Visit 16 (Day 238 ±4 Days) ..............................................69
7.16
Early Termination..................................................................................................70
8
QUALITY CONTROL AND ASSURANCE .................................................................71
9
DATA ANALYSIS / STATISTICAL METHODS.........................................................72
9.1
Sample Size Determination....................................................................................72
9.2
Analysis Populations..............................................................................................72
9.3
Comparison of Interest...........................................................................................72
9.4
Analysis of Disposition..........................................................................................73
9.5
Demographics and Baseline Characteristics Analyses ..........................................73
9.6
Analysis of Pharmacokinetic and Pharmacodynamic Endpoints...........................73
9.6.1
Pharmacokinetic Assessments:....................................................................73
9.6.2
Pharmacodynamic Assessments: .................................................................73
9.6.3
Immunogenicity Assessments:.....................................................................73
9.6.4
C1-INH, C4 and C1q Assessments:.............................................................73
9.7
Analysis of Efficacy Endpoints .............................................................................74
9.7.1
Efficacy Endpoints.......................................................................................74
9.8
Safety Analysis ......................................................................................................75
9.9
Analysis of Quality of Life Assessments...............................................................76
10
STUDY ADMINISTRATIVE STRUCTURE.................................................................77
10.1
Institutional Review Board/ Research Ethics Board/Independent Ethics 
Committee..............................................................................................................78
10.2
Ethical Conduct of the Study.................................................................................78
10.3
Subject Information and Consent...........................................................................78
10.4
Subject Confidentiality ..........................................................................................78
10.5
Study Monitoring...................................................................................................79
10.6
Case Report Forms and Study Records .................................................................79
10.7
Protocol Violations/Deviations..............................................................................80
10.8
Access to Source Documentation and On-Site Audits ..........................................80
10.9
Data Generation and Analysis ...............................................................................80
10.10 Retention of Data...................................................................................................81
10.11 Financial Disclosure...............................................................................................81
10.12 Publication and Disclosure Policy .........................................................................81
11
REFERENCE LIST .........................................................................................................82
12
APPENDICES .................................................................................................................84


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Clinical Trial Protocol: DX-2930-04
Final: 14 December 2015
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LIST OF IN-TEXT TABLES
Table 1.
Study Administrative Structure....................................................................77
LIST OF IN-TEXT FIGURES
Figure 1.
Schematic of the Open-Label Extension Study ...........................................36
LIST OF APPENDICES
Appendix 1
Study Activities Schedule..................................................................85
Appendix 2
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (Modified) 
(US National Institutes of Health; National Institute of Allergy and Infectious 
Diseases)
............................................................................................................88
Appendix 3
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Tables 
(Modified) (US National Institutes of Health; National Institute of Allergy and 
Infectious Diseases.....................................................................................................101
Appendix 4
HAE Attack Assessment and Reporting Procedures (HAARP)......115
Appendix 5
Summary of Planned Pivotal Study of DX-2930 in HAE Subjects.124


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AAE
Acquired angioedema
AE
Adverse event
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-t
AUC from time zero to the last quantifiable concentration in plasma at 
time t
AUC0-∞
AUC from time 0 to infinity
AUClast
AUC from time 0 to the last measurable concentration
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C1-INH
C1 inhibitor
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
Cmax
Maximum plasma drug concentration
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CRO
Clinical Research Organization
DMID
Division of Microbiology and Infectious Diseases
DP
Drug product
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EQ-5D
A standardized instrument for use as a measure of health outcome
ET
Early termination
FDA
Food and Drug Administration


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GCP
Good Clinical Practice
HAE
Hereditary angioedema
HIPAA
Health Information Portability and Accountability Act
HMWK
High molecular weight kininogen
HR
Heart rate
ICH
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgG1
Immunoglobulin G subclass 1
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IUD
Intrauterine device
IV
Intravenous
Ki
inhibition constant
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
OLE
Open-label extension
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PT
Prothrombin time
REB
Research ethics board
RBC
Red blood cell (count)
RR
Respiratory rate
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous


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SD
Standard deviation
SF-36
A multi-purpose short form healthy survey with 36 questions
SGOT
Serum glutamic oxaloacetic transaminase (AST)
SGPT
Serum glutamic pyruvic transaminase (ALT)
SOC
System Organ Class
SOP
Standard operating procedure
t½
Terminal elimination half-life
tmax
Time to maximum plasma concentration
TEAE
Treatment-Emergent Adverse Event
TT
Thrombin time
US
United States
Vd/F
Apparent volume of distribution during terminal phase after extravascular 
administration
WBC
White blood cell (count)
WHO
World Health Organization


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1
INTRODUCTION
1.1
DX-2930
DX-2930 is a fully human IgG1 recombinant monoclonal antibody that binds specifically to 
active plasma kallikrein. DX-2930 is being developed for prophylactic treatment of 
angioedema attacks in patients with hereditary angioedema (HAE), a serious and 
life-threatening disease.
1.2
Hereditary Angioedema
HAE is a long-term, debilitating, and life-threatening disease caused by mutations in the 
C1-inhibitor (C1-INH) gene, resulting in deficiency or dysfunction of C1-INH protein. HAE 
manifests clinically as unpredictable, intermittent attacks of subcutaneous or submucosal 
edema of the face, larynx, gastrointestinal tract, limbs and/or genitalia (Zuraw, 2008). 
Swelling may last up to five or more days; most patients suffer multiple attacks per year. 
HAE is an orphan disorder. The exact prevalence of HAE is unknown, but current estimates 
range from 1 per 10,000 to 1 per 150,000 persons, with many authors agreeing that 
1 per 50,000 is likely the closest estimate (Bygum, 2009; Goring et al., 1998; Lei et al., 2011; 
Nordenfelt et al., 2014; Roche et al., 2005). 
Swelling in the larynx can obstruct the airways and cause death from asphyxiation (Bork et 
al., 2012; Bork et al., 2000). Approximately 50% of all HAE patients will experience a 
laryngeal attack in their lifetime, and there is no way to predict which patients are at risk of a 
laryngeal attack (Bork et al., 2003; Bork et al., 2006). 
Abdominal attacks are often associated with nausea, vomiting, and severe pain; intestinal 
symptoms resembling abdominal emergencies may lead to unnecessary surgery (Zuraw, 
2008). 
Approximately 85% of patients have Type I HAE, characterized by very low production of 
functionally normal C1-INH protein, while the remaining approximately 15% of patients 
have Type II HAE and produce normal or elevated levels of a functionally impaired C1-INH 
(Zuraw, 2008). In patients with Types I and II HAE, uncontrolled plasma kallikrein 
generation results in excess bradykinin release from high-molecular weight kininogen 
(HMWK) and vascular leak mediated by bradykinin binding to the B2 receptor (B2-R) on the 
surface of endothelial cells (Zuraw, 2008). Clinical suspicion of Types I and II HAE can be 
confirmed by available blood tests. In addition to abnormalities in C1-INH level and 
function, plasma C4 levels are markedly reduced at all times in blood from most patients.
1.3
Therapeutic Rationale for DX-2930
Plasma kallikrein plays a critical role in the pathogenesis of HAE attacks (Davis, 2006; 
Kaplan and Joseph, 2010). In normal physiology, C1-INH regulates the activity of plasma 
kallikrein as well as a variety of other proteases, such as C1r, C1s, factor XIa, and factor 
XIIa. Plasma kallikrein regulates the release of bradykinin from HMWK. Due to a deficiency 


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of C1-INH in HAE, uncontrolled plasma kallikrein activity occurs and leads to the excessive 
generation of bradykinin. Bradykinin is a vasodilator which is thought to be responsible for 
the characteristic HAE symptoms of localized swelling, inflammation, and pain (Craig et al., 
2012; Zuraw et al., 2013). Intervening at the level of bradykinin production with a plasma 
kallikrein inhibitor therefore represents an attractive and rational therapeutic strategy for 
HAE. Indeed, the importance of plasma kallikrein as a drug target in HAE has been validated 
through the observed effectiveness of Kalbitor® (ecallantide), a peptide that specifically 
targets plasma kallikrein, which was approved by the FDA for the treatment of acute HAE 
attacks (Kalbitor® Package Insert, 2015). 
DX-2930 is a highly potent and specific inhibitor of plasma kallikrein (Ki = 125 pM). X-ray 
crystallography of DX-2930 combined with plasma kallikrein demonstrates DX-2930 
binding to the active site of kallikrein (Kenniston et al., 2014).
1.4
Safety Rationale for DX-2930
Safety data from the Phase 1a clinical study, a first-in-human study with DX-2930 in healthy 
subjects did not identify any safety concerns. Single doses up to 3 mg/kg of DX-2930 were 
well-tolerated. There were no dose-limiting toxicities, serious adverse events, or any other 
safety concerns identified.
Pharmacokinetic (PK) data from the Phase 1a (DX-2930-01) and Phase 1b (DX-2930-02) 
clinical studies in conjunction with data from the nonclinical toxicity studies support a wide 
safety margin. The mean Cmax for human subjects treated at a dose of 300 mg on Days 1 and 
15 was approximately 27 g/ mL. As comparison, a mean Cmax of 744 g/ mL was observed 
following dosing of monkeys with 50 mg/kg DX-2930 subcutaneous (SC) weekly for 6 
months resulting in a safety margin of approximately 28-fold. No toxicologically significant 
findings were observed in these treated animals or in any other nonclinical toxicity study to 
date for systemically administered DX-2930.
Safety data is also available from the Phase 1b study (DX-2930-02), a multiple-ascending 
dose study in HAE patients. In this study, two doses of DX-2930 up to 400 mg administered 
14 days apart were well-tolerated. There were no dose-limiting toxicities, serious adverse 
events in any DX-2930 treated subjects, or any other safety concerns identified in this study 
of HAE patients. Pharmacokinetic data from the 1b study found that the drug exposure 
following two administrations of DX-2930 (up to a maximum of 400 mg) was substantially 
less than that attained and evaluated in the nonclinical toxicity studies.
For additional detail regarding the safety rationale for DX-2930, please refer to the DX-2930 
Investigator’s Brochure.
1.5
DX-2930 Non-Clinical Pharmacology and Toxicology
For more detail regarding the nonclinical findings, please refer to the DX-2930 Investigator’s 
Brochure.


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1.6
DX-2930 Clinical Data
The clinical development program to date for DX-2930 consists of 2 studies to evaluate the 
safety, tolerability, and PK of DX-2930, including one completed Phase 1a single-ascending 
dose study in healthy subjects and a Phase 1b multiple-ascending dose study in HAE 
patients. These studies are summarized in the following sections.
1.6.1
Single-Ascending Dose Study in Healthy Subjects (DX-2930-01)
DX-2930-01 was a Phase 1a randomized, double-blind, placebo-controlled study in healthy 
subjects to evaluate the safety, tolerability, and PK following a single, SC dose of DX-2930. 
Participating subjects were randomized to receive placebo or active study drug within one of 
the following sequential, ascending dose cohorts: 0.1, 0.3, 1.0, or 3.0 mg/kg. For each dosing 
cohort, 6 subjects were randomized to receive active drug and 2 subjects to receive placebo. 
A total of 32 subjects enrolled in the study and were randomized. The treatment groups were 
well balanced for demographic characteristics. The actual dose of DX-2930 administered to 
subjects ranged from 6.2 mg (in the 0.1 mg/kg group) to 300 mg (in the 3.0 mg/kg group) 
across all cohorts.
Based on the safety analysis, a single administration of DX-2930 was well tolerated up to 
doses of 3.0 mg/kg without evidence of dose-limiting toxicity. There were no deaths, SAEs, 
or subject discontinuations due to adverse events (AEs) during the study. Furthermore, there 
was no significant imbalance between placebo and DX-2930 for any particular treatment-
emergent adverse event (TEAE). The most commonly reported TEAE was headache, which 
occurred at a rate of 25% for both DX-2930 and placebo.
The PK profile demonstrated linear, dose-dependent drug exposure with a mean half-life of 
approximately 17 to 21 days across dose groups. Results from two exploratory biomarker 
assays provide evidence for an important pharmacodynamic effect of DX-2930 in humans. 
For additional detail regarding the single dose, clinical study in healthy subjects, please refer 
to the DX-2930 Investigator’s Brochure.
1.6.2
Multiple-Ascending Dose Study in HAE Patients (DX-2930-02)
DX-2930-02 was a Phase 1b randomized, double-blind, placebo-controlled, multiple 
ascending-dose study in patients with HAE to evaluate safety, tolerability, and PK of SC 
DX-2930. Participating subjects were randomized 2:1 to receive either active study drug or 
placebo within one of the following sequential, ascending dose cohorts: 30, 100, 300, or 
400 mg (nominal 6 subjects per cohort). Each subject received 2 doses of study drug 
separated by 14 days. 
A total of 37 subjects were randomized and treated with DX-2930 or placebo. One subject in 
the 400 mg dose group received a single dose of DX-2930 and, following several 
unsuccessful attempts to schedule their second dose, was replaced. This subject returned for a 
single follow-up visit before being lost to follow-up for reasons not related to the study. 


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Routine C1-INH testing revealed that one other subject did not have HAE Type I or II, 
despite a historical lab test indicating otherwise.
Subject demographics were balanced in terms of age, race, ethnicity and BMI. There were 
slightly more females in the DX-2930 group than in the placebo group (66.7% versus 
53.8%). 
The most common AEs reported were HAE attacks, injection site pain, and headache. The 
rates were not appreciably higher in the DX-2930 subjects compared to placebo. Two 
subjects were reported to have 3 related severe TEAEs. One of these was a DX-2930 subject 
(30 mg) with injection site pain lasting 1 minute and one was a DX-2930 subject (400 mg) 
with worsening headache lasting 1 minute and night sweats.
No safety signals were identified for vital signs, physical examinations, clinical laboratory 
tests, or electrocardiograms (ECG). Results suggested DX-2930 was well tolerated in this 
study with no evidence of dose-limiting toxicity at doses up to 400 mg.
A total of 3 out of 92 post-dose samples (3.3%), obtained from 2 out of 23 subjects (8.7%), 
were confirmed to be anti-drug antibody-positive. No samples were positive for neutralizing 
activity.
The pharmacokinetic analysis for all subjects in the 30, 100, 300 and 400 mg doses showed
drug levels in HAE subjects were dose-dependent and exhibited a prolonged half-life of 
approximately 2 weeks, typical of a human monoclonal antibody. Cmax drug levels increased 
with increasing dose, as expected. These parameters were consistent with values obtained in 
healthy subjects in study DX-2930-01.
A Western blot assay showed pre-dose baseline levels of mean 2-chain HMWK in 
unactivated plasma collected from HAE patients was approximately 50%. A statistically 
significant reduction in 2-chain HMWK levels was observed on study days 8 and 22 in the 
300 and 400 mg dose groups compared to pre-dose levels, and approached levels similar to 
that observed in healthy subjects. This outcome demonstrated the pharmacodynamic activity 
of DX-2930 and its ability to effectively normalize the instability of HAE plasma in this 
assay. 
Primary efficacy analyses were based on subjects in the 300 mg, 400 mg, and placebo dose 
groups who reported having at least 2 attacks in the 3 months prior to study entry 
(0.15 attacks/week). Of those subjects treated with 300 or 400 mg DX-2930, 15 of 
16 subjects met these criteria. Of the placebo treated subjects, 11 of 13 subjects met these 
criteria. 
The baseline HAE attack rates (attacks/week) were 0.39 attacks per week in the placebo 
group, 0.33 attacks per week in the 300 mg group, 0.55 attacks per week in the 400 mg group 
and 0.49 attacks per week in the 300 and 400 mg combined group. During the pre-specified, 
primary efficacy interval of 6 weeks (from days 8 to 50; corresponding to a period of notable 
drug exposure), the HAE attack rate, adjusted for baseline attack rate, was 0 in the 300 mg 
group and 0.045 attacks per week in the 400 mg group, compared to 0.37 attacks per week in 


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the placebo group. This resulted in a 100% reduction vs placebo for the 300 mg DX-2930 
group (P < 0.0001) and an 88% reduction vs placebo for 400 mg DX-2930 (P = 0.005). 
During this primary efficacy interval, 100% of subjects in the 300 mg group (P = 0.026) and 
82% of subjects in the 400 mg group (P = 0.03) were attack-free compared with 27% of 
subjects in the placebo group.
The data from this study demonstrated proof of concept of the ability of DX-2930 to prevent 
acute attacks of HAE. A statistically significant finding of HAE attack prevention by DX-
2930 was observed. DX-2930 was well tolerated in HAE subjects up to 400 mg. Drug 
exposure appeared to be dose-proportional and consistent with the results obtained in healthy 
subjects in study DX-2930-01. Pharmacodynamic effect assays provided evidence that 
DX-2930 has a direct effect on plasma kallikrein activity in patient plasma.
For additional detail regarding the multiple dose, clinical study in HAE subjects, please refer 
to the DX-2930 Investigator’s Brochure.
1.7
Rationale for Open-Label Extension Study DX-2930-04
The open-label DX-2930 extension study will be preceded by the initiation of a pivotal, 
multi-center, double-blind, randomized, placebo-controlled parallel-arm study (DX-2930-03) 
evaluating the efficacy of DX-2930 in preventing acute angioedema attacks in patients with 
Type I or Type II HAE.  Further information on the DX-2930-03 study design can be found 
in Appendix 5.
Subjects who complete the DX-2930-03 treatment period will be offered the option of rolling 
into the open-label extension study, DX-2930-04.  A limited number of individuals with 
HAE Type I or Type II who were not enrolled in DX-2930-03 (up to 50) will be also 
enrolled. 
The rationale for this open-label extension study is to evaluate the long term safety and 
efficacy of repeated treatment with DX-2930.  For subjects rolling over from DX-2930 who 
were randomized to one of the active study arms, the duration of exposure will cover 1 full 
year.  For rollover subjects randomized to placebo in DX-2930-03, and for non-rollover 
subjects, the duration of exposure will cover 6 months.  Combined, the overall exposure 
between DX-2930-03 and DX-2930-04 provide a sizable dataset to evaluate DX-2930 as a 
life-long, chronic treatment for preventing acute attacks of HAE.  
This study also seeks to characterize the outer bounds of DX-2930 dosing frequency 
(possibly beyond 2 to 4 weeks) by assessing the duration of time between rollover subject’s 
first open-label dose and their first reported HAE attack.  Additionally, this study will assess
the immunogenicity of DX-2930 administered chronically as well as evaluate PK, PD and 
subject quality of life data following repeated administrations.


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2
STUDY OBJECTIVES
2.1
Primary Objective
To evaluate the long-term safety of repeated subcutaneous administrations of DX-2930.
2.2
Secondary Objectives
•
To evaluate the long-term efficacy of DX-2930 in preventing HAE attacks.
•
To characterize the outer bounds of dosing frequency for DX-2930.
2.3
Tertiary Objectives
•
To assess the immunogenicity of chronically administered DX-2930.
•
To evaluate the effect of DX-2930 upon quality of life assessments.
•
To evaluate Pharmacodynamic (PD) and Pharmacokinetic (PK) data following open-label 
DX-2930 dosing 


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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
3.1.1
Overview
This study is an open-label, long term safety and efficacy study to evaluate DX-2930 in 
preventing acute angioedema attacks in patients with Type I and Type II HAE. There are two 
types of subjects who will be enrolled into this study:
1. Subjects who rollover from the DX-2930-03 study.
2. Subjects who were not participants in DX-2930-03.
Roll-over Subjects:
Rollover subjects are subjects who complete the double-blind treatment period at Day 182 of 
the DX-2930-03 study and consent to enter DX-2930-04.  Subjects who discontinue from 
DX-2930-03 after enrollment are not eligible to enroll in DX-2930-04.  Willing subjects must 
sign informed consent for DX-2930-04 no later than the DX-2930-03 Day 182 treatment 
period study visit.  
The first DX-2930-04 visit for rollover subjects (Day 0) will occur on the same day as the 
DX-2930-03 Day 182 study visit. Rollover subjects will complete all DX-2930-03 final study 
assessments at which time they will be discharged from that study. No assessments 
conducted between the DX-2930-03 Day 182 study visit and the first DX-2930-04 visit 
(Day 0) will be duplicated.  Results of the final DX-2930-03 assessments will be used as the 
pre-dose results for Day 0 Dose 1 of DX-2930-04.
Subjects who are eligible to roll over into DX-2930-04 but elect not to may not enroll in 
DX-2930-04 at a later time.
All subjects, caregivers, Investigators and site personnel will remain blinded to the 
DX-2930-03 treatment assignment until the conclusion of the DX-2930-04 study.
Non-rollover subjects:
Up to 50 subjects who were not participants in the DX-2930-03 study will be permitted to 
enroll if they meet the eligibility requirements. Subjects who screen fail out of DX-2930-03 
for not meeting the minimum attack requirements during the run-in period must wait until 
enrollment for the double-blind study has ended before they can screen for DX-2930-04. The 
Sponsor may ease this restriction based on the enrollment rate observed in DX-2930-03.
Screening Period:
There is no screening period for rollover subjects.
Non-rollover subjects must provide informed consent and have screening assessments 
completed within 4 weeks prior to their first open-label dose.  Screened non-rollover subjects 
who are on long-term prophylactic (LTP) therapy for HAE are required to undergo a 


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minimum 2 week washout period prior to the start of the treatment period.  This LTP 
washout is permitted as long as the Investigator determines that doing so would not place the 
subject at any undue safety risk and the subject is at least 18 years of age.  The Investigator 
must confirm the subject has successfully completed the 2 week washout period and have no 
ongoing adverse events related to the washout before they can receive their first open-label 
dose.
Treatment Period:
Rollover Subjects: Following informed consent and pre-dose assessments, rollover subjects 
will receive a single open-label dose of 300 mg DX-2930 administered subcutaneously (SC). 
Subjects will not receive any additional DX-2930 doses until their first reported HAE attack.  
The duration of time between the first open-label dose and first reported HAE attack will 
vary by rollover subject.  All rollover subjects must adhere to the Study Activities Schedule, 
for the entire duration of the study.  However, until a rollover subject reports their first HAE 
attack, only scheduled study visits where the following tests and assessments are performed 
must be conducted at the investigative site: pregnancy testing, clinical laboratory testing, 
physical examination, 12-Lead ECG, QOL, PK, PD and anti-drug antibody sample 
collection.  All other scheduled study visits may be conducted via site check-in calls to 
collect information on adverse events, concomitant therapy, and HAE attack data.  Refer to 
Appendix 1 Study Activities Schedule.
Once a rollover subject reports their first HAE attack they will present to the investigative 
site for their second open-label dose of DX-2930 as quickly as subject and site schedules 
allow.  If the second dose is to be administered within the accepted ± 4 day window around a 
scheduled study visit, this treatment visit will represent that scheduled visit unless that 
scheduled visit has already occurred.  
For example, if the second dose is to be administered on Day 52, all of the tests and 
assessments scheduled for the Day 56 visit will be conducted.  This Day 52 visit to 
receive the second dose will count as the Day 56 visit. 
As another example, if the second dose is to be administered on Day 46, the subject can 
have this study visit count as their Day 42 visit if they have not already attended the 
Day 42 visit. If they have already attended the Day 42 visit, then this Day 46 visit will be 
considered an acceptable, extra study visit.
In the scenario that the second dose is to be administered outside of the accepted ±4 day 
window around a scheduled visit, this visit will not replace any scheduled visit and will thus 
represent an acceptable, extra study visit.  
For example, if the second dose is to be administered on Day 63, this visit will represent 
an acceptable, extra study visit.  
Regardless of the study day, at the visit in which the second open-label dose of DX-2930 is 
administered, the subject will undergo pre-dose assessments for vital signs, physical 


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examination, clinical laboratory testing, PK, PD, and anti-drug antibody. Vital signs will be 
obtained at 1 hour post-dosing. As with all study visits, information will be collected on 
adverse events, concomitant therapy, and HAE attack data.
Subsequent doses after dose 2 require a minimum of 10 days and maximum of 18 days 
between administrations, and should fall within the accepted ± 4 day window around study 
visits. 
For example, if the second dose is to be administered on Day 37, the third dose should be 
administered between Day 52 and Day 55, which would ensure both a dosing interval 
within 10 to 18 days from the second dose and a visit within the ±4 day window around 
the Day 56 study visit.  The fourth dose should then be administered between Day 66 and 
Day 73, which would ensure both a dosing interval within 10 to 18 days from the third 
dose and a visit within the ±4 day window around the Day 70 study visit.
Regardless of when a subject’s first HAE attack occurs, there will be a minimum of 10 days 
between their first open-label dose and their second open-label dose. Following their second 
open-label dose, subjects will continue to receive repeated SC administrations of open-label 
300 mg DX-2930 every 2 weeks for the remaining duration of the treatment period. The 
treatment period will last 26 weeks from the date of the first open-label dose. The number of 
doses administered during this period will vary by subject based on the date of each subject’s 
second dose, but will not exceed 13 doses. The Day 168 study visit is the last visit at which a 
dose may be administered.
Non-rollover Subjects: Once all screening assessments have been completed, eligibility 
confirmed and LTP washout completed (if applicable), non-rollover subjects will arrive at 
the study site and, following pre-dose assessments, receive an open-label dose of 300 mg 
DX-2930 administered SC.  Non-rollover subjects will continue to receive SC 
administrations of open-label 300 mg DX-2930 every 2 weeks throughout the duration of the 
treatment period.  A total of 13 doses will be administered with the last dose administered at 
the Day 168 study visit.
Follow-up Period:
After completion of the 26-week treatment period, all subjects will undergo safety 
evaluations during an 8-week follow-up period unless rolling over into another ongoing 
DX-2930 clinical study or access program that permits such a rollover. Figure 1 shows a 
schematic of the open-label extension study.


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Figure 1.
Schematic of the Open-Label Extension Study
Modifications to Open-Label Dosing:
If at any time an important dose-related safety signal is identified either from this study or 
DX-2930-03, the Sponsor may decide to switch the enrolled subjects who have not yet 
completed the treatment period, and any subsequent subjects, to receive a different open-
label DX-2930 dose and/or frequency.
In addition, based on the results of the DX-2930-03 study, the Sponsor may switch to a 
different dose and/or frequency.
3.1.2
Stopping Rules
3.1.2.1
Study Level Stopping Rules
Safety data, including SAEs and AESI, will be monitored regularly throughout the duration 
of the study. If any potential safety signal is identified as a result of monitoring in this study, 
or from any safety findings from the DX-2930-03 study, the Sponsor may take actions as 


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deemed appropriate, including suspending dosing in the study, while the potential risk is 
evaluated and a course of action has been determined.
3.1.2.2
Individual Stopping Rules
Dosing for any individual subject will be discontinued if the subject experiences a 
DX-2930-related SAE (or a DX-2930-related, clinically significant non-serious AE) that, in 
the assessment of the Investigator, warrants discontinuation from further dosing for that 
subject’s well-being. The Investigator has the ability to contact and consult with the Medical 
Monitor on such matters. Subjects will continue to be followed through the completion of all 
scheduled non-dosing visits, unless they request to be discontinued from the study.
3.1.3
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or other toxicity considered clinically relevant (AE, 
laboratory, physical examination, vital sign, or ECG finding) will be carefully monitored 
until resolution, which may include the following:
•
Additional clinical laboratory tests and/or other clinical investigations
•
Additional visits or extended duration of follow-up
•
Obtaining a specialist consultation
3.2
Rationale for Open-Label Extension Dose Selection
The dose selected for the open-label extension (300 mg every 2 weeks) is anticipated to be 
effective and safe as determined in the pivotal, double-blind DX-2930-03 trial. If at any time 
an important dose-related safety signal is identified either from this study or DX-2930-03, the 
Sponsor may decide to switch the enrolled subjects who have not yet completed the treatment 
period, and any subsequent subjects, to receive a different open-label DX-2930 dose and/or 
frequency.
Additionally, based on the efficacy results of the DX-2930-03 study, the Sponsor may switch 
to a different dose and/or frequency.
3.3
Individual Subject Dosing and Follow-Up
All subjects will receive open-label DX-2930 during a 26-week treatment period.  The 
number of doses that rollover subjects receive during this period will vary by subject but will 
not exceed 13 doses.  The last dose of open-label DX-2930 administered to these subjects 
may be given at the Day 168 study visit.  Non-rollover subjects will receive 300 mg 
DX-2930 every 2 weeks for a total of 13 doses, with the first dose administered on Day 0 and 
the final dose administered at the Day 168 study visit.
There will be a ±4 day window around each study visit. There will be a minimum of 10 days 
between any two doses. Excluding the time interval between the first and second open-label 
doses for rollover subjects, there will be a maximum of 18 days between any two doses. 
Subjects will be monitored at the study site through 1 hour post-dose.


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3.4
Study Duration for Individual Subjects
Following informed consent, subjects will either rollover from DX-2930-03 or undergo 
screening assessments (non-rollover subjects). Screening assessments for non-rollover 
subjects must occur within 4 weeks prior to the first open-label dose. Eligible subjects will be 
enrolled and undergo a 26-week treatment period. At the conclusion of the 26-week 
treatment period, subjects will be followed for an additional 8 weeks unless rolling over into 
another ongoing DX-2930 clinical study or access program that permits such a rollover.


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4
STUDY POPULATION SELECTION
4.1
Study Population
The study is expected to enroll subjects from the DX-2930-03 study, as well as up to 
50 additional subjects who were not enrolled in DX-2930-03.  The total enrollment is 
expected to be approximately 150 HAE Type I or II subjects.  Subjects will be 12 years of 
age or older who experience at least 1 attack per 12 weeks. HAE diagnosis will be confirmed 
through documented clinical history and diagnostic testing conducted either during screening 
or during participation in study DX-2930-02 or DX-2930-03.
The subject population includes subjects who are 12 to 17 years old. Like adults, children 
with HAE can suffer from recurrent and debilitating attacks. Symptoms may present very 
early in childhood, and upper airway angioedema has been reported in HAE patients as 
young as the age of 3 (Bork et al., 2003). In one case series of 49 pediatric HAE patients, 
23 had suffered at least one episode of airway angioedema by the age of 18 (Farkas, 2010). 
An important unmet medical need exists among children with HAE, especially adolescents, 
since the disease commonly worsens after puberty (Bennett and Craig, 2015; Zuraw, 2008).  
The study will aim to enroll at least 10 subjects who are 12 to 17 years of age, inclusive of 
subjects 12 to 17 years old who roll over from the DX-2930-03 study.
4.2
Inclusion Criteria
Subjects must meet the following criteria to be enrolled in this study:
1.
Male and female HAE subjects who are 12 years of age or older at the time of screening. 
2.
Documented diagnosis of disease HAE (Type I or II) based on all of the following:

Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria).

Diagnostic testing results obtained during screening (or a prior DX-2930 study) 
that confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level < 40% of 
the normal level. Subjects with functional C1-INH level 40-50% of the normal 
level may be enrolled if they also have a C4 level below the normal range.  
Subjects may be retested if results are incongruent with clinical history or 
believed by the Investigator to be confounded by LPT use. 

At least one of the following: Age at reported onset of first angioedema symptoms 
≤30 years, a family history consistent with HAE Type I or II, or C1q within 
normal range.
3.
A historical baseline HAE attack rate of at least 1 attack per 12 weeks.
4.
Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, 
understand, and sign an informed consent form.  Subjects age 12 to 17, whose caregiver 


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has provided informed consent, are willing and able to read, understand and sign an 
assent form.
5.
Males and females who are fertile and sexually active must adhere to contraception 
requirements for the duration of the study as follows:

Females of childbearing potential must agree to be abstinent or else use any two of 
the following medically acceptable forms of contraception from the screening period 
through 30 days after the final study visit: progestin-only oral contraceptive, condom 
with or without spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or 
intra-uterine device (IUD, all types). A female whose male partner has had a 
vasectomy must agree to use one additional form of medically acceptable 
contraception.

Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal 
for at least 12 months do not require contraception during the study.

Males, including males who are surgically sterile (post vasectomy), with female 
partners of childbearing potential must agree to be abstinent or else use a medically 
acceptable form of contraception from the screening period through 60 days after the 
final study visit. 
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. Discontinued from DX-2930-03 after enrollment for any reason.
2. If rolling over from DX-2930-03, presence of important safety concerns that would 
preclude participation in this study.
3. Concomitant diagnosis of another form of chronic, recurrent angioedema such as 
acquired angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), 
idiopathic angioedema, or recurrent angioedema associated with urticaria.
4. Dosing with an investigational drug (not including DX-2930) or exposure to an 
investigational device within 4 weeks prior screening.
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systemic absorption (such as oral contraceptives or hormonal 
replacement therapy) within 4 weeks prior to screening.
6. Use of long-term prophylactic therapy for HAE (C1-INH, attenuated androgens, or anti-
fibrinolytics) within 2 weeks prior to the start of the treatment period (Day 0). 


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7. Use of short-term prophylaxis for HAE by non-rollover subjects within 7 days prior to 
the start of the treatment period (Day 0).  Short-term prophylaxis is defined as C1-INH, 
attenuated androgens, or anti-fibrinolytics used to avoid angioedema complications from 
medically indicated procedures.
8. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) 
> 3x upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of 
normal, or total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a 
result of Gilbert’s Syndrome).
9. Pregnancy or breastfeeding.
10. Subject has any condition that, in the opinion of the Investigator or Sponsor, may 
compromise their safety or compliance, preclude successful conduct of the study, or 
interfere with interpretation of the results (e.g., history of substance abuse or dependence, 
a significant pre-existing illness or other major comorbidity that the Investigator 
considers may confound the interpretation of study results).


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5
STUDY TREATMENT(S)
5.1
Description of Treatment(s)
For detailed information regarding open-label DX-2930 administration, refer to the 
Pharmacy Manual.
DX-2930 is a sterile, preservative-free solution for injection, pH 6.0. The active ingredient, 
DX-2930, is formulated using the following compendial components:  30 mM sodium 
phosphate dibasic dihydrate, 19.6 mM citric acid, 50 mM histidine, 90 mM sodium chloride, 
0.01% Polysorbate 80. Each open label vial contains a nominal concentration of 150 mg 
DX-2930 active ingredient in 1 mL solution.
For each 300 mg dose of DX-2930, each subject will receive a total of 2 mL, which will be 
administered in a single 2.0 mL SC injection. The injection will be given in the upper arm, 
thigh or abdomen.
5.2
Dosing and Follow-Up Scheme
Details of subject dosing and follow-up are outlined in Section 3.1.1 and included in the 
Study Activities Schedule, Appendix 1. 
Rollover subjects will receive their first open label SC dose of 300 mg DX-2930 on Day 0.  
Subjects will not receive any additional DX-2930 doses until their first reported HAE attack.  
Following this attack subjects will receive open label SC doses of 300 mg DX-2930 every 
2 weeks until the end of the treatment period. 
The treatment period will last 26 weeks from the date of the first open-label dose.  The 
number of doses administered during this period will vary by subject based on the date of 
each subject’s second dose, but will not exceed 13 doses.  The Day 168 study visit is the last 
visit at which a dose may be administered.
Non-rollover subjects will receive their first open-label dose SC dose of 300 mg DX-2930 on 
Day 0 and will continue to receive SC administrations of open-label 300 mg DX-2930 every 
2 weeks throughout the duration of the treatment period.  A total of 13 doses will be 
administered with the last dose administered at the Day 168 study visit.
After completion of the 26-week treatment period, all subjects will undergo safety 
evaluations during an 8-week follow-up period unless rolling over into another ongoing 
DX-2930 clinical study or access program that permits such a rollover.
5.3
Method of Identifying Subjects
Subjects meeting all eligibility criteria will be enrolled in the study and sequentially assigned 
a unique site-based identification number.


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5.4
Prior and Concomitant Therapy
For subjects not rolling over from DX-2930-03, reasonable efforts will be made to determine 
all relevant treatments received by the subject from the time of screening through the final 
study visit. For subjects rolling over from DX-2930-03, concomitant therapy use will be 
carried forward from that study and will continue to be collected through the final study visit. 
All information on concomitant therapy (including all prescription/non-prescription 
medications, herbal medications and vitamin supplements) must be recorded on the subject’s 
eCRF and should include the name of the procedure or drug and duration of the treatment 
(start and stop dates). Concomitant treatments (non-pharmacological treatments) include any 
surgical or diagnostic procedures.
5.4.1
Allowed Therapies
The following therapies are allowed during the study:
•
Therapies for co-existing conditions, including those for acute attacks of HAE, are 
permitted if not excluded in Section 5.4.2.
•
The use of short-term prophylactic treatment for HAE will be permitted if medically 
indicated.  Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-
fibrinolytics used to avoid angioedema complications from medically indicated 
procedures.
•
Therapies to treat any AEs the subject experiences during the study are permitted.
5.4.2
Excluded Concomitant Therapies
Use of the following treatments will not be permitted during the study:
•
Long-term prophylaxis for HAE (e.g., use of C1-INH for long-term prophylaxis, 
attenuated androgens, or anti-fibrinolytics).
•
Angiotensin-converting enzyme (ACE) inhibitors.
•
Estrogen-containing medications with systemic absorption (such as oral contraceptives or 
hormonal replacement therapy).
•
Androgens (e.g., stanozolol, danazol, oxandrolone, methyltestosterone, testosterone).
•
Any other investigational drug or device.
5.5
Restrictions
5.5.1
Medical Interventions
Medical interventions deemed necessary by the Principal Investigator for the health and 
well-being of the subject will not be excluded during this study.


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5.5.2
Fluid and Food Intake 
There are no restrictions on fluid and food intake. Subjects may continue their usual dietary 
regimens.
5.5.3
Activity
There are no activity restrictions. Subjects may continue their usual activity regimens.
5.6
Treatment Compliance
All doses of open-label DX-2930 will be administered during clinic visits under the direct 
supervision of the Investigator or qualified site personnel designated by the Investigator. 
5.7
Packaging and Labeling
The open-label DX-2930 will be supplied by Dyax Corp. and packaged and labeled 
according to applicable local and regulatory requirements for investigational studies.
5.8
Storage and Accountability
All of the DX-2930 must be stored refrigerated (2ºC to 8ºC/36ºF to 46ºF) in the carton and 
protected from light, in a securely locked area, accessible to authorized persons only, until 
needed for dose preparation. Qualified site personnel will inventory the DX-2930 received 
and will maintain records of disposition of the drug, including dates, quantity and use.
5.9
Investigational Medicinal Product Retention at Study Site
The Investigator (or designee) is responsible for maintaining accurate accountability records 
of DX-2930 throughout the clinical study. All DX-2930 received at the site must be 
inventoried and accounted for in an accountability log provided by the Sponsor. All 
dispensing and accountability records will be available for Sponsor review. Drug 
accountability will be verified during on-site monitoring visits.
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used DX-2930 should be returned 
or destroyed at the investigational site, as specified by Sponsor. It is the Investigator’s 
responsibility to ensure that the Sponsor, or its representative, has provided written 
authorization that procedures for proper disposal of the DX-2930 have been established, and 
that appropriate records of the disposal are documented and maintained. No unused DX-2930 
may be disposed until fully accounted for by the Sponsor monitor (or designee).


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6
STUDY PROCEDURES
Please refer to the Study Activities Schedule, Appendix 1.
6.1
Informed Consent
The ICF must be executed prior to performing any study related activities and must be 
approved by the reviewing institutional review board (IRB), research ethics board (REB) or 
independent ethics committee (IEC). Subjects may withdraw consent at any time. 
Participation in the study may be terminated at any time without the subject’s consent as 
determined by the Investigator.
Subjects who are not rolling over from the double-blind DX-2930-03 study will provide 
informed consent at Screening. Subjects who are rolling over from the double-blind 
DX-2930-03 study will provide consent no later than the DX-2930-03 Day 182 study visit. 
Upon completion of the final assessments, the subjects will be discharged from the double-
blind study and will start participation in the OLE study and receive their first open-label 
dose.
6.2
Eligibility Review
The Investigator or qualified site personnel will confirm that all Inclusion and Exclusion 
criteria have been met.
6.3
Demographics and Medical History
Demographics: date of birth (alternately age or year of birth, if full date is not allowed to be
collected for legal reasons), sex,  race and ethnicity (where locally permitted) and medical 
history will be obtained at Screening from subjects not rolling over from DX-2930-03 and 
will be recorded on the source document and eCRF. Medical history will capture the 
subject’s current medical status (current disease processes), past medical status (past disease 
processes), history of surgery, allergies and concomitant medications. For subjects rolling 
over from DX-2930-03, these data will be carried forward from that study. 
6.4
HAE Attack Information Collection
The collection, reporting and assessment of attacks in this study will be done in accordance 
with the HAE Attack Assessment and Reporting Procedures (HAARP).  Site personnel will 
be trained on HAARP prior to screening and enrolling subjects at their site.
Site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide.  The 
patient (and caregiver) will confirm their understanding of what is required of them for 
reporting attacks to the site.
At screening, HAE attack history will be collected for non-rollover subjects. Information 
collected will include any prior history of laryngeal attacks, attack frequency, average 


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severity, predominant attack location(s), average duration, acute attack therapy use and 
history of long-term prophylaxis.
During the study, subjects (or caregivers) will be instructed to notify and report details to the 
study site within 72 hours of the onset of an attack. This includes the first attack experienced 
by rollover subjects following their first open-label dose.  In the situation that a subject is 
incapacitated following an attack, this information can be provided to the site by a family 
member or other individual with detailed knowledge of the event. If desired by the subject, 
memory aids may be provided to assist in tracking any HAE attacks experienced. 
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack:

Date and time symptoms of an attack were first experienced

Description of symptoms experienced, including location(s)

Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits

Any medications used to treat the attack

If the attack resolved, date and time the subject was no longer experiencing symptoms
Site personnel will review the information provided and solicit additional information as
necessary to document the attack, as described in HAARP.
Site personnel will contact rollover subjects approximately every 7 days following the first 
dose of open-label DX-2930 to solicit for any HAE attacks not already reported.  Site check-
ins will continue until the subject has received their second open-label dose. 
During each study visit, site personnel will solicit for any new HAE attack information that 
was not already provided to the site.
In this study, HAE attacks will be captured as AEs. All AEs, regardless of seriousness, 
severity, or causal relationship to DX-2930, will be recorded on the AE page of the 
eCRF. Any AE reported to the site meeting criteria for a serious adverse event must be 
reported to the Sponsor using the SAE Reporting Form in the EDC system within 24 hours of 
becoming aware of the event. For all serious adverse events that are reported as HAE 
attacks, the Principal Investigator or physician designee will review the event within 24 hours 
of initial notification and, in accordance with HAARP, evaluate if it represented a confirmed 
HAE attack. For all non-serious AEs that are reported as HAE attacks, the Principal 
Investigator or physician designee will review the event within 3 days of initial notification 
and, in accordance with HAARP, evaluate if it represented a confirmed HAE attack. If 
necessary for the evaluation, the Investigator or designee may contact the subject to receive 
additional information. Any subject-reported attack not confirmed by the Investigator or 


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physician designee must have an alternate AE diagnosis recorded.  All subject-reported and 
Investigator/ physician designee-confirmed HAE attacks will be recorded in the eCRF. 
Emergency department visits for HAE attacks and HAE attacks resulting in hospital 
admissions will be captured.
To be confirmed as an attack, the event must have symptoms or signs consistent with an 
attack in at least one of the following locations: 
•
Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso,
and/or genitourinary region
•
Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea
•
Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx
Despite the presence of these symptoms, the investigator or physician designee may still 
clinically determine that the event did not represent an attack if there are features that 
strongly refute such a diagnosis. For example, the reported event is accompanied by 
symptoms that are not consistent with an HAE attack (e.g., urticaria), the reported event 
persists well beyond the typical time course of an HAE attack (e.g., greater than 7 days), or 
there is a likely alternate etiology for the event (e.g., the subject’s abdominal symptoms are 
attributable to a viral gastroenteritis outbreak in the household). 
To be counted as a unique attack distinct from the previous attack, the new symptoms must 
occur at least 24 hours after resolution of the prior attack’s symptoms.
6.5
Vital Signs
Vital signs will be assessed by the Investigator or his/her qualified designee according to the 
Study Activities Schedule (Appendix 1). Routine vital sign assessments will be taken with 
the subject in the sitting or supine position after 5 minutes at rest and will include body 
temperature, heart rate (HR), blood pressure (BP) and respiratory rate (RR). BP should be 
determined using the same arm and the same equipment for each assessment.  For subjects 
who rollover from DX-2930-03, vital signs taken during the final study visit in DX-2930-03 
will serve as the Day 0 pre-dose vital signs in this study and will not be duplicated.
6.6
Physical Examination
A complete physical examination including height, weight and calculation of Body Mass 
Index (BMI) will be performed by the Investigator or his/her qualified designee according to 
the Study Activities Schedule (Appendix 1). The physical examination will include the 
following body systems:
•
Height and weight (at Screening visit only for non-rollover subjects)
•
General appearance


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•
Ears, nose, and throat
•
Head and neck
•
Ophthalmological
•
Respiratory
•
Cardiovascular
•
Abdomen
•
Neurological
•
Extremities
•
Dermatological
•
Lymphatic
For subjects who rollover from DX-2930-03, physical exam taken during the final study visit 
in DX-2930-03 will serve as the Day 0 pre-dose physical exam in this study and will not be 
duplicated.
6.7
Electrocardiography (ECG)
A standard 12-lead ECG (single recording) will be performed according to the Study 
Activities Schedule (Appendix 1). The date and time of each ECG and its results will be 
documented in the source documents and eCRF. Electrocardiograms will be sent to a central 
reading vendor for assessment.  For subjects who rollover from DX-2930-03, the ECG taken 
during the final study visit in DX-2930-03 will serve as the Day 0 pre-dose ECG in this study 
and will not be duplicated.
6.8
Clinical Laboratory Tests
6.8.1
Laboratory Parameters
Laboratory testing will be performed according to the Study Activities Schedule
(Appendix 1).
Laboratory testing includes general safety parameters (hematology, coagulation, urinalysis, 
and serum chemistry), pregnancy tests (in females of childbearing potential), C1-INH 
functional assay, C4 assay, C1q assay, PK sampling, PD sampling, and plasma anti-drug 
antibody testing. All laboratory tests will be performed using established and validated 
methods. 
When multiple sample collection types are performed at the same assessment time point, the 
samples will be drawn in the following order (depending on what sample types are to be 
collected at that time point): laboratory safety samples (hematology, coagulation, serum 
chemistry), C1-INH, C4, C1q, PK, anti-drug antibodies, PD. Aliquots from the PK, PD and 
anti-drug antibody samples may be retained as back-up for additional parameter testing if 
necessary. Subjects will be in a seated or supine position during blood collection. The total 
blood draw for each roll-over subject will be approximately 144 mL. The total blood draw 


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for each non roll-over subject will be approximately 157 mL. For subjects who rollover from 
DX-2930-03, testing performed during the final study visit in DX-2930-03 will serve as the 
Day 0 pre-dose laboratory testing in this study and will not be duplicated.
6.8.1.1
Hematology
•
Hemoglobin
•
Hematocrit
•
Red blood cell (RBC) count
•
White blood cell (WBC) count with differential
•
Mean corpuscular volume (MCV)
•
Mean corpuscular hemoglobin (MCH)
•
Mean corpuscular hemoglobin concentration (MCHC)
•
Absolute platelet count
6.8.1.2
Coagulation
•
Prothrombin time (PT)
•
Activated partial thromboplastin time (aPTT)
•
International Normalized Ratio (INR)
6.8.1.3
Chemistry
•
Albumin
•
Alkaline phosphatase
•
Alanine aminotransferase (ALT; SGPT)
•
Aspartate aminotransferase (AST; SGOT)
•
Bilirubin (total and direct)
•
Blood urea nitrogen (BUN)
•
Calcium
•
Carbon dioxide (CO2)
•
Chloride
•
Creatinine
•
Creatine phosphokinase (CPK)
•
Glucose
•
Phosphate
•
Magnesium
•
Potassium
•
Sodium


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•
Total protein
•
Uric acid
6.8.1.4
Urinalysis
•
Bilirubin
•
Glucose
•
Ketones
•
Blood 
•
Nitrite
•
pH
•
Protein
•
Specific gravity
•
Microscopy (if indicated by macroscopic findings)
6.8.1.5
Pregnancy Test
Pregnancy tests will be either serum or urine based.
6.8.1.6
C1-INH Functional Assay
Results of a C1-INH functional assay are required for eligibility assessment. Samples will be 
drawn at the Screening visit unless they were previously drawn in study DX-2930-02 or 
DX-2930-03. Results of the C1-INH functional assay from DX-2930-02 or DX-2930-03 may 
be used to confirm diagnosis in this study. Subjects may be retested if results are incongruent 
with clinical history or believed by the Investigator to be confounded by recent LTP use.
6.8.1.7
C4 Assay
Results of a C4 assay may be required for eligibility assessment.  The C4 sample will be 
drawn at the same time as the C1-INH sample is drawn during the Screening visit unless 
previously drawn in study DX-2930-02 or DX-2930-03.  Results of the C4 assay from 
DX-2930-02 or DX-2930-03 may be used to confirm diagnosis in this study.  Subjects may 
be retested if results are incongruent with clinical history or believed by the Investigator to be 
confounded by recent LTP use. 
6.8.1.8
C1q Assay
Results of a C1q assay may be required for eligibility assessment. Any subject who requires 
C1-INH and C4 assay results for diagnostic confirmation in this study will have C1q assay 
results obtained as well.  The C1q sample will be drawn at the same time as the C1 and C4 
sample is drawn during the Screening visit. 


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6.8.1.9
PK Sample Collection
As outlined in Section 6.9.
6.8.1.10
PD Sample Collection
As outlined in Section 6.10.
6.8.1.11
Plasma Anti-Drug Antibody Testing
As outlined in Section 6.11.
6.8.2
Sample Collection, Storage, and Shipping
Blood samples for laboratory assessments will be collected at the site by a trained 
phlebotomist designated and/or approved by the study Investigator. Details for the collection, 
processing, storage and shipment of samples for all laboratory determinations will be 
provided in the Laboratory Manual.
Biological material will be stored and secured in a manner that assures that unauthorized 
access is prohibited and the samples are not lost, allowed to deteriorate, or accidentally or 
illegally destroyed.
6.9
Pharmacokinetic Assessments
Blood samples for the measurement of plasma DX-2930 concentration will be obtained as 
specified in the Study Activities Schedule (Appendix 1).
6.10
Pharmacodynamic Assessments
To evaluate the PD effects of DX-2930 upon plasma kallikrein activity, blood samples will 
be obtained as specified in the Study Activities Schedule (Appendix 1).
6.11
Plasma Anti-Drug Antibody Testing 
Plasma samples for testing for formation of antibodies to DX-2930 will be obtained as 
specified in the Study Activities Schedule (Appendix 1).
6.12
Prior and Concomitant Therapy
The Sponsor representatives and Investigator at the site conducting the trial will review and 
evaluate prior and concomitant medication usage on an ongoing basis. For subjects not 
rolling over from DX-2930-03, all prescription, over-the-counter medications, herbals, and 
supplements that are being taken or have been taken by subjects from the time of screening 
through the duration of the study will be regarded as concomitant medications and must be 
documented on the source document and eCRF following informed consent.  For subjects 
rolling over from DX-2930-03, concomitant therapy use will be carried forward from that 
study and will continue to be collected through the duration of the study. 


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6.13
Investigational Medicinal Product Treatment
Instructions for safe handling of DX-2930, preparation of each subcutaneous dose and 
administration of DX-2930, are provided in the Pharmacy Manual. Preparation and 
dispensing of DX-2930 will be handled by qualified site personnel as directed by the 
Principal Investigator at the study site. The requirements for maintaining DX-2930 
accountability are provided in Section 5.8 of this protocol.
6.14
Quality of Life Assessments
Quality of life data will be collected using the EQ5D, SF-36 and the Angioedema Quality of
Life Questionnaire (AEQoL), as specified in the Study Activities Schedule (Appendix 1). For 
subjects who rollover from DX-2930-03, quality of life assessments obtained during the final 
study visit in DX-2930-03 will serve as the Day 0 pre-dose quality of life assessments in this 
study and will not be duplicated.
6.15
Adverse Event Reporting
Adverse events will be collected from signing of the informed consent through the last study 
visit.
6.15.1
Definitions
6.15.1.1
Adverse Event
An AE is any untoward medical occurrence in a clinical trial subject whether or not it 
appears to have a causal relationship with the treatment administered. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product or participation in a clinical study, whether or not directly related to the medicinal 
product or study participation.
•
AEs may be new events or may be pre-existing conditions that have become aggravated 
or have worsened in severity or frequency during the course of the study.
•
AEs may be clinically significant changes from baseline in physical examination, 
laboratory tests, or other diagnostic investigation (e.g., laboratory results, x-ray findings).
Laboratory abnormalities generally are not considered AEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. A clinically significant 
laboratory abnormality that is independent from a known underlying medical condition and 
that requires medical or surgical intervention, or leads to DX-2930 interruption or 
discontinuation, will in itself, be considered an AE. Laboratory or diagnostic testing 
abnormalities that reflect or are part of a known underlying medical condition are not, in 
themselves, AEs; rather, the underlying medical condition leading to the abnormalities would 
be reported as the AE.


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Pregnancy is not an AE; however, if a female subject becomes pregnant during the conduct 
of the study, the Investigator must notify the Sponsor according to the procedures provided in 
Section 6.15.5.2.
6.15.1.2
Serious Adverse Event
A SAE is any adverse experience occurring at any dose that results in any of the following 
outcomes:
•
Death
•
Life-threatening experience; Note: “Life-threatening” refers to a situation in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
might have caused death if it were more severe.
•
Requires inpatient hospitalization or prolongation of existing hospitalization; Note: Does 
not include hospitalization for observation with release within 24 hours. A scheduled 
hospitalization for a pre-existing condition that has not worsened during participation in 
the study does not meet this criterion. Pre-planned hospitalizations for an elective 
medical/surgical procedure or routine check-ups do not meet this criterion.
•
Results in persistent or significant disability or incapacity.
•
Is a congenital anomaly or birth defect.
•
Is considered to be an important medical event defined as those that may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the outcomes listed in the definition 
above.
6.15.1.3
Overdose
An overdose is defined as a significant variation from the recommended/scheduled dosage 
for a product. The dosing for this study will be conducted in a controlled clinical setting and 
an overdose is not anticipated. However, in the event of an accident, for this study, an 
overdose of DX-2930 is considered a dose that is two-fold higher than the intended dose for 
the subject.
6.15.1.4
Planned Hospitalization
A hospitalization planned by the subject prior to the first dose of open-label DX-2930 is 
considered a therapeutic intervention and not the result of a new SAE and should be recorded 
as medical history. If the planned hospitalization or procedure is executed as planned, the 
record in the subject’s medical history is considered complete. However, if the 
event/condition worsens during the trial, it must be reported as an AE.
6.15.1.5
Treatment-Emergent Adverse Events (TEAE)
An AE is treatment-emergent if the onset time is after first administration of open-label 
DX-2930 through the final follow-up visit or, in the event that onset time precedes first 
DX-2930 administration, the AE increases in severity during the open-label treatment period.


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For rollover subjects, any adverse event that started during the subject’s participation in 
DX-2930-03 and was ongoing at the time of the first open-label dose in DX-2930-04 will not 
be counted as an AE in DX-2930-04 unless that event has worsened in severity or frequency 
following the first open-label dose.  Adverse events that started during subject participation 
in DX-2930-03, resolved following the first open-label dose in DX-2930-04, and then 
subsequently reappeared in DX-2930-04 will be counted as a new TEAE in DX-2930-04.
6.15.1.6
Adverse Events of Special Interest (AESI)
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Investigators will report all AESI to Dyax, regardless of causality, using the same 
timelines as described for SAE reporting. The following describe the AESI and the criteria 
for reporting AESI. 
HYPERSENSITIVITY REACTIONS
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours, only if the 
reactions are suspected to be related to study drug.
EVENTS OF DISORDERED COAGULATION
Bleeding AESI
Athough aPTT prolongation due to plasma kallikrein inhibition is an artifactual in vitro
phenomenon, as a precautionary measure in evaluating the safety of DX-2930, bleeding 
events will be reported as AESI for this study. Investigators will report all diagnoses, or signs 
and symptoms when diagnoses cannot be determined, that are consistent with a clinical event 
of bleeding. Coagulation testing (aPTT, PT, INR) should be performed when possible, and 
when temporally reasonable, with any reports of bleeding or for clinical conditions possibly 
indicative of bleeding.
Hypercoagulable AESI
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot be 
determined, that are consistent with a thrombotic or embolic etiology. 
6.15.2
Monitoring
6.15.2.1
Monitoring of Adverse Events
Each subject will be monitored for the occurrence of AEs, including SAEs and AESI, from 
signing of the ICF through the final follow-up visit.


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•
Subjects will be questioned and/or examined by the Investigator or a qualified designee 
for evidence of AEs. The questioning of subjects with regard to the possible occurrence 
of AEs will be generalized such as, "How have you been feeling since your last visit?”  
The presence or absence of specific AEs should not be elicited from subjects.
•
Subjects having TEAEs will be monitored until resolution with relevant clinical 
assessments and laboratory tests, as determined by the Investigator.
•
AEs, actions taken as a result of AEs, and follow-up results must be recorded in the eCRF 
as well as in the subject's source documentation. Follow-up laboratory results should be 
filed with the subject's source documentation.
For any SAEs or AEs that require the subject to be discontinued from dosing, relevant
clinical assessments and laboratory tests will be repeated as clinically appropriate, until final 
resolution or stabilization of the event(s). Subjects will continue to be followed through 
completion of all scheduled visits.
6.15.2.2
Monitoring of Safety Laboratory Assessments
All safety laboratory assessments will be performed at a central laboratory. The clinical 
laboratory values will be reported to the Investigator who will review them for clinical 
significance and consideration of abnormal values as potential AEs.
6.15.3
Assessment of Adverse Events
6.15.3.1
Assessment of Severity
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe nausea). This is not the same as 
“serious,” which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning.
In this study, the severity of AEs will be assessed according to Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table, Draft, November 2007 (US National 
Institutes of Health: National Institute of Allergy and Infectious Diseases) (Appendix 2) and 
the Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Table, 
Draft, November 2007 (US National Institutes of Health: National Institute of Allergy and 
Infectious Diseases) (Appendix 3). For abnormalities not specifically found in the Toxicity 
Tables, the following general scale will be used to estimate grade of severity:
•
GRADE 1 (Mild): Transient or mild discomfort ; no medical intervention/therapy 
required
•
GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required
•
GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible 


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•
GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
Any treatment-emergent ECG abnormality that is considered by the Investigator as clinically 
significant and requiring intervention/therapy will be assessed as a severe AE.
6.15.3.2
Assessment of Causality
A medically qualified Investigator must assess the relationship of any AE (including SAEs) 
to the use of DX-2930, as related or not related, based on clinical judgment and using all 
available information, and may include consideration of the following factors:
•
Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors.
•
The temporal association between DX-2930 exposure and onset of the AE.
•
Whether the manifestations of the AE are consistent with known actions or toxicity of 
DX-2930.
•
The AE resolved or improved with decreasing the dose or stopping use of DX-2930 
(dechallenge). Judgment should be used if multiple products are discontinued at the same 
time.
The causal relationship between DX-2930 and the AE will be assessed using one of the 
following categories:
Not Related:  Factors consistent with an assessment of Not Related include:

Temporal relationship is lacking (e.g., the event did not occur within a 
reasonable time frame following administration of DX-2930); or

Other causative factors more likely explain the event (e.g., a pre-existing 
condition, other concomitant treatments).
Related:  Factors consistent with an assessment of Related include:

There is a positive temporal relationship (e.g., the event occurred within a 
reasonable time frame following administration of DX-2930); or

The AE is more likely explained by administration of DX-2930 than by 
another cause (i.e., the AE shows a pattern consistent with previous 
knowledge of DX-2930 or the class of DX-2930).
6.15.3.3
Assessment of Clinical Significance
Clinical significance of individual AEs will be determined by the Investigator, with 
discussion with the Medical Monitor as appropriate.


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6.15.4
Clinical Laboratory Adverse Events
Laboratory abnormalities generally are not considered AEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. A clinically significant 
laboratory abnormality that is independent from a known underlying medical condition and 
that requires medical or surgical intervention, or leads to DX-2930 treatment interruption or 
discontinuation, will be considered an AE.
When laboratory abnormalities are considered to be AEs, the DMID Adult Toxicity Table 
(Appendix 2) or DMID Pediatric Toxicity Tables (Appendix 3) will be used to assess 
severity. Where discrepancies in the upper limit of normal (ULN) and lower limit of normal 
(LLN) of laboratory ranges occur between those included in the DMID tables and those of 
the laboratory that performs the assays, the values provided by the laboratory will be used for 
assignment of severity grade. Clinical significance of individual laboratory AEs will be 
determined by the Investigator with input from the Medical Monitor as needed. 
Following is an exception to defining clinically significant, abnormal laboratory values as 
AEs:

APTT prolongation in the absence of any associated bleeding or other evidence of 
clinical relevance will not be considered a clinically significant laboratory abnormality or 
AE. In the appropriate physiologic setting, such as IV heparin therapy, aPTT can be used 
to monitor bleeding risk. However, as noted in the Investigators Brochure, aPTT 
prolongation due to plasma kallikrein inhibition is an artifactual in vitro phenomenon. 
Although plasma kallikrein drives fibrin formation in the aPTT assay, plasma 
kallikrein-driven coagulation does not appear to have hemostatic or other physiologically 
important functions in vivo. It is well documented that, in humans, deficiency of factor 
XII or prekallikrein (and thus plasma kallikrein) is not associated with abnormal 
bleeding, either spontaneous or during surgical procedures (Renne and Gruber, 2012). 
Despite the lack of clinical effect, deficiency of either protein is associated with marked 
prolongation of the aPTT. 
6.15.5
Reporting Investigator Safety Observations to the Sponsor
6.15.5.1
Reporting Non-serious Adverse Events
All AEs, regardless of seriousness, severity, or causal relationship to DX-2930, will be 
recorded on the AE page of the eCRF. In this study all HAE attacks reported by the subject, 
regardless of whether or not they are confirmed by the Investigator, will be captured as AEs.
6.15.5.2
Reporting Pregnancies
If a female subject or the female partner of a male subject becomes pregnant during the 
course of the study, the Investigator must report the pregnancy to the Dyax 
Pharmacovigilance Department using the Pregnancy Reporting Form within 24 hours of 
becoming aware of the event. The Investigator must obtain consent to collect pregnancy 
information (including the status of the newborn, if applicable).


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If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and 
submitted within 24 hours of becoming aware of the new information. The Investigator is 
required to follow the pregnancy through delivery. The outcome of the pregnancy and the 
status of the newborn (if applicable) will be reported on the Pregnancy Reporting Form 
within 24 hours of becoming aware.
6.15.5.3
Safety Observations Requiring Expedited Reporting by the Investigator to Dyax
Any occurrence of the following events or outcomes in a subject in the trial must be reported 
expeditiously by the Investigator or qualified designee to the Dyax Pharmacovigilance 
Department:
•
SAE
•
AESI
•
Overdose
•
Cancer
The Investigator is to report any expedited safety observations from the list above to Dyax 
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of 
the event.
Any SAE reported to the Dyax Pharmacovigilance Department using the SAE Reporting 
Form in the EDC system is to be recorded in the eCRF, as well as in the subject's source 
documentation along with any actions taken. If all required information on the form is not 
available at the time of the initial report, follow-up information will be completed in the EDC 
system.
The Investigator is required to follow SAEs until resolution regardless of whether the 
subjects are still participating in the study. SAE resolution is defined as:
•
Resolved with or without residual effects.
•
A return to baseline for a pre-existing condition.
•
Laboratory values have returned to baseline or stabilized.
•
The Investigator does not expect any further improvement or worsening of the event.
•
Fatal outcome—if an autopsy is performed; the autopsy report is requested to be provided 
to the sponsor as soon as it is available.
6.15.5.4
Expedited Reporting by the Sponsor to a Regulatory Health Authority
The Sponsor or designee will report relevant safety information to concerned health 
authorities in accordance with local laws and regulations.


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6.15.5.5
Safety Contact Information
24-Hour Medical Safety Contact for US and Canada
, M.D. 
Phone (US): 
Email: 
Calls or emails received weekends, holidays, or weekdays between 8:00 pm and 8:00 am Eastern 
(US) time will be responded to the morning of the following business day
24-Hour Medical Safety Contact for Europe and Middle East
, M.D. 
Phone: 
Email: 
Dyax Pharmacovigilance Department
Contacts: 
 or 
Email: 
Phone (US): 
6.15.5.6
Safety Notifications by the Sponsor to the Investigator
Investigators will receive prompt notification of any adverse experience related to DX-2930 
that is both serious and unexpected, or any finding that suggests a significant risk for 
subjects. The Investigator will promptly inform his / her IRB/REB/IEC of the notification 
and insert the notification in the Investigator’s Regulatory Binder in accordance with local 
regulations. 
6.16
Subject Withdrawal
The Investigator may withdraw a subject from DX-2930 treatment for any of the following 
reasons:
•
In the opinion of the Investigator, the subject is unable to comply with the requirements 
of the protocol for satisfactory completion or interpretation of study results (including use 
of prohibitive medications),
•
A serious or intolerable AE occurs,
•
A clinically significant change in a laboratory parameter occurs,
•
The Sponsor or Investigator terminates the study, or
•
The subject requests to be discontinued from the study.
Subjects will continue to be followed through completion of all scheduled visits, unless the 
subject requests to be discontinued from the study.


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6.17
Appropriateness of Measurements
This is a Phase 3 open-label extension study that is designed to evaluate the long-term safety 
and efficacy of DX-2930 in prophylactic therapy for angioedema attacks in subjects with 
HAE. DX-2930 is a recombinant, fully human IgG1, kappa light chain, monoclonal antibody. 
The open-label, non-controlled study design is a standard approach for extension studies that 
follow double-blind pivotal trials. Measures employed in this protocol are standard measures 
routinely used for the evaluation of the efficacy, safety and tolerability of an investigational 
product.  Measures employed for rollover subjects between the first and second open-label 
doses are appropriate to characterize the outer bounds of dosing frequency for DX-2930.


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7
STUDY ACTIVITIES
Study activities are summarized by study visit in Appendix 1 (Study Activities Schedule).
7.1
Screening Visit (Up to Day −28) For Non-Rollover Subjects
The following procedures and assessments are to be performed during the Screening Visit for 
subjects not rolling over from the DX-2930-03 study:
•
Informed consent (Section 6.1)
•
Eligibility review (Section 6.2)
•
Demographics and medical history (Section 6.3)
•
C1-INH functional assay, C4 and C1q sample collection (Section 6.8)
•
Pregnancy test, serum or urine (females) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Complete physical examination (Section 6.6); documentation of height and weight
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Prior and concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15); pre-existing signs and symptoms
•
Subjects who are on LTP for HAE must complete a minimum 2 week washout period, as 
confirmed by the Investigator, before entering the treatment period
For subjects rolling over from the double-blind DX-2930-03 study, no Screening visit is 
required as subjects will enter the OLE on the same day that their last DX-2930-03 study 
visit is completed. Diagnostic test results and demographic and medical history for these 
subjects will be carried forward from that study.
7.2
Start of Treatment Period: Visit 1, Dose 1 (Day 0)
The following procedures and assessments are to be performed on Day 0 prior to the first 
dose of DX-2930.  For subjects who rollover from DX-2930-03, all final assessments taken 
during the final study visit in DX-2930-03 will be used as the pre-dose results on Day 0 and 
will not be duplicated.
•
Informed consent (for subjects rolling over from the double-blind DX-2930-03 study) 
(Section 6.1)
•
Eligibility review (Section 6.2)
•
Urine pregnancy test (females) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)


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•
Complete physical examination (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK baseline sample collection (Section 6.9)
•
PD baseline sample collection (Section 6.10)
•
Baseline anti-drug antibody sample collection (Section 6.11)
•
Prior and concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
First dose of open-label DX-2930 (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)
7.3
Interval between Dose 1 and Dose 2 for Rollover Subjects
Rollover subjects must adhere to the Study Activities Schedule for the entire duration of the 
study.  Until a rollover subject reports their first HAE attack, study visits may be conducted 
via site check in calls, except for the following study visits which must be conducted at the 
investigative site:
•
Day 56
•
Day 98
•
Day 140
•
Day 182
The tests and assessments required at these visits are specified in the sections below.
Site check in calls may serve as any of the following study visits until the subject receives
their second open-label dose:
•
Day 14
•
Day 28


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•
Day 42
•
Day 70
•
Day 84
•
Day 112
•
Day 126
•
Day 154
•
Day 168
Site personnel will also contact rollover subjects approximately 7 days after each study visit 
(both site visits and check-in calls) until the subject receives their second open-label dose.
The following assessments are performed during all site calls:
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
7.4
Dose 2 of DX-2930 for Rollover Subjects
The duration of time between Dose 1 and Dose 2 will vary by subject based on when their 
first HAE attack occurs following Dose 1.  As a result, rollover subjects may not receive 
DX-2930 treatment at every dosing visit as outlined in the Study Activities Schedule.
Once a rollover subject reports their first HAE attack they will present to the investigative 
site for their second open-label dose of DX-2930 as quickly as subject and site schedules 
allow.  This treatment visit may be counted as a scheduled study visit, or as an acceptable 
extra study visit.  For details on determining whether the second dose is counted as a 
scheduled or extra study visit, refer to Section 3.1.1.  Regardless of when the second dose is 
administered, the following tests and assessments will be conducted pre-dose on the day it is 
administered:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Complete physical examination (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)


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The following tests and assessments will also be performed if the second dose occurs on a 
scheduled study visit for which they are required:
•
Urine pregnancy test (females) (Section 6.8)
•
12-Lead ECG (Section 6.7)
•
Quality of life assessments (Section 6.14)
After the required pre-dose tests and assessments are completed:
•
Second dose of open-label DX-2930 (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)
7.5
Visit 2 (Day 14 ±4 days); Dose 2 of DX-2930 for Non-Rollover 
Subjects
On Day 14 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)


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7.6
Continuation of Treatment Period: Visits 3 and 4 (Days 28 and 42, 
All ±4 Days)
On Days 28 and 42 the following procedures and assessments will be performed prior to 
DX-2930 treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1).  For non-rollover subjects these doses represent Dose 
3 and Dose 4. 
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)
7.7
Continuation of Treatment Period: Visit 5 (Day 56 ±4 Days)
On Day 56 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Complete physical examination (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 5.
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:


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•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)
7.8
Continuation of Treatment Period: Visits 6 and 7 (Days 70 and 84, 
All ±4 Days)
On Days 70 and 84 the following procedures and assessments will be performed prior to 
DX-2930 treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects these doses represent Dose 
6 and Dose 7.
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)
7.9
Continuation of Treatment Period: Visit 8 (Day 98 ±4 Days)
On Day 98 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Urine pregnancy test (females) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Complete physical examination (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)


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•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 8.
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)
7.10
Continuation of Treatment Period: Visits 9 and 10 (Days 112 and 
126, All ±4 Days)
On Days 112 and 126 the following procedures and assessments will be performed prior to 
DX-2930 treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects these doses represent 
Dose 9 and Dose 10.
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)
7.11
Continuation of Treatment Period: Visit 11 (Day 140 ±4 Days)
On Day 140 the following procedures and assessments will be performed prior to DX-2930 
treatment:


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•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Complete physical examination (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 
11.
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)
7.12
Continuation of Treatment Period: Visits 12 and 13 (Days 154 and 
168 All ±4 Days)
On Days 154 and 168 the following procedures and assessments will be performed prior to 
DX-2930 treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects these doses represent Dose 
12 and Dose 13.
After administration of DX-2930, the following post treatment procedures and assessments 
will be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
AE collection (Section 6.15)


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7.13
Completion of Treatment Period: Visit 14 (Day 182 ±4 Days)
On Day 182, the following procedures and assessments will be performed:

Urine pregnancy test (females) (Section 6.8) 

Vital signs including body temperature, HR, BP and RR (Section 6.5)

Complete physical examination (Section 6.6)

12-Lead ECG (Section 6.7)

Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)

PK sample collection (Section 6.9)

PD sample collection (Section 6.10)

Anti-drug antibody sample collection (Section 6.11)

Concomitant therapy (Section 6.12)

HAE attack information (Section 6.4)

AE collection (Section 6.15)

Quality of life assessments (Section 6.14)

Study Discharge: Subjects may have an opportunity to roll into an ongoing DX-2930 
clinical study or access program that permits such rollover.  Subjects who choose to do 
this will be discharged at this study visit. 
7.14
Follow-up Period: Visit 15 (Day 210 ±4 Days)
On Day 210 all rollover and non-rollover subjects who do not choose to roll over into another
ongoing DX-2930 clinical study or access program that permits such a rollover will receive a 
site check-in call.  During this call site personnel will collect information regarding the 
following: 
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.15)
7.15
Final Follow-up Visit: Visit 16 (Day 238 ±4 Days)
On Day 238 all rollover and non-rollover subjects who do not choose to roll over into another
ongoing DX-2930 clinical study or access program that permits such a rollover will complete 
a final study visit at the investigative site.

Urine pregnancy test (females) (Section 6.8) 


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
Vital signs including body temperature, HR, BP and RR (Section 6.5)

Complete physical examination (Section 6.6)

12-Lead ECG (Section 6.7)

Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)

PK sample collection (Section 6.9)

PD sample collection (Section 6.10)

Anti-drug antibody sample collection (Section 6.11)

Concomitant therapy (Section 6.12)

HAE attack information (Section 6.4)

AE collection (Section 6.15)

Quality of life assessments (Section 6.14)
7.16
Early Termination 
Subjects that terminate early from the study will undergo (if possible) all of the assessments 
and procedures scheduled for Day 182.


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8
QUALITY CONTROL AND ASSURANCE
The Sponsor (Dyax) and the Contract Research Organization (CRO) conducting trial 
management services, Rho, Inc., will implement a system of quality assurance that includes 
all elements described in this protocol. Within this system, SOPs from the Sponsor and CRO 
will be implemented to ensure that the clinical trial is conducted in compliance with 
regulatory requirements and Good Clinical Practices (GCP). Quality control will be applied 
to each stage of data handling to ensure that data are accurate, reliable and processed 
correctly. 
The site staff should assist in all aspects of audit/inspection.


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9
DATA ANALYSIS / STATISTICAL METHODS
9.1
Sample Size Determination
The study is expected to enroll subjects from the DX-2930-03 study, as well as up to 
50 additional subjects who were not enrolled in DX-2930-03.  The total enrollment is 
expected to be approximately 150 HAE Type I or II subjects.  No formal sample size 
calculation was performed.  The sample size is not based on any statistical considerations.  
This study is designed to evaluate the safety and efficacy of open-label treatment with 
DX-2930 in subjects who participated in DX-2930-03 and individuals who were not 
otherwise able to participate in DX-2930-03.
9.2
Analysis Populations
The analysis population will be based on subjects who receive at least one dose of DX-2930 
after entering the study.
9.3
Comparison of Interest
Because this study consists of a non-randomized, pre-selected population of subjects all 
receiving DX-2930, hypothesis testing will not be performed. The exception will be the 
secondary efficacy endpoint of time to first HAE attack for rollover subjects, as described in 
Section 9.7.
For disposition, demographic and safety analyses, subjects will be represented in the 
reporting of DX-2930-04 as follows:

Subjects who received 26 weeks of 300 mg DX-2930 every 2 weeks in DX-2930-03 
and up to 26 weeks of DX-2930 treatment in DX-2930-04.

Subjects who received 26 weeks of 300 mg DX-2930 every 4 week in DX-2930-03 
and up to 26 weeks of DX-2930 treatment in DX-2930-04.

Subjects who received 26 weeks of 150 mg DX-2930 every 4 weeks in DX-2930-03 
and up to 26 weeks of DX-2930 treatment in DX-2930-04.

Subjects received 26 weeks of placebo in DX-2930-03 and up to 26 weeks of 
DX-2930 treatment in DX-2930-04.

Subjects who received up to 26 weeks of DX-2930 treatment in DX-2930-04.
Data from the start of DX-2930 treatment through the final treatment period study visit (up to 
52 weeks for subjects whose treatment with DX-2930 was initiated in DX-2930-03) will be 
combined for safety evaluation of the overall DX-2930 exposure.


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9.4
Analysis of Disposition
The numbers of subjects completing or withdrawing, along with reasons for withdrawal, will 
be tabulated by treatment group as indicated in Section 9.3.
9.5
Demographics and Baseline Characteristics Analyses
Baseline and demographic variables will be descriptively summarized by treatment group as 
indicated in Section 9.3.
9.6
Analysis of Pharmacokinetic and Pharmacodynamic Endpoints
9.6.1
Pharmacokinetic Assessments:
Blood samples will be collected for the measurement of plasma DX-2930 concentrations 
prior to study drug administration on Day 0 and on Days 98 ±3, 182 ±3, as well as prior to 
Dose 2 for rollover subjects at whatever study visit that second dose occurs. An additional 
sample will be collected on Day 238 ±3 for subjects who complete the Follow-up Period.
Plasma concentrations of DX-2930 will be summarized with descriptive statistics by nominal 
PK sampling time.
9.6.2
Pharmacodynamic Assessments:
Blood samples will be collected to evaluate the pharmacodynamic effects of DX-2930 
through biomarker assays prior to study drug administration on Day 0 and on Days 98 ±3 and 
182 ±3, as well as prior to Dose 2 for rollover subjects at whatever study visit that second 
dose occurs. An additional sample will be collected on Day 238 ±3 for subjects who 
complete the Follow-up Period.
Plasma kallikrein activity will be summarized with descriptive statistics by nominal PD
sampling time.
9.6.3
Immunogenicity Assessments:
Blood samples will be collected to assay for the presence of anti-drug antibodies, including 
evaluation of neutralizing antibodies (if any confirmed positive anti-drug antibodies are 
detected) prior to DX-2930 administration on Day 0 and on Days 98 ±3 and 182 ±3, as well 
as prior to Dose 2 for rollover subjects at whatever study visit that second dose occurs. An 
additional sample will be collected on Day 238 ±3 for subjects who complete the Follow-up 
Period.
9.6.4
C1-INH, C4 and C1q Assessments:
Samples will be obtained for C1-INH, C4 and C1q assays at screening (or carried forward 
from the DX-2930-02 or DX-2930-03 studies) for eligibility assessment.


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9.7
Analysis of Efficacy Endpoints
9.7.1
Efficacy Endpoints
Efficacy variables will be evaluated by endpoint as outlined below.
The distribution of time from first open-label dose to first HAE attack will be determined for 
rollover subjects.  The estimation will be based on a standard Cox proportional hazards 
model where several baseline covariates will be tested including baseline attack rate prior to 
entering DX-2930-03, the treatment arm in DX-2930-03, the time since the last dose given in 
DX-2930-03, the time since the last HAE attack, and the rate of attacks during DX-2930-03. 
The distribution of time to first attack will be adjusted for any significant baseline (p < 0.05) 
covariates, and by examining the distribution separately by the treatment arm the patient was 
in during DX-2930-03. In this survival analysis, one observation (time to first attack) per 
subject will be generated.
For other efficacy endpoints, mean event rates will be assessed for all subjects (14 days post-
second dose to Day 182 for rollover subjects; Day 14 to Day 182 for non-rollover subjects).
In addition, for rollover subjects, the mean change from the documented values in 
DX-2930-03 at baseline (last measurement prior to randomization into DX-2930-03) and 
entry (last measurement in DX-2930-03 prior to enrollment into DX-2930-04) will be 
compared to the values assessed at DX-2930-04 time points from 14 days after the second 
dose in DX-2930-04 through Day 182 (i.e., 2 weeks after the final scheduled dose on 
Day 168). Changes will be calculated and presented as descriptive statistics for each 
DX-2930-03 treatment group (300 mg DX-2930 every 2 weeks, 300 mg DX-2930 every 
4 weeks, 150 mg DX-2930 every 4 weeks). For each time period, graphs will be constructed 
for mean changes in efficacy variables from baseline. Time periods will be defined as 
relative time from the DX-2930-03 baseline for those who participated.
For non-rollover subjects, efficacy variables will be presented as descriptive statistics only. 
Efficacy Endpoints
•
Time to first HAE attack for rollover subjects (based upon time from first open label 
study dose until first HAE attack)
•
Mean rate of HAE attacks for all subjects (14 days post-second dose to Day 182 for 
rollover subjects; Day 14 to Day 182 for non-rollover subjects
•
Mean rate of acute therapy usage for all subjects (14 days post-second dose to Day 182 
for rollover subjects; Day 14 to Day 182 for non-rollover subjects.
•
Mean rate of moderate or severe attacks for all subjects (14 days post-second dose to 
Day 182 for rollover subjects; Day 14 to Day 182 for non-rollover subjects
•
Mean rate of high-morbidity attacks for all subjects (14 days post-second dose to 
Day 182 for rollover subjects; Day 14 to Day 182 for non-rollover subjects; a high-
morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation 


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< 24 hours), hemodynamically significant (systolic blood pressure < 90, requires IV 
hydration, or associated with syncope or near-syncope) or laryngeal.
9.8
Safety Analysis
Evaluation of safety data will include all patients who received at least one dose of study 
medication. Clinical interpretation will be based upon review of displays of adverse events 
and laboratory values. Principal considerations in this evaluation will be time to onset, and 
investigator-reported relationship of either adverse events or laboratory abnormalities to 
study medication.
All Subjects:
Safety measures include AEs, concomitant medications, clinical laboratory tests, vital signs 
(blood pressure, heart rate, respiratory rate, and body temperature), physical examination 
findings, and ECGs.
Treatment-emergent AEs are defined as AEs with onset at the time of or following the start 
of treatment with DX-2930, or medical conditions present prior to the start of treatment but 
increasing in severity or relationship at the time of or following the start of treatment. The 
number and percentage of subjects with TEAEs will be displayed by body system and 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA®). 
Summaries in terms of severity and relationship to DX-2930 will also be provided. SAEs will 
be summarized separately in a similar fashion. Patient listings of AEs causing 
discontinuation of DX-2930 treatment, AEs resulting in death, SAEs and AESI will be 
produced.
AESI will be analyzed according to primary System Organ Classes (SOCs) and Preferred 
Terms (PTs) determined by the search of relevant Standardized MedDRA Queries (SMQs). 
Summary tables with SOCs and PTs, from the SMQ searches, will be generated 
presenting the number and percentage of subjects by AE, severity, seriousness, and 
relationship to study medication.
Usage of concomitant medications (other than rescue medications) will be summarized 
descriptively.
Actual values and change from Day 0 in vital signs and clinical laboratory tests will be 
summarized with descriptive statistics at each assessment obtained. For all laboratory tests, a 
shift table will be produced summarizing changes from normal to abnormal and vice-versa.
The number and percentage of subjects with normal, abnormal-not clinically significant, and 
abnormal-clinically significant ECG findings will be displayed. Other safety parameters, 
such as subject withdrawals will be summarized.
Rollover Subjects: Adverse events that started during subject participation in DX-2930-03 
and were ongoing at the time of first open-label dose in DX-2930-04 will not be counted as 
an AE in DX-2930-04 unless that event has worsened in severity or frequency following the 
first open-label dose.  Adverse events that started during subject participation in DX-2930-03 


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and resolved following the first open-label dose in DX-2930-04 and then subsequently 
started again in DX-2930-04 will be counted as a new AE in DX-2930-04.
The incidence of AEs in DX-2930-04 for subjects rolling over from each DX-2930-03 
treatment group (300 mg DX-2930 every 2 weeks vs. 300 mg DX-2930 every 4 weeks vs. 
150 mg DX-2930 every 4 weeks vs placebo) as well as evaluation of overall AEs in the 
combined group of all rollover subjects will be assessed. Changes from baseline (last 
measurement prior to the first dose of DX-2930 received, regardless of if it occurred in 
DX-2930-03 or DX-2930-04) to the DX-2930-04 time points for physical examination 
results, vital sign parameters, and clinical laboratory parameters will be summarized by 
DX-2930-03 treatment group and for the combined group of all rollover subjects. 
Non-rollover Subjects: Adverse events will be captured from the time of informed consent 
through the final study visit.  Adverse event tabular summaries will be based on all 
treatment-emergent AEs.
9.9
Analysis of Quality of Life Assessments
Quality of life data will be obtained using the EQ5D, SF-36, and Angioedema Quality of Life 
Questionnaire (AE-QoL) at pre-dose on Days 0, 98 ±3, and 182 ±3. An additional assessment 
will be conducted on Day 238 ±3 for subjects who complete the Follow-up Period.  Full 
details of the planned analyses using these quality of life assessments will be included in the 
SAP.


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10 STUDY ADMINISTRATIVE STRUCTURE
The study administration structure is provided in Table 1. 
Table 1.
Study Administrative Structure
Sponsor Contact:
, Clinical Development
55 Network Drive, Burlington, MA 01803
Phone: 
Email:  
Sponsor Medical Director:
, MD
, Medical Research
55 Network Drive, Burlington, MA 01803
Phone:  
Email:  
Medical Monitor (US, Canada):
, MD
Rho, Inc.
6330 Quadrangle Drive, Chapel Hill, NC 27517
Phone: 
Email: 
Medical Monitor (Jordan, Europe)
, M.D.
Voisin Consulting
3, rue des Longs Prés
92100 Boulogne, France
Phone: 
Email: 
Study Monitoring (US):
Rho, Inc.
6330 Quadrangle Drive, Chapel Hill, NC 27517
Phone: 
Study Monitoring (Jordan)
Triumpharma
07 Bldg., Al-Yarooty St.
P.O. Box 2233, Amman
11941, Jordan
Phone: 
, 
Study Monitoring (Canada)
Red Maple Trials Incorporated
1081 Carling Avenue, Suite 707
Ottawa, Ontario, Canada, K1Y4G2
Phone: 
Study Monitoring (Europe)
Dyax Corp
55 Network Drive, Burlington, MA 01803
Phone: 


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10.1
Institutional Review Board/ Research Ethics Board/Independent 
Ethics Committee
The protocol and all protocol amendments must be signed and dated by the Investigator and 
approved in writing by the IRB/REB/IEC in accordance with GCP prior to implementation. 
In addition, the IRB/REB/IEC must approve the written informed consent form, any consent 
form updates, subject recruitment materials (e.g., advertisements), and any written 
information to be provided to subjects prior to implementation. The Investigator must 
provide an annual report to the IRB/REB/IEC on the progress of the study including number 
of subjects enrolled, discontinued, and SAEs. It is required that a yearly review of the 
protocol by the IRB/REB/IEC be documented in a letter from the IRB/REB/IEC. The 
Investigator must provide notification to the IRB/REB/IEC of the completion, termination or 
discontinuation of the study.
10.2
Ethical Conduct of the Study
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor 
and the Investigator abide by the principles of the International Conference on Harmonisation 
(ICH) guidelines on GCP, applicable local regulatory requirements, and the Declaration of 
Helsinki (Version 2008). The clinical study also will be carried out in keeping with national 
and local legal requirements [in accordance with United States Investigational New Drug 
(IND) regulations (21 CFR 56)].
10.3
Subject Information and Consent
Before each subject is enrolled in the clinical study, written informed consent will be 
obtained according to the regulatory and legal requirements of the participating country. As 
part of this procedure, the Investigator must explain orally and in writing the nature, duration, 
and purpose of the study, and the action of the drug in such a manner that the study subject is 
aware of the potential risks, inconveniences, or AEs that may occur. The study subject should 
be informed that he/she is free to withdraw from the study at any time. He/she will receive all 
information that is required by federal regulations and ICH guidelines. The Investigator or 
designee will provide the Sponsor with a copy of the IRB/REB/IEC-approved informed 
consent form prior to the start of the study.
10.4
Subject Confidentiality
The anonymity of participating subjects must be maintained. Subjects will be specified on 
study documents by their subject number, initial or birth date (if allowed based on local data 
protection regulations), not by name. Documents that identify the subject (e.g., the signed 
informed consent document) must be maintained in confidence by the Investigator.
The Investigator agrees not to use or disclose protected health information other than as 
permitted or required by the subject authorization or as required by law.


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10.5
Study Monitoring
The Sponsor (or designee) will conduct a study initiation visit to verify the qualifications of 
the Investigator, inspect the facilities, and inform the Investigator of responsibilities and 
procedures for ensuring adequate and correct documentation.
The Investigator must prepare and maintain adequate and accurate records of all observations 
and other data pertinent to the clinical study for each study participant. Frequent 
communication between the clinical site and the Sponsor is essential to ensure that the safety 
of the study is monitored adequately. The Investigator will make all appropriate safety 
assessments on an ongoing basis. The Medical Monitor may review safety information as it 
becomes available throughout the study.
All aspects of the study will be carefully monitored with respect to GCP and SOPs for 
compliance with applicable government regulations. The Study Monitor will be an 
authorized individual designated by the Sponsor. The Study Monitor will have access to all 
records necessary to ensure integrity of the data and will periodically review the progress of 
the study with the Investigator.
10.6
Case Report Forms and Study Records
The Investigator will ensure the accuracy, completeness, and timeliness of the data reported 
to the Sponsor. Data collection processes and procedures will be reviewed and validated to 
ensure completeness, accuracy, reliability, and consistency. A complete audit trail will be 
maintained of all data changes. The Investigator or designee will cooperate with the 
Sponsor’s representative(s) for the periodic review of study documents to ensure the 
accuracy and completeness of the data capture system at each scheduled monitoring visit.
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the clinical sites by means of 
electronic or manual queries.
The Investigator or designee will prepare and maintain adequate and accurate study 
documents (medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
subject receiving randomized study dug.
The Investigator will allow Sponsor representatives, contract designees, authorized 
regulatory authority inspectors, and the IRB/REB/IEC to have direct access to all documents 
pertaining to the study.
A Trial Master File will be maintained by the Sponsor (or designee). All documents and 
other materials that pertain to the conduct of the trial quality of the data, and compliance with 
GCPs will be collected in the Trial Master File.


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10.7
Protocol Violations/Deviations
The Investigator will be instructed not to deviate from the protocol, except where necessary 
to eliminate an immediate hazard to study participants. Should other unexpected 
circumstances arise that will require deviation from protocol-specific procedures, the 
Investigator should contact their Sponsor representative to discuss the appropriate course of 
action. 
The Investigator should document all protocol deviations/violations in the subject’s eCRF 
and source documents. In the event of a significant deviation/violation, the Investigator 
should notify the Sponsor representative. Significant deviations/violations include, but are 
not limited to those that increase the health risk to the subject, or confound interpretation of 
primary study assessments. The Investigator will promptly report all changes in research 
activity and all unanticipated problems involving risks to human subjects or others to his or 
her IRB/REB/IEC.
10.8
Access to Source Documentation and On-Site Audits
Regulatory agencies may request access to all study records, including source documents, for 
inspection and copying, in keeping with country regulations. The Investigator should 
immediately notify the Sponsor representative of any announced or unannounced regulatory 
agency inspections. An auditing inspection may also be conducted by the Sponsor 
representative or designee. Any aspect of the trial may be subject to audit by the Sponsor 
and/or inspection by regulatory authorities or the IRB/REB/IEC. Such audits/inspections may 
take place at the Sponsor’s site(s), the CRO, or at the clinical sites, including laboratories, 
pharmacies and any other facilities used for the study. 
The Investigator will be responsible for the accuracy of the data entered in the eCRF. The 
Investigator will permit the designated Sponsor representatives and regulatory bodies to have 
direct access to the source documents to verify data represented in the eCRF.
10.9
Data Generation and Analysis
This study will be performed in accordance with regulatory requirements outlined in Food 
and Drug Administration (FDA) 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, 
21 CFR Part 312 and 21 CFR Part 11 as well as the ICH GCP E6 Guidelines. The study 
monitors will meet with the Investigators and staff shortly before the start of the trial to 
review the procedures for study conduct and documentation. During the study, the monitors 
will visit the sites to verify record keeping and adherence to the protocol. For this study, 
eCRFs will be used. The monitors will conduct 100% source document verification by 
comparing the eCRFs with the source documents to ensure accuracy and consistency. Edit 
check programs, other forms of electronic validation, manual listings and a query process 
will be executed to verify the accuracy of the database. The EDC system will maintain a full 
audit trail of electronic data changes. Access to all source documentation will be made 
available for monitoring and audit purposes.


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10.10 Retention of Data
All source documents (e.g., informed consent forms, laboratory reports, progress notes, 
medical histories, physical and diagnostic findings, diagnosis and pharmacy records, and 
DX-2930 dispensing/disposition records) that support data in the eCRFs of each study 
subject must be retained in the files of the responsible Investigator.
According to ICH guidelines, essential documents should be retained for a minimum of 
2 years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
medicinal product (IMP). However, these documents should be retained for a longer period if 
required by the applicable legal requirements.
If the responsible Investigator retires, relocates or for any other reason withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor representative must be notified in writing of the name 
and address of the new custodian, prior to the transfer.
10.11 Financial Disclosure
Study personnel on the Form FDA 1572 will complete a financial disclosure form 
(Form FDA 3455) at the beginning of the study and up to one year post completion of the 
study. New study personnel added to the Form 1572 must also meet these requirements.
10.12 Publication and Disclosure Policy
All information concerning DX-2930, Sponsor operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information, supplied to the 
Investigator by a Sponsor representative and not previously published, is considered 
confidential and remains the sole property of the Sponsor. The Investigator must agree to use 
this information only to accomplish this study, and must not use it for other purposes without 
the Sponsor’s advanced written consent.
The information developed in this study will be used by the Sponsor in connection with the 
continued development of DX-2930 and thus may be disclosed as required to other clinical 
Investigators or government regulatory agencies. To permit the information derived from the 
clinical studies to be used, the Investigator is obligated to provide the Sponsor with all data 
obtained in the study.


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11 REFERENCE LIST
Bennet G, Craig, T. Hereditary angioedema with a focus on the child. Allergy Asthma 
Proc. 2015 Jan-Feb; 36 (1):70-3.
Bork K, Hardt J, Schicketanz K-H, Ressel N. Clinical studies of sudden upper airway 
obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. 
Arch Int Med. 2003;163:1229-1235.
Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema 
due to C1-INH deficiency. J Allergy Clin Immunol. 2012;130(3):692-7.
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: New findings concerning 
symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274.
Bork K, Siedlecki K, Bosch S, Schopf RE, Kreuz W. Asphyxiation by laryngeal edema in 
patients with hereditary angioedema. Mayo Clin Proc. 2000;75(4):349-54.
Bygum A. Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol. 
2009;161(5):1153-8.
Craig T, Pursun EA, Bork K, Bowen T, Boysen H, Farkas H, et al. WAO Guideline for the 
Management of Hereditary Angioedema. World Allergy Organ J. 2012;5(12):182-199.
Davis AE, 3rd. Mechanism of angioedema in first complement component inhibitor 
deficiency. Immunol Allergy Clin North Am. 2006;26(4):633-51.
Farkas H.  Pediatric hereditary angioedema due to C1-inhibitor deficiency.  Allergy, Asthma 
& Clinical Immunology 2010, 6:18.
Goring HD, Bork K, Spath PJ, Bauer R, Ziemer A, Hintner H, et al. [Hereditary angioedema 
in the German-speaking region]. Hautarzt. 1998;49(2):114-22.
KALBITOR® (ecallantide) [package insert] Burlington, MA: Dyax Corp.; 2015
Kaplan AP, Joseph K. The bradykinin-forming cascade and its role in hereditary 
angioedema. Ann Allergy Asthma Immunol. 2010;104(3):193-204.
Kenniston JA, Faucette RR, Martik D, Comeau SR, Lindberg AP, Kopacz KJ, et al. 
Inhibition of plasma kallikrein by a highly specific active site blocking antibody. J Biol 
Chem. 2014;289(34):23596-608.
Lei WT, Shyur SD, Huang LH, Kao YH, Lo CY. Type I hereditary angioedema in Taiwan --
clinical, biological features and genetic study. Asian Pac J Allergy Immunol. 
2011;29(4):327-31.


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Final: 14 December 2015
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Nordenfelt P, Dawson S, Wahlgren CF, Lindfors A, Mallbris L, Bjorkander J. Quantifying 
the burden of disease and perceived health state in patients with hereditary angioedema in 
Sweden. Allergy Asthma Proc. 2014;35(2):185-90.
Renne T, Gruber A. Plasma kallikrein: novel functions for an old protease. Thromb Haemost. 
2012;107(6):1012-3.
Roche O, Blanch A, Caballero T, Sastre N, Callejo D, Lopez-Trascasa M. Hereditary 
angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in 
Spain. Ann Allergy Asthma Immunol. 2005;94(4):498-503.
Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-36.
Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, et al. A focused parameter 
update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting 
enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013;131(6):1491-1493 
e25.


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Final: 14 December 2015
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12 APPENDICES
Appendix 1
Study Activities Schedule
Appendix 2
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
(Modified) (US National Institutes of Health; National Institute of Allergy 
and Infectious Diseases)
Appendix 3
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Tables 
(Modified) (US National Institutes of Health; National Institute of Allergy 
and Infectious Diseases
Appendix 4
HAE Attack Assessment and Reporting Procedures (HAARP)
Appendix 5
Summary of Planned Pivotal Study of DX-2930 in HAE Subjects


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Appendix 1
Study Activities Schedule
Study Activities Schedule
Screening 
Visit1
Treatment Period
±4 days for each visit 
Follow-up Period2
±4 days for each 
visit
Tests and 
Assessments
Visit 1
Dose 1
Day 0
Site 
Check
-in3
Visit 2 
Dose 24
Day 14
Visit 3 
Dose 3
Day 28
Visit 4 
Dose 4
Day 42
Visit 5 
Dose 5
Day 56
Visit 6
Dose 6
Day 70
Visit 7 
Dose 7
Day 84
Visit 8 
Dose 8
Day 98
Visit 9
Dose 9
Day 112
Visit 10 
Dose 10
Day 126
Visit 11 
Dose 11
Day 140
Visit 12
Dose 12
Day 154
Visit 13 
Dose 13
Day168
Visit 14
Day 182
Visit 15
Day 2105
Visit 16
Day 238
Informed Consent6
X
Eligibility Review
X
X
Long-term 
prophylactic 
therapy washout7
X
DX-2930 
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
Demographic and 
Medical History
X
C1-INH, C1q and 
C4 Testing8
X
Pregnancy Test9 
(females)
X
X
X
X
X
Vital Signs10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examination11
X
X
X
X
X
X
X
Clinical 
Laboratory 
Testing12
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
Concomitant 
Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HAE Attack Data13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Assessments14
X
X
X
X


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Study Activities Schedule
Screening 
Visit1
Treatment Period
±4 days for each visit 
Follow-up Period2
±4 days for each 
visit
Tests and 
Assessments
Visit 1
Dose 1
Day 0
Site 
Check
-in3
Visit 2 
Dose 24
Day 14
Visit 3 
Dose 3
Day 28
Visit 4 
Dose 4
Day 42
Visit 5 
Dose 5
Day 56
Visit 6
Dose 6
Day 70
Visit 7 
Dose 7
Day 84
Visit 8 
Dose 8
Day 98
Visit 9
Dose 9
Day 112
Visit 10 
Dose 10
Day 126
Visit 11 
Dose 11
Day 140
Visit 12
Dose 12
Day 154
Visit 13 
Dose 13
Day168
Visit 14
Day 182
Visit 15
Day 2105
Visit 16
Day 238
PK Blood 
Sampling15
X
X
X
X
PD Sample 
Collection15
X
X
X
X
Plasma Anti-Drug 
Antibody Testing15
X
X
X
X
Discharge from 
Study16
X
ECG = Electrocardiogram; PK = Pharmacokinetic; PD = Pharmacodynamic
1. Screening visit is for non-rollover subjects only.  Screening visit can occur up to 28 days prior to first open-label dose.
2. The Follow-up Period is not required for subjects who choose to roll over into an ongoing DX-2930 clinical study or access program that permits such a rollover.
3. Site personnel will contact rollover subjects approximately every 7 days following the first dose of open-label DX-2930 to solicit for any HAE attacks not already reported.  Site 
check-in with rollover subjects will continue until the subject receives their second open-label dose. 
4. For rollover subjects, the timing of Dose 2 will vary by subject based on when their first HAE attack occurs following Dose 1.  Following the first reported HAE attack, subjects 
will begin receiving regular SC administrations of 300 mg DX-2930 every 2 weeks.  A minimum of 10 days between the first and second open-label doses is required. If the 
second dose is to be administered within the accepted ± 4 day window around a scheduled study visit, this treatment visit will represent that scheduled visit unless that scheduled 
visit has already occurred. If that scheduled visit has already occurred, or if the second dose is to be administered outside of the accepted ± 4 day window around a scheduled 
visit, this visit will not replace any scheduled visit and will thus represent an acceptable, extra study visit. Regardless, at the visit in which the second open-label dose of 
DX-2930 is administered, the subject will undergo pre-dose assessments for vital signs, physical examination, clinical laboratory testing, PK, PD, and anti-drug antibody. Vital 
signs will be obtained at 1 hour post-dosing. As with all study visits, information will be collected on adverse events, concomitant therapy, and HAE attack data. 
5. The Day 210 Visit is a site check-in for all rollover and non-rollover subjects.
6. Rollover subjects will provide consent no later than the Day 182 DX-2930-03 study visit.
7. Non-rollover subjects who are on long-term prophylactic (LTP) therapy for HAE are required to undergo a minimum 2 week washout period prior to the start of the treatment 
period.
8. Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment unless already collected as part of protocol DX-2930-02 or DX-2930-03.  
9. The pregnancy test will only be conducted in females of childbearing potential. Tests performed on Day 0 must be urine-based to confirm eligibility prior to first dose. Tests 
performed at screening, Day 98, Day 182, and Day 238 can be serum or urine-based.
10.There is a ± 15 minute window for all vital signs. Vital signs will be obtained prior to dosing and 1 hour after dosing.
11.Height and weight will be collected at the Screening visit only. Physical examinations will be conducted for all rollover and non-rollover subjects according to the study 
activities schedule.  In addition to the physical examinations specified in the study activities schedule, an additional physical examination will be conducted for these subjects 
prior to dosing on the day of their second open-label dose, at whatever study visit that occurs.


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12.Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis. Clinical laboratory testing will be conducted for all rollover and non-
rollover subjects according to the study activities schedule.  In addition to the testing specified in the study activities schedule, additional testing will be conducted for rollover 
subjects prior to dosing on the day of their second open-label dose, at whatever study visit that occurs.
13.Historical attack information will be collected at screening. During the study subjects (or caregivers) are instructed to report details of the attack to the study site within 72 hours 
of the onset of the attack. During study visits, site personnel will solicit for any new HAE attack information that was not given through prior subject contact with the site.
14.Quality of life data will be obtained using the EQ5D, SF-36, and Angioedema Quality of Life Questionnaire (AE-QoL).
15.PK, PD and Anti-drug Antibody PD samples will be drawn for all rollover and non-rollover subjects according to the study activities schedule.  In addition to the samples 
specified in the study activities schedule, an additional PK, PD and Anti-drug Antibody sample will be drawn for rollover subjects prior to dosing on the day of their second 
open-label dose, at whatever study visit that occurs.
16.Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures as Day 182 at their final study visit.


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Final: 14 December 2015
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Appendix 2
National Institute of Allergy and Infectious Diseases, 
Division of Microbiology and Infectious Diseases 
(DMID) Adult Toxicity Table (Modified) (US National 
Institutes of Health; National Institute of Allergy and 
Infectious Diseases)


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Final: 14 December 2015
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Appendix 3
National Institute of Allergy and Infectious Diseases, 
Division of Microbiology and Infectious Diseases 
(DMID) Pediatric Toxicity Tables (Modified) (US 
National Institutes of Health; National Institute of 
Allergy and Infectious Diseases


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Appendix 4
HAE Attack Assessment and Reporting Procedures 
(HAARP)


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Final: 14 December 2015
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Appendix 5
Summary of Planned Pivotal Study of DX-2930 in HAE 
Subjects
The proposed pivotal clinical study (DX-2930-03) is entitled “HELP StudyTM: A Multicenter, 
Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate 
DX-2930 For Long-Term Prophylaxis Against Acute Attacks of Hereditary Angioedema 
(HAE).” This study will be a multi-center, double-blind, randomized, placebo-controlled 
parallel-arm study evaluating the efficacy of DX-2930 in preventing acute angioedema 
attacks in patients with Type I or Type II HAE. The double-blind study is planned to be 
followed by the study described in the present protocol, an open-label extension (OLE) study
(DX-2930-04).
The primary objective of study DX-2930-03 is to evaluate the efficacy of DX-2930 in 
preventing HAE attacks. The secondary objective is to evaluate the safety of repeated SC 
administrations of DX-2930. The tertiary objectives are to evaluate the pharmacodynamic 
effects of chronically administered DX-2930; to assess the immunogenicity of chronically 
administered DX-2930; to evaluate the pharmacokinetics of chronically administered 
DX-2930; and to evaluate the effect of DX-2930 upon quality of life assessments.
Subjects aged 12 years and over with a documented diagnosis of Type I or Type II HAE who 
experience at least 1 attack per 4 weeks will be eligible for the study. Up to 120 subjects are 
planned for enrollment across approximately 60 sites in the United States, Canada, Italy, 
Germany, United Kingdom and Jordan.
Following informed consent, subjects will undergo screening assessments.  Subjects who are 
on long-term prophylactic therapy for HAE are required to undergo a minimum 2 week 
washout period prior to the start of the run-in period.  Subjects who are either not on long-
term prophylactic therapy for HAE, or have completed the required washout period will enter 
a run-in period of 4 weeks to determine the baseline HAE attack rate. The run-in period may 
be extended to 8 weeks if the minimum baseline attack rate is not achieved in the first 
4 weeks. HAE subjects will then be randomized 2:1 to receive repeated subcutaneous (SC) 
administrations of DX-2930 or placebo in a double-blind fashion.  Subjects who are 
randomized to DX-2930 will be assigned in a 1:1:1 ratio to one of three dose regimens: 
300 mg every 2 weeks, 300 mg every 4 weeks or 150 mg every 4 weeks.  Each subject will 
undergo a treatment period consisting of 13 doses of blinded study drug, for a period of 
26 weeks from the date of first dose on Day 0 through Day 182
Subjects may consent to rollover into the OLE study (present protocol DX-2930-04) upon 
completion of their participation in the double-blind treatment period.
The primary endpoint will be to compare the mean rate of investigator-confirmed HAE 
attacks observed in each DX-2930 treatment arm to that in the placebo arm during the 
efficacy assessment period (Day 14 through Day 182).
Figure 1 shows a schematic of the double-blind, pivotal study.


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Final: 14 December 2015
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Figure 1.
Overview of the Design of Pivotal Study DX-2930-03
Dose Rationale for Double-Blind, Pivotal Study DX-2930-03
The dose rationale is based on the pharmacodynamic bioactivity, PK, safety, and efficacy of 
DX-2930 from the Phase 1 clinical studies and nonclinical studies. Together, these attributes 
provide the rationale for the selected doses and regimens to achieve drug levels likely to 
prevent a majority of HAE attacks. Based on these considerations, 300 mg every 2 weeks, 
300 mg every 4 weeks, and 150 mg every 4 weeks were identified as the dosing regimens for 
evaluation,
The 3 proposed dose-regimen combinations provide a 6-fold range of steady-state trough 
concentrations and leverage both the biomarker and efficacy data generated in study 
DX-2930-02.  Evaluation of the DX-2930 plasma concentrations at the time of attacks 
reported by DX-2930 treated subjects in DX-2930-02 suggests that the 3 planned dosing 
regimens will provide a meaningful range of clinical response while avoiding non-
therapeutic or super-therapeutic doses and regimens


Clinical Trial Protocol: DX-2930-04 
Study Title: 
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-
Term Safety and Efficacy of DX-2930 for Prevention Against Acute 
Attacks of Hereditary Angioedema (HAE) 
Study Number: 
DX-2930-04 
Study Phase: 
Phase 3 
Product Name: 
DX-2930 
IND Number: 
116647 
EudraCT Number: 
2015-005255-27 
Indication: 
Prevention of angioedema attacks in patients with HAE 
Investigators: 
Multicenter 
Sponsor: 
Dyax Corp., an indirect, wholly-owned subsidiary of Shire plc. 
55 Network Drive, Burlington, MA 01803 USA 
Sponsor Contact: 
, MD 
, Clinical Development 
300 Shire Way, Lexington, MA 02421 USA 
Phone: 
 
Medical Monitor US 
and Canada: 
, MD 
, Clinical Development 
300 Shire Way, Lexington, MA 02421 USA 
Phone: 
 
Medical Monitor 
Europe and Jordan: 
, MD, MBA 
Voisin Consulting 
3, rue des Longs Prés 
92100 Boulogne, France 
Phone: 
 
Date: 
Original Protocol 
14 December 2015 
Amendment 1.0 
27 June 2016 
Confidentiality Statement 
This document is the property of Dyax Corp. The information in this document contains trade secrets and 
commercial information that are privileged or confidential and may not be disclosed without the express written 
permission of Dyax unless required by federal or state law or regulations. Any person to whom the information 
is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential. 
Page 1 of 151


DX-2930 
Clinical Trial Protocol: DX-2930-04 
CONFIDENTIAL 
Page2 
27 June2016 
PROTOCOL SIGNATURE PAGE 
Study Title: 
HELP Study Extension ™: An Open-Label Study to Evaluate the Long-
Term Safety and Efficacy ofDX-2930 for Prevention Against Acute 
Attacks of Hereditary Angioedema (HAE) 
Study Number: 
Amendment 1.0 Final 
Date: 
DX-2930-04 
27 June 2016 
This clinical study protocol was subject to critical review and has been approved by the Sponsor. 
The signature of the Sponsor representative indicates that the Sponsor will comply with all 
Sponsor obligations detailed in applicable regulations and guidelines and will ensure the 
investigator is informed of all relevant information that becomes available. 
Signed: 
Date: 
, MD 
, Clinical Development 
300 Shire Way, Lexington, MA 02421 USA 
I have read the foregoing protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study in compliance with the Declaration of Helsinki, Good 
Clinical Practice (GCP), and all applicable regulatory requirements and guidelines as outlined 
herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure they 
are fully informed regarding the drug and the conduct of the study. 
I will use only the informed consent form approved by Dyax Corp. and my Institutional Review 
Board (IRB), Research Ethics Board (REB) or Ethics Committee (EC) and will fulfill all 
responsibilities for submitting pertinent information to the IRB/REB/EC responsible for this 
study. 
I further agree that Dyax Corp. or their designees shall have access to any source documents 
from which eCRF information may have been generated. 
By signing this protocol, I agree to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of GCP to which it conforms. 
Signed: _______________ _ 
Date: ________ _ 
Investigator 
Address: 
Page 2 of 151 


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CONFIDENTIAL 
Page 3 
Clinical Trial Protocol: DX-2930-04 
27 June 2016 
SYNOPSIS 
Sponsor: 
Dyax Corp., an indirect, wholly-owned subsidiary of Shire plc. 
55 Network Drive, Burlington, MA 01803 USA 
Name of Finished Product: 
DX-2930 Drug Product (DP) 
Name of Active Ingredient: 
DX-2930 is a recombinant, Chinese hamster ovary (CHO) cell-expressed, fully human 
immunoglobulin G subclass 1 (IgG1), kappa light chain, monoclonal antibody. 
Names of Inactive Ingredients: 
Sodium phosphate dibasic dihydrate, citric acid monohydrate, L-histidine, sodium chloride, and 
Polysorbate 80 
Study Title: 
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-Term Safety and Efficacy 
of DX-2930 for Prevention Against Acute Attacks of Hereditary Angioedema (HAE) 
Study Number: 
DX-2930-04 
Study Phase: Phase 3 
Study Location: 
Approximately 60 study sites planned across North America, the European Union and the 
Middle East 
Primary Objective: 
To evaluate the long-term safety of repeated subcutaneous (SC) administrations of DX-2930 
Secondary Objectives: 
•
To evaluate the long-term efficacy of DX-2930 in preventing HAE attacks
•
To characterize the outer bounds of dosing frequency for DX-2930
Tertiary Objectives: 
•
To assess the immunogenicity of chronically administered DX-2930
•
To evaluate the effect of DX-2930 on health-related quality of life (QOL)
•
To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of SC
administration of DX-2930
•
To evaluate safety and efficacy in the non-rollover population of switching from long-term
prophylactic (LTP) treatment to DX-2930
•
To evaluate breakthrough attack characteristics while receiving DX-2930 compared to
historical baseline
•
To evaluate subject experience with self-administration of DX-2930 including ease of SC
administration of DX-2930
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CONFIDENTIAL 
Page 4 
Clinical Trial Protocol: DX-2930-04 
27 June 2016 
Study Design: 
DX-2930-04 is an open-label, long term safety and efficacy extension study of DX-2930-03, to 
evaluate the investigational medicinal product (IMP), DX-2930, in preventing acute angioedema 
attacks in patients with Type I and Type II HAE. There are two types of subjects who will be 
enrolled into this study: 
•
Subjects who rollover from the DX-2930-03 study
•
Subjects who are non-rollover (i.e., were not participants in DX-2930-03)
Rollover Subjects 
Rollover subjects are subjects who complete the double-blind treatment period at Day 182 of the 
DX-2930-03 study and consent to enter DX-2930-04.  Subjects who discontinue from 
DX-2930-03 after enrollment are not eligible to enroll in DX-2930-04.   
Willing subjects must sign informed consent for DX-2930-04 after Day 168 of study DX-2930-
03 and no later than the final DX-2930-03 Day 182 treatment period study visit.   
Subjects who are eligible to roll over into DX-2930-04 but elect not to, may not enroll in 
DX-2930-04 at a later time. The first DX-2930-04 visit for rollover subjects (Day 0) will occur 
on the same day as the DX-2930-03 Day 182 study visit. Rollover subjects will complete all 
DX-2930-03 final study assessments (Day 182) at which time they will be discharged from that 
study. No assessments conducted between the DX-2930-03 Day 182 study visit and the first 
DX-2930-04 visit (Day 0) will be duplicated. Results of the final DX-2930-03 assessments on 
Day 182 will be used as the pre-dose results for Day 0 Dose 1 of DX-2930-04. 
All subjects, caregivers, investigators and study site personnel will remain blinded to the 
DX-2930-03 treatment assignment until the conclusion of the DX-2930-04 study. 
Non-rollover subjects 
At least 50 subjects (up to a maximum of 100) who were not participants in the DX-2930-03 
study will be permitted to enroll if they meet the eligibility requirements. Subjects who screen 
fail out of DX-2930-03 for not meeting the minimum attack requirements during the run-in 
period must wait until enrollment for the double-blind study has ended before they can screen for 
DX-2930-04. The Sponsor may ease this restriction based on the enrollment rate observed in 
DX-2930-03. Subjects who are still in the run-in period for DX-2930-03 when enrollment for 
that study closes, as well as subjects on prior LTP who screen fail out of DX-2930-03 due to an 
inability to wash-out of their LTP, may screen for DX-2930-04 following discussion with the 
Sponsor medical monitor. 
Screening Period: 
There is no screening period for rollover subjects. 
Non-rollover subjects must provide informed consent and have screening assessments completed 
within 4 weeks prior to their first open-label dose.  Screened non-rollover subjects (adults and 
adolescents) who are on LTP with C1-INH therapy for HAE can continue their current LTP until 
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Clinical Trial Protocol: DX-2930-04 
27 June 2016 
Day 8 (or Day 15) such that subjects will have received 2 (or 4) doses of C1-INH.  For subjects 
who are on attenuated androgens (e.g., danazol) or anti-fibrinolytics (e.g., tranexamic acid), a 
similar tapering schedule is recommended. However, the taper can be prolonged by an additional 
week, if medically indicated, as long as androgen or anti-fibrinolytic therapy is stopped within 3 
weeks after receiving the first dose of DX-2930.   
Treatment Period: 
Rollover Subjects 
Following informed consent and pre-dose assessments, rollover subjects will receive a single 
open-label dose of 300 mg DX-2930 administered subcutaneously (SC) on Day 0.  Subjects will 
not receive any additional DX-2930 doses until their first reported, and investigator-confirmed, 
HAE attack.   
The duration of time between the first open-label dose and first reported HAE attack will vary by 
rollover subject.  All rollover subjects must adhere to the Study Activities Schedule for the entire 
duration of the study.  However, until a rollover subject reports their first HAE attack, only 
scheduled study visits where the following tests and assessments are performed must be 
conducted at the investigative site: pregnancy testing, clinical laboratory testing, physical 
examination, 12-Lead ECG, QoL, PK, PD and anti-drug antibody sample collection. All other 
scheduled study visits may be conducted via site check-in calls to collect information on adverse 
events, concomitant therapy, and HAE attack data.  See Study Activities Schedule for which 
visits must be conducted at the study site. 
Once a rollover subject reports their first HAE attack they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  If 
the second dose is to be administered within the accepted ±4 day window around a scheduled 
study visit, this treatment visit will represent that scheduled visit. If that scheduled visit has 
already occurred, the day of the visit will be considered an acceptable, extra study visit (i.e., an 
unscheduled visit).  Similarly, if the second dose is administered outside of the accepted ±4 day 
window around a scheduled visit, the day of the visit will be considered an acceptable extra 
unscheduled study visit, (i.e., this visit will not replace any scheduled visit).  
Regardless of the study day, at the visit in which the second open-label dose of DX-2930 is 
administered, the subject will undergo pre-dose assessments for vital signs, physical 
examination, clinical laboratory testing, and blood sampling for PK, PD, and anti-drug antibody 
assessments. Vital signs will be obtained at 1 hour post-dosing. As with all study visits, 
information will be collected on adverse events, concomitant therapy, and HAE attack data.  
Regardless of when a rollover subject’s first HAE attack occurs, there will be a minimum of 10 
days between their first open-label dose and their second open-label dose. Following their second 
dose, rollover subjects will continue to receive repeated SC administrations of open-label 300 mg 
DX-2930 every 2 weeks for the remaining duration of the treatment period per the scheduled 
dosing in the Study Activities Schedule. The treatment period will last 350 days from the date of 
the first open-label dose. The number of doses administered during this period will vary by 
subject based on the date of each subject’s second dose, but will not exceed 26 doses. The Day 
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350 study visit is the last visit at which a dose may be administered.  
Non-rollover Subjects 
Once all screening assessments have been completed and eligibility confirmed, non-rollover 
subjects will arrive at the study site and, following pre-dose assessments, receive an open-label 
dose of 300 mg DX-2930 administered SC on Day 0.  Non-rollover subjects will continue to 
receive SC administrations of open-label 300 mg DX-2930 every 2 weeks throughout the 
duration of the treatment period per the scheduled dosing in the Study Activities Schedule.  A 
total of 26 doses will be administered with the last dose administered at the Day 350 study visit. 
All Subjects: 
All doses (with the exception of the second dose for rollover subjects) require a minimum of 10 
days and maximum of 18 days between administrations, and should fall within the accepted ±4 
day window around study visits.  
If a subject experiences an acute angioedema attack at any time during the study that in the 
opinion of the investigator requires medical intervention, standard of care therapy should be 
provided based on subject’s medical history and per locally approved product information.  
Administration of DX-2930 and study procedures will continue without alteration to the protocol 
study activities schedule, even if a subject receives treatment for a breakthrough angioedema 
attack on the day of a scheduled dose of study drug (if self-administering) or scheduled study 
visit. 
Self-Administration 
All subjects (adolescent or adult) who are considered suitable candidates (i.e., those with a 
physical and mental capability of learning and willing to be trained) may be allowed to self-
administer treatment.  Subjects must complete appropriate training by the investigator or 
designee and understanding of the training must be confirmed by the investigator or designee. 
Subjects are allowed to initiate self-administration after receiving the first 2 doses of DX-2930 at 
the study site. Once initiated, subjects may self-administer subsequent doses of DX-2930 at the 
investigational site (when visits are scheduled study site visits) or the subject’s home or other 
agreed upon location (when the study permits off-site dosing). See Schedule of Activities for 
details. Adolescent subjects self-administering investigational product will be supervised by a 
parent/legal guardian/caregiver. Alternatively, a parent/legal guardian/caregiver, after completing 
appropriate training, will be allowed to administer DX-2930 to an adolescent without study site 
personnel supervision.  Site personnel will call subjects after the planned off-site self-
administrations to ensure the administration occurred, to collect AEs, concomitant medications, 
and to ensure all attacks have been appropriately documented. 
 
Throughout the study, study site personnel will document information in source documents (ie, 
the subject’s medical record) and eCRF regarding the subject’s experience with self-
administration and SC administration of DX-2930. 
 
Follow-up Period 
After completion of the 350 day treatment period, all subjects will undergo safety evaluations 
 
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during an 8-week follow-up period. 
Modifications to Open-Label Dosing 
If, at any time, an important dose-related safety signal is identified either from this study or 
DX-2930-03, the Sponsor may decide to switch the enrolled subjects who have not yet 
completed the treatment period, and any subsequent subjects, to receive a different open-label 
DX-2930 dose and/or frequency. 
In addition, based on the results of the DX-2930-03 study, the Sponsor may switch to a different 
dose and/or frequency.  
Study Population: 
The study is expected to enroll subjects from the DX-2930-03 study, as well as at least 50 (up to 
a maximum of 100) additional subjects who were not enrolled in DX-2930-03. The total 
enrollment is expected to be at least 150 but not more than 250 HAE Type I or II subjects. 
Subjects will be 12 years of age or older who experience at least 1 attack per 12 weeks. HAE 
diagnosis will be confirmed through documented clinical history and diagnostic testing 
conducted either during screening or during prior participation in study DX-2930-02 or DX-
2930-03.  The study will aim to enroll at least 15 subjects who are 12 to 17 years of age, 
inclusive of the estimated 10 subjects 12 to 17 years old who roll over from the DX-2930-03 
study. 
Criteria for Inclusion:  
Subjects must meet the following criteria to be enrolled in this study: 
1. Male and female HAE subjects who are 12 years of age or older at the time of screening.  
2. Documented diagnosis of HAE (Type I or II)  based on all of the following: 
• Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria). 
• Diagnostic testing results obtained during screening (or a prior DX-2930 study) that 
confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level < 40% of the 
normal level. Subjects with functional C1-INH level 40-50% of the normal level may 
be enrolled if they also have a C4 level below the normal range.  Subjects may be 
retested if results are incongruent with clinical history or believed by the investigator 
to be confounded by recent LTP use.  
• 
At least one of the following: Age at reported onset of first angioedema symptoms ≤ 
30 years, a family history consistent with HAE Type I or II, or C1q within normal 
range. 
3. A historical baseline HAE attack rate of at least 1 attack per 12 weeks. 
4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, 
understand, and sign an informed consent form. Subjects age 12 to 17, whose caregiver has 
provided informed consent, are willing and able to read, understand and sign an assent form. 
5. Males and females who are fertile and sexually active must adhere to contraception 
requirements for the duration of the study as follows: 
• Females of childbearing potential must agree to be abstinent or it is recommended to use 
highly effective forms of contraception from screening through 30 days after the final 
 
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study visit. This includes stable doses (for 3 months prior to study screening) of 
combined estrogen and progestin-containing hormonal contraception associated with 
inhibition of ovulation (oral, injectable or implantable), progestin-only hormonal 
contraception associated with inhibition of ovulation, intra-uterine device (IUD, all types) 
or intrauterine hormone releasing systems (IUS). Notes: 1) A female whose male partner 
has had a vasectomy must agree to use one additional form of medically acceptable 
contraception. 2) Use of a male condom with or without spermicide or cervical cap, 
diaphragm or sponge with spermicide or a combination (double barrier methods) are not 
considered highly effective. 
• Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study. 
• Males, including males who are surgically sterile (post vasectomy), with female partners 
of childbearing potential must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through 60 days after the final study 
visit. 
Criteria for Exclusion:  
Subjects who meet any of the following criteria will be excluded from the study: 
1. Discontinued from DX-2930-03 after enrollment for any reason. 
2. If rolling over from DX-2930-03, presence of important safety concerns that would preclude 
participation in this study. 
3. Concomitant diagnosis of another form of chronic, recurrent angioedema such as acquired 
angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), idiopathic 
angioedema, or recurrent angioedema associated with urticaria.  
4. Dosing with an investigational drug (not including DX-2930 or other HAE therapies) or 
exposure to an investigational device within 4 weeks prior to screening. 
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to study 
screening or any newly initiated or dose modification of estrogen-containing medications 
with systemic absorption (such as oral contraceptives or hormonal replacement therapy) 3 
months prior to the screening visit. 
6.  Unwilling to discontinue use of long-term prophylactic therapy for HAE (C1-INH, 
attenuated androgens, or anti-fibrinolytics) within 3 weeks after starting DX-2930 treatment.  
7. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3x 
upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of normal, or 
total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of 
Gilbert’s Syndrome). 
8. Pregnancy or breastfeeding. 
9. Subject has any condition that, in the opinion of the investigator or Sponsor, may 
compromise their safety or compliance, preclude successful conduct of the study, or interfere 
with interpretation of the results (e.g., history of substance abuse or dependence, a significant 
pre-existing illness or other major comorbidity that the investigator considers may confound 
the interpretation of study results). 
 
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Test Product; Dose; and Mode of Administration: 
DX-2930 is a sterile, preservative-free solution for injection, pH 6.0. The active ingredient, 
DX-2930, is formulated using the following compendial components:  30 mM sodium phosphate 
dibasic dihydrate, 19.6 mM citric acid, 50 mM histidine, 90 mM sodium chloride, 0.01% 
Polysorbate 80. Each open-label vial contains a nominal concentration of 150 mg DX-2930 
active ingredient in 1 mL solution. 
For each 300 mg dose of DX-2930, each subject will receive a total of 2 mL (2 vials), which will 
be administered in a single 2 mL SC injection. The injection will be given in the upper arm, thigh 
or abdomen. 
Self-Administration Option: Investigational product can be self-administered without supervision 
(parental supervision required for adolescent subject) after subjects receive appropriate training 
by the investigator or designee and their understanding is confirmed. Subjects are allowed to 
initiate self-administration after receiving the first 2 doses of DX-2930 at the study site and may 
continue to self-administer all subsequent doses (see Study Activities Schedule). 
Duration of Treatment: 
All subjects will receive open-label DX-2930 during a 350 day treatment period. The number of 
doses that rollover subjects receive during this period will vary by subject but will not exceed 26 
doses. The last dose of open-label DX-2930 administered to these subjects may be given at the 
Day 350 study visit. Non-rollover subjects will receive 300 mg DX-2930 every 2 weeks for a 
total of 26 doses, with the first dose administered on Day 0 and the final dose administered at the 
Day 350 study visit. 
There will be a ±4-day window around each study visit. There will be a minimum of 10 days 
between any two doses. Excluding the interval between the first and second open-label doses for 
rollover subjects, there will be a maximum of 18 days between any two doses. Subjects will be 
monitored at the study site through 1 hour post-dose for scheduled study site visits.  No 
monitoring of vital signs will be performed for subjects who elect to self-administer away from 
the investigational site. 
Duration of Study for Individual Subjects: 
Following informed consent, subjects will either rollover from DX-2930-03 or undergo 
screening assessments (non-rollover subjects). Screening assessments for non-rollover subjects 
must occur within 4 weeks prior to the first open-label dose. Eligible subjects will be enrolled 
and undergo a 350 day treatment period. At the conclusion of the 350 day treatment period, 
subjects will be followed for an additional 8 weeks.  
Prohibited Concomitant Treatments: 
Use of the following treatments will not be permitted during the study: 
• Long-term prophylaxis for HAE (e.g., use of C1-INH for LTP, attenuated androgens, or anti-
fibrinolytics) once LTP is discontinued (within 3 weeks following the first dose of DX-
2930).  
• Angiotensin-converting enzyme (ACE) inhibitors. 
• Initiating or changing the dose of estrogen-containing medications with systemic absorption 
 
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(such as oral contraceptives or hormonal replacement therapy) 3 months prior to study 
screening. 
• Use of androgens (e.g., stanozolol, danazol, oxandrolone, methyltestosterone, and 
testosterone) for non-HAE related medical conditions or for HAE after discontinuation 
during the first three weeks. 
• Any other investigational drug or device. 
The use of short-term prophylactic treatment for HAE will be permitted if medically indicated.  
Short-term (pre-procedure) prophylaxis is defined as use of C1-INH to avoid angioedema 
complications from medically indicated procedures. 
Management of Acute Attacks: 
Acute HAE attacks during the study are to be managed in accord with the investigator’s usual 
care of their patients, including use of acute attack therapies that the investigator deems as 
medically appropriate. Use of C1-INH will be permitted as an acute attack therapy but not as a 
long-term prophylactic therapy. Administration of DX-2930 and study procedures will continue 
without alteration to the protocol-specified study schedule, even if the subject has symptoms of 
an HAE attack the day of DX-2930 administration and/or receives treatment for an HAE attack.  
The administration of DX-2930 can also be re-scheduled as long as the minimum and maximum 
timeframe between doses are met based on patient preference or physician discretion. 
Safety Assessments: 
Safety assessments will include the following: 
• Adverse events (AEs), including serious adverse events (SAEs) and adverse events of special 
interest (AESI). SAEs and AESI will be reported to the Sponsor within 24 hours of becoming 
aware of the event. 
• Vital signs, including sitting or supine blood pressure (BP), heart rate (HR), body 
temperature, and respiratory rate (RR) 
• Physical examination 
• Clinical laboratory testing (hematology, serum chemistry, coagulation and urinalysis) 
• 12-Lead electrocardiogram (ECG) 
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Hypersensitivity reactions and events of disordered coagulation will be considered AESI. 
Pharmacokinetic (PK) Assessments: 
Blood samples will be collected for the measurement of plasma DX-2930 concentrations. 
Pharmacodynamic (PD) Assessments: 
Blood samples will be collected to evaluate the pharmacodynamic effects of DX-2930 through 
biomarker assays. 
Immunogenicity Assessments: 
Blood samples will be collected to assay for the presence of anti-drug antibodies, including 
evaluation of neutralizing antibodies (if any confirmed positive anti-drug antibodies are 
detected). 
 
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C1-INH, C1q and C4 Assessments: 
Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment, 
unless already collected as part of protocol DX-2930-02 or DX-2930-03.  
Quality of Life Assessments: 
Quality of life (QoL) assessments will be conducted using the Angioedema Quality of Life 
Questionnaire (AE-QoL), EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L), Work 
Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH), Hospital 
Anxiety and Depression Scale (HADS), and 12 Item Short Form Survey (SF-12). 
DX-2930 Injection Report and Self-Administration and Subcutaneous Injection Survey 
An injection report of the subject’s experience with self-administration and SC injection will be 
completed by the subject after all doses of DX-2930. 
 
In addition, assessment survey of subject experience with SC and self-administration injections 
of DX-2930 will be completed by the subject approximately every 6 months. 
Collection of HAE Attack Data: 
The collection, reporting and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP).  Study site personnel will be 
trained on HAARP prior to screening and enrolling subjects at their site. 
Study site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide.  The 
patient (and caregiver) will confirm their understanding of what is required of them for reporting 
attacks to the site. 
At screening, HAE attack history will be collected for non-rollover subjects. Information 
collected will include any prior history of laryngeal attacks, attack frequency, average severity, 
predominant attack location(s), triggers, average duration, acute attack therapy use and history of 
LTP (including duration of LTP, medication(s) and dose used for LTP, and frequency of attacks 
while receiving LTP).  If available, information will also be collected on HAE diagnosis (year of 
confirmation, how many years after onset of symptoms was diagnosis confirmed, or if subject 
was misdiagnosed). 
During the study, subjects (or caregivers) will be instructed to notify and report details to the 
study site within 72 hours of the onset of an attack. This includes the first attack experienced by 
rollover subjects following their first open-label dose.  In the situation that a subject is 
incapacitated following an attack, this information can be provided to the site by a family 
member or other individual with detailed knowledge of the event. If desired by the subject, 
memory aids may be provided to assist in tracking any HAE attacks experienced, but its use is 
not mandatory.  
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack: 
• Date and time symptoms of an attack were first experienced. 
 
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• Description of symptoms experienced, including location(s). 
• Impact on activity (work, school, social interactions) and whether any assistance or 
medical intervention was required, including hospitalizations, additional laboratory tests 
or emergency department visits. 
• Any medications used to treat the attack (both prescription and over the counter). 
• If the attack resolved, date and time the subject was no longer experiencing symptoms. 
Study site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP. 
Study site personnel will contact rollover subjects approximately every 7 days following the first 
dose of open-label DX-2930 to solicit for any HAE attacks not already reported.  Site check-ins 
will continue until the subject has received their second open-label dose. 
During each study visit, study site personnel will solicit for any new HAE attack information that 
was not already provided to the site. 
In this study, HAE attacks will be captured as AEs.  All AEs, regardless of seriousness, severity, 
or causal relationship to DX-2930, will be recorded on the AE page of the eCRF.  Any AE 
reported to the site meeting criteria for a serious adverse event must be reported to the Sponsor 
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of the 
event.  For all serious adverse events that are reported as HAE attacks, the investigator or 
physician designee will review the event within 24 hours of initial notification and, in 
accordance with HAARP, evaluate if it represented a confirmed HAE attack.  For all non-serious 
AEs that are reported as HAE attacks, the investigator or physician designee will review the 
event within 3 days of initial notification and, in accordance with HAARP, evaluate if it 
represented a confirmed HAE attack. If necessary for the evaluation, the investigator or designee 
may contact the subject to receive additional information.  Any subject-reported attack not 
confirmed by the investigator or physician designee must have an alternate AE diagnosis 
recorded.  All subject-reported and investigator/ physician designee-confirmed HAE attacks will 
be recorded in the eCRF.  
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured. 
To be confirmed as an attack, the event must have symptoms or signs consistent with an attack in 
at least one of the following locations:  
• Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region. 
• Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea. 
• Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
 
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tightening, or swelling of the tongue, palate, uvula, or larynx. 
Despite the presence of these symptoms, the investigator or physician designee may still 
clinically determine that the event did not represent an attack if there are features that strongly 
refute such a diagnosis. For example, the reported event is accompanied by symptoms that are 
not consistent with an HAE attack (e.g., urticaria), the reported event persists well beyond the 
typical time course of an HAE attack, or there is a likely alternate etiology for the event (e.g., the 
subject’s abdominal symptoms are attributable to a viral gastroenteritis outbreak in the 
household).  
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms. 
Interim Analyses and Data Monitoring 
A formal interim analysis will be conducted  at least 35 subjects have completed 12 months of 
consecutive exposure to DX-2930 across the combined DX-2930-03 and DX-2930-04 studies, 
and only after database lock of the DX-2930-03 study.  Subsequent interim analyses may be 
conducted to support administrative decisions and/or regulatory reporting as required.   
 
An independent Data Safety Monitoring Board (DSMB) has been established to provide 
ongoing, independent review and assessment of the safety data for the DX-2930-03 study. While 
an independent DSMB is not currently planned for this study, summary safety data from DX-
2930-04 may be reviewed by the DSMB established for the DX-2930-03 study as part of the 
collection of safety information available on DX-2930.  
Individual Stopping Rules: 
Dosing for any individual subject will be discontinued if the subject experiences a 
DX-2930-related SAE (or a DX-2930-related, clinically significant non-serious AE) that, in the 
assessment of the investigator, warrants discontinuation from further dosing for that subject’s 
well-being. The investigator has the ability to contact and consult with the Medical Monitor on 
such matters. Subjects will continue to be followed through the completion of all scheduled non-
dosing visits, unless they request to be discontinued from the study. 
Criteria for Evaluation: 
Safety Measures: 
• AEs including SAEs and AESI 
• Clinical Laboratory testing (hematology, clinical chemistry, coagulation and urinalysis) 
• Vitals signs including blood pressure, heart rate, oral body temperature and respiratory rate 
• Physical Examination 
• 12-lead ECG 
Efficacy Endpoints: 
• Time to first HAE attack for rollover subjects (based upon time from first open label study 
dose until first HAE attack)  
• Number of investigator confirmed HAE attacks during the treatment period 
 
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• Number of investigator confirmed HAE attacks requiring acute treatment during the 
treatment period 
• Number of moderate or severe HAE attacks during the treatment period 
• Number of high-morbidity HAE attacks during the treatment period; a high-morbidity HAE 
attack is defined as any attack that has at least one of the following characteristics: severe, 
results in hospitalization (except hospitalization for observation < 24 hours), 
hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal. 
 
Additional Measures: 
• Anti-drug antibody development 
• Pharmacokinetics (PK)  
• Pharmacodynamic (PD) effects 
• Quality of Life Assessments 
• DX-2930 Injection Report  
• DX-2930 Self-administration and Subcutaneous Injection Survey 
Analysis Populations: 
• The Safety Population will include all subjects who received any study drug after entering 
the DX-2930-04 study (i.e., any exposure to open-label DX-2930).    
 
• The Rollover Safety Population is the subset of subjects who participated in the DX-2930-03 
study and received any study drug after entering the DX-2930-04 study (i.e., any exposure to 
open-label DX-2930).  
 
• The Non-rollover Safety Population is the subset of subjects who entered the DX-2930-04 
study directly and received any study drug after entering the DX-2930-04 study (i.e., any 
exposure to open-label DX-2930).   
Sample Size Determination: 
No formal sample size calculation was performed.  The sample size is not based on any 
statistical considerations.  This study is designed to evaluate the safety and efficacy of open-label 
treatment with DX-2930 in subjects who participated in DX-2930-03 and individuals who were 
not otherwise able to participate in DX-2930-03. 
Statistical Methodology: 
Time to the first investigator-confirmed HAE attack will be analyzed using the Rollover Safety 
Population. 
 
Time to the first investigator-confirmed HAE attack (days) will be calculated from the date and 
time of the first open-label dose of DX-2930 to the date and time of the first investigator-
confirmed HAE attack after the first open-label dose.  Subjects who discontinue the study prior 
to experiencing their first on-study investigator-confirmed HAE attack will be censored at the 
date and time of study discontinuation.  Time to the first investigator-confirmed HAE attack will 
 
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be summarized using Kaplan-Meier methods. 
 
Multivariate and univariate Cox proportional hazards regression models will be employed to 
examine the impact of baseline covariates on the time to the first investigator-confirmed HAE 
attack, including but not limited to: baseline attack rate prior to entering DX-2930-03, the 
treatment group in DX-2930-03, the time since the last dose given in DX-2930-03, the time since 
the last HAE attack, and the rate of attacks during DX-2930-03. Results of this exploratory 
analysis will be summarized.   
 
Number of Investigator-confirmed HAE Attacks 
 
The number of investigator-confirmed HAE attacks during the treatment period (Day 0 through 
Day 350) expressed as a monthly HAE attack rate, will be analyzed using each analysis 
population. 
 
The monthly rate of investigator-confirmed HAE attacks during the treatment period will be 
calculated for each subject as the number of investigator-confirmed HAE attacks occurring 
during the treatment period divided by the number of days the subject contributed to the 
treatment period multiplied by 28 days.   
 
The baseline investigator-confirmed monthly HAE attack rate will be calculated for each subject 
as the number of investigator-confirmed monthly HAE attacks occurring during the pretreatment 
period for rollover subjects or historical reporting period for non-rollover subjects divided by the 
number of days the subject contributed to the pretreatment period for rollover subjects or 
historical reporting period for non-rollovers multiplied by 28 days. 
 
The baseline, treatment period, and treatment period change from baseline in the investigator-
confirmed HAE attack rate will be summarized for each analysis population. The summary will 
include the total number of investigator-confirmed HAE attacks reported during each period and 
subject-time in months that each subject contributed to each period. Figures will be created for 
each analysis population plotting the on-study investigator-confirmed HAE attacks reported 
during the treatment period relative to Day 0 for each subject. 
 
Similar summary tables will be presented for the following efficacy endpoints for each analysis 
population: 
• Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period. 
• Number of moderate or severe investigator-confirmed HAE attacks during the treatment 
period. 
• Number of high-morbidity investigator-confirmed HAE attacks during the treatment period; 
a high-morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation < 24 
hours), hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal. 
 
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Safety Analysis: 
Adverse Events 
 
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment.  
 
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.   
 
Related AEs are AEs classified as related to study drug by the investigator.  Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator. 
 
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE, 
any severe AE, and any related severe AE as well as the total number of events for each category 
will be summarized.  The number of deaths due to an AE, hospitalization due to an AE and study 
discontinuation due to an AE will be summarized.  
 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC, and PT. This tabulation will be repeated for related AEs, SAEs, related 
SAEs, severe AEs, and related severe AEs.  
 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions and 
disordered coagulation (hypercoagulability events and bleeding events).  Standardized MedDRA 
Queries (SMQ) for each AESI will be performed using the study data. The number and percentage 
of subjects with an AESI, as well as the total number of AESIs, will be summarized by SOC and PT. 
Separate summary tables will be created for each AESI and for those events with the SMQs 
classified as related, serious, related serious, severe, and related severe.  A listing detailing the 
PT within the SMQ will be provided. 
Laboratory Test Results, Vital Signs, and Electrocardiography Results 
 
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For 
rollover subjects previously exposed to DX-2930, baseline is the last non-missing value prior to 
first exposure to study drug in the DX-2930-03 study.       
   
Actual values and change from baseline in clinical laboratory test results and vital signs will be 
summarized by study visit.  
 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. Vital sign values will be classified according to 
clinical significance as determined by the investigator. The number of subjects with a non-
missing result, and the number and percentage of subjects within each category will be 
summarized by study visit.   
 
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The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG not performed, will be summarized by study 
visit.  
Other Analyses 
 
Plasma concentrations of DX-2930 and plasma kallikrein activity will be summarized by 
nominal PK and PD sampling times. 
  
The number and percentage of subjects with positive antibodies (and whether neutralizing or 
non-neutralizing) will be summarized by study visit and overall. 
 
Quality of life assessments will be summarized by study visit. 
Date of Original Protocol:  14 December 2015 
Date of Amendment 1:  27 June 2016 
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Study Activities Schedule 
 
                    Study Activities Schedule 
Tests and 
Assessments 
 
Treatment Period  
± 4 days for each visit 
Follow-
up 
±4 Days 
for 
each 
visit 
Non-rollover 
Screen 
Visit1 
 
 
 
Rollover  
- 
 
Check-
in2 
Visit: 
 1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 283 294 
Dose: 
 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
- 
- 
- 
Day: 
 0 
14 
28 
42 
56 
70 
84 
98 
112 126 140 154 168 182 196 210 224 238 252 266 280 294 308 322 336 350 364 378 392 
Informed 
Consent5 
X 
(X)6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Long-term 
prophylactic 
therapy 
continued7 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DX-2930 
Administration 
(rollover 
subjects) 
 
X 
 
(X)8,9 (X)10 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)10 (X)11 (X)10 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)11 (X)10 
 
 
 
DX-2930 
Administration 
(non-rollover) 
 
X 
 
X 
X10 
X11 X10 X11 X11 
X10 X11 
X10 X11 
X10 X11 
X10 X11 
X11 
X10 X11 
X11 
X10 X11 
X11 
X10 X11 
X11 
X10 
 
 
 
Demographic 
and Medical 
History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C1-INH, C1q 
and C4 
Testing12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Test13 (females)  
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
Vital Signs14 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
Physical 
Exam15 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
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                    Study Activities Schedule 
Tests and 
Assessments 
 
Treatment Period  
± 4 days for each visit 
Follow-
up 
±4 Days 
for 
each 
visit 
Non-rollover 
Screen 
Visit1 
 
 
 
Rollover  
- 
 
Check-
in2 
Visit: 
 1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 283 294 
Dose: 
 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
- 
- 
- 
Day: 
 0 
14 
28 
42 
56 
70 
84 
98 
112 126 140 154 168 182 196 210 224 238 252 266 280 294 308 322 336 350 364 378 392 
Clinical 
Laboratory 
Testing16 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
12-Lead ECG 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
Prior (4 weeks) 
and 
Concomitant 
Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAE Attack 
Data17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life 
Assessments18  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
SF-12 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
AE-QoL 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
HADS 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
WPAI-GH 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
DX-2930 
Injection 
Report19 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
DX-2930 Self-
administration 
and SC 
Injection 
Survey 20 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
PK, PD 
Collection, & 
Plasma Anti-
Drug Antibody 
Testing21 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
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                    Study Activities Schedule 
Tests and 
Assessments 
 
Treatment Period  
± 4 days for each visit 
Follow-
up 
±4 Days 
for 
each 
visit 
Non-rollover 
Screen 
Visit1 
 
 
 
Rollover  
- 
 
Check-
in2 
Visit: 
 1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 283 294 
Dose: 
 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
- 
- 
- 
Day: 
 0 
14 
28 
42 
56 
70 
84 
98 
112 126 140 154 168 182 196 210 224 238 252 266 280 294 308 322 336 350 364 378 392 
Discharge from 
Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE-QOL = Angioedema Quality of Life; ECG = Electrocardiogram; EQ-5D-5L = EuroQoL 5-Dimensional 5-Level; HADS = Hospital Anxiety and Depression Scale; PK = 
Pharmacokinetic; PD = Pharmacodynamic; SF-12 = Short Form-12 (v2); WPAI-GH = Work Productivity and Activity Impairment – General Health 
NOTE:  Shaded columns represent scheduled in-site visits for all subjects. Non-shaded columns indicate potential subject-elected off-site activity and/or self-administration dosing.  
NOTE:  “( )”s indicate activities that may occur as applicable (ie, activities for rollover subjects) 
1. 
Screening visit is for non-rollover subjects only.  Screening visit can occur up to 28 days prior to first open-label dose. 
2. 
Study site personnel will contact rollover subjects approximately every 7 days following the first dose of open-label DX-2930 to solicit for any HAE attacks not already 
 
reported.  Site check-in with rollover subjects will continue until the subject receives their second open label dose. 
3. 
Visit 28 is a site check-in call for all rollover and non-rollover subjects. 
4. 
Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures at Visit 29, their final study visit 
5. 
Rollover subjects must sign informed consent for DX-2930-04 after Day 168 of study DX-2930-03 and no later than the final DX-2930-03 Day 182 treatment period study 
 
visit. 
6. 
For rollover subjects Day 182 of the DX-2930-03 study is also Day 0 of the DX-2930-04 study and informed consent may be completed on this visit, if not already provided. 
7. 
Screened non-rollover subjects (adults and adolescents) who are on LTP with C1-INH therapy for HAE can continue their current LTP until Day 8 (or Day 15) such that 
 
subjects will have received 2 (or 4) doses of C1-INH.  For subjects who are on attenuated androgens (e.g., danazol) or anti-fibrinolytics (e.g., tranexamic acid), a similar 
 
tapering schedule is recommended. However, the taper can be prolonged by an additional week as long as androgen or anti-fibrinolytic therapy is stopped within 3 weeks of 
 
receiving the first dose of DX-2930. 
8. 
For rollover subjects, the timing of Dose 2 for will vary by subject based on when their first HAE attack occurs following Dose 1.  Following the first reported and 
 
investigator-confirmed attack, subjects will begin receiving regular SC administrations of 300 mg DX-2930 every 2 weeks. 
9. 
A minimum of 10 days between the first and second open-label doses is required. If the second dose is to be administered within the accepted ±4 day window around a 
 
scheduled study visit, this treatment visit will represent that scheduled visit unless that scheduled visit has already occurred. If that scheduled visit has already occurred, or if 
 
the second dose is to be administered outside of the accepted ± 4 day window around a scheduled visit, this visit will not replace any scheduled visit and will thus represent an 
 
acceptable, extra study visit (i.e., an unscheduled visit). Regardless, at the visit in which the second open-label dose of DX-2930 is administered, the subject will undergo pre-
 
dose assessments for vital signs, physical examination (performed in accordance with standards at the site), clinical laboratory testing, PK, PD, and anti-drug antibody. Vital 
 
signs will be obtained at 1 hour post-dosing. As with all study visits, information will be collected on adverse events, concomitant therapy, and HAE attack data.  
10. All subjects (adolescent or adult) who are considered suitable candidates (i.e., those with a physical and mental capability of learning and willing to be trained) may be 
 
allowed to self-administer DX-2930 after completing appropriate training by the investigator or designee and confirming their understanding. Subjects are allowed to initiate 
 
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self-administration after receiving the first 2 doses of DX-2930 at the study site and may elect to self-administer subsequent doses of DX-2930 at the investigational site 
 
(during scheduled study site visits; shaded columns).  
11. Subjects may self-administer DX-2930 at home or other agreed upon location (during optional off-site self-administration visits; non-shaded columns). Site personnel will call 
 
subjects after the planned self-administration to ensure the administration occurred, to collect AEs, concomitant medications, and to ensure all attacks have been appropriately 
 
documented. 
12. Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment unless already collected as part of protocol DX-2930-02 or DX-2930-03.   
13. The pregnancy test will only be conducted in females of childbearing potential.  Tests performed on Day 0 must be urine-based to confirm eligibility prior to first dose.  Tests 
 
performed at screening and on indicated visits can be serum or urine-based. 
14. There is a recommended ± 15 minute window for all vital signs. Vital signs will be obtained prior to dosing and 1 hour after dosing. Monitoring of vital signs will not be 
 
performed for subjects who elect to self-administer away from the investigative site at optional off-site visits (indicated non-shaded columns). Height and weight will be 
 
collected at the Screening visit only.  
15. Physical examinations will be conducted for all rollover and non-rollover subjects according to the study activities schedule and in accordance with standards at the site.  In 
 
addition to the physical examinations specified in the study activities schedule, an additional physical examination (performed in accordance with standards at the site) will be 
 
conducted for rollover subjects prior to dosing on the day of their second open-label dose, at whatever study visit that occurs. 
16. Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis (urinalysis does not need to be done as part of the clinical laboratory 
 
testing at Visits 14, 17, 20, and 23). Clinical laboratory testing will be conducted for all rollover and non-rollover subjects according to the study activities schedule.  In 
 
addition to the testing specified in the study activities schedule, additional testing will be conducted for rollover subjects prior to dosing on the day of their second open-label 
 
dose, at whatever study visit that occurs. 
17. Historical HAE attack information will be collected at screening. During the study, subjects (or caregivers) are instructed to report details of the attack to the study site within 
 
72 hours of the onset of the attack. During study visits, study site personnel will solicit for any new HAE attack information that has not already been reported to the site. 
18. Quality of life data will be obtained using the EQ-5D-5L, SF-12, AE-QoL, HADS, and WPAI-GH. 
19. Collect subject’s injection reports of their experience with DX-2930 self-administration and subcutaneous administration for all doses.  
20.  Collect subject’s injection surveys of their experience with DX-2930 self-administration and subcutaneous injection for indicated visits. 
21. PK, PD and Anti-drug Antibody PD samples will be drawn for all rollover and non-rollover subjects according to the study activities schedule.  In addition to the samples 
 
specified in the study activities schedule, an additional PK, PD and Anti-drug Antibody sample will be drawn for rollover subjects prior to dosing on the day of their second 
 
open-label dose, at whatever study visit that occurs
 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ...........................................................................................2 
SYNOPSIS .................................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................31 
1. 
INTRODUCTION ...........................................................................................................34 
1.1 
DX-2930 ................................................................................................................34 
1.2 
Hereditary Angioedema .........................................................................................34 
1.3 
Therapeutic Rationale for DX-2930 ......................................................................34 
1.4 
Safety Rationale for DX-2930 ...............................................................................35 
1.5 
DX-2930 Non-Clinical Pharmacology and Toxicology ........................................35 
1.6 
DX-2930 Clinical Data ..........................................................................................35 
1.6.1 
Single-Ascending Dose Study in Healthy Subjects (DX-2930-01) .............36 
1.6.2 
Multiple-Ascending Dose Study in HAE Patients (DX-2930-02) ...............36 
1.7 
Rationale for Open-Label Extension Study DX-2930-04 ......................................38 
2. 
STUDY OBJECTIVES ....................................................................................................39 
2.1 
Primary Objective ..................................................................................................39 
2.2 
Secondary Objectives .............................................................................................39 
2.3 
Tertiary Objectives .................................................................................................39 
3. 
INVESTIGATIONAL PLAN ..........................................................................................40 
3.1 
Overall Study Design and Plan ..............................................................................40 
3.1.1 
Overview ......................................................................................................40 
3.1.2 
Stopping Rules .............................................................................................44 
3.1.2.1 
Study Level Stopping Rules...............................................................44 
3.1.2.2 
Individual Stopping Rules..................................................................44 
3.1.3 
Follow-up for Subjects Meeting Stopping Criteria ......................................44 
3.2 
Rationale for Open-Label Extension Dose Selection ............................................44 
3.3 
Individual Subject Dosing and Follow-Up ............................................................44 
3.4 
Study Duration for Individual Subjects .................................................................45 
4. 
STUDY POPULATION SELECTION ...........................................................................46 
4.1 
Study Population ....................................................................................................46 
4.2 
Inclusion Criteria ...................................................................................................46 
4.3 
Exclusion Criteria ..................................................................................................47 
5. 
STUDY TREATMENT(S) ..............................................................................................49 
5.1 
Description of Treatment(s) ...................................................................................49 
5.2 
Dosing and Follow-Up Scheme .............................................................................49 
5.3 
Method of Identifying Subjects .............................................................................50 
5.4 
Prior and Concomitant Therapy .............................................................................50 
 
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5.4.1 
Allowed Therapies .......................................................................................50 
5.4.1.1 
Management of HAE Attacks ............................................................51 
5.4.2 
Excluded Concomitant Therapies ................................................................51 
5.5 
Restrictions ............................................................................................................51 
5.5.1 
Medical Interventions ..................................................................................51 
5.5.2 
Fluid and Food Intake ..................................................................................51 
5.5.3 
Activity ........................................................................................................51 
5.6 
Treatment Compliance ...........................................................................................51 
5.7 
Packaging and Labeling .........................................................................................52 
5.8 
Storage and Accountability ....................................................................................52 
5.9 
Investigational Medicinal Product Retention at Study Site ...................................52 
6. 
STUDY PROCEDURES .................................................................................................54 
6.1 
Informed Consent...................................................................................................54 
6.2 
Eligibility Review ..................................................................................................54 
6.3 
Demographics and Medical History ......................................................................54 
6.4 
HAE Attack Information Collection ......................................................................54 
6.5 
Vital Signs ..............................................................................................................56 
6.6 
Physical Examination.............................................................................................56 
6.7 
Electrocardiography (ECG) ...................................................................................57 
6.8 
Clinical Laboratory Tests .......................................................................................57 
6.8.1 
Laboratory Parameters .................................................................................57 
6.8.1.1 
Hematology ........................................................................................57 
6.8.1.2 
Coagulation ........................................................................................58 
6.8.1.3 
Chemistry ...........................................................................................58 
6.8.1.4 
Urinalysis ...........................................................................................58 
6.8.1.5 
Pregnancy Test ...................................................................................59 
6.8.1.6 
C1-INH Functional Assay..................................................................59 
6.8.1.7 
C4 Assay ............................................................................................59 
6.8.1.8 
C1q Assay ..........................................................................................59 
6.8.1.9 
PK Sample Collection ........................................................................59 
6.8.1.10 
PD Sample Collection ........................................................................59 
6.8.1.11 
Plasma Anti-Drug Antibody Testing .................................................59 
6.8.2 
Sample Collection, Storage, and Shipping ..................................................59 
6.9 
Pharmacokinetic Assessments ...............................................................................60 
6.10 
Pharmacodynamic Assessments ............................................................................60 
6.11 
Plasma Anti-Drug Antibody Testing .....................................................................60 
6.12 
Prior and Concomitant Therapy .............................................................................60 
6.13 
Investigational Medicinal Product Treatment ........................................................60 
6.14 
Quality of Life Assessments ..................................................................................60 
6.14.1 
Angioedema Quality of Life Questionnaire (AE-QoL) ...............................61 
 
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6.14.2 
EuroQoL 5-Diminsional 5-Level Measure (EQ-5D-5L) .............................61 
6.14.3 
Work Productivity and Activity Impairment – General Health (WPAI-GH) 
Questionnaire ...............................................................................................61 
6.14.4 
Hospital Anxiety and Depression Scale (HADS) ........................................61 
6.14.5 
12 Item Short Form v2 Health Survey (SF-12v2) .......................................61 
6.15 
DX-2930 Injection Report and Self-Administration and Subcutaneous Injection 
Survey ....................................................................................................................62 
6.15.1 
DX-2930 Injection Report ...........................................................................62 
6.15.2 
DX-2930 Self-administration and Subcutaneous Injection Survey .............62 
6.16 
Adverse Event Reporting .......................................................................................63 
6.16.1 
Definitions....................................................................................................63 
6.16.1.1 
Adverse Event ....................................................................................63 
6.16.1.2 
Serious Adverse Event .......................................................................63 
6.16.1.3 
Overdose ............................................................................................64 
6.16.1.4 
Planned Hospitalization .....................................................................64 
6.16.1.5 
Treatment-Emergent Adverse Events (TEAE) ..................................64 
6.16.1.6 
Adverse Events of Special Interest (AESI) ........................................64 
6.16.2 
Monitoring ...................................................................................................65 
6.16.2.1 
Monitoring of Adverse Events ...........................................................65 
6.16.2.2 
Monitoring of Safety Laboratory Assessments ..................................65 
6.16.3 
Assessment of Adverse Events ....................................................................66 
6.16.3.1 
Assessment of Severity ......................................................................66 
6.16.3.2 
Assessment of Causality ....................................................................66 
6.16.3.3 
Assessment of Clinical Significance ..................................................67 
6.16.4 
Clinical Laboratory Adverse Events ............................................................67 
6.16.5 
Reporting Investigator Safety Observations to the Sponsor ........................68 
6.16.5.1 
Reporting Non-serious Adverse Events .............................................68 
6.16.5.2 
Reporting Pregnancies .......................................................................68 
6.16.5.3 
Safety Observations Requiring Expedited Reporting by the 
Investigator to the Sponsor ................................................................68 
6.16.5.4 
Expedited Reporting by the Sponsor to a Regulatory Health 
Authority ............................................................................................69 
6.16.5.5 
Safety Contact Information ................................................................69 
6.16.5.6 
Safety Notifications by the Sponsor to the Investigator ....................69 
6.17 
Subject Withdrawal ................................................................................................69 
6.18 
Appropriateness of Measurements .........................................................................70 
7. 
STUDY ACTIVITIES .....................................................................................................71 
7.1 
Screening Visit (Up to Day −28) For Non-Rollover Subjects ...............................71 
7.2 
Start of Treatment Period: Visit 1, Dose 1 (Day 0) ...............................................71 
7.3 
Interval between Dose 1 and Dose 2 for Rollover Subjects ..................................72 
7.4 
Dose 2 of DX-2930 for Rollover Subjects .............................................................73 
7.5 
Visit 2 (Day 14 ±4 days); Dose 2 of DX-2930 for Non-Rollover Subjects ...........74 
 
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7.6 
Continuation of Treatment Period: Visit 3 (Day 28 ±4 Days) ...............................75 
7.7 
Continuation of Treatment Period: Visit 4 (Day 42 ±4 Days) ...............................75 
7.8 
Continuation of Treatment Period: Visit 5 (Day 56 ±4 Days) ...............................76 
7.9 
Continuation of Treatment Period: Visits 6 and 7 (Days 70 and 84, All ±4 Days)77 
7.10 
Continuation of Treatment Period: Visit 8 (Day 98 ±4 Days) ...............................77 
7.11 
Continuation of Treatment Period: Visit 9 (Day 112 ±4 Days) .............................78 
7.12 
Continuation of Treatment Period: Visit 10 (Day 126 ±4 Days) ...........................79 
7.13 
Continuation of Treatment Period: Visit 11 (Day 140 ±4 Days) ...........................79 
7.14 
Continuation of Treatment Period: Visit 12 (Day 154 ±4 Days) ...........................80 
7.15 
Continuation of Treatment Period: Visit 13 (Day 168 ±4 Days) ...........................80 
7.16 
Continuation of Treatment Period: Visit 14 (Day 182 ±4 Days) ...........................81 
7.17 
Continuation of Treatment Period: Visit 15 (Day 196 ±4 Days) ...........................82 
7.18 
Continuation of Treatment Period: Visit 16 (Day 210 ±4 Days) ...........................82 
7.19 
Continuation of Treatment Period: Visit 17 (Day 224 ±4 Days) ...........................83 
7.20 
Continuation of Treatment Period: Visit 18 (Day 238 ±4 Days) ...........................84 
7.21 
Continuation of Treatment Period: Visit 19 (Day 252 ±4 Days) ...........................84 
7.22 
Continuation of Treatment Period: Visit 20 (Day 266 ±4 Days) ...........................85 
7.23 
Continuation of Treatment Period: Visit 21 (Day 280 ±4 Days) ...........................86 
7.24 
Continuation of Treatment Period: Visit 22 (Day 294 ±4 Days) ...........................86 
7.25 
Continuation of Treatment Period: Visit 23 (Day 308 ±4 Days) ...........................87 
7.26 
Continuation of Treatment Period: Visit 24 (Day 322 ±4 Days) ...........................87 
7.27 
Continuation of Treatment Period: Visit 25 (Day 336 ±4 Days) ...........................88 
7.28 
Continuation of Treatment Period: Visit 26 (Day 350 ±4 Days) ...........................88 
7.29 
Completion of Treatment Period:  Visit 27 (Day 364 ±4 Days) ............................89 
7.30 
Follow-up Period:  Visit 28 (Day 378 ±4 Days) ....................................................90 
7.31 
Final Follow-up Visit:  Visit 29 (Day 392 ±4 Days) .............................................90 
7.32 
Early Termination ..................................................................................................90 
8. 
QUALITY CONTROL AND ASSURANCE .................................................................91 
9. 
DATA ANALYSIS / STATISTICAL METHODS .........................................................92 
9.1 
General Considerations ..........................................................................................92 
9.2 
Sample Size Determination ....................................................................................92 
9.3 
Method of Assigning Study Subjects to Treatment ...............................................92 
9.4 
Analysis Populations ..............................................................................................92 
9.4.1 
Safety Population .........................................................................................92 
9.4.2 
Rollover Safety Population ..........................................................................92 
9.4.3 
Non-rollover Safety Population ...................................................................93 
9.5 
Population Description and Exposure ....................................................................93 
9.5.1 
Subject Disposition ......................................................................................93 
 
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9.5.2 
Demographics and Other Baseline Characteristics ......................................93 
9.5.3 
Medical History ...........................................................................................93 
9.5.4 
Treatment Exposure and Compliance ..........................................................93 
9.5.5 
Prior and Concomitant Medications ............................................................93 
9.6 
Analysis of Efficacy ...............................................................................................93 
9.6.1 
Time to the First Investigator-confirmed HAE Attack ................................93 
9.6.2 
Number of Investigator-confirmed HAE Attacks ........................................94 
9.7 
Analysis of Safety ..................................................................................................95 
9.7.1 
Adverse Events ............................................................................................95 
9.7.2 
Laboratory Test Results ...............................................................................96 
9.7.3 
Vital Signs ....................................................................................................97 
9.7.4 
Electrocardiography .....................................................................................97 
9.8 
Other Analyses .......................................................................................................97 
9.8.1 
Analysis of Pharmacokinetic Data ...............................................................98 
9.8.2 
Analysis of Pharmacodynamic Data ............................................................98 
9.8.3 
Analysis of Immunogenicity Data ...............................................................98 
9.8.4 
Analysis of Quality of Life Assessments .....................................................98 
9.9 
Statistical/Analytic Considerations ........................................................................99 
9.9.1 
Interim Analyses and Data Monitoring ........................................................99 
9.9.2 
Multiple Comparisons/Multiplicity .............................................................99 
9.9.3 
Handling of Missing Data ............................................................................99 
9.9.4 
Adjustment for Covariates ...........................................................................99 
9.9.5 
Multicenter Studies ......................................................................................99 
9.9.6 
Subgroup Analyses ......................................................................................99 
9.9.7 
Sensitivity Analyses ...................................................................................100 
10. STUDY ADMINISTRATIVE STRUCTURE ...............................................................101 
10.1 
Institutional Review Board/ Research Ethics Board/Independent Ethics 
Committee ............................................................................................................101 
10.2 
Ethical Conduct of the Study ...............................................................................102 
10.3 
Subject Information and Consent.........................................................................102 
10.4 
Subject Confidentiality ........................................................................................102 
10.5 
Study Monitoring .................................................................................................102 
10.6 
Case Report Forms and Study Records ...............................................................103 
10.7 
Data Safety Monitoring Board .............................................................................103 
10.8 
Protocol Violations/Deviations ............................................................................104 
10.9 
Premature Closure of the Study ...........................................................................104 
10.10 Access to Source Documentation and On-Site Audits ........................................104 
10.11 Data Generation and Analysis .............................................................................105 
 
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10.12 Retention of Data .................................................................................................105 
10.13 Financial Disclosure .............................................................................................105 
10.14 Publication and Disclosure Policy .......................................................................106 
11. REFERENCE LIST .......................................................................................................107 
12. APPENDICES ...............................................................................................................109 
 
 
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LIST OF IN-TEXT TABLES 
Table 1: 
Study Administrative Structure ..................................................................101 
 
 
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LIST OF IN-TEXT FIGURES 
Figure 1: 
Schematic of the Open-Label Extension Study ...........................................43 
Figure 2: 
Overview of the Design of Pivotal Study DX-2930-03 .............................119 
 
 
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LIST OF APPENDICES 
Appendix 1 
Study Activities Schedule ................................................................110 
Appendix 2 
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infectious Diseases) .....................................................114 
Appendix 3 
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (Modified) (US National Institutes of Health; National 
Institute of Allergy and Infectious Diseases ....................................127 
Appendix 4 
HAE Attack Assessment and Reporting Procedures (HAARP) ......141 
Appendix 5 
Summary of Pivotal Study of DX-2930 in HAE Subjects ...............150 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAE 
Acquired angioedema 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
AE-QoL 
Angioedema Quality of Life Questionnaire 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase  
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C1-INH 
C1 inhibitor 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
Cmax 
Maximum plasma drug concentration 
CO2 
Carbon dioxide 
CPK 
Creatine phosphokinase 
CRO 
Clinical Research Organization 
DMID 
Division of Microbiology and Infectious Diseases 
DP 
Drug product 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EQ-5D-5L 
EuroQoL 5-Dimensional 5-Level; a standardized instrument for use as a 
measure of health outcome 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HAE 
Hereditary angioedema 
 
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HMWK 
High molecular weight kininogen 
HR 
Heart rate 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG1 
Immunoglobulin G subclass 1 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone releasing systems 
IV 
Intravenous 
Ki 
inhibition constant 
LTP 
Long-term prophylactic/Long-term prophylaxis 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
OLE 
Open-label extension 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
PVRM 
Pharmacovigilance and Risk Management 
QoL 
Quality of life 
REB 
Research ethics board 
RBC 
Red blood cell (count) 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
 
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SC 
Subcutaneous 
SF-12 
Short Form-12; a multi-purpose short form health survey with 12 
questions 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SMQ 
Standard MedDRA query 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States 
WBC 
White blood cell (count) 
WPAI-GH 
Work Productivity and Activity Impairment – General Health 
 
 
 
 
 
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1. 
INTRODUCTION 
1.1 
DX-2930 
DX-2930 is a fully human IgG1 recombinant monoclonal antibody that binds specifically to 
active plasma kallikrein. DX-2930 is being developed for prophylactic treatment of angioedema 
attacks in patients with hereditary angioedema (HAE), a serious and life-threatening disease. 
1.2 
Hereditary Angioedema 
HAE is a long-term, debilitating, and life-threatening disease caused by mutations in the 
C1-inhibitor (C1-INH) gene, resulting in deficiency or dysfunction of C1-INH protein. HAE 
manifests clinically as unpredictable, intermittent attacks of subcutaneous or submucosal edema 
of the face, larynx, gastrointestinal tract, limbs and/or genitalia (Zuraw, 2008). Swelling may last 
up to five or more days; most patients suffer multiple attacks per year. HAE is an orphan 
disorder. The exact prevalence of HAE is unknown, but current estimates range from 1 per 
10,000 to 1 per 150,000 persons, with many authors agreeing that 1 per 50,000 is likely the 
closest estimate (Bygum, 2009; Goring et al., 1998; Lei et al., 2011; Nordenfelt et al., 2014; 
Roche et al., 2005).  
Swelling in the larynx can obstruct the airways and cause death from asphyxiation (Bork et al., 
2012; Bork et al., 2000). Approximately 50% of all HAE patients will experience a laryngeal 
attack in their lifetime, and there is no way to predict which patients are at risk of a laryngeal 
attack (Bork et al., 2003; Bork et al., 2006).  
Abdominal attacks are often associated with nausea, vomiting, diarrhea and severe pain; 
intestinal symptoms resembling abdominal emergencies may lead to unnecessary surgery 
(Zuraw, 2008).  
Approximately 85% of patients have Type I HAE, characterized by very low production of 
functionally normal C1-INH protein, while the remaining approximately 15% of patients have 
Type II HAE and produce normal or elevated levels of a functionally impaired C1-INH (Zuraw, 
2008). In patients with Types I and II HAE, uncontrolled plasma kallikrein generation results in 
excess bradykinin release from high-molecular weight kininogen (HMWK) and vascular leak 
mediated by bradykinin binding to the B2 receptor (B2-R) on the surface of endothelial cells 
(Zuraw, 2008). Clinical suspicion of Types I and II HAE can be confirmed by available blood 
tests. In addition to abnormalities in C1-INH level and function, plasma C4 levels are often 
reduced in blood from most patients. 
1.3 
Therapeutic Rationale for DX-2930 
Plasma kallikrein plays a critical role in the pathogenesis of HAE attacks (Davis, 2006; Kaplan 
and Joseph, 2010). In normal physiology, C1-INH regulates the activity of plasma kallikrein as 
well as a variety of other proteases, such as C1r, C1s, factor XIa, and factor XIIa. Plasma 
kallikrein regulates the release of bradykinin from HMWK. Due to a deficiency of C1-INH in 
HAE, uncontrolled plasma kallikrein activity occurs and leads to the excessive generation of 
bradykinin. Bradykinin is a vasodilator which is thought to be responsible for the characteristic 
HAE symptoms of localized swelling, inflammation, and pain (Craig et al., 2012; Zuraw et al., 
 
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2013). Intervening at the level of bradykinin production with a plasma kallikrein inhibitor 
therefore represents an attractive and rational therapeutic strategy for HAE. Indeed, the 
importance of plasma kallikrein as a drug target in HAE has been validated through the observed 
effectiveness of Kalbitor® (ecallantide), a peptide that specifically targets plasma kallikrein, 
which was approved by the FDA for the treatment of acute HAE attacks (Kalbitor® Package 
Insert, 2015).  
DX-2930 is a highly potent and specific inhibitor of plasma kallikrein (Ki = 125 pM). X-ray 
crystallography of DX-2930 combined with plasma kallikrein demonstrates DX-2930 binding to 
the active site of kallikrein (Kenniston et al., 2014). 
1.4 
Safety Rationale for DX-2930 
Safety data from the Phase 1a clinical study, a first-in-human study with DX-2930 in healthy 
subjects did not identify any safety concerns. Single doses up to 3 mg/kg of DX-2930 were well-
tolerated. There were no dose-limiting toxicities, serious adverse events, or any other safety 
concerns identified. 
Pharmacokinetic (PK) data from the Phase 1a (DX-2930-01) and Phase 1b (DX-2930-02) 
clinical studies in conjunction with data from the nonclinical toxicity studies support a wide 
safety margin. The mean Cmax for human subjects treated at a dose of 300 mg on Days 1 and 15 
was approximately 27 µg/ mL. As comparison, a mean Cmax of 744 µg/ mL was observed 
following dosing of monkeys with 50 mg/kg DX-2930 subcutaneous (SC) weekly for 6 months 
resulting in a safety margin of approximately 28-fold. No toxicologically significant findings 
were observed in these treated animals or in any other nonclinical toxicity study to date for 
systemically administered DX-2930. 
Safety data is also available from the Phase 1b study (DX-2930-02), a multiple-ascending dose 
study in HAE patients. In this study, two doses of DX-2930 up to 400 mg administered 14 days 
apart were well-tolerated. There were no dose-limiting toxicities, serious adverse events in any 
DX-2930 treated subjects, or any other safety concerns identified in this study of HAE patients. 
Pharmacokinetic data from the 1b study found that the drug exposure following two 
administrations of DX-2930 (up to a maximum of 400 mg) was substantially less than that 
attained and evaluated in the nonclinical toxicity studies. 
For additional detail regarding the safety rationale for DX-2930, please refer to the DX-2930 
Investigator’s Brochure. 
1.5 
DX-2930 Non-Clinical Pharmacology and Toxicology 
For more detail regarding the nonclinical findings, please refer to the DX-2930 Investigator’s 
Brochure. 
1.6 
DX-2930 Clinical Data 
The clinical development program to date for DX-2930 consists of 2 studies to evaluate the 
safety, tolerability, and PK of DX-2930, including one completed Phase 1a single-ascending 
 
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dose study in healthy subjects and a Phase 1b multiple-ascending dose study in HAE patients. 
These studies are summarized in the following sections. 
1.6.1 
Single-Ascending Dose Study in Healthy Subjects (DX-2930-01) 
DX-2930-01 was a Phase 1a randomized, double-blind, placebo-controlled study in healthy 
subjects to evaluate the safety, tolerability, and PK following a single, SC dose of DX-2930. 
Participating subjects were randomized to receive placebo or active study drug within one of the 
following sequential, ascending dose cohorts: 0.1, 0.3, 1.0, or 3.0 mg/kg. For each dosing cohort, 
6 subjects were randomized to receive active drug and 2 subjects to receive placebo.  
A total of 32 subjects enrolled in the study and were randomized. The treatment groups were 
well balanced for demographic characteristics. The actual dose of DX-2930 administered to 
subjects ranged from 6.2 mg (in the 0.1 mg/kg group) to 300 mg (in the 3.0 mg/kg group) across 
all cohorts. 
Based on the safety analysis, a single administration of DX-2930 was well tolerated up to doses 
of 3.0 mg/kg without evidence of dose-limiting toxicity. There were no deaths, SAEs, or subject 
discontinuations due to adverse events (AEs) during the study. Furthermore, there was no 
significant imbalance between placebo and DX-2930 for any particular treatment-emergent 
adverse event (TEAE). The most commonly reported TEAE was headache, which occurred at a 
rate of 25% for both DX-2930 and placebo. 
The PK profile demonstrated linear, dose-dependent drug exposure with a mean half-life of 
approximately 17 to 21 days across dose groups. Results from two exploratory biomarker assays 
provide evidence for an important pharmacodynamic effect of DX-2930 in humans.  
For additional detail regarding the single dose, clinical study in healthy subjects, please refer to 
the DX-2930 Investigator’s Brochure. 
1.6.2 
Multiple-Ascending Dose Study in HAE Patients (DX-2930-02) 
DX-2930-02 was a Phase 1b randomized, double-blind, placebo-controlled, multiple ascending-
dose study in patients with HAE to evaluate safety, tolerability, and PK of SC DX-2930. 
Participating subjects were randomized 2:1 to receive either active study drug or placebo within 
one of the following sequential, ascending dose cohorts: 30, 100, 300, or 400 mg (nominal 6 
subjects per cohort). Each subject received 2 doses of study drug separated by 14 days.  
A total of 37 subjects were randomized and treated with DX-2930 or placebo. One subject in the 
400 mg dose group received a single dose of DX-2930 and, following several unsuccessful 
attempts to schedule their second dose, was replaced. This subject returned for a single follow-up 
visit before being lost to follow-up for reasons not related to the study. Routine C1-INH testing 
revealed that one other subject did not have HAE Type I or II, despite a historical lab test 
indicating otherwise.  
Subject demographics were balanced in terms of age, race, ethnicity and BMI. There were 
slightly more females in the DX-2930 group than in the placebo group (66.7% versus 53.8%).  
 
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The most common AEs reported were HAE attacks, injection site pain, and headache. The rates 
were not appreciably higher in the DX-2930 subjects compared to placebo. Two subjects were 
reported to have 3 related severe TEAEs. One of these was a DX-2930 subject (30 mg) with 
injection site pain lasting 1 minute and one was a DX-2930 subject (400 mg) with worsening 
headache lasting 1 minute and night sweats. 
No safety signals were identified for vital signs, physical examinations, clinical laboratory tests, 
or electrocardiograms (ECG). Results suggested DX-2930 was well tolerated in this study with 
no evidence of dose-limiting toxicity at doses up to 400 mg. 
A total of 3 out of 92 post-dose samples (3.3%), obtained from 2 out of 23 subjects (8.7%), were 
confirmed to be anti-drug antibody-positive. No samples were positive for neutralizing activity. 
The pharmacokinetic analysis for all subjects in the 30, 100, 300 and 400 mg doses showed drug 
levels in HAE subjects were dose-dependent and exhibited a prolonged half-life of 
approximately 2 weeks, typical of a human monoclonal antibody. Cmax drug levels increased with 
increasing dose, as expected. These parameters were consistent with values obtained in healthy 
subjects in study DX-2930-01. 
A Western blot assay showed pre-dose baseline levels of mean 2-chain HMWK in unactivated 
plasma collected from HAE patients was approximately 50%. A statistically significant reduction 
in 2-chain HMWK levels was observed on study days 8 and 22 in the 300 and 400 mg dose 
groups compared to pre-dose levels, and approached levels similar to that observed in healthy 
subjects. This outcome demonstrated the pharmacodynamic activity of DX-2930 and its ability 
to effectively normalize the instability of HAE plasma in this assay.  
Primary efficacy analyses were based on subjects in the 300 mg, 400 mg, and placebo dose 
groups who reported having at least 2 attacks in the 3 months prior to study entry 
(0.15 attacks/week). Of those subjects treated with 300 or 400 mg DX-2930, 15 of 16 subjects 
met these criteria. Of the placebo treated subjects, 11 of 13 subjects met these criteria.  
The baseline HAE attack rates (attacks/week) were 0.39 attacks per week in the placebo group, 
0.33 attacks per week in the 300 mg group, 0.55 attacks per week in the 400 mg group and 0.49 
attacks per week in the 300 and 400 mg combined group. During the pre-specified, primary 
efficacy interval of 6 weeks (from days 8 to 50; corresponding to a period of notable drug 
exposure), the HAE attack rate, adjusted for baseline attack rate, was 0 in the 300 mg group and 
0.045 attacks per week in the 400 mg group, compared to 0.37 attacks per week in the placebo 
group. This resulted in a 100% reduction vs placebo for the 300 mg DX-2930 group (P < 0.0001) 
and an 88% reduction vs placebo for 400 mg DX-2930 (P = 0.005). During this primary efficacy 
interval, 100% of subjects in the 300 mg group (P = 0.026) and 82% of subjects in the 400 mg 
group (P = 0.03) were attack-free compared with 27% of subjects in the placebo group. 
The data from this study demonstrated proof of concept of the ability of DX-2930 to prevent 
acute attacks of HAE. A statistically significant finding of HAE attack prevention by DX-2930 
was observed. DX-2930 was well tolerated in HAE subjects up to 400 mg. Drug exposure 
appeared to be dose-proportional and consistent with the results obtained in healthy subjects in 
 
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study DX-2930-01. Pharmacodynamic effect assays provided evidence that DX-2930 has a direct 
effect on plasma kallikrein activity in patient plasma. 
For additional detail regarding the multiple dose, clinical study in HAE subjects, please refer to 
the DX-2930 Investigator’s Brochure. 
1.7 
Rationale for Open-Label Extension Study DX-2930-04 
The open-label DX-2930 extension study will be preceded by the initiation of a pivotal, multi-
center, double-blind, randomized, placebo-controlled parallel-arm study (DX-2930-03) 
evaluating the efficacy of DX-2930 in preventing acute angioedema attacks in patients with Type 
I or Type II HAE.  Further information on the DX-2930-03 study design can be found in 
Appendix 5. 
Subjects who complete the DX-2930-03 treatment period will be offered the option of rolling 
into the open-label extension study, DX-2930-04.  In addition, a limited number of individuals 
with HAE Type I or Type II who were not enrolled in DX-2930-03 (up to 100) will be also 
enrolled.  
The rationale for this open-label extension study is to evaluate the long-term safety of repeated 
subcutaneous treatment with DX-2930 and the long-term efficacy of DX-2930 in preventing 
HAE attacks.  For subjects rolling over from DX-2930-03 who were randomized to one of the 
active study arms, the total duration of exposure across both studies will cover 18 months.  For 
rollover subjects randomized to placebo in DX-2930-03, and for non-rollover subjects, the total 
duration of exposure will cover 12 months.  Combined, the overall exposure between 
DX-2930-03 and DX-2930-04 will provide a sizable dataset to evaluate DX-2930 as a life-long, 
chronic treatment for preventing acute attacks of HAE.   
This study seeks to evaluate the outer bounds of DX-2930 dosing frequency (possibly beyond 
2 to 4 weeks) by assessing the duration of time between a rollover subject’s first open-label dose 
and their first reported HAE attack.  In addition, characteristics of all HAE attacks will be 
reported and compared to the subject’s historical baseline (for non-rollover subjects) or attack 
history based on attacks reported in the DX-2930-03 study (for rollover subjects). 
For non-rollover subjects, the study will evaluate the safety and efficacy of switching from a 
long-term prevention therapy (eg, C1-INH, anti-fibrinolytics, androgens) to DX-2930 dosing, 
while evaluating breakthrough attack characteristics compared to historical baseline both prior to 
and during co-administration  with their LTP therapy regimen and while receiving DX-2930 
alone.  
For all subjects, the study will also assess immunogenicity of chronically administered DX-2930, 
PK and PD, subject health-related quality of life (QoL), subject experience with self-
administration and ease of SC administration with DX-2930.  
 
 
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2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the long-term safety of repeated subcutaneous (SC) administrations of DX-2930 
2.2 
Secondary Objectives 
• To evaluate the long-term efficacy of DX-2930 in preventing HAE attacks 
• To characterize the outer bounds of dosing frequency for DX-2930 
 
2.3 
Tertiary Objectives 
• To assess the immunogenicity of chronically administered DX-2930 
• To evaluate the effect of DX-2930 on health-related quality of life (QoL) 
• To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of SC 
administration of DX-2930 
• To evaluate safety and efficacy in the non-rollover population of switching from long-term 
prophylactic (LTP) treatment to DX-2930  
• To evaluate breakthrough attack characteristics while receiving DX-2930 compared to 
historical baseline 
• To evaluate subject experience with self-administration of DX-2930 including ease of SC 
administration of DX-2930 
 
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3. 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
3.1.1 
Overview 
DX-2930-04 is an open-label, long term safety and efficacy extension study of DX-2930-03, to 
evaluate the investigational medicinal product (IMP), DX-2930, in preventing acute angioedema 
attacks in patients with Type I and Type II HAE. There are two types of subjects who will be 
enrolled into this study: 
• Subjects who rollover from the DX-2930-03 study 
• Subjects who are non-rollover (i.e., were not participants in DX-2930-03)  
Rollover Subjects 
Rollover subjects are subjects who complete the double-blind treatment period at Day 182 of the 
DX-2930-03 study and consent to enter DX-2930-04.  Subjects who discontinue from DX-2930-
03 after enrollment are not eligible to enroll in DX-2930-04.   
Subjects should be asked about their interest in the DX-2930-04 study after enrollment into 
DX-2930-03 to anticipate enrollment and preparedness for DX-2930-04.  Willing subjects must 
sign informed consent for DX-2930-04 after Day 168 of study DX-2930-03 and no later than the 
final DX-2930-03 Day 182 treatment period study visit.   
The first DX-2930-04 visit for rollover subjects (Day 0) will occur on the same day as the 
DX-2930-03 Day 182 study visit. Rollover subjects will complete all DX-2930-03 final study 
assessments (Day 182) at which time they will be discharged from that study. No assessments 
conducted between the DX-2930-03 Day 182 study visit and the first DX-2930-04 visit (Day 0) 
will be duplicated.  Results of the final DX-2930-03 assessments on Day 182 will be used as the 
pre-dose results for Day 0 of DX-2930-04. 
All subjects, caregivers, investigators and study site personnel will remain blinded to the 
DX-2930-03 treatment assignment until the conclusion of the DX-2930-04 study. 
Non-rollover subjects 
At least 50 subjects (up to a maximum of 100) who were not participants in the DX-2930-03 
study will be permitted to enroll if they meet the eligibility requirements. Subjects who screen 
fail out of DX-2930-03 for not meeting the minimum attack requirements during the run-in 
period must wait until enrollment for the double-blind study has ended before they can screen for 
DX-2930-04. The Sponsor may ease this restriction based on the enrollment rate observed in 
DX-2930-03. Subjects who are still in the run-in period for DX-2930-03 when enrollment for 
that study closes, as well as subjects on prior LTP who screen fail out of DX-2930-03 due to an 
inability to wash-out of their LTP, may screen for DX-2930-04 following discussion with the 
Sponsor medical monitor. 
 
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Screening Period: 
Rollover subjects 
There is no screening period for rollover subjects. 
 
Non-rollover subjects  
Non-rollover subjects must provide informed consent and have screening assessments completed 
within 4 weeks prior to their first open-label dose.  Screened non-rollover subjects (adults and 
adolescents) who are on LTP with C1-INH therapy for HAE can continue their current LTP until 
Day 8 (or Day 15) such that subjects will have received 2 (or 4) doses of C1-INH.  For subjects 
who are on attenuated androgens (e.g., danazol) or anti-fibrinolytics (e.g., tranexamic acid); a 
similar tapering schedule is recommended. However, the taper can be prolonged by an additional 
week as long as androgen or anti-fibrinolytic therapy is stopped within 3 weeks of receiving the 
first dose of DX-2930.   
 
Treatment Period: 
Rollover Subjects 
Following informed consent and pre-dose assessments, rollover subjects will receive a single 
open-label dose of DX-2930 administered subcutaneously (SC) on Day 0. Subjects will not 
receive any additional DX-2930 doses until their first reported and investigator confirmed HAE 
attack.  As such, the total number of doses within the 350 day treatment period will vary by 
rollover subject. 
The duration of time between the first open-label dose and first reported HAE attack will vary by 
rollover subject.  All rollover subjects must adhere to the Study Activities Schedule, for the 
entire duration of the study.  However, until a rollover subject reports their first HAE attack, only 
scheduled study visits where the following tests and assessments are performed must be 
conducted at the investigative site: pregnancy testing, clinical laboratory testing, physical 
examination, 12-Lead ECG, QoL, PK, PD and anti-drug antibody sample collection.  All other 
scheduled study visits may be conducted via site check-in calls to collect information on adverse 
events, concomitant therapy, and HAE attack data.  See Study Activities Schedule for which 
visits must be conducted at the study site. 
Once a rollover subject reports their first HAE attack they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  If 
the second dose is to be administered within the accepted ± 4 day window around a scheduled 
study visit, this treatment visit will represent that scheduled visit. If that scheduled visit has 
already occurred, the day of the visit will be considered an acceptable, extra study visit.   
In the event that the second dose is to be administered outside of the accepted ±4 day window 
around a scheduled visit, the day of the visit will be considered an acceptable extra study visit 
(i.e., this visit will not replace any scheduled visit).  
Regardless of the study day, at the visit in which the second open-label dose of DX-2930 is 
administered, the subject will undergo pre-dose assessments for vital signs, physical 
 
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examination, clinical laboratory testing, and blood sampling for PK, PD, and anti-drug antibody 
assessments. Vital signs will be obtained at 1 hour post-dosing. As with all study visits, 
information will be collected on adverse events, concomitant therapy, and HAE attack data. 
Non-rollover Subjects 
Once all screening assessments have been completed and eligibility confirmed, non-rollover 
subjects will arrive at the study site and, following pre-dose assessments, receive an open-label 
dose of 300 mg DX-2930 administered SC on Day 0.  Non-rollover subjects will continue to 
receive SC administrations of open-label 300 mg DX-2930 every 2 weeks throughout the 
duration of the treatment period.  A total of 26 doses will be administered with the last dose 
administered at the Day 350 study visit. 
All Subjects: 
For all subjects, subsequent doses after the second dose require a minimum of 10 days and 
maximum of 18 days between administrations, and should fall within the accepted ± 4 day 
window around study visits.  
After the second DX-2930 dose is given either within the study window (±4 days) or an 
acceptable extra study visit, the 3rd dose must be administered at the next pre-defined study visit 
according to the schedule of assessments. 
Regardless of when a subject’s first HAE attack occurs, there will be a minimum of 10 days 
between their first open-label dose and their second open-label dose. Following their second 
open-label dose, subjects will continue to receive repeated SC administrations of open-label DX-
2930 every 2 weeks for the remaining duration of the treatment period. The treatment period will 
last 350 days from the date of the first open-label dose. The number of doses administered during 
this period will vary by subject based on the date of each subject’s second dose, but will not 
exceed 26 doses. The Day 350 study visit is the last visit at which a dose may be administered. 
Self-Administration 
All subjects (adolescent or adult) who are considered suitable candidates (i.e., those with a 
physical and mental capability of learning and willing to be trained) may be allowed to self-
administer treatment. Subjects must complete appropriate training by the investigator or designee 
and have their understanding of the procedures confirmed by the investigator or designee. 
Subjects are allowed to initiate self-administration after receiving the first 2 doses of DX-2930 at 
the study site. Once initiated, subjects may self-administer subsequent doses of DX-2930 at the 
investigational site (when visits are scheduled study site visits) or the subject’s home or other 
agreed upon location (when the study permits off-site dosing). See Schedule of Activities for 
details. Adolescent subjects self-administering DX-2930 will be supervised by a parent/legal 
guardian/caregiver. Alternatively, a parent/legal guardian/caregiver, after completing appropriate 
training, will be allowed to administer the investigational product to an adolescent without study 
site personnel supervision. Site personnel will call subjects after the planned self-administration 
to ensure the administration occurred, to collect AEs, concomitant medications, and to ensure all 
attacks have been appropriately documented. 
 
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Follow-up Period 
After completion of the 350 day treatment period, all subjects will undergo safety evaluations 
during an 8-week follow-up period.  Figure 1 shows a schematic of the open-label extension 
study. 
 
Figure 1: Schematic of the Open-Label Extension Study 
 
 
Modifications to Open-Label Dosing 
If at any time an important dose-related safety signal is identified either from this study or 
DX-2930-03, the Sponsor may decide to switch the enrolled subjects who have not yet 
completed the treatment period, and any subsequent subjects, to receive a different open-label 
dose and/or frequency. 
In addition, based on the results of the DX-2930-03 study, the Sponsor may switch to a different 
dose and/or frequency. 
 
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3.1.2 
Stopping Rules 
3.1.2.1 
Study Level Stopping Rules 
Safety data, including SAEs and AESI, will be monitored regularly throughout the duration of 
the study. If any potential safety signal is identified as a result of monitoring in this study, or 
from any safety findings from the DX-2930-03 study, or following DSMB review, the Sponsor 
may take actions as deemed appropriate, including suspending dosing in the study, while the 
potential risk is evaluated and a course of action has been determined. 
3.1.2.2 
Individual Stopping Rules 
Dosing for any individual subject will be discontinued if the subject experiences a 
DX-2930-related SAE (or DX-2930-related, clinically significant non-serious AE) that, in the 
assessment of the investigator or DSMB recommendation, warrants discontinuation from further 
dosing for that subject’s well-being. The investigator has the ability to contact and consult with 
the Medical Monitor on such matters. Subjects will continue to be followed through the 
completion of all scheduled non-dosing visits, unless they request to be discontinued from the 
study. 
3.1.3 
Follow-up for Subjects Meeting Stopping Criteria 
Subjects that develop either an SAE or other toxicity considered clinically relevant (AE, 
laboratory, physical examination, vital sign, or ECG finding) will be carefully monitored until 
resolution, which may include the following: 
• Additional clinical laboratory tests and/or other clinical investigations 
• Additional visits or extended duration of follow-up 
• Obtaining a specialist consultation 
 
3.2 
Rationale for Open-Label Extension Dose Selection 
The dose selected for the open-label extension (300 mg every 2 weeks) is anticipated to be 
effective and safe as determined in the pivotal, double-blind DX-2930-03 trial. If at any time an 
important dose-related safety signal is identified either from this study or DX-2930-03, the 
Sponsor may decide to switch the enrolled subjects who have not yet completed the treatment 
period, and any subsequent subjects, to receive a different open-label DX-2930 dose and/or 
frequency. 
Additionally, based on the efficacy results of the DX-2930-03 study, the Sponsor may switch to 
a different dose and/or frequency. 
3.3 
Individual Subject Dosing and Follow-Up 
All subjects will receive open-label DX-2930 during a 350 day treatment period.  The number of 
doses that rollover subjects receive during this period will vary by subject but will not exceed 26 
doses.  The last dose of open-label DX-2930 administered to these subjects may be given at the 
Day 350 study visit.  Non-rollover subjects will receive DX-2930 every 2 weeks for a total of 26 
doses, with the first dose administered on Day 0 and the final dose administered at the Day 350 
study visit. 
 
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There will be a ±4 day window around each study visit. There will be a minimum of 10 days 
between any two doses. Excluding the time interval between the first and second open-label 
doses for rollover subjects, there will be a maximum of 18 days between any two doses. Subjects 
will be monitored at the study site through 1 hour post-dose. 
All subjects (adolescent or adult) who are considered suitable candidates (i.e., those with a 
physical and mental capability of learning and willing to be trained) may be allowed to self-
administer treatment after completing appropriate training by the investigator or designee and 
confirming their understanding. Subjects are allowed to initiate self-administration after 
receiving the first 2 doses of DX-2930 at the study site. Once initiated, subjects may continue to 
self-administer subsequent doses of DX-2930. Subjects who elect to self-administer 
investigational product will be provided the necessary supplies (see Section 5.7 and Section 
6.15.1). 
 
3.4 
Study Duration for Individual Subjects 
Following informed consent, subjects will either rollover from DX-2930-03 or undergo 
screening assessments (non-rollover subjects). Screening assessments for non-rollover subjects 
must occur within 4 weeks prior to the first open-label dose. Eligible subjects will be enrolled 
and undergo a 350 day treatment period. At the conclusion of the 350 day treatment period, 
subjects will be followed for an additional 8 weeks. 
 
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4. 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study is expected to enroll subjects from the DX-2930-03 study, as well as at least 50 (up to 
a maximum of 100) additional subjects who were not enrolled in DX-2930-03.  The total 
enrollment is expected to be approximately 150, but not more than 250 HAE Type I or II 
subjects.  Subjects will be 12 years of age or older who experience at least 1 attack per 12 weeks. 
HAE diagnosis will be confirmed through documented clinical history and diagnostic testing 
conducted either during screening or during participation in study DX-2930-02 or DX-2930-03. 
The subject population includes subjects who are 12 to 17 years old. Like adults, children with 
HAE can suffer from recurrent and debilitating attacks. Symptoms may present very early in 
childhood, and upper airway angioedema has been reported in HAE patients as young as the age 
of 3 (Bork et al., 2003). In one case series of 49 pediatric HAE patients, 23 had suffered at least 
one episode of airway angioedema by the age of 18 (Farkas, 2010). An important unmet medical 
need exists among children with HAE, especially adolescents, since the disease commonly 
worsens after puberty (Bennett and Craig, 2015; Zuraw, 2008).  The study will aim to enroll at 
least 15 subjects who are 12 to 17 years of age, inclusive of the estimated 10 subjects 12 to 17 
years old who roll over from the DX-2930-03 study.  
4.2 
Inclusion Criteria 
Subjects must meet the following criteria to be enrolled in this study: 
1. Male and female HAE subjects who are 12 years of age or older at the time of screening.  
2. Documented diagnosis of disease HAE (Type I or II) based on all of the following: 
• Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria). 
• Diagnostic testing results obtained during screening (or a prior DX-2930 study) that 
confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level < 40% of the 
normal level. Subjects with functional C1-INH level 40-50% of the normal level may 
be enrolled if they also have a C4 level below the normal range.  Subjects may be 
retested if results are incongruent with clinical history or believed by the investigator 
to be confounded by LPT use.  
• At least one of the following: Age at reported onset of first angioedema symptoms 
≤ 30 years, a family history consistent with HAE Type I or II, or C1q within normal 
range. 
3. A historical baseline HAE attack rate of at least 1 attack per 12 weeks. 
4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, 
understand, and sign an informed consent form.  Subjects age 12 to 17, whose caregiver has 
provided informed consent, are willing and able to read, understand and sign an assent form. 
 
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5. Males and females who are fertile and sexually active must adhere to contraception 
requirements for the duration of the study as follows: 
• Females of childbearing potential must agree to be abstinent or it is recommended to use 
highly effective forms of contraception from the screening period through 30 days after 
the final study visit.  This includes stable doses (for 3 months prior to study screening) of 
combined estrogen and progestin-containing hormonal contraception associated with 
inhibition of ovulation (oral, injectable or implantable), progestin-only hormonal 
contraception associated with inhibition of ovulation, intra-uterine device (IUD, all types) 
or intrauterine hormone releasing systems (IUS). Notes: 1) A female whose male partner 
has had a vasectomy must agree to use one additional form of medically acceptable 
contraception. 2) Use of a male condom with or without spermicide or cervical cap, 
diaphragm or sponge with spermicide or a combination (double barrier methods) are not 
considered highly effective. 
• Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study. 
• Males, including males who are surgically sterile (post vasectomy), with female partners 
of childbearing potential must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through 60 days after the final study 
visit.  
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Discontinued from DX-2930-03 after enrollment for any reason. 
2. If rolling over from DX-2930-03, presence of important safety concerns that would preclude 
participation in this study. 
3. Concomitant diagnosis of another form of chronic, recurrent angioedema such as acquired 
angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), idiopathic 
angioedema, or recurrent angioedema associated with urticaria. 
4. Dosing with an investigational drug (not including DX-2930 or other HAE therapies) or 
exposure to an investigational device within 4 weeks prior screening. 
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to 
screening or any newly initiated or dose modification of estrogen-containing medications 
with systemic absorption (such as oral contraceptives or hormonal replacement therapy) 3 
months prior to the screening visit. 
6. Unwilling to discontinue use of long-term prophylactic therapy for HAE (C1-INH, attenuated 
androgens, or anti-fibrinolytics) within 3 weeks after starting DX-2930 treatment. 
 
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7. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3x 
upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of normal, or 
total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of 
Gilbert’s Syndrome). 
8. Pregnancy or breastfeeding. 
9. Subject has any condition that, in the opinion of the investigator or Sponsor, may 
compromise their safety or compliance, preclude successful conduct of the study, or interfere 
with interpretation of the results (e.g., history of substance abuse or dependence, a significant 
pre-existing illness or other major comorbidity that the investigator considers may confound 
the interpretation of study results). 
 
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5. 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
For detailed information regarding open-label DX-2930 administration, refer to the Pharmacy 
Manual. 
DX-2930 is a sterile, preservative-free solution for injection, pH 6.0. The active ingredient, 
DX-2930, is formulated using the following compendial components:  30 mM sodium phosphate 
dibasic dihydrate, 19.6 mM citric acid, 50 mM histidine, 90 mM sodium chloride, 0.01% 
Polysorbate 80. Each open label vial contains a nominal concentration of 150 mg DX-2930 
active ingredient in 1 mL solution. 
For each 300 mg dose of DX-2930, each subject will receive a total of 2 mL (2 vials), which will 
be administered in a single 2 mL SC injection. The injection will be given in the upper arm, thigh 
or abdomen. 
Self-Administration 
All subjects (adolescent or adult) who are considered suitable candidates (i.e., those with a 
physical and mental capability of learning and willing to be trained) may be allowed to 
self-administer treatment after completing appropriate training by the investigator or designee 
and demonstrating the comprehension to self-administer. Subjects are allowed to initiate self-
administration after receiving the first 2 doses of DX-2930 at the study site. Once initiated, 
subjects may continue to self-administer subsequent doses of DX-2930 at the investigational site 
(when visits are scheduled study site visits) or the subject’s home or other agreed upon location 
(when the study permits off-site dosing). See Schedule of Activities for details. Adolescent 
subjects self-administering investigational product will be supervised by a parent/legal 
guardian/caregiver. Alternatively, a parent/legal guardian/caregiver, after completing appropriate 
training, will be allowed to administer DX-2930 to an adolescent without study site personnel 
supervision. Site personnel will call subjects after the planned self-administration to ensure the 
administration occurred, to collect AEs, concomitant medications, and to ensure all attacks have 
been appropriately documented. 
 
Throughout the study, study site personnel will document information in the subject’s medical 
record and eCRF regarding the subject’s experience with self-administration and SC 
administration of DX-2930. 
5.2 
Dosing and Follow-Up Scheme 
Details of subject dosing and follow-up are outlined in Section 3.1.1 and included in the Study 
Activities Schedule, Appendix 1.  
Rollover subjects will receive their first open label SC dose of DX-2930 on Day 0.  Subjects will 
not receive any additional DX-2930 doses until their first reported HAE attack.  The second dose 
of DX-2930 may be administered at an unscheduled visit if it is outside of the accepted ±4 day 
window around a scheduled visit. Following this attack subjects will receive open label SC doses 
of DX-2930 every 2 weeks until the end of the treatment period. Subsequent dosing after Dose 2 
requires a minimum of 10 days and a maximum of 18 days between administrations. 
 
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Regardless of when a rollover subject’s first HAE attack occurs, there will be a minimum of 
10 days between their first open-label dose and their second open-label dose. Following their 
second dose, rollover subjects will continue to receive repeated SC administrations of open-label 
300 mg DX-2930 every 2 weeks for the remaining duration of the treatment period per the 
scheduled dosing in the Study Activities Schedule. The treatment period will last 350 days from 
the date of the first open-label dose. The number of doses administered during this period will 
vary by subject based on the date of each subject’s second dose, but will not exceed 26 doses. 
The Day 350 study visit is the last visit at which a dose may be administered.  
Non-rollover subjects will receive their first open-label dose SC dose of DX-2930 on Day 0 and 
will continue to receive SC administrations of open-label DX-2930 every 2 weeks throughout the 
duration of the treatment period.  A total of 26 doses will be administered with the last dose 
administered at the Day 350 study visit. 
After completion of the 350 day treatment period, all subjects will undergo safety evaluations 
during an 8-week follow-up period. 
5.3 
Method of Identifying Subjects 
Subjects meeting all eligibility criteria will be enrolled in the study and sequentially assigned a 
unique site-based identification number. 
5.4 
Prior and Concomitant Therapy 
For subjects not rolling over from DX-2930-03, reasonable efforts will be made to determine all 
relevant treatments received by the subject from 4 weeks prior to screening through the final 
study visit. For subjects rolling over from DX-2930-03, concomitant therapy use will be carried 
forward from that study and will continue to be collected through the final study visit.  
All information on prior and concomitant therapy (including all prescription/non-prescription 
medications, herbal medications and vitamin supplements) must be recorded on the subject’s 
eCRF and should include the name of the procedure or drug and duration of the treatment (start 
and stop dates). Concomitant treatments (non-pharmacological treatments) include any surgical 
or diagnostic procedures. 
5.4.1 
Allowed Therapies 
The following therapies are allowed during the study: 
• Therapies for co-existing conditions, including those for acute attacks of HAE, as described 
in Section 5.4.1.1 are permitted if not excluded in Section 5.4.2. The use of short-term 
prophylactic treatment for HAE will be permitted if medically indicated.  Short-term (pre-
procedure) prophylaxis is defined as use of C1-INH to avoid angioedema complications from 
medically indicated procedures. 
• Therapies to treat any AEs the subject experiences during the study are permitted. 
 
 
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5.4.1.1 
Management of HAE Attacks 
Acute HAE attacks during the study are to be managed in accord with the investigator’s usual 
care of their patients, including use of acute attack therapies that the investigator deems as 
medically appropriate. Use of C1-INH will be permitted as an acute attack therapy but not as a 
LTP therapy. Administration of DX-2930 and study procedures will continue without alteration 
to the protocol-specified study schedule, even if the subject has symptoms of an HAE attack the 
day of DX-2930 administration and/or receives treatment for an HAE attack. The administration 
of DX-2930 can also be re-scheduled as long as the minimum and maximum timeframe between 
doses are met based on patient preference or physician discretion. 
 
5.4.2 
Excluded Concomitant Therapies 
Use of the following treatments will not be permitted during the study: 
• Long-term prophylaxis for HAE (e.g., use of C1-INH for LTP, attenuated androgens, or 
anti-fibrinolytics) once LTP is discontinued (within 3 weeks following first dose of 
DX-2930). 
• Angiotensin-converting enzyme (ACE) inhibitors. 
• Initiating or changing the dose of estrogen-containing medications with systemic absorption 
(such as oral contraceptives or hormonal replacement therapy) 3 months prior to the 
screening visit. 
• Use of androgens (e.g., stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) 
for non-HAE related medical conditions or for HAE after discontinuation during the first 
3 weeks. 
• Any other investigational drug or device. 
 
5.5 
Restrictions 
5.5.1 
Medical Interventions 
Medical interventions deemed necessary by the investigator for the health and well-being of the 
subject will not be excluded during this study. 
5.5.2 
Fluid and Food Intake  
There are no restrictions on fluid and food intake. Subjects may continue their usual dietary 
regimens. 
5.5.3 
Activity 
There are no activity restrictions. Subjects may continue their usual activity regimens. 
5.6 
Treatment Compliance 
All doses of open-label DX-2930 administered at the investigational site will be under the direct 
supervision of the investigator or qualified study site personnel designated by the investigator. 
 
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Subjects are allowed to initiate self-administration after receiving the first 2 doses of DX-2930 at 
the study site. Once initiated, subjects may continue to self-administer subsequent doses of 
DX-2930 at the investigational site (when visits are scheduled study site visits) or the subject’s 
home or other agreed upon location (when the study permits off-site dosing). See Schedule of 
Activities for details. For all subjects, subsequent doses after the second dose require a minimum 
of 10 days and maximum of 18 days between administrations, and should fall within the 
accepted ±4 day window around study visits.  
For rollover subjects, after the second DX-2930 dose is given either within the study window 
(±4 days) or an acceptable extra study visit, the 3rd dose must be administered at the next pre-
defined study visit according to the schedule of assessments. 
5.7 
Packaging and Labeling 
The open-label DX-2930 will be supplied by the Sponsor and prepackaged in a study kit for 
investigational studies. Each study kit will contain 1 vial of investigational product.  Both the 
vials and carton (kit) will be appropriately labeled according to local regulations and bear the 
unique study drug kit number. The investigative site will also be provided with ancillary supplies 
including syringes, needles, and alcohol wipes. The site has the option of using needles of a 
different gauge to aid subject comfort with each SC injection. Subjects who elect to self-
administer investigational product will be provided the following supplies as applicable: 
• 1 to 2 dose(s) supply of investigational product 
• Ancillary supplies, including syringes, needles, alcohol pads, a temperature monitoring 
device, and a container for sharps disposal 
• Transport container for investigational product 
• Subject accountability form to record investigational product storage conditions and 
administration details 
All used and unused vials should be returned to the study kit cartons/boxes and transported to the 
site for drug accountability.  Written instructions on DX-2930 handling and self-administration 
procedures will be provided to trained subjects prior to initiating self-administration.  Refer to 
the Pharmacy Manual for additional details on DX-2930 and its administration. 
 
5.8 
Storage and Accountability 
All DX-2930 will be shipped refrigerated to the study site and must be stored at 2ºC to 8ºC/36ºF 
to 46ºF in the carton and protected from light. Storage must be in a securely locked area, 
accessible to authorized persons only, until needed for dose preparation. See Section 5.7 and 
Section 6.15.1 for details. 
 
5.9 
Investigational Medicinal Product Retention at Study Site 
The investigator (or designee) is responsible for maintaining accurate accountability records of 
DX-2930 throughout the clinical study. All DX-2930 received at the site must be inventoried and 
accounted for in an accountability log provided by the Sponsor. All dispensing and 
accountability records will be available for Sponsor review. Drug accountability will be verified 
during on-site monitoring visits. 
 
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Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used DX-2930 should be returned or 
destroyed at the investigational site, as specified by Sponsor. It is the investigator’s responsibility 
to ensure that the Sponsor, or its representative, has provided written authorization that 
procedures for proper disposal of DX-2930 have been established, and that appropriate records 
of the disposal are documented and maintained. No unused DX-2930 may be disposed until fully 
accounted for by the Sponsor monitor (or designee). 
 
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6. 
STUDY PROCEDURES 
Please refer to the Study Activities Schedule, Appendix 1. 
6.1 
Informed Consent 
The ICF must be executed prior to performing any study related activities and must be approved 
by the reviewing institutional review board (IRB), research ethics board (REB) or independent 
ethics committee (IEC). Subjects may withdraw consent at any time. Participation in the study 
may be terminated at any time without the subject’s consent as determined by the investigator. 
Subjects who are not rolling over from the double-blind DX-2930-03 study will provide 
informed consent at Screening. Subjects who are rolling over from the double-blind DX-2930-03 
study will provide consent after Day 168 of study DX-2930-03 and no later than the final 
DX-2930-03 Day 182 study visit. Upon completion of the final assessments, the subjects will be 
discharged from the double-blind study and will start participation in the OLE study and receive 
their first open-label dose. 
6.2 
Eligibility Review 
The investigator or qualified study site personnel will confirm that all Inclusion and Exclusion 
criteria have been met. 
6.3 
Demographics and Medical History  
Demographics: date of birth (alternately age or year of birth, if full date is not allowed to be 
collected for legal reasons), sex,  race and ethnicity (where locally permitted) and medical 
history will be obtained at Screening from subjects not rolling over from DX-2930-03 and will 
be recorded on the source document and eCRF. Medical history will capture the subject’s current 
medical status (current disease processes), past medical status (past disease processes), history of 
surgery, allergies and concomitant medications. For subjects rolling over from DX-2930-03, 
these data will be carried forward from that study.  
6.4 
HAE Attack Information Collection 
The collection, reporting and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP).  Study site personnel will be 
trained on HAARP prior to screening and enrolling subjects at their site. 
Study site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide.  The 
patient (and caregiver) will confirm their understanding of what is required of them for reporting 
attacks to the site. 
At screening, HAE attack history will be collected for non-rollover subjects. Information 
collected will include any prior history of laryngeal attacks, attack frequency, average severity, 
predominant attack location(s), triggers, average duration, acute attack therapy use and history of 
LTP (including duration of LTP, medication(s) and dose used for LTP, and frequency of attacks 
 
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while receiving LTP).  If available, information will also be collected on HAE diagnosis (year of 
confirmation, how many years after onset of symptoms was diagnosis confirmed, or if subject 
was misdiagnosed). 
During the study, subjects (or caregivers) will be instructed to notify and report details to the 
study site within 72 hours of the onset of an attack. This includes the first attack experienced by 
rollover subjects following their first open-label dose.  In the situation that a subject is 
incapacitated following an attack, this information can be provided to the site by a family 
member or other individual with detailed knowledge of the event. If desired by the subject, 
memory aids can be provided to assist in tracking any HAE attacks experienced.  
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack: 
• Date and time symptoms of an attack were first experienced 
• Description of symptoms experienced, including location(s) 
• Impact on activity (work, school, social interactions) and whether any assistance or 
medical intervention was required, including hospitalizations, additional laboratory tests, 
or emergency department visits 
• Any medications used to treat the attack (both prescription and over the counter) 
• If the attack resolved, date and time the subject was no longer experiencing symptoms 
Study site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP. 
For rollover subjects, study site personnel will contact rollover subjects approximately every 
7 days following the first dose of open-label until the subject has received their second open 
label dose.  This is to insure accurate reporting for any HAE attacks not already reported by the 
subject as required within 72 hours.  During each study visit, study site personnel will solicit for 
any new HAE attack information that was not already provided to the site. 
In this study, HAE attacks will be captured as AEs.  All AEs, regardless of seriousness, severity, 
or causal relationship to DX-2930, will be recorded on the AE page of the eCRF.  Any AE 
reported to the site meeting criteria for a serious adverse event must be reported to the Sponsor 
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of the 
event.  For all serious adverse events that are reported as HAE attacks, the investigator or 
physician designee will review the event within 24 hours of initial notification and, in 
accordance with HAARP, evaluate if it represented a confirmed HAE attack.  For all non-serious 
AEs that are reported as HAE attacks, the investigator or physician designee will review the 
event within 3 days of initial notification and, in accordance with HAARP, evaluate if it 
represented a confirmed HAE attack. If necessary for the evaluation, the investigator or designee 
may contact the subject to receive additional information.  Any subject-reported attack not 
confirmed by the investigator or physician designee must have an alternate AE diagnosis 
 
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recorded.  All subject-reported and investigator/ physician designee-confirmed HAE attacks will 
be recorded in the eCRF.  
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured. 
To be confirmed as an attack, the event must have symptoms or signs consistent with an attack in 
at least one of the following locations:  
• Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region 
• Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea 
• Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx 
 
Despite the presence of these symptoms, the investigator or physician designee may still 
clinically determine that the event did not represent an attack if there are features that strongly 
refute such a diagnosis. For example, the reported event is accompanied by symptoms that are 
not consistent with an HAE attack (e.g., urticaria), the reported event persists well beyond the 
typical time course of an HAE attack, or there is a likely alternate etiology for the event (e.g., the 
subject’s abdominal symptoms are attributable to a viral gastroenteritis outbreak in the 
household).  
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms. 
6.5 
Vital Signs 
Vital signs will be assessed by the investigator or his/her qualified designee according to the 
Study Activities Schedule (Appendix 1) unless the subject has elected to self-administer for that 
visit. Routine vital sign assessments will be taken with the subject in the sitting or supine 
position after 5 minutes at rest and will include body temperature, heart rate (HR), blood 
pressure (BP) and respiratory rate (RR). BP should be determined using the same arm and the 
same equipment for each assessment.  For subjects who rollover from DX-2930-03, vital signs 
taken during the final study visit in DX-2930-03 will serve as the Day 0 pre-dose vital signs in 
this study and will not be duplicated. 
6.6 
Physical Examination 
A physical examination including height, weight and calculation of Body Mass Index (BMI) will 
be performed by the investigator or his/her qualified designee according to the Study Activities 
Schedule (Appendix 1). The physical examination will be performed in accordance with 
standards at the site.  
 
 
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For subjects who rollover from DX-2930-03, the physical exam taken during the final study visit 
in DX-2930-03 will serve as the Day 0 pre-dose physical exam in this study and will not be 
duplicated. 
6.7 
Electrocardiography (ECG) 
A standard 12-lead ECG (single recording) will be performed according to the Study Activities 
Schedule (Appendix 1). The date and time of each ECG and its results will be documented in the 
source documents and eCRF. Electrocardiograms will be sent to a central reading vendor for 
assessment.  For subjects who rollover from DX-2930-03, the ECG taken during the final study 
visit in DX-2930-03 will serve as the Day 0 pre-dose ECG in this study and will not be 
duplicated. 
6.8 
Clinical Laboratory Tests 
6.8.1 
Laboratory Parameters 
Laboratory testing will be performed according to the Study Activities Schedule (Appendix 1). 
Laboratory testing includes general safety parameters (hematology, coagulation, urinalysis, and 
serum chemistry), pregnancy tests (in females of childbearing potential), C1-INH functional 
assay, C4 assay, C1q assay, PK sampling, PD sampling, and plasma anti-drug antibody testing. 
All laboratory tests will be performed using established and validated methods.  
When multiple sample collection types are performed at the same assessment time point, the 
samples will be drawn in the following order (depending on what sample types are to be 
collected at that time point): laboratory safety samples (hematology, coagulation, serum 
chemistry), C1-INH, C4, C1q, PK, anti-drug antibodies, PD. Aliquots from the PK, PD and anti-
drug antibody samples may be retained as back-up for additional parameter testing if necessary. 
Subjects will be in a seated or supine position during blood collection. The total blood draw for 
each rollover subject will be approximately 269.8 mL. The total blood draw for each non roll-
over subject will be approximately 283 mL. For subjects who rollover from DX-2930-03, testing 
performed during the final study visit in DX-2930-03 will serve as the Day 0 pre-dose laboratory 
testing in this study and will not be duplicated. 
6.8.1.1 
Hematology 
• Hemoglobin 
• Hematocrit 
• Red blood cell (RBC) count 
• White blood cell (WBC) count with differential 
• Mean corpuscular volume (MCV) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration (MCHC) 
• Absolute platelet count 
 
 
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6.8.1.2 
Coagulation 
• Prothrombin time (PT) 
• Activated partial thromboplastin time (aPTT) 
• International Normalized Ratio (INR) 
 
6.8.1.3 
Chemistry 
• Albumin 
• Alkaline phosphatase 
• Alanine aminotransferase (ALT; SGPT) 
• Aspartate aminotransferase (AST; SGOT) 
• Bilirubin (total and direct) 
• Blood urea nitrogen (BUN) 
• Calcium 
• Carbon dioxide (CO2) 
• Chloride 
• Creatinine 
• Creatine phosphokinase (CPK) 
• Glucose 
• Phosphate 
• Magnesium 
• Potassium 
• Sodium 
• Total protein 
• Uric acid 
 
6.8.1.4 
Urinalysis 
• Bilirubin 
• Glucose 
• Ketones 
• Blood  
• Nitrite 
• pH 
• Protein 
• Specific gravity 
• Microscopy (if indicated by macroscopic findings) 
 
 
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Urinalysis does not need to be done as part of the clinical laboratory testing at Visits 14, 17, 20, 
and 23. 
6.8.1.5 
Pregnancy Test 
Pregnancy tests will be either serum or urine based. 
6.8.1.6 
C1-INH Functional Assay 
Results of a C1-INH functional assay are required for eligibility assessment. Samples will be 
drawn at the Screening visit unless they were previously drawn in study DX-2930-02 or 
DX-2930-03. Results of the C1-INH functional assay from DX-2930-02 or DX-2930-03 may be 
used to confirm diagnosis in this study. Subjects may be retested if results are incongruent with 
clinical history or believed by the investigator to be confounded by recent LTP use. 
6.8.1.7 
C4 Assay 
Results of a C4 assay may be required for eligibility assessment.  The C4 sample will be drawn 
at the same time as the C1-INH sample is drawn during the Screening visit unless previously 
drawn in study DX-2930-02 or DX-2930-03.  Results of the C4 assay from DX-2930-02 or 
DX-2930-03 may be used to confirm diagnosis in this study.  Subjects may be retested if results 
are incongruent with clinical history or believed by the investigator to be confounded by recent 
LTP use.  
6.8.1.8 
C1q Assay 
Results of a C1q assay may be required for eligibility assessment. Any subject who requires 
C1-INH and C4 assay results for diagnostic confirmation in this study will have C1q assay 
results obtained as well.  The C1q sample will be drawn at the same time as the C1 and C4 
sample is drawn during the Screening visit.  
6.8.1.9 
PK Sample Collection 
As outlined in Section 6.9. 
6.8.1.10 
PD Sample Collection 
As outlined in Section 6.10. 
6.8.1.11 
Plasma Anti-Drug Antibody Testing 
As outlined in Section 6.11. 
6.8.2 
Sample Collection, Storage, and Shipping 
Blood samples for laboratory assessments will be collected at the site by a trained phlebotomist 
designated and/or approved by the study investigator. Details for the collection, processing, 
storage and shipment of samples for all laboratory determinations will be provided in the 
Laboratory Manual. 
 
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Biological material will be stored and secured in a manner that assures that unauthorized access 
is prohibited and the samples are not lost, allowed to deteriorate, or accidentally or illegally 
destroyed. 
6.9 
Pharmacokinetic Assessments 
Blood samples for the measurement of plasma DX-2930 concentration will be obtained as 
specified in the Study Activities Schedule (Appendix 1). 
6.10 
Pharmacodynamic Assessments 
To evaluate the PD effects of DX-2930 upon plasma kallikrein activity, blood samples will be 
obtained as specified in the Study Activities Schedule (Appendix 1). 
6.11 
Plasma Anti-Drug Antibody Testing  
Plasma samples for testing for formation of antibodies to DX-2930 will be obtained as specified 
in the Study Activities Schedule (Appendix 1). 
6.12 
Prior and Concomitant Therapy 
The Sponsor representatives and investigator at the site conducting the trial will review and 
evaluate prior (4 weeks prior to study screening) and concomitant medication usage on an 
ongoing basis. For subjects not rolling over from DX-2930-03, all prescription, over-the-counter 
medications, herbals, and supplements that are being taken or have been taken by subjects from 
the time of screening through the duration of the study will be regarded as concomitant 
medications and must be documented on the source document and eCRF following informed 
consent.  For subjects rolling over from DX-2930-03, concomitant therapy use will be carried 
forward from that study and will continue to be collected through the duration of the study.  
6.13 
Investigational Medicinal Product Treatment 
Instructions for safe handling of DX-2930, preparation of each subcutaneous dose and 
administration of DX-2930, are provided in the Pharmacy Manual. Preparation and dispensing of 
DX-2930 will be handled by qualified study site personnel or by subjects who are self-
administering after receiving appropriate training by the investigator or designee at the study site. 
The requirements for maintaining DX-2930 accountability are provided in Section 6.15.1(for 
subjects self-administering) and Section 5.7 and Section 5.8 of this protocol. 
6.14 
Quality of Life Assessments 
Quality of life (QoL) assessments will be conducted using the Angioedema Quality of Life 
Questionnaire (AE-QoL), EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L), Work 
Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH), Hospital 
Anxiety and Depression Scale (HADS), and 12 Item Short Form Survey (SF-12). See Study 
Activities Schedule (Appendix 1). For subjects who rollover from DX-2930-03, quality of life 
assessments obtained during the final study visit in DX-2930-03 will serve as the Day 0 pre-dose 
quality of life assessments in this study and will not be duplicated. 
 
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6.14.1 
Angioedema Quality of Life Questionnaire (AE-QoL) 
The AE-QoL is a self-administered, symptom-specific tool developed and validated to assess 
quality of life (QoL) impairment in recurrent angioedema patients (Weller et al. 2012). The AE-
QoL consists of 17 questions covering four domains/dimensions (functioning, fatigue/mood, 
fear/shame, nutrition). Each of the 17 items has a five-point Likert-type response scale ranging 
from 1 (Never) to 5 (Very Often). The AE-QoL is scored to produce a score for each domain and 
a total score ranging from 0 to 100, with higher scores indicating stronger impairment. It takes 5 
minutes to complete the AE-QoL. 
6.14.2 
EuroQoL 5-Diminsional 5-Level Measure (EQ-5D-5L) 
The EQ-5D-5L is a self-administered standardized measure of health status comprised of a 
descriptive system and a Visual Analogue Scale (VAS). The descriptive system consists of five 
health related quality of life dimensions (i.e., mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression). Each dimension is rated on a 5-point response scale 
(5 levels) indicating severity of problems, where 1 is “no problems” and 5 is “extreme 
problems”. The EQ-5D VAS is a measure of overall self-rated health status on a 20-cm vertical 
VAS with endpoints labelled “the best health you can imagine” and “the worst health you can 
imagine”. The VAS ranges from 0 to 100, with higher scores indicative of better overall health. 
6.14.3 
Work Productivity and Activity Impairment – General Health (WPAI-GH) 
Questionnaire 
The WPAI-GH is a 6-item instrument assessing work and activity impairment due to health 
problems during the past 7 days. The instrument elicits four main scores in relation to general 
health specifically: absenteeism (the percentage of work time missed because of one's health in 
the past seven days), presenteeism (the percentage of impairment experienced while at work in 
the past seven days because of one's health), overall work productivity loss (an overall 
impairment estimate that is a combination of absenteeism and presenteeism), and activity 
impairment (the percentage of impairment in daily activities because of one's health in the past 
seven days) (Reilly et al. 1993). 
6.14.4 
Hospital Anxiety and Depression Scale (HADS) 
The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale to detect states of 
depression, anxiety and emotional distress amongst patients who were being treated for a variety 
of clinical problems (Zigmond and Snaith 1983). The scale has a total of 14 items. Seven of the 
items relate to anxiety and seven relate to depression.  The responses are scored on a scale of 0–3 
(3 indicates higher symptom frequencies). Scores for each subscale (anxiety and depression) 
range from 0 to 21 with scores categorized as follows: normal 0–7, mild 8–10, moderate 11–14, 
and severe 15–21. Scores for the entire scale (emotional distress) range from 0 to 42, with higher 
scores indicating more distress. This scale reflects how a patient has been feeling during the past 
week. 
 
6.14.5 
12 Item Short Form v2 Health Survey (SF-12v2) 
The SF-12v2 Health Survey is a reliable and valid generic measure of functional health and well-
being. The SF-12v2 consists of 12 questions, all selected from the SF-36 Health Survey (Ware et 
al. 1996). The SF-12v2 yields eight health domains (vitality, physical functioning, bodily pain, 
 
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general health perceptions, physical role functioning, emotional role functioning, and mental 
health summary measures. Physical and Mental Health Composite Scores (PCS & MCS) can be 
computed using the scores of twelve questions and range from 0 to 100, where a zero score 
indicates the lowest level of health measured by the scales and 100 indicates the highest level of 
health. The standard form of the instrument asks patients to reply to questions according to how 
they have felt over the last 4 weeks. 
 
6.15 
DX-2930 Injection Report and Self-Administration and Subcutaneous Injection 
Survey 
Assessments of subject experience with self-administration and SC injections of DX-2930 will 
be conducted. 
6.15.1 
DX-2930 Injection Report 
The investigator or designee will train subjects who elect to self-administer DX-2930 on the 
following: 
• Transportation and recommended storage conditions of investigational product from the 
study site to the home location. 
• Maintenance of accurate records regarding each administration of investigational product 
including supply identification (ie, lot/kit number), date and time of injection, injection 
site location, infusion time, and if applicable, any reason the self-administration could not 
be completed as instructed. 
• Retention of all used and unused vials of investigational product for drug accountability 
purposes.  
After receiving appropriate training and demonstrating their understanding of self-
administration, subjects are allowed to self-administer DX-2930 after receiving the first 2 doses 
of DX-2930 at the study site (administered by study personnel). For those subjects who choose to 
self-administer or have a parent/legal guardian/caregiver administer DX-2930, subjects must 
complete an assessment of their experience with self-administration and subcutaneous injection 
for each dose received. Study personnel will document the subject’s responses in the subjects’ 
medical record and eCRF. 
6.15.2 
DX-2930 Self-administration and Subcutaneous Injection Survey 
Subjects will complete an assessment on their overall experience with self-administration and 
experience with receiving SC injections of DX-2930 approximately every 6 months during the 
study. For subjects who have previously received LTP with C1-INH products via IV 
administration, they will be asked to indicate the preferred route for medication administration. 
Study personnel will document the subject’s responses in the subjects’ medical record and eCRF. 
In addition, investigators will be asked to indicate their preference (SC, IV, or no preference) on 
the route to administer medications to prevent angioedema attacks. 
 
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6.16 
Adverse Event Reporting 
Adverse events will be collected from signing of the informed consent through the last study 
visit. 
6.16.1 
Definitions 
6.16.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a clinical trial subject whether or not it appears to 
have a causal relationship with the treatment administered.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product or 
participation in a clinical study, whether or not directly related to the medicinal product or study 
participation. 
• AEs may be new events or may be pre-existing conditions that have become aggravated or 
have worsened in severity or frequency during the course of the study. 
• AEs may be clinically significant changes from baseline in physical examination, laboratory 
tests, or other diagnostic investigation (e.g., laboratory results, x-ray findings). 
Laboratory abnormalities generally are not considered AEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. A clinically significant laboratory 
abnormality that is independent from a known underlying medical condition and that requires 
medical or surgical intervention, or leads to DX-2930 interruption or discontinuation, will in 
itself, be considered an AE. Laboratory or diagnostic testing abnormalities that reflect or are part 
of a known underlying medical condition are not, in themselves, AEs; rather, the underlying 
medical condition leading to the abnormalities would be reported as the AE. 
Pregnancy is not an AE; however, if a female subject becomes pregnant during the conduct of 
the study, the investigator must notify the Sponsor according to the procedures provided in 
Section 6.16.5.2. 
6.16.1.2 
Serious Adverse Event 
A SAE is any adverse experience occurring at any dose that results in any of the following 
outcomes: 
• Death 
• Life-threatening experience; Note: “Life-threatening” refers to a situation in which the 
subject was at risk of death at the time of the event; it does not refer to an event that might 
have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization; Note: Does not 
include hospitalization for observation with release within 24 hours. A scheduled 
hospitalization for a pre-existing condition that has not worsened during participation in the 
study does not meet this criterion. Pre-planned hospitalizations for an elective 
medical/surgical procedure or routine check-ups do not meet this criterion. 
 
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• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is considered to be an important medical event defined as those that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed in the definition above. 
 
6.16.1.3 
Overdose 
An overdose is defined as a significant variation from the recommended/scheduled dosage for a 
product. The dosing for this study will be conducted in a controlled clinical setting and an 
overdose is not anticipated. However, in the event of an accident, for this study, an overdose of 
DX-2930 is considered a dose that is two-fold higher than the intended dose for the subject. 
6.16.1.4 
Planned Hospitalization 
A hospitalization planned by the subject prior to the first dose of open-label DX-2930 is 
considered a therapeutic intervention and not the result of a new SAE and should be recorded as 
medical history. If the planned hospitalization or procedure is executed as planned, the record in 
the subject’s medical history is considered complete. However, if the event/condition worsens 
during the trial, it must be reported as an AE. 
6.16.1.5 
Treatment-Emergent Adverse Events (TEAE) 
An AE is treatment-emergent if the onset time is after first administration of open-label DX-2930 
through the final follow-up visit or, in the event that onset time precedes first DX-2930 
administration, the AE increases in severity during the open-label treatment period. 
For rollover subjects, any adverse event that started during the subject’s participation in 
DX-2930-03 and was ongoing at the time of the first open-label dose in DX-2930-04 will not be 
counted as an AE in DX-2930-04 unless that event has worsened in severity or frequency 
following the first open-label dose.  Adverse events that started during subject participation in 
DX-2930-03, resolved following the first open-label dose in DX-2930-04, and then subsequently 
reappeared in DX-2930-04 will be counted as a new TEAE in DX-2930-04. 
6.16.1.6 
Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Investigators will report all AESI to the Sponsor, regardless of causality, using the same 
timelines as described for SAE reporting. The following describe the AESI and the criteria for 
reporting AESI.  
HYPERSENSITIVITY REACTIONS 
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours, only if the reactions 
are suspected to be related to study drug. 
 
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EVENTS OF DISORDERED COAGULATION 
Bleeding AESI 
Although aPTT prolongation due to plasma kallikrein inhibition is an artifactual in vitro 
phenomenon, as a precautionary measure in evaluating the safety of DX-2930, bleeding events 
will be reported as AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with a clinical event of 
bleeding. Coagulation testing (aPTT, PT, INR) should be performed when possible, and when 
temporally reasonable, with any reports of bleeding or for clinical conditions possibly indicative 
of bleeding. 
Hypercoagulable AESI 
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot be 
determined, that are consistent with a thrombotic or embolic etiology.  
6.16.2 
Monitoring 
6.16.2.1 
Monitoring of Adverse Events 
Each subject will be monitored for the occurrence of AEs, including SAEs and AESI, from 
signing of the ICF through the final follow-up visit. 
• Subjects will be questioned and/or examined by the investigator or a qualified designee for 
evidence of AEs. The questioning of subjects with regard to the possible occurrence of AEs 
will be generalized such as, "How have you been feeling since your last visit?”  The presence 
or absence of specific AEs should not be elicited from subjects. 
• Subjects having TEAEs will be monitored until resolution with relevant clinical assessments 
and laboratory tests, as determined by the investigator. 
• AEs, actions taken as a result of AEs, and follow-up results must be recorded in the eCRF as 
well as in the subject's source documentation. Follow-up laboratory results should be filed 
with the subject's source documentation. 
 
For any SAEs or AEs that require the subject to be discontinued from dosing, relevant clinical 
assessments and laboratory tests will be repeated as clinically appropriate, until final resolution 
or stabilization of the event(s). Subjects will continue to be followed through completion of all 
scheduled visits. 
6.16.2.2 
Monitoring of Safety Laboratory Assessments 
All safety laboratory assessments will be performed at a central laboratory. The clinical 
laboratory values will be reported to the investigator who will review them for clinical 
significance and consideration of abnormal values as potential AEs. 
 
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6.16.3 
Assessment of Adverse Events 
6.16.3.1 
Assessment of Severity 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe nausea). This is not the same as “serious,” which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning. 
In this study, the severity of AEs will be assessed according to Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table, Draft, November 2007 (US National 
Institutes of Health: National Institute of Allergy and Infectious Diseases) (Appendix 2) and the 
Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Table, Draft, 
November 2007 (US National Institutes of Health: National Institute of Allergy and Infectious 
Diseases) (Appendix 3). For abnormalities not specifically found in the Toxicity Tables, the 
following general scale will be used to estimate grade of severity: 
• GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required 
• GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
• GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible  
• GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
 
Any treatment-emergent ECG abnormality that is considered by the investigator as clinically 
significant and requiring intervention/therapy will be assessed as a severe AE. 
6.16.3.2 
Assessment of Causality 
A medically qualified investigator must assess the relationship of any AE (including SAEs) to 
the use of DX-2930, as related or not related, based on clinical judgment and using all available 
information, and may include consideration of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic factors. 
• The temporal association between DX-2930 exposure and onset of the AE. 
• Whether the manifestations of the AE are consistent with known actions or toxicity of 
DX-2930. 
• The AE resolved or improved with decreasing the dose or stopping use of DX-2930 
(dechallenge). Judgment should be used if multiple products are discontinued at the same 
time. 
 
The causal relationship between DX-2930 and the AE will be assessed using one of the 
following categories: 
 
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Not Related:  Factors consistent with an assessment of Not Related include: 
• Temporal relationship is lacking (e.g., the event did not occur within a reasonable 
time frame following administration of DX-2930); or 
• Other causative factors more likely explain the event (e.g., a pre-existing 
condition, other concomitant treatments). 
Related:  Factors consistent with an assessment of Related include: 
• There is a positive temporal relationship (e.g., the event occurred within a 
reasonable time frame following administration of DX-2930); or 
• The AE is more likely explained by administration of DX-2930 than by another 
cause (i.e., the AE shows a pattern consistent with previous knowledge of 
DX-2930 or the class of DX-2930). 
6.16.3.3 
Assessment of Clinical Significance 
Clinical significance of individual AEs will be determined by the investigator, with discussion 
with the Medical Monitor as appropriate. 
6.16.4 
Clinical Laboratory Adverse Events 
Laboratory abnormalities generally are not considered AEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. A clinically significant laboratory 
abnormality that is independent from a known underlying medical condition and that requires 
medical or surgical intervention, or leads to DX-2930 interruption or discontinuation, will be 
considered an AE. 
When laboratory abnormalities are considered to be AEs, the DMID Adult Toxicity Table 
(Appendix 2) or DMID Pediatric Toxicity Tables (Appendix 3) will be used to assess severity. 
Where discrepancies in the upper limit of normal (ULN) and lower limit of normal (LLN) of 
laboratory ranges occur between those included in the DMID tables and those of the laboratory 
that performs the assays, the values provided by the laboratory will be used for assignment of 
severity grade. Clinical significance of individual laboratory AEs will be determined by the 
investigator with input from the Medical Monitor as needed.  
Following is an exception to defining clinically significant, abnormal laboratory values as AEs: 
• APTT prolongation in the absence of any associated bleeding or other evidence of clinical 
relevance will not be considered a clinically significant laboratory abnormality or AE. In the 
appropriate physiologic setting, such as IV heparin therapy, aPTT can be used to monitor 
bleeding risk. However, as noted in the Investigators Brochure, aPTT prolongation due to 
plasma kallikrein inhibition is an artifactual in vitro phenomenon. Although plasma kallikrein 
drives fibrin formation in the aPTT assay, plasma kallikrein-driven coagulation does not 
appear to have hemostatic or other physiologically important functions in vivo. It is well 
documented that, in humans, deficiency of factor XII or prekallikrein (and thus plasma 
kallikrein) is not associated with abnormal bleeding, either spontaneous or during surgical 
procedures (Renne and Gruber, 2012). Despite the lack of clinical effect, deficiency of either 
protein is associated with marked prolongation of the aPTT.  
 
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6.16.5 
Reporting Investigator Safety Observations to the Sponsor 
6.16.5.1 
Reporting Non-serious Adverse Events 
All AEs, regardless of seriousness, severity, or causal relationship to DX-2930, will be recorded 
on the AE page of the eCRF. In this study all HAE attacks reported by the subject, regardless of 
whether or not they are confirmed by the investigator, will be captured as AEs. 
6.16.5.2 
Reporting Pregnancies 
If a female subject or the female partner of a male subject becomes pregnant during the course of 
the study, the investigator must report the pregnancy to the Sponsor’s Pharmacovigilance 
Department using the Pregnancy Reporting Form within 24 hours of becoming aware of the 
event. The investigator must obtain consent to collect pregnancy information (including the 
status of the newborn, if applicable). 
If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and submitted 
within 24 hours of becoming aware of the new information. The investigator is required to 
follow the pregnancy through delivery. The outcome of the pregnancy and the status of the 
newborn (if applicable) will be reported on the Pregnancy Reporting Form within 24 hours of 
becoming aware. 
6.16.5.3 
Safety Observations Requiring Expedited Reporting by the Investigator to 
the Sponsor 
Any occurrence of the following events or outcomes in a subject in the trial must be reported 
expeditiously by the investigator or qualified designee to the Sponsor’s Pharmacovigilance 
Department: 
• SAE 
• AESI 
• Overdose 
• Cancer 
 
The investigator is to report any expedited safety observations from the list above to the Sponsor 
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of the 
event. 
Any SAE reported to the Sponsor Pharmacovigilance Department using the SAE Reporting 
Form in the EDC system is to be recorded in the eCRF, as well as in the subject's source 
documentation along with any actions taken. If all required information on the form is not 
available at the time of the initial report, follow-up information will be completed in the EDC 
system. 
The investigator is required to follow SAEs until resolution regardless of whether the subjects 
are still participating in the study. SAE resolution is defined as: 
• Resolved with or without residual effects. 
 
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• A return to baseline for a pre-existing condition. 
• Laboratory values have returned to baseline or stabilized. 
• The investigator does not expect any further improvement or worsening of the event. 
• Fatal outcome—if an autopsy is performed; the autopsy report is requested to be provided to 
the sponsor as soon as it is available. 
 
6.16.5.4 
Expedited Reporting by the Sponsor to a Regulatory Health Authority 
The Sponsor or designee will report relevant safety information to concerned health authorities 
in accordance with local laws and regulations. 
6.16.5.5 
Safety Contact Information 
24-Hour Medical Safety Contact for US and Canada 
, MD 
, Clinical Development 
300 Shire Way, MA 02421 USA 
Phone: 
 
Email: 
 
Calls or emails received weekends, holidays, or weekdays between 8:00 pm and 8:00 am Eastern (US) 
time will be responded to the morning of the following business day 
 
24-Hour Medical Safety Contact for Europe and Middle East 
, MD, MBA 
 
Phone: 
 
 
Sponsor Pharmacovigilance Department 
Email: 
 
 
6.16.5.6 
Safety Notifications by the Sponsor to the Investigator 
Investigators will receive prompt notification of any adverse experience related to DX-2930 that 
is both serious and unexpected, or any finding that suggests a significant risk for subjects. The 
investigator will promptly inform his / her IRB/REB/IEC of the notification and insert the 
notification in the Investigator’s Regulatory Binder in accordance with local regulations.  
6.17 
Subject Withdrawal 
The investigator may withdraw a subject from DX-2930 treatment for any of the following 
reasons: 
• In the opinion of the investigator, the subject is unable to comply with the requirements of 
the protocol for satisfactory completion or interpretation of study results (including use of 
prohibitive medications), 
 
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• A serious or intolerable AE occurs, 
• A clinically significant change in a laboratory parameter occurs, 
• The Sponsor or investigator terminates the study, or 
• The subject requests to be discontinued from the study. 
 
Subjects will continue to be followed through completion of all scheduled visits, unless the 
subject requests to be discontinued from the study. 
6.18 
Appropriateness of Measurements 
This is a Phase 3 open-label extension study that is designed to evaluate the long-term safety and 
efficacy of DX-2930 in prophylactic therapy for angioedema attacks in subjects with HAE. 
DX-2930 is a recombinant, fully human IgG1, kappa light chain, monoclonal antibody. The 
open-label, non-controlled study design is a standard approach for extension studies that follow 
double-blind pivotal trials. Measures employed in this protocol are standard measures routinely 
used for the evaluation of the efficacy, safety and tolerability of an investigational product.  
Measures employed for rollover subjects between the first and second open-label doses are 
appropriate to characterize the outer bounds of dosing frequency for DX-2930. 
 
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7. 
STUDY ACTIVITIES 
Study activities are summarized by study visit in Appendix 1 (Study Activities Schedule). 
7.1 
Screening Visit (Up to Day −28) For Non-Rollover Subjects 
The following procedures and assessments are to be performed during the Screening Visit for 
subjects not rolling over from the DX-2930-03 study: 
• Informed consent (Section 6.1) 
• Eligibility review (Section 6.2) 
• Demographics and medical history (Section 6.3) 
• C1-INH functional assay, C4 and C1q sample collection (Section 6.8) 
• Pregnancy test, serum or urine (females) (Section 6.8) 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6); documentation of height and weight 
• 12-Lead ECG (Section 6.7) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• Prior and concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16); pre-existing signs and symptoms 
• Subjects who are on LTP for HAE must complete a minimum 2 week washout period, as 
confirmed by the investigator, before entering the treatment period 
For subjects rolling over from the double-blind DX-2930-03 study, no Screening visit is required 
as subjects will enter the OLE on the same day that their last DX-2930-03 study visit is 
completed. Diagnostic test results and demographic and medical history for these subjects will be 
carried forward from that study. 
7.2 
Start of Treatment Period: Visit 1, Dose 1 (Day 0) 
The following procedures and assessments are to be performed on Day 0 prior to the first dose of 
DX-2930.  For subjects who rollover from DX-2930-03, all final assessments taken during the 
final study visit in DX-2930-03 will be used as the pre-dose results on Day 0 and will not be 
duplicated. 
• Informed consent (for subjects rolling over from the double-blind DX-2930-03 study; this is 
Day 182 of that study) (Section 6.1) 
• Eligibility review (Section 6.2) 
• Urine pregnancy test (females) (Section 6.8) 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
 
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• 12-Lead ECG (Section 6.7) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• PK baseline sample collection (Section 6.9) 
• PD baseline sample collection (Section 6.10) 
• Baseline anti-drug antibody sample collection (Section 6.11) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• First dose of open-label DX-2930 (Section 5.1) 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2 
• AE collection (Section 6.16) 
7.3 
Interval between Dose 1 and Dose 2 for Rollover Subjects 
Rollover subjects must adhere to the Study Activities Schedule for the entire duration of the 
study.  Until a rollover subject reports their first HAE attack, study visits may be conducted via 
site check in calls, except for the following study visits which must be conducted at the 
investigative site: 
• Day 14 
• Day 28 
• Day 56 
• Day 98 
• Day 126 
• Day 154 
• Day 182 
• Day 224 
• Day 266 
• Day 308 
 
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• Day 350 
 
The tests and assessments required at these visits are specified in the sections below. 
Site check in calls may serve as any of the following study visits until the subject receives their 
second open-label dose: 
• Day 42 
• Day 70 
• Day 84 
• Day 112 
• Day 140 
• Day 168 
• Day 196 
• Day 210 
• Day 238 
• Day 252 
• Day 280 
• Day 294 
• Day 322 
• Day 336 
Study site personnel will also contact rollover subjects approximately 7 days after each study 
visit (both site visits and check-in calls) until the subject receives their second open-label dose. 
 
The following assessments are performed during all site calls: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
7.4 
Dose 2 of DX-2930 for Rollover Subjects 
The duration of time between Dose 1 and Dose 2 will vary by subject based on when their first 
HAE attack occurs following Dose 1.  As a result, rollover subjects may not receive DX-2930 
treatment at every dosing visit as outlined in the Study Activities Schedule. 
Once a rollover subject reports their first HAE attack they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  This 
treatment visit may be counted as a scheduled study visit, or as an acceptable extra study visit.  
For details on determining whether the second dose is counted as a scheduled or extra study visit, 
refer to Section 3.1.1.  Regardless of when the second dose is administered, the following tests 
and assessments will be conducted pre-dose on the day it is administered: 
 
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• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• PK sample collection (Section 6.9) 
• PD sample collection (Section 6.10) 
• Anti-drug antibody sample collection (Section 6.11) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
The following tests and assessments will also be performed if the second dose occurs on a 
scheduled study visit for which they are required: 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• 12-Lead ECG (Section 6.7) 
• Quality of life assessments (Section 6.14) 
After the required pre-dose tests and assessments are completed: 
• Second dose of open-label DX-2930 (Section 5.1) 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2)  
• AE collection (Section 6.16) 
7.5 
Visit 2 (Day 14 ±4 days); Dose 2 of DX-2930 for Non-Rollover Subjects 
On Day 14 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
 
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After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1) 
 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1) 
• AE collection (Section 6.16) 
7.6 
Continuation of Treatment Period: Visit 3 (Day 28 ±4 Days) 
On Day 28 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Pregnancy test, serum or urine (females) (Section 6.8) 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1).  For non-rollover subjects this dose represents Dose 3.  
At this visit, subjects have the option to self-administer at the investigational site.  
 
After administration of DX-2930, the following post-treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.  
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
7.7 
Continuation of Treatment Period: Visit 4 (Day 42 ±4 Days) 
On Day 42 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
 
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• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1).  For non-rollover subjects this dose represents Dose 4. At 
this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.8 
Continuation of Treatment Period: Visit 5 (Day 56 ±4 Days) 
On Day 56 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Pregnancy test, serum or urine (females) (Section 6.8) 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 5. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose 
 
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• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
7.9 
Continuation of Treatment Period: Visits 6 and 7 (Days 70 and 84, All ±4 Days) 
On Days 70 and 84 the following procedures and assessments will be performed prior to 
DX-2930 treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects these doses represent Dose 6 
and Dose 7. At this visit, subjects have the option to self-administer DX-2930 either at the 
investigational site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
7.10 
Continuation of Treatment Period: Visit 8 (Day 98 ±4 Days) 
On Day 98 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Pregnancy test, serum or urine (females) (Section 6.8) 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• 12-Lead ECG (Section 6.7) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• PK sample collection (Section 6.9) 
• PD sample collection (Section 6.10) 
• Anti-drug antibody sample collection (Section 6.11) 
 
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• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 8. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2)  
• AE collection (Section 6.16) 
7.11 
Continuation of Treatment Period: Visit 9 (Day 112 ±4 Days) 
On Day 112 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 9. At 
this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
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7.12 
Continuation of Treatment Period: Visit 10 (Day 126 ±4 Days) 
On Day 126 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 10. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.13 
Continuation of Treatment Period: Visit 11 (Day 140 ±4 Days) 
On Day 140 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 11. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
 
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• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
7.14 
Continuation of Treatment Period: Visit 12 (Day 154 ±4 Days) 
On Day 154 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 12. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
7.15 
 Continuation of Treatment Period: Visit 13 (Day 168 ±4 Days) 
On Day 168 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
 
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After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 13. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.16 
Continuation of Treatment Period: Visit 14 (Day 182 ±4 Days) 
On Day 182, the following procedures and assessments will be performed: 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• 12-Lead ECG (Section 6.7) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• PK sample collection (Section 6.9) 
• PD sample collection (Section 6.10) 
• Anti-drug antibody sample collection (Section 6.11) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 14. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
 
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• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2 
• AE collection (Section 6.16) 
 
7.17 
Continuation of Treatment Period: Visit 15 (Day 196 ±4 Days) 
On Day 196 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 15. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.18 
Continuation of Treatment Period: Visit 16 (Day 210 ±4 Days) 
On Day 210 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
 
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• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 16. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
7.19 
Continuation of Treatment Period: Visit 17 (Day 224 ±4 Days) 
On Day 224 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 17. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
 
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7.20 
Continuation of Treatment Period: Visit 18 (Day 238 ±4 Days) 
On Day 238 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 18. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
 
7.21 
Continuation of Treatment Period: Visit 19 (Day 252 ±4 Days) 
On Day 252 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 19. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
 
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• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.22 
Continuation of Treatment Period: Visit 20 (Day 266 ±4 Days) 
On Day 266 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• 12-Lead ECG (Section 6.7) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• PK sample collection (Section 6.9) 
• PD sample collection (Section 6.10) 
• Anti-drug antibody sample collection (Section 6.11) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 20. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2)  
• AE collection (Section 6.16) 
 
 
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7.23 
Continuation of Treatment Period: Visit 21 (Day 280 ±4 Days) 
On Day 280 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 21. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.24 
Continuation of Treatment Period: Visit 22 (Day 294 ±4 Days) 
On Day 294 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 22. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
 
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• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.25 
Continuation of Treatment Period: Visit 23 (Day 308 ±4 Days) 
On Day 308 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 23. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.26 
Continuation of Treatment Period: Visit 24 (Day 322 ±4 Days) 
On Day 322 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
 
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After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 24. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.27 
Continuation of Treatment Period: Visit 25 (Day 336 ±4 Days) 
On Day 336 the following procedures and assessments will be performed prior to DX-2930 
treatment: 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 25. 
At this visit, subjects have the option to self-administer DX-2930 either at the investigational 
site or the subject’s home or other agreed upon location. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• AE collection (Section 6.16) 
 
7.28 
Continuation of Treatment Period: Visit 26 (Day 350 ±4 Days) 
On Day 350, the following procedures and assessments will be performed prior to DX-2930 
treatment: 
 
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• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• 12-Lead ECG (Section 6.7) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
• Quality of life assessments (Section 6.14)  
After the preceding procedures and assessments are completed: 
• Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 26 
(final dose). At this visit, subjects have the option to self-administer DX-2930 at the 
investigational site. 
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed: 
• Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
• Concomitant therapy (Section 6.12) 
• DX-2930 Injection Report (Section 6.15.1)  
• DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2)  
• AE collection (Section 6.16) 
 
7.29 
Completion of Treatment Period:  Visit 27 (Day 364 ±4 Days) 
On Day 364 the following procedures and assessments will be performed: 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• 12-Lead ECG (Section 6.7) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• PK sample collection (Section 6.9) 
• PD sample collection (Section 6.10) 
• Anti-drug antibody sample collection (Section 6.11) 
 
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• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
 
7.30 
Follow-up Period:  Visit 28 (Day 378 ±4 Days) 
On Day 378 all rollover and non-rollover subjects will receive a site check-in call.  During this 
call study site personnel will collect information regarding the following:  
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• AE collection (Section 6.16) 
7.31 
Final Follow-up Visit:  Visit 29 (Day 392 ±4 Days) 
On Day 392 all rollover and non-rollover subjects will complete a final study visit at the 
investigative site. 
• Pregnancy test, serum or urine (females) (Section 6.8)  
• Vital signs including body temperature, HR, BP and RR (Section 6.5) 
• Physical examination (Section 6.6) 
• 12-Lead ECG (Section 6.7) 
• Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8) 
• PK sample collection (Section 6.9) 
• PD sample collection (Section 6.10) 
• Anti-drug antibody sample collection (Section 6.11) 
• Concomitant therapy (Section 6.12) 
• HAE attack information (Section 6.4) 
• Quality of life assessments (Section 6.14) 
• AE collection (Section 6.16) 
• Study Discharge: Subjects will be discharged at this study visit.  
7.32 
Early Termination  
Subjects that terminate early from the study will undergo (if possible) all of the assessments and 
procedures scheduled for Day 392. 
 
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8. 
QUALITY CONTROL AND ASSURANCE 
The Sponsor and the Contract Research Organization (CRO) conducting trial management 
services, Rho, Inc., will implement a system of quality assurance that includes all elements 
described in this protocol. Within this system, SOPs from the Sponsor and CRO will be 
implemented to ensure that the clinical trial is conducted in compliance with regulatory 
requirements and Good Clinical Practices (GCP). Quality control will be applied to each stage of 
data handling to ensure that data are accurate, reliable and processed correctly.  
The site staff should assist in all aspects of audit/inspection. 
 
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9. 
DATA ANALYSIS / STATISTICAL METHODS 
9.1 
General Considerations 
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, Cary, 
North Carolina, USA). 
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. Where applicable, estimates from statistical model of least 
squares means, standard errors, and 95% confidence intervals for least squares means will be 
provided. Time-to-event data will be summarized using Kaplan-Meier estimates of the 25th, 50th 
(median), and 75th percentiles with associated two-sided 95% confidence intervals, as well as 
percentage of censored observations. Plots of the Kaplan-Meier curves and supporting data 
listings detailing each subject’s contribution to the analysis will be provided.  
Formal hypothesis testing will not be performed.  Any hypothesis testing will be exploratory in 
nature and resulting p-values will be considered descriptive. 
9.2 
Sample Size Determination 
No formal sample size calculation was performed.  The sample size is not based on any 
statistical considerations.  This study is designed to evaluate the safety and efficacy of open-label 
treatment with DX-2930 in subjects who participated in DX-2930-03 (rollover subjects) and 
individuals who were not otherwise able to participate in DX-2930-03 (non-rollover subjects). 
9.3 
Method of Assigning Study Subjects to Treatment 
Subjects meeting all eligibility criteria will be enrolled in the study and sequentially assigned a 
unique site-based identification number. 
9.4 
Analysis Populations 
9.4.1 
Safety Population 
The Safety Population will include all subjects who received any study drug after entering the 
DX-2930-04 study (i.e., any exposure to open-label DX-2930).   Unless otherwise specified, 
summary tabulations conducted with the Safety Population will be presented by the subject’s 
study entry type (rollover or non-rollover) and overall. 
9.4.2 
Rollover Safety Population 
The Rollover Safety Population is the subset of subjects who participated in the DX-2930-03 
study and received any study drug after entering the DX-2930-04 study (i.e., any exposure to 
open-label DX-2930). Unless otherwise specified, summary tabulations conducted with the 
Rollover Safety Population will be presented by the subject’s prior treatment group from the 
DX-2930-03 study (DX-2930 300 mg every 2 weeks, DX-2930 300 mg every 4 weeks, DX-2930 
150 mg every 4 weeks, and Placebo). 
 
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9.4.3 
Non-rollover Safety Population 
The Non-rollover Safety Population is the subset of subjects who entered the DX-2930-04 study 
directly and received any study drug after entering the DX-2930-04 study (i.e., any exposure to 
open-label DX-2930).  Unless otherwise specified, summary tabulations conducted with the 
Non-rollover Safety Population will be presented by subject’s prior type of LTP therapy prior to 
study entry (C1-INH, Androgens, Anti-fibrinolytics, and Not on LTP). 
9.5 
Population Description and Exposure 
9.5.1 
Subject Disposition 
The numbers of subjects treated with study drug, completed the study and discontinued 
prematurely by reason will be summarized for each analysis population. 
9.5.2 
Demographics and Other Baseline Characteristics 
Baseline and demographic variables will be summarized for each analysis population. 
9.5.3 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by system organ class (SOC) and preferred term (PT) for each analysis 
population. 
9.5.4 
Treatment Exposure and Compliance 
Treatment compliance and the extent of exposure to study drug will be described by the 
percentage of planned doses received by the subject, total number of doses received by the 
subject, and the number and percentage of subjects that received at least 80% of planned doses, 
summarized for each analysis population. 
9.5.5 
Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD).  The number and percentage of subjects with prior or concomitant medications will be 
summarized by therapeutic class and preferred term for each analysis population.  A separate, 
similar table will be provided for the subset of concomitant medications classified as rescue 
medications. 
9.6 
Analysis of Efficacy 
9.6.1 
Time to the First Investigator-confirmed HAE Attack 
Time to the first investigator-confirmed HAE attack will be analyzed using the Rollover Safety 
Population. 
Time to the first investigator-confirmed HAE attack (days) will be calculated from the date and 
time of the first open-label dose of DX-2930 to the date and time of the first investigator-
confirmed HAE attack after the first open-label dose.  Subjects who discontinue the study prior 
to experiencing their first on-study investigator-confirmed HAE attack will be censored at the 
 
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date and time of study discontinuation.  Time to the first investigator-confirmed HAE attack will 
be summarized using Kaplan-Meier methods. 
Multivariate and univariate Cox proportional hazards regression models will be employed to 
examine the impact of baseline covariates on the time to the first investigator-confirmed HAE 
attack, including but not limited to: baseline attack rate prior to entering DX-2930-03, the 
treatment group in DX-2930-03, the time since the last dose given in DX-2930-03, the time since 
the last HAE attack, and the rate of attacks during DX-2930-03. Results of this exploratory 
analysis will be summarized.   
9.6.2 
Number of Investigator-confirmed HAE Attacks 
The number of investigator-confirmed HAE attacks during the treatment period (Day 0 through 
Day 350) expressed as a monthly HAE attack rate, will be analyzed using each analysis 
population. 
The treatment period investigator-confirmed HAE attack rate will be calculated for each subject 
as the number of investigator-confirmed HAE attacks occurring during the treatment period 
divided by the number of days the subject contributed to the treatment period multiplied by 28 
days.   
The baseline investigator-confirmed HAE attack rate will be calculated for each subject as the 
number of investigator-confirmed HAE attacks occurring during the pretreatment period for 
rollover subjects or historical reporting period for non-rollover subjects divided by the number of 
days the subject contributed to the pretreatment period for rollover subjects or historical 
reporting period for non-rollovers multiplied by 28 days. 
The baseline, treatment period, and treatment period change from baseline in the investigator-
confirmed HAE attack rate will be summarized for each analysis population. The summary will 
include the total number of investigator-confirmed HAE attacks reported during each period and 
subject-time in months that each subject contributed to each period. Figures will be created for 
each analysis population plotting the on-study investigator-confirmed HAE attacks reported 
during the treatment period relative to Day 0 for each subject. 
In addition, the number of investigator-confirmed HAE attacks per month (defined as 28 days) 
will be summarized descriptively by month (per 28 day interval) for each analysis population. 
The summary will include the number, change from baseline, and percent change from baseline 
of investigator-confirmed HAE attacks. Investigator-confirmed HAE attacks will be grouped into 
28-day intervals using the start date of the HAE attack. The date of the first exposure to study 
drug in this study will be used as the start of the first interval and end of the interval will be the 
date of first exposure to study drug in this study plus 28 days. Each successive interval will start 
the last day of the prior interval plus 1 day and end 28 days later.  
Similar summary tables will be presented for the following efficacy endpoints for each analysis 
population: 
• Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period. 
 
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• Number of moderate or severe investigator-confirmed HAE attacks during the treatment 
period. 
• Number of high-morbidity investigator-confirmed HAE attacks during the treatment period; 
a high-morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation < 24 
hours), hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal. 
 
9.7 
Analysis of Safety 
9.7.1 
Adverse Events 
Adverse events will be coded using the MedDRA coding dictionary.  Separate summaries will be 
presented for each analysis population. 
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not.  If a determination cannot be made using the non-missing 
date parts as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.   
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.   
 
Related AEs are AEs classified as related to study drug by the investigator.  Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator. 
 
For this analysis, AEs will be classified to one of three analysis periods: 
 
• Pretreatment Period AEs will include AEs starting at or after informed consent to those 
starting before the first exposure to open-label DX-2930 in this study (AEs starting prior to 
treatment on Day 0).  This analysis period is only applicable for the Non-rollover Safety 
Population in this study.  
• Treatment Period AEs will include all AEs starting at or after the first exposure to open-label 
DX-2930 in this study to those starting before or at the subject’s last visit date during the 
treatment period in this study (AEs starting at or after treatment on Day 0 to the Day 350 
visit).  
• Follow-up Period AEs will include all AEs starting at or after the subject’s last visit date of 
the treatment period in this study (AEs starting after the Day 350 visit).  
 
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For AEs with partial onset times, non-missing date parts will be used to determine if the AE falls 
within the period. If a determination cannot be made using the non-missing date parts as to if the 
AE falls within the period, the AE will be conservatively counted as a treatment-period AE.  
 
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE,  
any severe AE,  and any related severe AE will as well as the total number of events for each 
category will be summarized for each analysis period.  The number of deaths due to an AE, 
hospitalization due to an AE and study discontinuation due to an AE will be summarized for 
each analysis period.  
 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC, and PT for each analysis period. This tabulation will be repeated for 
related AEs, SAEs, related SAEs, severe AEs, and related severe AEs for treatment period and 
follow-up period AEs.  
 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized for treatment period AEs only. This tabulation will be repeated for related AEs and 
serious AEs for treatment period AEs.  
 
All AEs will be provided in subject listings. Listings will be presented separately for each 
analysis period.  In addition, subject listings of AEs causing discontinuation of study medication, 
AEs leading to death, SAEs, related AEs, severe AEs, and AEs of special interest (AESIs) will 
be produced.  
 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions and 
disordered coagulation (hypercoagulability events and bleeding events).  Standardized MedDRA 
Queries (SMQ) for each AESI will be performed using the study data. The number and percentage 
of subjects with an AESI, as well as the total number of AESIs, will be summarized by SOC and PT 
for each analysis period. Separate summary tables will be created for each AESI and for those 
events with the SMQs classified as related, serious, related serious, severe, and related severe.  A 
listing detailing the PT within the SMQ will be provided. 
9.7.2 
Laboratory Test Results 
Laboratory test results will be summarized using the Safety Population. 
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For rollover 
subjects previously exposed to DX-2930, baseline is the last non-missing value prior to first exposure 
to study drug in the DX-2930-03 study.         
Actual values and change from baseline clinical laboratory tests will be summarized by study 
visit. If more than one laboratory result is reported per study visit per parameter, the last non-missing 
result will be selected for analysis  
Laboratory test results will be classified according to the reference ranges and clinical significance as 
determined by the investigator. The number of subjects with a non-missing result, and the number 
and percentage of subjects with a clinically significant result less than the lower limit of normal, non-
clinically significant result less than the lower limit of normal, within the normal range, non-
 
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clinically significant result more than the upper limit of normal, and clinically significant result more 
than the upper limit of normal will be summarized by study visit. If more than one laboratory result is 
reported per study visit per parameter, the result yielding the most severe classification will be 
selected for analysis.  
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study visit per parameter, the result yielding the most 
severe classification will be selected for analysis.  
 
Subjects with clinically significant abnormal laboratory test results will be listed.  This listing will 
include all results of the laboratory parameter that was abnormal and determined to be clinically 
significant by the investigator for a subject across study visit to identify any trends. 
 
9.7.3 
Vital Signs 
Vital signs will be summarized using the Safety Population. 
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For rollover 
subjects previously exposed to DX-2930, baseline is the last non-missing value prior to first exposure 
to study drug in the DX-2930-03 study. 
 
Actual values and changes from baseline in vital signs will be summarized by study visit and 
study time point. All vital sign data will be presented in subject listings. 
 
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage of 
subjects with a non-clinically significant result and clinically significant result will be summarized by 
study visit and study time point. If more than one vital sign result is reported per study visit and study 
time point per parameter, the result yielding the most severe classification will be selected for 
analysis.  
Subjects with clinically significant vital sign values will be listed.  This listing will include all results 
of the vital sign parameter that was determined by the investigator to be clinically significant for a 
subject across study time points to identify any trends. 
9.7.4 
Electrocardiography 
Electrocardiography results will be summarized using the Safety Population. 
 
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG no performed, will be summarized by study 
visit. Subjects with clinically significant ECG results will be listed.  This listing will include all 
results for a subject across study time points to identify any trends. 
9.8 
Other Analyses 
Additional analyses of pharmacokinetic (PK) and pharmacodynamic (PD) data will be described 
in a separate PK/PD report. 
Additional analysis of quality of life (QoL) data will be described in a separate QoL report.  
 
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9.8.1 
Analysis of Pharmacokinetic Data 
Plasma concentrations of DX-2930 will be summarized by nominal PK sampling time using the 
Safety Population.  
9.8.2 
Analysis of Pharmacodynamic Data 
Plasma kallikrein activity will be summarized by nominal PD sampling time using the Safety 
Population. 
9.8.3 
Analysis of Immunogenicity Data 
The number and percentage of positive antibodies will be summarized by study visit and overall 
using the Safety Population. 
 
9.8.4 
Analysis of Quality of Life Assessments 
Quality of life assessments will be summarized using the Safety Population. 
 
The number and percentage of subjects at each level of the EQ-5D-5L dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) will be summarized by study 
visit. In addition, the VAS score for the subject’s self-rated health will be summarized by study 
visit.   
 
The responses to the SF-12 for each item will be tabulated by study visit using the Safety 
Population.  In addition, Physical and Mental Health Composite Scores (PCS & MCS) will be 
computed using the scores of twelve questions and range from 0 to 100, where a zero score 
indicates the lowest level of health measured by the scales and 100 indicates the highest level of 
health. 
 
Responses to the HADS for each item will be tabulated by study visit. In addition, continuous 
and categorical (0-7: normal, 8-10: mild, 11-14: moderate, 15-21: severe) total scores based on 
the items related to depression and anxiety, will be summarized by study visit.  Each item in the 
questionnaire is scored from 0-3, with total scores between 0-21 for either depression or anxiety.  
Scores for the entire scale (emotional distress) will also be presented.  Total score for the entire 
scale range from 0 to 42, with higher scores indicating more distress. 
 
Responses to the WPAI-GH for each item will be summarized by study visit.  In addition, four 
main scores in relation to general health will be summarized by study visit. Scores will be 
calculated as absenteeism (percentage work time missed due to health), presenteeism (percent 
impairment while working due to health), work productivity loss (percent overall work 
impairment due to health), and activity impairment (percent activity impairment due to health).  
The scores are percentages with higher values indicating greater percentage impairment.  Only 
respondents who report being full-time or part-time employed provide data for absenteeism, 
presenteeism, and overall work productivity loss.  All respondents provide data for activity 
impairment.   
 
Responses to the AE-QoL for each item will be tabulated by study visit.  In addition, the domain 
scores (functioning, fatigue/mood, fears/shame, nutrition) and total score will be summarized by 
 
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study visit. Each item in the questionnaire is scored from 0-4, with domain and total scores 
calculated using a linear transformation to a 0-100 scale. 
 
9.9 
Statistical/Analytic Considerations 
9.9.1 
Interim Analyses and Data Monitoring 
A formal interim analysis will be conducted when at least 35 subjects have completed 12 months 
of consecutive exposure to DX-2930 across the combined DX-2930-03 and DX-2930-04 studies, 
and only after database lock of the DX-2930-03 study.  Subsequent interim analyses may be 
conducted to support administrative decisions and/or regulatory reporting as required.   
 
An independent Data Safety Monitoring Board (DSMB) has been established to provide 
ongoing, independent review and assessment of the safety data for the DX-2930-03 study. While 
an independent DSMB is not currently planned for this study, summary safety data from 
DX-2930-04 may be reviewed by the DSMB established for the DX-2930-03 study as part of the 
collection of safety information available on DX-2930.  
9.9.2 
Multiple Comparisons/Multiplicity 
No adjustment for multiple comparisons will be performed.  Any statistical testing will be 
considered exploratory. 
9.9.3 
Handling of Missing Data 
All available data will be included in the analysis.  No imputation of missing data will be 
performed. 
9.9.4 
Adjustment for Covariates 
The impact of baseline covariates on the time to the first investigator-confirmed HAE attack will 
be explored to identify and assess the importance of potential prognostic factors. 
9.9.5 
Multicenter Studies 
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis. 
9.9.6 
Subgroup Analyses 
Subgroup analyses are planned for the number of investigator-confirmed HAE attacks during the 
treatment period and adverse events using the Safety Population.  
The following subgroups will be used: 
• Age Group (<18, 18 to <40, 40 to <65, ≥65 years) 
• Sex (Male, Female) 
• Race Group (White, Other) 
• Weight Group (<50, 50 to <75, 75 to <100, ≥100 kg) 
 
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• BMI Group (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2) 
• Baseline HAE Attack Rate (1 to <2, 2 to <3, ≥3 attacks/month) 
• HAE Type (Type I, Type II, Unspecified) 
• Geographic Region (US, Canada, Jordan, Europe) 
• DX-2930 Administration Type (Health Care Provider, Self-administration) 
 
9.9.7 
Sensitivity Analyses 
The following sensitivity analyses will be performed on the number of investigator-confirmed 
HAE attacks during the treatment period for each analysis population to evaluate the robustness 
of the results. Data summaries will parallel those described for the number of investigator-
confirmed HAE attacks during the treatment period efficacy endpoint.   
1. The analysis will be repeated counting HAE attacks occurring on Day 14 after administration 
of study drug through Day 350, instead of Day 0 to Day 350.  For this analysis, the period of 
analysis would be a subset of the treatment period, defined as Day 14 to Day 350. 
2. The analysis will be repeated counting HAE attacks occurring on Day 7 after administration 
of study drug through Day 350, instead of Day 0 to Day 350. For this analysis, the period of 
analysis would be a subset of the treatment period, defined as Day 7 to Day 350. 
3. The analysis will be repeated using all subject reported HAE attacks instead of limiting the 
analysis to those attacks that were investigator-confirmed. 
 
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10. 
STUDY ADMINISTRATIVE STRUCTURE 
The study administration structure is provided in Table 1.  
Table 1: 
Study Administrative Structure 
Sponsor Contact/Sponsor Medical 
Director: 
, MD 
, Clinical Development 
300 Shire Way, Lexington, MA 02421 USA 
Phone: 
 
Medical Monitor (US, Canada): 
, MD 
, Clinical Development 
300 Shire Way, Lexington, MA 02421 USA 
Phone: 
 
Medical Monitor (Jordan, Europe) 
, MD, MBA 
Voisin Consulting 
3, rue des Longs Prés 
92100 Boulogne, France 
Phone: 
 
Study Monitoring (US): 
Rho, Inc. 
6330 Quadrangle Drive, Chapel Hill, NC 27517 
Phone: 
 
Study Monitoring (Jordan) 
Triumpharma 
07 Bldg., Al-Yarooty St. 
P.O. Box 2233, Amman 
11941, Jordan 
Phone: 
, 
 
Study Monitoring (Canada) 
 Red Maple Trials Incorporated 
1081 Carling Avenue, Suite 707 
Ottawa, Ontario, Canada, K1Y4G2 
Phone: 
 
Study Monitoring (Europe) 
Dyax Corp 
55 Network Drive, Burlington, MA 01803 
Phone: 
 
 
10.1 
Institutional Review Board/ Research Ethics Board/Independent Ethics Committee 
The protocol and all protocol amendments must be signed and dated by the investigator and 
approved in writing by the IRB/REB/IEC in accordance with GCP prior to implementation. In 
addition, the IRB/REB/IEC must approve the written informed consent form, any consent form 
updates, subject recruitment materials (e.g., advertisements), and any written information to be 
provided to subjects prior to implementation. The investigator must provide an annual report to 
the IRB/REB/IEC on the progress of the study including number of subjects enrolled, 
discontinued, and SAEs. It is required that a yearly review of the protocol by the IRB/REB/IEC 
 
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be documented in a letter from the IRB/REB/IEC. The investigator must provide notification to 
the IRB/REB/IEC of the completion, termination or discontinuation of the study. 
10.2 
Ethical Conduct of the Study 
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor and 
the investigator abide by the principles of the International Conference on Harmonisation (ICH) 
guidelines on GCP, applicable local regulatory requirements, and the Declaration of Helsinki 
(Version 2008). The clinical study also will be carried out in keeping with national and local 
legal requirements [in accordance with United States Investigational New Drug (IND) 
regulations (21 CFR 56)]. 
10.3 
Subject Information and Consent 
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
according to the regulatory and legal requirements of the participating country. As part of this 
procedure, the investigator must explain orally and in writing the nature, duration, and purpose 
of the study, and the action of the drug in such a manner that the study subject is aware of the 
potential risks, inconveniences, or AEs that may occur. The study subject should be informed 
that he/she is free to withdraw from the study at any time. He/she will receive all information 
that is required by federal regulations and ICH guidelines. Subjects who are under the age of 18 
(or lower if age of consent is less than 18 in a specific country) and whose legal guardian or 
caretaker has provided written informed consent will provide their assent to participate. The 
investigator or designee will provide the Sponsor with a copy of the IRB/REB/IEC-approved 
informed consent form prior to the start of the study. 
10.4 
Subject Confidentiality 
The anonymity of participating subjects must be maintained. Subjects will be specified on study 
documents by their subject number, initial or birth date (if allowed based on local data protection 
regulations), not by name. Documents that identify the subject (e.g., the signed informed consent 
document) must be maintained in confidence by the investigator. 
The investigator agrees not to use or disclose protected health information other than as 
permitted or required by the subject authorization or as required by law. 
10.5 
Study Monitoring 
The Sponsor (or designee) will conduct a study initiation visit to verify the qualifications of the 
investigator, inspect the facilities, and inform the investigator of responsibilities and procedures 
for ensuring adequate and correct documentation. 
The investigator must prepare and maintain adequate and accurate records of all observations 
and other data pertinent to the clinical study for each study participant. Frequent communication 
between the clinical site and the Sponsor is essential to ensure that the safety of the study is 
monitored adequately. The investigator will make all appropriate safety assessments on an 
ongoing basis. The Medical Monitor may review safety information as it becomes available 
throughout the study. 
 
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All aspects of the study will be carefully monitored with respect to GCP and SOPs for 
compliance with applicable government regulations. The Study Monitor will be an authorized 
individual designated by the Sponsor. The Study Monitor will have access to all records 
necessary to ensure integrity of the data and will periodically review the progress of the study 
with the investigator. 
10.6 
Case Report Forms and Study Records 
The investigator will ensure the accuracy, completeness, and timeliness of the data reported to 
the Sponsor. Data collection processes and procedures will be reviewed and validated to ensure 
completeness, accuracy, reliability, and consistency. A complete audit trail will be maintained of 
all data changes. The investigator or designee will cooperate with the Sponsor’s representative(s) 
for the periodic review of study documents to ensure the accuracy and completeness of the data 
capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the clinical sites by means of 
electronic or manual queries. 
The investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE and concomitant medication reporting, raw data collection forms, 
etc.) designed to record all observations and other pertinent data for each subject receiving 
randomized study drug. 
The investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB/REB/IEC to have direct access to all documents pertaining to 
the study. 
A Trial Master File will be maintained by the Sponsor (or designee). All documents and other 
materials that pertain to the conduct of the trial quality of the data, and compliance with GCPs 
will be collected in the Trial Master File. 
10.7 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) has been established to provide 
ongoing, independent review and assessment of the safety data for the DX-2930-03 study. While 
an independent DSMB is not currently planned for this study, summary safety data from 
DX-2930-04 may be reviewed by the DSMB established for the DX-2930-03 study as part of the 
collection of safety information available on DX-2930.  
The DSMB will adhere to a prospectively determined Charter, which will be written by the 
Sponsor and approved by the DSMB. The Charter will define the responsibilities of the DSMB 
and Sponsor, the number and timing of the DSMB meetings, the conduct of the meetings, and 
the data sets to be reviewed by the DSMB. Further details regarding the DSMB can be found in 
the DSMB charter. 
 
 
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10.8 
Protocol Violations/Deviations 
The investigator will be instructed not to deviate from the protocol, except where necessary to 
eliminate an immediate hazard to study participants. Should other unexpected circumstances 
arise that will require deviation from protocol-specific procedures, the investigator should 
contact their Sponsor representative to discuss the appropriate course of action.  
The investigator should document all protocol deviations/violations in the subject’s eCRF and 
source documents or the Investigator Site File if appropriate. In the event of a significant 
deviation/violation, the investigator should notify the Sponsor representative. Significant 
deviations/violations include, but are not limited to those that increase the health risk to the 
subject, or confound interpretation of primary study assessments. The investigator will promptly 
report all changes in research activity and all unanticipated problems involving risks to human 
subjects or others to his or her IRB/REB/IEC. 
10.9 
Premature Closure of the Study 
If the Sponsor, investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable patient risk, 
the study may be terminated overall or at a specific site after appropriate consultation between 
the Sponsor and the investigator(s). In addition, a decision on the part of the Sponsor to suspend 
or discontinue development of the investigational product may be made at any time. Conditions 
that may warrant termination of the study or site include, but are not limited to, the following: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in 
the study 
• Failure of the investigator to comply with pertinent global regulations 
• Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities 
• Insufficient adherence by the investigator to protocol requirements 
 
10.10 Access to Source Documentation and On-Site Audits 
Regulatory agencies may request access to all study records, including source documents, for 
inspection and copying, in keeping with country regulations. The investigator should 
immediately notify the Sponsor representative of any announced or unannounced regulatory 
agency inspections. An auditing inspection may also be conducted by the Sponsor representative 
or designee. Any aspect of the trial may be subject to audit by the Sponsor and/or inspection by 
regulatory authorities or the IRB/REB/IEC. Such audits/inspections may take place at the 
Sponsor’s site(s), the CRO, or at the clinical sites, including laboratories, pharmacies and any 
other facilities used for the study.  
 
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The investigator will be responsible for the accuracy of the data entered in the eCRF. The 
investigator will permit the designated Sponsor representatives and regulatory bodies to have 
direct access to the source documents to verify data represented in the eCRF. 
10.11 Data Generation and Analysis 
This study will be performed in accordance with regulatory requirements outlined in Food and 
Drug Administration (FDA) 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, 21 CFR Part 312 
and 21 CFR Part 11 as well as the ICH GCP E6 Guidelines. The study monitors will meet with 
the investigators and staff shortly before the start of the trial to review the procedures for study 
conduct and documentation. During the study, the monitors will visit the sites to verify record 
keeping and adherence to the protocol. For this study, eCRFs will be used. The monitors will 
conduct 100% source document verification by comparing the eCRFs with the source documents 
to ensure accuracy and consistency. Edit check programs, other forms of electronic validation, 
manual listings and a query process will be executed to verify the accuracy of the database. The 
EDC system will maintain a full audit trail of electronic data changes. Access to all source 
documentation will be made available for monitoring and audit purposes. 
10.12 Retention of Data 
All source documents (e.g., informed consent forms, laboratory reports, progress notes, medical 
histories, physical and diagnostic findings, diagnosis and pharmacy records, and DX-2930 
dispensing/disposition records) that support data in the eCRFs of each study subject must be 
retained in the files of the responsible investigator. 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the DX-2930. However, these documents 
should be retained for a longer period if required by the applicable legal requirements. 
If the responsible investigator retires, relocates or for any other reason withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor representative must be notified in writing of the name and 
address of the new custodian, prior to the transfer. 
10.13 Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the Sponsor. The 
following information is collected: any significant payments from the Sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the Sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
 
 
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10.14 Publication and Disclosure Policy 
All information concerning DX-2930, Sponsor operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information, supplied to the 
investigator by a Sponsor representative and not previously published, is considered confidential 
and remains the sole property of the Sponsor. The investigator must agree to use this information 
only to accomplish this study, and must not use it for other purposes without the Sponsor’s 
advanced written consent. A description of this clinical study may also be available on the 
externally facing public websites and registries. A summary of the study results may be 
potentially disclosed as per local and country specific requirements. 
The information developed in this study will be used by the Sponsor in connection with the 
continued development of DX-2930 and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. To permit the information derived from the 
clinical studies to be used, the investigator is obligated to provide the Sponsor with all data 
obtained in the study. 
 
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11. 
REFERENCE LIST 
Bennet G, Craig, T. Hereditary angioedema with a focus on the child. Allergy Asthma 
Proc. 2015 Jan-Feb; 36 (1):70-3. 
Bork K, Hardt J, Schicketanz K-H, Ressel N. Clinical studies of sudden upper airway obstruction 
in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Int Med. 
2003;163:1229-1235. 
 
Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to 
C1-INH deficiency. J Allergy Clin Immunol. 2012;130(3):692-7. 
 
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: New findings concerning 
symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274. 
 
Bork K, Siedlecki K, Bosch S, Schopf RE, Kreuz W. Asphyxiation by laryngeal edema in 
patients with hereditary angioedema. Mayo Clin Proc. 2000;75(4):349-54. 
 
Bygum A. Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol. 
2009;161(5):1153-8. 
 
Craig T, Pursun EA, Bork K, Bowen T, Boysen H, Farkas H, et al. WAO Guideline for the 
Management of Hereditary Angioedema. World Allergy Organ J. 2012;5(12):182-199. 
 
Davis AE, 3rd. Mechanism of angioedema in first complement component inhibitor deficiency. 
Immunol Allergy Clin North Am. 2006;26(4):633-51. 
 
Farkas H.  Pediatric hereditary angioedema due to C1-inhibitor deficiency.  Allergy, Asthma & 
Clinical Immunology 2010, 6:18. 
 
Goring HD, Bork K, Spath PJ, Bauer R, Ziemer A, Hintner H, et al. [Hereditary angioedema in 
the German-speaking region]. Hautarzt. 1998;49(2):114-22. 
 
KALBITOR® (ecallantide) [package insert] Burlington, MA: Dyax Corp.; 2015 
 
Kaplan AP, Joseph K. The bradykinin-forming cascade and its role in hereditary angioedema. 
Ann Allergy Asthma Immunol. 2010;104(3):193-204. 
 
Kenniston JA, Faucette RR, Martik D, Comeau SR, Lindberg AP, Kopacz KJ, et al. Inhibition of 
plasma kallikrein by a highly specific active site blocking antibody. J Biol Chem. 
2014;289(34):23596-608. 
 
Lei WT, Shyur SD, Huang LH, Kao YH, Lo CY. Type I hereditary angioedema in Taiwan -- 
clinical, biological features and genetic study. Asian Pac J Allergy Immunol. 2011;29(4):327-31. 
 
 
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Nordenfelt P, Dawson S, Wahlgren CF, Lindfors A, Mallbris L, Bjorkander J. Quantifying the 
burden of disease and perceived health state in patients with hereditary angioedema in Sweden. 
Allergy Asthma Proc. 2014;35(2):185-90. 
 
Reilly MC, Zbrozek AS, Dukes EM 1993. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics; 4(5): 353-65. 
 
Renne T, Gruber A. Plasma kallikrein: novel functions for an old protease. Thromb Haemost. 
2012;107(6):1012-3. 
 
Roche O, Blanch A, Caballero T, Sastre N, Callejo D, Lopez-Trascasa M. Hereditary 
angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in 
Spain. Ann Allergy Asthma Immunol. 2005;94(4):498-503. 
 
Ware J Jr, Kosinski M, Keller SD 1996. A 12-Item Short-Form Health Survey: construction of 
scales and preliminary tests of reliability and validity. Med Care; 34(3): 220-33. 
 
Weller K, Groffik A, Magerl M, et al. 2012. Development and construct validation of the 
angioedema quality of life questionnaire. Allergy; 67(10): 1289-98. 
 
Zigmond AS, Snaith RP 1983. The hospital anxiety and depression scale. Acta Psychiatr Scand; 
67(6): 361-70. 
 
Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-36. 
 
Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, et al. A focused parameter 
update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting 
enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013;131(6):1491-1493 e25. 
 
 
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12. 
APPENDICES 
Appendix 1 
Study Activities Schedule 
Appendix 2 
National Institute of Allergy and Infectious Diseases, Division of Microbiology 
and Infectious Diseases (DMID) Adult Toxicity Table (Modified) (US National 
Institutes of Health; National Institute of Allergy and Infectious Diseases) 
Appendix 3 
National Institute of Allergy and Infectious Diseases, Division of Microbiology 
and Infectious Diseases (DMID) Pediatric Toxicity Tables (Modified) (US 
National Institutes of Health; National Institute of Allergy and Infectious 
Diseases 
Appendix 4 
HAE Attack Assessment and Reporting Procedures (HAARP) 
Appendix 5 
Summary of Pivotal Study of DX-2930 in HAE Subjects 
 
 
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Appendix 1
Study Activities Schedule
Study Activities Schedule
Tests and 
Assessments
Treatment Period 
± 4 days for each visit
Follow-
up
±4 Days 
for 
each 
visit
Non-rollover
Screen 
Visit1
Rollover 
-
Check-
in2
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27 283 294
Dose:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-
-
-
Day:
0
14
28
42
56
70
84
98
112
126
140
154
168
182
196
210
224
238
252
266
280
294
308
322
336
350 364 378 392
Informed 
Consent5
X
(X)6
Eligibility 
Review
X
X
Long-term 
prophylactic 
therapy 
continued7
X
X
X
DX-2930 
Administration 
(rollover 
subjects)
X
(X)8,9 (X)10 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)10 (X)11 (X)10 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)11 (X)10
DX-2930 
Administration
(non-rollover)
X
X
X10
X11
X10
X11
X11
X10
X11
X10
X11
X10
X11
X10
X11
X11
X10
X11
X11
X10
X11
X11
X10
X11
X11
X10
Demographic 
and Medical 
History 
X
C1-INH, C1q 
and C4 
Testing12
X
Pregnancy 
Test13 (females)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Exam15
X
X
X
X
X
X
X
X
X
X
X
X
Clinical 
Laboratory 
Testing16
X
X
X
X
X
X
X
X
X
X
X
X
X
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Study Activities Schedule
Tests and 
Assessments
Treatment Period 
± 4 days for each visit
Follow-
up
±4 Days 
for 
each 
visit
Non-rollover
Screen 
Visit1
Rollover 
-
Check-
in2
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27 283 294
Dose:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-
-
-
Day:
0
14
28
42
56
70
84
98
112
126
140
154
168
182
196
210
224
238
252
266
280
294
308
322
336
350 364 378 392
12-Lead ECG
X
X
X
X
X
X
X
X
Prior (4 weeks) 
and 
Concomitant 
Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HAE Attack 
Data17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Assessments18
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
X
X
SF-12
X
X
X
X
X
X
X
X
X
X
X
X
AE-QoL
X
X
X
X
X
X
X
X
X
X
X
X
HADS
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-GH
X
X
X
X
X
X
X
X
X
X
X
X
DX-2930 
Injection 
Report19
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DX-2930 Self-
administration 
and SC 
Injection 
Survey 20
X
X
X
X
X
PK, PD 
Collection, & 
Plasma Anti-
Drug Antibody 
Testing21
X
X
X
X
X
X
Discharge from 
Study
X
Page 111 of 151


DX-2930
CONFIDENTIAL
Page 112
Clinical Trial Protocol: DX-2930-04
27 June 2016
AE-QOL = Angioedema Quality of Life; ECG = Electrocardiogram; EQ-5D-5L = EuroQoL 5-Dimensional 5-Level; HADS = Hospital Anxiety and Depression Scale; PK = 
Pharmacokinetic; PD = Pharmacodynamic; SF-12 = Short Form-12 (v2); WPAI-GH = Work Productivity and Activity Impairment – General Health
NOTE:  Shaded columns represent scheduled in-site visits for all subjects. Non-shaded columns indicate potential subject-elected off-site activity and/or self-administration dosing. 
NOTE:  “( )”s indicate activities that may occur as applicable (ie, activities for rollover subjects)
13. Screening visit is for non-rollover subjects only.  Screening visit can occur up to 28 days prior to first open-label dose.
14. Study site personnel will contact rollover subjects approximately every 7 days following the first dose of open-label DX-2930 to solicit for any HAE attacks not already
reported.  Site check-in with rollover subjects will continue until the subject receives their second open label dose.
15. Visit 28 is a site check-in call for all rollover and non-rollover subjects.
16. Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures at Visit 29, their final study visit
17. Rollover subjects must sign informed consent for DX-2930-04 after Day 168 of study DX-2930-03 and no later than the final DX-2930-03 Day 182 treatment period study
visit.
18. For rollover subjects Day 182 of the DX-2930-03 study is also Day 0 of the DX-2930-04 study and informed consent may be completed on this visit, if not already provided.
19. Screened non-rollover subjects (adults and adolescents) who are on LTP with C1 INH therapy for HAE can continue their current LTP until Day 8 (or Day 15) such that
subjects will have received 2 (or 4) doses of C1 INH.  For subjects who are on attenuated androgens (e.g., danazol) or anti-fibrinolytics (e.g., tranexamic acid), a similar
tapering schedule is recommended. However, the taper can be prolonged by an additional week as long as androgen or anti-fibrinolytic therapy is stopped within 3 weeks of
receiving the first dose of DX-2930.
20. For rollover subjects, the timing of Dose 2 for will vary by subject based on when their first HAE attack occurs following Dose 1.  Following the first reported and
investigator-confirmed attack, subjects will begin receiving regular SC administrations of 300 mg DX-2930 every 2 weeks.
21. A minimum of 10 days between the first and second open-label doses is required. If the second dose is to be administered within the accepted ±4 day window around a
scheduled study visit, this treatment visit will represent that scheduled visit unless that scheduled visit has already occurred. If that scheduled visit has already occurred, or if
the second dose is to be administered outside of the accepted ± 4 day window around a scheduled visit, this visit will not replace any scheduled visit and will thus represent an
acceptable, extra study visit (i.e., an unscheduled visit). Regardless, at the visit in which the second open-label dose of DX-2930 is administered, the subject will undergo pre-
dose assessments for vital signs, physical examination (performed in accordance with standards at the site), clinical laboratory testing, PK, PD, and anti-drug antibody. Vital
signs will be obtained at 1 hour post-dosing. As with all study visits, information will be collected on adverse events, concomitant therapy, and HAE attack data.
22. All subjects (adolescent or adult) who are considered suitable candidates (i.e., those with a physical and mental capability of learning and willing to be trained) may be
allowed to self-administer DX-2930 after completing appropriate training by the investigator or designee and confirming their understanding. Subjects are allowed to initiate
self-administration after receiving the first 2 doses of DX-2930 at the study site and may elect to self-administer subsequent doses of DX-2930 at the investigational site
(during scheduled study site visits; shaded columns).
23. Subjects may self-administer DX-2930 at home or other agreed upon location (during optional off-site self-administration visits; non-shaded columns). Site personnel will call
subjects after the planned self-administration to ensure the administration occurred, to collect AEs, concomitant medications, and to ensure all attacks have been appropriately
documented.
24. Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment unless already collected as part of protocol DX-2930-02 or DX-2930-03.
25. The pregnancy test will only be conducted in females of childbearing potential.  Tests performed on Day 0 must be urine-based to confirm eligibility prior to first dose.  Tests
performed at screening and on indicated visits can be serum or urine-based.
26. There is a recommended ± 15 minute window for all vital signs. Vital signs will be obtained prior to dosing and 1 hour after dosing. Monitoring of vital signs will not be
performed for subjects who elect to self-administer away from the investigative site at optional off-site visits (indicated non-shaded columns). Height and weight will be
collected at the Screening visit only.
Page 112 of 151


DX-2930
CONFIDENTIAL
Page 113
Clinical Trial Protocol: DX-2930-04
27 June 2016
27. Physical examinations will be conducted for all rollover and non-rollover subjects according to the study activities schedule and in accordance with standards at the site.  In
addition to the physical examinations specified in the study activities schedule, an additional physical examination (performed in accordance with standards at the site) will be
conducted for rollover subjects prior to dosing on the day of their second open-label dose, at whatever study visit that occurs.
28. Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis (urinalysis does not need to be done as part of the clinical laboratory
testing at Visits 14, 17, 20, and 23). Clinical laboratory testing will be conducted for all rollover and non-rollover subjects according to the study activities schedule.  In
addition to the testing specified in the study activities schedule, additional testing will be conducted for rollover subjects prior to dosing on the day of their second open-label
dose, at whatever study visit that occurs.
29. Historical HAE attack information will be collected at screening. During the study, subjects (or caregivers) are instructed to report details of the attack to the study site within
72 hours of the onset of the attack. During study visits, study site personnel will solicit for any new HAE attack information that has not already been reported to the site.
30. Quality of life data will be obtained using the EQ-5D-5L, SF-12, AE-QoL, HADS, and WPAI-GH.
31.
Collect subject’s injection reports of their experience with DX-2930 self-administration and subcutaneous administration for all doses.
32.
Collect subject’s injection surveys of their experience with DX-2930 self-administration and subcutaneous injection for indicated visits.
33.
PK, PD and Anti-drug Antibody PD samples will be drawn for all rollover and non-rollover subjects according to the study activities schedule.  In addition to the samples
specified in the study activities schedule, an additional PK, PD and Anti-drug Antibody sample will be drawn for rollover subjects prior to dosing on the day of their second
open-label dose, at whatever study visit that occurs.
Page 113 of 151


DX-2930
CONFIDENTIAL
Page 114
Clinical Trial Protocol: DX-2930-04
27 June 2016
Appendix 2
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infectious Diseases)
Page 114 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials.  This toxicity table is not comprehensive and 
should not be applied directly to all trials.   
When selecting a toxicity table, the following are some of the items that must be taken into 
consideration: 
•
The population being studied
o
Does the clinical trial evaluate healthy subjects, subjects with a particular disease
or condition?
•
The stage of test article development
o
Is the clinical trial a Phase I, II, III or IV?
•
The type of test article
o
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent?
•
The prior human and preclinical experience with the test article
o
Are there any specific findings that require adjustment of the toxicity table?
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal 
values at the single site. Multi-center clinical trials should reconcile among their laboratory normal 
values when evaluating a healthy volunteer population. 
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when 
selecting or developing a toxicity table for a DMID-sponsored trial. 
Page 115 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to 
estimate grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to 
moderate 
limitation 
in 
activity - some assistance may be needed; no or minimal 
medical intervention/therapy required 
GRADE 3 
Severe  
 
Marked limitation in activity, some 
assistance usually required; medical intervention/therapy 
required, hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme 
limitation 
in 
activity, 
significant 
assistance 
required; 
significant 
medical 
intervention/therapy required, hospitalization or hospice 
care probable 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening 
include, but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, 
disseminated intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, 
severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s 
Common Toxicity Criteria (CTC), and World Health Organization (WHO)) have 
been adapted for use by the Division of Microbiology and Infectious Diseases 
(DMID) and modified to better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to 
the “Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
Page 116 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
 6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-49,999/mm3 
<20,000/mm3 
WBCs  
11,000-13,000/ 
mm3 
13,000- 
15,000 /mm3 
15,000- 
30,000/mm3 
>30,000 or 
<1,000 /mm3 
% Polymorphonuclear 
Leucocytes + Band Cells 
 > 80% 
90 – 95% 
>95% 
---------- 
Abnormal 
Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
    ---------- 
Fibrinogen 
associated with 
gross bleeding or 
with 
disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin 
Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x 
ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
Page 117 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CHEMISTRIES 
   
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hyponatremia 
 
130-135 mEq/L 
 
 123-129 
mEq/L 
 
116-122 mEq/L 
 
< 116 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypernatremia 
 
146-150 mEq/L 
 
151-157 mEq/L 
 
158-165 mEq/L 
 
> 165 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypokalemia 
 
3.0 - 3.4 mEq/L 
 
2.5 - 2.9 mEq/L 
 
2.0 - 2.4 mEq/L  
or intensive 
replacement 
therapy or 
hospitalization 
required 
 
< 2.0 mEq/L or 
abnormal 
potassium with 
 paresis, ileus or 
life-threatening 
arrhythmia 
 
Hyperkalemia 
 
5.6 - 6.0 mEq/L 
 
6.1 - 6.5 mEq/L 
 
6.6 - 7.0 mEq/l 
 
> 7.0 mEq/L 
or abnormal 
potassium  with 
life-threatening 
arrhythmia 
 
Hypoglycemia 
 
55-64 mg/dL 
 
40-54 mg/dL 
 
30-39 mg/dL 
 
<30 mg/dL or 
abnormal glucose 
with mental 
status changes or 
coma 
 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
 
116 - 160 mg/dL 
 
161- 250 
mg/dL 
 
251 - 500 mg/dL 
 
> 500 mg/dL or 
abnormal glucose 
with ketoacidosis 
 or seizures 
 
Hypocalcemia 
(corrected for albumin) 
 
8.4 - 7.8 mg/dL 
 
7.7 - 7.0 mg/dL 
 
6.9 - 6.1 mg/dL 
 
< 6.1 mg/dL 
or abnormal 
calcium with life 
threatening 
arrhythmia or 
tetany 
 
 
 
 
 
 
Page 118 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
CHEMISTRIES (continued) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or 
abnormal calcium 
with life 
threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or 
replacement Rx 
required 
1.0 -1.4 mg/dL  
intensive therapy 
or 
hospitalization 
required 
< 1.0 mg/dL or 
abnormal 
phosphate with 
life-threatening 
arrhythmia 
Hyperbilirubinemia (when 
accompanied by any increase 
in other liver function test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia (when 
other liver function are in the  
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x 
ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or 
dialysis required 
Page 119 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
ENZYMES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
URINALYSIS 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ 
 or 
200 mg - 1 gm 
loss/day 
2-3+ 
or 
1- 2 gm 
loss/day 
4+ 
 or  
2-3.5 gm loss/day 
nephrotic 
syndrome 
or 
> 3.5 gm loss/day 
Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots 
>10 rbc/hpf 
gross, with or 
without clots, OR 
red blood cell casts 
obstructive or 
required 
transfusion 
Page 120 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CARDIOVASCULAR 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cardiac Rhythm 
 
 
 
asymptomatic, 
transient signs, 
no 
Rx required 
 
recurrent/persistent; 
symptomatic Rx 
required 
 
unstable 
dysrythmia; 
hospitalization 
and treatment 
required 
 
Hypertension 
 
transient increase 
> 20 mm/Hg; no 
treatment 
 
recurrent, 
chronic 
increase 
 > 20mm/Hg. 
/treatment 
required 
 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
 
end organ 
damage or 
hospitalization 
required 
 
Hypotension 
 
transient 
orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
 
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable 
with oral fluid 
treatment 
 
requires IV fluids; 
no hospitalization 
required 
 
mean arterial 
pressure  
<60mm/ Hg or 
end organ 
damage or shock;   
requires 
hospitalization 
and vasopressor 
treatment 
 
Pericarditis 
 
minimal effusion 
 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
 
symptomatic 
effusion; pain; 
EKG changes 
 
tamponade; 
pericardiocentesis 
or surgery 
required 
 
Hemorrhage, Blood Loss 
 
microscopic/occult 
 
mild, no 
transfusion 
 
gross blood loss; 
1-2 units transfused 
 
massive blood 
loss; > 3 units 
transfused 
Page 121 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
RESPIRATORY 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cough  
 
transient- no 
treatment 
 
persistent 
cough; 
treatment 
responsive 
 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
 
Bronchospasm, Acute 
 
transient; no 
treatment; 
70% - 80% FEV1  
of peak flow 
 
requires 
treatment; 
normalizes with 
bronchodilator; 
FEV1 50% - 
70% 
(of peak flow) 
 
no normalization 
with 
bronchodilator; 
FEV1 25% - 50% 
of peak flow; or  
retractions present 
 
cyanosis: FEV1 
< 25% 
of peak flow or 
intubation 
necessary 
Dyspnea 
 
dyspnea on 
exertion 
dyspnea with 
normal activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
Page 122 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
GASTROINTESTINAL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Nausea 
 
mild or transient; 
maintains 
reasonable intake 
 
moderate 
discomfort; 
intake 
decreased 
significantly; 
some activity 
limited 
 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
 
Vomiting 
 
1 episode in 24 
hours 
2-5 episodes in 
24 hours 
>6 episodes in 24 
hours or needing 
IV fluids 
 
 
 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral 
nutrition 
 
Constipation 
 
requiring stool 
softener or dietary 
modification 
requiring 
laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
 
obstruction or 
toxic megacolon 
 
Diarrhea 
 
mild or transient; 
3-4 loose 
stools/day or mild 
diarrhea last < 1 
week 
 
moderate or 
persistent; 5-7 
loose stools/day 
or diarrhea 
lasting >1 week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
 
 
hypotensive 
shock or 
physiologic 
consequences 
requiring 
hospitalization   
 
Oral Discomfort/Dysphagia 
 
mild discomfort; 
no difficulty 
swallowing 
 
some limits on 
eating/drinking 
 
eating/talking very 
limited; unable to 
swallow solid 
foods 
 
unable to drink 
fluids; requires 
IV fluids 
 
 
Page 123 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
NEUROLOGICAL 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Neuro-Cerebellar 
 
slight 
incoordination 
dysdiadochokinesis 
 
intention 
tremor, 
dysmetria, 
slurred speech; 
nystagmus 
 
locomotor ataxia 
 
incapacitated 
 
Psychiatric 
 
mild anxiety or 
depression 
 
moderate 
anxiety or 
depression; 
therapy 
required; 
change in 
normal routine 
 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
 
acute psychosis 
requiring 
hospitalization;  
or suicidal 
gesture/attempt 
or hallucinations 
 
Muscle Strength 
 
subjective 
weakness 
no objective 
symptoms/ signs 
 
mild objective  
signs/symptoms 
no decrease in 
function 
 
objective weakness 
function limited 
 
paralysis 
Paresthesia (burning, tingling, 
etc.) 
mild discomfort; 
no treatment  
required 
moderate 
discomfort; 
non-narcotic 
analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision 
and/or hearing 
moderate 
impairment 
(mod decreased 
sensation, e.g., 
vibratory, 
pinprick, 
hot/cold to 
ankles) and/or 
joint position or 
mild 
impairment that 
is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod degree 
in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs 
and trunk; 
paralysis;  or 
seizures 
Page 124 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
MUSCULOSKELATEL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Arthralgia 
(joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics 
and/or pain 
interfering with 
function but not 
with activities 
of daily living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain 
with 
inflammation, 
erythema or 
joint swelling – 
interfering with 
function, but 
not with 
activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of  
activity 
muscle 
tenderness (at 
other than 
injection site) 
or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 125 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
SKIN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, 
dry 
desquamation 
vesiculation or 
moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, 
mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected 
Stevens-Johnson 
or  necrosis 
requiring surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
Erythema 
< 15mm 
15-30 mm 
>30mm 
Edema 
< 15mm 
15-30 mm 
>30mm 
Rash at Injection Site 
< 15mm 
15-30 mm 
>30mm 
Pruritus 
slight itching at 
injection site 
moderate 
itching at 
injection 
extremity 
itching over entire 
body 
SYSTEMIC 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without 
rash 
localized 
urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, 
moderate; 
treatment 
required 
severe; responds to 
initial narcotic 
therapy 
intractable; 
requires repeated 
narcotic therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 
103 - 105 F 
> 40 C or 
> 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 
50% > 48 hours 
normal activity 
decreased > 50% 
can’t work 
unable to care for 
self 
Page 126 of 151


DX-2930
CONFIDENTIAL
Page 127
Clinical Trial Protocol: DX-2930-04
27 June 2016
Appendix 3
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (Modified) (US National Institutes of Health; National 
Institute of Allergy and Infectious Diseases
Page 127 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
1
 
 
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials.  This toxicity table is not comprehensive and should 
not be applied directly to all trials.   
  
When selecting a toxicity table, the following are some of the items that must be taken into consideration: 
  
• 
The population being studied  
o 
Does the clinical trial evaluate healthy subjects, subjects with a particular disease or 
condition?  
• 
The stage of test article development  
o 
Is the clinical trial a Phase I (is it for the fisrt time in human subjects?) , II, III or IV? 
• 
The type of test article  
o 
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent?  
• 
The prior human and preclinical experience with the test article 
o 
Are there any specific findings that require adjustment of the toxicity table?  
o 
Has it been approved for this indication in adult population? 
  
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal values at the 
single site. Multi-center clinical trials should reconcile among their laboratory normal values when 
evaluating a healthy volunteer population. 
  
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when selecting 
or developing a toxicity table for a DMID-sponsored trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 128 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
2
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to moderate limitation in activity - 
some assistance may be needed; no or minimal medical 
intervention/therapy required 
GRADE 3 
Severe  
 
Marked 
limitation 
in 
activity, 
some 
assistance usually required; medical intervention/therapy required, 
hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme limitation in activity, significant 
assistance required; significant 
medical 
intervention/therapy 
required, hospitalization or hospice care probable 
GRADE 5                              Death 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening include, 
but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria (CTC), and World Health Organization (WHO)) have been adapted for 
use by the Division of Microbiology and Infectious Diseases (DMID) and modified to 
better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
Page 129 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
3 
(Selected Values for children less than or equal  
to 3 months of age – does not apply for preterm infants)  
 
 
For all parameters not listed on this table, please refer 
 to the DMID Toxicity Table for children > 3 months of age. 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin 
1-7 days old 
13.0-14.0 gm/dL 
12.0-12.9 gm/dL 
<12 gm/dL 
Cardiac Failure  
secondary to Anemia 
8-21 days old 
12.0-13.0 gm/dL 
10.0-11.9 gm/dL 
<10.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
22-35 days old 
9.5-10.5 gm/dL 
8.0-9.4 gm/dL 
<8.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
36-60 days old 
8.5-9.4 gm/dL 
7.0-8.4 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
61-90 days old 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
Abs Neutrophil Ct 
1 day old 
5000-7000/mm3 
3000-4999/mm3 
1500-2999/mm3 
<1500/mm3 
2-6 days old 
1750-2500/mm3 
1250-1749/mm3 
750-1249/mm3 
<750/mm3 
7-60 days old 
1200-1800/mm3 
900-1199/mm3 
500-899/mm3 
<500/mm3 
61-90 days old 
750-1200/mm3 
400-749/mm3 
250-399/mm3 
<250/mm3 
Bilirubin (Fractionated bilirubin test must be preformed when total bilirubin is elevated) 
<7 days old 
. 
20-25mg/dL 
26-30 mg/dL 
>30 mg/dL 
7-60 days old 
1.1-1.9xN 
2.0-2.9Xn 
3.0-7.5xN 
>7.5xN 
61-90 days old 
1.1-1.9xN 
2.0-2.9xN 
3.0-7.5xN 
>7.5xN 
 
Page 130 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
4
(Selected Values for children less than or equal  
to 3 months of age)  
 
 
HEMATOLOGY (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Creatinine 
<7 days old 
1.0-1.7 mg/dL 
1.8-2.4 mg/dL 
2.5-3.0 mg/dL 
>3.0 mg/dL 
7-60 days old 
0.5-0.9 mg/dL 
1.0-1.4 mg/dL 
1.5-2.0 mg/dL 
>2.0 mg/dL 
61-90 days old 
0.6-0.8 mg/dL 
0.9-1.1 mg/dL 
1.2-1.5 mg/dL 
>1.5 mg/dL 
Cr Clearance 
<7 days old 
35-40 ml/min 
30-34 ml/min 
25-29 ml/min 
<25 ml/min 
7-60 days old 
45-50 ml/min 
40-44 ml/min 
35-39 ml/min 
<35 ml/min 
61-90 days old 
60-75 ml/min 
50-59 ml/min 
35-49 ml/min 
<35 ml/min 
Hypocalcemia 
<7 days old 
6.5–6.9 mEq/L 
6.0-6.4 mEq/L 
5.5-5.9 mEq/L 
<5.5 mEq/L 
7-60 days old 
7.6-8.0 mEq/L 
7.0-7.5 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
61-90 days old 
7.8-8.4 mEq/L 
7.0-7.7 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
Hypercalcemia 
<7 days old 
12.0-12.4 mEq/L 
12.5-12.9 mEq/L 
13.0-13.5 mEq/L 
>13.5 mEq/L 
7-60 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
61-90 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
 
 
 
Page 131 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
5
 
 (Greater than 3 months of age) 
 
LOCAL REACTIONS 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Induration 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Erythema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Edema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Rash at Injection Site 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Pruritus 
Slight itching at 
injection site 
Moderate itching at 
injection extremity 
Itching at injection 
extremity and other 
sites 
Itching over entire 
body 
 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin for 
children greater than 
months and less than 
2 years of age 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Hemoglobin for 
children greater that 2 
years of age 
10-10.9 gm/dL 
7.0-9.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Absolute Neutrophil 
Count 
750-1200/mm3  
400-749/mm3 
250-399/mm3 
<250/mm3 
Platelets 
------- 
50,000-75,000/mm3 
25,000-49,999/mm3 
<25,000/mm3 
Prothrombin Time 
(PT) 
1.1-1.2 x ULN 
1.3 -1.5 x ULN 
1.6 -3.0 x ULN 
>3.0 x ULN 
Partial 
Thromboplastin Time 
(PTT) 
1.1-1.6 x ULN 
1.7-2.3 x ULN 
2.4 -3.0 x ULN 
>3.0 x ULN 
Page 132 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
6
 (Greater than 3 months of age)  
 
GASTROINTESTINAL  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Bilirubin (when 
accompanied by any 
increase in other liver 
function test) 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x ULN 
 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
Bilirubin (when other 
liver function are in 
the  normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
AST (SGOT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
ALT (SGPT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
GGT 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
Pancreatic Amylase 
1.1-1.4 x ULN 
1.5-1.9 x ULN 
2.0-3.0 x ULN 
>3.0 x ULN 
Uric Acid 
7.5-9.9mg/dL 
10-12.4 mg/dL 
12.5-15.0 mg/dL 
>15.0 mg/dL 
CPK 
See Neuromuscular Toxicity 
Appetite 
----------------- 
Decreased appetite 
Appetite very 
decreased, no solid 
food taken 
No solid or liquid taken  
Abdominal Pain 
Mild 
Moderate-  
No Treatment Needed 
Moderate-  
Treatment Needed 
Severe-  
Hospitalized for treatment 
Diarrhea 
Slight change in 
consistency and/or 
frequency of stools 
Liquid stools 
Liquid stools greater 
that 4x the amount or 
number normal for 
this child 
Liquid stools greater than 8x 
the amount or number 
normal for this child  
 
Page 133 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
7
 (Greater than 3 months of age)  
 
GASTROINTESTINAL (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Constipation 
Slight change in the 
consistency/frequency 
of stool 
Hard, dry stools with 
a change in frequency 
Abdominal pain 
Distention and 
Vomiting 
Nausea 
Mild 
Moderate-  
Decreased oral intake 
Severe-Little  
oral intake 
Unable to ingest food  
or fluid for more than 
24 hours 
Vomiting 
1 episode/day 
2-3 episodes  
per day 
4-6 episodes per day  
Greater than 6 episodes 
per day or Intractable 
Vomiting 
Page 134 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
8
 (Greater than 3 months of age)  
 
ELECTROLYTES 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
CREATININE  
3 Months -2 Years of 
age  
0.6-0.8 x ULN 
0.9-1.1 x ULN 
1.2-1.5 x ULN 
>1.5 x ULN 
2 Years- 12 Years of 
age 
0.7-1.0 x ULN 
1.1-1.6 x ULN 
1.7-2.0 x ULN 
>2.0 x ULN 
Greater than  
12 Years of age 
1.0-1.7 x ULN 
1.8-2.4 x ULN 
2.5-3.5 x ULN 
>3.5 x ULN 
 
Page 135 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
9
 (Greater than 3 months of age)  
 
ELECTROLYTES  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hypernatremia 
 
<145-149 mEq/L 
150-155 mEq/L 
>155 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyponatremia 
 
130-135 mEq/L 
129-124 mEq/L 
<124 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyperkalemia 
5.0-5.9 mEq/L 
6.0-6.4 mEq/L 
6.5-7.0 mEq/L 
>7.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythamia 
Hypokalemia 
3.0-3-5 mEq/L 
2.5-2.9 mEq/L 
2.0-2.4 mEq/L 
<2.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythmia 
Hypercalcemia 
10.5-11.2mg/dL 
11.3-11.9 mg/dL 
12.0-12.9 mg/dL 
>13.0 mg/dL 
Hypocalcemia 
7.8-8.4 mg/dL 
7.0-7.7 mg/dL 
6.0-6.9 mg/dL 
<6.0 mg/dL 
Hypomagnesemia 
1.2-1.4 mEq/L 
0.9-1.1 mEq/L 
0.6-0.8 mEq/L 
<0.6 mEq/L or 
abnormal magnesium 
AND cardiac 
arrhythmia 
Hypoglycemia 
55-65 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose 
AND mental status 
changes 
Hyperglycemia 
116-159 mg/dL 
160-249 mg/dL 
250-400 mg/dL 
>400 mg/dL or 
ketoacidosis 
Proteinuria 
Tr-1+  
or 
 <150 mg/day 
2+  
or 
150-499 mg/day 
3+  
or  
500-1000 mg/day 
4+ 
 or 
 Nephrotic syndrome 
>1000 mg/day 
Hematuria 
Microscopic <25 
Microscopic >25 
 
Gross hematuria 
Page 136 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
10 
cells/hpf 
cells/hpf 
 
Page 137 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
11 
 (Greater than 3 months of age) 
 
CENTRAL NERVOUS SYSTEM (CNS) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Generalized CNS 
Symptoms 
 
 
Dizziness 
Hypotonic, 
hyporesponsive 
episodes;   
Seizures; 
Apnea/Bradycardia; 
Inconsolable crying > 
3 hrs; 
Headache  
Mild 
Moderate, Responds 
to non-narcotic 
analgesia 
Moderate to Severe,  
Responds to narcotic 
analgesia 
Intractable 
Level of Activity 
 
Slightly irritable OR 
slightly subdued 
Very irritable OR 
Lethargic 
Inconsolable OR 
Obtunded 
Visual 
 
Blurriness, diplopia, 
or horizontal 
nystagmus of < 1 
hour duration, with 
spontaneous 
resolution 
More than 1 episode 
of Grade 2 
symptoms per week, 
or an episode of 
Grade 2 symptoms 
lasting more than  
1 hour with 
spontaneous 
resolution by 4 
hours or vertical 
nystagmus 
Decrease in visual 
acuity, visual field 
deficit, or oculogyric 
crisis  
Myelopathy 
 
None 
None 
Myelopathic/spinal 
cord symptoms, such 
as: pyramidal tract 
weakness and 
disinhibition, sensory 
level, loss of 
proprioception, 
bladder/bowel 
dysfunction 
Page 138 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
12 
(Greater than 3 months of age) 
 
PERIPHERAL NERVOUS SYSTEM  
PARAMETER 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Neuropathy/  
Lower Motor 
Neuropathy 
 
Mild transient  
Paresthesia only 
Persistent or 
progressive 
paresthesias, burning 
sensation in feet, or 
mild dysesthesia; no 
weakness; mild to 
moderate deep 
tendon reflex 
changes; no sensory 
loss 
Onset of significant 
weakness, decrease or 
loss of DTRs, sensory 
loss in "stocking 
glove" distribution, 
radicular sensory loss, 
multiple cranial nerve 
involvement; bladder 
or bowel dysfunction, 
fasciculations, 
respiratory 
embarrassment from 
chest wall weakness. 
Myopathy or 
Neuromuscular 
Junction Impairment 
Normal or mild 
 (<2 x ULN) CPK 
elevation 
Mild proximal 
weakness and/or 
atrophy not affecting 
gross motor function. 
Mild myalgias, +/- 
mild CPK elevation 
(<2 x ULN)  
Proximal muscle 
weakness and/or 
atrophy affecting 
motor function +/- 
CPK elevation; or 
severe myalgias with 
CPK >2 x ULN;  
Onset of myasthenia-
like symptoms 
(fatigable weakness 
with external, variable 
ophthalmoplegia 
and/or ptosis), or 
neuromuscular 
junction blockade 
(acute paralysis) 
symptoms 
 
Page 139 of 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
13 
 (Greater than 3 months of age)  
 
OTHER  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Allergy 
Pruritus without Rash 
Pruritic Rash 
Mild Urticaria 
Severe Urticaria  
Anaphylaxis, 
Angioedema 
Drug Fever (Rectal) 
. 
38.5-40C 
101.3 – 104.0F 
Greater than 40.0C 
Greater than 104.0F 
Sustained Fever:  
Equal or greater than 
40C (104.0F) for 
longer than 5 days 
Cutaneous 
Localized rash 
Diffuse 
maculopapular 
Rash 
Generalized urticaria 
Stevens-Johnson 
Syndrome or Erythema 
multiforme 
Stomatitis 
Mild discomfort 
Painful, difficulty 
swallowing, but able 
to eat and drink  
Painful: unable to 
swallow solids 
Painful:  unable to 
swallow liquids; 
requires IV fluids 
Clinical symptoms 
not otherwise 
specified in this table 
No therapy; monitor 
condition 
May require minimal 
intervention and 
monitoring 
Requires medical care 
and possible 
hospitalization 
Requires active 
medical intervention, 
hospitalization, or 
hospice care 
Laboratory values not 
otherwise specified in 
this table 
Abnormal, but 
requiring no 
immediate 
intervention; follow 
Sufficiently abnormal 
to require evaluation 
as to causality and 
perhaps mild 
therapeutic 
intervention, but not 
of sufficient severity 
to warrant immediate 
changes in study drug 
Sufficiently severe to 
require evaluation 
and treatment, 
including at least 
temporary suspension 
of study drug 
Life-threatening 
severity; Requires 
immediate evaluation, 
treatment, and usually 
hospitalization; Study 
drug must be stopped 
immediately and 
should not be restarted 
until the abnormality is 
clearly felt to be 
caused by some other 
mechanism that study 
drug 
 
 
 
Page 140 of 151


DX-2930
CONFIDENTIAL
Page 141
Clinical Trial Protocol: DX-2930-04
27 June 2016
Appendix 4
HAE Attack Assessment and Reporting Procedures (HAARP)
Page 141 of 151


DX-2930 
 
 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
 
HAE Attack Assessment and Reporting Procedures 
(HAARP) 
Title: 
HAE Attack Assessment and Reporting Procedures (HAARP) 
Product Name: 
DX-2930 
Indication: 
Prevention of angioedema attacks in patients with HAE 
Sponsor: 
Dyax Corp.  
55 Network Drive 
Burlington, MA 01803 
Original Date: 
14 September 2015 
Version: 
v1.0 
 
Confidentiality Statement 
This document is the property of Dyax Corp. The information in this document contains trade secrets and 
commercial information that are privileged or confidential and may not be disclosed without the express written 
permission of Dyax unless required by federal or state law or regulations. Any person to whom the information 
is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential. 
 
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DX-2930 
 
 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
TABLE OF CONTENTS 
1 
PURPOSE ..........................................................................................................................3 
2 
DEFINITION OF AN ATTACK .......................................................................................3 
3 
REPORTING AND ASSESSMENT OF ATTACK DATA .............................................3 
3.1 
Subject-Reported Symptoms ...................................................................................4 
3.1.1 
Attack Information .........................................................................................4 
3.1.2 
Worsening Symptoms ....................................................................................5 
3.1.3 
Subject Training .............................................................................................5 
3.1.4 
Reporting Multiple Attacks............................................................................5 
3.1.5 
Caregiver Report ............................................................................................5 
3.1.6 
Subject Contact with Sites .............................................................................5 
3.2 
Site Contact with the Subject ...................................................................................5 
3.2.1 
Review of subject report of symptoms ..........................................................6 
3.2.2 
Documenting a Reported Attack ....................................................................6 
3.2.3 
Site Training...................................................................................................7 
3.3 
HAE attacks as Adverse Events ...............................................................................7 
4 
INVESTIGATOR ATTACK ASSESSMENT ..................................................................8 
 
 
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DX-2930 
 
 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
1 
PURPOSE 
This document applies to clinical trials that involve investigator adjudication/assessment of 
angioedema attacks. The purpose of this document is to provide a definition of an HAE 
attack and to define a standardized set of procedures for the reporting and assessment of 
events reported by subjects to determine whether those events are true HAE attacks. 
2 
DEFINITION OF AN ATTACK 
To be confirmed as an HAE attack, the event must have symptoms or signs consistent with 
an attack in at least one of the following locations:  
• Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region 
• Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea 
• Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx 
Despite the presence of these symptoms, the investigator may still determine clinically that 
the event did not represent an HAE attack if there are features that strongly refute such a 
diagnosis. For example, the reported event is accompanied by symptoms that are not 
consistent with an attack (e.g., urticaria), the reported event persists well beyond the typical 
time course of an attack (e.g., greater than 7 days), or there is a likely alternate etiology for 
the event (e.g., the subject’s abdominal symptoms are attributable to a viral gastroenteritis 
outbreak in the household). 
To be counted as a unique attack distinct from their previous attack, the new symptoms must 
occur at least 24 hours after resolution of the prior attack’s symptoms.  
Attack resolution is defined as the subject no longer having symptoms of the attack. 
Prodromal symptoms by themselves are not considered an attack. 
Patient report of use of acute HAE attack treatment for an attack by itself is not confirmation 
that an attack occurred. 
3 
REPORTING AND ASSESSMENT OF ATTACK DATA 
At screening for applicable clinical trials, subject HAE attack history will be collected by the 
site for entry into the clinical database. Information collected will include any prior history of 
laryngeal attacks, attack frequency, average severity, predominant location(s), average 
duration, acute attack therapy use, and history of long-term prophylaxis. 
During the relevant study periods, as defined in the applicable study protocol, subjects (or 
caregivers, for subjects < 18 years old) will be instructed to contact the site within 72 hours 
of the start of symptoms of an attack. In the situation that a subject is incapacitated and is 
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DX-2930 
 
 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
unable to contact the site, a family member or other individual with detailed knowledge of 
the event can provide the information. If desired by the subject, memory aids may be 
provided to assist in tracking any HAE attacks subject’s experience. Any tools or devices the 
subject uses to track this information are not intended to serve as source documents for the 
study.  
Site personnel will review the information provided by the subject or caregiver and solicit 
additional information as necessary to document the attack.  Information documented by the 
site will be considered source for the study.  
A designated individual at the site (the collector) will contact the subject or caregiver on a 
regular basis as defined in the study protocol, regardless of whether or not the subject has 
reported any attacks, in order to solicit for any attacks that may have occurred but were not 
reported. In addition, during each study visit, site personnel will solicit for any new attack 
information that was not provided through previous contact with the subject or caregiver. 
The Investigator or designee (the assessor) will review the attack information and evaluate if 
the event represents a confirmed HAE attack. If necessary for the evaluation, the investigator 
or designee may contact the subject to receive additional information.  
3.1 
Subject-Reported Symptoms 
Subjects and caregivers can use any existing methods by which they track information about 
their attacks, or, if requested, memory aids can be provided by the study site. However, 
subjects (or a caregiver) will need to track attacks in such a way as to be able to contact the 
study site as soon as possible, but not later than 72 hours (3 full days) after the first 
symptoms appear, to report the information. 
3.1.1 
Attack Information 
The following information should be provided by the subject (or caregiver) at the time they 
are reporting an attack to the site: 
• Date and time symptoms of an attack were first experienced 
• Description of symptoms experienced, including location(s) 
• Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits 
• Any medications used to treat the attack 
• If the attack resolved, date and time the subject was no longer experiencing symptoms  
Subjects do not have to wait for their symptoms to completely resolve to report an attack. 
Information about ongoing symptoms can be obtained by the site during the check-in call 
and/ or at a scheduled study visit. Subjects should not withhold or delay any treatment they 
would normally receive to treat their attack in order contact the site. 
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HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
3.1.2 
Worsening Symptoms 
The site may request the subject call them back if they experience worsening symptoms 
and/ or new symptoms for a reported attack. Otherwise, the new information will be captured 
during the next check-in call or scheduled study visit. Subjects may contact the site on their 
own to provide information about any worsening symptoms. 
3.1.3 
Subject Training 
During screening, site personnel will train subjects on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide.  The 
patient will confirm their understanding of what is required of them for reporting attacks to 
the site.  Sites will assess the subject’s compliance with the reporting requirements 
throughout the study and may retrain the subject if necessary in order to maintain the 
integrity of the data provided to the site. 
3.1.4 
Reporting Multiple Attacks 
If a subject experiences symptoms they attribute to more than one unique attack they can 
report this as multiple attacks to the site.  Based on the definition of an attack as stated in 
Section 2, it will be the determination of the investigator or designee as to whether events 
reported as being separate are confirmed as separate attacks or not. 
3.1.5 
Caregiver Report 
During screening, site personnel will train subject caregivers (if applicable) on identifying 
symptoms of an attack, the requirements for reporting attacks and the information they will 
be expected to provide.  The caregiver will confirm their understanding of what is required of 
them for reporting attacks to the site. Sites will assess the caregiver’s compliance with the 
reporting requirements throughout the study and may retrain the caregiver if necessary in 
order to maintain the integrity of the data provided to the site. 
3.1.6 
Subject Contact with Sites 
Site personnel will establish a recommended method and time window for each subject to 
contact the site to report any symptoms of an attack. Sites will establish a primary contact 
person and, if possible, a back-up person, with contact information. Back-up plans, including 
call backs and/ or use of back-up contacts, should be established in case the subject is unable 
to reach someone at the site.  
3.2 
Site Contact with the Subject 
Sites will establish a recommended day and time window for check-in calls between study 
visits. The date and time for check-ins can be modified based on when the last contact with 
the subject was made, as outlined in the study protocol. When the site is contacted by a 
subject reporting symptoms of an attack the site should make sure they have the ability to 
record the information provided in a complete and accurate way. Back-up plans should be 
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HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
established in case the subject misses a call from the site. A study schedule for each subject’s 
on-site visits will be provided to the subject by the site. 
3.2.1 
Review of subject report of symptoms 
During contact with the subject, whether subject-initiated or a regular check-in, site 
personnel should ask the subject to provide them information about new or ongoing HAE 
attacks experienced. 
The site will try to obtain all information necessary to document the attack completely. 
Missing information may impact the assessment of any attack and should be avoided 
whenever possible. 
3.2.2 
Documenting a Reported Attack 
Complete and accurate documentation of each reported attack is important to making an 
Investigator assessment of the attack. The site should document the following information 
about each attack reported by the subject or caregiver:  
•
Date and time of contact with the subject
•
Date and time the subject first experienced symptoms
•
Description of symptoms experienced, including location(s)
•
Impact on activity and whether any assistance was required
•
If the attack has resolved or is ongoing.  If the attack has resolved, the date and time the
subject was no longer experiencing any symptoms of the attack
•
Names of any medications used to treat the attack including HAE acute therapy or other
non-HAE treatments
•
If hospitalization occurred
•
If a trip to the emergency department occurred
Additional probing questions about what the subject experienced to determine: 
•
If the subject only experienced prodromal symptoms
•
If  the subject experienced anything different than their typical attack
•
If there were any possible alternative etiologies of the symptoms. For example, a viral
gastroenteritis outbreak in the household could explain abdominal symptoms
The overall severity of the subject’s attack will be determined by the site using the following 
definitions: 
- 
Mild: Transient or mild discomfort  
- 
Moderate: Mild to moderate limitation in activity - some assistance needed 
- 
Severe: Marked limitation in activity, assistance required 
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DX-2930 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
The site will also document the date and time of investigator or designee review, the official 
designation of the event as an attack or not, and if applicable, the reason why an event is not 
considered an attack.  
All reported attacks will be entered by site personnel into the electronic case report form 
(eCRF). 
3.2.3 
Site Training 
Site personnel responsible for collecting attack information about subject HAE attacks will 
need to pass a “Collector” training assessment covering the following: 
•
definition of an HAE attack
•
requirements of subjects and caretakers for reporting attacks
•
reporting worsening symptoms and multiple attacks
•
information to be collected from subjects and caregivers as well as the additional probing
questions to gather context for the attack information provided
•
assessment of attack severity
•
entry of the attack data into the eCRF
•
reporting HAE attacks as adverse events
•
requirements for Investigator assessment of attacks
Trainings will be conducted prior to sites screening subjects.  Trainings will be documented 
in the Trial Master File. Investigators and designees will be trained on these procedures as 
well and must pass an “Assessor” training in order to officially assess attacks for this study. 
All responsible persons involved in the collection of information from subjects or assessing 
attacks must be listed on FDA Form 1572. 
3.3 
HAE attacks as Adverse Events 
At the time of each contact and scheduled study visit, site personnel will ask if the subject 
experienced any adverse events or changes to the medications they are taking. 
HAE attacks will be captured as AEs.  All AEs, regardless of seriousness, severity, or causal 
relationship to study drug, will be recorded on the AE page of the eCRF. 
Any AE reported to the site meeting criteria for a serious adverse event must be reported to 
Dyax using the SAE Reporting Form in the EDC system within 24 hours of becoming aware 
of the event.  For all serious adverse events that are reported as HAE attacks, the Principal 
Investigator or physician designee will review the event within 24 hours of initial notification 
and, in accordance with HAARP, evaluate if it represented a confirmed HAE attack. 
For all non-serious AEs that are reported as HAE attacks, the Principal Investigator or 
physician designee will review the event within 3 days of initial notification and, in 
accordance with HAARP, evaluate if it represented a confirmed HAE attack. If necessary for 
the evaluation, the Investigator or designee may contact the subject for additional 
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HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
information. Any subject-reported attack not confirmed by the Investigator must have an 
alternate AE diagnosis recorded.  All subject-reported and Investigator-confirmed HAE 
attacks will be recorded in the eCRF. 
4 
INVESTIGATOR ATTACK ASSESSMENT 
The Principal Investigator for a study site may identify a physician designee to assess patient 
symptom information and make attack determinations. Sites should be limited to two 
individuals responsible for assessing attacks, one of them being the Principal Investigator. 
Assessors must be experienced with HAE and familiar with the study subject’s disease 
history.  
The assessor must review the information and determine whether the event is an actual attack 
or not. If needed, the assessor can contact the subject and/or caregiver to clarify information 
or ask for any additional detail. The determination will be documented along with the date 
and time the determination was made. Any event deemed not an attack must be accompanied 
by an explanation and alternative diagnosis by the assessor.  
When reviewing subject information, the assessor will follow the definitions of an attack as 
outlined in these procedures and, taking all available information about the event into 
consideration, will determine if it is a confirmed attack. The assessment of the attack is the 
Investigator or designee’s own, and not the opinion of the subject, the subject’s caregiver or 
any other site personnel. Assessors may consult with one another about a particular subject’s 
attack but only one assessor makes the documented determination. It is possible for both the 
Principal Investigator and physician designee to assess different attacks for the same subject. 
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DX-2930
CONFIDENTIAL
Page 150
Clinical Trial Protocol: DX-2930-04
27 June 2016
Appendix 5
Summary of Pivotal Study of DX-2930 in HAE Subjects
The proposed pivotal clinical study (DX-2930-03) is entitled “HELP StudyTM: A Multicenter, 
Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate DX-2930 
For Long-Term Prophylaxis Against Acute Attacks of Hereditary Angioedema (HAE).” This 
study will be a multi-center, double-blind, randomized, placebo-controlled parallel-arm study 
evaluating the efficacy of DX-2930 in preventing acute angioedema attacks in patients with Type 
I or Type II HAE. The double-blind study is planned to be followed by the study described in the 
present protocol, an open-label extension (OLE) study (DX-2930-04).
The primary objective of study DX-2930-03 is to evaluate the efficacy of DX-2930 in preventing 
HAE attacks. The secondary objective is to evaluate the safety of repeated SC administrations of 
DX-2930. The tertiary objectives are to evaluate the pharmacodynamic effects of chronically 
administered DX-2930; to assess the immunogenicity of chronically administered DX-2930; to 
evaluate the pharmacokinetics of chronically administered DX-2930; and to evaluate the effect 
of DX-2930 upon quality of life assessments.
Subjects aged 12 years and over with a documented diagnosis of Type I or Type II HAE who 
experience at least 1 attack per 4 weeks will be eligible for the study. Up to 120 subjects are 
planned for enrollment across approximately 60 sites in the United States, Canada, Italy, 
Germany, United Kingdom and Jordan.
Following informed consent, subjects will undergo screening assessments.  Subjects who are on 
long-term prophylactic therapy for HAE are required to undergo a minimum 2 week washout 
period prior to the start of the run-in period.  Subjects who are either not on long-term 
prophylactic therapy for HAE, or have completed the required washout period will enter a run-in 
period of 4 weeks to determine the baseline HAE attack rate. The run-in period may be extended 
to 8 weeks if the minimum baseline attack rate is not achieved in the first 4 weeks. HAE subjects 
will then be randomized 2:1 to receive repeated subcutaneous (SC) administrations of DX-2930 
or placebo in a double-blind fashion.  Subjects who are randomized to DX-2930 will be assigned 
in a 1:1:1 ratio to one of three dose regimens: 300 mg every 2 weeks, 300 mg every 4 weeks or 
150 mg every 4 weeks.  Each subject will undergo a treatment period consisting of 13 doses of 
blinded study drug, for a period of 26 weeks from the date of first dose on Day 0 through Day 
182
Subjects may consent to rollover into the OLE study (present protocol DX-2930-04) upon 
completion of their participation in the double-blind treatment period.
The primary endpoint will be to compare the mean rate of investigator-confirmed HAE attacks 
observed in each DX-2930 treatment arm to that in the placebo arm during the efficacy 
assessment period (Day 14 through Day 182).
Figure 2 shows a schematic of the double-blind, pivotal study.
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DX-2930
CONFIDENTIAL
Page 151
Clinical Trial Protocol: DX-2930-04
27 June 2016
Figure 2: Overview of the Design of Pivotal Study DX-2930-03
Dose Rationale for Double-Blind, Pivotal Study DX-2930-03
The dose rationale is based on the pharmacodynamic bioactivity, PK, safety, and efficacy of DX-
2930 from the Phase 1 clinical studies and nonclinical studies. Together, these attributes provide 
the rationale for the selected doses and regimens to achieve drug levels likely to prevent a 
majority of HAE attacks. Based on these considerations, 300 mg every 2 weeks, 300 mg every 4 
weeks, and 150 mg every 4 weeks were identified as the dosing regimens for evaluation,
The 3 proposed dose-regimen combinations provide a 6-fold range of steady-state trough 
concentrations and leverage both the biomarker and efficacy data generated in study DX-2930-
02. Evaluation of the DX-2930 plasma concentrations at the time of attacks reported by DX-
2930 treated subjects in DX-2930-02 suggests that the 3 planned dosing regimens will provide a 
meaningful range of clinical response while avoiding non-therapeutic or super-therapeutic doses 
and regimens
Page 151 of 151


Clinical Trial Protocol: DX-2930-04
Study Title:
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-
Term Safety and Efficacy of DX-2930 for Prevention Against Acute 
Attacks of Hereditary Angioedema (HAE)
Study Number:
DX-2930-04
Study Phase:
Phase 3 
Product Name:
DX-2930
IND Number:
116647
EudraCT Number:
2015-005255-27
Indication:
Prevention of angioedema attacks in patients with HAE
Investigators:
Multicenter
Sponsor:
Dyax Corp., an indirect, wholly-owned subsidiary of Shire plc.
55 Network Drive, Burlington, MA 01803 USA
Sponsor Contact:
, MD
, Clinical Development
300 Shire Way, Lexington, MA 02421 USA
Phone: 
Global Medical 
Monitor:
, MD
300 Shire Way, Lexington, MA 02421 USA
Phone: 
Date:
Original Protocol
14 December 2015 
Amendment 1.0
27 June 2016
Amendment 2.0
20 January 2017
Confidentiality Statement
This document is the property of Dyax Corp. The information in this document contains trade secrets and 
commercial information that are privileged or confidential and may not be disclosed without the express written 
permission of Dyax unless required by federal or state law or regulations. Any person to whom the information 
is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential.


Page2 
PROTOCOL SIGNATURE PAGE 
Study Title: 
HELP Study Extension™: An Open-Label Study to Evaluate 
the Long-Term Safety and Efficacy ofDX-2930 for Prevention 
Against Acute Attacks of Hereditary Angioedema (HAE) 
Study Number: 
DX-2930-04 
Amendment 2.0 Final Date: 
20 January 2017 
This clinical study protocol was subject to critical review and has been approved by the Sponsor. 
The signature of the Sponsor representative indicates that the Sponsor will comply with all 
Sponsor obligations detailed in applicable regulations and guidelines and will ensure the 
investigator is informed of all relevant information that becomes available. 
MD 
 
, Clinical Development 
300 Shire Way, Lexington, MA 02421 USA 
Date: 
I have read the foregoing protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study in compliance with the Declaration of Helsinki, Good 
Clinical Practice (GCP), and all applicable regulatory requirements and guidelines as outlined 
herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure they 
are fully informed regarding the drug and the conduct of the study. 
I will use only the informed consent form approved by Dyax Corp. and my Institutional Review 
Board (IRB), Research Ethics Board (REB) or Ethics Committee (EC) and will fulfill all 
responsibilities for submitting pertinent information to the IRB/REB/EC responsible for this 
study. 
I further agree that Dyax Corp. or their designees shall have access to any source documents 
from which eCRF information may have been generated. 
By signing this protocol, I agree to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of GCP to which it conforms. 
Signed: _______________ _ 
Date:. ________ _ 
Investigator 
Address: 
Shire
CONFIDENTIAL
Page 2
Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017


Shire 
CONFIDENTIAL 
Page 3 
Clinical Trial Protocol Amendment 2 
DX-2930-04 
 
20 Jan 2017 
 
AMENDMENT SUMMARY AND RATIONALE 
Amendment 2 to Protocol DX-2930-04 includes the following revisions: 
• Updated administrative structure and contact information 
• Clarification that female rollover subjects of childbearing potential may continue to use 
the effective birth control method used during Study DX-2930-03 
• Editorial changes throughout the protocol to remove inconsistencies in the protocol text 
and ensure all agreed changes from Amendment 1 and administrative letters are 
accurately presented across all sections. 
 
Noteworthy changes to the protocol related to the topics above are captured in the table 
below. Additional minor revisions in grammar, spelling, punctuation, and format have been 
made for clarity and are not reflected in the summary of changes. 
 
Summary of Changes from Previous Version 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 
2 
Amendment Date 
20 Jan 2017 
Global/Country/Site 
Specific 
Global 
Description and Rationale for Change 
Section(s) Affected by 
Change 
Updated administrative information to reflect current contact information, 
including contact information for the 24-Hour Global Medical Monitor and 
Back-Up Global Medical Monitor and Sponsor Contact. 
Title Page, Section 
6.16.5.5, Section 10 
Included clarifying note that female rollover subjects (those who previously 
participated in Study DX-2930-03) of childbearing potential may continue to use 
the effective birth control method used during Study DX-2930-03.  
Synopsis, 
Section 4.2 
Introduced the international nonproprietary name “lanadelumab.” 
Synopsis, Section 5.1 
Clarified that sites will call subjects within approximately 3 days of planned off-
site self-administrations. 
Synopsis, Section 4.1, 
Section 5.1, Section 5.6 
Clarified that adolescent subjects should complete the WPAI-GH questionnaire 
and use the term “school” instead of “work” when filling out this questionnaire.  
These data will be analyzed separately. 
Section 6.14.3 
Refined language on interim analyses options to allow for interim analyses to be 
performed as appropriate for regulatory reporting and/or internal administrative 
decisions. 
Synopsis, Section 9.9.1 
The following editorial changes were made to remove inconsistencies in the text and to ensure all agreed 
changes from Amendment 1 and administrative letters are accurately presented across all sections 
Removed the duplicate Study Activities Schedule from Appendix 1 and changed 
in-text references/linking to the Study Activities Schedule from Appendix 1, to 
ensure a single location for the Study Activities Schedule. 
Entire protocol, Appendix 
1 
Corrected the numbers in Figure 1 to correctly present the length of treatment 
period. 
Figure 1 
Corrected text regarding the treatment period duration: the treatment period is 
364 days, with the last dose of study drug administered on Day 350. 
Synopsis, entire protocol 


Shire
CONFIDENTIAL
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Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
20 Jan 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Added text from Section 3.1.1. to the synopsis for clarity; specifically, that the 3rd
dose must be administered at the next pre-defined study visit according to the 
Study Activities Schedule.
Synopsis
Clarified that subjects in Study DX-2930-03 can be consented for enrollment in 
Study DX-2930-04 on or after Day 168 of Study DX-2930-03.
Synopsis, Table 1
(footnote “5”), Section 
3.1.1, Section 6.1,Section 
7.2
Revised text in Section 3.1.1 to match correct text in Synopsis, including text 
regarding standard of care treatment for subjects who experience an acute attack 
of HAE during the study.
Synopsis, Section 3.1.1
Updated wording regarding the enrollment number for non-rollover subjects from 
“up to a maximum of 100” to “approximately 100” in total.
Synopsis, Section 3.1.1, 
Section 4.1
Corrected text regarding the follow-up period: the follow-up period is 4 weeks 
from the last visit of the protocol-defined treatment period. Removed inconsistent 
text that erroneously mentioned an 8-week follow up period.
Synopsis, 
Section 3.1.1, Section 3.4, 
and Section 5.2
Removed text indicating that the Sponsor would provide ancillary supplies to 
sites since the sites are responsible for sourcing them.
Section 5.7
Clarified text to align with Study Activities Schedule; specifically, subject 
surveys on their experience with SC and self-administration injections of DX-
2930 are to be completed by the subject during the study.
Synopsis,
Section 6.15.2
Clarified text to align with Study Activities Schedule; specifically, that vital signs 
will be monitored both prior to dosing and at 1 hour post-dosing when dosing 
occurs at the investigational site, with a ±15 minutes window for all vital signs. 
Vital signs are not monitored when subjects elect to self-administer study drug 
away from the site.
Section 6.5, Section 7
itemization per visit
Clarified text to align with Study Activities Schedule; specifically, that weight is
collected during each physical exam.
Table 1, Section 6.6, 
Section 7
Clarified text to align with Study Activities Schedule; specifically, that height is 
only collected at the Screening visit.
Table 1, Section 6.6, 
Section 7.1
Clarified text to align with Study Activities Schedule; specifically, that
pregnancy tests performed on Day 0 must be urine-based to confirm eligibility 
prior to dosing while subsequent pregnancy tests can be urine or serum-based.
Section 6.8.1.5
Removed outdated contact information from safety reporting text.
Section 6.16.5.5
Removed remnant text regarding the requirement to complete a 2-week wash-out 
period before entering the treatment period for non-rollover subjects on LTP for 
HAE. Washout period does not exist for non-rollover subjects.
Section 7.1
Removed remnant text regarding the requirement for urinalysis for Visits 14, 17, 
20, and 23. Urinalysis is not required at these visits.
Section 7.16, Section
7.19, Section 7.22, and 
Section 7.25
Removed text indicating a subject could self-administer study drug at their home 
or other agreed upon location and that no monitoring of vital signs will be 
performed for Visit 17 since this is a mandated investigational site visit.
Section 7.19


Shire
CONFIDENTIAL
Page 5
Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
20 Jan 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Removed safety analysis category called “pretreatment group” since a 
pretreatment period does not exist in this study.
Section 9.7.1
See Appendix 1 for protocol history, including amendments.


Shire
CONFIDENTIAL
Page 6
Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017
SYNOPSIS
Sponsor:
Dyax Corp., an indirect, wholly-owned subsidiary of Shire plc.
55 Network Drive, Burlington, MA 01803 USA
Name of Finished Product:
DX-2930 Drug Product (DP)
Name of Active Ingredient:
DX-2930 (lanadelumab) is a recombinant, Chinese hamster ovary (CHO) cell-expressed, fully 
human immunoglobulin G subclass 1 (IgG1), kappa light chain, monoclonal antibody.
Names of Inactive Ingredients:
Sodium phosphate dibasic dihydrate, citric acid monohydrate, L-histidine, sodium chloride, and 
Polysorbate 80
Study Title:
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-Term Safety and Efficacy 
of DX-2930 for Prevention Against Acute Attacks of Hereditary Angioedema (HAE)
Study Number:
DX-2930-04
Study Phase: Phase 3
Study Location:
Approximately 60 study sites planned across North America, the European Union, and the 
Middle East
Primary Objective:
To evaluate the long-term safety of repeated subcutaneous (SC) administrations of DX-2930
Secondary Objectives:
•
To evaluate the long-term efficacy of DX-2930 in preventing HAE attacks
•
To characterize the outer bounds of dosing frequency for DX-2930
Tertiary Objectives:
•
To assess the immunogenicity of chronically administered DX-2930
•
To evaluate the effect of DX-2930 on health-related quality of life (QoL)
•
To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SC 
administration of DX-2930 
•
To evaluate safety and efficacy in the non-rollover population of switching from long-term 
prophylactic (LTP) treatment to DX-2930 
•
To evaluate breakthrough attack characteristics while receiving DX-2930 compared to 
historical baseline
•
To evaluate subject experience with self-administration of DX-2930 including ease of SC 
administration of DX-2930


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Study Design:
Study DX-2930-04 is an open-label, long term safety and efficacy extension study of Study DX-
2930-03, to evaluate the investigational medicinal product (IMP), DX-2930, in preventing acute 
angioedema attacks in patients with Type I and Type II HAE. There are two types of subjects 
who will be enrolled into this study:
•
Subjects who rollover from Study DX-2930-03 
•
Subjects who are non-rollover (ie, were not participants in Study DX-2930-03) 
Rollover Subjects
Rollover subjects are subjects who complete the double-blind treatment period at Day 182 of 
Study DX-2930-03 and consent to enter Study DX-2930-04.  Subjects who discontinue from 
Study DX-2930-03 after enrollment are not eligible to enroll in Study DX-2930-04.  
Subjects should be asked about their interest in Study DX-2930-04 study after enrollment into 
Study DX-2930-03 to anticipate enrollment and preparedness for Study DX-2930-04. Willing 
subjects must sign informed consent for Study DX-2930-04 on or after Day 168 of Study DX-
2930-03.  
Subjects who are eligible to roll over into Study DX-2930-04 but elect not to, may not enroll in 
Study DX-2930-04 at a later time. The first Study DX-2930-04 visit for rollover subjects (Day 0) 
will occur on the same day as the Study DX-2930-03 Day 182 study visit. Rollover subjects will 
complete all Study DX-2930-03 final study assessments (Day 182) at which time they will be 
discharged from that study. No assessments conducted between the Study DX-2930-03 Day 182 
study visit and the first Study DX-2930-04 visit (Day 0) will be duplicated. Results of the final 
Study DX-2930-03 assessments on Day 182 will be used as the pre-dose results for Day 0 of 
Study DX-2930-04.
All subjects, caregivers, investigators and study site personnel will remain blinded to the Study
DX-2930-03 treatment assignment until the conclusion of Study DX-2930-04.
Non-rollover subjects
At least 50 subjects (to approximately 100) who were not participants in Study DX-2930-03 will 
be permitted to enroll if they meet the eligibility requirements. Subjects who screen fail out of 
Study DX-2930-03 for not meeting the minimum attack requirements during the run-in period 
must wait until enrollment for the double-blind study has ended before they can screen for Study
DX-2930-04. The Sponsor may ease this restriction based on the enrollment rate observed in 
Study DX-2930-03. Subjects who are still in the run-in period for Study DX-2930-03 when 
enrollment for that study closes, as well as subjects on prior LTP who screen fail out of Study
DX-2930-03 due to an inability to wash-out of their LTP, may screen for Study DX-2930-04 
following discussion with the Sponsor medical monitor.


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Screening Period:
Rollover Subjects
There is no screening period for rollover subjects.
Non-rollover Subjects
Non-rollover subjects must provide informed consent and have screening assessments completed 
within 4 weeks prior to their first open-label dose. Screened non-rollover subjects (adults and 
adolescents) who are on LTP with C1-INH therapy for HAE can continue their current LTP until 
Day 8 (or Day 15) such that subjects will have received 2 (or 4) doses of C1-INH. For subjects 
who are on attenuated androgens (eg, danazol) or anti-fibrinolytics (eg, tranexamic acid), a 
similar tapering schedule is recommended. However, the taper can be prolonged by an additional 
week, if medically indicated, as long as androgen or anti-fibrinolytic therapy is stopped within 3 
weeks after receiving the first dose of DX-2930.  
Treatment Period:
Rollover Subjects
Following informed consent and pre-dose assessments, rollover subjects will receive a single 
open-label dose of 300 mg DX-2930 administered subcutaneously (SC) on Day 0.  Subjects will 
not receive any additional DX-2930 doses until their first reported, and investigator-confirmed, 
HAE attack.  As such, the total number of doses within the treatment period will vary by rollover 
subject.
The duration of time between the first open-label dose and first reported HAE attack will vary by 
rollover subject.  All rollover subjects must adhere to the Study Activities Schedule for the entire 
duration of the study.  However, until a rollover subject reports their first HAE attack, only 
scheduled study visits where the following tests and assessments are performed must be 
conducted at the investigative site: pregnancy testing, clinical laboratory testing, physical 
examination, 12-Lead ECG, QoL, PK, PD and anti-drug antibody sample collection. All other 
scheduled study visits may be conducted via site check-in calls to collect information on adverse 
events, concomitant therapy, and HAE attack data.  See Study Activities Schedule for which 
visits must be conducted at the study site.
Once a rollover subject reports their first HAE attack they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  If 
the second dose is to be administered within the accepted ±4 day window around a scheduled 
study visit, this treatment visit will represent that scheduled visit. If that scheduled visit has 
already occurred, the day of the visit will be considered an acceptable, extra study visit (ie, an 
unscheduled visit).  Similarly, if the second dose is administered outside of the accepted ±4 day 
window around a scheduled visit, the day of the visit will be considered an acceptable extra 
unscheduled study visit, (ie, this visit will not replace any scheduled visit).
Regardless of the study day, at the visit in which the second open-label dose of DX-2930 is 
administered, the subject will undergo pre-dose assessments for vital signs, physical 
examination, clinical laboratory testing, blood sampling for PK, PD, and anti-drug antibody. 
Vital signs will be obtained at 1 hour post-dosing. As with all study visits, information will be 
collected on adverse events, concomitant therapy, and HAE attack data. 


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Regardless of when a rollover subject’s first HAE attack occurs, there will be a minimum of 10 
days between their first open-label dose and their second open-label dose. Following their second 
open-label dose, rollover subjects will continue to receive repeated SC administrations of open-
label 300 mg DX-2930 every 2 weeks for the remaining duration of the treatment period per the 
scheduled dosing in the Study Activities Schedule. The treatment period will last 364 days from 
the date of the first open-label dose. The number of doses administered during this period will 
vary by subject based on the date of each subject’s second dose, but will not exceed 26 doses. 
The Day 350 study visit is the last visit at which a dose may be administered. 
Non-rollover Subjects
Once all screening assessments have been completed and eligibility confirmed, non-rollover 
subjects will arrive at the study site and, following pre-dose assessments, receive an open-label 
dose of 300 mg DX-2930 administered SC on Day 0. Non-rollover subjects will continue to 
receive SC administrations of open-label 300 mg DX-2930 every 2 weeks throughout the 
duration of the treatment period per the scheduled dosing in the Study Activities Schedule. A 
total of 26 doses will be administered with the last dose administered at the Day 350 study visit.
All Subjects:
All doses (with the exception of the second dose for rollover subjects) require a minimum of 10 
days and maximum of 18 days between administrations, and should fall within the accepted ±4 
day window around study visits.
After the second DX-2930 dose is given either within the study window (±4 days) or an 
acceptable extra study visit, the 3rd dose must be administered at the next pre-defined study visit 
according to the schedule of assessments.
If a subject experiences an acute angioedema attack at any time during the study that in the 
opinion of the investigator requires medical intervention, standard of care therapy should be 
provided based on subject’s medical history and per locally approved product information. 
Administration of DX-2930 and study procedures will continue without alteration to the protocol 
study activities schedule, even if a subject receives treatment for a breakthrough angioedema 
attack on the day of a scheduled dose of study drug (if self-administering) or scheduled study 
visit.
Self Administration
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a 
physical and mental capability of learning and willing to be trained) may be allowed to self-
administer treatment. Subjects must complete appropriate training by the investigator or designee 
and understanding of the training must be confirmed by the investigator or designee. Subjects are 
allowed to initiate self-administration at the subject’s home or other agreed upon location after 
receiving the first 2 doses of DX-2930 at the study site. Once initiated, subjects may self-
administer subsequent doses of DX-2930 at the investigational site (when visits are scheduled 
study site visits) or the subject’s home or other agreed upon location (when the study permits off-
site dosing). See Schedule of Activities for details. Adolescent subjects self-administering 
investigational product will be supervised by a parent/legal guardian/caregiver. Alternatively, a 


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parent/legal guardian/caregiver, after completing appropriate training, will be allowed to 
administer DX-2930 to an adolescent without study site personnel supervision. Site personnel 
will call subjects within approximately 3 days of the planned off-site self-administrations to 
ensure the administration occurred, to collect AEs, concomitant medications, and to ensure all 
attacks have been appropriately documented.
Throughout the study, study site personnel will document information in source documents (ie, 
the subject’s medical record) and eCRF regarding the subject’s experience with self-
administration and SC administration of DX-2930.
Follow-up Period
After completion of the treatment period, all subjects will undergo safety evaluations during a 4-
week follow-up period.
Modifications to Open-Label Dosing
If, at any time, an important dose-related safety signal is identified either from this study or 
Study DX-2930-03, the Sponsor may decide to switch the enrolled subjects who have not yet 
completed the treatment period, and any subsequent subjects, to receive a different open-label 
DX-2930 dose and/or frequency.
In addition, based on the results of Study DX-2930-03, the Sponsor may switch to a different 
dose and/or frequency. 
Study Population:
The study is expected to enroll subjects from Study DX-2930-03, as well as at least 50 (to 
approximately 100) additional subjects who were not enrolled in Study DX-2930-03. The total 
enrollment is expected to be at least 150 but not more than 250 HAE Type I or II subjects. 
Subjects will be 12 years of age or older who experience at least 1 attack per 12 weeks. HAE 
diagnosis will be confirmed through documented clinical history and diagnostic testing 
conducted either during screening or during prior participation in Study DX-2930-02 or Study
DX-2930-03.  The study will aim to enroll at least 15 subjects who are 12 to 17 years of age, 
inclusive of the estimated 10 subjects 12 to 17 years old who are expected to roll over from 
Study DX-2930-03.
Criteria for Inclusion:
Subjects must meet the following criteria to be enrolled in this study:
1. Male and female HAE subjects who are 12 years of age or older at the time of screening. 
2. Documented diagnosis of HAE (Type I or II)  based on all of the following:

Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria).

Diagnostic testing results obtained during screening (or a prior DX-2930 study) that 
confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level < 40% of the 
normal level. Subjects with functional C1-INH level 40-50% of the normal level may 
be enrolled if they also have a C4 level below the normal range.  Subjects may be 
retested if results are incongruent with clinical history or believed by the investigator 
to be confounded by recent LTP use. 


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
At least one of the following: Age at reported onset of first angioedema symptoms ≤ 
30 years, a family history consistent with HAE Type I or II, or C1q within normal 
range.
3. A historical baseline HAE attack rate of at least 1 attack per 12 weeks.
4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, 
understand, and sign an informed consent form. Subjects age 12 to 17, whose caregiver has 
provided informed consent, are willing and able to read, understand and sign an assent form.
5. Males and females who are fertile and sexually active must adhere to contraception 
requirements for the duration of the study as follows:

Females* of childbearing potential must agree to be abstinent or it is recommended to use 
highly effective forms of contraception from screening through 30 days after the final 
study visit. This includes stable doses (for 3 months prior to study screening) of 
combined estrogen and progestin-containing hormonal contraception associated with 
inhibition of ovulation (oral, injectable or implantable), progestin-only hormonal 
contraception associated with inhibition of ovulation, intra-uterine device (IUD, all types) 
or intrauterine hormone releasing systems (IUS). Notes: 1) A female whose male partner 
has had a vasectomy must agree to use one additional form of medically acceptable 
contraception. 2) Use of a male condom with or without spermicide or cervical cap, 
diaphragm or sponge with spermicide or a combination (double barrier methods) are not 
considered highly effective.

Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study.

Males, including males who are surgically sterile (post vasectomy), with female partners 
of childbearing potential must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through 60 days after the final study 
visit.
*NOTE:  Female rollover subjects (those who previously participated in Study DX-2930-
03) of childbearing potential may continue to use the effective birth control method used 
during Study DX2930-03.
Criteria for Exclusion:
Subjects who meet any of the following criteria will be excluded from the study:
1. Discontinued from Study DX-2930-03 after enrollment for any reason.
2. If rolling over from Study DX-2930-03, presence of important safety concerns that would 
preclude participation in this study.
3. Concomitant diagnosis of another form of chronic, recurrent angioedema such as acquired 
angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), idiopathic 
angioedema, or recurrent angioedema associated with urticaria. 
4. Dosing with an investigational drug (not including DX-2930 or other HAE therapies) or 
exposure to an investigational device within 4 weeks prior to screening.
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to study 
screening or any newly initiated or dose modification of estrogen-containing medications 
with systemic absorption (such as oral contraceptives or hormonal replacement therapy) 3 


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months prior to the screening visit.
6. Unwilling to discontinue use of long-term prophylactic therapy for HAE (C1-INH, attenuated 
androgens, or anti-fibrinolytics) within 3 weeks after starting DX-2930 treatment. 
7. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3x 
upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of normal, or 
total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of 
Gilbert’s Syndrome).
8. Pregnancy or breastfeeding.
9. Subject has any condition that, in the opinion of the investigator or Sponsor, may 
compromise their safety or compliance, preclude successful conduct of the study, or interfere 
with interpretation of the results (eg, history of substance abuse or dependence, a significant 
pre-existing illness or other major comorbidity that the investigator considers may confound 
the interpretation of study results).
Test Product; Dose; and Mode of Administration:
DX-2930 is a sterile, preservative-free solution for injection, pH 6.0. The active ingredient, 
DX-2930, is formulated using the following compendial components:  30 mM sodium phosphate 
dibasic dihydrate, 19.6 mM citric acid, 50 mM histidine, 90 mM sodium chloride, 0.01% 
Polysorbate 80. Each open-label vial contains a nominal concentration of 150 mg DX-2930 
active ingredient in 1 mL solution.
For each 300 mg dose of DX-2930, each subject will receive a total of 2 mL (2 vials), which will 
be administered in a single 2 mL SC injection. The injection will be given in the upper arm, thigh 
or abdomen.
Self-Administration Option: Investigational product can be self-administered without supervision
(parental supervision required for adolescent subjects) after subjects receive appropriate training
by the investigator or designee and their understanding is confirmed. Subjects are allowed to 
initiate offsite self-administration after receiving the first 2 doses of DX-2930 at the study site 
and may continue to self-administer all subsequent doses (see Study Activities Schedule).
Duration of Treatment:
All subjects will receive open-label DX-2930 during a 364 day treatment period. The number of 
doses that rollover subjects receive during this period will vary by subject but will not exceed 26 
doses. The last dose of open-label DX-2930 administered to these subjects may be given at the 
Day 350 study visit. Non-rollover subjects will receive 300 mg DX-2930 every 2 weeks for a 
total of 26 doses, with the first dose administered on Day 0 and the final dose administered at the 
Day 350 study visit.
There will be a ±4-day window around each study visit. There will be a minimum of 10 days 
between any two doses. Excluding the interval between the first and second open-label doses for 
rollover subjects, there will be a maximum of 18 days between any two doses. Subjects will be 
monitored at the study site through 1 hour post-dose for scheduled study site visits.  No 
monitoring of vital signs will be performed for subjects who elect to self-administer away from 
the investigational site.


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Duration of Study for Individual Subjects:
Following informed consent, subjects will either rollover from DX-2930-03 or undergo 
screening assessments (non-rollover subjects). Screening assessments for non-rollover subjects 
must occur within 4 weeks prior to the first open-label dose. Eligible subjects will be enrolled 
and undergo a 364 day treatment period. At the conclusion of the treatment period, subjects will 
be followed for an additional 4 weeks. 
Prohibited Concomitant Treatments:
Use of the following treatments will not be permitted during the study:
•
Long-term prophylaxis for HAE (eg, use of C1-INH for LTP, attenuated androgens, or anti-
fibrinolytics) once LTP is discontinued (within 3 weeks following the first dose of DX-
2930). 
•
Angiotensin-converting enzyme (ACE) inhibitors.
•
Initiating or changing the dose of estrogen-containing medications with systemic absorption 
(such as oral contraceptives or hormonal replacement therapy) 3 months prior to study 
screening.
•
Use of androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, and 
testosterone) for non-HAE related medical conditions or for HAE after discontinuation 
during the first three weeks.
•
Any other investigational drug or device.
The use of short-term prophylactic treatment for HAE will be permitted if medically indicated.  
Short-term (pre-procedure) prophylaxis is defined as use of C1-INH to avoid angioedema 
complications from medically indicated procedures.
Management of Acute Attacks:
Acute HAE attacks during the study are to be managed in accord with the investigator’s usual 
care of their patients, including use of acute attack therapies that the investigator deems as 
medically appropriate. Use of C1-INH will be permitted as an acute attack therapy but not as a 
long-term prophylactic therapy. Administration of DX-2930 and study procedures will continue 
without alteration to the protocol-specified study schedule, even if the subject has symptoms of 
an HAE attack the day of DX-2930 administration and/or receives treatment for an HAE attack.  
The administration of DX-2930 can also be re-scheduled as long as the minimum and maximum 
timeframe between doses are met based on subject preference or physician discretion.
Safety Assessments:
Safety assessments will include the following:
•
Adverse events (AEs), including serious adverse events (SAEs) and adverse events of special 
interest (AESI). SAEs and AESI will be reported to the Sponsor within 24 hours of becoming 
aware of the event.
•
Vital signs, including sitting or supine blood pressure (BP), heart rate (HR), body 
temperature, and respiratory rate (RR)
•
Physical examination
•
Clinical laboratory testing (hematology, serum chemistry, coagulation, and urinalysis)


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•
12-Lead electrocardiogram (ECG)
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Hypersensitivity reactions and events of disordered coagulation will be considered AESI.
Pharmacokinetic (PK) Assessments:
Blood samples will be collected for the measurement of plasma DX-2930 concentrations.
Pharmacodynamic (PD) Assessments:
Blood samples will be collected to evaluate the pharmacodynamic effects of DX-2930 through 
biomarker assays.
Immunogenicity Assessments:
Blood samples will be collected to assay for the presence of anti-drug antibodies, including 
evaluation of neutralizing antibodies (if any confirmed positive anti-drug antibodies are 
detected).
C1-INH, C1q and C4 Assessments:
Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment, 
unless already collected as part of protocol DX-2930-02 or DX-2930-03. 
Quality of Life Assessments:
Quality of life (QoL) assessments will be conducted using the Angioedema Quality of Life 
Questionnaire (AE-QoL), EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L), Work 
Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH), Hospital 
Anxiety and Depression Scale (HADS), and 12 Item Short Form Survey (SF-12).
DX-2930 Injection Report and Self-Administration and Subcutaneous Injection Survey
An injection report of the subject’s experience with self-administration and SC injection will be 
completed by the subject after all doses of DX-2930.
In addition, assessment survey of subject experience with SC and self-administration injections 
of DX-2930 will be completed by the subject as indicated in the Study Activities Schedule.
Collection of HAE Attack Data:
The collection, reporting and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP). Study site personnel will be 
trained on HAARP prior to screening and enrolling subjects at their site.
Study site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide. The 
subject (and caregiver) will confirm their understanding of what is required of them for reporting 
attacks to the site.
At screening, HAE attack history will be collected for non-rollover subjects. Information 
collected will include any prior history of laryngeal attacks, attack frequency, average severity, 
predominant attack location(s), triggers, average duration, acute attack therapy use and history of 
LTP (including duration of LTP, medication(s) and dose used for LTP, and frequency of attacks 
while receiving LTP). If available, information will also be collected on HAE diagnosis (year of 
confirmation, how many years after onset of symptoms was diagnosis confirmed, or if subject 


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was misdiagnosed).
During the study, subjects (or caregivers) will be instructed to notify and report details to the 
study site within 72 hours of the onset of an attack. This includes the first attack experienced by 
rollover subjects following their first open-label dose. In the situation that a subject is 
incapacitated following an attack, this information can be provided to the site by a family 
member or other individual with detailed knowledge of the event. If desired by the subject, 
memory aids may be provided to assist in tracking any HAE attacks experienced, but their use is 
not mandatory.
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack:

Date and time symptoms of an attack were first experienced.

Description of symptoms experienced, including location(s).

Impact on activity (work, school, social interactions) and whether any assistance or 
medical intervention was required, including hospitalizations, additional laboratory tests 
or emergency department visits.

Any medications used to treat the attack (both prescription and over the counter).

If the attack resolved, date and time the subject was no longer experiencing symptoms.
Study site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP.
Study site personnel will contact rollover subjects approximately every 7 days following the first 
dose of open-label DX-2930 to solicit for any HAE attacks not already reported.  Site check-ins 
will continue until the subject has received their second open-label dose.
During each study visit, study site personnel will solicit for any new HAE attack information that 
was not already provided to the site.
In this study, HAE attacks will be captured as AEs. All AEs, regardless of seriousness, severity, 
or causal relationship to DX-2930, will be recorded on the AE page of the eCRF. Any AE 
reported to the site meeting criteria for a serious adverse event must be reported to the Sponsor 
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of the 
event. For all serious adverse events that are reported as HAE attacks, the investigator or 
physician designee will review the event within 24 hours of initial notification and, in 
accordance with HAARP, evaluate if it represented a confirmed HAE attack. For all non-serious 
AEs that are reported as HAE attacks, the investigator or physician designee will review the 
event within 3 days of initial notification and, in accordance with HAARP, evaluate if it 
represented a confirmed HAE attack. If necessary for the evaluation, the investigator or designee 
may contact the subject to receive additional information. Any subject-reported attack not 
confirmed by the investigator or physician designee must have an alternate AE diagnosis 


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recorded.  All subject-reported and investigator/ physician designee-confirmed HAE attacks will 
be recorded in the eCRF. 
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured.
To be confirmed as an attack, the event must have symptoms or signs consistent with an attack in 
at least one of the following locations: 
•
Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region.
•
Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea.
•
Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx.
Despite the presence of these symptoms, the investigator or physician designee may still 
clinically determine that the event did not represent an attack if there are features that strongly 
refute such a diagnosis. For example, the reported event is accompanied by symptoms that are 
not consistent with an HAE attack (eg, urticaria), the reported event persists well beyond the 
typical time course of an HAE attack, or there is a likely alternate etiology for the event (eg, the 
subject’s abdominal symptoms are attributable to a viral gastroenteritis outbreak in the 
household). 
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.
Interim Analyses and Data Monitoring
Interim analyses may be conducted to support administrative decisions and/or regulatory 
reporting when a reasonable number of subjects have completed 12 months of consecutive 
exposure to DX-2930 across the combined DX-2930-03 and DX-2930-04 studies, and only after 
database lock of Study DX-2930-03. 
An independent Data Safety Monitoring Board (DSMB) has been established to provide 
ongoing, independent review and assessment of the safety data for Study DX-2930-03. While an 
independent DSMB is not currently planned for this study, summary safety data from Study DX-
2930-04 may be reviewed by the Study DX-2930-03 DSMB as part of the collection of safety 
information available on DX-2930. 
Individual Stopping Rules:
Dosing for any individual subject will be discontinued if the subject experiences a 
DX-2930-related SAE (or a DX-2930-related, clinically significant non-serious AE) that, in the 
assessment of the investigator, warrants discontinuation from further dosing for that subject’s 
well-being. The investigator has the ability to contact and consult with the Medical Monitor on 
such matters. Subjects will continue to be followed through the completion of all scheduled non-
dosing visits, unless they request to be discontinued from the study.


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Criteria for Evaluation:
Safety Measures:
•
AEs including SAEs and AESI
•
Clinical laboratory testing (hematology, clinical chemistry, coagulation, and urinalysis)
•
Vitals signs including blood pressure, heart rate, oral body temperature, and respiratory rate
•
Physical Examination
•
12-lead ECG
Efficacy Endpoints:
•
Time to first HAE attack for rollover subjects (based upon time from first open label study 
dose until first HAE attack)
•
Number of investigator-confirmed HAE attacks during the treatment period
•
Number of investigator confirmed HAE attacks requiring acute treatment during the 
treatment period
•
Number of moderate or severe HAE attacks during the treatment period
•
Number of high-morbidity HAE attacks during the treatment period; a high-morbidity HAE 
attack is defined as any attack that has at least one of the following characteristics: severe, 
results in hospitalization (except hospitalization for observation < 24 hours), 
hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal.
Additional Measures:
•
Anti-drug antibody development
•
Pharmacokinetics (PK) effects
•
Pharmacodynamic (PD) effects
•
Quality of Life Assessments
•
DX-2930 Injection Report 
•
DX-2930 Self-administration and Subcutaneous Injection Survey
Analysis Populations:

The Safety Population will include all subjects who received any study drug after entering 
the Study DX-2930-04 (ie, any exposure to open-label DX-2930).   

The Rollover Safety Population is the subset of subjects who participated in Study DX-2930-
03 and received any study drug after entering Study DX-2930-04 (ie, any exposure to open-
label DX-2930). 

The Non-rollover Safety Population is the subset of subjects who entered Study DX-2930-04 
directly and received any study drug after entering Study DX-2930-04 (ie, any exposure to 
open-label DX-2930).  


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Clinical Trial Protocol Amendment 2
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Sample Size Determination:
No formal sample size calculation was performed.  The sample size is not based on any 
statistical considerations.  This study is designed to evaluate the safety and efficacy of open-label 
treatment with DX-2930 in subjects who participated in Study DX-2930-03 and individuals who 
were not otherwise able to participate in Study DX-2930-03.
Statistical Methodology:
Time to the first investigator-confirmed HAE attack will be analyzed using the Rollover Safety 
Population.
Time to the first investigator-confirmed HAE attack (days) will be calculated from the date and 
time of the first open-label dose of DX-2930 to the date and time of the first investigator-
confirmed HAE attack after the first open-label dose.  Subjects who discontinue the study prior 
to experiencing their first on-study investigator-confirmed HAE attack will be censored at the 
date and time of study discontinuation.  Time to the first investigator-confirmed HAE attack will 
be summarized using Kaplan-Meier methods.
Multivariate and univariate Cox proportional hazards regression models will be employed to 
examine the impact of baseline covariates on the time to the first investigator-confirmed HAE 
attack, including but not limited to: baseline attack rate prior to entering Study DX-2930-03, the 
treatment group in Study DX-2930-03, the time since the last dose given in Study DX-2930-03, 
the time since the last HAE attack, and the rate of attacks during Study DX-2930-03. Results of 
this exploratory analysis will be summarized.  
Number of Investigator-confirmed HAE Attacks
The number of investigator-confirmed HAE attacks during the treatment period (Day 0 through 
Day 364) expressed as a monthly HAE attack rate, will be analyzed using each analysis 
population.
The monthly rate of investigator-confirmed HAE attacks during the treatment period will be 
calculated for each subject as the number of investigator-confirmed HAE attacks occurring 
during the treatment period divided by the number of days the subject contributed to the 
treatment period multiplied by 28 days.  
The baseline investigator-confirmed monthly HAE attack rate will be calculated for each subject 
as the number of investigator-confirmed monthly HAE attacks occurring during the pretreatment 
period for rollover subjects or historical reporting period for non-rollover subjects divided by the 
number of days the subject contributed to the pretreatment period for rollover subjects or 
historical reporting period for non-rollovers multiplied by 28 days.
The baseline, treatment period, and treatment period change from baseline in the investigator-
confirmed HAE attack rate will be summarized for each analysis population. The summary will 
include the total number of investigator-confirmed HAE attacks reported during each period and 
subject-time in months that each subject contributed to each period. Figures will be created for 


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Clinical Trial Protocol Amendment 2
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20 Jan 2017
each analysis population plotting the on-study investigator-confirmed HAE attacks reported 
during the treatment period relative to Day 0 for each subject.
Similar summary tables will be presented for the following efficacy endpoints for each analysis 
population:
•
Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period.
•
Number of moderate or severe investigator-confirmed HAE attacks during the treatment 
period.
•
Number of high-morbidity investigator-confirmed HAE attacks during the treatment period; 
a high-morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation < 24 
hours), hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal.
Safety Analysis:
Adverse Events
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. 
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.  
Related AEs are AEs classified as related to study drug by the investigator. Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator.
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE, 
any severe AE, and any related severe AE as well as the total number of events for each category 
will be summarized.  The number of deaths due to an AE, hospitalization due to an AE and study 
discontinuation due to an AE will be summarized. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC, and PT. This tabulation will be repeated for related AEs, SAEs, related 
SAEs, severe AEs, and related severe AEs. 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions and 
disordered coagulation (hypercoagulability events and bleeding events).  Standardized MedDRA 
Queries (SMQ) for each AESI will be performed using the study data. The number and percentage 
of subjects with an AESI, as well as the total number of AESIs, will be summarized by SOC and PT. 
Separate summary tables will be created for each AESI and for those events with the SMQs 
classified as related, serious, related serious, severe, and related severe.  A listing detailing the 
PT within the SMQ will be provided.


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Clinical Trial Protocol Amendment 2
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Laboratory Test Results, Vital Signs, and Electrocardiography Results
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For 
rollover subjects previously exposed to DX-2930, baseline is the last non-missing value prior to 
first exposure to study drug in Study DX-2930-03.      
  
Actual values and change from baseline in clinical laboratory test results and vital signs will be 
summarized by study visit. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. Vital sign values will be classified according to 
clinical significance as determined by the investigator. The number of subjects with a non-
missing result, and the number and percentage of subjects within each category will be 
summarized by study visit.  
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG not performed, will be summarized by study 
visit. 
Other Analyses
Plasma concentrations of DX-2930 and plasma kallikrein activity will be summarized by 
nominal PK and PD sampling times.
The number and percentage of subjects with positive antibodies (and whether neutralizing or 
non-neutralizing) will be summarized by study visit and overall.
Quality of life assessments will be summarized by study visit.
Date of Original Protocol:  14 December 2015
Date of Amendment 1:  27 June 2016
Date of Amendment 2:  20 January 2017


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Clinical Trial Protocol Amendment 2
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Table 1
Study Activities Schedule
                    Study Activities Schedule
Tests and 
Assessments
Treatment Period 
± 4 days for each visit
Follow
-up
±4 
Days 
for 
each 
visit
Non-rollover Screen 
Visit1
Rollover 
-
Check
-in2
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27 283 294
Dose:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-
-
-
Day:
0
14
28
42
56
70
84
98
112 126 140 154 168 182 196 210 224 238 252 266 280 294 308 322 336 350 36
4
37
8
39
2
Informed 
Consent5
X
(X
)6
Eligibility 
Review
X
X
Long-term 
prophylactic 
therapy 
continued7
X
X
X
DX-2930 
Administration 
(rollover 
subjects)
X
(X)8,9 (X)10 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)10 (X)11 (X)10 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)11 (X)10 (X)11 (X)11 (X)10
DX-2930 
Administration
(non-rollover)
X
X
X10
X11
X10
X11
X11
X10
X11
X10
X11
X10
X11
X10
X11
X11
X10
X11
X11
X10
X11
X11
X10
X11
X11
X10
Demographic 
and Medical 
History 
X
C1-INH, C1q 
and C4 
Testing12
X
Pregnancy 
Test13 (females)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Exam15
X
X
X
X
X
X
X
X
X
X
X
X


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Clinical Trial Protocol Amendment 2
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Table 1
Study Activities Schedule
                    Study Activities Schedule
Tests and 
Assessments
Treatment Period 
± 4 days for each visit
Follow
-up
±4 
Days 
for 
each 
visit
Non-rollover Screen 
Visit1
Rollover 
-
Check
-in2
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27 283 294
Dose:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-
-
-
Day:
0
14
28
42
56
70
84
98
112 126 140 154 168 182 196 210 224 238 252 266 280 294 308 322 336 350 36
4
37
8
39
2
Clinical 
Laboratory 
Testing16
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
X
X
Prior (4 weeks) 
and 
Concomitant 
Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HAE Attack 
Data17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Assessments18
   EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
X
X
   SF-12
X
X
X
X
X
X
X
X
X
X
X
X
   AE-QoL
X
X
X
X
X
X
X
X
X
X
X
X
   HADS
X
X
X
X
X
X
X
X
X
X
X
X
   WPAI-GH
X
X
X
X
X
X
X
X
X
X
X
X
DX-2930 
Injection 
Report19
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017
Table 1
Study Activities Schedule
                    Study Activities Schedule
Tests and 
Assessments
Treatment Period 
± 4 days for each visit
Follow
-up
±4 
Days 
for 
each 
visit
Non-rollover Screen 
Visit1
Rollover 
-
Check
-in2
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27 283 294
Dose:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-
-
-
Day:
0
14
28
42
56
70
84
98
112 126 140 154 168 182 196 210 224 238 252 266 280 294 308 322 336 350 36
4
37
8
39
2
DX-2930 Self-
administration 
and SC 
Injection 
Survey 20
X
X
X
X
X
PK, PD 
Collection, & 
Plasma Anti-
Drug Antibody 
Testing21
X
X
X
X
X
X
Discharge 
from Study
X
AE-QOL = Angioedema Quality of Life; ECG = Electrocardiogram; EQ-5D-5L = EuroQoL 5-Dimensional 5-Level; HADS = Hospital Anxiety and Depression Scale; PK = 
Pharmacokinetic; PD = Pharmacodynamic; SF-12 = Short Form-12; WPAI-GH = Work Productivity and Activity Impairment – General Health
NOTE:  Shaded columns represent scheduled in-site visits for all subjects. Non-shaded columns indicate potential subject-elected off-site activity and/or self-administration dosing. 
NOTE:  “( )”s indicate activities that may occur as applicable (ie, activities for rollover subjects)
1. Screening visit is for non-rollover subjects only.  Screening visit can occur up to 28 days prior to first open-label dose.
2. Study site personnel will contact rollover subjects approximately every 7 days following the first dose of open-label DX-2930 to solicit for any HAE attacks 
not already reported.  Site check-in with rollover subjects will continue until the subject receives their second open label dose.
3. Visit 28 is a site check-in call for all rollover and non-rollover subjects.
4. Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures at Visit 29, the final study visit.
5. Rollover subjects must sign informed consent for Study DX-2930-04 on or after Day 168 of Study DX-2930-03.
6. For rollover subjects Day 182 of Study DX-2930-03 is also Day 0 of Study DX-2930-04 and informed consent may be completed on this visit, if not already 
provided.
7. Screened non-rollover subjects (adults and adolescents) who are on LTP with C1-INH therapy for HAE can continue their current LTP until Day 8 (or Day 
15) such that subjects will have received 2 (or 4) doses of C1-INH.  For subjects who are on attenuated androgens (eg, danazol) or anti-fibrinolytics (eg, 


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Clinical Trial Protocol Amendment 2
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20 Jan 2017
Table 1
Study Activities Schedule
                    Study Activities Schedule
Tests and 
Assessments
Treatment Period 
± 4 days for each visit
Follow
-up
±4 
Days 
for 
each 
visit
Non-rollover Screen 
Visit1
Rollover 
-
Check
-in2
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27 283 294
Dose:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-
-
-
Day:
0
14
28
42
56
70
84
98
112 126 140 154 168 182 196 210 224 238 252 266 280 294 308 322 336 350 36
4
37
8
39
2
tranexamic acid), a similar tapering schedule is recommended. However, the taper can be prolonged by an additional week as long as androgen or anti-
fibrinolytic therapy is stopped within 3 weeks of receiving the first dose of DX-2930.
8. For rollover subjects, the timing of Dose 2 for will vary by subject based on when their first HAE attack occurs following Dose 1.  Following the first 
reported and investigator-confirmed attack, subjects will begin receiving regular SC administrations of 300 mg DX-2930 every 2 weeks.
9. A minimum of 10 days between the first and second open-label doses is required. If the second dose is to be administered within the accepted ±4 day 
window around a scheduled study visit, this treatment visit will represent that scheduled visit unless that scheduled visit has already occurred. If that 
scheduled visit has already occurred, or if the second dose is to be administered outside of the accepted ± 4 day window around a scheduled visit, this visit 
will not replace any scheduled visit and will thus represent an acceptable, extra study visit (ie, an unscheduled visit). Regardless, at the visit in which the 
second open-label dose of DX-2930 is administered, the subject will undergo pre-dose assessments for vital signs, physical examination (performed in 
accordance with standards at the site), clinical laboratory testing, PK, PD, and anti-drug antibody. Vital signs will be obtained at 1 hour post-dosing. As with 
all study visits, information will be collected on adverse events, concomitant therapy, and HAE attack data. 
10. All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a physical and mental capability of learning and willing to be 
trained) may be allowed to self-administer DX-2930 after completing appropriate training by the investigator or designee and confirming their 
understanding. Subjects are allowed to initiate home self-administration after receiving the first 2 doses of DX-2930 at the study site and may elect to self-
administer subsequent doses of DX-2930 at the investigational site (during scheduled study site visits; shaded columns). 
11. Subjects may self-administer DX-2930 at home or other agreed upon location (during optional off-site self-administration visits; non-shaded columns). Site 
personnel will call subjects within approximately 3 days of the planned self-administration to ensure the administration occurred, to collect AEs, 
concomitant medications, and to ensure all attacks have been appropriately documented.
12. Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment unless already collected as part of Study DX-2930-02 or 
Study DX-2930-03.  
13. The pregnancy test will only be conducted in females of childbearing potential.  Tests performed on Day 0 must be urine-based to confirm eligibility prior to 
first dose. Tests performed at screening and on indicated visits can be serum or urine-based.
14. There is a recommended ± 15 minute window for all vital signs. Vital signs will be obtained prior to dosing and 1 hour after dosing. Monitoring of vital 
signs will not be performed for subjects who elect to self-administer away from the investigative site at optional off-site visits (indicated non-shaded 


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Clinical Trial Protocol Amendment 2
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20 Jan 2017
Table 1
Study Activities Schedule
                    Study Activities Schedule
Tests and 
Assessments
Treatment Period 
± 4 days for each visit
Follow
-up
±4 
Days 
for 
each 
visit
Non-rollover Screen 
Visit1
Rollover 
-
Check
-in2
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27 283 294
Dose:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-
-
-
Day:
0
14
28
42
56
70
84
98
112 126 140 154 168 182 196 210 224 238 252 266 280 294 308 322 336 350 36
4
37
8
39
2
columns). 
15. Physical examinations, including weight, will be conducted for all rollover and non-rollover subjects according to the study activities schedule and in 
accordance with standards at the site.  In addition to the physical examinations specified in the study activities schedule, an additional physical examination 
(performed in accordance with standards at the site) will be conducted for rollover subjects prior to dosing on the day of their second open-label dose, at 
whatever study visit that occurs.  Height will be collected at the Screening visit only. 
16. Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis (urinalysis does not need to be done as part of the 
clinical laboratory testing at Visits 14, 17, 20, and 23). Clinical laboratory testing will be conducted for all rollover and non-rollover subjects according to 
the study activities schedule. In addition to the testing specified in the study activities schedule, additional testing will be conducted for rollover subjects 
prior to dosing on the day of their second open-label dose, at whatever study visit that occurs.
17. Historical HAE attack information will be collected at screening. During the study, subjects (or caregivers) are instructed to report details of the attack to the 
study site within 72 hours of the onset of the attack. During study visits, study site personnel will solicit for any new HAE attack information that has not 
already been reported to the site.
18. Quality of life data will be obtained using the EQ-5D-5L, SF-12, AE-QoL, HADS, and WPAI-GH.
19. Collect subject’s injection reports of their experience with DX-2930 self-administration and subcutaneous administration for all doses. 
20. Collect subject’s injection surveys of their experience with DX-2930 self-administration and subcutaneous injection for indicated visits.
21. PK, PD, and anti-drug antibody samples will be drawn for all rollover and non-rollover subjects according to the study activities schedule.  In addition to the 
samples specified in the study activities schedule, an additional PK, PD and anti-drug antibody sample will be drawn for rollover subjects prior to dosing on 
the day of their second open-label dose, at whatever study visit that occurs


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Clinical Trial Protocol Amendment 2
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
AMENDMENT SUMMARY AND RATIONALE ........................................................................3
SYNOPSIS.......................................................................................................................................6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................33
1.
INTRODUCTION..................................................................................................................36
1.1
DX-2930...................................................................................................................36
1.2
Hereditary Angioedema ...........................................................................................36
1.3
Therapeutic Rationale for DX-2930.........................................................................36
1.4
Safety Rationale for DX-2930..................................................................................37
1.5
DX-2930 Non-Clinical Pharmacology and Toxicology...........................................37
1.6
DX-2930 Clinical Data.............................................................................................37
1.6.1
Single-Ascending Dose Study in Healthy Subjects (DX-2930-01).......................38
1.6.2
Multiple-Ascending Dose Study in HAE Patients (DX-2930-02).........................38
1.7
Rationale for Open-Label Extension Study DX-2930-04........................................40
2.
STUDY OBJECTIVES ..........................................................................................................41
2.1
Primary Objective ....................................................................................................41
2.2
Secondary Objectives...............................................................................................41
2.3
Tertiary Objectives...................................................................................................41
3.
INVESTIGATIONAL PLAN.................................................................................................42
3.1
Overall Study Design and Plan ................................................................................42
3.1.1
Overview................................................................................................................42
3.1.2
Stopping Rules.......................................................................................................46
3.1.2.1
Study Level Stopping Rules...................................................................46
3.1.2.2
Individual Stopping Rules......................................................................46
3.1.3
Follow-up for Subjects Meeting Stopping Criteria................................................46
3.2
Rationale for Open-Label Extension Dose Selection...............................................46
3.3
Individual Subject Dosing and Follow-Up...............................................................47
3.4
Study Duration for Individual Subjects....................................................................47
4.
STUDY POPULATION SELECTION ..................................................................................48
4.1
Study Population ......................................................................................................48
4.2
Inclusion Criteria......................................................................................................48
4.3
Exclusion Criteria.....................................................................................................49
5.
STUDY TREATMENT(S).....................................................................................................51
5.1
Description of Treatment(s) .....................................................................................51
5.2
Dosing and Follow-Up Scheme ...............................................................................51


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5.3
Method of Identifying Subjects................................................................................52
5.4
Prior and Concomitant Therapy...............................................................................52
5.4.1
Allowed Therapies.................................................................................................52
5.4.1.1
Management of HAE Attacks ................................................................53
5.4.2
Excluded Concomitant Therapies..........................................................................53
5.5
Restrictions...............................................................................................................53
5.5.1
Medical Interventions ............................................................................................53
5.5.2
Fluid and Food Intake............................................................................................53
5.5.3
Activity ..................................................................................................................53
5.6
Treatment Compliance .............................................................................................54
5.7
Packaging and Labeling ...........................................................................................54
5.8
Storage and Accountability ......................................................................................54
5.9
Investigational Medicinal Product Retention at Study Site .....................................55
6.
STUDY PROCEDURES........................................................................................................56
6.1
Informed Consent.....................................................................................................56
6.2
Eligibility Review ....................................................................................................56
6.3
Demographics and Medical History.........................................................................56
6.4
HAE Attack Information Collection ........................................................................56
6.5
Vital Signs................................................................................................................58
6.6
Physical Examination...............................................................................................58
6.7
Electrocardiography (ECG)......................................................................................59
6.8
Clinical Laboratory Tests.........................................................................................59
6.8.1
Laboratory Parameters...........................................................................................59
6.8.1.1
Hematology ............................................................................................59
6.8.1.2
Coagulation ............................................................................................60
6.8.1.3
Chemistry ...............................................................................................60
6.8.1.4
Urinalysis ...............................................................................................60
6.8.1.5
Pregnancy Test .......................................................................................61
6.8.1.6
C1-INH Functional Assay......................................................................61
6.8.1.7
C4 Assay ................................................................................................61
6.8.1.8
C1q Assay ..............................................................................................61
6.8.1.9
PK Sample Collection ............................................................................61
6.8.1.10
PD Sample Collection ............................................................................61
6.8.1.11
Plasma Anti-Drug Antibody Testing......................................................61
6.8.2
Sample Collection, Storage, and Shipping ............................................................61
6.9
Pharmacokinetic Assessments..................................................................................62
6.10
Pharmacodynamic Assessments...............................................................................62
6.11
Plasma Anti-Drug Antibody Testing........................................................................62


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6.12
Prior and Concomitant Therapy...............................................................................62
6.13
Investigational Medicinal Product Treatment..........................................................62
6.14
Quality of Life Assessments ....................................................................................62
6.14.1 Angioedema Quality of Life Questionnaire (AE-QoL).........................................63
6.14.2 EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L) ......................................63
6.14.3 Work Productivity and Activity Impairment – General Health (WPAI-GH) 
Questionnaire.........................................................................................................63
6.14.4 Hospital Anxiety and Depression Scale (HADS)..................................................63
6.14.5 12 Item Short Form v2 Health Survey (SF-12v2) .................................................64
6.15
DX-2930 Injection Report and Self-Administration and Subcutaneous 
Injection Survey .......................................................................................................64
6.15.1 DX-2930 Injection Report .....................................................................................64
6.15.2 DX-2930 Self-administration and Subcutaneous Injection Survey.......................64
6.16
Adverse Event Reporting .........................................................................................65
6.16.1 Definitions..............................................................................................................65
6.16.1.1
Adverse Event ........................................................................................65
6.16.1.2
Serious Adverse Event ...........................................................................65
6.16.1.3
Overdose.................................................................................................66
6.16.1.4
Planned Hospitalization..........................................................................66
6.16.1.5
Treatment-Emergent Adverse Events (TEAE).......................................66
6.16.1.6
Adverse Events of Special Interest (AESI)............................................66
6.16.2 Monitoring .............................................................................................................67
6.16.2.1
Monitoring of Adverse Events ...............................................................67
6.16.2.2
Monitoring of Safety Laboratory Assessments......................................68
6.16.3 Assessment of Adverse Events..............................................................................68
6.16.3.1
Assessment of Severity ..........................................................................68
6.16.3.2
Assessment of Causality.........................................................................68
6.16.3.3
Assessment of Clinical Significance......................................................69
6.16.4 Clinical Laboratory Adverse Events......................................................................69
6.16.5 Reporting Investigator Safety Observations to the Sponsor..................................70
6.16.5.1
Reporting Non-serious Adverse Events .................................................70
6.16.5.2
Reporting Pregnancies............................................................................70
6.16.5.3
Safety Observations Requiring Expedited Reporting by the 
Investigator to the Sponsor.....................................................................70
6.16.5.4
Expedited Reporting by the Sponsor to a Regulatory Health 
Authority ................................................................................................71
6.16.5.5
Safety Contact Information ....................................................................71
6.16.5.6
Safety Notifications by the Sponsor to the Investigator.........................71


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6.17
Subject Withdrawal..................................................................................................71
6.18
Appropriateness of Measurements...........................................................................72
7.
STUDY ACTIVITIES............................................................................................................73
7.1
Screening Visit (Up to Day −28) For Non-Rollover Subjects .................................73
7.2
Start of Treatment Period: Visit 1, Dose 1 (Day 0)..................................................73
7.3
Interval between Dose 1 and Dose 2 for Rollover Subjects.....................................74
7.4
Dose 2 of DX-2930 for Rollover Subjects...............................................................75
7.5
Visit 2 (Day 14 ±4 days); Dose 2 of DX-2930 for Non-Rollover Subjects.............76
7.6
Continuation of Treatment Period: Visit 3 (Day 28 ±4 Days) .................................77
7.7
Continuation of Treatment Period: Visit 4 (Day 42 ±4 Days) .................................78
7.8
Continuation of Treatment Period: Visit 5 (Day 56 ±4 Days) .................................78
7.9
Continuation of Treatment Period: Visits 6 and 7 (Days 70 and 84, All 
±4 Days) ...................................................................................................................79
7.10
Continuation of Treatment Period: Visit 8 (Day 98 ±4 Days) .................................79
7.11
Continuation of Treatment Period: Visit 9 (Day 112 ±4 Days) ...............................80
7.12
Continuation of Treatment Period: Visit 10 (Day 126 ±4 Days) .............................81
7.13
Continuation of Treatment Period: Visit 11 (Day 140 ±4 Days) .............................81
7.14
Continuation of Treatment Period: Visit 12 (Day 154 ±4 Days) .............................82
7.15
Continuation of Treatment Period: Visit 13 (Day 168 ±4 Days) .............................83
7.16
Continuation of Treatment Period: Visit 14 (Day 182 ±4 Days) .............................83
7.17
Continuation of Treatment Period: Visit 15 (Day 196 ±4 Days) .............................84
7.18
Continuation of Treatment Period: Visit 16 (Day 210 ±4 Days) .............................85
7.19
Continuation of Treatment Period: Visit 17 (Day 224 ±4 Days) .............................85
7.20
Continuation of Treatment Period: Visit 18 (Day 238 ±4 Days) .............................86
7.21
Continuation of Treatment Period: Visit 19 (Day 252 ±4 Days) .............................86
7.22
Continuation of Treatment Period: Visit 20 (Day 266 ±4 Days) .............................87
7.23
Continuation of Treatment Period: Visit 21 (Day 280 ±4 Days) .............................88
7.24
Continuation of Treatment Period: Visit 22 (Day 294 ±4 Days) .............................88
7.25
Continuation of Treatment Period: Visit 23 (Day 308 ±4 Days) .............................89
7.26
Continuation of Treatment Period: Visit 24 (Day 322 ±4 Days) .............................89
7.27
Continuation of Treatment Period: Visit 25 (Day 336 ±4 Days) .............................90
7.28
Continuation of Treatment Period: Visit 26 (Day 350 ±4 Days) .............................91
7.29
Completion of Treatment Period:  Visit 27 (Day 364 ±4 Days) ..............................91
7.30
Follow-up Period:  Visit 28 (Day 378 ±4 Days) ......................................................92
7.31
Final Follow-up Visit:  Visit 29 (Day 392 ±4 Days)................................................92
7.32
Early Termination ....................................................................................................93
8.
QUALITY CONTROL AND ASSURANCE ........................................................................94
9.
DATA ANALYSIS / STATISTICAL METHODS................................................................95


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9.1
General Considerations ............................................................................................95
9.2
Sample Size Determination......................................................................................95
9.3
Method of Assigning Study Subjects to Treatment .................................................95
9.4
Analysis Populations................................................................................................95
9.4.1
Safety Population...................................................................................................95
9.4.2
Rollover Safety Population....................................................................................95
9.4.3
Non-rollover Safety Population.............................................................................96
9.5
Population Description and Exposure......................................................................96
9.5.1
Subject Disposition................................................................................................96
9.5.2
Demographics and Other Baseline Characteristics................................................96
9.5.3
Medical History .....................................................................................................96
9.5.4
Treatment Exposure and Compliance....................................................................96
9.5.5
Prior and Concomitant Medications ......................................................................96
9.6
Analysis of Efficacy.................................................................................................96
9.6.1
Time to the First Investigator-confirmed HAE Attack..........................................96
9.6.2
Number of Investigator-confirmed HAE Attacks..................................................97
9.7
Analysis of Safety ....................................................................................................98
9.7.1
Adverse Events ......................................................................................................98
9.7.2
Laboratory Test Results.........................................................................................99
9.7.3
Vital Signs............................................................................................................100
9.7.4
Electrocardiography.............................................................................................100
9.8
Other Analyses .......................................................................................................100
9.8.1
Analysis of Pharmacokinetic Data.......................................................................101
9.8.2
Analysis of Pharmacodynamic Data....................................................................101
9.8.3
Analysis of Immunogenicity Data .......................................................................101
9.8.4
Analysis of Quality of Life Assessments.............................................................101
9.9
Statistical/Analytic Considerations ........................................................................102
9.9.1
Interim Analyses and Data Monitoring................................................................102
9.9.2
Multiple Comparisons/Multiplicity .....................................................................102
9.9.3
Handling of Missing Data....................................................................................102
9.9.4
Adjustment for Covariates...................................................................................102
9.9.5
Multicenter Studies..............................................................................................102
9.9.6
Subgroup Analyses ..............................................................................................102
9.9.7
Sensitivity Analyses.............................................................................................103
10. STUDY ADMINISTRATIVE STRUCTURE .....................................................................104
10.1
Institutional Review Board/ Research Ethics Board/Independent Ethics 
Committee..............................................................................................................104
10.2
Ethical Conduct of the Study .................................................................................105


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10.3
Subject Information and Consent...........................................................................105
10.4
Subject Confidentiality...........................................................................................105
10.5
Study Monitoring ...................................................................................................105
10.6
Case Report Forms and Study Records..................................................................106
10.7
Data Safety Monitoring Board ...............................................................................106
10.8
Protocol Violations/Deviations ..............................................................................107
10.9
Premature Closure of the Study .............................................................................107
10.10
Access to Source Documentation and On-Site Audits...........................................107
10.11
Data Generation and Analysis................................................................................108
10.12
Retention of Data ...................................................................................................108
10.13
Financial Disclosure...............................................................................................108
10.14
Publication and Disclosure Policy..........................................................................109
11. REFERENCE LIST..............................................................................................................110
12. APPENDICES ......................................................................................................................112


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LIST OF IN-TEXT TABLES
Table 1
Study Activities Schedule..............................................................................21
Table 2 
Study Administrative Structure ...................................................................104
LIST OF IN-TEXT FIGURES
Figure 1
Schematic of the Open-Label Extension Study.............................................45
Figure 2
Overview of the Design of Pivotal Study DX-2930-03 ..............................154
LIST OF APPENDICES
APPENDIX 1
Protocol History...........................................................................................113
APPENDIX 2
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infectious Diseases).................................................................117
APPENDIX 3
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (Modified) (US National Institutes of Health; National Institute 
of Allergy and Infectious Diseases..............................................................130
APPENDIX 4
HAE Attack Assessment and Reporting Procedures (HAARP)..................144
APPENDIX 5
Summary of Pivotal Study DX-2930-03 in Subjects with HAE.................153


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AAE
Acquired angioedema
ACE
Angiotensin converting enzyme
AE
Adverse event
AESI
Adverse Event of Special Interest
AE-QoL
Angioedema Quality of Life Questionnaire
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C1-INH
C1 inhibitor
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
Cmax
Maximum plasma drug concentration
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CRO
Clinical Research Organization
DMID
Division of Microbiology and Infectious Diseases
DP
Drug product
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EQ-5D-5L
EuroQoL 5-Dimensional 5-Level; a standardized instrument for use as a measure of health 
outcome
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HADS
Hospital Anxiety and Depression Scale
HAE
Hereditary angioedema


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HMWK
High molecular weight kininogen
HR
Heart rate
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG1
Immunoglobulin G subclass 1
IMP
Investigational medicinal product
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine hormone releasing systems
IV
Intravenous
Ki
inhibition constant
LTP
Long-term prophylactic/Long-term prophylaxis
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
OLE
Open-label extension
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PT
Prothrombin time
PVRM
Pharmacovigilance and Risk Management
QoL
Quality of life
REB
Research ethics board
RBC
Red blood cell (count)
RR
Respiratory rate
SAE
Serious adverse event
SAP
Statistical Analysis Plan


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SC
Subcutaneous
SF-12
Short Form-12; a multi-purpose short form health survey with 12 questions
SGOT
Serum glutamic oxaloacetic transaminase (AST)
SGPT
Serum glutamic pyruvic transaminase (ALT)
SMQ
Standard MedDRA query
SOC
System Organ Class
SOP
Standard operating procedure
TEAE
Treatment-Emergent Adverse Event
US
United States
WBC
White blood cell (count)
WPAI-GH
Work Productivity and Activity Impairment – General Health


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1.
INTRODUCTION
1.1
DX-2930
DX-2930 is a fully human IgG1 recombinant monoclonal antibody that binds specifically to 
active plasma kallikrein. DX-2930 is being developed for prophylactic treatment of angioedema 
attacks in patients with hereditary angioedema (HAE), a serious and life-threatening disease.
1.2
Hereditary Angioedema
HAE is a long-term, debilitating, and life-threatening disease caused by mutations in the 
C1-inhibitor (C1-INH) gene, resulting in deficiency or dysfunction of C1-INH protein. HAE 
manifests clinically as unpredictable, intermittent attacks of subcutaneous or submucosal edema 
of the face, larynx, gastrointestinal tract, limbs and/or genitalia (Zuraw, 2008). Swelling may last 
up to five or more days; most patients suffer multiple attacks per year. HAE is an orphan 
disorder. The exact prevalence of HAE is unknown, but current estimates range from 1 per 
10,000 to 1 per 150,000 persons, with many authors agreeing that 1 per 50,000 is likely the 
closest estimate (Bygum, 2009; Goring et al., 1998; Lei et al., 2011; Nordenfelt et al., 2014; 
Roche et al., 2005). 
Swelling in the larynx can obstruct the airways and cause death from asphyxiation (Bork et al., 
2000; Bork et al., 2012). Approximately 50% of all patients with HAE will experience a 
laryngeal attack in their lifetime, and there is no way to predict which patients are at risk of a 
laryngeal attack (Bork et al., 2003; Bork et al., 2006). 
Abdominal attacks are often associated with nausea, vomiting, diarrhea, and severe pain; 
intestinal symptoms resembling abdominal emergencies may lead to unnecessary surgery 
(Zuraw, 2008). 
Approximately 85% of patients with HAE have Type I HAE, characterized by very low 
production of functionally normal C1-INH protein, while the remaining approximately 15% of 
patients with HAE have Type II HAE and produce normal or elevated levels of a functionally 
impaired C1-INH (Zuraw, 2008). In patients with Types I and II HAE, uncontrolled plasma 
kallikrein generation results in excess bradykinin release from high-molecular weight kininogen 
(HMWK) and vascular leak mediated by bradykinin binding to the B2 receptor (B2-R) on the 
surface of endothelial cells (Zuraw, 2008). Clinical suspicion of Types I and II HAE can be 
confirmed by available blood tests. In addition to abnormalities in C1-INH level and function, 
plasma C4 levels are often reduced in blood from most patients with HAE.
1.3
Therapeutic Rationale for DX-2930
Plasma kallikrein plays a critical role in the pathogenesis of HAE attacks (Davis, 2006; Kaplan 
and Joseph, 2010). In normal physiology, C1-INH regulates the activity of plasma kallikrein as 
well as a variety of other proteases, such as C1r, C1s, factor XIa, and factor XIIa. Plasma 
kallikrein regulates the release of bradykinin from HMWK. Due to a deficiency of C1-INH in 
HAE, uncontrolled plasma kallikrein activity occurs and leads to the excessive generation of 
bradykinin. Bradykinin is a vasodilator which is thought to be responsible for the characteristic 


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HAE symptoms of localized swelling, inflammation, and pain (Craig et al., 2012; Zuraw et al., 
2013). Intervening at the level of bradykinin production with a plasma kallikrein inhibitor 
therefore represents an attractive and rational therapeutic strategy for HAE. Indeed, the 
importance of plasma kallikrein as a drug target in HAE has been validated through the observed 
effectiveness of Kalbitor® (ecallantide), a peptide that specifically targets plasma kallikrein, 
which was approved by the FDA for the treatment of acute HAE attacks (Kalbitor®, 2015). 
DX-2930 is a highly potent and specific inhibitor of plasma kallikrein (Ki = 125 pM). X-ray 
crystallography of DX-2930 combined with plasma kallikrein demonstrates DX-2930 binding to 
the active site of kallikrein (Kenniston et al., 2014).
1.4
Safety Rationale for DX-2930
Safety data from the Phase 1a clinical study, a first-in-human study with DX-2930 in healthy 
subjects, did not identify any safety concerns. Single doses up to 3 mg/kg of DX-2930 were well-
tolerated. There were no dose-limiting toxicities, serious adverse events, or any other safety 
concerns identified.
Pharmacokinetic (PK) data from the Phase 1a (DX-2930-01) and Phase 1b (DX-2930-02) 
clinical studies in conjunction with data from the nonclinical toxicity studies support a wide 
safety margin. The mean Cmax for human subjects treated at a dose of 300 mg on Days 1 and 15 
was approximately 27 g/mL. As comparison, a mean Cmax of 744 g/ mL was observed 
following dosing of monkeys with 50 mg/kg DX-2930 subcutaneous (SC) weekly for 6 months
resulting in a safety margin of approximately 28-fold. No toxicologically significant findings 
were observed in these treated animals or in any other nonclinical toxicity study to date for
systemically administered DX-2930.
Safety data is also available from the Phase 1b study (DX-2930-02), a multiple-ascending dose 
study in patients with HAE. In this study, two doses of DX-2930 up to 400 mg administered 14 
days apart were well-tolerated. There were no dose-limiting toxicities, serious adverse events in 
any DX-2930 treated subjects, or any other safety concerns identified in this study of patients 
with HAE. Pharmacokinetic data from the 1b study found that the drug exposure following two 
administrations of DX-2930 (up to a maximum of 400 mg) was substantially less than that 
attained and evaluated in the nonclinical toxicity studies.
For additional detail regarding the safety rationale for DX-2930, please refer to the DX-2930 
Investigator’s Brochure.
1.5
DX-2930 Non-Clinical Pharmacology and Toxicology
For more detail regarding the nonclinical findings, please refer to the DX-2930 Investigator’s 
Brochure.
1.6
DX-2930 Clinical Data
The clinical development program to date for DX-2930 consists of 2 studies to evaluate the 
safety, tolerability, and PK of DX-2930, including one completed Phase 1a single-ascending 


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dose study in healthy subjects and a Phase 1b multiple-ascending dose study in patients with 
HAE. These studies are summarized in the following sections.
1.6.1
Single-Ascending Dose Study in Healthy Subjects (DX-2930-01)
DX-2930-01 was a Phase 1a randomized, double-blind, placebo-controlled study in healthy 
subjects to evaluate the safety, tolerability, and PK following a single, SC dose of DX-2930. 
Participating subjects were randomized to receive placebo or active study drug within one of the 
following sequential, ascending dose cohorts: 0.1, 0.3, 1.0, or 3.0 mg/kg. For each dosing cohort, 
6 subjects were randomized to receive active drug and 2 subjects to receive placebo. 
A total of 32 subjects enrolled in the study and were randomized. The treatment groups were 
well balanced for demographic characteristics. The actual dose of DX-2930 administered to 
subjects ranged from 6.2 mg (in the 0.1 mg/kg group) to 300 mg (in the 3.0 mg/kg group) across 
all cohorts.
Based on the safety analysis, a single administration of DX-2930 was well tolerated up to doses 
of 3.0 mg/kg without evidence of dose-limiting toxicity. There were no deaths, SAEs, or subject 
discontinuations due to adverse events (AEs) during the study. Furthermore, there was no 
significant imbalance between placebo and DX-2930 for any particular treatment-emergent 
adverse event (TEAE). The most commonly reported TEAE was headache, which occurred at a 
rate of 25% for both DX-2930 and placebo.
The PK profile demonstrated linear, dose-dependent drug exposure with a mean half-life of 
approximately 17 to 21 days across dose groups. Results from two exploratory biomarker assays 
provide evidence for an important pharmacodynamic effect of DX-2930 in humans. 
For additional detail regarding the single dose, clinical study in healthy subjects, please refer to 
the DX-2930 Investigator’s Brochure.
1.6.2
Multiple-Ascending Dose Study in HAE Patients (DX-2930-02)
DX-2930-02 was a Phase 1b randomized, double-blind, placebo-controlled, multiple ascending-
dose study in patients with HAE to evaluate safety, tolerability, and PK of SC DX-2930. 
Participating subjects were randomized 2:1 to receive either active study drug or placebo within 
one of the following sequential, ascending dose cohorts: 30, 100, 300, or 400 mg (nominal 6 
subjects per cohort). Each subject received 2 doses of study drug separated by 14 days. 
A total of 37 subjects were randomized and treated with DX-2930 or placebo. One subject in the 
400 mg dose group received a single dose of DX-2930 and, following several unsuccessful 
attempts to schedule their second dose, was replaced. This subject returned for a single follow-up 
visit before being lost to follow-up for reasons not related to the study. Routine C1-INH testing 
revealed that one other subject did not have HAE Type I or II, despite a historical lab test 
indicating otherwise.
Subject demographics were balanced in terms of age, race, ethnicity and BMI. There were 
slightly more females in the DX-2930 group than in the placebo group (66.7% versus 53.8%). 


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The most common AEs reported were HAE attacks, injection site pain, and headache. The rates 
were not appreciably higher in the DX-2930 subjects compared to placebo. Two subjects were 
reported to have 3 related severe TEAEs. One of these was a DX-2930 subject (30 mg) with 
injection site pain lasting 1 minute and one was a DX-2930 subject (400 mg) with worsening 
headache lasting 1 minute and night sweats.
No safety signals were identified for vital signs, physical examinations, clinical laboratory tests, 
or electrocardiograms (ECG). Results suggested DX-2930 was well tolerated in this study with 
no evidence of dose-limiting toxicity at doses up to 400 mg.
A total of 3 out of 92 post-dose samples (3.3%), obtained from 2 out of 23 subjects (8.7%), were 
confirmed to be anti-drug antibody-positive. No samples were positive for neutralizing activity.
The pharmacokinetic analysis for all subjects in the 30, 100, 300, and 400 mg doses showed drug 
levels in HAE subjects were dose-dependent and exhibited a prolonged half-life of 
approximately 2 weeks, typical of a human monoclonal antibody. Cmax drug levels increased with 
increasing dose, as expected. These parameters were consistent with values obtained in healthy 
subjects in Study DX-2930-01.
A Western blot assay showed pre-dose baseline levels of mean 2-chain HMWK in unactivated 
plasma collected from patients with HAE was approximately 50%. A statistically significant 
reduction in 2-chain HMWK levels was observed on study days 8 and 22 in the 300 and 400 mg 
dose groups compared to pre-dose levels, and approached levels similar to that observed in 
healthy subjects. This outcome demonstrated the pharmacodynamic activity of DX-2930 and its 
ability to effectively normalize the instability of HAE plasma in this assay. 
Primary efficacy analyses were based on subjects in the 300 mg, 400 mg, and placebo dose 
groups who reported having at least 2 attacks in the 3 months prior to study entry 
(0.15 attacks/week). Of those subjects treated with 300 or 400 mg DX-2930, 15 of 16 subjects 
met these criteria. Of the placebo treated subjects, 11 of 13 subjects met these criteria. 
The baseline HAE attack rates (attacks/week) were 0.39 attacks per week in the placebo group, 
0.33 attacks per week in the 300 mg group, 0.55 attacks per week in the 400 mg group and 0.49 
attacks per week in the 300 and 400 mg combined group. During the pre-specified, primary 
efficacy interval of 6 weeks (from days 8 to 50; corresponding to a period of notable drug 
exposure), the HAE attack rate, adjusted for baseline attack rate, was 0 in the 300 mg group and 
0.045 attacks per week in the 400 mg group, compared to 0.37 attacks per week in the placebo 
group. This resulted in a 100% reduction vs placebo for the 300 mg DX-2930 group (P < 0.0001) 
and an 88% reduction vs placebo for 400 mg DX-2930 (P = 0.005). During this primary efficacy 
interval, 100% of subjects in the 300 mg group (P = 0.026) and 82% of subjects in the 400 mg 
group (P = 0.03) were attack-free compared with 27% of subjects in the placebo group.
The data from this study demonstrated proof of concept of the ability of DX-2930 to prevent 
acute attacks of HAE. A statistically significant finding of HAE attack prevention by DX-2930 
was observed. DX-2930 was well tolerated in HAE subjects up to 400 mg. Drug exposure 
appeared to be dose-proportional and consistent with the results obtained in healthy subjects in 


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Study DX-2930-01. Pharmacodynamic effect assays provided evidence that DX-2930 has a 
direct effect on plasma kallikrein activity in patient plasma.
For additional detail regarding Study DX-2930-02, please refer to the DX-2930 Investigator’s 
Brochure.
1.7
Rationale for Open-Label Extension Study DX-2930-04
The open-label DX-2930 extension study will be preceded by the initiation of a pivotal, multi-
center, double-blind, randomized, placebo-controlled parallel-arm study (Study DX-2930-03) 
evaluating the efficacy of DX-2930 in preventing acute angioedema attacks in patients with Type 
I or Type II HAE.  Further information on Study DX-2930-03 design can be found in Appendix 
5.
Subjects who complete the Study DX-2930-03 treatment period will be offered the option of 
rolling into the open-label extension study, Study DX-2930-04.  In addition, a limited number of 
individuals with HAE Type I or Type II who were not enrolled in Study DX-2930-03 (up to 
approximately100) will be also enrolled. 
The rationale for this open-label extension study is to evaluate the long-term safety of repeated 
subcutaneous treatment with DX-2930 and the long-term efficacy of DX-2930 in preventing 
HAE attacks.  For subjects rolling over from DX-2930-03 who were randomized to one of the 
active study arms, the total duration of exposure across both studies will cover 18 months.  For 
rollover subjects randomized to placebo in DX-2930-03, and for non-rollover subjects, the total 
duration of exposure will cover 12 months.  Combined, the overall exposure between Study 
DX-2930-03 and Study DX-2930-04 will provide a sizable dataset to evaluate DX-2930 as a life-
long, chronic treatment for preventing acute attacks of HAE.  
This study seeks to evaluate the outer bounds of DX-2930 dosing frequency (possibly beyond 
2 to 4 weeks) by assessing the duration of time between a rollover subject’s first open-label dose 
and their first reported HAE attack.  In addition, characteristics of all HAE attacks will be 
reported and compared to the subject’s historical baseline (for non-rollover subjects) or attack
history based on attacks reported in Study DX-2930-03 (for rollover subjects).
For non-rollover subjects, the study will evaluate the safety and efficacy of switching from a 
long-term prevention therapy (eg, C1-INH, anti-fibrinolytics, androgens) to DX-2930 dosing, 
while evaluating breakthrough attack characteristics compared to historical baseline both prior to 
and during co-administration  with their LTP therapy regimen and while receiving DX-2930 
alone.
For all subjects, the study will also assess immunogenicity of chronically administered DX-2930, 
PK and PD, subject health-related quality of life (QoL), subject experience with self-
administration, and ease of SC administration with DX-2930.


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2.
STUDY OBJECTIVES
2.1
Primary Objective
To evaluate the long-term safety of repeated subcutaneous (SC) administrations of DX-2930
2.2
Secondary Objectives
•
To evaluate the long-term efficacy of DX-2930 in preventing HAE attacks
•
To characterize the outer bounds of dosing frequency for DX-2930
2.3
Tertiary Objectives
•
To assess the immunogenicity of chronically administered DX-2930
•
To evaluate the effect of DX-2930 on health-related quality of life (QoL)
•
To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of SC 
administration of DX-2930
•
To evaluate safety and efficacy in the non-rollover population of switching from long-term 
prophylactic (LTP) treatment to DX-2930 
•
To evaluate breakthrough attack characteristics while receiving DX-2930 compared to 
historical baseline
•
To evaluate subject experience with self-administration of DX-2930 including ease of SC 
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3.
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
3.1.1
Overview
Study DX-2930-04 is an open-label, long term safety and efficacy extension study of DX-2930-
03, to evaluate the investigational medicinal product (IMP), DX-2930, in preventing acute 
angioedema attacks in patients with Type I and Type II HAE. There are two types of subjects 
who will be enrolled into this study:
•
Subjects who rollover from Study DX-2930-03 
•
Subjects who are non-rollover (ie, were not participants in Study DX-2930-03) 
Rollover Subjects
Rollover subjects are subjects who complete the double-blind treatment period at Day 182 of 
Study DX-2930-03 and consent to enter Study DX-2930-04.  Subjects who discontinue from
Study DX-2930-03 after enrollment are not eligible to enroll in Study DX-2930-04.  
Subjects should be asked about their interest in Study DX-2930-04 after enrollment into Study 
DX-2930-03 to anticipate enrollment and preparedness for Study DX-2930-04.  Willing subjects 
must sign informed consent for Study DX-2930-04 on or after Day 168 of Study DX-2930-03.  
Subjects who are eligible to roll over into Study DX-2930-04 but elect not to, may not enroll in 
Study DX-2930-04 at a later time. The first Study DX-2930-04 visit for rollover subjects (Day 0) 
will occur on the same day as Study DX-2930-03 Day 182 study visit. Rollover subjects will 
complete all Study DX-2930-03 final study assessments (Day 182) at which time they will be 
discharged from that study. No assessments conducted between Study DX-2930-03 Day 182 
study visit and the first Study DX-2930-04 visit (Day 0) will be duplicated.  Results of the final 
DX-2930-03 assessments on Day 182 will be used as the pre-dose results for Day 0 of Study 
DX-2930-04.
All subjects, caregivers, investigators and study site personnel will remain blinded to the 
DX-2930-03 treatment assignment until the conclusion of Study DX-2930-04.
Non-rollover subjects
At least 50 subjects (to approximately 100) who were not participants in Study DX-2930-03 will 
be permitted to enroll if they meet the eligibility requirements. Subjects who screen fail out of 
Study DX-2930-03 for not meeting the minimum attack requirements during the run-in period 
must wait until enrollment for the double-blind study has ended before they can screen for Study 
DX-2930-04. The Sponsor may ease this restriction based on the enrollment rate observed in 
Study DX-2930-03. Subjects who are still in the run-in period for Study DX-2930-03 when 
enrollment for that study closes, as well as subjects on prior LTP who screen fail out of Study
DX-2930-03 due to an inability to wash-out of their LTP, may screen for Study DX-2930-04 
following discussion with the Sponsor medical monitor.


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Screening Period:
Rollover subjects
There is no screening period for rollover subjects.
Non-rollover subjects
Non-rollover subjects must provide informed consent and have screening assessments completed 
within 4 weeks prior to their first open-label dose.  Screened non-rollover subjects (adults and 
adolescents) who are on LTP with C1-INH therapy for HAE can continue their current LTP until 
Day 8 (or Day 15) such that subjects will have received 2 (or 4) doses of C1-INH.  For subjects 
who are on attenuated androgens (eg, danazol) or anti-fibrinolytics (eg, tranexamic acid); a 
similar tapering schedule is recommended. However, the taper can be prolonged by an additional 
week, if medically indicated, as long as androgen or anti-fibrinolytic therapy is stopped within 3 
weeks of receiving the first dose of DX-2930.  
Treatment Period:
Rollover Subjects
Following informed consent and pre-dose assessments, rollover subjects will receive a single 
open-label dose of DX-2930 administered subcutaneously (SC) on Day 0. Subjects will not 
receive any additional DX-2930 doses until their first reported and investigator confirmed HAE 
attack.  As such, the total number of doses within the treatment period will vary by rollover 
subject.
The duration of time between the first open-label dose and first reported HAE attack will vary by 
rollover subject.  All rollover subjects must adhere to the Study Activities Schedule, for the 
entire duration of the study.  However, until a rollover subject reports their first HAE attack, only 
scheduled study visits where the following tests and assessments are performed must be 
conducted at the investigative site: pregnancy testing, clinical laboratory testing, physical 
examination, 12-Lead ECG, QoL, PK, PD and anti-drug antibody sample collection.  All other 
scheduled study visits may be conducted via site check-in calls to collect information on adverse 
events, concomitant therapy, and HAE attack data.  See Study Activities Schedule for which 
visits must be conducted at the study site.
Once a rollover subject reports their first HAE attack they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  If 
the second dose is to be administered within the accepted ± 4 day window around a scheduled 
study visit, this treatment visit will represent that scheduled visit. If that scheduled visit has 
already occurred, the day of the visit will be considered an acceptable, extra study visit.  
In the event that the second dose is to be administered outside of the accepted ±4 day window 
around a scheduled visit, the day of the visit will be considered an acceptable extra study visit 
(ie, this visit will not replace any scheduled visit). 


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Regardless of the study day, at the visit in which the second open-label dose of DX-2930 is 
administered, the subject will undergo pre-dose assessments for vital signs, physical 
examination, clinical laboratory testing, and blood sampling for PK, PD, and anti-drug antibody. 
Vital signs will be obtained at 1 hour post-dosing. As with all study visits, information will be 
collected on adverse events, concomitant therapy, and HAE attack data.
Regardless of when a rollover subject’s first HAE attack occurs, there will be a minimum of 10 
days between their first open-label dose and their second open-label dose. Following their second 
open-label dose, rollover subjects will continue to receive repeated SC administrations of open-
label DX-2930 every 2 weeks for the remaining duration of the treatment period per the 
scheduled dosing in the Study Activities Schedule. The treatment period will last 364 days from 
the date of the first open-label dose. The number of doses administered during this period will 
vary by subject based on the date of each subject’s second dose, but will not exceed 26 doses. 
The Day 350 study visit is the last visit at which a dose may be administered.
Non-rollover Subjects
Once all screening assessments have been completed and eligibility confirmed, non-rollover 
subjects will arrive at the study site and, following pre-dose assessments, receive an open-label 
dose of 300 mg DX-2930 administered SC on Day 0.  Non-rollover subjects will continue to 
receive SC administrations of open-label 300 mg DX-2930 every 2 weeks throughout the 
duration of the treatment period per the scheduled dosing in the Study Activities Schedule.  A 
total of 26 doses will be administered with the last dose administered at the Day 350 study visit.
All Subjects:
All doses (with the exception of the second dose for rollover subjects) require a minimum of 10 
days and maximum of 18 days between administrations, and should fall within the accepted ± 4 
day window around study visits. 
After the second DX-2930 dose is given either within the study window (±4 days) or an 
acceptable extra study visit, the 3rd dose must be administered at the next pre-defined study visit 
according to the schedule of assessments.
If a subject experiences an acute angioedema attack at any time during the study that in the 
opinion of the investigator requires medical intervention, standard of care therapy should be 
provided based on subject’s medical history and per locally approved product information. 
Administration of DX-2930 and study procedures will continue without alteration to the protocol 
study activities schedule, even if a subject receives treatment for a breakthrough angioedema 
attack on the day of a scheduled dose of study drug (if self-administering) or scheduled study 
visit.
Self-Administration
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a 
physical and mental capability of learning and willing to be trained) may be allowed to self-
administer treatment. Subjects must complete appropriate training by the investigator or designee 
and have their understanding of the procedures confirmed by the investigator or designee. 
Subjects are allowed to initiate self-administration at the subject’s home or other agreed upon 


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location after receiving the first 2 doses of DX-2930 at the study site. Once initiated, subjects 
may self-administer subsequent doses of DX-2930 at the investigational site (when visits are 
scheduled study site visits) or the subject’s home or other agreed upon location (when the study 
permits off-site dosing). See the Schedule of Activities for details. Adolescent subjects self-
administering DX-2930 will be supervised by a parent/legal guardian/caregiver. Alternatively, a 
parent/legal guardian/caregiver, after completing appropriate training, will be allowed to 
administer the investigational product to an adolescent without study site personnel supervision.
Site personnel will call subjects within approximately 3 days of the planned off-site self-
administrations to ensure the administration occurred, to collect AEs, concomitant medications, 
and to ensure all attacks have been appropriately documented.  Throughout the study, study site 
personnel will document information in source documents (ie, the subject’s medical record) and 
eCRF regarding the subject’s experience with self-administration and SC administration of DX-
2930.
Follow-up Period
After completion of the treatment period, all subjects will undergo safety evaluations during a 4-
week follow-up period. Figure 1 shows a schematic of the open-label extension study.
Figure 1
Schematic of the Open-Label Extension Study


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Modifications to Open-Label Dosing
If, at any time, an important dose-related safety signal is identified either from this study or 
Study DX-2930-03, the Sponsor may decide to switch the enrolled subjects who have not yet 
completed the treatment period, and any subsequent subjects, to receive a different open-label 
dose and/or frequency.
In addition, based on the results of Study DX-2930-03, the Sponsor may switch to a different 
dose and/or frequency.
3.1.2
Stopping Rules
3.1.2.1
Study Level Stopping Rules
Safety data, including SAEs and AESI, will be monitored regularly throughout the duration of 
the study. If any potential safety signal is identified as a result of monitoring in this study, or 
from any safety findings from Study DX-2930-03, or following DSMB review, the Sponsor may 
take actions as deemed appropriate, including suspending dosing in the study, while the potential 
risk is evaluated and a course of action has been determined.
3.1.2.2
Individual Stopping Rules
Dosing for any individual subject will be discontinued if the subject experiences a 
DX-2930-related SAE (or DX-2930-related, clinically significant non-serious AE) that, in the 
assessment of the investigator or DSMB recommendation, warrants discontinuation from further 
dosing for that subject’s well-being. The investigator has the ability to contact and consult with 
the Medical Monitor on such matters. Subjects will continue to be followed through the 
completion of all scheduled non-dosing visits, unless they request to be discontinued from the 
study.
3.1.3
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or other toxicity considered clinically relevant (AE, 
laboratory, physical examination, vital sign, or ECG finding) will be carefully monitored until 
resolution, which may include the following:
•
Additional clinical laboratory tests and/or other clinical investigations
•
Additional visits or extended duration of follow-up
•
Obtaining a specialist consultation
3.2
Rationale for Open-Label Extension Dose Selection
The dose selected for the open-label extension (300 mg every 2 weeks) is anticipated to be 
effective and safe as determined in the pivotal, double-blind DX-2930-03 study. If at any time an 
important dose-related safety signal is identified either from this study or Study DX-2930-03, the 
Sponsor may decide to switch the enrolled subjects who have not yet completed the treatment 
period, and any subsequent subjects, to receive a different open-label DX-2930 dose and/or 
frequency.


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Additionally, based on the efficacy results of Study DX-2930-03, the Sponsor may switch to a 
different dose and/or frequency.
3.3
Individual Subject Dosing and Follow-Up
All subjects will receive open-label DX-2930 during a 364 day treatment period.  The number of 
doses that rollover subjects receive during this period will vary by subject but will not exceed 26 
doses.  The last dose of open-label DX-2930 administered to these subjects may be given at the 
Day 350 study visit.  Non-rollover subjects will receive DX-2930 every 2 weeks for a total of 26 
doses, with the first dose administered on Day 0 and the final dose administered at the Day 350 
study visit.
There will be a ±4 day window around each study visit. There will be a minimum of 10 days 
between any two doses. Excluding the time interval between the first and second open-label 
doses for rollover subjects, there will be a maximum of 18 days between any two doses. Subjects 
will be monitored at the study site through 1 hour post-dose.
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a 
physical and mental capability of learning and willing to be trained) may be allowed to self-
administer treatment after completing appropriate training by the investigator or designee and
confirming their understanding. Subjects are allowed to initiate self-administration at the 
subject’s home or other agreed upon location after receiving the first 2 doses of DX-2930 at the 
study site. Once initiated, subjects may continue to self-administer subsequent doses of DX-
2930. Subjects who elect to self-administer investigational product will be provided the 
necessary supplies (see Section 5.7 and Section 6.15.1).
3.4
Study Duration for Individual Subjects
Following informed consent, subjects will either rollover from Study DX-2930-03 or undergo 
screening assessments (non-rollover subjects). Screening assessments for non-rollover subjects 
must occur within 4 weeks prior to the first open-label dose. Eligible subjects will be enrolled 
and undergo a 364 day treatment period. At the conclusion of the treatment period, subjects will 
be followed for an additional 4 weeks.


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4.
STUDY POPULATION SELECTION
4.1
Study Population
The study is expected to enroll subjects from Study DX-2930-03, as well as at least 50 (to 
approximately100) additional subjects who were not enrolled in Study DX-2930-03.  The total
enrollment is expected to be at least 150, but not more than 250 HAE Type I or II subjects.  
Subjects will be 12 years of age or older who experience at least 1 attack per 12 weeks. HAE 
diagnosis will be confirmed through documented clinical history and diagnostic testing 
conducted either during screening or during participation in Study DX-2930-02 or Study DX-
2930-03.
The subject population includes subjects who are 12 to 17 years old. Like adults, children with 
HAE can suffer from recurrent and debilitating attacks. Symptoms may present very early in 
childhood, and upper airway angioedema has been reported in patients with HAE as young as the 
age of 3 (Bork et al., 2003). In one case series of 49 pediatric patients with HAE, 23 had suffered 
at least one episode of airway angioedema by the age of 18 (Farkas, 2010). An important unmet 
medical need exists among children with HAE, especially adolescents, since the disease 
commonly worsens after puberty (Bennett and Craig, 2015; Zuraw, 2008).  The study will aim to 
enroll at least 15 subjects who are 12 to 17 years of age, inclusive of the estimated 10 subjects 12 
to 17 years old who are expected to roll over from Study DX-2930-03.
4.2
Inclusion Criteria
Subjects must meet the following criteria to be enrolled in this study:
1. Male and female HAE subjects who are 12 years of age or older at the time of screening. 
2. Documented diagnosis of disease HAE (Type I or II) based on all of the following:

Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria).

Diagnostic testing results obtained during screening (or a prior DX-2930 study) that 
confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level < 40% of the 
normal level. Subjects with functional C1-INH level 40-50% of the normal level may 
be enrolled if they also have a C4 level below the normal range.  Subjects may be 
retested if results are incongruent with clinical history or believed by the investigator 
to be confounded by LTP use. 

At least one of the following: Age at reported onset of first angioedema symptoms 
≤30 years, a family history consistent with HAE Type I or II, or C1q within normal 
range.
3. A historical baseline HAE attack rate of at least 1 attack per 12 weeks.


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4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, 
understand, and sign an informed consent form.  Subjects age 12 to 17, whose caregiver has 
provided informed consent, are willing and able to read, understand and sign an assent form.
5. Males and females who are fertile and sexually active must adhere to contraception 
requirements for the duration of the study as follows:

Females* of childbearing potential must agree to be abstinent or it is recommended to use 
highly effective forms of contraception from the screening period through 30 days after 
the final study visit.  This includes stable doses (for 3 months prior to study screening) of 
combined estrogen and progestin-containing hormonal contraception associated with 
inhibition of ovulation (oral, injectable or implantable), progestin-only hormonal 
contraception associated with inhibition of ovulation, intra-uterine device (IUD, all types) 
or intrauterine hormone releasing systems (IUS). Notes: 1) A female whose male partner 
has had a vasectomy must agree to use one additional form of medically acceptable 
contraception. 2) Use of a male condom with or without spermicide or cervical cap, 
diaphragm or sponge with spermicide or a combination (double barrier methods) are not 
considered highly effective.

Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study.

Males, including males who are surgically sterile (post vasectomy), with female partners 
of childbearing potential must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through 60 days after the final study 
visit. 
*NOTE:  Female rollover subjects (those who previously participated in Study DX-2930-
03) of childbearing potential may continue to use the birth control method used during 
Study DX-2930-03.
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. Discontinued from Study DX-2930-03 after enrollment for any reason.
2. If rolling over from Study DX-2930-03, presence of important safety concerns that would 
preclude participation in this study.
3. Concomitant diagnosis of another form of chronic, recurrent angioedema such as acquired 
angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), idiopathic 
angioedema, or recurrent angioedema associated with urticaria.


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4. Dosing with an investigational drug (not including DX-2930 or other HAE therapies) or 
exposure to an investigational device within 4 weeks prior screening.
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to 
screening or any newly initiated or dose modification of estrogen-containing medications 
with systemic absorption (such as oral contraceptives or hormonal replacement therapy) 3 
months prior to the screening visit.
6. Unwilling to discontinue use of long-term prophylactic therapy for HAE (C1-INH, attenuated 
androgens, or anti-fibrinolytics) within 3 weeks after starting DX-2930 treatment.
7. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3x 
upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of normal, or 
total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of 
Gilbert’s Syndrome).
8. Pregnancy or breastfeeding.
9. Subject has any condition that, in the opinion of the investigator or Sponsor, may 
compromise their safety or compliance, preclude successful conduct of the study, or interfere 
with interpretation of the results (eg, history of substance abuse or dependence, a significant 
pre-existing illness or other major comorbidity that the investigator considers may confound 
the interpretation of study results).


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5.
STUDY TREATMENT(S)
5.1
Description of Treatment(s)
For detailed information regarding open-label DX-2930 (lanadelumab) administration, refer to 
the Pharmacy Manual.
DX-2930 is a sterile, preservative-free solution for injection, pH 6.0. The active ingredient, 
DX-2930, is formulated using the following compendial components:  30 mM sodium phosphate
dibasic dihydrate, 19.6 mM citric acid, 50 mM histidine, 90 mM sodium chloride, 0.01% 
Polysorbate 80. Each open-label vial contains a nominal concentration of 150 mg DX-2930 
active ingredient in 1 mL solution.
For each 300 mg dose of DX-2930, each subject will receive a total of 2 mL (2 vials), which will 
be administered in a single 2 mL SC injection. The injection will be given in the upper arm, thigh 
or abdomen.
Self-Administration
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a 
physical and mental capability of learning and willing to be trained) may be allowed to 
self-administer treatment after completing appropriate training by the investigator or designee 
and demonstrating the comprehension to self-administer. Subjects are allowed to initiate self-
administration at the subject’s home or other agreed upon location after receiving the first 2 
doses of DX-2930 at the study site. Once initiated, subjects may continue to self-administer 
subsequent doses of DX-2930 at the investigational site (when visits are scheduled study site 
visits) or the subject’s home or other agreed upon location (when the study permits off-site 
dosing). See Schedule of Activities for details. Adolescent subjects self-administering 
investigational product will be supervised by a parent/legal guardian/caregiver. Alternatively, a 
parent/legal guardian/caregiver, after completing appropriate training, will be allowed to 
administer DX-2930 to an adolescent without study site personnel supervision. Site personnel 
will call subjects within approximately 3 days of the planned off-site self-administrations to 
ensure the administration occurred, to collect AEs, concomitant medications, and to ensure all
attacks have been appropriately documented.
Throughout the study, study site personnel will document information in the subject’s medical 
record and eCRF regarding the subject’s experience with self-administration and SC 
administration of DX-2930.
5.2
Dosing and Follow-Up Scheme
Details of subject dosing and follow-up are outlined in Section 3.1.1 and included in the Study 
Activities Schedule, Table 1. 
Rollover subjects will receive their first open label SC dose of DX-2930 on Day 0.  Subjects will 
not receive any additional DX-2930 doses until their first reported HAE attack. The second dose 
of DX-2930 may be administered at an unscheduled visit if it is outside of the accepted ±4 day 
window around a scheduled visit. Following this attack subjects will receive open label SC doses 


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of DX-2930 every 2 weeks until the end of the treatment period. Subsequent dosing after Dose 2 
requires a minimum of 10 days and a maximum of 18 days between administrations.
Regardless of when a rollover subject’s first HAE attack occurs, there will be a minimum of 
10 days between their first open-label dose and their second open-label dose. Following their 
second dose, rollover subjects will continue to receive repeated SC administrations of open-label 
300 mg DX-2930 every 2 weeks for the remaining duration of the treatment period per the 
scheduled dosing in the Study Activities Schedule. The treatment period will last 364 days from 
the date of the first open-label dose. The number of doses administered during this period will 
vary by subject based on the date of each subject’s second dose, but will not exceed 26 doses. 
The Day 350 study visit is the last visit at which a dose may be administered. 
Non-rollover subjects will receive their first open-label dose SC dose of DX-2930 on Day 0 and 
will continue to receive SC administrations of open-label DX-2930 every 2 weeks throughout the 
duration of the treatment period.  A total of 26 doses will be administered with the last dose 
administered at the Day 350 study visit.
After completion of the treatment period, all subjects will undergo safety evaluations during a 4-
week follow-up period.
5.3
Method of Identifying Subjects
Subjects meeting all eligibility criteria will be enrolled in the study and sequentially assigned a 
unique site-based identification number.
5.4
Prior and Concomitant Therapy
For subjects not rolling over from Study DX-2930-03, reasonable efforts will be made to 
determine all relevant treatments received by the subject from 4 weeks prior to screening through 
the final study visit. For subjects rolling over from Study DX-2930-03, concomitant therapy use 
will be carried forward from that study and will continue to be collected through the final study 
visit. 
All information on prior and concomitant therapy (including all prescription/non-prescription 
medications, herbal medications and vitamin supplements) must be recorded on the subject’s 
eCRF and should include the name of the procedure or drug and duration of the treatment (start 
and stop dates). Concomitant treatments (non-pharmacological treatments) include any surgical 
or diagnostic procedures.
5.4.1
Allowed Therapies
The following therapies are allowed during the study:
•
Therapies for co-existing conditions, including those for acute attacks of HAE, as described 
in Section 5.4.1.1 are permitted if not excluded in Section 5.4.2. The use of short-term 
prophylactic treatment for HAE will be permitted if medically indicated.  Short-term (pre-


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procedure) prophylaxis is defined as use of C1-INH to avoid angioedema complications from 
medically indicated procedures.
•
Therapies to treat any AEs the subject experiences during the study are permitted.
5.4.1.1
Management of HAE Attacks
Acute HAE attacks during the study are to be managed in accord with the investigator’s usual 
care of their patients, including use of acute attack therapies that the investigator deems as 
medically appropriate. Use of C1-INH will be permitted as an acute attack therapy but not as a 
LTP therapy. Administration of DX-2930 and study procedures will continue without alteration 
to the protocol-specified study schedule, even if the subject has symptoms of an HAE attack the 
day of DX-2930 administration and/or receives treatment for an HAE attack. The administration 
of DX-2930 can also be re-scheduled as long as the minimum and maximum timeframe between 
doses are met based on patient preference or physician discretion.
5.4.2
Excluded Concomitant Therapies
Use of the following treatments will not be permitted during the study:
•
Long-term prophylaxis for HAE (eg, use of C1-INH for LTP, attenuated androgens, or 
anti-fibrinolytics) once LTP is discontinued (within 3 weeks following first dose of 
DX-2930).
•
Angiotensin-converting enzyme (ACE) inhibitors.
•
Initiating or changing the dose of estrogen-containing medications with systemic absorption 
(such as oral contraceptives or hormonal replacement therapy) 3 months prior to the 
screening visit.
•
Use of androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) for 
non-HAE related medical conditions or for HAE after discontinuation during the first 
3 weeks.
•
Any other investigational drug or device.
5.5
Restrictions
5.5.1
Medical Interventions
Medical interventions deemed necessary by the investigator for the health and well-being of the 
subject will not be excluded during this study.
5.5.2
Fluid and Food Intake 
There are no restrictions on fluid and food intake. Subjects may continue their usual dietary 
regimens.
5.5.3
Activity
There are no activity restrictions. Subjects may continue their usual activity regimens.


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5.6
Treatment Compliance
All doses of open-label DX-2930 administered at the investigational site will be under the direct 
supervision of the investigator or qualified study site personnel designated by the investigator.
Subjects are allowed to initiate self-administration at the subject’s home or other agreed upon 
location after receiving the first 2 doses of DX-2930 at the study site. Once initiated, subjects 
may continue to self-administer subsequent doses of DX-2930 at the investigational site (when 
visits are scheduled study site visits) or the subject’s home or other agreed upon location (when 
the study permits offsite dosing). Site personnel will call subjects within approximately 3 days of
the planned off-site self-administrations to ensure the administration occurred, to collect AEs, 
concomitant medications, and to ensure all attacks have been appropriately documented. See 
Schedule of Activities for details. For all subjects, subsequent doses after the second dose require 
a minimum of 10 days and maximum of 18 days between administrations, and should fall within 
the accepted ±4 day window around study visits. 
For rollover subjects, after the second DX-2930 dose is given either within the study window 
(±4 days) or an acceptable extra study visit, the 3rd dose must be administered at the next pre-
defined study visit according to the schedule of assessments.
5.7
Packaging and Labeling
The open-label DX-2930 will be supplied by the Sponsor and prepackaged in a study kit for 
investigational studies. Each study kit will contain 1 vial of investigational product.  Both the 
vials and carton (kit) will be appropriately labeled according to local regulations and bear the 
unique study drug kit number. The investigative site will provide ancillary supplies including 
syringes, needles, and alcohol wipes to subjects. The site has the option of using needles of a 
different gauge to aid subject comfort with each SC injection. Subjects who elect to self-
administer investigational product will be provided the following supplies as applicable:
•
1 to 2 dose(s) supply of investigational product
•
Ancillary supplies, including syringes, needles, alcohol pads, a temperature monitoring 
device, and a container for sharps disposal
•
Subject accountability form to record investigational product storage conditions and 
administration details
All used and unused vials should be returned to the study kit cartons/boxes and transported to the 
site for drug accountability.  Written instructions on DX-2930 handling and self-administration 
procedures will be provided to trained subjects prior to initiating self-administration.  Refer to 
the Pharmacy Manual for additional details on DX-2930 and its administration.
5.8
Storage and Accountability
All DX-2930 will be shipped refrigerated to the study site and must be stored at 2ºC to 8ºC/36ºF 
to 46ºF in the carton and protected from light. Storage must be in a securely locked area, 
accessible to authorized persons only, until needed for dose preparation. See Section 5.7 and 
Section 6.15.1 for details.


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5.9
Investigational Medicinal Product Retention at Study Site
The investigator (or designee) is responsible for maintaining accurate accountability records of 
DX-2930 throughout the clinical study. All DX-2930 received at the site must be inventoried and 
accounted for in an accountability log provided by the Sponsor. All dispensing and 
accountability records will be available for Sponsor review. Drug accountability will be verified 
during on-site monitoring visits.
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used DX-2930 should be returned or 
destroyed at the investigational site, as specified by Sponsor. It is the investigator’s responsibility 
to ensure that the Sponsor, or its representative, has provided written authorization that 
procedures for proper disposal of DX-2930 have been established, and that appropriate records 
of the disposal are documented and maintained. No unused DX-2930 may be disposed until fully 
accounted for by the Sponsor monitor (or designee).


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6.
STUDY PROCEDURES
Please refer to Table 1: Study Activities Schedule.
6.1
Informed Consent
The ICF must be executed prior to performing any study related activities and must be approved 
by the reviewing institutional review board (IRB), research ethics board (REB), or independent 
ethics committee (IEC). Subjects may withdraw consent at any time. Participation in the study 
may be terminated at any time without the subject’s consent as determined by the investigator.
Subjects who are not rolling over from the double-blind DX-2930-03 study will provide 
informed consent at Screening. Subjects who are rolling over from the double-blind DX-2930-03 
study will provide consent on or after Day 168 of Study DX-2930-03. Upon completion of the 
final assessments, the subjects will be discharged from the double-blind study and will start 
participation in the OLE study and receive their first open-label dose.
6.2
Eligibility Review
The investigator or qualified study site personnel will confirm that all Inclusion and Exclusion 
criteria have been met.
6.3
Demographics and Medical History
Demographics: date of birth (alternately age or year of birth, if full date is not allowed to be 
collected for legal reasons), sex, race, and ethnicity (where locally permitted) and medical 
history will be obtained at Screening from subjects not rolling over from Study DX-2930-03 and 
will be recorded on the source document and eCRF. Medical history will capture the subject’s 
current medical status (current disease processes), past medical status (past disease processes), 
history of surgery, allergies and concomitant medications. For subjects rolling over from Study 
DX-2930-03, these data will be carried forward from that study. 
6.4
HAE Attack Information Collection
The collection, reporting and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP).  Study site personnel will be 
trained on HAARP prior to screening and enrolling subjects at their site.
Study site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide.  The 
subject (and caregiver) will confirm their understanding of what is required of them for reporting 
attacks to the site.
At screening, HAE attack history will be collected for non-rollover subjects. Information 
collected will include any prior history of laryngeal attacks, attack frequency, average severity, 
predominant attack location(s), triggers, average duration, acute attack therapy use and history of 
LTP (including duration of LTP, medication(s) and dose used for LTP, and frequency of attacks 


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while receiving LTP).  If available, information will also be collected on HAE diagnosis (year of 
confirmation, how many years after onset of symptoms was diagnosis confirmed, or if subject 
was misdiagnosed).
During the study, subjects (or caregivers) will be instructed to notify and report details to the 
study site within 72 hours of the onset of an attack. This includes the first attack experienced by 
rollover subjects following their first open-label dose.  In the situation that a subject is 
incapacitated following an attack, this information can be provided to the site by a family 
member or other individual with detailed knowledge of the event. If desired by the subject,
memory aids may be provided to assist in tracking any HAE attacks experienced, but their use is 
not mandatory.
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack:
•
Date and time symptoms of an attack were first experienced
•
Description of symptoms experienced, including location(s)
•
Impact on activity (work, school, social interactions) and whether any assistance or medical 
intervention was required, including hospitalizations, additional laboratory tests, or 
emergency department visits
•
Any medications used to treat the attack (both prescription and over the counter)
•
If the attack resolved, date and time the subject was no longer experiencing symptoms
Study site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP.
Study site personnel will contact rollover subjects approximately every 7 days following the first 
dose of open-label until the subject has received their second open label dose.  This is to insure 
accurate reporting for any HAE attacks not already reported by the subject as required within 72 
hours.  During each study visit, study site personnel will solicit for any new HAE attack 
information that was not already provided to the site.
In this study, HAE attacks will be captured as AEs. All AEs, regardless of seriousness, severity, 
or causal relationship to DX-2930, will be recorded on the AE page of the eCRF. Any AE 
reported to the site meeting criteria for a serious adverse event must be reported to the Sponsor 
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of the 
event. For all serious adverse events that are reported as HAE attacks, the investigator or 
physician designee will review the event within 24 hours of initial notification and, in 
accordance with HAARP, evaluate if it represented a confirmed HAE attack. For all non-serious 
AEs that are reported as HAE attacks, the investigator or physician designee will review the 
event within 3 days of initial notification and, in accordance with HAARP, evaluate if it 
represented a confirmed HAE attack. If necessary for the evaluation, the investigator or designee 
may contact the subject to receive additional information. Any subject-reported attack not 
confirmed by the investigator or physician designee must have an alternate AE diagnosis 


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recorded.  All subject-reported and investigator/ physician designee-confirmed HAE attacks will 
be recorded in the eCRF. 
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured.
To be confirmed as an attack, the event must have symptoms or signs consistent with an attack in 
at least one of the following locations: 
•
Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region
•
Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea
•
Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx
Despite the presence of these symptoms, the investigator or physician designee may still 
clinically determine that the event did not represent an attack if there are features that strongly 
refute such a diagnosis. For example, the reported event is accompanied by symptoms that are 
not consistent with an HAE attack (eg, urticaria), the reported event persists well beyond the 
typical time course of an HAE attack, or there is a likely alternate etiology for the event (eg, the 
subject’s abdominal symptoms are attributable to a viral gastroenteritis outbreak in the 
household). 
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.
6.5
Vital Signs
Vital signs prior to dosing and at 1 hour post-dosing (±15 min) will be assessed by the 
investigator or his/her qualified designee according to the Study Activities Schedule (Table 1) 
unless the subject has elected to self-administer off-site for that visit. Routine vital sign 
assessments will be taken with the subject in the sitting or supine position after 5 minutes at rest 
and will include body temperature, heart rate (HR), blood pressure (BP) and respiratory rate 
(RR). BP should be determined using the same arm and the same equipment for each assessment.  
For subjects who rollover from Study DX-2930-03, vital signs taken during the final study visit 
in Study DX-2930-03 will serve as the Day 0 pre-dose vital signs in this study and will not be 
duplicated.  
6.6
Physical Examination
A physical examination including height, weight, and calculation of Body Mass Index (BMI) 
will be performed by the investigator or his/her qualified designee according to the Study 
Activities Schedule (Table 1). The physical examination will be performed in accordance with 
standards at the site. 


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For subjects who rollover from Study DX-2930-03, the physical exam taken during the final 
study visit in Study DX-2930-03 will serve as the Day 0 pre-dose physical exam in this study 
and will not be duplicated.  Weight should be collected at every exam.
6.7
Electrocardiography (ECG)
A standard 12-lead ECG (single recording) will be performed according to the Study Activities 
Schedule (Table 1). The date and time of each ECG and its results will be documented in the 
source documents and eCRF. Electrocardiograms will be sent to a central reading vendor for 
assessment. For subjects who rollover from Study DX-2930-03, the ECG taken during the final 
study visit in Study DX-2930-03 will serve as the Day 0 pre-dose ECG in this study and will not 
be duplicated.
6.8
Clinical Laboratory Tests
6.8.1
Laboratory Parameters
Laboratory testing will be performed according to the Study Activities Schedule (Table 1).
Laboratory testing includes general safety parameters (hematology, coagulation, urinalysis, and 
serum chemistry), pregnancy tests (in females of childbearing potential), C1-INH functional 
assay, C4 assay, C1q assay, PK sampling, PD sampling, and plasma anti-drug antibody testing. 
All laboratory tests will be performed using established and validated methods. 
When multiple sample collection types are performed at the same assessment time point, the 
samples will be drawn in the following order (depending on what sample types are to be 
collected at that time point): laboratory safety samples (hematology, coagulation, serum 
chemistry), C1-INH, C4, C1q, PK, anti-drug antibodies, PD. Aliquots from the PK, PD and anti-
drug antibody samples may be retained as back-up for additional parameter testing if necessary. 
Subjects will be in a seated or supine position during blood collection. The total blood draw for 
each rollover subject will be approximately 269.8 mL. The total blood draw for each non roll-
over subject will be approximately 283 mL. For subjects who rollover from Study DX-2930-03, 
testing performed during the final study visit in Study DX-2930-03 will serve as the Day 0 pre-
dose laboratory testing in this study and will not be duplicated.
6.8.1.1
Hematology
•
Hemoglobin
•
Hematocrit
•
Red blood cell (RBC) count
•
White blood cell (WBC) count with differential
•
Mean corpuscular volume (MCV)
•
Mean corpuscular hemoglobin (MCH)
•
Mean corpuscular hemoglobin concentration (MCHC)
•
Absolute platelet count


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6.8.1.2
Coagulation
•
Prothrombin time (PT)
•
Activated partial thromboplastin time (aPTT)
•
International Normalized Ratio (INR)
6.8.1.3
Chemistry
•
Albumin
•
Alkaline phosphatase
•
Alanine aminotransferase (ALT; SGPT)
•
Aspartate aminotransferase (AST; SGOT)
•
Bilirubin (total and direct)
•
Blood urea nitrogen (BUN)
•
Calcium
•
Carbon dioxide (CO2)
•
Chloride
•
Creatinine
•
Creatine phosphokinase (CPK)
•
Glucose
•
Phosphate
•
Magnesium
•
Potassium
•
Sodium
•
Total protein
•
Uric acid
6.8.1.4
Urinalysis
•
Bilirubin
•
Glucose
•
Ketones
•
Blood 
•
Nitrite
•
pH
•
Protein
•
Specific gravity
•
Microscopy (if indicated by macroscopic findings)


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Urinalysis does not need to be done as part of the clinical laboratory testing at Visits 14, 17, 20, 
and 23.
6.8.1.5
Pregnancy Test
Pregnancy tests will be either serum or urine based according to the Study Activities Schedule
(Table 1).
6.8.1.6
C1-INH Functional Assay
Results of a C1-INH functional assay are required for eligibility assessment. Samples will be 
drawn at the Screening visit unless they were previously drawn in Study DX-2930-02 or Study 
DX-2930-03. Results of the C1-INH functional assay from DX-2930-02 or Study DX-2930-03 
may be used to confirm diagnosis in this study. Subjects may be retested if results are 
incongruent with clinical history or believed by the investigator to be confounded by recent LTP 
use.
6.8.1.7
C4 Assay
Results of a C4 assay may be required for eligibility assessment.  The C4 sample will be drawn 
at the same time as the C1-INH sample is drawn during the Screening visit unless previously 
drawn in Study DX-2930-02 or Study DX-2930-03.  Results of the C4 assay from DX-2930-02 
or Study DX-2930-03 may be used to confirm diagnosis in this study.  Subjects may be retested 
if results are incongruent with clinical history or believed by the investigator to be confounded 
by recent LTP use. 
6.8.1.8
C1q Assay
Results of a C1q assay may be required for eligibility assessment. Any subject who requires 
C1-INH and C4 assay results for diagnostic confirmation in this study will have C1q assay 
results obtained as well.  The C1q sample will be drawn at the same time as the C1 and C4 
sample is drawn during the Screening visit. 
6.8.1.9
PK Sample Collection
As outlined in Section 6.9.
6.8.1.10
PD Sample Collection
As outlined in Section 6.10.
6.8.1.11
Plasma Anti-Drug Antibody Testing
As outlined in Section 6.11.
6.8.2
Sample Collection, Storage, and Shipping
Blood samples for laboratory assessments will be collected at the site by a trained site staff 
designated and/or approved by the study investigator. Details for the collection, processing, 
storage and shipment of samples for all laboratory determinations will be provided in the 
Laboratory Manual.


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Biological material will be stored and secured in a manner that assures that unauthorized access 
is prohibited and the samples are not lost, allowed to deteriorate, or accidentally or illegally 
destroyed.
6.9
Pharmacokinetic Assessments
Blood samples for the measurement of plasma DX-2930 concentration will be obtained as 
specified in the Study Activities Schedule (Table 1).
6.10
Pharmacodynamic Assessments
To evaluate the PD effects of DX-2930 upon plasma kallikrein activity, blood samples will be 
obtained as specified in the Study Activities Schedule (Table 1).
6.11
Plasma Anti-Drug Antibody Testing 
Plasma samples for testing for formation of antibodies to DX-2930 will be obtained as specified 
in the Study Activities Schedule (Table 1).
6.12
Prior and Concomitant Therapy
The Sponsor representatives and investigator at the site conducting the trial will review and 
evaluate prior (4 weeks prior to study screening) and concomitant medication usage on an 
ongoing basis. For subjects not rolling over from Study DX-2930-03, all prescription, over-the-
counter medications, herbals, and supplements that are being taken or have been taken by 
subjects from 4 weeks prior to screening through the duration of the study will be regarded as 
concomitant medications and must be documented on the source document and eCRF following 
informed consent.  For subjects rolling over from Study DX-2930-03, concomitant therapy use
will be carried forward from that study and will continue to be collected through the duration of 
the study. 
6.13
Investigational Medicinal Product Treatment
Instructions for safe handling of DX-2930, preparation of each subcutaneous dose and 
administration of DX-2930, are provided in the Pharmacy Manual. Preparation and dispensing of 
DX-2930 will be handled by qualified study site personnel or by subjects who are self-
administering after receiving appropriate training by the investigator or designee at the study site.
The requirements for maintaining DX-2930 accountability are provided in Section 6.15.1 (for 
subjects self-administering) and Section 5.7 and Section 5.8 of this protocol.
6.14
Quality of Life Assessments
Quality of life (QoL) assessments will be conducted using the Angioedema Quality of Life 
Questionnaire (AE-QoL), EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L), Work 
Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH), Hospital 
Anxiety and Depression Scale (HADS), and 12 Item Short Form Survey (SF-12). See Study 
Activities Schedule (Table 1). For subjects who rollover from Study DX-2930-03, quality of life 


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assessments obtained during the final study visit in Study DX-2930-03 will serve as the Day 0 
pre-dose quality of life assessments in this study and will not be duplicated.
6.14.1
Angioedema Quality of Life Questionnaire (AE-QoL)
The AE-QoL is a self-administered, symptom-specific tool developed and validated to assess 
quality of life (QoL) impairment in patients with recurrent angioedema (Weller et al., 2012). The 
AE-QoL consists of 17 questions covering four domains/dimensions (functioning, fatigue/mood, 
fear/shame, nutrition). Each of the 17 items has a five-point Likert-type response scale ranging 
from 1 (Never) to 5 (Very Often). The AE-QoL is scored to produce a score for each domain and 
a total score ranging from 0 to 100, with higher scores indicating stronger impairment. It takes 5 
minutes to complete the AE-QoL.
6.14.2
EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L)
The EQ-5D-5L is a self-administered standardized measure of health status comprised of a 
descriptive system and a Visual Analogue Scale (VAS). The descriptive system consists of five 
health related quality of life dimensions (ie, mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression). Each dimension is rated on a 5-point response scale (5 levels) indicating 
severity of problems, where 1 is “no problems” and 5 is “extreme problems”. The EQ-5D VAS is 
a measure of overall self-rated health status on a 20-cm vertical VAS with endpoints labelled 
“the best health you can imagine” and “the worst health you can imagine”. The VAS ranges from 
0 to 100, with higher scores indicative of better overall health.
6.14.3
Work Productivity and Activity Impairment – General Health (WPAI-GH)
Questionnaire
The WPAI-GH is a 6-item instrument assessing work and activity impairment due to health 
problems during the past 7 days. The instrument elicits four main scores in relation to general 
health specifically: absenteeism (the percentage of work time missed because of one's health in 
the past seven days), presenteeism (the percentage of impairment experienced while at work in 
the past seven days because of one's health), overall work productivity loss (an overall 
impairment estimate that is a combination of absenteeism and presenteeism), and activity 
impairment (the percentage of impairment in daily activities because of one's health in the past 
seven days) (Reilly et al., 1993). Adolescent subjects should complete the WPAI questionnaire 
and use the term “school” instead of “work” when filling out this questionnaire.  These data will 
be analyzed separately.
6.14.4
Hospital Anxiety and Depression Scale (HADS)
The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale to detect states of 
depression, anxiety, and emotional distress amongst patients who were being treated for a variety 
of clinical problems (Zigmond and Snaith, 1983). The scale has a total of 14 items. Seven of the 
items relate to anxiety and seven relate to depression.  The responses are scored on a scale of 0–3 
(3 indicates higher symptom frequencies). Scores for each subscale (anxiety and depression) 
range from 0 to 21 with scores categorized as follows: normal 0–7, mild 8–10, moderate 11–14, 
and severe 15–21. Scores for the entire scale (emotional distress) range from 0 to 42, with higher 
scores indicating more distress. This scale reflects how a subject has been feeling during the past 
week.


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6.14.5
12 Item Short Form v2 Health Survey (SF-12v2)
The SF-12v2 Health Survey is a reliable and valid generic measure of functional health and well-
being. The SF-12v2 consists of 12 questions, all selected from the SF-36 Health Survey (Ware et 
al., 1996). The SF-12v2 yields eight health domains (vitality, physical functioning, bodily pain, 
general health perceptions, physical role functioning, emotional role functioning, and mental 
health summary measures. Physical and Mental Health Composite Scores (PCS & MCS) can be 
computed using the scores of twelve questions and range from 0 to 100, where a zero score 
indicates the lowest level of health measured by the scales and 100 indicates the highest level of 
health. The standard form of the instrument asks subjects to reply to questions according to how 
they have felt over the last 4 weeks.
6.15
DX-2930 Injection Report and Self-Administration and Subcutaneous Injection 
Survey
Assessments of subject experience with self-administration and SC injections of DX-2930 will 
be conducted.
6.15.1
DX-2930 Injection Report
The investigator or designee will train subjects who elect to self-administer DX-2930 on the 
following:
•
Transportation and recommended storage conditions of investigational product from the 
study site to the offsite location.
•
Maintenance of accurate records regarding each administration of investigational product 
including supply identification (ie, lot/kit number), date and time of injection, injection site 
location, infusion time, and if applicable, any reason the self-administration could not be 
completed as instructed.
•
Retention of all used and unused vials of investigational product for drug accountability 
purposes.
After receiving appropriate training and demonstrating their understanding of self-
administration, subjects are allowed to self-administer DX-2930 after receiving the first 2 doses 
of DX-2930 at the study site (administered by study personnel). For those subjects who choose to 
self-administer or have a parent/legal guardian/caregiver administer DX-2930, subjects must 
complete an assessment of their experience with self-administration and subcutaneous injection
for each dose received. Study personnel will document the subject’s responses in the subjects’ 
medical record and eCRF.
6.15.2
DX-2930 Self-administration and Subcutaneous Injection Survey
Subjects will complete an assessment on their overall experience with self-administration and 
experience with receiving SC injections of DX-2930 according to the Study Activities Schedule
during the study. For subjects who have previously received LTP with C1-INH products via IV
administration, they will be asked to indicate the preferred route for medication administration. 
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In addition, investigators will be asked to indicate their preference (SC, IV, or no preference) on 
the route to administer medications to prevent angioedema attacks.
6.16
Adverse Event Reporting
Adverse events will be collected from signing of the informed consent through the last study 
visit.
6.16.1
Definitions
6.16.1.1
Adverse Event
An AE is any untoward medical occurrence in a clinical trial subject whether or not it appears to 
have a causal relationship with the treatment administered. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product or 
participation in a clinical study, whether or not directly related to the medicinal product or study 
participation.
•
AEs may be new events or may be pre-existing conditions that have become aggravated or 
have worsened in severity or frequency during the course of the study.
•
AEs may be clinically significant changes from baseline in physical examination, laboratory 
tests, or other diagnostic investigation (eg, laboratory results, x-ray findings).
Laboratory abnormalities generally are not considered AEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. A clinically significant laboratory 
abnormality that is independent from a known underlying medical condition and that requires 
medical or surgical intervention, or leads to DX-2930 interruption or discontinuation, will in 
itself, be considered an AE. Laboratory or diagnostic testing abnormalities that reflect or are part 
of a known underlying medical condition are not, in themselves, AEs; rather, the underlying 
medical condition leading to the abnormalities would be reported as the AE.
Pregnancy is not an AE; however, if a female subject becomes pregnant during the conduct of 
the study, the investigator must notify the Sponsor according to the procedures provided in 
Section 6.16.5.2.
6.16.1.2
Serious Adverse Event
A SAE is any adverse experience occurring at any dose that results in any of the following 
outcomes:
•
Death
•
Life-threatening experience; Note: “Life-threatening” refers to a situation in which the 
subject was at risk of death at the time of the event; it does not refer to an event that might 
have caused death if it were more severe.
•
Requires inpatient hospitalization or prolongation of existing hospitalization; Note: Does not 
include hospitalization for observation with release within 24 hours. A scheduled 


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hospitalization for a pre-existing condition that has not worsened during participation in the 
study does not meet this criterion. Pre-planned hospitalizations for an elective 
medical/surgical procedure or routine check-ups do not meet this criterion.
•
Results in persistent or significant disability or incapacity.
•
Is a congenital anomaly or birth defect.
•
Is considered to be an important medical event defined as those that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed in the definition above.
6.16.1.3
Overdose
An overdose is defined as a significant variation from the recommended/scheduled dosage for a 
product. The dosing for this study will be conducted in a controlled clinical setting and an 
overdose is not anticipated. However, in the event of an accident, for this study, an overdose of 
DX-2930 is considered a dose that is two-fold higher than the intended dose for the subject.
6.16.1.4
Planned Hospitalization
A hospitalization planned by the subject prior to the first dose of open-label DX-2930 is 
considered a therapeutic intervention and not the result of a new SAE and should be recorded as 
medical history. If the planned hospitalization or procedure is executed as planned, the record in 
the subject’s medical history is considered complete. However, if the event/condition worsens 
during the trial, it must be reported as an AE.
6.16.1.5
Treatment-Emergent Adverse Events (TEAE)
An AE is treatment-emergent if the onset time is after first administration of open-label DX-2930
through the final follow-up visit or, in the event that onset time precedes first DX-2930 
administration, the AE increases in severity during the open-label treatment period.
For rollover subjects, any adverse event that started during the subject’s participation in Study 
DX-2930-03 and was ongoing at the time of the first open-label dose in Study DX-2930-04 will 
not be counted as an AE in Study DX-2930-04 unless that event has worsened in severity or 
frequency following the first open-label dose.  Adverse events that started during subject 
participation in Study DX-2930-03, resolved following the first open-label dose in Study DX-
2930-04, and then subsequently reappeared in Study DX-2930-04 will be counted as a new 
TEAE in Study DX-2930-04.
6.16.1.6
Adverse Events of Special Interest (AESI)
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Investigators will report all AESI to the Sponsor, regardless of causality, using the same 
timelines as described for SAE reporting. The following describe the AESI and the criteria for 
reporting AESI. 


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HYPERSENSITIVITY REACTIONS
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours, only if the reactions 
are suspected to be related to study drug.
EVENTS OF DISORDERED COAGULATION
Bleeding AESI
Although aPTT prolongation due to plasma kallikrein inhibition is an artifactual in vitro
phenomenon, as a precautionary measure in evaluating the safety of DX-2930, bleeding events 
will be reported as AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with a clinical event of 
bleeding. Coagulation testing (aPTT, PT, INR) should be performed when possible, and when 
temporally reasonable, with any reports of bleeding or for clinical conditions possibly indicative 
of bleeding.
Hypercoagulable AESI
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot be 
determined, that are consistent with a thrombotic or embolic etiology. 
6.16.2
Monitoring
6.16.2.1
Monitoring of Adverse Events
Each subject will be monitored for the occurrence of AEs, including SAEs and AESI, from 
signing of the ICF through the final follow-up visit.
•
Subjects will be questioned and/or examined by the investigator or a qualified designee for 
evidence of AEs. The questioning of subjects with regard to the possible occurrence of AEs 
will be generalized such as, "How have you been feeling since your last visit?”  The presence 
or absence of specific AEs should not be elicited from subjects.
•
Subjects having TEAEs will be monitored until resolution with relevant clinical assessments 
and laboratory tests, as determined by the investigator.
•
AEs, actions taken as a result of AEs, and follow-up results must be recorded in the eCRF as 
well as in the subject's source documentation. Follow-up laboratory results should be filed 
with the subject's source documentation.
For any SAEs or AEs that require the subject to be discontinued from dosing, relevant clinical 
assessments and laboratory tests will be repeated as clinically appropriate, until final resolution 
or stabilization of the event(s). Subjects will continue to be followed through completion of all 
scheduled visits.


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6.16.2.2
Monitoring of Safety Laboratory Assessments
All safety laboratory assessments will be performed at a central laboratory. The clinical 
laboratory values will be reported to the investigator who will review them for clinical 
significance and consideration of abnormal values as potential AEs.
6.16.3
Assessment of Adverse Events
6.16.3.1
Assessment of Severity
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe nausea). This is not the same as “serious,” which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning.
In this study, the severity of AEs will be assessed according to Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table, Draft, November 2007 (US National 
Institutes of Health: National Institute of Allergy and Infectious Diseases) (Appendix 1, 
Appendix 2) and the Division of Microbiology and Infectious Diseases (DMID) Pediatric 
Toxicity Table, Draft, November 2007 (US National Institutes of Health: National Institute of 
Allergy and Infectious Diseases) (Appendix 3). For abnormalities not specifically found in the 
Toxicity Tables, the following general scale will be used to estimate grade of severity:
•
GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required
•
GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required
•
GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible 
•
GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable
Any treatment-emergent ECG abnormality that is considered by the investigator as clinically 
significant and requiring intervention/therapy will be assessed as a severe AE.
All HAE attacks will be captured as AEs and assessed with DMID & HAE Attack Assessment 
and Reporting Procedures (HAARP) criteria.
6.16.3.2
Assessment of Causality
A medically qualified investigator must assess the relationship of any AE (including SAEs) to 
the use of DX-2930, as related or not related, based on clinical judgment and using all available 
information, and may include consideration of the following factors:
•
Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic factors.
•
The temporal association between DX-2930 exposure and onset of the AE.


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•
Whether the manifestations of the AE are consistent with known actions or toxicity of 
DX-2930.
•
The AE resolved or improved with decreasing the dose or stopping use of DX-2930
(dechallenge). Judgment should be used if multiple products are discontinued at the same 
time.
The causal relationship between DX-2930 and the AE will be assessed using one of the 
following categories:
Not Related:  Factors consistent with an assessment of Not Related include:

Temporal relationship is lacking (eg, the event did not occur within a reasonable 
time frame following administration of DX-2930); or

Other causative factors more likely explain the event (eg, a pre-existing condition, 
other concomitant treatments).
Related:  Factors consistent with an assessment of Related include:

There is a positive temporal relationship (eg, the event occurred within a 
reasonable time frame following administration of DX-2930); or

The AE is more likely explained by administration of DX-2930 than by another 
cause (ie, the AE shows a pattern consistent with previous knowledge of 
DX-2930 or the class of DX-2930).
6.16.3.3
Assessment of Clinical Significance
Clinical significance of individual AEs will be determined by the investigator, with discussion 
with the Medical Monitor as appropriate.
6.16.4
Clinical Laboratory Adverse Events
Laboratory abnormalities generally are not considered AEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. A clinically significant laboratory 
abnormality that is independent from a known underlying medical condition and that requires 
medical or surgical intervention, or leads to DX-2930 interruption or discontinuation, will be 
considered an AE.
When laboratory abnormalities are considered to be AEs, the DMID Adult Toxicity Table 
(Appendix 2) or DMID Pediatric Toxicity Tables (Appendix 3) will be used to assess severity. 
Where discrepancies in the upper limit of normal (ULN) and lower limit of normal (LLN) of 
laboratory ranges occur between those included in the DMID tables and those of the laboratory 
that performs the assays, the values provided by the laboratory will be used for assignment of 
severity grade. Clinical significance of individual laboratory AEs will be determined by the 
investigator with input from the Medical Monitor as needed. 
Following is an exception to defining clinically significant, abnormal laboratory values as AEs:


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
APTT prolongation in the absence of any associated bleeding or other evidence of clinical 
relevance will not be considered a clinically significant laboratory abnormality or AE. In the 
appropriate physiologic setting, such as IV heparin therapy, aPTT can be used to monitor 
bleeding risk. However, as noted in the Investigators Brochure, aPTT prolongation due to 
plasma kallikrein inhibition is an artifactual in vitro phenomenon. Although plasma kallikrein 
drives fibrin formation in the aPTT assay, plasma kallikrein-driven coagulation does not 
appear to have hemostatic or other physiologically important functions in vivo. It is well 
documented that, in humans, deficiency of factor XII or prekallikrein (and thus plasma 
kallikrein) is not associated with abnormal bleeding, either spontaneous or during surgical 
procedures (Renne and Gruber, 2012). Despite the lack of clinical effect, deficiency of either 
protein is associated with marked prolongation of the aPTT. 
6.16.5
Reporting Investigator Safety Observations to the Sponsor
6.16.5.1
Reporting Non-serious Adverse Events
All AEs, regardless of seriousness, severity, or causal relationship to DX-2930, will be recorded 
on the AE page of the eCRF. In this study all HAE attacks reported by the subject, regardless of 
whether or not they are confirmed by the investigator, will be captured as AEs.
6.16.5.2
Reporting Pregnancies
If a female subject or the female partner of a male subject becomes pregnant during the course of 
the study, the investigator must report the pregnancy to the Sponsor’s Pharmacovigilance 
Department using the Pregnancy Reporting Form within 24 hours of becoming aware of the 
event. The investigator must obtain consent to collect pregnancy information (including the 
status of the newborn, if applicable).
If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and submitted 
within 24 hours of becoming aware of the new information. The investigator is required to 
follow the pregnancy through delivery. The outcome of the pregnancy and the status of the 
newborn (if applicable) will be reported on the Pregnancy Reporting Form within 24 hours of 
becoming aware.
6.16.5.3
Safety Observations Requiring Expedited Reporting by the Investigator to 
the Sponsor
Any occurrence of the following events or outcomes in a subject in the trial must be reported 
expeditiously by the investigator or qualified designee to the Sponsor’s Pharmacovigilance 
Department:
•
SAE
•
AESI
•
Overdose
•
Cancer


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The investigator is to report any expedited safety observations from the list above to the Sponsor
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of the 
event.
Any SAE reported to the Sponsor Pharmacovigilance Department using the SAE Reporting 
Form in the EDC system is to be recorded in the eCRF, as well as in the subject's source 
documentation along with any actions taken. If all required information on the form is not 
available at the time of the initial report, follow-up information will be completed in the EDC 
system.
The investigator is required to follow SAEs until resolution regardless of whether the subjects 
are still participating in the study. SAE resolution is defined as:
•
Resolved with or without residual effects.
•
A return to baseline for a pre-existing condition.
•
Laboratory values have returned to baseline or stabilized.
•
The investigator does not expect any further improvement or worsening of the event.
•
Fatal outcome—if an autopsy is performed; the autopsy report is requested to be provided to 
the Sponsor as soon as it is available.
6.16.5.4
Expedited Reporting by the Sponsor to a Regulatory Health Authority
The Sponsor or designee will report relevant safety information to concerned health authorities 
in accordance with local laws and regulations.
6.16.5.5
Safety Contact Information
24-Hour Global Safety Contact: Pharmacovigilance Department
Email:
Telephone (US) 
6.16.5.6
Safety Notifications by the Sponsor to the Investigator
Investigators will receive prompt notification of any adverse experience related to DX-2930 that 
is both serious and unexpected, or any finding that suggests a significant risk for subjects. The 
investigator will promptly inform his / her IRB/REB/IEC of the notification and insert the 
notification in the Investigator’s Regulatory Binder in accordance with local regulations. 
6.17
Subject Withdrawal
The investigator may withdraw a subject from DX-2930 treatment for any of the following 
reasons:
•
In the opinion of the investigator, the subject is unable to comply with the requirements of 
the protocol for satisfactory completion or interpretation of study results (including use of 
prohibitive medications),
•
A serious or intolerable AE occurs,


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•
A clinically significant change in a laboratory parameter occurs,
•
The Sponsor or investigator terminates the study, or
•
The subject requests to be discontinued from the study.
Subjects will continue to be followed through completion of all scheduled visits, unless the 
subject requests to be discontinued from the study.
6.18
Appropriateness of Measurements
This is a Phase 3 open-label extension study that is designed to evaluate the long-term safety and 
efficacy of DX-2930 in prophylactic therapy for angioedema attacks in subjects with HAE. 
DX-2930 is a recombinant, fully human IgG1, kappa light chain, monoclonal antibody. The 
open-label, non-controlled study design is a standard approach for extension studies that follow 
double-blind pivotal trials. Measures employed in this protocol are standard measures routinely 
used for the evaluation of the efficacy, safety and tolerability of an investigational product.  
Measures employed for rollover subjects between the first and second open-label doses are 
appropriate to characterize the outer bounds of dosing frequency for DX-2930.


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7.
STUDY ACTIVITIES
Study activities are summarized by study visit in Study Activities Schedule (Table 1).
7.1
Screening Visit (Up to Day −28) For Non-Rollover Subjects
The following procedures and assessments are to be performed during the Screening Visit for 
subjects not rolling over from Study DX-2930-03:
•
Informed consent (Section 6.1)
•
Eligibility review (Section 6.2)
•
Demographics and medical history (Section 6.3)
•
C1-INH functional assay, C4 and C1q sample collection (Section 6.8)
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including height and weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Prior and concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16); pre-existing signs and symptoms
For subjects rolling over from the double-blind DX-2930-03 study, no Screening visit is required 
as subjects will enter the OLE on the same day that their last Study DX-2930-03 study visit is 
completed. Diagnostic test results and demographic and medical history for these subjects will be 
carried forward from that study.
7.2
Start of Treatment Period: Visit 1, Dose 1 (Day 0)
The following procedures and assessments are to be performed on Day 0 prior to the first dose of 
DX-2930.  For subjects who rollover from Study DX-2930-03, all final assessments taken during 
the final study visit in Study DX-2930-03 will be used as the pre-dose results on Day 0 and will 
not be duplicated.
•
Informed consent (for subjects rolling over from the double-blind DX-2930-03 study; this 
can be on or after Day 168 of that study) (Section 6.1)
•
Eligibility review (Section 6.2)
•
Urine pregnancy test (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)


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•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK baseline sample collection (Section 6.9)
•
PD baseline sample collection (Section 6.10)
•
Baseline anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
First dose of open-label DX-2930 (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2)
•
AE collection (Section 6.16)
7.3
Interval between Dose 1 and Dose 2 for Rollover Subjects
Rollover subjects must adhere to the Study Activities Schedule for the entire duration of the 
study.  Until a rollover subject reports their first HAE attack, study visits may be conducted via 
site check in calls, except for the following study visits which must be conducted at the 
investigative site:
•
Day 14
•
Day 28
•
Day 56
•
Day 98
•
Day 126
•
Day 154
•
Day 182
•
Day 224
•
Day 266
•
Day 308
•
Day 350


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The tests and assessments required at these visits are specified in the sections below.
Site check in calls may serve as any of the following study visits until the subject receives their 
second open-label dose:
•
Day 42
•
Day 70
•
Day 84
•
Day 112
•
Day 140
•
Day 168
•
Day 196
•
Day 210
•
Day 238
•
Day 252
•
Day 280
•
Day 294
•
Day 322
•
Day 336
Study site personnel will also contact rollover subjects approximately 7 days after each study 
visit (both site visits and check-in calls) until the subject receives their second open-label dose.
The following assessments are performed during all site calls:
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
7.4
Dose 2 of DX-2930 for Rollover Subjects
The duration of time between Dose 1 and Dose 2 will vary by subject based on when their first 
HAE attack occurs following Dose 1.  As a result, rollover subjects may not receive DX-2930
treatment at every dosing visit as outlined in the Study Activities Schedule.
Once a rollover subject reports their first HAE attack they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  This 
treatment visit may be counted as a scheduled study visit, or as an acceptable extra study visit.  
For details on determining whether the second dose is counted as a scheduled or extra study visit, 
refer to Section 3.1.1.  Regardless of when the second dose is administered, the following tests 
and assessments will be conducted pre-dose on the day it is administered:


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•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
The following tests and assessments will also be performed if the second dose occurs on a 
scheduled study visit for which they are required:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
12-Lead ECG (Section 6.7)
•
Quality of life assessments (Section 6.14)
After the required pre-dose tests and assessments are completed:
•
Second dose of open-label DX-2930 (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.5
Visit 2 (Day 14 ±4 days); Dose 2 of DX-2930 for Non-Rollover Subjects
On Day 14 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)


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After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1)
•
AE collection (Section 6.16)
7.6
Continuation of Treatment Period: Visit 3 (Day 28 ±4 Days)
On Day 28 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1).  For non-rollover subjects this dose represents Dose 3. 
At this visit, subjects have the option to self-administer at the investigational site.
After administration of DX-2930, the following post-treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)


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7.7
Continuation of Treatment Period: Visit 4 (Day 42 ±4 Days)
On Day 42 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1).  For non-rollover subjects this dose represents Dose 4. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.8
Continuation of Treatment Period: Visit 5 (Day 56 ±4 Days)
On Day 56 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:


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•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 5. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.9
Continuation of Treatment Period: Visits 6 and 7 (Days 70 and 84, All ±4 Days)
On Days 70 and 84 the following procedures and assessments will be performed prior to 
DX-2930 treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects these doses represent Dose 6 
and Dose 7. At this visit, subjects have the option to self-administer DX-2930 at the 
investigational site or the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.10
Continuation of Treatment Period: Visit 8 (Day 98 ±4 Days)
On Day 98 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)


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•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 8. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2) 
•
AE collection (Section 6.16)
7.11
Continuation of Treatment Period: Visit 9 (Day 112 ±4 Days)
On Day 112 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 9. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.


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After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.12
Continuation of Treatment Period: Visit 10 (Day 126 ±4 Days)
On Day 126 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 10.
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.13
Continuation of Treatment Period: Visit 11 (Day 140 ±4 Days)
On Day 140 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)


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•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 11.
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.14
Continuation of Treatment Period: Visit 12 (Day 154 ±4 Days)
On Day 154 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 12.
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 


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•
AE collection (Section 6.16)
7.15
Continuation of Treatment Period: Visit 13 (Day 168 ±4 Days)
On Day 168 the following procedures and assessments will be performed prior to DX-2930
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 13.
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.16
Continuation of Treatment Period: Visit 14 (Day 182 ±4 Days)
On Day 182, the following procedures and assessments will be performed:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, and serum chemistry (Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)


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•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 14. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2
•
AE collection (Section 6.16)
7.17
Continuation of Treatment Period: Visit 15 (Day 196 ±4 Days)
On Day 196 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 15. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)


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7.18
Continuation of Treatment Period: Visit 16 (Day 210 ±4 Days)
On Day 210 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 16. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 

AE collection (Section 6.16)
7.19
Continuation of Treatment Period: Visit 17 (Day 224 ±4 Days)
On Day 224 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Laboratory testing including hematology, coagulation, and serum chemistry (Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 17. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.


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After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.20
Continuation of Treatment Period: Visit 18 (Day 238 ±4 Days)
On Day 238 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 18. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.21
Continuation of Treatment Period: Visit 19 (Day 252 ±4 Days)
On Day 252 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)


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After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 19. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.22
Continuation of Treatment Period: Visit 20 (Day 266 ±4 Days)
On Day 266 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, and serum chemistry (Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 20. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.


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•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2) 
•
AE collection (Section 6.16)
7.23
Continuation of Treatment Period: Visit 21 (Day 280 ±4 Days)
On Day 280 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 21. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.24
Continuation of Treatment Period: Visit 22 (Day 294 ±4 Days)
On Day 294 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:


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•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 22. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.25
Continuation of Treatment Period: Visit 23 (Day 308 ±4 Days)
On Day 308 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Laboratory testing including hematology, coagulation, and serum chemistry (Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 23. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.26
Continuation of Treatment Period: Visit 24 (Day 322 ±4 Days)
On Day 322 the following procedures and assessments will be performed prior to DX-2930 
treatment:


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•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 24. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.27
Continuation of Treatment Period: Visit 25 (Day 336 ±4 Days)
On Day 336 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 25. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)


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•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.28
Continuation of Treatment Period: Visit 26 (Day 350 ±4 Days)
On Day 350, the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 26 
(final dose). At this visit, subjects have the option to self-administer DX-2930 at the 
investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2) 
•
AE collection (Section 6.16)
7.29
Completion of Treatment Period:  Visit 27 (Day 364 ±4 Days)
On Day 364 the following procedures and assessments will be performed; note that DX-2930
will not be administered during this visit:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)


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•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
7.30
Follow-up Period:  Visit 28 (Day 378 ±4 Days)
On Day 378 all rollover and non-rollover subjects will receive a site check-in call.  During this 
call study site personnel will collect information regarding the following: 
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
7.31
Final Follow-up Visit:  Visit 29 (Day 392 ±4 Days)
On Day 392 all rollover and non-rollover subjects will complete a final study visit at the 
investigative site.
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
Quality of life assessments (Section 6.14)
•
AE collection (Section 6.16)
•
Study Discharge: Subjects will be discharged at this study visit. 


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7.32
Early Termination 
Subjects that terminate early from the study will undergo (if possible) all of the assessments and 
procedures scheduled for Day 392.


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8.
QUALITY CONTROL AND ASSURANCE
The Sponsor and the Contract Research Organization (CRO) conducting trial management 
services, Rho, Inc., will implement a system of quality assurance that includes all elements 
described in this protocol. Within this system, SOPs from the Sponsor and CRO will be 
implemented to ensure that the clinical trial is conducted in compliance with regulatory 
requirements and Good Clinical Practices (GCP). Quality control will be applied to each stage of 
data handling to ensure that data are accurate, reliable and processed correctly. 
The site staff should assist in all aspects of audit/inspection.


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9.
DATA ANALYSIS / STATISTICAL METHODS
9.1
General Considerations
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, Cary, 
North Carolina, USA).
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. Where applicable, estimates from statistical model of least 
squares means, standard errors, and 95% confidence intervals for least squares means will be 
provided. Time-to-event data will be summarized using Kaplan-Meier estimates of the 25th, 50th 
(median), and 75th percentiles with associated two-sided 95% confidence intervals, as well as 
percentage of censored observations. Plots of the Kaplan-Meier curves and supporting data 
listings detailing each subject’s contribution to the analysis will be provided. 
Formal hypothesis testing will not be performed.  Any hypothesis testing will be exploratory in 
nature and resulting p-values will be considered descriptive.
9.2
Sample Size Determination
No formal sample size calculation was performed.  The sample size is not based on any 
statistical considerations.  This study is designed to evaluate the safety and efficacy of open-label 
treatment with DX-2930 in subjects who participated in Study DX-2930-03 (rollover subjects) 
and individuals who were not otherwise able to participate in Study DX-2930-03 (non-rollover 
subjects).
9.3
Method of Assigning Study Subjects to Treatment
Subjects meeting all eligibility criteria will be enrolled in the study and sequentially assigned a 
unique site-based identification number.
9.4
Analysis Populations
9.4.1
Safety Population
The Safety Population will include all subjects who received any study drug after entering Study 
DX-2930-04(ie, any exposure to open-label DX-2930).   Unless otherwise specified, summary 
tabulations conducted with the Safety Population will be presented by the subject’s study entry 
type (rollover or non-rollover) and overall.
9.4.2
Rollover Safety Population
The Rollover Safety Population is the subset of subjects who participated in Study DX-2930-03 
and received any study drug after entering Study DX-2930-04(ie, any exposure to open-label 
DX-2930). Unless otherwise specified, summary tabulations conducted with the Rollover Safety 
Population will be presented by the subject’s prior treatment group from Study DX-2930-03 


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(DX-2930 300 mg every 2 weeks, DX-2930 300 mg every 4 weeks, DX-2930 150 mg every 4 
weeks, and Placebo).
9.4.3
Non-rollover Safety Population
The Non-rollover Safety Population is the subset of subjects who directly entered Study DX-
2930-04 and received any study drug after entering Study DX-2930-04 (ie, any exposure to 
open-label DX-2930).  Unless otherwise specified, summary tabulations conducted with the 
Non-rollover Safety Population will be presented by subject’s prior type of LTP therapy prior to 
study entry (C1-INH, androgens, anti-fibrinolytics, and not on LTP).
9.5
Population Description and Exposure
9.5.1
Subject Disposition
The numbers of subjects treated with study drug, completed the study and discontinued 
prematurely by reason will be summarized for each analysis population.
9.5.2
Demographics and Other Baseline Characteristics
Baseline and demographic variables will be summarized for each analysis population.
9.5.3
Medical History
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by system organ class (SOC) and preferred term (PT) for each analysis 
population.
9.5.4
Treatment Exposure and Compliance
Treatment compliance and the extent of exposure to study drug will be described by the 
percentage of planned doses received by the subject, total number of doses received by the 
subject, and the number and percentage of subjects that received at least 80% of planned doses, 
summarized for each analysis population.
9.5.5
Prior and Concomitant Medications
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD).  The number and percentage of subjects with prior or concomitant medications will be 
summarized by therapeutic class and preferred term for each analysis population.  A separate, 
similar table will be provided for the subset of concomitant medications classified as rescue 
medications.
9.6
Analysis of Efficacy
9.6.1
Time to the First Investigator-confirmed HAE Attack
Time to the first investigator-confirmed HAE attack will be analyzed using the Rollover Safety 
Population.


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Time to the first investigator-confirmed HAE attack (days) will be calculated from the date and 
time of the first open-label dose of DX-2930 to the date and time of the first investigator-
confirmed HAE attack after the first open-label dose.  Subjects who discontinue the study prior 
to experiencing their first on-study investigator-confirmed HAE attack will be censored at the 
date and time of study discontinuation.  Time to the first investigator-confirmed HAE attack will 
be summarized using Kaplan-Meier methods.
Multivariate and univariate Cox proportional hazards regression models will be employed to 
examine the impact of baseline covariates on the time to the first investigator-confirmed HAE 
attack, including but not limited to: baseline attack rate prior to entering Study DX-2930-03, the 
treatment group in Study DX-2930-03, the time since the last dose given in Study DX-2930-03, 
the time since the last HAE attack, and the rate of attacks during Study DX-2930-03 . Results of 
this exploratory analysis will be summarized.  
9.6.2
Number of Investigator-confirmed HAE Attacks
The number of investigator-confirmed HAE attacks during the treatment period (Day 0 through 
Day 364) expressed as a monthly HAE attack rate, will be analyzed using each analysis 
population.
The treatment period investigator-confirmed HAE attack rate will be calculated for each subject 
as the number of investigator-confirmed HAE attacks occurring during the treatment period 
divided by the number of days the subject contributed to the treatment period multiplied by 28 
days.  
The baseline investigator-confirmed HAE attack rate will be calculated for each subject as the 
number of investigator-confirmed HAE attacks occurring during the pretreatment period for 
rollover subjects or historical reporting period for non-rollover subjects divided by the number of 
days the subject contributed to the pretreatment period for rollover subjects or historical 
reporting period for non-rollovers multiplied by 28 days.
The baseline, treatment period, and treatment period change from baseline in the investigator-
confirmed HAE attack rate will be summarized for each analysis population. The summary will 
include the total number of investigator-confirmed HAE attacks reported during each period and 
subject-time in months that each subject contributed to each period. Figures will be created for 
each analysis population plotting the on-study investigator-confirmed HAE attacks reported 
during the treatment period relative to Day 0 for each subject.
In addition, the number of investigator-confirmed HAE attacks per month (defined as 28 days) 
will be summarized descriptively by month (per 28 day interval) for each analysis population. 
The summary will include the number, change from baseline, and percent change from baseline 
of investigator-confirmed HAE attacks. Investigator-confirmed HAE attacks will be grouped into 
28-day intervals using the start date of the HAE attack. The date of the first exposure to study 
drug in this study will be used as the start of the first interval and end of the interval will be the 
date of first exposure to study drug in this study plus 28 days. Each successive interval will start 
the last day of the prior interval plus 1 day and end 28 days later. 


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Similar summary tables will be presented for the following efficacy endpoints for each analysis 
population:
•
Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period.
•
Number of moderate or severe investigator-confirmed HAE attacks during the treatment 
period.
•
Number of high-morbidity investigator-confirmed HAE attacks during the treatment period; 
a high-morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation < 24 
hours), hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal.
9.7
Analysis of Safety
9.7.1
Adverse Events
Adverse events will be coded using the MedDRA coding dictionary.  Separate summaries will be 
presented for each analysis population.
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not.  If a determination cannot be made using the non-missing 
date parts as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.  
Related AEs are AEs classified as related to study drug by the investigator.  Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator.
For this analysis, AEs will be classified to one of two analysis periods:
•
Treatment Period AEs will include all AEs starting at or after the first exposure to open-label
DX-2930 in this study to those starting before or at the subject’s last visit date during the 
treatment period in this study (AEs starting at or after treatment on Day 0 to the Day 364
visit). 
Follow-up Period AEs will include all AEs starting at or after the subject’s last visit date of the 
treatment period in this study (AEs starting after the Day 364 visit). 


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For AEs with partial onset times, non-missing date parts will be used to determine if the AE falls 
within the period. If a determination cannot be made using the non-missing date parts as to if the 
AE falls within the period, the AE will be conservatively counted as a treatment-period AE. 
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE,  
any severe AE,  and any related severe AE will as well as the total number of events for each 
category will be summarized for each analysis period.  The number of deaths due to an AE, 
hospitalization due to an AE and study discontinuation due to an AE will be summarized for 
each analysis period. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC, and PT for each analysis period. This tabulation will be repeated for 
related AEs, SAEs, related SAEs, severe AEs, and related severe AEs for treatment period and 
follow-up period AEs. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized for treatment period AEs only. This tabulation will be repeated for related AEs and 
serious AEs for treatment period AEs. 
All AEs will be provided in subject listings. Listings will be presented separately for each 
analysis period.  In addition, subject listings of AEs causing discontinuation of study medication, 
AEs leading to death, SAEs, related AEs, severe AEs, and AEs of special interest (AESIs) will 
be produced. 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions and 
disordered coagulation (hypercoagulability events and bleeding events).  Standardized MedDRA 
Queries (SMQ) for each AESI will be performed using the study data. The number and percentage 
of subjects with an AESI, as well as the total number of AESIs, will be summarized by SOC and PT
for each analysis period. Separate summary tables will be created for each AESI and for those 
events with the SMQs classified as related, serious, related serious, severe, and related severe.  A 
listing detailing the PT within the SMQ will be provided.
9.7.2
Laboratory Test Results
Laboratory test results will be summarized using the Safety Population.
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For rollover 
subjects previously exposed to DX-2930, baseline is the last non-missing value prior to first exposure 
to study drug in Study DX-2930-03.        
Actual values and change from baseline clinical laboratory tests will be summarized by study 
visit. If more than one laboratory result is reported per study visit per parameter, the last non-missing 
result will be selected for analysis.
Laboratory test results will be classified according to the reference ranges and clinical significance as 
determined by the investigator. The number of subjects with a non-missing result, and the number 
and percentage of subjects with a clinically significant result less than the lower limit of normal, non-
clinically significant result less than the lower limit of normal, within the normal range, non-


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clinically significant result more than the upper limit of normal, and clinically significant result more 
than the upper limit of normal will be summarized by study visit. If more than one laboratory result is 
reported per study visit per parameter, the result yielding the most severe classification will be 
selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study visit per parameter, the result yielding the 
most severe classification will be selected for analysis. 
Subjects with clinically significant abnormal laboratory test results will be listed.  This listing 
will include all results of the laboratory parameter that was abnormal and determined to be 
clinically significant by the investigator for a subject across study visit to identify any trends.
9.7.3
Vital Signs
Vital signs will be summarized using the Safety Population.
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For 
rollover subjects previously exposed to DX-2930, baseline is the last non-missing value prior to 
first exposure to study drug in Study DX-2930-03.
Actual values and changes from baseline in vital signs will be summarized by study visit and 
study time point. All vital sign data will be presented in subject listings.
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage of 
subjects with a non-clinically significant result and clinically significant result will be summarized by 
study visit and study time point. If more than one vital sign result is reported per study visit and study 
time point per parameter, the result yielding the most severe classification will be selected for 
analysis. 
Subjects with clinically significant vital sign values will be listed.  This listing will include all results 
of the vital sign parameter that was determined by the investigator to be clinically significant for a 
subject across study time points to identify any trends.
9.7.4
Electrocardiography
Electrocardiography results will be summarized using the Safety Population.
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG no performed, will be summarized by study 
visit. Subjects with clinically significant ECG results will be listed.  This listing will include all 
results for a subject across study time points to identify any trends.
9.8
Other Analyses
Additional analyses of pharmacokinetic (PK) and pharmacodynamic (PD) data will be described 
in a separate PK/PD report.


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Additional analysis of quality of life (QoL) data will be described in a separate QoL report. 
9.8.1
Analysis of Pharmacokinetic Data
Plasma concentrations of DX-2930 will be summarized by nominal PK sampling time using the 
Safety Population. 
9.8.2
Analysis of Pharmacodynamic Data
Plasma kallikrein activity will be summarized by nominal PD sampling time using the Safety 
Population.
9.8.3
Analysis of Immunogenicity Data
The number and percentage of positive antibodies will be summarized by study visit and overall 
using the Safety Population.
9.8.4
Analysis of Quality of Life Assessments
Quality of life assessments will be summarized using the Safety Population.
The number and percentage of subjects at each level of the EQ-5D-5L dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) will be summarized by study 
visit. In addition, the VAS score for the subject’s self-rated health will be summarized by study 
visit.  
The responses to the SF-12 for each item will be tabulated by study visit using the Safety 
Population.  In addition, Physical and Mental Health Composite Scores (PCS & MCS) will be 
computed using the scores of twelve questions and range from 0 to 100, where a zero score 
indicates the lowest level of health measured by the scales and 100 indicates the highest level of 
health.
Responses to the HADS for each item will be tabulated by study visit. In addition, continuous 
and categorical (0-7: normal, 8-10: mild, 11-14: moderate, 15-21: severe) total scores based on 
the items related to depression and anxiety, will be summarized by study visit.  Each item in the 
questionnaire is scored from 0-3, with total scores between 0-21 for either depression or anxiety. 
Scores for the entire scale (emotional distress) will also be presented.  Total score for the entire 
scale range from 0 to 42, with higher scores indicating more distress.
Responses to the WPAI-GH for each item will be summarized by study visit.  In addition, four 
main scores in relation to general health will be summarized by study visit. Scores will be 
calculated as absenteeism (percentage work time missed due to health), presenteeism (percent 
impairment while working due to health), work productivity loss (percent overall work 
impairment due to health), and activity impairment (percent activity impairment due to health).  
The scores are percentages with higher values indicating greater percentage impairment.  Only 
respondents who report being full-time or part-time employed provide data for absenteeism, 
presenteeism, and overall work productivity loss.  All respondents provide data for activity 
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Responses to the AE-QoL for each item will be tabulated by study visit.  In addition, the domain 
scores (functioning, fatigue/mood, fears/shame, nutrition) and total score will be summarized by 
study visit. Each item in the questionnaire is scored from 0-4, with domain and total scores 
calculated using a linear transformation to a 0-100 scale.
9.9
Statistical/Analytic Considerations
9.9.1
Interim Analyses and Data Monitoring
Interim analyses may be conducted to support administrative decisions and/or regulatory 
reporting when a reasonable number of subjects have completed 12 months of consecutive 
exposure to DX-2930 across the combined DX-2930-03 and DX-2930-04 studies, and only after 
database lock of Study DX-2930-03. 
An independent Data Safety Monitoring Board (DSMB) has been established to provide 
ongoing, independent review and assessment of the safety data for Study DX-2930-03. While an 
independent DSMB is not currently planned for this study, summary safety data from Study DX-
2930-04 may be reviewed by the DSMB established for Study DX-2930-03 as part of the 
collection of safety information available on DX-2930.
9.9.2
Multiple Comparisons/Multiplicity
No adjustment for multiple comparisons will be performed.  Any statistical testing will be 
considered exploratory.
9.9.3
Handling of Missing Data
All available data will be included in the analysis.  No imputation of missing data will be 
performed.
9.9.4
Adjustment for Covariates
The impact of baseline covariates on the time to the first investigator-confirmed HAE attack will 
be explored to identify and assess the importance of potential prognostic factors.
9.9.5
Multicenter Studies
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis.
9.9.6
Subgroup Analyses
Subgroup analyses are planned for the number of investigator-confirmed HAE attacks during the 
treatment period and adverse events using the Safety Population. The following subgroups will 
be used:
•
Age Group (<18, 18 to <40, 40 to <65, ≥65 years)
•
Sex (Male, Female)
•
Race Group (White, Other)


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•
Weight Group (<50, 50 to <75, 75 to <100, ≥100 kg)
•
BMI Group (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2)
•
Baseline HAE Attack Rate (1 to <2, 2 to <3, ≥3 attacks/month)
•
HAE Type (Type I, Type II, Unspecified)
•
Geographic Region (US, Canada, Jordan, Europe)
•
DX-2930 Administration Type (Health Care Provider, Self-administration)
9.9.7
Sensitivity Analyses
The following sensitivity analyses will be performed on the number of investigator-confirmed 
HAE attacks during the treatment period for each analysis population to evaluate the robustness 
of the results. Data summaries will parallel those described for the number of investigator-
confirmed HAE attacks during the treatment period efficacy endpoint.  
1. The analysis will be repeated counting HAE attacks occurring on Day 14 after administration 
of study drug through Day 364, instead of Day 0 to Day 364.  For this analysis, the period of 
analysis would be a subset of the treatment period, defined as Day 14 to Day 364.
2. The analysis will be repeated counting HAE attacks occurring on Day 7 after administration 
of study drug through Day 364, instead of Day 0 to Day 364. For this analysis, the period of 
analysis would be a subset of the treatment period, defined as Day 7 to Day 364.
3. The analysis will be repeated using all subject reported HAE attacks instead of limiting the 
analysis to those attacks that were investigator-confirmed.


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10. STUDY ADMINISTRATIVE STRUCTURE
The study administration structure is provided in Table 2. 
Table 2
Study Administrative Structure
Sponsor Contact:
, MD
, Clinical Development
300 Shire Way, Lexington, MA 02421 USA
Phone: 
Global Medical Monitor:
, MD
300 Shire Way, Lexington, MA 02421 USA
Phone:
Study Monitoring (US):
Rho, Inc.
6330 Quadrangle Drive, Chapel Hill, NC 27517
Phone: 
Study Monitoring (Jordan)
Triumpharma
07 Bldg., Al-Yarooty St.
P.O. Box 2233, Amman
11941, Jordan
Phone: 
, 
Study Monitoring (Canada)
Red Maple Trials Incorporated
1081 Carling Avenue, Suite 707
Ottawa, Ontario, Canada, K1Y4G2
Phone: 
Study Monitoring (Europe)
Dyax Corp.
55 Network Drive, Burlington, MA 01803
Phone: 
10.1
Institutional Review Board/ Research Ethics Board/Independent Ethics Committee
The protocol and all protocol amendments must be signed and dated by the investigator and 
approved in writing by the IRB/REB/IEC in accordance with GCP prior to implementation. In 
addition, the IRB/REB/IEC must approve the written informed consent form, any consent form 
updates, subject recruitment materials (eg, advertisements), and any written information to be 
provided to subjects prior to implementation. The investigator must provide an annual report to 
the IRB/REB/IEC on the progress of the study including number of subjects enrolled, 
discontinued, and SAEs. It is required that a yearly review of the protocol by the IRB/REB/IEC 
be documented in a letter from the IRB/REB/IEC. The investigator must provide notification to 
the IRB/REB/IEC of the completion, termination or discontinuation of the study.


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10.2
Ethical Conduct of the Study
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor and 
the investigator abide by the principles of the International Conference on Harmonisation (ICH) 
guidelines on GCP, applicable local regulatory requirements, and the Declaration of Helsinki 
(Version 2008). The clinical study also will be carried out in keeping with national and local 
legal requirements [in accordance with United States Investigational New Drug (IND) 
regulations (21 CFR 56)].
10.3
Subject Information and Consent
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
according to the regulatory and legal requirements of the participating country. As part of this 
procedure, the investigator must explain orally and in writing the nature, duration, and purpose 
of the study, and the action of the drug in such a manner that the study subject is aware of the 
potential risks, inconveniences, or AEs that may occur. The study subject should be informed 
that he/she is free to withdraw from the study at any time. He/she will receive all information 
that is required by federal regulations and ICH guidelines. Subjects who are under the age of 18 
(or lower if age of consent is less than 18 in a specific country) and whose legal guardian or 
caretaker has provided written informed consent will provide their assent to participate. The
investigator or designee will provide the Sponsor with a copy of the IRB/REB/IEC-approved 
informed consent form prior to the start of the study.
10.4
Subject Confidentiality
The anonymity of participating subjects must be maintained. Subjects will be specified on study 
documents by their subject number, initial or birth date (if allowed based on local data protection 
regulations), not by name. Documents that identify the subject (eg, the signed informed consent 
document) must be maintained in confidence by the investigator.
The investigator agrees not to use or disclose protected health information other than as 
permitted or required by the subject authorization or as required by law.
10.5
Study Monitoring
The Sponsor (or designee) will conduct a study initiation visit to verify the qualifications of the 
investigator, inspect the facilities, and inform the investigator of responsibilities and procedures 
for ensuring adequate and correct documentation.
The investigator must prepare and maintain adequate and accurate records of all observations 
and other data pertinent to the clinical study for each study participant. Frequent communication 
between the clinical site and the Sponsor is essential to ensure that the safety of the study is 
monitored adequately. The investigator will make all appropriate safety assessments on an 
ongoing basis. The Medical Monitor may review safety information as it becomes available 
throughout the study.


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All aspects of the study will be carefully monitored with respect to GCP and SOPs for 
compliance with applicable government regulations. The Study Monitor will be an authorized 
individual designated by the Sponsor. The Study Monitor will have access to all records 
necessary to ensure integrity of the data and will periodically review the progress of the study 
with the investigator.
10.6
Case Report Forms and Study Records
The investigator will ensure the accuracy, completeness, and timeliness of the data reported to 
the Sponsor. Data collection processes and procedures will be reviewed and validated to ensure 
completeness, accuracy, reliability, and consistency. A complete audit trail will be maintained of 
all data changes. The investigator or designee will cooperate with the Sponsor’s representative(s) 
for the periodic review of study documents to ensure the accuracy and completeness of the data 
capture system at each scheduled monitoring visit.
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the clinical sites by means of 
electronic or manual queries.
The investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE and concomitant medication reporting, raw data collection forms, 
etc.) designed to record all observations and other pertinent data for each subject receiving 
randomized study drug.
The investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB/REB/IEC to have direct access to all documents pertaining to 
the study.
A Trial Master File will be maintained by the Sponsor (or designee). All documents and other 
materials that pertain to the conduct of the trial quality of the data, and compliance with GCPs 
will be collected in the Trial Master File.
10.7
Data Safety Monitoring Board
An independent Data Safety Monitoring Board (DSMB) has been established to provide 
ongoing, independent review and assessment of the safety data for Study DX-2930-03. While an 
independent DSMB is not currently planned for this study, summary safety data from Study DX-
2930-04 may be reviewed by the DSMB established for Study DX-2930-03 as part of the 
collection of safety information available on DX-2930. 
The DSMB will adhere to a prospectively determined Charter, which will be written by the 
Sponsor and approved by the DSMB. The Charter will define the responsibilities of the DSMB 
and Sponsor, the number and timing of the DSMB meetings, the conduct of the meetings, and 
the data sets to be reviewed by the DSMB. Further details regarding the DSMB can be found in 
the DSMB charter.


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10.8
Protocol Violations/Deviations
The investigator will be instructed not to deviate from the protocol, except where necessary to 
eliminate an immediate hazard to study participants. Should other unexpected circumstances 
arise that will require deviation from protocol-specific procedures, the investigator should 
contact their Sponsor representative to discuss the appropriate course of action. 
The investigator should document all protocol deviations/violations in the subject’s eCRF and 
source documents or the Investigator Site File if appropriate. In the event of a significant 
deviation/violation, the investigator should notify the Sponsor representative. Significant 
deviations/violations include, but are not limited to those that increase the health risk to the 
subject, or confound interpretation of primary study assessments. The investigator will promptly 
report all changes in research activity and all unanticipated problems involving risks to human 
subjects or others to his or her IRB/REB/IEC.
10.9
Premature Closure of the Study
If the Sponsor, investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated overall or at a specific site after appropriate consultation between 
the Sponsor and the investigator(s). In addition, a decision on the part of the Sponsor to suspend 
or discontinue development of the investigational product may be made at any time. Conditions 
that may warrant termination of the study or site include, but are not limited to, the following:
•
The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in 
the study
•
Failure of the investigator to comply with pertinent global regulations
•
Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities
•
Insufficient adherence by the investigator to protocol requirements
10.10 Access to Source Documentation and On-Site Audits
Regulatory agencies may request access to all study records, including source documents, for 
inspection and copying, in keeping with country regulations. The investigator should 
immediately notify the Sponsor representative of any announced or unannounced regulatory 
agency inspections. An auditing inspection may also be conducted by the Sponsor representative 
or designee. Any aspect of the trial may be subject to audit by the Sponsor and/or inspection by 
regulatory authorities or the IRB/REB/IEC. Such audits/inspections may take place at the 
Sponsor’s site(s), the CRO, or at the clinical sites, including laboratories, pharmacies and any 
other facilities used for the study. 


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The investigator will be responsible for the accuracy of the data entered in the eCRF. The 
investigator will permit the designated Sponsor representatives and regulatory bodies to have
direct access to the source documents to verify data represented in the eCRF.
10.11 Data Generation and Analysis
This study will be performed in accordance with regulatory requirements outlined in Food and 
Drug Administration (FDA) 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, 21 CFR Part 312 
and 21 CFR Part 11 as well as the ICH GCP E6 Guidelines. The study monitors will meet with 
the investigators and staff shortly before the start of the trial to review the procedures for study 
conduct and documentation. During the study, the monitors will visit the sites to verify record 
keeping and adherence to the protocol. For this study, eCRFs will be used. The monitors will 
conduct 100% source document verification by comparing the eCRFs with the source documents 
to ensure accuracy and consistency. Edit check programs, other forms of electronic validation, 
manual listings and a query process will be executed to verify the accuracy of the database. The 
EDC system will maintain a full audit trail of electronic data changes. Access to all source 
documentation will be made available for monitoring and audit purposes.
10.12 Retention of Data
All source documents (eg, informed consent forms, laboratory reports, progress notes, medical 
histories, physical and diagnostic findings, diagnosis and pharmacy records, and DX-2930
dispensing/disposition records) that support data in the eCRFs of each study subject must be 
retained in the files of the responsible investigator.
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the DX-2930. However, these documents 
should be retained for a longer period if required by the applicable legal requirements.
If the responsible investigator retires, relocates or for any other reason withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor representative must be notified in writing of the name and 
address of the new custodian, prior to the transfer.
10.13 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the Sponsor. The 
following information is collected: any significant payments from the Sponsor or subsidiaries
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the Sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).


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20 Jan 2017
10.14 Publication and Disclosure Policy
All information concerning DX-2930, Sponsor operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information, supplied to the 
investigator by a Sponsor representative and not previously published, is considered confidential 
and remains the sole property of the Sponsor. The investigator must agree to use this information 
only to accomplish this study, and must not use it for other purposes without the Sponsor’s 
advanced written consent. A description of this clinical study may also be available on the 
externally facing public websites and registries. A summary of the study results may be 
potentially disclosed as per local and country specific requirements.
The information developed in this study will be used by the Sponsor in connection with the 
continued development of DX-2930 and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. To permit the information derived from the 
clinical studies to be used, the investigator is obligated to provide the Sponsor with all data 
obtained in the study.


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11. REFERENCE LIST
Bennett, G. & Craig, T. 2015. Hereditary angioedema with a focus on the child. Allergy Asthma 
Proc, 36, 70-3.
Bork, K., Hardt, J., Schicketanz, K. H. & Ressel, N. 2003. Clinical studies of sudden upper 
airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor 
deficiency. Arch Intern Med, 163, 1229-35.
Bork, K., Hardt, J. & Witzke, G. 2012. Fatal laryngeal attacks and mortality in hereditary 
angioedema due to C1-INH deficiency. J Allergy Clin Immunol, 130, 692-7.
Bork, K., Meng, G., Staubach, P. & Hardt, J. 2006. Hereditary angioedema: new findings 
concerning symptoms, affected organs, and course. Am J Med, 119, 267-74.
Bork, K., Siedlecki, K., Bosch, S., Schopf, R. E. & Kreuz, W. 2000. Asphyxiation by laryngeal 
edema in patients with hereditary angioedema. Mayo Clin Proc, 75, 349-54.
Bygum, A. 2009. Hereditary angio-oedema in Denmark: a nationwide survey. The British 
journal of dermatology, 161, 1153-8.
Craig, T., Aygoren-Pursun, E., Bork, K., Bowen, T., Boysen, H., Farkas, H., Grumach, A., 
Katelaris, C. H., Lockey, R., Longhurst, H., Lumry, W., Magerl, M., Martinez-Saguer, I., 
Ritchie, B., Nast, A., Pawankar, R., Zuraw, B. & Maurer, M. 2012. WAO Guideline for 
the Management of Hereditary Angioedema. World Allergy Organ J, 5, 182-99.
Davis, A. E., 3rd 2006. Mechanism of angioedema in first complement component inhibitor 
deficiency. Immunology and allergy clinics of North America, 26, 633-51.
Farkas, H. 2010. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma
Clin Immunol, 6, 18.
Goring, H. D., Bork, K., Spath, P. J., Bauer, R., Ziemer, A., Hintner, H. & Wuthrich, B. 1998. 
Hereditary angioedema in the German-speaking region. Hautarzt, 49, 114-22.
Kalbitor® 2015. Package Insert. Burlington, MA: Dyax Corp.
Kaplan, A. P. & Joseph, K. 2010. The bradykinin-forming cascade and its role in hereditary 
angioedema. Ann Allergy Asthma Immunol, 104, 193-204.
Kenniston, J. A., Faucette, R. R., Martik, D., Comeau, S. R., Lindberg, A. P., Kopacz, K. J., 
Conley, G. P., Chen, J., Viswanathan, M., Kastrapeli, N., Cosic, J., Mason, S., DiLeo, M., 
Abendroth, J., Kuzmic, P., Ladner, R. C., Edwards, T. E., TenHoor, C., Adelman, B. A., 
Nixon, A. E. & Sexton, D. J. 2014. Inhibition of plasma kallikrein by a highly specific 
active site blocking antibody. J Biol Chem, 289, 23596-608.
Lei, W. T., Shyur, S. D., Huang, L. H., Kao, Y. H. & Lo, C. Y. 2011. Type I hereditary 
angioedema in Taiwan -- clinical, biological features and genetic study. Asian Pac J 
Allergy Immunol, 29, 327-31.
Nordenfelt, P., Dawson, S., Wahlgren, C. F., Lindfors, A., Mallbris, L. & Bjorkander, J. 2014. 
Quantifying the burden of disease and perceived health state in patients with hereditary 
angioedema in Sweden. Allergy Asthma Proc, 35, 185-90.
Reilly, M. C., Zbrozek, A. S. & Dukes, E. M. 1993. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics, 4, 353-65.
Renne, T. & Gruber, A. 2012. Plasma kallikrein: novel functions for an old protease. Thromb 
Haemost, 107, 1012-3.
Roche, O., Blanch, A., Caballero, T., Sastre, N., Callejo, D. & Lopez-Trascasa, M. 2005. 
Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to 
the prevalence in Spain. Ann Allergy Asthma Immunol, 94, 498-503.


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20 Jan 2017
Ware, J., Jr., Kosinski, M. & Keller, S. D. 1996. A 12-Item Short-Form Health Survey: 
construction of scales and preliminary tests of reliability and validity. Med Care, 34, 220-
33.
Weller, K., Groffik, A., Magerl, M., Tohme, N., Martus, P., Krause, K., Metz, M., Staubach, P. 
& Maurer, M. 2012. Development and construct validation of the angioedema quality of 
life questionnaire. Allergy, 67, 1289-98.
Zigmond, A. S. & Snaith, R. P. 1983. The hospital anxiety and depression scale. Acta Psychiatr 
Scand, 67, 361-70.
Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.
Zuraw, B. L., Bernstein, J. A., Lang, D. M., Craig, T., Dreyfus, D., Hsieh, F., Khan, D., Sheikh, 
J., Weldon, D., Bernstein, D. I., Blessing-Moore, J., Cox, L., Nicklas, R. A., 
Oppenheimer, J., Portnoy, J. M., Randolph, C. R., Schuller, D. E., Spector, S. L., Tilles, 
S. A., Wallace, D., American Academy of Allergy, A., Immunology, American College 
of Allergy, A. & Immunology 2013. A focused parameter update: hereditary angioedema, 
acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated 
angioedema. J Allergy Clin Immunol, 131, 1491-3.


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12. APPENDICES
Appendix 1
Protocol History
Appendix 2
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Tables 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infection Diseases)
Appendix 3
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Tables 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infection Diseases)
Appendix 4
HAE Attack Assessment and Reporting Procedures (HAARP)
Appendix 5
Summary of Pivotal Study DX-2930-03 in Subjects with HAE


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APPENDIX 1
Protocol History
Amendment Summary and Rationale
Amendment 1 to Protocol DX-2930-04 expanded upon the scope of the original protocol. Key 
revisions included extension of the study from 6 months to approximately 1 year, a 
corresponding increase in the number of study drug doses a subject may receive, allowance for 
subjects to elect self-administration both at and away from the site after completion and 
understanding of training, addition of 3 tertiary objectives, and revision of statistical 
methodology to accommodate changes in efficacy and other endpoints to allow for a more robust 
analysis.
Noteworthy changes to the protocol are captured in the table below. Additional minor revisions 
in grammar, spelling, punctuation, and format have been made for clarity and are not reflected in 
the summary of changes.
Document
Date
Global/Country/Site Specific
Original Protocol
Amendment 1.0
Amendment 2.0
14 December 2015
27 June 2016
20 Jan 2017
Global
Global
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
27 June 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
Administrative updates related to changes in parties responsible for the study (eg, 
Sponsor, Sponsor Contact/Medical Director, and Medical Monitor) were made to 
reflect current information.
Title page, Protocol 
Signature Page, Section 10 
Study Administrative 
Structure
Study location was updated to reflect study sites planned across regions rather 
than individual countries.
Synopsis Study Location
The tertiary objective to evaluate the effect of DX-2930 on health-related quality 
of life (QoL) was rephrased for clarity.
Synopsis Tertiary 
Objectives and Section 2.3 
Tertiary Objectives
The tertiary objective to characterize the Pharmacokinetic (PK) and 
Pharmacodynamic (PD) profile of DX-2930 was clarified to indicate 
administration would be subcutaneous.
Synopsis Tertiary 
Objectives and Section 2.3 
Tertiary Objectives
Three additional tertiary objectives were added to obtain more comprehensive 
information:

To evaluate safety and efficacy in the non-rollover population of 
switching from long-term prophylactic (LTP) treatment to DX-2930

To evaluate breakthrough attack characteristics while receiving DX-2930 
compared to historical baseline

To evaluate subject experience with self-administration of DX-2930 
including ease of SC administration of DX-2930
Synopsis Tertiary 
Objectives and Section 2.3 
Tertiary Objectives


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
27 June 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
The number of non-rollover subjects allowed in DX-2930-04 was increased to at 
least 50 subjects with up to a maximum of 100 subjects.
Synopsis Study Design, 
Section 3.1.1 Overview
The number of non-rollover subjects was increased from at least 50 subjects up to 
a maximum of 100 subjects. Enrollment of subjects 12 to 17 years age was revised 
to be at least 15 including the estimated 10 rollover subjects from Study DX-2930-
03.  Therefore, the total enrollment for the study was updated to be at least 150, 
but not more than 250.
Synopsis Study Population 
and Section 4.1 Study 
Population
Revised to allow non-rollover subjects to continue long-term prophylactic HAE 
therapy with C1-INH, androgens or anti-fibrinolytics, for 2 weeks; initiation of 
tapering and discontinuation of LTP must occur within 3 weeks of receiving the 
first dose of DX-2930.
Synopsis Study Design, 
Section 3.1.1 Overview
Clarified that rollover subjects who experience their first attack outside the 
window of accepted scheduled visits are allowed to have an extra (unscheduled) 
study visit.
Synopsis Treatment 
Period, Section 3.1.1 
Overview
The study has been extended in duration from 6 months to approximately one year 
and subsequently the number of doses of study drug a subject may receive has 
been increased.
Synopsis Duration of 
Treatment and Duration of 
Study for Individual 
Subjects, Study Activities 
Schedule
The study was expanded to allow subjects to self-administer doses of DX-2930 
without supervision after receiving the first 2 doses of DX-2930 at the study site.  
Subjects must be considered suitable candidates; receive training; confirm 
understanding; and record specific information regarding subcutaneous 
administration and experience with self-administration.  Subjects who elect to self-
administer investigational product will be provided with supplies and be instructed 
on investigational product transport, storage, treatment compliance, and retention 
of all used and unused product vials for drug accountability purposes. Written 
instructions on DX-2930 handling and self-administration procedures will be 
provided to trained subjects prior to initiating self-administration.  Vital signs will 
not be monitored for doses self-administered away from the investigational site.  
Synopsis Self-
Administration, Section 
3.1.1


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
27 June 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
Since no data on embryo-fetal development toxicity are available for DX-2930, 
the clinical trial facilitation group’s (CTFG) provided recommendations related to 
contraception and pregnancy testing.  The inclusion criterion for contraception 
requirements was modified to emphasize the use of highly effective contraceptive 
measures and details for allowances (including stable estrogen doses) during 
treatment and until the end of relevant systemic exposure for women of 
childbearing potential. It was also clarified that the use of a male condom with or 
without spermicide or cervical cap, diaphragm, or sponge with spermicide or a 
combination (double-barrier methods) is not considered highly effective.  
Additional pregnancy tests (urine or serum) were also added for monitoring of 
pregnancy during treatment.
Synopsis Criteria for 
Inclusion, Section 4.2
Management of acute attacks was clarified to indicate that administration of the 
investigational product and study procedures will continue without alteration to 
the protocol-specified study schedule, even if the subject has HAE symptoms or 
receives treatment for an HAE attack.
Synopsis, Management of 
Acute Attacks, Section 
5.4.1.1
Additional information was added to the study collection of data for HAE attacks
to obtain more comprehensive information.
Section 6.4
Efficacy endpoints were revised from mean rates to number of attacks. 
Synopsis Statistical 
Methodology, Section 
9.6.2
Where appropriate, “Dyax” was replaced with the generic term of “the Sponsor.”
Entire protocol Sections 1-
10
A section on management of HAE attacks was added to Study Treatment(s).
Synopsis Management of 
Acute Attacks, Section 
5.4.1.1
The study has been extended to incorporate an additional 6 months of treatment 
with DX-2930.  Therefore the Study Activities Schedule has been revised to 
accommodate study assessments at dosing Visits 14-26.  Follow-up visits 
(following end of treatment) are now occurring at Days 264, 378, and 392 (Visits 
27, 28, and 29).
Study Activities Table, 
Section 7
The exclusion criterion prohibiting dosing with an investigational drug or 
exposure to an investigational device with 4 weeks prior to screening was clarified 
to not include DX-2930 or other HAE therapies.
Synopsis Exclusion 
Criteria, Section 4.3
The analysis population was clarified and is based on subjects who receive any 
exposure to DX-2930 in this study.
Synopsis Analysis 
Populations, Section 9.4
Data analysis and statistical methodology was revised to accommodate changes in 
efficacy or other study endpoints and to allow for more robust analyses.  
Synopsis Statistical 
Methodology  , Section 9.6
An interim analysis was added and will be conducted when at least 35 subjects 
complete 12 months of DX-2930 exposure.
Synopsis Interim Analysis 
and Data Monitoring, 
Section 9.9.1


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
27 June 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
The efficacy evaluation period was updated to begin at Day 0 instead of Day 14 to 
be consistent with the intent-to-treat analysis principle.
Synopsis Statistical 
Methodology, Section 
9.6.2
Quality of life assessments were revised and expanded to include EQ-5D-5L, SF-
12, HADS, WPAI-GH and AE-QoL.
Synopsis Quality of Life 
Assessments, Section 6.14
An injection report and self-administration and SC injection survey were added to 
the study activities schedule and study procedures.
Synopsis DX-2930 
Injection Report and Self-
Administration and 
Subcutaneous Injection 
Survey, Section 6.15
Details on collection of prior medications were added to indicate documentation 
should extend to 4 weeks prior to study screening for non-rollover subjects.
Section 5.4
Information on packaging and labeling was expanded to detail the supplies for 
self-administration.
Section 5.7
Clarifying language was added to subject information and consent to indicate that 
subjects under 18 years will provide their assent to participate in the study if their 
legal guardian or caretaker has provided written informed consent.
Section 10.3 Subject 
Information and Consent
A new section was added for a Data Safety Monitoring Board (DSMB) who will 
provide an independent review of safety
Section 10.7 Data Safety 
Monitoring Board
To ensure subject safety, information on premature closure of the study was added 
to indicate some examples of conditions under which the study may be terminated 
overall or at a specific site after consultation between the Sponsor and 
investigators.
Section 10.9 Premature 
Closures of the Study
Financial disclosure language was updated to be consistent with 21 CFR 54 2(b) 
(1998).
Section 10.13 Financial 
Disclosure
Study Results/Publication Policy was updated to include language regarding 
posting of appropriate study information on applicable websites by the Sponsor. 
Additional detail on publication and disclosure of study information was added to 
indicate potential for public information.
Section 10.14 Publication 
and Disclosure Policy


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APPENDIX 2
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infectious Diseases)


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials.  This toxicity table is not comprehensive and 
should not be applied directly to all trials.   
When selecting a toxicity table, the following are some of the items that must be taken into 
consideration: 
•
The population being studied
o
Does the clinical trial evaluate healthy subjects, subjects with a particular disease
or condition?
•
The stage of test article development
o
Is the clinical trial a Phase I, II, III or IV?
•
The type of test article
o
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent?
•
The prior human and preclinical experience with the test article
o
Are there any specific findings that require adjustment of the toxicity table?
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal 
values at the single site. Multi-center clinical trials should reconcile among their laboratory normal 
values when evaluating a healthy volunteer population. 
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when 
selecting or developing a toxicity table for a DMID-sponsored trial. 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to 
estimate grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to 
moderate 
limitation 
in 
activity - some assistance may be needed; no or minimal 
medical intervention/therapy required 
GRADE 3 
Severe  
 
Marked limitation in activity, some 
assistance usually required; medical intervention/therapy 
required, hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme 
limitation 
in 
activity, 
significant 
assistance 
required; 
significant 
medical 
intervention/therapy required, hospitalization or hospice 
care probable 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening 
include, but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, 
disseminated intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, 
severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s 
Common Toxicity Criteria (CTC), and World Health Organization (WHO)) have 
been adapted for use by the Division of Microbiology and Infectious Diseases 
(DMID) and modified to better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to 
the “Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
 6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-
99,999/mm3 
50,000-
74,999/mm3 
20,000-49,999/mm3 
<20,000/mm3 
WBCs  
11,000-13,000/ 
mm3 
13,000- 
15,000 /mm3 
15,000- 
30,000/mm3 
>30,000 or 
<1,000 /mm3 
% Polymorphonuclear 
Leucocytes + Band Cells 
 > 80% 
90 – 95% 
>95% 
---------- 
Abnormal 
Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
    ---------- 
Fibrinogen 
associated with 
gross bleeding or 
with 
disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin 
Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x 
ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CHEMISTRIES 
   
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hyponatremia 
 
130-135 mEq/L 
 
 123-129 
mEq/L 
 
116-122 mEq/L 
 
< 116 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypernatremia 
 
146-150 mEq/L 
 
151-157 mEq/L 
 
158-165 mEq/L 
 
> 165 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypokalemia 
 
3.0 - 3.4 mEq/L 
 
2.5 - 2.9 mEq/L 
 
2.0 - 2.4 mEq/L  
or intensive 
replacement 
therapy or 
hospitalization 
required 
 
< 2.0 mEq/L or 
abnormal 
potassium with 
 paresis, ileus or 
life-threatening 
arrhythmia 
 
Hyperkalemia 
 
5.6 - 6.0 mEq/L 
 
6.1 - 6.5 mEq/L 
 
6.6 - 7.0 mEq/l 
 
> 7.0 mEq/L 
or abnormal 
potassium  with 
life-threatening 
arrhythmia 
 
Hypoglycemia 
 
55-64 mg/dL 
 
40-54 mg/dL 
 
30-39 mg/dL 
 
<30 mg/dL or 
abnormal glucose 
with mental 
status changes or 
coma 
 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
 
116 - 160 mg/dL 
 
161- 250 
mg/dL 
 
251 - 500 mg/dL 
 
> 500 mg/dL or 
abnormal glucose 
with ketoacidosis 
 or seizures 
 
Hypocalcemia 
(corrected for albumin) 
 
8.4 - 7.8 mg/dL 
 
7.7 - 7.0 mg/dL 
 
6.9 - 6.1 mg/dL 
 
< 6.1 mg/dL 
or abnormal 
calcium with life 
threatening 
arrhythmia or 
tetany 
 
 
 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
CHEMISTRIES (continued) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or 
abnormal calcium 
with life 
threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or 
replacement Rx 
required 
1.0 -1.4 mg/dL  
intensive therapy 
or 
hospitalization 
required 
< 1.0 mg/dL or 
abnormal 
phosphate with 
life-threatening 
arrhythmia 
Hyperbilirubinemia (when 
accompanied by any increase 
in other liver function test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia (when 
other liver function are in the  
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x 
ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or 
dialysis required 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
ENZYMES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
URINALYSIS 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ 
 or 
200 mg - 1 gm 
loss/day 
2-3+ 
or 
1- 2 gm 
loss/day 
4+ 
 or  
2-3.5 gm loss/day 
nephrotic 
syndrome 
or 
> 3.5 gm loss/day 
Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots 
>10 rbc/hpf 
gross, with or 
without clots, OR 
red blood cell casts 
obstructive or 
required 
transfusion 
Page 123


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CARDIOVASCULAR 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cardiac Rhythm 
 
 
 
asymptomatic, 
transient signs, 
no 
Rx required 
 
recurrent/persistent; 
symptomatic Rx 
required 
 
unstable 
dysrythmia; 
hospitalization 
and treatment 
required 
 
Hypertension 
 
transient increase 
> 20 mm/Hg; no 
treatment 
 
recurrent, 
chronic 
increase 
 > 20mm/Hg. 
/treatment 
required 
 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
 
end organ 
damage or 
hospitalization 
required 
 
Hypotension 
 
transient 
orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
 
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable 
with oral fluid 
treatment 
 
requires IV fluids; 
no hospitalization 
required 
 
mean arterial 
pressure  
<60mm/ Hg or 
end organ 
damage or shock;   
requires 
hospitalization 
and vasopressor 
treatment 
 
Pericarditis 
 
minimal effusion 
 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
 
symptomatic 
effusion; pain; 
EKG changes 
 
tamponade; 
pericardiocentesis 
or surgery 
required 
 
Hemorrhage, Blood Loss 
 
microscopic/occult 
 
mild, no 
transfusion 
 
gross blood loss; 
1-2 units transfused 
 
massive blood 
loss; > 3 units 
transfused 
Page 124


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
RESPIRATORY 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cough  
 
transient- no 
treatment 
 
persistent 
cough; 
treatment 
responsive 
 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
 
Bronchospasm, Acute 
 
transient; no 
treatment; 
70% - 80% FEV1  
of peak flow 
 
requires 
treatment; 
normalizes with 
bronchodilator; 
FEV1 50% - 
70% 
(of peak flow) 
 
no normalization 
with 
bronchodilator; 
FEV1 25% - 50% 
of peak flow; or  
retractions present 
 
cyanosis: FEV1 
< 25% 
of peak flow or 
intubation 
necessary 
Dyspnea 
 
dyspnea on 
exertion 
dyspnea with 
normal activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
Page 125


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
GASTROINTESTINAL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Nausea 
 
mild or transient; 
maintains 
reasonable intake 
 
moderate 
discomfort; 
intake 
decreased 
significantly; 
some activity 
limited 
 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
 
Vomiting 
 
1 episode in 24 
hours 
2-5 episodes in 
24 hours 
>6 episodes in 24 
hours or needing 
IV fluids 
 
 
 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral 
nutrition 
 
Constipation 
 
requiring stool 
softener or dietary 
modification 
requiring 
laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
 
obstruction or 
toxic megacolon 
 
Diarrhea 
 
mild or transient; 
3-4 loose 
stools/day or mild 
diarrhea last < 1 
week 
 
moderate or 
persistent; 5-7 
loose stools/day 
or diarrhea 
lasting >1 week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
 
 
hypotensive 
shock or 
physiologic 
consequences 
requiring 
hospitalization   
 
Oral Discomfort/Dysphagia 
 
mild discomfort; 
no difficulty 
swallowing 
 
some limits on 
eating/drinking 
 
eating/talking very 
limited; unable to 
swallow solid 
foods 
 
unable to drink 
fluids; requires 
IV fluids 
 
 
Page 126


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
NEUROLOGICAL 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Neuro-Cerebellar 
 
slight 
incoordination 
dysdiadochokinesis 
 
intention 
tremor, 
dysmetria, 
slurred speech; 
nystagmus 
 
locomotor ataxia 
 
incapacitated 
 
Psychiatric 
 
mild anxiety or 
depression 
 
moderate 
anxiety or 
depression; 
therapy 
required; 
change in 
normal routine 
 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
 
acute psychosis 
requiring 
hospitalization;  
or suicidal 
gesture/attempt 
or hallucinations 
 
Muscle Strength 
 
subjective 
weakness 
no objective 
symptoms/ signs 
 
mild objective  
signs/symptoms 
no decrease in 
function 
 
objective weakness 
function limited 
 
paralysis 
Paresthesia (burning, tingling, 
etc.) 
mild discomfort; 
no treatment  
required 
moderate 
discomfort; 
non-narcotic 
analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision 
and/or hearing 
moderate 
impairment 
(mod decreased 
sensation, e.g., 
vibratory, 
pinprick, 
hot/cold to 
ankles) and/or 
joint position or 
mild 
impairment that 
is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod degree 
in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs 
and trunk; 
paralysis;  or 
seizures 
Page 127


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
MUSCULOSKELATEL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Arthralgia 
(joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics 
and/or pain 
interfering with 
function but not 
with activities 
of daily living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain 
with 
inflammation, 
erythema or 
joint swelling – 
interfering with 
function, but 
not with 
activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of  
activity 
muscle 
tenderness (at 
other than 
injection site) 
or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 128


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
SKIN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, 
dry 
desquamation 
vesiculation or 
moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, 
mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected 
Stevens-Johnson 
or  necrosis 
requiring surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
Erythema 
< 15mm 
15-30 mm 
>30mm 
Edema 
< 15mm 
15-30 mm 
>30mm 
Rash at Injection Site 
< 15mm 
15-30 mm 
>30mm 
Pruritus 
slight itching at 
injection site 
moderate 
itching at 
injection 
extremity 
itching over entire 
body 
SYSTEMIC 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without 
rash 
localized 
urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, 
moderate; 
treatment 
required 
severe; responds to 
initial narcotic 
therapy 
intractable; 
requires repeated 
narcotic therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 
103 - 105 F 
> 40 C or 
> 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 
50% > 48 hours 
normal activity 
decreased > 50% 
can’t work 
unable to care for 
self 
Page 129


DX-2930
CONFIDENTIAL
Page 127
Clinical Trial Protocol: DX-2930-04
27 June 2016
Appendix 3
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (Modified) (US National Institutes of Health; National 
Institute of Allergy and Infectious Diseases
130
Shire
CONFIDENTIAL
Page 
Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
1
 
 
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials.  This toxicity table is not comprehensive and should 
not be applied directly to all trials.   
  
When selecting a toxicity table, the following are some of the items that must be taken into consideration: 
  
• 
The population being studied  
o 
Does the clinical trial evaluate healthy subjects, subjects with a particular disease or 
condition?  
• 
The stage of test article development  
o 
Is the clinical trial a Phase I (is it for the fisrt time in human subjects?) , II, III or IV? 
• 
The type of test article  
o 
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent?  
• 
The prior human and preclinical experience with the test article 
o 
Are there any specific findings that require adjustment of the toxicity table?  
o 
Has it been approved for this indication in adult population? 
  
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal values at the 
single site. Multi-center clinical trials should reconcile among their laboratory normal values when 
evaluating a healthy volunteer population. 
  
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when selecting 
or developing a toxicity table for a DMID-sponsored trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 131


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
2
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to moderate limitation in activity - 
some assistance may be needed; no or minimal medical 
intervention/therapy required 
GRADE 3 
Severe  
 
Marked 
limitation 
in 
activity, 
some 
assistance usually required; medical intervention/therapy required, 
hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme limitation in activity, significant 
assistance required; significant 
medical 
intervention/therapy 
required, hospitalization or hospice care probable 
GRADE 5                              Death 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening include, 
but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria (CTC), and World Health Organization (WHO)) have been adapted for 
use by the Division of Microbiology and Infectious Diseases (DMID) and modified to 
better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
Page 132


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
3 
(Selected Values for children less than or equal  
to 3 months of age – does not apply for preterm infants)  
 
 
For all parameters not listed on this table, please refer 
 to the DMID Toxicity Table for children > 3 months of age. 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin 
1-7 days old 
13.0-14.0 gm/dL 
12.0-12.9 gm/dL 
<12 gm/dL 
Cardiac Failure  
secondary to Anemia 
8-21 days old 
12.0-13.0 gm/dL 
10.0-11.9 gm/dL 
<10.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
22-35 days old 
9.5-10.5 gm/dL 
8.0-9.4 gm/dL 
<8.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
36-60 days old 
8.5-9.4 gm/dL 
7.0-8.4 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
61-90 days old 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
Abs Neutrophil Ct 
1 day old 
5000-7000/mm3 
3000-4999/mm3 
1500-2999/mm3 
<1500/mm3 
2-6 days old 
1750-2500/mm3 
1250-1749/mm3 
750-1249/mm3 
<750/mm3 
7-60 days old 
1200-1800/mm3 
900-1199/mm3 
500-899/mm3 
<500/mm3 
61-90 days old 
750-1200/mm3 
400-749/mm3 
250-399/mm3 
<250/mm3 
Bilirubin (Fractionated bilirubin test must be preformed when total bilirubin is elevated) 
<7 days old 
. 
20-25mg/dL 
26-30 mg/dL 
>30 mg/dL 
7-60 days old 
1.1-1.9xN 
2.0-2.9Xn 
3.0-7.5xN 
>7.5xN 
61-90 days old 
1.1-1.9xN 
2.0-2.9xN 
3.0-7.5xN 
>7.5xN 
 
Page 133


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
4
(Selected Values for children less than or equal  
to 3 months of age)  
 
 
HEMATOLOGY (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Creatinine 
<7 days old 
1.0-1.7 mg/dL 
1.8-2.4 mg/dL 
2.5-3.0 mg/dL 
>3.0 mg/dL 
7-60 days old 
0.5-0.9 mg/dL 
1.0-1.4 mg/dL 
1.5-2.0 mg/dL 
>2.0 mg/dL 
61-90 days old 
0.6-0.8 mg/dL 
0.9-1.1 mg/dL 
1.2-1.5 mg/dL 
>1.5 mg/dL 
Cr Clearance 
<7 days old 
35-40 ml/min 
30-34 ml/min 
25-29 ml/min 
<25 ml/min 
7-60 days old 
45-50 ml/min 
40-44 ml/min 
35-39 ml/min 
<35 ml/min 
61-90 days old 
60-75 ml/min 
50-59 ml/min 
35-49 ml/min 
<35 ml/min 
Hypocalcemia 
<7 days old 
6.5–6.9 mEq/L 
6.0-6.4 mEq/L 
5.5-5.9 mEq/L 
<5.5 mEq/L 
7-60 days old 
7.6-8.0 mEq/L 
7.0-7.5 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
61-90 days old 
7.8-8.4 mEq/L 
7.0-7.7 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
Hypercalcemia 
<7 days old 
12.0-12.4 mEq/L 
12.5-12.9 mEq/L 
13.0-13.5 mEq/L 
>13.5 mEq/L 
7-60 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
61-90 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
 
 
 
Page 134


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
5
 
 (Greater than 3 months of age) 
 
LOCAL REACTIONS 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Induration 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Erythema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Edema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Rash at Injection Site 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Pruritus 
Slight itching at 
injection site 
Moderate itching at 
injection extremity 
Itching at injection 
extremity and other 
sites 
Itching over entire 
body 
 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin for 
children greater than 
months and less than 
2 years of age 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Hemoglobin for 
children greater that 2 
years of age 
10-10.9 gm/dL 
7.0-9.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Absolute Neutrophil 
Count 
750-1200/mm3  
400-749/mm3 
250-399/mm3 
<250/mm3 
Platelets 
------- 
50,000-75,000/mm3 
25,000-49,999/mm3 
<25,000/mm3 
Prothrombin Time 
(PT) 
1.1-1.2 x ULN 
1.3 -1.5 x ULN 
1.6 -3.0 x ULN 
>3.0 x ULN 
Partial 
Thromboplastin Time 
(PTT) 
1.1-1.6 x ULN 
1.7-2.3 x ULN 
2.4 -3.0 x ULN 
>3.0 x ULN 
Page 135


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
6
 (Greater than 3 months of age)  
 
GASTROINTESTINAL  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Bilirubin (when 
accompanied by any 
increase in other liver 
function test) 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x ULN 
 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
Bilirubin (when other 
liver function are in 
the  normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
AST (SGOT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
ALT (SGPT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
GGT 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
Pancreatic Amylase 
1.1-1.4 x ULN 
1.5-1.9 x ULN 
2.0-3.0 x ULN 
>3.0 x ULN 
Uric Acid 
7.5-9.9mg/dL 
10-12.4 mg/dL 
12.5-15.0 mg/dL 
>15.0 mg/dL 
CPK 
See Neuromuscular Toxicity 
Appetite 
----------------- 
Decreased appetite 
Appetite very 
decreased, no solid 
food taken 
No solid or liquid taken  
Abdominal Pain 
Mild 
Moderate-  
No Treatment Needed 
Moderate-  
Treatment Needed 
Severe-  
Hospitalized for treatment 
Diarrhea 
Slight change in 
consistency and/or 
frequency of stools 
Liquid stools 
Liquid stools greater 
that 4x the amount or 
number normal for 
this child 
Liquid stools greater than 8x 
the amount or number 
normal for this child  
 
Page 136


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
7
 (Greater than 3 months of age)  
 
GASTROINTESTINAL (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Constipation 
Slight change in the 
consistency/frequency 
of stool 
Hard, dry stools with 
a change in frequency 
Abdominal pain 
Distention and 
Vomiting 
Nausea 
Mild 
Moderate-  
Decreased oral intake 
Severe-Little  
oral intake 
Unable to ingest food  
or fluid for more than 
24 hours 
Vomiting 
1 episode/day 
2-3 episodes  
per day 
4-6 episodes per day  
Greater than 6 episodes 
per day or Intractable 
Vomiting 
Page 137


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
8
 (Greater than 3 months of age)  
 
ELECTROLYTES 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
CREATININE  
3 Months -2 Years of 
age  
0.6-0.8 x ULN 
0.9-1.1 x ULN 
1.2-1.5 x ULN 
>1.5 x ULN 
2 Years- 12 Years of 
age 
0.7-1.0 x ULN 
1.1-1.6 x ULN 
1.7-2.0 x ULN 
>2.0 x ULN 
Greater than  
12 Years of age 
1.0-1.7 x ULN 
1.8-2.4 x ULN 
2.5-3.5 x ULN 
>3.5 x ULN 
 
Page 138


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
9
 (Greater than 3 months of age)  
 
ELECTROLYTES  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hypernatremia 
 
<145-149 mEq/L 
150-155 mEq/L 
>155 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyponatremia 
 
130-135 mEq/L 
129-124 mEq/L 
<124 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyperkalemia 
5.0-5.9 mEq/L 
6.0-6.4 mEq/L 
6.5-7.0 mEq/L 
>7.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythamia 
Hypokalemia 
3.0-3-5 mEq/L 
2.5-2.9 mEq/L 
2.0-2.4 mEq/L 
<2.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythmia 
Hypercalcemia 
10.5-11.2mg/dL 
11.3-11.9 mg/dL 
12.0-12.9 mg/dL 
>13.0 mg/dL 
Hypocalcemia 
7.8-8.4 mg/dL 
7.0-7.7 mg/dL 
6.0-6.9 mg/dL 
<6.0 mg/dL 
Hypomagnesemia 
1.2-1.4 mEq/L 
0.9-1.1 mEq/L 
0.6-0.8 mEq/L 
<0.6 mEq/L or 
abnormal magnesium 
AND cardiac 
arrhythmia 
Hypoglycemia 
55-65 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose 
AND mental status 
changes 
Hyperglycemia 
116-159 mg/dL 
160-249 mg/dL 
250-400 mg/dL 
>400 mg/dL or 
ketoacidosis 
Proteinuria 
Tr-1+  
or 
 <150 mg/day 
2+  
or 
150-499 mg/day 
3+  
or  
500-1000 mg/day 
4+ 
 or 
 Nephrotic syndrome 
>1000 mg/day 
Hematuria 
Microscopic <25 
Microscopic >25 
 
Gross hematuria 
Page 139


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
10 
cells/hpf 
cells/hpf 
 
Page 140


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
11 
 (Greater than 3 months of age) 
 
CENTRAL NERVOUS SYSTEM (CNS) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Generalized CNS 
Symptoms 
 
 
Dizziness 
Hypotonic, 
hyporesponsive 
episodes;   
Seizures; 
Apnea/Bradycardia; 
Inconsolable crying > 
3 hrs; 
Headache  
Mild 
Moderate, Responds 
to non-narcotic 
analgesia 
Moderate to Severe,  
Responds to narcotic 
analgesia 
Intractable 
Level of Activity 
 
Slightly irritable OR 
slightly subdued 
Very irritable OR 
Lethargic 
Inconsolable OR 
Obtunded 
Visual 
 
Blurriness, diplopia, 
or horizontal 
nystagmus of < 1 
hour duration, with 
spontaneous 
resolution 
More than 1 episode 
of Grade 2 
symptoms per week, 
or an episode of 
Grade 2 symptoms 
lasting more than  
1 hour with 
spontaneous 
resolution by 4 
hours or vertical 
nystagmus 
Decrease in visual 
acuity, visual field 
deficit, or oculogyric 
crisis  
Myelopathy 
 
None 
None 
Myelopathic/spinal 
cord symptoms, such 
as: pyramidal tract 
weakness and 
disinhibition, sensory 
level, loss of 
proprioception, 
bladder/bowel 
dysfunction 
Page 141


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
12 
(Greater than 3 months of age) 
 
PERIPHERAL NERVOUS SYSTEM  
PARAMETER 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Neuropathy/  
Lower Motor 
Neuropathy 
 
Mild transient  
Paresthesia only 
Persistent or 
progressive 
paresthesias, burning 
sensation in feet, or 
mild dysesthesia; no 
weakness; mild to 
moderate deep 
tendon reflex 
changes; no sensory 
loss 
Onset of significant 
weakness, decrease or 
loss of DTRs, sensory 
loss in "stocking 
glove" distribution, 
radicular sensory loss, 
multiple cranial nerve 
involvement; bladder 
or bowel dysfunction, 
fasciculations, 
respiratory 
embarrassment from 
chest wall weakness. 
Myopathy or 
Neuromuscular 
Junction Impairment 
Normal or mild 
 (<2 x ULN) CPK 
elevation 
Mild proximal 
weakness and/or 
atrophy not affecting 
gross motor function. 
Mild myalgias, +/- 
mild CPK elevation 
(<2 x ULN)  
Proximal muscle 
weakness and/or 
atrophy affecting 
motor function +/- 
CPK elevation; or 
severe myalgias with 
CPK >2 x ULN;  
Onset of myasthenia-
like symptoms 
(fatigable weakness 
with external, variable 
ophthalmoplegia 
and/or ptosis), or 
neuromuscular 
junction blockade 
(acute paralysis) 
symptoms 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
13 
 (Greater than 3 months of age)  
 
OTHER  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Allergy 
Pruritus without Rash 
Pruritic Rash 
Mild Urticaria 
Severe Urticaria  
Anaphylaxis, 
Angioedema 
Drug Fever (Rectal) 
. 
38.5-40C 
101.3 – 104.0F 
Greater than 40.0C 
Greater than 104.0F 
Sustained Fever:  
Equal or greater than 
40C (104.0F) for 
longer than 5 days 
Cutaneous 
Localized rash 
Diffuse 
maculopapular 
Rash 
Generalized urticaria 
Stevens-Johnson 
Syndrome or Erythema 
multiforme 
Stomatitis 
Mild discomfort 
Painful, difficulty 
swallowing, but able 
to eat and drink  
Painful: unable to 
swallow solids 
Painful:  unable to 
swallow liquids; 
requires IV fluids 
Clinical symptoms 
not otherwise 
specified in this table 
No therapy; monitor 
condition 
May require minimal 
intervention and 
monitoring 
Requires medical care 
and possible 
hospitalization 
Requires active 
medical intervention, 
hospitalization, or 
hospice care 
Laboratory values not 
otherwise specified in 
this table 
Abnormal, but 
requiring no 
immediate 
intervention; follow 
Sufficiently abnormal 
to require evaluation 
as to causality and 
perhaps mild 
therapeutic 
intervention, but not 
of sufficient severity 
to warrant immediate 
changes in study drug 
Sufficiently severe to 
require evaluation 
and treatment, 
including at least 
temporary suspension 
of study drug 
Life-threatening 
severity; Requires 
immediate evaluation, 
treatment, and usually 
hospitalization; Study 
drug must be stopped 
immediately and 
should not be restarted 
until the abnormality is 
clearly felt to be 
caused by some other 
mechanism that study 
drug 
 
 
 
Page 143


DX-2930
CONFIDENTIAL
Page 141
Clinical Trial Protocol: DX-2930-04
27 June 2016
Appendix 4
HAE Attack Assessment and Reporting Procedures (HAARP)
144
Shire
CONFIDENTIAL
Page 
Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017


DX-2930 
 
 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
 
HAE Attack Assessment and Reporting Procedures 
(HAARP) 
Title: 
HAE Attack Assessment and Reporting Procedures (HAARP) 
Product Name: 
DX-2930 
Indication: 
Prevention of angioedema attacks in patients with HAE 
Sponsor: 
Dyax Corp.  
55 Network Drive 
Burlington, MA 01803 
Original Date: 
14 September 2015 
Version: 
v1.0 
 
Confidentiality Statement 
This document is the property of Dyax Corp. The information in this document contains trade secrets and 
commercial information that are privileged or confidential and may not be disclosed without the express written 
permission of Dyax unless required by federal or state law or regulations. Any person to whom the information 
is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential. 
 
Confidential 
Page 1 of 8 
Dyax Corp. 
Page 145


DX-2930 
 
 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
TABLE OF CONTENTS 
1 
PURPOSE ..........................................................................................................................3 
2 
DEFINITION OF AN ATTACK .......................................................................................3 
3 
REPORTING AND ASSESSMENT OF ATTACK DATA .............................................3 
3.1 
Subject-Reported Symptoms ...................................................................................4 
3.1.1 
Attack Information .........................................................................................4 
3.1.2 
Worsening Symptoms ....................................................................................5 
3.1.3 
Subject Training .............................................................................................5 
3.1.4 
Reporting Multiple Attacks............................................................................5 
3.1.5 
Caregiver Report ............................................................................................5 
3.1.6 
Subject Contact with Sites .............................................................................5 
3.2 
Site Contact with the Subject ...................................................................................5 
3.2.1 
Review of subject report of symptoms ..........................................................6 
3.2.2 
Documenting a Reported Attack ....................................................................6 
3.2.3 
Site Training...................................................................................................7 
3.3 
HAE attacks as Adverse Events ...............................................................................7 
4 
INVESTIGATOR ATTACK ASSESSMENT ..................................................................8 
 
 
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DX-2930 
 
 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
1 
PURPOSE 
This document applies to clinical trials that involve investigator adjudication/assessment of 
angioedema attacks. The purpose of this document is to provide a definition of an HAE 
attack and to define a standardized set of procedures for the reporting and assessment of 
events reported by subjects to determine whether those events are true HAE attacks. 
2 
DEFINITION OF AN ATTACK 
To be confirmed as an HAE attack, the event must have symptoms or signs consistent with 
an attack in at least one of the following locations:  
• Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region 
• Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea 
• Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx 
Despite the presence of these symptoms, the investigator may still determine clinically that 
the event did not represent an HAE attack if there are features that strongly refute such a 
diagnosis. For example, the reported event is accompanied by symptoms that are not 
consistent with an attack (e.g., urticaria), the reported event persists well beyond the typical 
time course of an attack (e.g., greater than 7 days), or there is a likely alternate etiology for 
the event (e.g., the subject’s abdominal symptoms are attributable to a viral gastroenteritis 
outbreak in the household). 
To be counted as a unique attack distinct from their previous attack, the new symptoms must 
occur at least 24 hours after resolution of the prior attack’s symptoms.  
Attack resolution is defined as the subject no longer having symptoms of the attack. 
Prodromal symptoms by themselves are not considered an attack. 
Patient report of use of acute HAE attack treatment for an attack by itself is not confirmation 
that an attack occurred. 
3 
REPORTING AND ASSESSMENT OF ATTACK DATA 
At screening for applicable clinical trials, subject HAE attack history will be collected by the 
site for entry into the clinical database. Information collected will include any prior history of 
laryngeal attacks, attack frequency, average severity, predominant location(s), average 
duration, acute attack therapy use, and history of long-term prophylaxis. 
During the relevant study periods, as defined in the applicable study protocol, subjects (or 
caregivers, for subjects < 18 years old) will be instructed to contact the site within 72 hours 
of the start of symptoms of an attack. In the situation that a subject is incapacitated and is 
Confidential 
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DX-2930 
 
 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
unable to contact the site, a family member or other individual with detailed knowledge of 
the event can provide the information. If desired by the subject, memory aids may be 
provided to assist in tracking any HAE attacks subject’s experience. Any tools or devices the 
subject uses to track this information are not intended to serve as source documents for the 
study.  
Site personnel will review the information provided by the subject or caregiver and solicit 
additional information as necessary to document the attack.  Information documented by the 
site will be considered source for the study.  
A designated individual at the site (the collector) will contact the subject or caregiver on a 
regular basis as defined in the study protocol, regardless of whether or not the subject has 
reported any attacks, in order to solicit for any attacks that may have occurred but were not 
reported. In addition, during each study visit, site personnel will solicit for any new attack 
information that was not provided through previous contact with the subject or caregiver. 
The Investigator or designee (the assessor) will review the attack information and evaluate if 
the event represents a confirmed HAE attack. If necessary for the evaluation, the investigator 
or designee may contact the subject to receive additional information.  
3.1 
Subject-Reported Symptoms 
Subjects and caregivers can use any existing methods by which they track information about 
their attacks, or, if requested, memory aids can be provided by the study site. However, 
subjects (or a caregiver) will need to track attacks in such a way as to be able to contact the 
study site as soon as possible, but not later than 72 hours (3 full days) after the first 
symptoms appear, to report the information. 
3.1.1 
Attack Information 
The following information should be provided by the subject (or caregiver) at the time they 
are reporting an attack to the site: 
• Date and time symptoms of an attack were first experienced 
• Description of symptoms experienced, including location(s) 
• Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits 
• Any medications used to treat the attack 
• If the attack resolved, date and time the subject was no longer experiencing symptoms  
Subjects do not have to wait for their symptoms to completely resolve to report an attack. 
Information about ongoing symptoms can be obtained by the site during the check-in call 
and/ or at a scheduled study visit. Subjects should not withhold or delay any treatment they 
would normally receive to treat their attack in order contact the site. 
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DX-2930 
 
 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
 
 
 
 
3.1.2 
Worsening Symptoms 
The site may request the subject call them back if they experience worsening symptoms 
and/ or new symptoms for a reported attack. Otherwise, the new information will be captured 
during the next check-in call or scheduled study visit. Subjects may contact the site on their 
own to provide information about any worsening symptoms. 
3.1.3 
Subject Training 
During screening, site personnel will train subjects on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide.  The 
patient will confirm their understanding of what is required of them for reporting attacks to 
the site.  Sites will assess the subject’s compliance with the reporting requirements 
throughout the study and may retrain the subject if necessary in order to maintain the 
integrity of the data provided to the site. 
3.1.4 
Reporting Multiple Attacks 
If a subject experiences symptoms they attribute to more than one unique attack they can 
report this as multiple attacks to the site.  Based on the definition of an attack as stated in 
Section 2, it will be the determination of the investigator or designee as to whether events 
reported as being separate are confirmed as separate attacks or not. 
3.1.5 
Caregiver Report 
During screening, site personnel will train subject caregivers (if applicable) on identifying 
symptoms of an attack, the requirements for reporting attacks and the information they will 
be expected to provide.  The caregiver will confirm their understanding of what is required of 
them for reporting attacks to the site. Sites will assess the caregiver’s compliance with the 
reporting requirements throughout the study and may retrain the caregiver if necessary in 
order to maintain the integrity of the data provided to the site. 
3.1.6 
Subject Contact with Sites 
Site personnel will establish a recommended method and time window for each subject to 
contact the site to report any symptoms of an attack. Sites will establish a primary contact 
person and, if possible, a back-up person, with contact information. Back-up plans, including 
call backs and/ or use of back-up contacts, should be established in case the subject is unable 
to reach someone at the site.  
3.2 
Site Contact with the Subject 
Sites will establish a recommended day and time window for check-in calls between study 
visits. The date and time for check-ins can be modified based on when the last contact with 
the subject was made, as outlined in the study protocol. When the site is contacted by a 
subject reporting symptoms of an attack the site should make sure they have the ability to 
record the information provided in a complete and accurate way. Back-up plans should be 
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DX-2930 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
established in case the subject misses a call from the site. A study schedule for each subject’s 
on-site visits will be provided to the subject by the site. 
3.2.1 
Review of subject report of symptoms 
During contact with the subject, whether subject-initiated or a regular check-in, site 
personnel should ask the subject to provide them information about new or ongoing HAE 
attacks experienced. 
The site will try to obtain all information necessary to document the attack completely. 
Missing information may impact the assessment of any attack and should be avoided 
whenever possible. 
3.2.2 
Documenting a Reported Attack 
Complete and accurate documentation of each reported attack is important to making an 
Investigator assessment of the attack. The site should document the following information 
about each attack reported by the subject or caregiver:  
•
Date and time of contact with the subject
•
Date and time the subject first experienced symptoms
•
Description of symptoms experienced, including location(s)
•
Impact on activity and whether any assistance was required
•
If the attack has resolved or is ongoing.  If the attack has resolved, the date and time the
subject was no longer experiencing any symptoms of the attack
•
Names of any medications used to treat the attack including HAE acute therapy or other
non-HAE treatments
•
If hospitalization occurred
•
If a trip to the emergency department occurred
Additional probing questions about what the subject experienced to determine: 
•
If the subject only experienced prodromal symptoms
•
If  the subject experienced anything different than their typical attack
•
If there were any possible alternative etiologies of the symptoms. For example, a viral
gastroenteritis outbreak in the household could explain abdominal symptoms
The overall severity of the subject’s attack will be determined by the site using the following 
definitions: 
- 
Mild: Transient or mild discomfort  
- 
Moderate: Mild to moderate limitation in activity - some assistance needed 
- 
Severe: Marked limitation in activity, assistance required 
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DX-2930 
HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
The site will also document the date and time of investigator or designee review, the official 
designation of the event as an attack or not, and if applicable, the reason why an event is not 
considered an attack.  
All reported attacks will be entered by site personnel into the electronic case report form 
(eCRF). 
3.2.3 
Site Training 
Site personnel responsible for collecting attack information about subject HAE attacks will 
need to pass a “Collector” training assessment covering the following: 
•
definition of an HAE attack
•
requirements of subjects and caretakers for reporting attacks
•
reporting worsening symptoms and multiple attacks
•
information to be collected from subjects and caregivers as well as the additional probing
questions to gather context for the attack information provided
•
assessment of attack severity
•
entry of the attack data into the eCRF
•
reporting HAE attacks as adverse events
•
requirements for Investigator assessment of attacks
Trainings will be conducted prior to sites screening subjects.  Trainings will be documented 
in the Trial Master File. Investigators and designees will be trained on these procedures as 
well and must pass an “Assessor” training in order to officially assess attacks for this study. 
All responsible persons involved in the collection of information from subjects or assessing 
attacks must be listed on FDA Form 1572. 
3.3 
HAE attacks as Adverse Events 
At the time of each contact and scheduled study visit, site personnel will ask if the subject 
experienced any adverse events or changes to the medications they are taking. 
HAE attacks will be captured as AEs.  All AEs, regardless of seriousness, severity, or causal 
relationship to study drug, will be recorded on the AE page of the eCRF. 
Any AE reported to the site meeting criteria for a serious adverse event must be reported to 
Dyax using the SAE Reporting Form in the EDC system within 24 hours of becoming aware 
of the event.  For all serious adverse events that are reported as HAE attacks, the Principal 
Investigator or physician designee will review the event within 24 hours of initial notification 
and, in accordance with HAARP, evaluate if it represented a confirmed HAE attack. 
For all non-serious AEs that are reported as HAE attacks, the Principal Investigator or 
physician designee will review the event within 3 days of initial notification and, in 
accordance with HAARP, evaluate if it represented a confirmed HAE attack. If necessary for 
the evaluation, the Investigator or designee may contact the subject for additional 
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HAE Attack Assessment and Reporting Procedures (HAARP) 
14 September 2015 
information. Any subject-reported attack not confirmed by the Investigator must have an 
alternate AE diagnosis recorded.  All subject-reported and Investigator-confirmed HAE 
attacks will be recorded in the eCRF. 
4 
INVESTIGATOR ATTACK ASSESSMENT 
The Principal Investigator for a study site may identify a physician designee to assess patient 
symptom information and make attack determinations. Sites should be limited to two 
individuals responsible for assessing attacks, one of them being the Principal Investigator. 
Assessors must be experienced with HAE and familiar with the study subject’s disease 
history.  
The assessor must review the information and determine whether the event is an actual attack 
or not. If needed, the assessor can contact the subject and/or caregiver to clarify information 
or ask for any additional detail. The determination will be documented along with the date 
and time the determination was made. Any event deemed not an attack must be accompanied 
by an explanation and alternative diagnosis by the assessor.  
When reviewing subject information, the assessor will follow the definitions of an attack as 
outlined in these procedures and, taking all available information about the event into 
consideration, will determine if it is a confirmed attack. The assessment of the attack is the 
Investigator or designee’s own, and not the opinion of the subject, the subject’s caregiver or 
any other site personnel. Assessors may consult with one another about a particular subject’s 
attack but only one assessor makes the documented determination. It is possible for both the 
Principal Investigator and physician designee to assess different attacks for the same subject. 
Confidential 
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Shire
CONFIDENTIAL
Page 153
Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017
APPENDIX 5
Summary of Pivotal Study DX-2930-03 in Subjects with HAE
The proposed pivotal clinical study (Study DX-2930-03) is entitled “HELP StudyTM: A 
Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to 
Evaluate DX-2930 For Long-Term Prophylaxis Against Acute Attacks of Hereditary 
Angioedema (HAE).” This study will be a multi-center, double-blind, randomized, placebo-
controlled parallel-arm study evaluating the efficacy of DX-2930 in preventing acute 
angioedema attacks in patients with Type I or Type II HAE. The double-blind study is planned to 
be followed by the study described in the present protocol, an open-label extension (OLE) study
(DX-2930-04).
The primary objective of Study DX-2930-03 is to evaluate the efficacy of DX-2930 in 
preventing HAE attacks. The secondary objective is to evaluate the safety of repeated SC 
administrations of DX-2930. The tertiary objectives are to evaluate the pharmacodynamic effects 
of chronically administered DX-2930; to assess the immunogenicity of chronically administered 
DX-2930; to evaluate the pharmacokinetics of chronically administered DX-2930; and to 
evaluate the effect of DX-2930 upon quality of life assessments.
Subjects aged 12 years and over with a documented diagnosis of Type I or Type II HAE who 
experience at least 1 attack per 4 weeks will be eligible for the study. Up to 120 subjects are 
planned for enrollment across approximately 60 sites in the United States, Canada, Italy, 
Germany, United Kingdom and Jordan.
Following informed consent, subjects will undergo screening assessments.  Subjects who are on 
long-term prophylactic therapy for HAE are required to undergo a minimum 2 week washout 
period prior to the start of the run-in period.  Subjects who are either not on long-term 
prophylactic therapy for HAE, or have completed the required washout period will enter a run-in 
period of 4 weeks to determine the baseline HAE attack rate. The run-in period may be extended 
to 8 weeks if the minimum baseline attack rate is not achieved in the first 4 weeks. HAE subjects 
will then be randomized 2:1 to receive repeated subcutaneous (SC) administrations of DX-2930 
or placebo in a double-blind fashion.  Subjects who are randomized to DX-2930 will be assigned 
in a 1:1:1 ratio to one of three dose regimens: 300 mg every 2 weeks, 300 mg every 4 weeks or 
150 mg every 4 weeks.  Each subject will undergo a treatment period consisting of 13 doses of 
blinded study drug, for a period of 26 weeks from the date of first dose on Day 0 through Day 
182
Subjects may consent to rollover into the OLE study (present protocol DX-2930-04) upon 
completion of their participation in the double-blind treatment period.
The primary endpoint will be to compare the number of investigator-confirmed HAE attacks 
observed in each DX-2930 treatment arm to that in the placebo arm during the efficacy 
assessment period (Day 0 through Day 182).
Figure 2 shows a schematic of the double-blind, pivotal study.


Shire
CONFIDENTIAL
Page 154
Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017
Figure 2
Overview of the Design of Pivotal Study DX-2930-03
Dose Rationale for Double-Blind, Pivotal Study DX-2930-03
The dose rationale is based on the pharmacodynamic bioactivity, PK, safety, and efficacy of DX-
2930 from the Phase 1 clinical studies and nonclinical studies. Together, these attributes provide 
the rationale for the selected doses and regimens to achieve drug levels likely to prevent a 
majority of HAE attacks. Based on these considerations, 300 mg every 2 weeks, 300 mg every 4 
weeks, and 150 mg every 4 weeks were identified as the dosing regimens for evaluation,
The 3 proposed dose-regimen combinations provide a 6-fold range of steady-state trough 
concentrations and leverage both the biomarker and efficacy data generated in Study DX-2930-
02.  Evaluation of the DX-2930 plasma concentrations at the time of attacks reported by DX-
2930 treated subjects in DX-2930-02 suggests that the 3 planned dosing regimens will provide a 
meaningful range of clinical response while avoiding non-therapeutic or super-therapeutic doses 
and regimens.


Clinical Trial Protocol: DX-2930-04
Study Title:
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-
Term Safety and Efficacy of DX-2930 for Prevention Against Acute 
Attacks of Hereditary Angioedema (HAE)
Study Number:
DX-2930-04
Study Phase:
Phase 3 
Product Name:
DX-2930 (SHP643)
IND Number:
116647
EudraCT Number:
2015-005255-27
Indication:
Prevention of angioedema attacks in patients with HAE
Investigators:
Multicenter
Sponsor:
Dyax Corp. (an indirect, wholly owned subsidiary of Shire plc.)
300 Shire Way, Lexington, MA 02421
Sponsor Contact:
, MD
, Clinical Development
300 Shire Way, Lexington, MA 02421 USA
Phone: 
Global Medical 
Monitor:
, MD
300 Shire Way, Lexington, MA 02421 USA
Phone: 
Date:
Original Protocol
14 December 2015 
Amendment 1.0
27 June 2016
Amendment 2.0
20 January 2017
Amendment 3.0
29 June 2017
Confidentiality Statement
This document is the property of Dyax Corp, an indirect, wholly owned subsidiary of Shire plc. The 
information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed without the express written permission of Dyax unless required by federal 
or state law or regulations. Any person to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. These restrictions on 
disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.


Study Title: 
HELP Study ExtensionTM: An Open-Label Study to Evaluate 
the Long-Term Safety and Efficacy ofDX-2930 for Prevention 
Against Acute Attacks of Hereditary Angioedema (RAE) 
Study Number: 
DX-2930-04 
Amendment 3.0 Final Date: 
29 June 2017 
This clinical study protocol was subject to critical review and has been approved by the Sponsor. 
The signature of the Sponsor representative indicates that the Sponsor will comply with all 
Sponsor obligations detailed in applicable regulations and guidelines and will ensure the 
investigator is informed of all relevant information that becomes available. 
Clinical Dev
nt 
y, Lexington, MA 02421 USA 
I have read the foregoing protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study in compliance with the Declaration of Helsinki, Good 
Clinical Practice (GCP), and all applicable regulatory requirements and guidelines as outlined 
herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure they 
are fully informed regarding the drug and the conduct of the study. 
I will use only the informed consent form approved by Dyax Corp. and my Institutional Review 
Board (IRB), Research Ethics Board (REB) or Ethics Committee (EC) and will fulfill all 
responsibilities for submitting pertinent information to the IRBIREB/EC responsible for this 
study. 
I further agree that Dyax Corp. or their designees shall have access to any source documents 
from which eCRF information may have been generated. 
By signing this protocol, I agree to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of GCP to which it conforms. 
Signed: _______________ _ 
Date: ________ _ 
Investigator 
Address: 
Shire
CONFIDENTIAL
Page 2
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
PROTOCOL SIGNATURE PAGE


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CONFIDENTIAL
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Clinical Trial Protocol Amendment 3
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AMENDMENT SUMMARY AND RATIONALE
The purpose of this amendment is to add new objectives and related measurements, add quality 
of life (QoL) endpoints, and extend the study from 12 months to 30 months to continue to obtain 
data  important for the assessment of DX-2930 (ie, safety and efficacy data).
Noteworthy changes to the protocol are captured in the table below. Additional minor revisions 
in grammar, spelling, punctuation, and format have been made for clarity and are not reflected in 
the summary of changes.
Summary of Changes from Previous Version
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
29 June 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
A new tertiary objective and related measurement have been added to evaluate 
exploratory biomarker(s) of angioedema disease-state bioactivity in blood. Additional 
biomarker assessments have been added to the study to evaluate the effect of DX-
2930 on disease activity. 

Objective: To evaluate exploratory biomarker(s) of angioedema disease-state 
bioactivity in blood
Measurement: Exploratory biomarker(s) of angioedema disease state bioactivity 
in plasma and serum
A new tertiary efficacy objective and related measurement have been added to better 
understand the clinical response to rescue medications while on DX-2930 therapy.

Objective: To assess the clinical response of rescue medications for the treatment 
of acute angioedema attacks while on DX-2930 therapy (applicable for subjects 
≥18 years of age)
Measurement: Subject response to rescue medications
A new tertiary objective has been added to assess subjects’ satisfaction with DX-
2930. 

Objective: To assess treatment satisfaction
Measurement: Treatment satisfaction will be measured using Treatment 
Satisfaction Questionnaire for Medication (TSQM-9). The TSQM-9 is a 9-item 
validated instrument.
A new tertiary objective has been added to assess subjects’ and investigators’ overall 
perception of treatment response.

Objective: To assess global impression of treatment response
Measurement: Global Impression of Treatment Response will be measured by a 
1-item question to assess overall perception of treatment response.
A new tertiary objective has been added to assess control of angioedema among study 
subjects.

Objective: To assess control of angioedema
Synopsis, Section 2, 
Section 6, Section 9.8, 
Table 1, Table 2


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
29 June 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Measurement: The control of angioedema will be measured using the 
Angioedema control test (AECT).
A new tertiary objective and related measurement have been added to evaluate 
subject experience and ease of use of the prefilled syringe, if utilized. 

Objective: To evaluate subject experience and ease of use of the prefilled 
syringe, if available
Measurement: Subject experience with the prefilled syringe 
Synopsis, Section 2, 
Section 3.3, Section 5.1, 
Section 5.7, Section 6, 
Section 9.8, Table 1, Table
2
A brief exit interview has been added to obtain information about subjects’ 
overall experience with DX-2930 studies and any changes in signs and 
symptoms during the between-attack period and related changes to subject 
health.
Section 6, Table 1, Table 2
The treatment period has been extended from 12 to 30 months to 
accommodate the additional changes to the study described above. 
Entire protocol, Table 1, 
Table 2, Section 7
Table 2 has been added to present the schedule of assessments to be 
performed from Day 365 through Day 952. To reduce site burden, the 
frequency of required on-site visits in the second year has been reduced 
relative to the first year.  Key refinements represented in Table 2 include:

The frequency of on-site visits has been decreased so that subjects are 
only required to come to the clinic once every 2 months (instead of once 
a month or once every third visit, as appropriate for each subject)
The requirement that each attack be confirmed by the investigator within 72 
hours for non-serious AE attacks has been expanded to 7 calendar days. 
(Note: This refers only to confirmation of attacks, not reporting of SAEs or 
AEs.)  ECGs will be assessed through Day 364, at the end of the study, and 
when clinically required.
Table 2
For purposes of internal consistency, Table 1 also reflects the updated 
requirement that each attack be confirmed by the investigator within 7 
calendar days for non-serious AE attacks.
Table 1
A clarification note has been added to Inclusion Criteria 2 to ensure proper 
documentation occurs for subjects previously treated with C1-INH:
“It is understood that C1-INH therapy may alter the lab results of C1-INH and 
investigator's discretion in collaboration with Medical Monitor is advised for 
proper documentation of eligibility.”
Synopsis, Table 1, Section
4.2, Section 6.8.1.6
Potential modifications to open-label dosing have been expanded to include 
the following: “In addition, an individual subject’s dose may be modified 
based on a benefit-risk assessment and recommendation from the treating 
physician. Consultation with and approval by the Sponsor's Medical Monitor
is required.”
Synopsis, Section 3.1.1
The following subgroup analysis has been added to the statistical section for 
Section 9.9.6


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Clinical Trial Protocol Amendment 3
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
29 June 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
consistency with statistical analysis used in Study DX-2930-03: 
“•
History of laryngeal HAE attacks (history of laryngeal attack, no history 
of laryngeal attack)”
Updated the address to: 300 Shire Way, Lexington, MA 02421 USA
Added clarification that Dyax Corp. is now an indirect, wholly owned subsidiary 
of Shire plc.
Title page, Synopsis,
Section 10, Table 3,
Appendix 4
The first and second sentences of Section 3.2 were updated for clarity and 
consistency with the protocol.
Appendix 4 (Section 3.2)
See Appendix 1 for protocol history, including amendments.


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SYNOPSIS
Sponsor:
Dyax Corp., an indirect, wholly owned subsidiary of Shire plc.
300 Shire Way, Lexington, MA 02421 USA
Name of Finished Product:
DX-2930 Drug Product (DP)
Name of Active Ingredient:
DX-2930 (lanadelumab) is a recombinant, Chinese hamster ovary (CHO) cell-expressed, fully 
human immunoglobulin G subclass 1 (IgG1), kappa light chain, monoclonal antibody.
Names of Inactive Ingredients:
Sodium phosphate dibasic dihydrate, citric acid monohydrate, L-histidine, sodium chloride, and 
Polysorbate 80
Study Title:
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-Term Safety and Efficacy 
of DX-2930 for Prevention Against Acute Attacks of Hereditary Angioedema (HAE)
Study Number:
DX-2930-04
Study Phase: Phase 3
Study Location:
Approximately 60 study sites planned across North America, the European Union, and the 
Middle East
Primary Objective:
To evaluate the long-term safety of repeated subcutaneous (SC) administrations of DX-2930
Secondary Objectives:
•
To evaluate the long-term efficacy of DX-2930 in preventing HAE attacks
•
To characterize the outer bounds of dosing frequency for DX-2930
Tertiary Objectives:
•
To assess the immunogenicity of chronically administered DX-2930
•
To evaluate the effect of DX-2930 on health-related quality of life (QoL)
•
To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SC 
administration of DX-2930 
•
To evaluate safety and efficacy in the non-rollover population of switching from long-term 
prophylactic (LTP) treatment to DX-2930 
•
To evaluate breakthrough attack characteristics while receiving DX-2930 compared to 
historical baseline
•
To evaluate subject experience with self-administration of DX-2930 including ease of SC 
administration of DX-2930
•
To evaluate exploratory  biomarker(s) of angioedema disease-state bioactivity in plasma and 


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serum
•
To evaluate subject experience and ease of use of the prefilled syringe, if available
•
To assess the clinical response of rescue medications for the treatment of acute angioedema 
attacks while on DX-2930 therapy (applicable for subjects ≥18 years of age)
•
To assess treatment satisfaction
•
To assess global impression of treatment response
•
To assess control of angioedema
Study Design:
Study DX-2930-04 is an open-label, long-term safety and efficacy extension study of Study 
DX-2930-03, to evaluate the investigational medicinal product (IMP), DX-2930, in preventing 
acute angioedema attacks in patients with Type I and Type II HAE. There are two types of 
subjects who will be enrolled into this study:
•
Subjects who rollover from Study DX-2930-03 
•
Subjects who are non-rollover (ie, were not participants in Study DX-2930-03) 
Rollover Subjects
Rollover subjects are subjects who complete the double-blind treatment period at Day 182 of 
Study DX-2930-03 and consent to enter Study DX-2930-04.  Subjects who discontinue from 
Study DX-2930-03 after enrollment are not eligible to enroll in Study DX-2930-04.  
Subjects should be asked about their interest in Study DX-2930-04 study after enrollment into 
Study DX-2930-03 to anticipate enrollment and preparedness for Study DX-2930-04. Willing 
subjects must sign informed consent for Study DX-2930-04 on or after Day 168 of Study
DX-2930-03.  
Subjects who are eligible to roll over into Study DX-2930-04 but elect not to, may not enroll in 
Study DX-2930-04 at a later time. The first Study DX-2930-04 visit for rollover subjects (Day 0) 
will occur on the same day as the Study DX-2930-03 Day 182 study visit. Rollover subjects will 
complete all Study DX-2930-03 final study assessments (Day 182) at which time they will be 
discharged from that study. No assessments conducted between the Study DX-2930-03 Day 182 
study visit and the first Study DX-2930-04 visit (Day 0) will be duplicated. Results of the final 
Study DX-2930-03 assessments on Day 182 will be used as the pre-dose results for Day 0 of 
Study DX-2930-04.
All subjects, caregivers, investigators and study site personnel will remain blinded to the Study
DX-2930-03 treatment assignment until the conclusion of Study DX-2930-04.
Non-rollover subjects
At least 50 subjects (to approximately 100) who were not participants in Study DX-2930-03 will 
be permitted to enroll if they meet the eligibility requirements. Subjects who screen fail out of 
Study DX-2930-03 for not meeting the minimum attack requirements during the run-in period 
must wait until enrollment for the double-blind study has ended before they can screen for Study
DX-2930-04. The Sponsor may ease this restriction based on the enrollment rate observed in 


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Study DX-2930-03. Subjects who are still in the run-in period for Study DX-2930-03 when 
enrollment for that study closes, as well as subjects on prior LTP who screen fail out of Study 
DX-2930-03 due to an inability to wash-out of their LTP, may screen for Study DX-2930-04 
following discussion with the Sponsor medical monitor.
Screening Period:
Rollover Subjects
There is no screening period for rollover subjects.
Non-rollover Subjects
Non-rollover subjects must provide informed consent and have screening assessments completed 
within 4 weeks prior to their first open-label dose. Screened non-rollover subjects (adults and 
adolescents) who are on LTP with C1-INH therapy for HAE can continue their current LTP until 
Day 8 (or Day 15) such that subjects will have received 2 (or 4) doses of C1-INH. (It is 
understood that C1-INH therapy may alter the lab results of C1-INH assessments; therefore, the 
investigator's discretion in collaboration with Medical Monitor is advised for proper 
documentation of eligibility). For subjects who are on attenuated androgens (eg, danazol) or anti-
fibrinolytics (eg, tranexamic acid), a similar tapering schedule is recommended. However, the 
taper can be prolonged by an additional week, if medically indicated, as long as androgen or anti-
fibrinolytic therapy is stopped within 3 weeks after receiving the first dose of DX-2930.  
Treatment Period:
Rollover Subjects
Following informed consent and pre-dose assessments, rollover subjects will receive a single 
open-label dose of 300 mg DX-2930 administered subcutaneously (SC) on Day 0. Subjects will 
not receive any additional DX-2930 doses until their first reported, and investigator-confirmed 
HAE attack. As such, the total number of doses within the treatment period will vary by rollover 
subject.
The duration of time between the first open-label dose and first reported HAE attack will vary by 
rollover subject.  All rollover subjects must adhere to the Study Activities Schedules (Table 1 
and Table 2) for the entire duration of the study.  However, until a rollover subject reports their 
first HAE attack, only scheduled study visits where the following tests and assessments are 
performed must be conducted at the investigative site: pregnancy testing, clinical laboratory 
testing, physical examination, 12-Lead ECG, QoL, PK, PD, and anti-drug antibody sample 
collection. All other scheduled study visits may be conducted via site check-in calls to collect 
information on adverse events, concomitant therapy, and HAE attack data.  See Study Activities 
Schedules (Table 1 and Table 2) for which visits must be conducted at the study site.
Once a rollover subject reports their first HAE attack they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  If 
the second dose is to be administered within the accepted ±4 day window around a scheduled 
study visit, this treatment visit will represent that scheduled visit. If that scheduled visit has 
already occurred, the day of the visit will be considered an acceptable, extra study visit (ie, an 
unscheduled visit).  Similarly, if the second dose is administered outside of the accepted ±4 day 
window around a scheduled visit, the day of the visit will be considered an acceptable extra 


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unscheduled study visit, (ie, this visit will not replace any scheduled visit). 
Regardless of the study day, at the visit in which the second open-label dose of DX-2930 is 
administered, the subject will undergo pre-dose assessments for vital signs, physical 
examination, clinical laboratory testing, blood sampling for PK, PD, and anti-drug antibody. 
Vital signs will be obtained at 1 hour post-dosing. As with all study visits, information will be 
collected on adverse events, concomitant therapy, and HAE attack data. 
Regardless of when a rollover subject’s first HAE attack occurs, there will be a minimum of 
10 days between their first open-label dose and their second open-label dose. Following their 
second open-label dose, rollover subjects will continue to receive repeated SC administrations of 
open-label 300 mg DX-2930 every 2 weeks for the remaining duration of the treatment period 
per the scheduled dosing in the Study Activities Schedules. The treatment period will last up to 
924 days from the date of the first open-label dose. The number of doses administered during 
this period will vary by subject based on the date of each subject’s second dose, but will not 
exceed 66 doses. The Day 910 study visit is the last visit at which a dose may be administered. 
Non-rollover Subjects
Once all screening assessments have been completed and eligibility confirmed, non-rollover 
subjects will arrive at the study site and, following pre-dose assessments, receive an open-label 
dose of 300 mg DX-2930 administered SC on Day 0. Non-rollover subjects will continue to 
receive SC administrations of open-label 300 mg DX-2930 every 2 weeks throughout the 
duration of the treatment period per the scheduled dosing in the Study Activities Schedules.
All Subjects:
All doses (with the exception of the second dose for rollover subjects) require a minimum of 
10 days and maximum of 18 days between administrations and should fall within the accepted 
±4 day window around study visits.
After the second DX-2930 dose is given either within the study window (±4 days) or an 
acceptable extra study visit, the 3rd dose must be administered at the next pre-defined study visit 
according to the schedule of assessments.
If a subject experiences an acute angioedema attack at any time during the study that in the 
opinion of the investigator requires medical intervention, standard of care therapy should be 
provided based on subject’s medical history and per locally approved product information. 
Administration of DX-2930 and study procedures will continue without alteration to the protocol 
study activities schedules, even if a subject receives treatment for a breakthrough angioedema 
attack on the day of a scheduled dose of study drug (if self-administering) or scheduled study 
visit.
Self Administration
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a 
physical and mental capability of learning and willing to be trained) may be allowed to self-
administer treatment. Subjects must complete appropriate training by the investigator or designee 
and understanding of the training must be confirmed by the investigator or designee. Subjects are 


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allowed to initiate self-administration at the subject’s home, or other agreed upon location after 
receiving the first 2 doses of DX-2930 at the study site. Once initiated, subjects may self-
administer subsequent doses of DX-2930 at the investigational site (when visits are scheduled 
study site visits) or the subject’s home or other agreed upon location (when the study permits off-
site dosing). See Schedule of Activities for details. Adolescent subjects self-administering 
investigational product will be supervised by a parent/legal guardian/caregiver. Alternatively, a 
parent/legal guardian/caregiver, after completing appropriate training, will be allowed to 
administer DX-2930 to an adolescent without study site personnel supervision. Site personnel 
will call subjects within approximately 3 days after the planned off-site self-administrations to 
ensure the administration occurred, to collect AEs, concomitant medications, and to ensure all 
attacks have been appropriately documented.
Throughout the study, study site personnel will document information in source documents (ie, 
the subject’s medical record) and eCRF regarding the subject’s experience with self-
administration and SC administration of DX-2930.
Subjects may be offered the opportunity to utilize a prefilled syringe (if available) for self-
administration of DX-2930.
Follow-up Period
After completion of the treatment period, all subjects will undergo safety evaluations during a 
4-week follow-up period.
Modifications to Open-Label Dosing
If, at any time, a dose-related safety signal is identified either from this study or Study
DX-2930-03, the Sponsor may decide to modify the open-label DX-2930 dose and/or frequency. 
In addition, an individual subject’s dose may be modified based on a benefit-risk assessment and 
recommendation from the treating physician. Consultation with and approval by the Sponsor’s 
Medical Monitor is required.
In addition, based on the results of Study DX-2930-03, the Sponsor may switch to a different 
dose and/or frequency. 
Study Population:
The study is expected to enroll subjects from Study DX-2930-03, as well as at least 50 (to 
approximately 100) additional subjects who were not enrolled in Study DX-2930-03. The total 
enrollment is expected to be at least 150 but not more than 250 HAE Type I or II subjects. 
Subjects will be 12 years of age or older who experience at least 1 attack per 12 weeks. HAE 
diagnosis will be confirmed through documented clinical history and diagnostic testing 
conducted either during screening or during prior participation in Study DX-2930-02 or Study
DX-2930-03. The study will aim to enroll at least 15 subjects who are 12 to 17 years of age, 
inclusive of the estimated 10 subjects 12 to 17 years old who are expected to roll over from 
Study DX-2930-03.
Criteria for Inclusion:
Subjects must meet the following criteria to be enrolled in this study:
1. Male and female HAE subjects who are 12 years of age or older at the time of screening. 


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2. Documented diagnosis of HAE (Type I or II)  based on all of the following:

Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria).

Diagnostic testing results obtained during screening (or a prior DX-2930 study) that 
confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level < 40% of the 
normal level. Subjects with functional C1-INH level 40-50% of the normal level may 
be enrolled if they also have a C4 level below the normal range.  Subjects may be 
retested if results are incongruent with clinical history or believed by the investigator 
to be confounded by recent LTP use. (It is understood that C1-INH therapy may alter 
the lab results of C1-INH assessments; therefore, the investigator's discretion in 
collaboration with Medical Monitor is advised for proper documentation of 
eligibility).

At least one of the following: Age at reported onset of first angioedema symptoms 
≤30 years, a family history consistent with HAE Type I or II, or C1q within normal 
range.
3. A historical baseline HAE attack rate of at least 1 attack per 12 weeks.
4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, 
understand, and sign an informed consent form. Subjects age 12 to 17, whose caregiver has 
provided informed consent, are willing and able to read, understand and sign an assent form.
5. Males and females who are fertile and sexually active must adhere to contraception 
requirements for the duration of the study as follows:

Females* of childbearing potential must agree to be abstinent, or it is recommended to 
use highly effective forms of contraception from screening through 30 days after the final 
study visit. This includes stable doses (for 3 months prior to study screening) of 
combined estrogen and progestin-containing hormonal contraception associated with 
inhibition of ovulation (oral, injectable or implantable), progestin-only hormonal 
contraception associated with inhibition of ovulation, intra-uterine device (IUD, all types) 
or intrauterine hormone releasing systems (IUS). Notes: 1) A female whose male partner 
has had a vasectomy must agree to use one additional form of medically acceptable 
contraception. 2) Use of a male condom with or without spermicide or cervical cap, 
diaphragm or sponge with spermicide or a combination (double barrier methods) are not 
considered highly effective.

Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study.

Males, including males who are surgically sterile (post vasectomy), with female partners 
of childbearing potential must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through 60 days after the final study 
visit.
*NOTE:  Female rollover subjects (those who previously participated in Study DX-2930-
03) of childbearing potential may continue to use the effective birth control method used 
during Study DX-2930-03.


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Criteria for Exclusion:
Subjects who meet any of the following criteria will be excluded from the study:
1. Discontinued from Study DX-2930-03 after enrollment for any reason.
2. If rolling over from Study DX-2930-03, presence of important safety concerns that would 
preclude participation in this study.
3. Concomitant diagnosis of another form of chronic, recurrent angioedema such as acquired 
angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), idiopathic 
angioedema, or recurrent angioedema associated with urticaria. 
4. Dosing with an investigational drug (not including DX-2930 or other HAE therapies) or 
exposure to an investigational device within 4 weeks prior to screening.
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to study 
screening or any newly initiated or dose modification of estrogen-containing medications 
with systemic absorption (such as oral contraceptives or hormonal replacement therapy) 3 
months prior to the screening visit.
6. Unwilling to discontinue use of long-term prophylactic therapy for HAE (C1-INH, attenuated 
androgens, or anti-fibrinolytics) within 3 weeks after starting DX-2930 treatment. 
7. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3x 
upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of normal, or 
total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of 
Gilbert’s Syndrome).
8. Pregnancy or breastfeeding.
9. Subject has any condition that, in the opinion of the investigator or Sponsor, may 
compromise their safety or compliance, preclude successful conduct of the study, or interfere 
with interpretation of the results (eg, history of substance abuse or dependence, a significant 
pre-existing illness or other major comorbidity that the investigator considers may confound 
the interpretation of study results).


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Test Product; Dose; and Mode of Administration:
DX-2930 is a sterile, preservative-free solution for injection, pH 6.0. The active ingredient, 
DX-2930, is formulated using the following compendial components: 30 mM sodium phosphate 
dibasic dihydrate, 19.6 mM citric acid, 50 mM histidine, 90 mM sodium chloride, 
0.01% Polysorbate 80. Each open-label vial contains a nominal concentration of 150 mg 
DX-2930 active ingredient in 1 mL solution OR 300 mg DX-2930 active ingredient in 2 mL 
solution.
For each 300 mg dose of DX-2930, each subject will receive a total of 2 mL, which will be 
administered in a single 2-mL SC injection. 
The injection will be given in the upper arm, thigh or abdomen.
Self-Administration Option: Investigational product can be self-administered without supervision 
(parental supervision required for adolescent subjects) after subjects receive appropriate training 
by the investigator or designee and their understanding is confirmed. Subjects are allowed to 
initiate offsite self-administration after receiving the first 2 doses of DX-2930 at the study site 
and may continue to self-administer all subsequent doses (see Study Activities Schedules).
Duration of Treatment:
All subjects will receive open-label DX-2930 during a treatment period of up to 924 days. 
The last dose of open-label DX-2930 administered to rollover subjects may be given at the Day 
910 study visit. Non-rollover subjects will receive 300 mg DX-2930 every 2 weeks for up to 
66 doses, with the first dose administered on Day 0 and the final dose administered at the Day 
910 study visit.
There will be a ± 4-day window around each study visit. There will be a minimum of 10 days 
between any two doses. Excluding the interval between the first and second open-label doses for 
rollover subjects, there will be a maximum of 18 days between any two doses. Subjects will be 
monitored at the study site through 1 hour post-dose for scheduled study site visits.  No 
monitoring of vital signs will be performed for subjects who elect to self-administer away from 
the investigational site.
Duration of Study for Individual Subjects:
Following informed consent, subjects will either rollover from DX-2930-03 or undergo 
screening assessments (non-rollover subjects). Screening assessments for non-rollover subjects 
must occur within 4 weeks prior to the first open-label dose. Eligible subjects will be enrolled 
and undergo a treatment period of up to 924 days. At the conclusion of the treatment period, 
subjects will be followed for an additional 4 weeks. 
Prohibited Concomitant Treatments:
Use of the following treatments will not be permitted during the study:
•
Long-term prophylaxis for HAE (eg, use of C1-INH for LTP, attenuated androgens, or anti-
fibrinolytics) once LTP is discontinued (within 3 weeks following the first dose of 
DX-2930). 
•
Angiotensin-converting enzyme (ACE) inhibitors.


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•
Initiating or changing the dose of estrogen-containing medications with systemic absorption 
(such as oral contraceptives or hormonal replacement therapy) 3 months prior to study 
screening.
•
Use of androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, and 
testosterone) for non-HAE related medical conditions or for HAE after discontinuation 
during the first three weeks.
•
Any other investigational drug or device.
The use of short-term prophylactic treatment for HAE will be permitted if medically indicated. 
Short-term (pre-procedure) prophylaxis is defined as the use of C1-INH to avoid angioedema 
complications from medically indicated procedures.
Management of Acute Attacks:
Acute HAE attacks during the study are to be managed in accord with the investigator’s usual 
care of their patients, including the use of acute attack therapies that the investigator deems as 
medically appropriate. Use of C1-INH will be permitted as an acute attack therapy but not as a 
long-term prophylactic therapy. Administration of DX-2930 and study procedures will continue 
without alteration to the protocol-specified study schedule, even if the subject has symptoms of 
an HAE attack the day of DX-2930 administration and/or receives treatment for an HAE attack. 
The administration of DX-2930 can also be re-scheduled as long as the minimum and maximum 
timeframe between doses are met based on subject preference or physician discretion.
Safety Assessments:
Safety assessments will include the following:
•
Adverse events (AEs), including serious adverse events (SAEs) and adverse events of special 
interest (AESI). SAEs and AESI will be reported to the Sponsor within 24 hours of becoming 
aware of the event.
•
Vital signs, including sitting or supine blood pressure (BP), heart rate (HR), body 
temperature, and respiratory rate (RR)
•
Physical examination
•
Clinical laboratory testing (hematology, serum chemistry, coagulation, and urinalysis)
•
12-Lead electrocardiogram (ECG) 
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Hypersensitivity reactions and events of disordered coagulation will be considered AESI.
Pharmacokinetic (PK) Assessments:
Blood samples will be collected for the measurement of plasma DX-2930 concentrations.
Pharmacodynamic (PD) Assessments:
Blood samples will be collected to evaluate the pharmacodynamic effects of DX-2930 through 
biomarker assays.
Immunogenicity Assessments:
Blood samples will be collected to assay for the presence of anti-drug antibodies, including 
evaluation of neutralizing antibodies (if any confirmed positive anti-drug antibodies are 
detected).


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C1-INH, C4, and C1q and Exploratory Biomarker Assessments:
Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment, 
unless already collected as part of protocol DX-2930-02 or DX-2930-03. C1-INH, C1q, C4 and 
exploratory biomarkers will be measured throughout the study and at the end of the study to 
evaluate the effect of DX-2930 on these biomarkers of disease activity.
Quality of Life Assessments:
Quality of life (QoL) assessments will be conducted using the Angioedema Quality of Life 
Questionnaire (AE-QoL), EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L), Work 
Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH), Hospital 
Anxiety and Depression Scale (HADS), and 12 Item Short Form Survey (SF-12), the 
Angioedema Control Test (AECT), the Global Impression of Treatment Response, and 
Treatment Satisfaction Questionnaire for Medication (TSQM-9). Additionally, subjects will 
complete a brief exit interview to obtain data on the subjects’ experience in the DX-2930 studies.
DX-2930 Injection Report and Self-Administration and Subcutaneous Injection Survey
An injection report of the subject’s experience with self-administration and SC injection will be 
completed by the subject after all doses of DX-2930.
In addition, an assessment survey of the subject experience with SC and self-administration 
injections of DX-2930, and the prefilled syringe (if utilized), will be completed by the subject as 
indicated in the Study Activities Schedules.
Collection of HAE Attack Data:
The collection, reporting and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP). Study site personnel will be 
trained on HAARP prior to screening and enrolling subjects at their site.
Study site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide. The 
subject (and caregiver) will confirm their understanding of what is required of them for reporting 
attacks to the site.
At screening, HAE attack history will be collected for non-rollover subjects. Information 
collected will include any prior history of laryngeal attacks, attack frequency, average severity, 
predominant attack location(s), triggers, average duration, acute attack therapy use and history of 
LTP (including duration of LTP, medication(s) and dose used for LTP, and frequency of attacks 
while receiving LTP). If available, information will also be collected on HAE diagnosis (year of 
confirmation, how many years after onset of symptoms was diagnosis confirmed, or if subject 
was misdiagnosed).
During the study, subjects (or caregivers) will be instructed to notify and report details to the 
study site within 72 hours of the onset of an attack. This includes the first attack experienced by 
rollover subjects following their first open-label dose. In the situation that a subject is 
incapacitated following an attack, this information can be provided to the site by a family 
member or other individual with detailed knowledge of the event. If desired by the subject, 
memory aids may be provided to assist in tracking any HAE attacks experienced, but their use is 


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not mandatory. 
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack:

Date and time symptoms of an attack were first experienced.

Description of symptoms experienced, including location(s).

Impact on activity (work, school, social interactions) and whether any assistance or 
medical intervention was required, including hospitalizations, additional laboratory tests 
or emergency department visits.

Any medications used to treat the attack (both prescription and over the counter).

If the attack resolved, date and time the subject was no longer experiencing symptoms.
Study site personnel will review the information provided and solicit additional information as 
necessary to document the attack as described in HAARP.
Study site personnel will contact rollover subjects approximately every 7 days following the first 
dose of open-label DX-2930 to solicit for any HAE attacks not already reported.  Site check-ins 
will continue until the subject has received their second open-label dose.
During each study visit, study site personnel will solicit for any new attack information that was 
not already provided to the site.
In this study, HAE attacks will be captured as AEs. All AEs, regardless of seriousness, severity, 
or causal relationship to DX-2930, will be recorded on the AE page of the eCRF. Any AE 
reported to the site meeting criteria for a serious adverse event must be reported to the Sponsor 
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of the 
event.
In addition to reporting AEs and SAEs as described above, the investigator or physician designee 
is also required to evaluate each attack within 7 calendar days and evaluate if it represents a 
confirmed HAE attack in accordance with HAARP. If necessary for the evaluation, the 
investigator or designee may contact the subject to receive additional information. Any subject-
reported attack not confirmed by the investigator or physician designee must have an alternate 
AE diagnosis recorded.  All subject-reported and investigator/ physician designee-confirmed 
HAE attacks will be recorded in the eCRF. 
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured.
To be confirmed as an attack, the event must have symptoms or signs consistent with an attack in 
at least one of the following locations: 


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•
Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region.
•
Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea.
•
Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx.
Despite the presence of these symptoms, the investigator or physician designee may still 
clinically determine that the event did not represent an attack if there are features that strongly 
refute such a diagnosis. For example, the reported event is accompanied by symptoms that are 
not consistent with an HAE attack (eg, urticaria), the reported event persists well beyond the 
typical time course of an HAE attack, or there is a likely alternate etiology for the event (eg, the 
subject’s abdominal symptoms are attributable to a viral gastroenteritis outbreak in the 
household). 
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.
Interim Analyses and Data Monitoring
Interim analyses may be conducted when a reasonable number of subjects have completed at 
least 12 months of consecutive exposure to DX-2930 across the combined DX-2930-03 and 
DX-2930-04 studies, and only after database lock of Study DX-2930-03. Interim analyses may 
be performed to support administrative decisions and/or regulatory reporting.
An independent Data Safety Monitoring Board (DSMB) has been established to provide 
ongoing, independent review and assessment of the safety data for Study DX-2930-03. While an 
independent DSMB is not currently planned for this study, summary safety data from Study DX-
2930-04 may be reviewed by the Study DX-2930-03 DSMB as part of the collection of safety 
information available on DX-2930. 
Individual Stopping Rules:
Dosing for any individual subject will be discontinued if the subject experiences a 
DX-2930-related SAE (or a DX-2930-related, clinically significant non-serious AE) that, in the 
assessment of the investigator, warrants discontinuation from further dosing for that subject’s 
well-being. The investigator has the ability to contact and consult with the Medical Monitor on 
such matters. Subjects will continue to be followed through the completion of all scheduled non-
dosing visits, unless they request to be discontinued from the study.
Criteria for Evaluation:
Safety Measures:
•
AEs including SAEs and AESI
•
Clinical laboratory testing (hematology, clinical chemistry, coagulation, and urinalysis)
•
Vitals signs including blood pressure, heart rate, oral body temperature, and respiratory rate
•
Physical Examination
•
12-lead ECG 


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Efficacy Endpoints:
•
Time to first HAE attack for rollover subjects (based upon time from first open label study 
dose until first HAE attack)
•
Number of investigator-confirmed HAE attacks during the treatment period
•
Number of investigator confirmed HAE attacks requiring acute treatment during the 
treatment period
•
Number of moderate or severe HAE attacks during the treatment period
•
Number of high-morbidity HAE attacks during the treatment period; a high-morbidity HAE 
attack is defined as any attack that has at least one of the following characteristics: severe, 
results in hospitalization (except hospitalization for observation < 24 hours), 
hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal.
Additional Measures:
•
Anti-drug antibody development
•
Pharmacokinetics (PK) effects
•
Pharmacodynamic (PD) effects
•
Quality of Life Assessments
•
DX-2930 Injection Report 
•
DX-2930 Self-administration and Subcutaneous Injection Survey
•
Exploratory biomarker(s) of angioedema disease-state bioactivity in plasma and serum
•
Subject response to prefilled syringe, if available
•
Subject response to rescue medication 
•
Subject treatment satisfaction
•
Subject and Investigator Global Impression of Treatment Response survey
•
Subject assessment of angioedema control
Analysis Populations:

The Safety Population will include all subjects who received any study drug after entering 
the Study DX-2930-04 (ie, any exposure to open-label DX-2930).   

The Rollover Safety Population is the subset of subjects who participated in Study DX-2930-
03 and received any study drug after entering Study DX-2930-04 (ie, any exposure to open-
label DX-2930). 

The Non-rollover Safety Population is the subset of subjects who entered Study DX-2930-04 
directly and received any study drug after entering Study DX-2930-04 (ie, any exposure to 
open-label DX-2930).  


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Sample Size Determination:
No formal sample size calculation was performed.  The sample size is not based on any 
statistical considerations.  This study is designed to evaluate the safety and efficacy of open-label 
treatment with DX-2930 in subjects who participated in Study DX-2930-03 and individuals who 
were not otherwise able to participate in Study DX-2930-03.
Statistical Methodology: 
Time to the first investigator-confirmed HAE attack will be analyzed using the Rollover Safety 
Population.
Time to the first investigator-confirmed HAE attack (days) will be calculated from the date and 
time of the first open-label dose of DX-2930 to the date and time of the first investigator-
confirmed HAE attack after the first open-label dose.  Subjects who discontinue the study prior 
to experiencing their first on-study investigator-confirmed HAE attack will be censored at the 
date and time of study discontinuation.  Time to the first investigator-confirmed HAE attack will 
be summarized using Kaplan-Meier methods.
Multivariate and univariate Cox proportional hazards regression models will be employed to 
examine the impact of baseline covariates on the time to the first investigator-confirmed HAE 
attack, including but not limited to: baseline attack rate prior to entering Study DX-2930-03, the 
treatment group in Study DX-2930-03, the time since the last dose given in Study DX-2930-03, 
the time since the last HAE attack, and the rate of attacks during Study DX-2930-03. Results of 
this exploratory analysis will be summarized.  
Number of Investigator-confirmed HAE Attacks
The number of investigator-confirmed HAE attacks during the treatment period (Day 0 through 
Day 924) expressed as a monthly HAE attack rate, will be analyzed using each analysis 
population.
The monthly rate of investigator-confirmed HAE attacks during the treatment period will be 
calculated for each subject as the number of investigator-confirmed HAE attacks occurring 
during the treatment period divided by the number of days the subject contributed to the 
treatment period multiplied by 28 days.  
The baseline investigator-confirmed monthly HAE attack rate will be calculated for each subject 
as the number of investigator-confirmed monthly HAE attacks occurring during the pretreatment 
period for rollover subjects or historical reporting period for non-rollover subjects divided by the 
number of days the subject contributed to the pretreatment period for rollover subjects or 
historical reporting period for non-rollovers multiplied by 28 days.
The baseline, treatment period, and treatment period change from baseline in the investigator-
confirmed HAE attack rate will be summarized for each analysis population. The summary will 
include the total number of investigator-confirmed HAE attacks reported during each period and 
subject-time in months that each subject contributed to each period. Figures will be created for 
each analysis population plotting the on-study investigator-confirmed HAE attacks reported 


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during the treatment period relative to Day 0 for each subject.
Similar summary tables will be presented for the following efficacy endpoints for each analysis 
population:
•
Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period.
•
Number of moderate or severe investigator-confirmed HAE attacks during the treatment 
period.
•
Number of high-morbidity investigator-confirmed HAE attacks during the treatment period; 
a high-morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation 
< 24 hours), hemodynamically significant (systolic blood pressure < 90, requires IV 
hydration, or associated with syncope or near-syncope) or laryngeal.
Safety Analysis:
Adverse Events
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. 
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.  
Related AEs are AEs classified as related to study drug by the investigator. Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator.
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE, 
any severe AE, any related severe AE, and any investigator-reported AESI, as well as the total 
number of events for each category will be summarized.  The number of deaths due to an AE, 
hospitalization due to an AE and study discontinuation due to an AE will be summarized. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC, and PT. This tabulation will be repeated for related AEs, SAEs, related 
SAEs, severe AEs, and related severe AEs. 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions and 
disordered coagulation (hypercoagulability events and bleeding events).  Standardized MedDRA 
Queries (SMQ) for each AESI will be performed using the study data. The number and percentage 
of subjects with an AESI, as well as the total number of AESIs, will be summarized by SOC and PT. 
Separate summary tables will be created for each AESI and for those events with the SMQs 
classified as related, serious, related serious, severe, and related severe.  A listing detailing the 
PT within the SMQ will be provided.
Laboratory Test Results, Vital Signs, and Electrocardiography Results


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Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For 
rollover subjects previously exposed to DX-2930, baseline is the last non-missing value prior to 
first exposure to study drug in Study DX-2930-03.      
  
Actual values and change from baseline in clinical laboratory test results and vital signs will be 
summarized by study visit. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. Vital sign values will be classified according to 
clinical significance as determined by the investigator. The number of subjects with a non-
missing result, and the number and percentage of subjects within each category will be 
summarized by study visit.  
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG not performed will be summarized by study 
visit.
Other Analyses
Plasma concentrations of DX-2930 and plasma kallikrein activity will be summarized by 
nominal PK and PD sampling times.
The number and percentage of subjects with positive antibodies (and whether neutralizing or 
non-neutralizing) and exploratory biomarkers will be summarized by study visit and overall.
Quality of life assessments will be summarized by study visit.
Date of Original Protocol:  14 December 2015
Date of Amendment 1:  27 June 2016
Date of Amendment 2:  20 January 2017
Date of Amendment 3: 29 June 2017


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Table 1
Study Activities Schedule –Day -28 through Day 365
Activities Occurring at
Treatment Period, Visit Window ± 4 days                      = scheduled in-site visits for all subjects. 
        = potential subject-elected off-site activity and/or self-administration dosing.
See 
Protocol 
Section 
below
for details
Non Rollover Visit
Scra
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
18
19
20
21
22
23
24
25
26
27 
Rollover Visit
-
Chkb
Dose Number
-
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
18
19
20
21
22
23
24
25
26
27
Study Day (± 4 days)
-28
0
14
28 
42
56 70 84 98 112 126 140 154 168 182 196 210 224
238
252
266
280
294
308
322
336
350
364
Informed Consentc
•
•
6.1
Eligibility Reviewd
•
•
6.2
Long-term prophylactic therapy cont’dd
•
•
•
3.1.1
DX-2930-04 Administratione, f
(rollover subjects) g
•
• 
• • • • • • • • • • • • • • • 
• 
• 
• 
•
• 
• 
• 
• 
• 
• 5.1
(non-rollover subjects)d
•
• 
• • • • • • • • • • • • • •
•
•
•
•
•
•
•
•
•
•
• 5.1
Demographic and Medical Historyh
•
6.3
Pregnancy Testi (females) 
•
•i
•
•
•
•
•
•
•
•
•
•
• 6.8
Vital Signsj
•
•
•
•
• • • • • • • • • • • • •
•
•
•
•
•
•
•
•
•
•
• 6.5
Physical Examk
•
•
•
•
•
•
•
•
•
• 6.6
Clinical Laboratory Testingl
•
•
•
•
•
•
•
•
•
•
• 6.8
12-Lead ECGm
•
•
•
•
•
• 6.7
Prior (4 wks) & Concomitant Therapy 
•
•
•
•
•
• • • • • • • • • • • • •
•
•
•
•
•
•
•
•
•
•
• 6.12
Adverse Events
•
•
•
•
•
• • • • • • • • • • • • •
•
•
•
•
•
•
•
•
•
•
• 6.16
HAE Attack Datan
•
•
•
•
•
• • • • • • • • • • • • •
•
•
•
•
•
•
•
•
•
•
• 6.4
Quality of Life
AE-QoL, EQ-5D-5L, WPAI-GH, 
HADS, SF-12
•
•
•
•
•
•
•
•
•
•
• 6.14.1-
6.14.5
AECT, TSQM-9, Global 
Impression of Treatment Response
• 6.14.6-
6.14.8
DX-2930 Injection Report
•
•
•
• • • • • • • • • • • • •
•
•
•
•
•
•
•
•
•
•
• 6.15.1
DX-2930 Self-administration & SC 
Injection Survey
•
•
•
•
• 6.15.2
PK, PD, ADA,o & Biomarkerp Sample 
collection
•
•
•
•
•
• 6.8-11


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Table 1
Study Activities Schedule –Day -28 through Day 365
Abbreviations:  ADA = anti-drug antibody; AECT = Angioedema Control Test; AE-QOL = Angioedema Quality of Life; Chk = check-in; Cont’d = 
continued; ECG = Electrocardiogram; EQ-5D-5L = EuroQoL 5-Dimensional 5-Level; HADS = Hospital Anxiety and Depression Scale; PK = 
Pharmacokinetic; PD = Pharmacodynamic; Scr=screening visit; Scr=screening; SF-12 = Short Form-12; Treatment Satisfaction Questionnaire for 
Medication= TSQM-9; WPAI-GH = Work Productivity and Activity Impairment – General Health
a
Screening visit is for non-rollover subjects only.  Screening visit can occur up to 28 days prior to first open-label dose.
b
Study site personnel will contact rollover subjects approximately every 7 days following the first dose of open-label DX-2930 to solicit for any 
HAE attacks not already reported.  Site check-in with rollover subjects will continue until the subject receives their second open label dose.
c
Rollover subjects must sign informed consent for Study DX-2930-04 on or after Day 168 of Study DX-2930-03.  Day 182 of Study DX-2930-03 
is also Day 0 of Study DX-2930-04, and informed consent may be completed on this visit, if not already provided.
d
Screened non-rollover subjects (adults and adolescents) who are on LTP with C1-INH therapy for HAE can continue their current LTP until Day 
8 (or Day 15) such that subjects will have received 2 (or 4) doses of C1-INH. For subjects who are on attenuated androgens (eg, danazol) or anti-
fibrinolytics (eg, tranexamic acid), a similar tapering schedule is recommended. However, the taper can be prolonged by an additional week as 
long as androgen or anti-fibrinolytic therapy is stopped within 3 weeks of receiving the first dose of DX-2930. Since C1-INH therapy may alter 
the lab results of C1-INH assessments, the investigator's discretion in collaboration with Medical Monitor is advised for proper documentation of 
eligibility.
e
Doses are administered every 14 ± 4 days. All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a physical and 
mental capability of learning and willing to be trained) may be allowed to self-administer DX-2930 after (1) completing appropriate training by 
the investigator or designee, (2) confirming their understanding, and (3) receiving the first 2 doses of DX-2930 at the study site. Subjects are then 
allowed to initiate home self-administration and may elect to self-administer subsequent doses of DX-2930 at the investigational site. Subjects 
who receive a new product format (ie, a single vial or a PFS) will receive additional training in how to self-administer with that format.
f
Site personnel will call subjects within approximately 3 days after the planned self-administration to ensure the administration occurred, to collect 
AEs, concomitant medications, and to ensure all attacks have been appropriately documented.
g
Rollover subjects will not receive Dose 2 until they have experienced the first reported, investigator-confirmed attack. In addition, a minimum of 
10 days is required between Dose 1 and Dose 2. If the second dose is to be administered within the accepted ±4 day window around a scheduled 
study visit, this treatment visit will represent that scheduled visit unless that scheduled visit has already occurred. If that scheduled visit has 
already occurred, or if the second dose is to be administered outside of the accepted ± 4 day window around a scheduled visit, this visit will not 
replace any scheduled visit and will thus represent an acceptable, extra study visit (ie, an unscheduled visit). Regardless, at the visit in which the 
second open-label dose of DX-2930 is administered, the subject will undergo pre-dose assessments for vital signs, physical examination 
(performed in accordance with standards at the site), clinical laboratory testing, PK, PD, biomarkers and anti-drug antibody. Vital signs will be 
obtained at 1 hour post-dosing. As with all study visits, information will be collected on adverse events, concomitant therapy, and HAE attack 
data. Following Dose 2, subjects will begin regular administrations every 2 weeks.
h
For rollover subjects, demography data from DX-2930-03 will be re-entered for DX-2930-04. However, medical history reported in the DX2930-
03 study will not be re-entered into the CRF for DX-2930-04; only new medical history data will be entered.
i
The pregnancy test will only be conducted in females of childbearing potential.  Tests performed on Day 0 must be urine-based to confirm 
eligibility prior to first dose. Tests performed at screening and on indicated visits could be serum or urine-based.


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Table 1
Study Activities Schedule –Day -28 through Day 365
j
There is a recommended ± 15 minute window for all vital signs. Vital signs will be obtained prior to dosing and 1 hour after dosing. 
Monitoring of vital signs will not be performed for subjects who elect to self-administer away from the investigative site at optional off-site visits 
(indicated non-shaded columns).
k
Physical examinations, including weight, will be conducted for all rollover and non-rollover subjects according to the study activities schedule 
and in accordance with standards at the site.  In addition to the physical examinations specified in the study activities schedule, an additional 
physical examination (performed in accordance with standards at the site) will be conducted for rollover subjects prior to dosing on the day of 
their second open-label dose, at whatever study visit that occurs.  Height will be collected at the Screening visit only.
l
Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis (urinalysis does not need to be done as part of 
the clinical laboratory testing at Visits 14, 17, 20, and 23). Clinical laboratory testing will be conducted for all rollover and non-rollover subjects 
according to the study activities schedule. In addition to the testing specified in the study activities schedule, additional testing will be conducted 
for rollover subjects prior to dosing on the day of their second open-label dose, at whatever study visit that occurs.
m
In addition to the timepoints shown, ECG is to be performed when clinically indicated.
n
Historical HAE attack information will be collected at screening for non-rollover subjects. 
During the study, subjects (or caregivers) are instructed to report details of the attack to the study site within 72 hours of the onset of the attack. 
During study visits, study site personnel will solicit for any new HAE attack information that has not already been reported to the site. Study site 
personnel will utilize the HAARP guidelines in order to confirm the HAE attack within 7 days. 
o
PK, PD, biomarker, and anti-drug antibody samples will be drawn for all rollover and non-rollover subjects at the visits shown. An additional 
sample will be drawn for rollover subjects prior to dosing on the day of their second open-label dose, at whatever study visit that occurs.
p
Samples for C1-INH, C4, and C1q assays will be collected at screening for eligibility. In addition, C1-INH, C4, C1q, and other biomarkers will be 
collected at Visit 14, and Visit 27, as applicable. Samples need not be obtained at screening for eligibility assessment if they were already 
collected as part of Study DX-2930-02 or Study DX-2930-03.


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Table 2
Study Activities Schedule for Day 366 through Day 952
Activities Occurring at
Treatment Period, Visit Window ± 4 days for each visit
Follow 
Up 
Period
See 
Protocol  
Section 
below
for 
details
                   = scheduled in-site visits for all subjects. 
                      = potential subject-elected off-site activity and/or self-administration dosing.
Visit
28
29 
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67 
68a
69
EOS
ETb
Study Day (± 4 days)
378
392
406
420
434
448
462
476
490
504
518
532
546
560
574
588
602
616
630
644
658
672
686
700
714
728
742
756
770
784
798
812
826
840
854
868
882
896
910
924
938
952
DX-2930 Administrationc,d
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
5.1
Physical Exame
•
•
•
•
•
•
•
•
•
•
•
•
6.6
Pregnancy Testf (females) 
•
•
•
•
•
•
•
•
•
•
•
•
6.8
Vital Signsg
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
6.5
Concomitant Therapy
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
6.12
Adverse Events
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
6.16
HAE Attack Datah
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
6.4
Clinical Laboratory 
Testingi
•
•
•
•
•
•
•
•
•
•
•
•
6.8
PK, PD Collection, ADA 
Testing & Biomarkersj
•
•
•
•
•
•
•
6.8-11
12-Lead ECG
•
6.7
Quality of Life
AE-QoL, EQ-5D-5L, 
WPAI-GH, HADS, SF-
12
•
•
•
•
•
•
•
•
•
•
•
6.14
AECT
•
•
•
•
•
•
•
•
•
•
•
6.14.6
TSQM-9
•
•
6.14.7
Global Impression of 
Treatment Response
•
6.14.8
Exit Interview
•
6.14.9
Site Check In Callk
•
•
•
•
•
•
•
•
•
•
•
•
DX-2930 Injection Reportl
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
6.15.1
DX-2930 Self-admin & SC 
•
•
•
•
•
•
•
•
•
•
6.15.2


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Table 2
Study Activities Schedule for Day 366 through Day 952
Injection Surveyl, PFS 
Survey
Discharge from Study
•
7.35
Abbreviations: AECT=Angioedema Control Test; EOS = End of Study; ET = Early Termination; PFS = prefilled syringe; Self-admin = Self-administration; 
Treatment Satisfaction Questionnaire for Medication = TSQM-9 
NOTE: Although the first visit shown on this Schedule is at Day 378, this schedule covers the entire period following the end of the previous schedule. Certain 
assessments should be collected continuously throughout the study (for example, AEs) are collected continuously throughout the study.
a
Visit 68 is a site check-in call for all rollover and non-rollover subjects.
b
Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures at Visit 69, the final study visit.
c
Doses are administered every 14 ± 4 days.
d
All subjects (adolescent or adult) who are considered suitable candidates (i.e., those with a physical and mental capability of learning and willing 
to be trained) may self-administer DX-2930 at all visits following the training described in Table 1. Subjects who receive a new product format (ie, 
a single vial or a PFS) will receive additional training in how to self-administer with that format. Subjects may administer at home or other agreed 
upon location (during off-site self-administration visits; non-shaded columns). Subjects can opt to be seen in clinic for this visit.
e
Physical examinations, including weight, will be conducted for all rollover and non-rollover subjects according to the study activities schedule and 
in accordance with standards at the site. 
f
The pregnancy test will only be conducted in females of childbearing potential. Tests performed at screening and indicated visits could be serum or 
urine-based.
g
There is a recommended ± 15-minute window for all vital signs. Vital signs will be obtained prior to dosing and 1 hour after dosing. 
Monitoring of vital signs will not be performed for subjects who elect to self-administer away from the investigative site at optional off-site visits 
(indicated non-shaded columns).
h
During the study, subjects (or caregivers) are instructed to report details of the attack to the study site within 72 hours of the onset of the attack. 
During study visits, study site personnel will solicit for any new HAE attack information that has not already been reported to the site. Study site 
personnel will utilize the HAARP guidelines in order to confirm the HAE attack within 7 days.
i
Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis (urinalysis is performed as part of the clinical 
laboratory testing at Visits 42, 54, 66, 69).
j
Biomarker samples for C1-INH, C4, and C1q assays will be collected at Visits 34, 42, 50, 58, 66, 67, and 69.
k
Site personnel will call subjects within approximately 3 days after the planned self-administration to ensure the administration occurred, to collect 
AEs, concomitant medications, and to ensure all attacks have been appropriately documented.
l
Collect subject's injection reports of their experience with DX-2930 self-administration, subcutaneous administration, and prefilled syringe (if 
relevant) for all doses.


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
AMENDMENT SUMMARY AND RATIONALE ........................................................................3
SYNOPSIS.......................................................................................................................................6
TABLE OF CONTENTS...............................................................................................................27
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................34
1.
INTRODUCTION..................................................................................................................37
1.1
DX-2930...................................................................................................................37
1.2
Hereditary Angioedema ...........................................................................................37
1.3
Therapeutic Rationale for DX-2930.........................................................................37
1.4
Safety Rationale for DX-2930..................................................................................38
1.5
DX-2930 Non-Clinical Pharmacology and Toxicology...........................................38
1.6
DX-2930 Clinical Data.............................................................................................38
1.6.1
Single-Ascending Dose Study in Healthy Subjects (DX-2930-01).......................39
1.6.2
Multiple-Ascending Dose Study in HAE Patients (DX-2930-02).........................39
1.7
Rationale for Open-Label Extension Study DX-2930-04........................................41
2.
STUDY OBJECTIVES ..........................................................................................................42
2.1
Primary Objective ....................................................................................................42
2.2
Secondary Objectives...............................................................................................42
2.3
Tertiary Objectives...................................................................................................42
3.
INVESTIGATIONAL PLAN.................................................................................................43
3.1
Overall Study Design and Plan ................................................................................43
3.1.1
Overview................................................................................................................43
3.1.2
Stopping Rules.......................................................................................................47
3.1.2.1
Study Level Stopping Rules...................................................................47
3.1.2.2
Individual Stopping Rules......................................................................48
3.1.3
Follow-up for Subjects Meeting Stopping Criteria................................................48
3.2
Rationale for Open-Label Extension Dose Selection...............................................48
3.3
Individual Subject Dosing and Follow-Up...............................................................48
3.4
Study Duration for Individual Subjects....................................................................49
4.
STUDY POPULATION SELECTION ..................................................................................50
4.1
Study Population ......................................................................................................50
4.2
Inclusion Criteria......................................................................................................50
4.3
Exclusion Criteria.....................................................................................................51
5.
STUDY TREATMENT(S).....................................................................................................53
5.1
Description of Treatment(s) .....................................................................................53
5.2
Dosing and Follow-Up Scheme ...............................................................................53


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5.3
Method of Identifying Subjects................................................................................54
5.4
Prior and Concomitant Therapy...............................................................................54
5.4.1
Allowed Therapies.................................................................................................54
5.4.1.1
Management of HAE Attacks ................................................................55
5.4.2
Excluded Concomitant Therapies..........................................................................55
5.5
Restrictions...............................................................................................................55
5.5.1
Medical Interventions ............................................................................................55
5.5.2
Fluid and Food Intake............................................................................................55
5.5.3
Activity ..................................................................................................................55
5.6
Treatment Compliance .............................................................................................56
5.7
Packaging and Labeling ...........................................................................................56
5.8
Storage and Accountability ......................................................................................56
5.9
Investigational Medicinal Product Retention at Study Site .....................................57
6.
STUDY PROCEDURES........................................................................................................58
6.1
Informed Consent.....................................................................................................58
6.2
Eligibility Review ....................................................................................................58
6.3
Demographics and Medical History.........................................................................58
6.4
HAE Attack Information Collection ........................................................................58
6.5
Vital Signs................................................................................................................60
6.6
Physical Examination...............................................................................................60
6.7
Electrocardiography (ECG)......................................................................................61
6.8
Clinical Laboratory Tests.........................................................................................61
6.8.1
Laboratory Parameters...........................................................................................61
6.8.1.1
Hematology ............................................................................................61
6.8.1.2
Coagulation ............................................................................................61
6.8.1.3
Chemistry ...............................................................................................62
6.8.1.4
Urinalysis ...............................................................................................62
6.8.1.5
Pregnancy Test .......................................................................................63
6.8.1.6
Biomarkers .............................................................................................63
6.8.1.7
PK Sample Collection ............................................................................63
6.8.1.8
PD Sample Collection ............................................................................63
6.8.1.9
Plasma Anti-Drug Antibody Testing......................................................64
6.8.2
Sample Collection, Storage, and Shipping ............................................................64
6.9
Pharmacokinetic Assessments..................................................................................64
6.10
Pharmacodynamic Assessments...............................................................................64
6.11
Plasma Anti-Drug Antibody Testing........................................................................64
6.12
Prior and Concomitant Therapy...............................................................................64
6.13
Investigational Medicinal Product Treatment..........................................................64


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6.14
Quality of Life Assessments ....................................................................................65
6.14.1 Angioedema Quality of Life Questionnaire (AE-QoL).........................................65
6.14.2 EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L) ......................................65
6.14.3 Work Productivity and Activity Impairment – General Health (WPAI-GH) 
Questionnaire.........................................................................................................65
6.14.4 Hospital Anxiety and Depression Scale (HADS)..................................................66
6.14.5 12 Item Short Form v2 Health Survey (SF-12v2) .................................................66
6.14.6 Angioedema Control Test (AECT)........................................................................66
6.14.7 Treatment Satisfaction Questionnaire for Medication (TSQM-9).........................66
6.14.8 Global Impression of Treatment Response............................................................66
6.14.9 Exit Interview.........................................................................................................67
6.15
DX-2930 Injection Report and Self-Administration and Subcutaneous 
Injection Survey .......................................................................................................67
6.15.1 DX-2930 Injection Report .....................................................................................67
6.15.2 DX-2930 Self-administration and Subcutaneous Injection Survey.......................67
6.16
Adverse Event Reporting .........................................................................................68
6.16.1 Definitions..............................................................................................................68
6.16.1.1
Adverse Event ........................................................................................68
6.16.1.2
Serious Adverse Event ...........................................................................68
6.16.1.3
Overdose.................................................................................................69
6.16.1.4
Planned Hospitalization..........................................................................69
6.16.1.5
Treatment-Emergent Adverse Events (TEAE).......................................69
6.16.1.6
Adverse Events of Special Interest (AESI)............................................69
6.16.2 Monitoring .............................................................................................................70
6.16.2.1
Monitoring of Adverse Events ...............................................................70
6.16.2.2
Monitoring of Safety Laboratory Assessments......................................71
6.16.3 Assessment of Adverse Events..............................................................................71
6.16.3.1
Assessment of Severity ..........................................................................71
6.16.3.2
Assessment of Causality.........................................................................71
6.16.3.3
Assessment of Clinical Significance......................................................72
6.16.4 Clinical Laboratory Adverse Events......................................................................72
6.16.5 Reporting Investigator Safety Observations to the Sponsor..................................73
6.16.5.1
Reporting Non-serious Adverse Events .................................................73
6.16.5.2
Reporting Pregnancies............................................................................73
6.16.5.3
Safety Observations Requiring Expedited Reporting by the 
Investigator to the Sponsor.....................................................................73
6.16.5.4
Expedited Reporting by the Sponsor to a Regulatory Health 
Authority ................................................................................................74


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6.16.5.5
Safety Contact Information ....................................................................74
6.16.5.6
Safety Notifications by the Sponsor to the Investigator.........................74
6.17
Subject Withdrawal..................................................................................................74
6.18
Appropriateness of Measurements...........................................................................75
7.
STUDY ACTIVITIES............................................................................................................76
7.1
Screening Visit (Up to Day −28)..............................................................................76
7.2
Start of Treatment Period: Visit 1, Dose 1 (Day 0)..................................................76
7.3
Interval between Dose 1 and Dose 2 for Rollover Subjects.....................................77
7.4
Dose 2 of DX-2930 for Rollover Subjects...............................................................78
7.5
Visit 2 (Day 14 ±4 days); Dose 2 of DX-2930 for Non-Rollover Subjects.............79
7.6
Continuation of Treatment Period: Visit 3 (Day 28 ±4 Days) .................................80
7.7
Continuation of Treatment Period: Visit 4 (Day 42 ±4 Days) .................................80
7.8
Continuation of Treatment Period: Visit 5 (Day 56 ±4 Days) .................................81
7.9
Continuation of Treatment Period: Visits 6 and 7 (Days 70 and 84, All 
±4 Days) ...................................................................................................................82
7.10
Continuation of Treatment Period: Visit 8 (Day 98 ±4 Days) .................................82
7.11
Continuation of Treatment Period: Visit 9 (Day 112 ±4 Days) ...............................83
7.12
Continuation of Treatment Period: Visit 10 (Day 126 ±4 Days) .............................84
7.13
Continuation of Treatment Period: Visit 11 (Day 140 ±4 Days) .............................84
7.14
Continuation of Treatment Period: Visit 12 (Day 154 ±4 Days) .............................85
7.15
Continuation of Treatment Period: Visit 13 (Day 168 ±4 Days) .............................86
7.16
Continuation of Treatment Period: Visit 14 (Day 182 ±4 Days) .............................86
7.17
Continuation of Treatment Period: Visit 15 (Day 196 ±4 Days) .............................87
7.18
Continuation of Treatment Period: Visit 16 (Day 210 ±4 Days) .............................88
7.19
Continuation of Treatment Period: Visit 17 (Day 224 ±4 Days) .............................88
7.20
Continuation of Treatment Period: Visit 18 (Day 238 ±4 Days) .............................89
7.21
Continuation of Treatment Period: Visit 19 (Day 252 ±4 Days) .............................89
7.22
Continuation of Treatment Period: Visit 20 (Day 266 ±4 Days) .............................90
7.23
Continuation of Treatment Period: Visit 21 (Day 280 ±4 Days) .............................91
7.24
Continuation of Treatment Period: Visit 22 (Day 294 ±4 Days) .............................91
7.25
Continuation of Treatment Period: Visit 23 (Day 308 ±4 Days) .............................92
7.26
Continuation of Treatment Period: Visit 24 (Day 322 ±4 Days) .............................92
7.27
Continuation of Treatment Period: Visit 25 (Day 336 ±4 Days) .............................93
7.28
Continuation of Treatment Period: Visit 26 (Day 350 ±4 Days) .............................94
7.29
Continuation of Treatment Period: Visit 27 (Day 364 ±4 Days) .............................94
7.30
Continuation of Treatment Period: Visits 28 and 29 (Day 378 and 392 ±4 
Days) ........................................................................................................................95


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7.31
Continuation of Treatment Period: On-Site Activities (Between Visit 30 and 
Visit 66)....................................................................................................................96
7.32
Continuation of Treatment Period: Potential Off-Site Activities (Between 
Visit 31 and Visit 65) ...............................................................................................97
7.33
Completion of Treatment Period:  Visit 67 (Day 924 ±4 Days) ..............................98
7.34
Follow-up Period:  Visit 68 (Day 938 ±4 Days) ......................................................99
7.35
Final Follow-up Visit:  Visit 69 (Day 952 ±4 Days)................................................99
7.36
Early Termination ..................................................................................................100
8.
QUALITY CONTROL AND ASSURANCE ......................................................................101
9.
DATA ANALYSIS / STATISTICAL METHODS..............................................................102
9.1
General Considerations ..........................................................................................102
9.2
Sample Size Determination....................................................................................102
9.3
Method of Assigning Study Subjects to Treatment ...............................................102
9.4
Analysis Populations..............................................................................................102
9.4.1
Safety Population.................................................................................................102
9.4.2
Rollover Safety Population..................................................................................102
9.4.3
Non-rollover Safety Population...........................................................................103
9.5
Population Description and Exposure....................................................................103
9.5.1
Subject Disposition..............................................................................................103
9.5.2
Demographics and Other Baseline Characteristics..............................................103
9.5.3
Medical History ...................................................................................................103
9.5.4
Treatment Exposure and Compliance..................................................................103
9.5.5
Prior and Concomitant Medications ....................................................................103
9.6
Analysis of Efficacy...............................................................................................103
9.6.1
Time to the First Investigator-confirmed HAE Attack........................................103
9.6.2
Number of Investigator-confirmed HAE Attacks................................................104
9.7
Analysis of Safety ..................................................................................................105
9.7.1
Adverse Events ....................................................................................................105
9.7.2
Laboratory Test Results.......................................................................................106
9.7.3
Vital Signs............................................................................................................107
9.7.4
Electrocardiography.............................................................................................107
9.8
Other Analyses .......................................................................................................107
9.8.1
Analysis of Pharmacokinetic Data.......................................................................108
9.8.2
Analysis of Pharmacodynamic Data....................................................................108
9.8.3
Analysis of Biomarker Data.................................................................................108
9.8.4
Analysis of Immunogenicity Data .......................................................................108
9.8.5
Analysis of Quality of Life Assessments.............................................................108
9.8.6
Analysis of Experience with Study Drug Self-administration.............................109


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9.8.7
Analysis of Subject Experience with Pre-filled Syringe Use (if Available)........109
9.8.8
Analysis of Subject Response to Rescue medication ..........................................109
9.9
Statistical/Analytic Considerations ........................................................................110
9.9.1
Interim Analyses and Data Monitoring................................................................110
9.9.2
Multiple Comparisons/Multiplicity .....................................................................110
9.9.3
Handling of Missing Data....................................................................................110
9.9.4
Adjustment for Covariates...................................................................................110
9.9.5
Multicenter Studies..............................................................................................110
9.9.6
Subgroup Analyses ..............................................................................................110
9.9.7
Sensitivity Analyses.............................................................................................111
10. STUDY ADMINISTRATIVE STRUCTURE .....................................................................112
10.1
Institutional Review Board/ Research Ethics Board/Independent Ethics 
Committee..............................................................................................................112
10.2
Ethical Conduct of the Study .................................................................................113
10.3
Subject Information and Consent...........................................................................113
10.4
Subject Confidentiality...........................................................................................113
10.5
Study Monitoring ...................................................................................................113
10.6
Case Report Forms and Study Records..................................................................114
10.7
Data Safety Monitoring Board ...............................................................................114
10.8
Protocol Violations/Deviations ..............................................................................115
10.9
Premature Closure of the Study .............................................................................115
10.10
Access to Source Documentation and On-Site Audits...........................................115
10.11
Data Generation and Analysis................................................................................116
10.12
Retention of Data ...................................................................................................116
10.13
Financial Disclosure...............................................................................................116
10.14
Publication and Disclosure Policy..........................................................................117
11. REFERENCE LIST..............................................................................................................118
12. APPENDICES ......................................................................................................................120


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LIST OF IN-TEXT TABLES
Table 1
Study Activities Schedule –Day -28 through Day 365 .................................22
Table 2 
Study Activities Schedule for Day 366 through Day 952 .............................25
Table 3 
Study Administrative Structure ...................................................................112
LIST OF IN-TEXT FIGURES
Figure 1
Schematic of the Open-Label Extension Study.............................................47
Figure 2
Overview of the Design of Pivotal Study DX-2930-03 ..............................131
LIST OF APPENDICES
APPENDIX 1
Protocol History...........................................................................................121
APPENDIX 2
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infectious Diseases).................................................................127
APPENDIX 3
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (Modified) (US National Institutes of Health; National Institute 
of Allergy and Infectious Diseases..............................................................140
APPENDIX 4
HAE Attack Assessment and Reporting Procedures (HAARP)..................154
APPENDIX 5
Summary of Pivotal Study DX-2930-03 in Subjects with HAE.................163


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AAE
Acquired angioedema
ACE
Angiotensin converting enzyme
AE
Adverse event
AECT
Angioedema Control Test
AESI
Adverse Event of Special Interest
AE-QoL
Angioedema Quality of Life Questionnaire
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C1-INH
C1 inhibitor
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
Cmax
Maximum plasma drug concentration
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CRO
Clinical Research Organization
DMID
Division of Microbiology and Infectious Diseases
DP
Drug product
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EQ-5D-5L
EuroQoL 5-Dimensional 5-Level; a standardized instrument for use as a measure of health 
outcome
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HAARP
HAE Attack Assessment and Reporting Procedures


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HADS
Hospital Anxiety and Depression Scale
HAE
Hereditary angioedema
cHMWK
High molecular weight 2-chain kininogen
HR
Heart rate
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG1
Immunoglobulin G subclass 1
IMP
Investigational medicinal product
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine hormone releasing systems
IV
Intravenous
Ki
inhibition constant
LTP
Long-term prophylactic/Long-term prophylaxis
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
OLE
Open-label extension
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PT
Prothrombin time
PVRM
Pharmacovigilance and Risk Management
QoL
Quality of life
REB
Research ethics board
RBC
Red blood cell (count)
RR
Respiratory rate


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SAE
Serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SF-12
Short Form-12; a multi-purpose short form health survey with 12 questions
SGOT
Serum glutamic oxaloacetic transaminase (AST)
SGPT
Serum glutamic pyruvic transaminase (ALT)
SMQ
Standard MedDRA query
SOC
System Organ Class
SOP
Standard operating procedure
TEAE
Treatment-Emergent Adverse Event
TSQM-9
Treatment Satisfaction Questionnaire for Medication version 9
US
United States
WBC
White blood cell (count)
WPAI-GH
Work Productivity and Activity Impairment – General Health


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1.
INTRODUCTION
1.1
DX-2930
DX-2930 is a fully human IgG1 recombinant monoclonal antibody that binds specifically to 
active plasma kallikrein. DX-2930 is being developed for prophylactic treatment of angioedema 
attacks in patients with hereditary angioedema (HAE), a serious and life-threatening disease.
1.2
Hereditary Angioedema
HAE is a long-term, debilitating, and life-threatening disease caused by mutations in the 
C1-inhibitor (C1-INH) gene, resulting in deficiency or dysfunction of C1-INH protein. HAE 
manifests clinically as unpredictable, intermittent attacks of subcutaneous or submucosal edema 
of the face, larynx, gastrointestinal tract, limbs and/or genitalia (Zuraw 2008). Swelling may last 
up to five or more days; most patients suffer multiple attacks per year. HAE is an orphan 
disorder. The exact prevalence of HAE is unknown, but current estimates range from 1 per 
10,000 to 1 per 150,000 persons, with many authors agreeing that 1 per 50,000 is likely the 
closest estimate (Bygum 2009; Goring et al. 1998; Lei et al. 2011; Nordenfelt et al. 2014; Roche 
et al. 2005). 
Swelling in the larynx can obstruct the airways and cause death from asphyxiation (Bork et al. 
2000; Bork et al. 2012). Approximately 50% of all patients with HAE will experience a 
laryngeal attack in their lifetime, and there is no way to predict which patients are at risk of a 
laryngeal attack (Bork et al. 2003; Bork et al. 2006). 
Abdominal attacks are often associated with nausea, vomiting, diarrhea, and severe pain; 
intestinal symptoms resembling abdominal emergencies may lead to unnecessary surgery (Zuraw 
2008). 
Approximately 85% of patients with HAE have Type I HAE, characterized by very low 
production of functionally normal C1-INH protein, while the remaining approximately 15% of 
patients with HAE have Type II HAE and produce normal or elevated levels of a functionally 
impaired C1-INH (Zuraw 2008). In patients with Types I and II HAE, uncontrolled plasma 
kallikrein generation results in excess bradykinin release from high-molecular weight 2-chain 
kininogen (HMWK) and vascular leak mediated by bradykinin binding to the B2 receptor (B2-R) 
on the surface of endothelial cells (Zuraw 2008). Clinical suspicion of Types I and II HAE can 
be confirmed by available blood tests. In addition to abnormalities in C1-INH level and function, 
plasma C4 levels are often reduced in blood from most patients with HAE.
1.3
Therapeutic Rationale for DX-2930
Plasma kallikrein plays a critical role in the pathogenesis of HAE attacks (Davis 2006; Kaplan 
and Joseph 2010). In normal physiology, C1-INH regulates the activity of plasma kallikrein as 
well as a variety of other proteases, such as C1r, C1s, factor XIa, and factor XIIa. Plasma 
kallikrein regulates the release of bradykinin from HMWK. Due to a deficiency of C1-INH in 
HAE, uncontrolled plasma kallikrein activity occurs and leads to the excessive generation of 
bradykinin. Bradykinin is a vasodilator which is thought to be responsible for the characteristic 


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HAE symptoms of localized swelling, inflammation, and pain (Craig et al. 2012; Zuraw et al. 
2013). Intervening at the level of bradykinin production with a plasma kallikrein inhibitor 
therefore represents an attractive and rational therapeutic strategy for HAE. Indeed, the 
importance of plasma kallikrein as a drug target in HAE has been validated through the observed 
effectiveness of Kalbitor® (ecallantide), a peptide that specifically targets plasma kallikrein, 
which was approved by the FDA for the treatment of acute HAE attacks (Kalbitor® 2015). 
DX-2930 is a highly potent and specific inhibitor of plasma kallikrein (Ki = 125 pM). X-ray 
crystallography of DX-2930 combined with plasma kallikrein demonstrates DX-2930 binding to 
the active site of kallikrein (Kenniston et al. 2014).
1.4
Safety Rationale for DX-2930
Safety data from the Phase 1a clinical study, a first-in-human study with DX-2930 in healthy 
subjects, did not identify any safety concerns. Single doses up to 3 mg/kg of DX-2930 were well-
tolerated. There were no dose-limiting toxicities, serious adverse events, or any other safety 
concerns identified.
Pharmacokinetic (PK) data from the Phase 1a (DX-2930-01) and Phase 1b (DX-2930-02) 
clinical studies in conjunction with data from the nonclinical toxicity studies support a wide 
safety margin. The mean Cmax for human subjects treated at a dose of 300 mg on Days 1 and 15 
was approximately 27 g/mL. As comparison, a mean Cmax of 744 g/ mL was observed 
following dosing of monkeys with 50 mg/kg DX-2930 subcutaneous (SC) weekly for 6 months 
resulting in a safety margin of approximately 28-fold. No toxicologically significant findings 
were observed in these treated animals or in any other nonclinical toxicity study to date for 
systemically administered DX-2930.
Safety data is also available from the Phase 1b study (DX-2930-02), a multiple-ascending dose 
study in patients with HAE. In this study, two doses of DX-2930 up to 400 mg administered 
14 days apart were well-tolerated. There were no dose-limiting toxicities, serious adverse events 
in any DX-2930 treated subjects, or any other safety concerns identified in this study of patients 
with HAE. Pharmacokinetic data from the 1b study found that the drug exposure following two 
administrations of DX-2930 (up to a maximum of 400 mg) was substantially less than that 
attained and evaluated in the nonclinical toxicity studies.
For additional detail regarding the safety rationale for DX-2930, please refer to the DX-2930 
Investigator’s Brochure.
1.5
DX-2930 Non-Clinical Pharmacology and Toxicology
For more detail regarding the nonclinical findings, please refer to the DX-2930 Investigator’s 
Brochure.
1.6
DX-2930 Clinical Data
The clinical development program to date for DX-2930 consists of 2 studies to evaluate the 
safety, tolerability, and PK of DX-2930, including one completed Phase 1a single-ascending 


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dose study in healthy subjects and a Phase 1b multiple-ascending dose study in patients with 
HAE. These studies are summarized in the following sections.
1.6.1
Single-Ascending Dose Study in Healthy Subjects (DX-2930-01)
DX-2930-01 was a Phase 1a randomized, double-blind, placebo-controlled study in healthy 
subjects to evaluate the safety, tolerability, and PK following a single, SC dose of DX-2930. 
Participating subjects were randomized to receive placebo or active study drug within one of the 
following sequential, ascending dose cohorts: 0.1, 0.3, 1.0, or 3.0 mg/kg. For each dosing cohort, 
6 subjects were randomized to receive active drug and 2 subjects to receive placebo. 
A total of 32 subjects enrolled in the study and were randomized. The treatment groups were 
well balanced for demographic characteristics. The actual dose of DX-2930 administered to 
subjects ranged from 6.2 mg (in the 0.1 mg/kg group) to 300 mg (in the 3.0 mg/kg group) across 
all cohorts.
Based on the safety analysis, a single administration of DX-2930 was well tolerated up to doses 
of 3.0 mg/kg without evidence of dose-limiting toxicity. There were no deaths, SAEs, or subject 
discontinuations due to adverse events (AEs) during the study. Furthermore, there was no 
significant imbalance between placebo and DX-2930 for any particular treatment-emergent 
adverse event (TEAE). The most commonly reported TEAE was headache, which occurred at a 
rate of 25% for both DX-2930 and placebo.
The PK profile demonstrated linear, dose-dependent drug exposure with a mean half-life of 
approximately 17 to 21 days across dose groups. Results from two exploratory biomarker assays 
provide evidence for an important pharmacodynamic effect of DX-2930 in humans. 
For additional detail regarding the single dose, clinical study in healthy subjects, please refer to 
the DX-2930 Investigator’s Brochure.
1.6.2
Multiple-Ascending Dose Study in HAE Patients (DX-2930-02)
DX-2930-02 was a Phase 1b randomized, double-blind, placebo-controlled, multiple ascending-
dose study in patients with HAE to evaluate safety, tolerability, and PK of SC DX-2930. 
Participating subjects were randomized 2:1 to receive either active study drug or placebo within 
one of the following sequential, ascending dose cohorts: 30, 100, 300, or 400 mg (nominal 6 
subjects per cohort). Each subject received 2 doses of study drug separated by 14 days. 
A total of 37 subjects were randomized and treated with DX-2930 or placebo. One subject in the 
400 mg dose group received a single dose of DX-2930 and, following several unsuccessful 
attempts to schedule their second dose, was replaced. This subject returned for a single follow-up 
visit before being lost to follow-up for reasons not related to the study. Routine C1-INH testing 
revealed that one other subject did not have HAE Type I or II, despite a historical lab test 
indicating otherwise.
Subject demographics were balanced in terms of age, race, ethnicity and BMI. There were 
slightly more females in the DX-2930 group than in the placebo group (66.7% versus 53.8%). 


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The most common AEs reported were HAE attacks, injection site pain, and headache. The rates 
were not appreciably higher in the DX-2930 subjects compared to placebo. Two subjects were 
reported to have 3 related severe TEAEs. One of these was a DX-2930 subject (30 mg) with 
injection site pain lasting 1 minute and one was a DX-2930 subject (400 mg) with worsening 
headache lasting 1 minute and night sweats.
No safety signals were identified for vital signs, physical examinations, clinical laboratory tests, 
or electrocardiograms (ECG). Results suggested DX-2930 was well tolerated in this study with 
no evidence of dose-limiting toxicity at doses up to 400 mg.
A total of 3 out of 92 post-dose samples (3.3%), obtained from 2 out of 23 subjects (8.7%), were 
confirmed to be anti-drug antibody-positive. No samples were positive for neutralizing activity.
The pharmacokinetic analysis for all subjects in the 30, 100, 300, and 400 mg doses showed drug 
levels in HAE subjects were dose-dependent and exhibited a prolonged half-life of 
approximately 2 weeks, typical of a human monoclonal antibody. Cmax drug levels increased with 
increasing dose, as expected. These parameters were consistent with values obtained in healthy 
subjects in Study DX-2930-01.
A Western blot assay showed pre-dose baseline levels of mean 2-chain HMWK in unactivated 
plasma collected from patients with HAE was approximately 50%. A statistically significant 
reduction in 2-chain HMWK levels was observed on study days 8 and 22 in the 300 and 400 mg 
dose groups compared to pre-dose levels, and approached levels similar to that observed in 
healthy subjects. This outcome demonstrated the pharmacodynamic activity of DX-2930 and its 
ability to effectively normalize the instability of HAE plasma in this assay. 
Primary efficacy analyses were based on subjects in the 300 mg, 400 mg, and placebo dose 
groups who reported having at least 2 attacks in the 3 months prior to study entry 
(0.15 attacks/week). Of those subjects treated with 300 or 400 mg DX-2930, 15 of 16 subjects 
met these criteria. Of the placebo treated subjects, 11 of 13 subjects met these criteria. 
The baseline HAE attack rates (attacks/week) were 0.39 attacks per week in the placebo group, 
0.33 attacks per week in the 300 mg group, 0.55 attacks per week in the 400 mg group and 
0.49 attacks per week in the 300 and 400 mg combined group. During the pre-specified, primary 
efficacy interval of 6 weeks (from days 8 to 50; corresponding to a period of notable drug 
exposure), the HAE attack rate, adjusted for baseline attack rate, was 0 in the 300 mg group and 
0.045 attacks per week in the 400 mg group, compared to 0.37 attacks per week in the placebo 
group. This resulted in a 100% reduction vs placebo for the 300 mg DX-2930 group (P < 0.0001) 
and an 88% reduction vs placebo for 400 mg DX-2930 (P = 0.005). During this primary efficacy 
interval, 100% of subjects in the 300 mg group (P = 0.026) and 82% of subjects in the 400 mg 
group (P = 0.03) were attack-free compared with 27% of subjects in the placebo group.
The data from this study demonstrated proof of concept of the ability of DX-2930 to prevent 
acute attacks of HAE. A statistically significant finding of HAE attack prevention by DX-2930 
was observed. DX-2930 was well tolerated in HAE subjects up to 400 mg. Drug exposure 
appeared to be dose-proportional and consistent with the results obtained in healthy subjects in 


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Study DX-2930-01. Pharmacodynamic effect assays provided evidence that DX-2930 has a 
direct effect on plasma kallikrein activity in patient plasma.
For additional detail regarding Study DX-2930-02, please refer to the DX-2930 Investigator’s 
Brochure.
1.7
Rationale for Open-Label Extension Study DX-2930-04
The open-label DX-2930 extension study will be preceded by the initiation of a pivotal, multi-
center, double-blind, randomized, placebo-controlled parallel-arm study (Study DX-2930-03) 
evaluating the efficacy of DX-2930 in preventing acute angioedema attacks in patients with Type 
I or Type II HAE. Further information on Study DX-2930-03 design can be found in Appendix 
5.
Subjects who complete the Study DX-2930-03 treatment period will be offered the option of 
rolling into the open-label extension study, Study DX-2930-04.  In addition, a limited number of 
individuals with HAE Type I or Type II who were not enrolled in Study DX-2930-03 (up to 
approximately100) will be also enrolled. 
The rationale for this open-label extension study is to evaluate the long-term safety of repeated 
subcutaneous treatment with DX-2930 and the long-term efficacy of DX-2930 in preventing 
HAE attacks.  For subjects rolling over from DX-2930-03 who were randomized to one of the 
active study arms, the total duration of exposure across both studies will cover 36 months.  For 
rollover subjects randomized to placebo in DX-2930-03, and for non-rollover subjects, the total 
duration of exposure will cover 30 months.  Combined, the overall exposure between Study 
DX-2930-03 and Study DX-2930-04 will provide a sizable dataset to evaluate DX-2930 as a life-
long, chronic treatment for preventing acute attacks of HAE.  
This study seeks to evaluate the outer bounds of DX-2930 dosing frequency (possibly beyond 
2 to 4 weeks) by assessing the duration of time between a rollover subject’s first open-label dose 
and their first reported HAE attack.  In addition, characteristics of all HAE attacks will be 
reported and compared to the subject’s historical baseline (for non-rollover subjects) or attack 
history based on attacks reported in Study DX-2930-03 (for rollover subjects).
For non-rollover subjects, the study will evaluate the safety and efficacy of switching from a 
long-term prevention therapy (eg, C1-INH, anti-fibrinolytics, androgens) to DX-2930 dosing, 
while evaluating breakthrough attack characteristics compared to historical baseline both prior to 
and during co-administration  with their LTP therapy regimen and while receiving DX-2930 
alone. 
For all subjects, the study will also assess immunogenicity of chronically administered DX-2930, 
PK and PD, biomarkers of angioedema disease state bioactivity, subject response to the pre-filled 
syringe (if available), subject response to rescue medications, subject health-related quality of 
life (QoL), subject experience with self-administration, ease of SC administration with DX-2930 
subject treatment satisfaction, subjects’ and investigators’ global impression of treatment 
response, subject assessment of angioedema control, and an exit interview of subjects. 


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2.
STUDY OBJECTIVES
2.1
Primary Objective
To evaluate the long-term safety of repeated subcutaneous (SC) administrations of DX-2930
2.2
Secondary Objectives
•
To evaluate the long-term efficacy of DX-2930 in preventing HAE attacks
•
To characterize the outer bounds of dosing frequency for DX-2930
2.3
Tertiary Objectives
•
To assess the immunogenicity of chronically administered DX-2930
•
To evaluate the effect of DX-2930 on health-related quality of life (QoL)
•
To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of SC 
administration of DX-2930
•
To evaluate safety and efficacy in the non-rollover population of switching from long-term 
prophylactic (LTP) treatment to DX-2930 
•
To evaluate breakthrough attack characteristics while receiving DX-2930 compared to 
historical baseline
•
To evaluate subject experience with self-administration of DX-2930 including ease of SC 
administration of DX-2930
•
To evaluate exploratory  biomarker(s) of angioedema disease-state bioactivity in plasma and 
serum
•
To evaluate subject experience and ease of use of the prefilled syringe, if available
•
To assess the clinical response of rescue medications for the treatment of acute angioedema 
attacks while on DX-2930 therapy (applicable for subjects ≥18 years of age)
•
To assess treatment satisfaction
•
To assess global impression of treatment response
•
To assess control of angioedema


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3.
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
3.1.1
Overview
Study DX-2930-04 is an open-label, long-term safety and efficacy extension study of DX-2930-
03, to evaluate the investigational medicinal product (IMP), DX-2930, in preventing acute 
angioedema attacks in patients with Type I and Type II HAE. There are two types of subjects 
who will be enrolled into this study:
•
Subjects who rollover from Study DX-2930-03 
•
Subjects who are non-rollover (ie, were not participants in Study DX-2930-03) 
Rollover Subjects
Rollover subjects are subjects who complete the double-blind treatment period at Day 182 of 
Study DX-2930-03 and consent to enter Study DX-2930-04.  Subjects who discontinue from 
Study DX-2930-03 after enrollment are not eligible to enroll in Study DX-2930-04.  
Subjects should be asked about their interest in Study DX-2930-04 after enrollment into Study 
DX-2930-03 to anticipate enrollment and preparedness for Study DX-2930-04.  Willing subjects 
must sign informed consent for Study DX-2930-04 on or after Day 168 of Study DX-2930-03.  
Subjects who are eligible to roll over into Study DX-2930-04 but elect not to, may not enroll in 
Study DX-2930-04 at a later time. The first Study DX-2930-04 visit for rollover subjects (Day 0) 
will occur on the same day as Study DX-2930-03 Day 182 study visit. Rollover subjects will 
complete all Study DX-2930-03 final study assessments (Day 182) at which time they will be 
discharged from that study. No assessments conducted between Study DX-2930-03 Day 182 
study visit and the first Study DX-2930-04 visit (Day 0) will be duplicated.  Results of the final 
DX-2930-03 assessments on Day 182 will be used as the pre-dose results for Day 0 of Study 
DX-2930-04.
All subjects, caregivers, investigators and study site personnel will remain blinded to the 
DX-2930-03 treatment assignment until the conclusion of Study DX-2930-04.
Non-rollover subjects
At least 50 subjects (to approximately 100) who were not participants in Study DX-2930-03 will 
be permitted to enroll if they meet the eligibility requirements. Subjects who screen fail out of 
Study DX-2930-03 for not meeting the minimum attack requirements during the run-in period 
must wait until enrollment for the double-blind study has ended before they can screen for Study 
DX-2930-04. The Sponsor may ease this restriction based on the enrollment rate observed in 
Study DX-2930-03. Subjects who are still in the run-in period for Study DX-2930-03 when 
enrollment for that study closes, as well as subjects on prior LTP who screen fail out of Study 
DX-2930-03 due to an inability to wash-out of their LTP, may screen for Study DX-2930-04 
following discussion with the Sponsor medical monitor.


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Screening Period:
Rollover subjects
There is no screening period for rollover subjects.
Non-rollover subjects 
Non-rollover subjects must provide informed consent and have screening assessments completed 
within 4 weeks prior to their first open-label dose.  Screened non-rollover subjects (adults and 
adolescents) who are on LTP with C1-INH therapy for HAE can continue their current LTP until 
Day 8 (or Day 15) such that subjects will have received 2 (or 4) doses of C1-INH.  For subjects 
who are on attenuated androgens (eg, danazol) or anti-fibrinolytics (eg, tranexamic acid); a 
similar tapering schedule is recommended. However, the taper can be prolonged by an additional 
week, if medically indicated, as long as androgen or anti-fibrinolytic therapy is stopped within 
3 weeks of receiving the first dose of DX-2930.  
Treatment Period:
Rollover Subjects
Following informed consent and pre-dose assessments, rollover subjects will receive a single 
open-label dose of DX-2930 administered subcutaneously (SC) on Day 0. Subjects will not 
receive any additional DX-2930 doses until their first reported and investigator confirmed HAE 
attack.  As such, the total number of doses within the treatment period will vary by rollover 
subject.
The duration of time between the first open-label dose and first reported HAE attack will vary by 
rollover subject.  All rollover subjects must adhere to the Study Activities Schedules (Table 1
and Table 2), for the entire duration of the study.  However, until a rollover subject reports their 
first HAE attack, only scheduled study visits where the following tests and assessments are 
performed must be conducted at the investigative site: pregnancy testing, clinical laboratory 
testing, physical examination, 12-Lead ECG, QoL, PK, PD and anti-drug antibody sample 
collection.  All other scheduled study visits may be conducted via site check-in calls to collect 
information on adverse events, concomitant therapy, and HAE attack data.  See Study Activities 
Schedules (Table 1 and Table 2) for which visits must be conducted at the study site.
Once a rollover subject reports their first HAE attack they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  If 
the second dose is to be administered within the accepted ± 4 day window around a scheduled 
study visit, this treatment visit will represent that scheduled visit. If that scheduled visit has 
already occurred, the day of the visit will be considered an acceptable, extra study visit.  
In the event that the second dose is to be administered outside of the accepted ±4 day window 
around a scheduled visit, the day of the visit will be considered an acceptable extra study visit 
(ie, this visit will not replace any scheduled visit). 


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Regardless of the study day, at the visit in which the second open-label dose of DX-2930 is 
administered, the subject will undergo pre-dose assessments for vital signs, physical 
examination, clinical laboratory testing, and blood sampling for PK, PD, and anti-drug antibody. 
Vital signs will be obtained at 1 hour post-dosing. As with all study visits, information will be 
collected on adverse events, concomitant therapy, and HAE attack data.
Regardless of when a rollover subject’s first HAE attack occurs, there will be a minimum of 
10 days between their first open-label dose and their second open-label dose. Following their 
second open-label dose, rollover subjects will continue to receive repeated SC administrations of 
open-label DX-2930 every 2 weeks for the remaining duration of the treatment period per the 
scheduled dosing in the Study Activities Schedules (Table 1 and Table 2). The treatment period 
will last up to 924 days from the date of the first open-label dose. The number of doses 
administered during this period will vary by subject based on the date of each subject’s second 
dose, but will not exceed 66 doses. The Day 910 study visit is the last visit at which a dose may 
be administered.
Non-rollover Subjects
Once all screening assessments have been completed and eligibility confirmed, non-rollover 
subjects will arrive at the study site and, following pre-dose assessments, receive an open-label 
dose of 300 mg DX-2930 administered SC on Day 0. Non-rollover subjects will continue to 
receive SC administrations of open-label 300 mg DX-2930 every 2 weeks throughout the 
duration of the treatment period per the scheduled dosing in the Study Activities Schedules. Up 
to 66 doses will be administered with the last dose administered at the Day 910 study visit.
All Subjects:
All doses (with the exception of the second dose for rollover subjects) require a minimum of 
10 days and maximum of 18 days between administrations, and should fall within the accepted 
± 4 day window around study visits. 
After the second DX-2930 dose is given either within the study window (±4 days) or an 
acceptable extra study visit, the 3rd dose must be administered at the next pre-defined study visit 
according to the schedule of assessments.
If a subject experiences an acute angioedema attack at any time during the study that in the
opinion of the investigator requires medical intervention, standard of care therapy should be 
provided based on subject’s medical history and per locally approved product information. 
Administration of DX-2930 and study procedures will continue without alteration to the protocol 
Study Activities Schedules (Table 1 and Table 2), even if a subject receives treatment for a 
breakthrough angioedema attack on the day of a scheduled dose of study drug (if self-
administering) or scheduled study visit.
Self-Administration
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a 
physical and mental capability of learning and willing to be trained) may be allowed to self-
administer treatment. Subjects must complete appropriate training by the investigator or designee 
and have their understanding of the procedures confirmed by the investigator or designee. 


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Subjects are allowed to initiate self-administration at the subject’s home or other agreed upon 
location after receiving the first 2 doses of DX-2930 at the study site. Once initiated, subjects 
may self-administer subsequent doses of DX-2930 at the investigational site (when visits are 
scheduled study site visits) or the subject’s home or other agreed upon location (when the study 
permits off-site dosing). 
Adolescent subjects self-administering DX-2930 will be supervised by a parent/legal 
guardian/caregiver. Alternatively, a parent/legal guardian/caregiver, after completing appropriate 
training, will be allowed to administer the investigational product to an adolescent without study 
site personnel supervision. 
Site personnel will call subjects within approximately 3 days after the planned off-site self-
administrations to ensure the administration occurred, to collect AEs, concomitant medications, 
and to ensure all attacks have been appropriately documented.  Throughout the study, study site 
personnel will document information in source documents (ie, the subject’s medical record) and 
eCRF regarding the subject’s experience with self-administration and SC administration of 
DX-2930.
Follow-up Period
After completion of the treatment period, all subjects will undergo safety evaluations during a 
4-week follow-up period.  Figure 1 shows a schematic of the open-label extension study.


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Figure 1
Schematic of the Open-Label Extension Study
Modifications to Open-Label Dosing
If, at any time, a dose-related safety signal is identified either from this study or Study
DX-2930-03, the Sponsor may decide to modify the open-label DX-2930 dose and/or frequency. 
In addition, an individual subject’s dose may be modified based on a benefit-risk assessment and
recommendation from the treating physician. Consultation with and approval by the Sponsor’s 
medical monitor is required.
In addition, based on the results of Study DX-2930-03, the Sponsor may switch to a different 
dose and/or frequency.
3.1.2
Stopping Rules
3.1.2.1
Study Level Stopping Rules
Safety data, including SAEs and AESI, will be monitored regularly throughout the duration of 
the study. If any potential safety signal is identified as a result of monitoring in this study, or 


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from any safety findings from Study DX-2930-03, or following DSMB review, the Sponsor may 
take actions as deemed appropriate, including suspending dosing in the study, while the potential 
risk is evaluated and a course of action has been determined.
3.1.2.2
Individual Stopping Rules
Dosing for any individual subject will be discontinued if the subject experiences a 
DX-2930-related SAE (or DX-2930-related, clinically significant non-serious AE) that, in the 
assessment of the investigator or DSMB recommendation, warrants discontinuation from further 
dosing for that subject’s well-being. The investigator has the ability to contact and consult with 
the Medical Monitor on such matters. Subjects will continue to be followed through the 
completion of all scheduled non-dosing visits, unless they request to be discontinued from the 
study.
3.1.3
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or other toxicity considered clinically relevant (AE, 
laboratory, physical examination, vital sign, or ECG finding) will be carefully monitored until 
resolution, which may include the following:
•
Additional clinical laboratory tests and/or other clinical investigations
•
Additional visits or extended duration of follow-up
•
Obtaining a specialist consultation
3.2
Rationale for Open-Label Extension Dose Selection
The dose selected for the open-label extension (300 mg every 2 weeks) is anticipated to be 
effective and safe as determined in the pivotal, double-blind DX-2930-03 study. If at any time an 
important dose-related safety signal is identified either from this study or Study DX-2930-03, the 
Sponsor may decide to switch the enrolled subjects who have not yet completed the treatment 
period, and any subsequent subjects, to receive a different open-label DX-2930 dose and/or 
frequency.
Additionally, based on the efficacy results of Study DX-2930-03, the Sponsor may switch to a 
different dose and/or frequency.
3.3
Individual Subject Dosing and Follow-Up
All subjects will receive open-label DX-2930 during a treatment period of up to 924 days. The
number of doses that rollover subjects receive during this period will vary by subject but will not 
exceed 66 doses. The last dose of open-label DX-2930 administered to these subjects may be 
given at the Day 910 study visit. Non-rollover subjects will receive DX-2930 every 2 weeks for 
up to 66 doses, with the first dose administered on Day 0 and the final dose administered at the 
Day 910 study visit.
There will be a ±4 day window around each study visit. There will be a minimum of 10 days 
between any two doses. Excluding the time interval between the first and second open-label 


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doses for rollover subjects, there will be a maximum of 18 days between any two doses. Subjects 
will be monitored at the study site through 1 hour post-dose.
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a 
physical and mental capability of learning and willing to be trained) may be allowed to self-
administer treatment after completing appropriate training by the investigator or designee and 
confirming their understanding. Subjects are allowed to initiate self-administration at the 
subject’s home or other agreed upon location after receiving the first 2 doses of DX-2930 at the 
study site. Once initiated, subjects may continue to self-administer subsequent doses of 
DX-2930. Subjects who elect to self-administer investigational product will be provided the 
necessary supplies (see Section 5.7 and Section 6.15.1). Subjects who receive a new product 
format (ie, a single vial or a PFS) will receive additional training in how to self-administer with 
that format.
3.4
Study Duration for Individual Subjects
Following informed consent, subjects will either rollover from Study DX-2930-03 or undergo 
screening assessments (non-rollover subjects). Screening assessments for non-rollover subjects 
must occur within 4 weeks prior to the first open-label dose. Eligible subjects will be enrolled 
and undergo a treatment period of up to 924 days. At the conclusion of the treatment period, 
subjects will be followed for an additional 4 weeks.


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4.
STUDY POPULATION SELECTION
4.1
Study Population
The study is expected to enroll subjects from Study DX-2930-03, as well as at least 50 (to 
approximately100) additional subjects who were not enrolled in Study DX-2930-03.  The total 
enrollment is expected to be at least 150, but not more than 250 HAE Type I or II subjects.  
Subjects will be 12 years of age or older who experience at least 1 attack per 12 weeks. HAE 
diagnosis will be confirmed through documented clinical history and diagnostic testing 
conducted either during screening or during participation in Study DX-2930-02 or Study DX-
2930-03.
The subject population includes subjects who are 12 to 17 years old. Like adults, children with 
HAE can suffer from recurrent and debilitating attacks. Symptoms may present very early in 
childhood, and upper airway angioedema has been reported in patients with HAE as young as the 
age of 3 (Bork et al. 2003). In one case series of 49 pediatric patients with HAE, 23 had suffered 
at least one episode of airway angioedema by the age of 18 (Farkas 2010). An important unmet 
medical need exists among children with HAE, especially adolescents, since the disease 
commonly worsens after puberty (Bennett and Craig 2015; Zuraw 2008).  The study will aim to 
enroll at least 15 subjects who are 12 to 17 years of age, inclusive of the estimated 10 subjects 
12 to 17 years old who are expected to roll over from Study DX-2930-03. 
4.2
Inclusion Criteria
Subjects must meet the following criteria to be enrolled in this study:
1. Male and female HAE subjects who are 12 years of age or older at the time of screening. 
2. Documented diagnosis of disease HAE (Type I or II) based on all of the following:

Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria).

Diagnostic testing results obtained during screening (or a prior DX-2930 study) that 
confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level < 40% of the 
normal level. Subjects with functional C1-INH level 40-50% of the normal level may 
be enrolled if they also have a C4 level below the normal range.  Subjects may be 
retested if results are incongruent with clinical history or believed by the investigator 
to be confounded by LTP use. (It is understood that C1-INH therapy may alter the lab 
results of C1-INH assessments; therefore, the investigator's discretion in collaboration 
with Medical Monitor is advised for proper documentation of eligibility).

At least one of the following: Age at reported onset of first angioedema symptoms 
≤30 years, a family history consistent with HAE Type I or II, or C1q within normal 
range.
3. A historical baseline HAE attack rate of at least 1 attack per 12 weeks.


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4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, 
understand, and sign an informed consent form.  Subjects age 12 to 17, whose caregiver has 
provided informed consent, are willing and able to read, understand and sign an assent form.
5. Males and females who are fertile and sexually active must adhere to contraception 
requirements for the duration of the study as follows:

Females* of childbearing potential must agree to be abstinent or it is recommended to use 
highly effective forms of contraception from the screening period through 30 days after 
the final study visit.  This includes stable doses (for 3 months prior to study screening) of 
combined estrogen and progestin-containing hormonal contraception associated with 
inhibition of ovulation (oral, injectable or implantable), progestin-only hormonal 
contraception associated with inhibition of ovulation, intra-uterine device (IUD, all types) 
or intrauterine hormone releasing systems (IUS). Notes: 1) A female whose male partner 
has had a vasectomy must agree to use one additional form of medically acceptable 
contraception. 2) Use of a male condom with or without spermicide or cervical cap, 
diaphragm or sponge with spermicide or a combination (double barrier methods) are not 
considered highly effective.

Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study.

Males, including males who are surgically sterile (post vasectomy), with female partners 
of childbearing potential must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through 60 days after the final study 
visit. 
*NOTE:  Female rollover subjects (those who previously participated in Study DX-2930-
03) of childbearing potential may continue to use the birth control method used during 
Study DX-2930-03.
4.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. Discontinued from Study DX-2930-03 after enrollment for any reason.
2. If rolling over from Study DX-2930-03, presence of important safety concerns that would 
preclude participation in this study.
3. Concomitant diagnosis of another form of chronic, recurrent angioedema such as acquired 
angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), idiopathic 
angioedema, or recurrent angioedema associated with urticaria.


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4. Dosing with an investigational drug (not including DX-2930 or other HAE therapies) or 
exposure to an investigational device within 4 weeks prior screening.
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to 
screening or any newly initiated or dose modification of estrogen-containing medications 
with systemic absorption (such as oral contraceptives or hormonal replacement therapy) 3 
months prior to the screening visit.
6. Unwilling to discontinue use of long-term prophylactic therapy for HAE (C1-INH, attenuated 
androgens, or anti-fibrinolytics) within 3 weeks after starting DX-2930 treatment.
7. Any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3x 
upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of normal, or 
total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of 
Gilbert’s Syndrome).
8. Pregnancy or breastfeeding.
9. Subject has any condition that, in the opinion of the investigator or Sponsor, may 
compromise their safety or compliance, preclude successful conduct of the study, or interfere 
with interpretation of the results (eg, history of substance abuse or dependence, a significant 
pre-existing illness or other major comorbidity that the investigator considers may confound 
the interpretation of study results).


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5.
STUDY TREATMENT(S)
5.1
Description of Treatment(s)
For detailed information regarding open-label DX-2930 (lanadelumab) administration, refer to 
the Pharmacy Manual.
DX-2930 is a sterile, preservative-free solution for injection, pH 6.0. The active ingredient, 
DX-2930, is formulated using the following compendial components:  30 mM sodium phosphate 
dibasic dihydrate, 19.6 mM citric acid, 50 mM histidine, 90 mM sodium chloride, 0.01% 
Polysorbate 80. Each open-label vial contains a nominal concentration of either 150 mg 
DX-2930 active ingredient in 1 mL solution or 300 mg in 2 mL solution.
For each 300 mg dose of DX-2930, each subject will receive a total of 2 mL, which will be 
administered in a single 2 mL SC injection. The subject may receive the dose as either 2 vials 
containing 150 mg in 1 mL each, or 1 vial containing 300 mg in 2 mL. If available, subjects may 
receive a PFS instead of vial(s). The injection will be given in the upper arm, thigh or abdomen. 
Self-Administration
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a 
physical and mental capability of learning and willing to be trained) may be allowed to 
self-administer treatment after completing appropriate training by the investigator or designee 
and demonstrating the comprehension to self-administer. Subjects are allowed to initiate self-
administration at the subject’s home or other agreed upon location after receiving the first 2 
doses of DX-2930 at the study site. Once initiated, subjects may continue to self-administer 
subsequent doses of DX-2930 at the investigational site (when visits are scheduled study site 
visits) or the subject’s home or other agreed upon location (when the study permits off-site 
dosing). See Study Activities Schedule (Table 1) for details. Subjects who receive a new product 
format (ie, a single vial or a PFS) will receive additional training in how to self-administer with 
that format. Adolescent subjects self-administering investigational product will be supervised by 
a parent/legal guardian/caregiver. Alternatively, a parent/legal guardian/caregiver, after 
completing appropriate training, will be allowed to administer DX-2930 to an adolescent without 
study site personnel supervision. Site personnel will call subjects within approximately 3 days 
after the planned off-site self-administrations to ensure the administration occurred, to collect 
AEs, concomitant medications, and to ensure all attacks have been appropriately documented.
Throughout the study, study site personnel will document information in the subject’s medical 
record and eCRF regarding the subject’s experience with self-administration and SC 
administration of DX-2930 and experience with the PFS, if applicable.
5.2
Dosing and Follow-Up Scheme
Details of subject dosing and follow-up are outlined in Section 3.1.1 and included in the 
Study Activities Schedules (Table 1 and Table 2).
Rollover subjects will receive their first open label SC dose of DX-2930 on Day 0.  Subjects will 
not receive any additional DX-2930 doses until their first reported HAE attack.  The second dose 


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of DX-2930 may be administered at an unscheduled visit if it is outside of the accepted ±4 day 
window around a scheduled visit. Following this attack subjects will receive open label SC doses 
of DX-2930 every 2 weeks until the end of the treatment period. Subsequent dosing after Dose 2 
requires a minimum of 10 days and a maximum of 18 days between administrations.
Regardless of when a rollover subject’s first HAE attack occurs, there will be a minimum of 
10 days between their first open-label dose and their second open-label dose. Following their 
second dose, rollover subjects will continue to receive repeated SC administrations of open-label 
300 mg DX-2930 every 2 weeks for the remaining duration of the treatment period per the 
scheduled dosing in the Study Activities Schedules. The treatment period will last up to 924 days 
from the date of the first open-label dose. The number of doses administered during this period 
will vary by subject based on the date of each subject’s second dose, but will not exceed 66 
doses. The Day 910 study visit is the last visit at which a dose may be administered. 
Non-rollover subjects will receive their first open-label dose SC dose of DX-2930 on Day 0 and 
will continue to receive SC administrations of open-label DX-2930 every 2 weeks throughout the 
duration of the treatment period. Up to 66 doses will be administered with the last dose 
administered at the Day 910 study visit.
After completion of the treatment period, all subjects will undergo safety evaluations during a 
4-week follow-up period.
5.3
Method of Identifying Subjects
Subjects meeting all eligibility criteria will be enrolled in the study and sequentially assigned a 
unique site-based identification number.
5.4
Prior and Concomitant Therapy
For subjects not rolling over from Study DX-2930-03, reasonable efforts will be made to 
determine all relevant treatments received by the subject from 4 weeks prior to screening through 
the final study visit. For subjects rolling over from Study DX-2930-03, concomitant therapy use 
will be carried forward from that study and will continue to be collected through the final study 
visit. 
All information on prior and concomitant therapy (including all prescription/non-prescription 
medications, herbal medications and vitamin supplements) must be recorded on the subject’s 
eCRF and should include the name of the procedure or drug and duration of the treatment (start 
and stop dates). Concomitant treatments (non-pharmacological treatments) include any surgical
or diagnostic procedures.
5.4.1
Allowed Therapies
The following therapies are allowed during the study:
•
Therapies for co-existing conditions, including those for acute attacks of HAE, as described 
in Section 5.4.1.1 are permitted if not excluded in Section 5.4.2. The use of short-term 


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prophylactic treatment for HAE will be permitted if medically indicated.  Short-term (pre-
procedure) prophylaxis is defined as use of C1-INH to avoid angioedema complications from 
medically indicated procedures.
•
Therapies to treat any AEs the subject experiences during the study are permitted.
5.4.1.1
Management of HAE Attacks
Acute HAE attacks during the study are to be managed in accord with the investigator’s usual 
care of their patients, including use of acute attack therapies that the investigator deems as 
medically appropriate. Use of C1-INH will be permitted as an acute attack therapy but not as a 
LTP therapy. Administration of DX-2930 and study procedures will continue without alteration 
to the protocol-specified study schedule, even if the subject has symptoms of an HAE attack the 
day of DX-2930 administration and/or receives treatment for an HAE attack. The administration 
of DX-2930 can also be re-scheduled as long as the minimum and maximum timeframe between 
doses are met based on patient preference or physician discretion.
5.4.2
Excluded Concomitant Therapies
Use of the following treatments will not be permitted during the study:
•
Long-term prophylaxis for HAE (eg, use of C1-INH for LTP, attenuated androgens, or 
anti-fibrinolytics) once LTP is discontinued (within 3 weeks following first dose of 
DX-2930).
•
Angiotensin-converting enzyme (ACE) inhibitors.
•
Initiating or changing the dose of estrogen-containing medications with systemic absorption 
(such as oral contraceptives or hormonal replacement therapy) 3 months prior to the 
screening visit.
•
Use of androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) for 
non-HAE related medical conditions or for HAE after discontinuation during the first 
3 weeks.
•
Any other investigational drug or device.
5.5
Restrictions
5.5.1
Medical Interventions
Medical interventions deemed necessary by the investigator for the health and well-being of the 
subject will not be excluded during this study.
5.5.2
Fluid and Food Intake 
There are no restrictions on fluid and food intake. Subjects may continue their usual dietary 
regimens.
5.5.3
Activity
There are no activity restrictions. Subjects may continue their usual activity regimens.


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5.6
Treatment Compliance
All doses of open-label DX-2930 administered at the investigational site will be under the direct 
supervision of the investigator or qualified study site personnel designated by the investigator.
Subjects are allowed to initiate self-administration at the subject’s home or other agreed upon 
location after receiving the first 2 doses of DX-2930 at the study site. Once initiated, subjects 
may continue to self-administer subsequent doses of DX-2930 at the investigational site (when 
visits are scheduled study site visits) or the subject’s home or other agreed upon location (when 
the study permits offsite dosing). Site personnel will call subjects within approximately 3 days 
after the planned off-site self-administrations to ensure the administration occurred, to collect 
AEs, concomitant medications, and to ensure all attacks have been appropriately documented. 
See Study Activities Schedules (Table 1 and Table 2) for details. For all subjects, subsequent 
doses after the second dose require a minimum of 10 days and maximum of 18 days between 
administrations, and should fall within the accepted ±4 day window around study visits. 
For rollover subjects, after the second DX-2930 dose is given either within the study window 
(±4 days) or an acceptable extra study visit, the 3rd dose must be administered at the next pre-
defined study visit according to the schedule of assessments.
5.7
Packaging and Labeling
The open-label DX-2930 will be supplied by the Sponsor and prepackaged in a study kit for 
investigational studies. Each study kit will contain 1 vial (or pre-filled syringe, if available) of 
investigational product. Both the vials and carton (kit) will be appropriately labeled according to 
local regulations and bear the unique study drug kit number. The investigative site will provide 
ancillary supplies including syringes, needles, and alcohol wipes to subjects. The site has the 
option of using needles of a different gauge to aid subject comfort with each SC injection. 
Subjects who elect to self-administer investigational product will be provided the following 
supplies as applicable:
•
1 to 2 dose(s) supply of investigational product
•
Ancillary supplies, including syringes, needles, alcohol pads, a temperature monitoring 
device, and a container for sharps disposal
•
Subject accountability form to record investigational product storage conditions and 
administration details
All used and unused vials should be returned to the study kit cartons/boxes and transported to the 
site for drug accountability.  Written instructions on DX-2930 handling and self-administration 
procedures will be provided to trained subjects prior to initiating self-administration.  Refer to 
the Pharmacy Manual for additional details on DX-2930 and its administration.
5.8
Storage and Accountability
All DX-2930 will be shipped refrigerated to the study site and must be stored at 2ºC to 8ºC/36ºF 
to 46ºF in the carton and protected from light. Storage must be in a securely locked area, 


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accessible to authorized persons only, until needed for dose preparation. See Section 5.7 and 
Section 6.15.1 for details.
5.9
Investigational Medicinal Product Retention at Study Site
The investigator (or designee) is responsible for maintaining accurate accountability records of 
DX-2930 throughout the clinical study. All DX-2930 received at the site must be inventoried and 
accounted for in an accountability log provided by the Sponsor. All dispensing and 
accountability records will be available for Sponsor review. Drug accountability will be verified 
during on-site monitoring visits.
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used DX-2930 should be returned or 
destroyed at the investigational site, as specified by Sponsor. It is the investigator’s responsibility 
to ensure that the Sponsor, or its representative, has provided written authorization that 
procedures for proper disposal of DX-2930 have been established, and that appropriate records 
of the disposal are documented and maintained. No unused DX-2930 may be disposed until fully 
accounted for by the Sponsor monitor (or designee).


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6.
STUDY PROCEDURES
Please refer to the Study Activities Schedules (Table 1 and Table 2).
6.1
Informed Consent
The ICF must be executed prior to performing any study related activities and must be approved 
by the reviewing institutional review board (IRB), research ethics board (REB), or independent 
ethics committee (IEC). Subjects may withdraw consent at any time. Participation in the study 
may be terminated at any time without the subject’s consent as determined by the investigator.
Subjects who are not rolling over from the double-blind DX-2930-03 study will provide 
informed consent at Screening. Subjects who are rolling over from the double-blind DX-2930-03 
study will provide consent on or after Day 168 of Study DX-2930-03. Upon completion of the 
final assessments, the subjects will be discharged from the double-blind study and will start 
participation in the OLE study and receive their first open-label dose.
6.2
Eligibility Review
The investigator or qualified study site personnel will confirm that all Inclusion and Exclusion 
criteria have been met.
6.3
Demographics and Medical History 
Demographics: date of birth (alternately age or year of birth, if full date is not allowed to be 
collected for legal reasons), sex, race, and ethnicity (where locally permitted) and medical 
history will be obtained at Screening from subjects not rolling over from Study DX-2930-03 and 
will be recorded on the source document and eCRF. Medical history will capture the subject’s 
current medical status (current disease processes), past medical status (past disease processes), 
history of surgery, allergies and concomitant medications. For subjects rolling over from Study 
DX-2930-03, these data will be carried forward from that study. 
6.4
HAE Attack Information Collection
The collection, reporting, and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP).  Study site personnel will be 
trained on HAARP prior to screening and enrolling subjects at their site.
Study site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide.  The 
subject (and caregiver) will confirm their understanding of what is required of them for reporting 
attacks to the site.
At screening, HAE attack history will be collected for non-rollover subjects. Information 
collected will include any prior history of laryngeal attacks, attack frequency, average severity, 
predominant attack location(s), triggers, average duration, acute attack therapy use and history of 
LTP (including duration of LTP, medication(s) and dose used for LTP, and frequency of attacks 


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while receiving LTP).  If available, information will also be collected on HAE diagnosis (year of 
confirmation, how many years after onset of symptoms was diagnosis confirmed, or if subject 
was misdiagnosed).
During the study, subjects (or caregivers) will be instructed to notify and report details to the 
study site within 72 hours of the onset of an attack. This includes the first attack experienced by 
rollover subjects following their first open-label dose.  In the situation that a subject is 
incapacitated following an attack, this information can be provided to the site by a family 
member or other individual with detailed knowledge of the event. If desired by the subject, 
memory aids may be provided to assist in tracking any HAE attacks experienced, but their use is 
not mandatory. 
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack:
•
Date and time symptoms of an attack were first experienced
•
Description of symptoms experienced, including location(s)
•
Impact on activity (work, school, social interactions) and whether any assistance or medical 
intervention was required, including hospitalizations, additional laboratory tests, or 
emergency department visits
•
Any medications used to treat the attack (both prescription and over the counter)
•
If the attack resolved, date and time the subject was no longer experiencing symptoms
Study site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP.
Study site personnel will contact rollover subjects approximately every 7 days following the first 
dose of open-label until the subject has received their second open label dose.  This is to ensure 
accurate reporting for any HAE attacks not already reported by the subject as required within 
72 hours.  During each study visit, study site personnel will solicit for any new HAE attack 
information that was not already provided to the site.
In this study, HAE attacks will be captured as AEs. All AEs, regardless of seriousness, severity, 
or causal relationship to DX-2930, will be recorded on the AE page of the eCRF. Any AE 
reported to the site meeting criteria for a serious adverse event must be reported to the Sponsor 
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of the 
event. For all adverse events that are reported as HAE attacks, the investigator or physician 
designee will review the event within 7 days of initial notification and, in accordance with 
HAARP, evaluate if it represented a confirmed HAE attack. If necessary for the evaluation, the 
investigator or designee may contact the subject to receive additional information. Any subject-
reported attack not confirmed by the investigator or physician designee must have an alternate 
AE diagnosis recorded.  All subject-reported and investigator/ physician designee-confirmed 
HAE attacks will be recorded in the eCRF. 


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Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured.
To be confirmed as an attack, the event must have symptoms or signs consistent with an attack in 
at least one of the following locations: 
•
Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region
•
Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea
•
Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx
Despite the presence of these symptoms, the investigator or physician designee may still 
clinically determine that the event did not represent an attack if there are features that strongly 
refute such a diagnosis. For example, the reported event is accompanied by symptoms that are 
not consistent with an HAE attack (eg, urticaria), the reported event persists well beyond the 
typical time course of an HAE attack, or there is a likely alternate etiology for the event (eg, the 
subject’s abdominal symptoms are attributable to a viral gastroenteritis outbreak in the 
household). 
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.
6.5
Vital Signs
Vital signs prior to dosing and at 1 hour post-dosing (±15 min) will be assessed by the 
investigator or his/her qualified designee according to the Study Activities Schedules (Table 1
and Table 2) unless the subject has elected to self-administer off-site for that visit. Routine vital 
sign assessments will be taken with the subject in the sitting or supine position after 5 minutes at 
rest and will include body temperature, heart rate (HR), blood pressure (BP) and respiratory rate 
(RR). BP should be determined using the same arm and the same equipment for each assessment.  
For subjects who rollover from Study DX-2930-03, vital signs taken during the final study visit 
in Study DX-2930-03 will serve as the Day 0 pre-dose vital signs in this study and will not be 
duplicated.  
6.6
Physical Examination
A physical examination including height, weight, and calculation of Body Mass Index (BMI) 
will be performed by the investigator or his/her qualified designee according to the Study 
Activities Schedules (Table 1 and Table 2). The physical examination will be performed in 
accordance with standards at the site. 
For subjects who rollover from Study DX-2930-03, the physical exam taken during the final 
study visit in Study DX-2930-03  will serve as the Day 0 pre-dose physical exam in this study 
and will not be duplicated.  Weight should be collected at every exam.


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6.7
Electrocardiography (ECG)
A standard 12-lead ECG (single recording) will be performed according to the Study Activities 
Schedules (Table 1 and Table 2). The date and time of each ECG and its results will be 
documented in the source documents and eCRF. Electrocardiograms will be sent to a central 
reading vendor for assessment or will be assessed on site. For subjects who rollover from Study 
DX-2930-03, the ECG taken during the final study visit in Study DX-2930-03 will serve as the 
Day 0 pre-dose ECG in this study and will not be duplicated.
6.8
Clinical Laboratory Tests
6.8.1
Laboratory Parameters
Laboratory testing will be performed according to the Study Activities Schedules (Table 1 and 
Table 2). 
Laboratory testing includes general safety parameters (hematology, coagulation, urinalysis, and 
serum chemistry), pregnancy tests (in females of childbearing potential), PK sampling, PD 
sampling, plasma anti-drug antibody testing, and biomarker testing. All laboratory tests will be 
performed using established and validated methods. 
When multiple sample collection types are performed at the same assessment time point, the 
samples will be drawn in the following order (depending on what sample types are to be 
collected at that time point): laboratory safety samples (hematology, coagulation, serum 
chemistry), C1-INH, C4, C1q, PK, anti-drug antibodies, PD, and biomarker samples. Aliquots 
from the samples may be retained as back-up for additional parameter testing if necessary. 
Subjects will be in a seated or supine position during blood collection. For subjects who rollover 
from Study DX-2930-03, testing performed during the final study visit in Study DX-2930-03 
will serve as the Day 0 pre-dose laboratory testing in this study and will not be duplicated.
6.8.1.1
Hematology
•
Hemoglobin
•
Hematocrit
•
Red blood cell (RBC) count
•
White blood cell (WBC) count with differential
•
Mean corpuscular volume (MCV)
•
Mean corpuscular hemoglobin (MCH)
•
Mean corpuscular hemoglobin concentration (MCHC)
•
Absolute platelet count
•
6.8.1.2
Coagulation
•
Prothrombin time (PT)


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•
Activated partial thromboplastin time (aPTT)
•
International Normalized Ratio (INR)
6.8.1.3
Chemistry
•
Albumin
•
Alkaline phosphatase
•
Alanine aminotransferase (ALT; SGPT)
•
Aspartate aminotransferase (AST; SGOT)
•
Bilirubin (total and direct)
•
Blood urea nitrogen (BUN)
•
Calcium
•
Carbon dioxide (CO2)
•
Chloride
•
Creatinine
•
Creatine phosphokinase (CPK)
•
Glucose
•
Phosphate
•
Magnesium
•
Potassium
•
Sodium
•
Total protein
•
Uric acid
6.8.1.4
Urinalysis
•
Bilirubin
•
Glucose
•
Ketones
•
Blood 
•
Nitrite
•
pH
•
Protein
•
Specific gravity
•
Microscopy (if indicated by macroscopic findings)
Samples for urinalysis will be drawn during the study according to the Study Activities 
Schedules (Table 1 and Table 2).


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6.8.1.5
Pregnancy Test
Pregnancy tests will be either serum or urine based according to the Study Activities Schedules 
(Table 1 and Table 2).
6.8.1.6
Biomarkers
EXPLORATORY BIOMARKERS
Samples for exploratory biomarker measurement will be drawn during the study according to the 
Study Activities Schedules (Table 1 and Table 2).
C1-INH FUNCTIONAL ASSAY
Results of a C1-INH functional assay are required for eligibility assessment and will be assessed 
during the study according to the Study Activities Schedules (Table 1 and Table 2). 
Samples will be drawn at the Screening visit unless they were previously drawn in Study 
DX-2930-02 or Study DX-2930-03. Results of the C1-INH functional assay from DX-2930-02 
or Study DX-2930-03 may be used to confirm diagnosis in this study. Subjects may be retested if 
results are incongruent with clinical history or believed by the investigator to be confounded by 
recent LTP use. Because C1-INH therapy may alter the lab results of C1-INH assessments, the 
investigator's discretion in collaboration with Medical Monitor is advised for proper 
documentation of eligibility.
C4 ASSAY
Results of a C4 assay may be required for eligibility assessment and will be assessed during the 
study according to the Study Activities Schedules (Table 1 and Table 2). 
The C4 sample will be drawn at the same time as the C1-INH sample is drawn during the 
Screening visit unless previously drawn in Study DX-2930-02 or Study DX-2930-03.  Results of 
the C4 assay from DX-2930-02 or Study DX-2930-03 may be used to confirm diagnosis in this 
study.  Subjects may be retested if results are incongruent with clinical history or believed by the 
investigator to be confounded by recent LTP use. 
C1Q ASSAY
Results of a C1q assay may be required for eligibility assessment. Any subject who requires 
C1-INH and C4 assay results for diagnostic confirmation in this study will have C1q assay 
results obtained as well. The C1q sample will be drawn at the same time as the C1 and C4 
sample is drawn during the Screening visit. 
6.8.1.7
PK Sample Collection
As outlined in Section 6.9.
6.8.1.8
PD Sample Collection
As outlined in Section 6.10.


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6.8.1.9
Plasma Anti-Drug Antibody Testing
As outlined in Section 6.11.
6.8.2
Sample Collection, Storage, and Shipping
Blood samples for laboratory assessments will be collected at the site by a trained site staff 
designated and/or approved by the study investigator. Details for the collection, processing, 
storage and shipment of samples for all laboratory determinations will be provided in the 
Laboratory Manual.
Biological material will be stored and secured in a manner that assures that unauthorized access 
is prohibited and the samples are not lost, allowed to deteriorate, or accidentally or illegally 
destroyed.
6.9
Pharmacokinetic Assessments
Blood samples for the measurement of plasma DX-2930 concentration will be obtained as 
specified in the Study Activities Schedules (Table 1 and Table 2).
6.10
Pharmacodynamic Assessments
To evaluate the PD effects of DX-2930 upon plasma kallikrein activity, blood samples will be 
obtained as specified in the Study Activities Schedules.
6.11
Plasma Anti-Drug Antibody Testing 
Plasma samples for testing for formation of antibodies to DX-2930 will be obtained as specified 
in the Study Activities Schedules. Additional testing may be required in patients who have 
positive ADA.
6.12
Prior and Concomitant Therapy
The Sponsor representatives and investigator at the site conducting the trial will review and 
evaluate prior (4 weeks prior to study screening) and concomitant medication usage on an 
ongoing basis. For subjects not rolling over from Study DX-2930-03, all prescription, over-the-
counter medications, herbals, and supplements that are being taken or have been taken by 
subjects from 4 weeks prior to screening through the duration of the study will be regarded as 
concomitant medications and must be documented on the source document and eCRF following 
informed consent.  For subjects rolling over from Study DX-2930-03, concomitant therapy use 
will be carried forward from that study and will continue to be collected through the duration of 
the study. 
6.13
Investigational Medicinal Product Treatment
Instructions for safe handling of DX-2930, preparation of each subcutaneous dose and 
administration of DX-2930, are provided in the Pharmacy Manual. Preparation and dispensing of 
DX-2930 will be handled by qualified study site personnel or by subjects who are self-


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administering after receiving appropriate training by the investigator or designee at the study site. 
The requirements for maintaining DX-2930 accountability are provided in Section 6.15.1 (for 
subjects self-administering) and Section 5.7 and Section 5.8 of this protocol.
6.14
Quality of Life Assessments
Quality of life (QoL) assessments will be conducted using the Angioedema Quality of Life 
Questionnaire (AE-QoL), EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L), Work 
Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH), Hospital 
Anxiety and Depression Scale (HADS), and 12 Item Short Form Survey (SF-12). See Study 
Activities Schedules (Table 1 and Table 2). For subjects who rollover from Study DX-2930-03, 
quality of life assessments obtained during the final study visit in Study DX-2930-03 will serve 
as the Day 0 pre-dose quality of life assessments in this study and will not be duplicated.
6.14.1
Angioedema Quality of Life Questionnaire (AE-QoL)
The AE-QoL is a self-administered, symptom-specific tool developed and validated to assess 
quality of life (QoL) impairment in patients with recurrent angioedema (Weller et al. 2012). The 
AE-QoL consists of 17 questions covering four domains/dimensions (functioning, fatigue/mood, 
fear/shame, nutrition). Each of the 17 items has a five-point Likert-type response scale ranging 
from 1 (Never) to 5 (Very Often). The AE-QoL is scored to produce a score for each domain and 
a total score ranging from 0 to 100, with higher scores indicating stronger impairment. It takes 5 
minutes to complete the AE-QoL.
6.14.2
EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L)
The EQ-5D-5L is a self-administered standardized measure of health status comprised of a 
descriptive system and a Visual Analogue Scale (VAS). The descriptive system consists of five 
health related quality of life dimensions (ie, mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression). Each dimension is rated on a 5-point response scale (5 levels) indicating 
severity of problems, where 1 is “no problems” and 5 is “extreme problems”. The EQ-5D VAS is 
a measure of overall self-rated health status on a 20-cm vertical VAS with endpoints labelled 
“the best health you can imagine” and “the worst health you can imagine”. The VAS ranges from 
0 to 100, with higher scores indicative of better overall health.
6.14.3
Work Productivity and Activity Impairment – General Health (WPAI-GH) 
Questionnaire
The WPAI-GH is a 6-item instrument assessing work and activity impairment due to health 
problems during the past 7 days. The instrument elicits four main scores in relation to general 
health specifically: absenteeism (the percentage of work time missed because of one's health in 
the past seven days), presenteeism (the percentage of impairment experienced while at work in 
the past seven days because of one's health), overall work productivity loss (an overall 
impairment estimate that is a combination of absenteeism and presenteeism), and activity 
impairment (the percentage of impairment in daily activities because of one's health in the past 
seven days) (Reilly et al. 1993). Adolescent subjects should complete the WPAI questionnaire 
and use the term “school” instead of “work” when filling out this questionnaire.  These data will 
be analyzed separately.


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6.14.4
Hospital Anxiety and Depression Scale (HADS)
The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale to detect states of 
depression, anxiety, and emotional distress amongst patients who were being treated for a variety 
of clinical problems (Zigmond and Snaith 1983). The scale has a total of 14 items. Seven of the 
items relate to anxiety and seven relate to depression.  The responses are scored on a scale of 0–3 
(3 indicates higher symptom frequencies). Scores for each subscale (anxiety and depression) 
range from 0 to 21 with scores categorized as follows: normal 0–7, mild 8–10, moderate 11–14, 
and severe 15–21. Scores for the entire scale (emotional distress) range from 0 to 42, with higher 
scores indicating more distress. This scale reflects how a subject has been feeling during the past 
week.
6.14.5
12 Item Short Form v2 Health Survey (SF-12v2)
The SF-12v2 Health Survey is a reliable and valid generic measure of functional health and well-
being. The SF-12v2 consists of 12 questions, all selected from the SF-36 Health Survey (Ware et 
al. 1996). The SF-12v2 yields eight health domains (vitality, physical functioning, bodily pain, 
general health perceptions, physical role functioning, emotional role functioning, and mental 
health summary measures. Physical and Mental Health Composite Scores (PCS & MCS) can be 
computed using the scores of twelve questions and range from 0 to 100, where a zero score 
indicates the lowest level of health measured by the scales and 100 indicates the highest level of 
health. The standard form of the instrument asks subjects to reply to questions according to how 
they have felt over the last 4 weeks.
6.14.6
Angioedema Control Test (AECT)
The Angioedema Control Test (AECT) is a patient reported outcome measure. The concept of 
the AECT is comparable to those of the well-established Asthma Control Test (ACT) and 
Urticaria Control Test (UCT) (Nathan et al. 2004; Weller et al. 2014). The AECT could be used 
to assess control of angioedema among patients with recurrent angioedema (including hereditary 
angioedema) and to aid treatment decisions. The AECT consists of up to 10 questions. Each 
question has 5 answer options (verbal rating scale) that are scored from 0 to 4 points, which 
ultimately comprise the total AECT score.
6.14.7
Treatment Satisfaction Questionnaire for Medication (TSQM-9)
The TSQM-9 is a validated 9-item questionnaire developed to measure subjects’ satisfaction 
with their medication and includes three scale scores: effectiveness, convenience, and global 
satisfaction (Bharmal et al. 2009). Scale scores for each of the 3 scales, as well as a combined 
score are calculated separately. Scores are transformed to a 0 to 100 scale, where higher scores 
indicate greater treatment satisfaction. The TSQM-9 has been applied in clinical studies in 
several chronic conditions.
6.14.8
Global Impression of Treatment Response
The subjects’ and investigators’ global impression of treatment response will be assessed using a 
one-item question. The item will assess overall perception of treatment response. Assessment 
will be performed separately by the subject and investigator. The subjects and investigators will 
be asked to think of “today” while rating the question (or an appropriate translation, as 


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applicable): “Overall, how would you rate your response to the study medication?” There will be 
five response options; namely, poor; fair; good; very good, excellent. 
6.14.9
Exit Interview
At the last follow-up visit, subjects will be asked about their overall experience with DX-2930 
studies and any changes in signs and symptoms related to HAE and related impact on subjects 
health during the between-attack period in order to assess opportunities to improve the future 
studies. The exit interview will capture subject experience in general. These questions will ask 
about HAE control, changes pertaining to wellness between attacks, response to triggers, 
prodrome, and overall sense of vitality or energy level, or activity level. 
6.15
DX-2930 Injection Report and Self-Administration and Subcutaneous Injection 
Survey
Assessments of subject experience with self-administration and SC injections of DX-2930 will 
be conducted.
6.15.1
DX-2930 Injection Report
The investigator or designee will train subjects who elect to self-administer DX-2930 on the 
following:
•
Transportation and recommended storage conditions of investigational product from the 
study site to the offsite location.
•
Maintenance of accurate records regarding each administration of investigational product 
including supply identification (ie, lot/kit number), date and time of injection, injection site 
location, infusion time, and if applicable, any reason the self-administration could not be 
completed as instructed.
•
Retention of all used and unused vials of investigational product for drug accountability 
purposes.
After receiving appropriate training and demonstrating their understanding of self-
administration, subjects are allowed to self-administer DX-2930 after receiving the first 2 doses 
of DX-2930 at the study site (administered by study personnel). 
For those subjects who choose to self-administer or have a parent/legal guardian/caregiver 
administer DX-2930, subjects must complete an assessment of their experience with self-
administration and subcutaneous injection for each dose received. Study personnel will 
document the subject’s responses in the subjects’ medical record and eCRF.
6.15.2
DX-2930 Self-administration and Subcutaneous Injection Survey
Subjects will complete an assessment on their overall experience with self-administration and 
experience with receiving SC injections of DX-2930 according to the Study Activities Schedules 
(Table 1 and Table 2) during the study. Subjects who received a PFS will be asked to describe 
the overall experience using the PFS including aspects of administration. For subjects who have 
previously received LTP with C1-INH products via IV administration, they will be asked to 
indicate the preferred route for medication administration. Study personnel will document the 


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subject’s responses in the subjects’ medical record and eCRF. In addition, investigators will be 
asked to indicate their preference (SC, IV, or no preference) on the route to administer 
medications to prevent angioedema attacks.
6.16
Adverse Event Reporting
Adverse events will be collected from signing of the informed consent through the last study 
visit.
6.16.1
Definitions
6.16.1.1
Adverse Event
An AE is any untoward medical occurrence in a clinical trial subject whether or not it appears to 
have a causal relationship with the treatment administered. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product or 
participation in a clinical study, whether or not directly related to the medicinal product or study 
participation.
•
AEs may be new events or may be pre-existing conditions that have become aggravated or 
have worsened in severity or frequency during the course of the study.
•
AEs may be clinically significant changes from baseline in physical examination, laboratory 
tests, or other diagnostic investigation (eg, laboratory results, x-ray findings).
Laboratory abnormalities generally are not considered AEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. A clinically significant laboratory 
abnormality that is independent from a known underlying medical condition and that requires 
medical or surgical intervention, or leads to DX-2930 interruption or discontinuation, will in 
itself, be considered an AE. Laboratory or diagnostic testing abnormalities that reflect or are part 
of a known underlying medical condition are not, in themselves, AEs; rather, the underlying 
medical condition leading to the abnormalities would be reported as the AE.
Pregnancy is not an AE; however, if a female subject becomes pregnant during the conduct of 
the study, the investigator must notify the Sponsor according to the procedures provided in 
Section 6.16.5.2.
6.16.1.2
Serious Adverse Event
A SAE is any adverse experience occurring at any dose that results in any of the following 
outcomes:
•
Death
•
Life-threatening experience; Note: “Life-threatening” refers to a situation in which the 
subject was at risk of death at the time of the event; it does not refer to an event that might 
have caused death if it were more severe.


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•
Requires inpatient hospitalization or prolongation of existing hospitalization; Note: Does not 
include hospitalization for observation with release within 24 hours. A scheduled 
hospitalization for a pre-existing condition that has not worsened during participation in the 
study does not meet this criterion. Pre-planned hospitalizations for an elective 
medical/surgical procedure or routine check-ups do not meet this criterion.
•
Results in persistent or significant disability or incapacity.
•
Is a congenital anomaly or birth defect.
•
Is considered to be an important medical event defined as those that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed in the definition above.
6.16.1.3
Overdose
An overdose is defined as a significant variation from the recommended/scheduled dosage for a 
product. The dosing for this study will be conducted in a controlled clinical setting and an 
overdose is not anticipated. However, in the event of an accident, for this study, an overdose of 
DX-2930 is considered a dose that is two-fold higher than the intended dose for the subject.
6.16.1.4
Planned Hospitalization
A hospitalization planned by the subject prior to the first dose of open-label DX-2930 is 
considered a therapeutic intervention and not the result of a new SAE and should be recorded as 
medical history. If the planned hospitalization or procedure is executed as planned, the record in 
the subject’s medical history is considered complete. However, if the event/condition worsens 
during the trial, it must be reported as an AE.
6.16.1.5
Treatment-Emergent Adverse Events (TEAE)
An AE is treatment-emergent if the onset time is after first administration of open-label DX-2930 
through the final follow-up visit or, in the event that onset time precedes first DX-2930 
administration, the AE increases in severity during the open-label treatment period.
For rollover subjects, any adverse event that started during the subject’s participation in Study 
DX-2930-03 and was ongoing at the time of the first open-label dose in Study DX-2930-04 will 
not be counted as an AE in Study DX-2930-04 unless that event has worsened in severity or 
frequency following the first open-label dose.  Adverse events that started during subject 
participation in Study DX-2930-03, resolved following the first open-label dose in Study DX-
2930-04, and then subsequently reappeared in Study DX-2930-04 will be counted as a new 
TEAE in Study DX-2930-04.
6.16.1.6
Adverse Events of Special Interest (AESI)
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Investigators will report all AESI to the Sponsor, regardless of causality, using the same 
timelines as described for SAE reporting. The following describe the AESI and the criteria for 
reporting AESI. 


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HYPERSENSITIVITY REACTIONS
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours, only if the reactions 
are suspected to be related to study drug.
EVENTS OF DISORDERED COAGULATION
Bleeding AESI
Although aPTT prolongation due to plasma kallikrein inhibition is an artifactual in vitro
phenomenon, as a precautionary measure in evaluating the safety of DX-2930, bleeding events 
will be reported as AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with a clinical event of 
bleeding. Coagulation testing (aPTT, PT, INR) should be performed when possible, and when 
temporally reasonable, with any reports of bleeding or for clinical conditions possibly indicative 
of bleeding.
Hypercoagulable AESI
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot be 
determined, that are consistent with a thrombotic or embolic etiology. 
6.16.2
Monitoring
6.16.2.1
Monitoring of Adverse Events
Each subject will be monitored for the occurrence of AEs, including SAEs and AESI, from 
signing of the ICF through the final follow-up visit.
•
Subjects will be questioned and/or examined by the investigator or a qualified designee for 
evidence of AEs. The questioning of subjects with regard to the possible occurrence of AEs 
will be generalized such as, "How have you been feeling since your last visit?”  The presence 
or absence of specific AEs should not be elicited from subjects.
•
Subjects having TEAEs will be monitored until resolution with relevant clinical assessments 
and laboratory tests, as determined by the investigator.
•
AEs, actions taken as a result of AEs, and follow-up results must be recorded in the eCRF as 
well as in the subject's source documentation. Follow-up laboratory results should be filed 
with the subject's source documentation.
For any SAEs or AEs that require the subject to be discontinued from dosing, relevant clinical 
assessments and laboratory tests will be repeated as clinically appropriate, until final resolution 
or stabilization of the event(s). Subjects will continue to be followed through completion of all 
scheduled visits.


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6.16.2.2
Monitoring of Safety Laboratory Assessments
All safety laboratory assessments will be performed at a central laboratory. The clinical 
laboratory values will be reported to the investigator who will review them for clinical 
significance and consideration of abnormal values as potential AEs.
6.16.3
Assessment of Adverse Events
6.16.3.1
Assessment of Severity
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe nausea). This is not the same as “serious,” which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning.
In this study, the severity of AEs will be assessed according to Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table, Draft, November 2007 (US National 
Institutes of Health: National Institute of Allergy and Infectious Diseases) (Appendix 1, 
Appendix 2) and the Division of Microbiology and Infectious Diseases (DMID) Pediatric 
Toxicity Table, Draft, November 2007 (US National Institutes of Health: National Institute of 
Allergy and Infectious Diseases) (Appendix 3). For abnormalities not specifically found in the 
Toxicity Tables, the following general scale will be used to estimate grade of severity:
•
GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required
•
GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required
•
GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible 
•
GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable
Any treatment-emergent ECG abnormality that is considered by the investigator as clinically 
significant and requiring intervention/therapy will be assessed as a severe AE.
All HAE attacks will be captured as AEs and assessed with DMID & HAE Attack Assessment 
and Reporting Procedures (HAARP) criteria.
6.16.3.2
Assessment of Causality
A medically qualified investigator must assess the relationship of any AE (including SAEs) to 
the use of DX-2930, as related or not related, based on clinical judgment and using all available 
information, and may include consideration of the following factors:
•
Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic factors.
•
The temporal association between DX-2930 exposure and onset of the AE.


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•
Whether the manifestations of the AE are consistent with known actions or toxicity of 
DX-2930.
•
The AE resolved or improved with decreasing the dose or stopping use of DX-2930 
(dechallenge). Judgment should be used if multiple products are discontinued at the same 
time.
The causal relationship between DX-2930 and the AE will be assessed using one of the 
following categories:
Not Related:  Factors consistent with an assessment of Not Related include:

Temporal relationship is lacking (eg, the event did not occur within a reasonable 
time frame following administration of DX-2930); or

Other causative factors more likely explain the event (eg, a pre-existing condition, 
other concomitant treatments).
Related:  Factors consistent with an assessment of Related include:

There is a positive temporal relationship (eg, the event occurred within a 
reasonable time frame following administration of DX-2930); or

The AE is more likely explained by administration of DX-2930 than by another 
cause (ie, the AE shows a pattern consistent with previous knowledge of 
DX-2930 or the class of DX-2930).
6.16.3.3
Assessment of Clinical Significance
Clinical significance of individual AEs will be determined by the investigator, with discussion 
with the Medical Monitor as appropriate.
6.16.4
Clinical Laboratory Adverse Events
Laboratory abnormalities generally are not considered AEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. A clinically significant laboratory 
abnormality that is independent from a known underlying medical condition and that requires 
medical or surgical intervention, or leads to DX-2930 interruption or discontinuation, will be 
considered an AE.
When laboratory abnormalities are considered to be AEs, the DMID Adult Toxicity Table 
(Appendix 2) or DMID Pediatric Toxicity Tables (Appendix 3) will be used to assess severity. 
Where discrepancies in the upper limit of normal (ULN) and lower limit of normal (LLN) of 
laboratory ranges occur between those included in the DMID tables and those of the laboratory 
that performs the assays, the values provided by the laboratory will be used for assignment of 
severity grade. Clinical significance of individual laboratory AEs will be determined by the 
investigator with input from the Medical Monitor as needed. 
Following is an exception to defining clinically significant, abnormal laboratory values as AEs:


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
APTT prolongation in the absence of any associated bleeding or other evidence of clinical 
relevance will not be considered a clinically significant laboratory abnormality or AE. In the 
appropriate physiologic setting, such as IV heparin therapy, aPTT can be used to monitor 
bleeding risk. However, as noted in the Investigators Brochure, aPTT prolongation due to 
plasma kallikrein inhibition is an artifactual in vitro phenomenon. Although plasma kallikrein 
drives fibrin formation in the aPTT assay, plasma kallikrein-driven coagulation does not 
appear to have hemostatic or other physiologically important functions in vivo. It is well 
documented that, in humans, deficiency of factor XII or prekallikrein (and thus plasma 
kallikrein) is not associated with abnormal bleeding, either spontaneous or during surgical 
procedures (Renne and Gruber 2012). Despite the lack of clinical effect, deficiency of either 
protein is associated with marked prolongation of the aPTT. 
6.16.5
Reporting Investigator Safety Observations to the Sponsor
6.16.5.1
Reporting Non-serious Adverse Events
All AEs, regardless of seriousness, severity, or causal relationship to DX-2930, will be recorded 
on the AE page of the eCRF. In this study all HAE attacks reported by the subject, regardless of 
whether or not they are confirmed by the investigator, will be captured as AEs.
6.16.5.2
Reporting Pregnancies
If a female subject or the female partner of a male subject becomes pregnant during the course of 
the study, the investigator must report the pregnancy to the Sponsor’s Pharmacovigilance 
Department using the Pregnancy Reporting Form within 24 hours of becoming aware of the 
event. The investigator must obtain consent to collect pregnancy information (including the 
status of the newborn, if applicable).
If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and submitted 
within 24 hours of becoming aware of the new information. The investigator is required to 
follow the pregnancy through delivery. The outcome of the pregnancy and the status of the 
newborn (if applicable) will be reported on the Pregnancy Reporting Form within 24 hours of 
becoming aware.
6.16.5.3
Safety Observations Requiring Expedited Reporting by the Investigator to 
the Sponsor
Any occurrence of the following events or outcomes in a subject in the trial must be reported 
expeditiously by the investigator or qualified designee to the Sponsor’s Pharmacovigilance 
Department:
•
SAE
•
AESI
•
Overdose
•
Cancer


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The investigator is to report any expedited safety observations from the list above to the Sponsor 
using the SAE Reporting Form in the EDC system within 24 hours of becoming aware of the 
event.
Any SAE reported to the Sponsor Pharmacovigilance Department using the SAE Reporting 
Form in the EDC system is to be recorded in the eCRF, as well as in the subject's source 
documentation along with any actions taken. If all required information on the form is not 
available at the time of the initial report, follow-up information will be completed in the EDC 
system.
The investigator is required to follow SAEs until resolution regardless of whether the subjects 
are still participating in the study. SAE resolution is defined as:
•
Resolved with or without residual effects.
•
A return to baseline for a pre-existing condition.
•
Laboratory values have returned to baseline or stabilized.
•
The investigator does not expect any further improvement or worsening of the event.
•
Fatal outcome—if an autopsy is performed; the autopsy report is requested to be provided to 
the Sponsor as soon as it is available.
6.16.5.4
Expedited Reporting by the Sponsor to a Regulatory Health Authority
The Sponsor or designee will report relevant safety information to concerned health authorities 
in accordance with local laws and regulations.
6.16.5.5
Safety Contact Information
24-Hour Global Safety Contact: Pharmacovigilance Department
Email: 
 
Telephone (US) 
6.16.5.6
Safety Notifications by the Sponsor to the Investigator
Investigators will receive prompt notification of any adverse experience related to DX-2930 that 
is both serious and unexpected, or any finding that suggests a significant risk for subjects. The 
investigator will promptly inform his / her IRB/REB/IEC of the notification and insert the 
notification in the Investigator’s Regulatory Binder in accordance with local regulations. 
6.17
Subject Withdrawal
The investigator may withdraw a subject from DX-2930 treatment for any of the following 
reasons:
•
In the opinion of the investigator, the subject is unable to comply with the requirements of 
the protocol for satisfactory completion or interpretation of study results (including use of 
prohibitive medications),
•
A serious or intolerable AE occurs,


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•
A clinically significant change in a laboratory parameter occurs,
•
The Sponsor or investigator terminates the study, or
•
The subject requests to be discontinued from the study.
Subjects will continue to be followed through completion of all scheduled visits, unless the 
subject requests to be discontinued from the study.
6.18
Appropriateness of Measurements
This is a Phase 3 open-label extension study that is designed to evaluate the long-term safety and 
efficacy of DX-2930 in prophylactic therapy for angioedema attacks in subjects with HAE. 
DX-2930 is a recombinant, fully human IgG1, kappa light chain, monoclonal antibody. The 
open-label, non-controlled study design is a standard approach for extension studies that follow 
double-blind pivotal trials. Measures employed in this protocol are standard measures routinely 
used for the evaluation of the efficacy, safety and tolerability of an investigational product.  
Measures employed for rollover subjects between the first and second open-label doses are 
appropriate to characterize the outer bounds of dosing frequency for DX-2930.


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7.
STUDY ACTIVITIES
Study activities are summarized by study visit in Study Activities Schedules (Table 1 and Table 
2).
7.1
Screening Visit (Up to Day −28) 
For subjects not rolling over from Study DX-2930-03, the procedures and assessments described 
in the Study Activities Schedule (Table 1) should be followed:
•
Informed consent (Section 6.1)
•
Eligibility review (Section 6.2)
•
Demographics and medical history (Section 6.3)
•
C1-INH functional assay, C4 and C1q sample collection (Section 6.8)
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including height and weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry, and urinalysis 
(Section 6.8)
•
Prior and concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16); pre-existing signs and symptoms
For subjects rolling over from the double-blind DX-2930-03 study, no Screening visit is required 
as subjects will enter the OLE on the same day that their last Study DX-2930-03 study visit is 
completed. Diagnostic test results and demographic and medical history for these subjects will be 
carried forward from that study.
7.2
Start of Treatment Period: Visit 1, Dose 1 (Day 0)
The following procedures and assessments are to be performed on Day 0 prior to the first dose of 
DX-2930.  For subjects who rollover from Study DX-2930-03, all final assessments taken during 
the final study visit in Study DX-2930-03 will be used as the pre-dose results on Day 0 and will 
not be duplicated.
•
Informed consent (for subjects rolling over from the double-blind DX-2930-03 study; this 
can be on or after Day 168 of that study) (Section 6.1)
•
Eligibility review (Section 6.2)
•
Urine pregnancy test (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)


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•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK baseline sample collection (Section 6.9)
•
PD baseline sample collection (Section 6.10)
•
Baseline anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
First dose of open-label DX-2930 (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2)
•
AE collection (Section 6.16)
7.3
Interval between Dose 1 and Dose 2 for Rollover Subjects
Rollover subjects must adhere to the Study Activities Schedule (Table 1) for the entire duration 
of the study. Until a rollover subject reports their first HAE attack, study visits may be conducted 
via site check in calls, except for the following study visits which must be conducted at the 
investigative site:

Day 14

Day 28

Day 56

Day 98

Day 126

Day 154

Day 182

Day 224

Day 266

Day 308

Day 364


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The tests and assessments required at these visits are specified in the sections below. 
Site check in calls may serve as any of the following study visits until the subject receives their 
second open-label dose:

Day 42

Day 70

Day 84

Day 112

Day 140

Day 168

Day 196

Day 210

Day 238

Day 252

Day 280

Day 294

Day 322

Day 336 

Day 350
Study site personnel will also contact rollover subjects approximately 7 days after each study 
visit (both site visits and check-in calls) until the subject receives their second open-label dose.
The following assessments are performed during all site calls:
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
7.4
Dose 2 of DX-2930 for Rollover Subjects
The duration of time between Dose 1 and Dose 2 will vary by subject based on when their first 
HAE attack occurs following Dose 1.  As a result, rollover subjects may not receive DX-2930 
treatment at every dosing visit as outlined in the Study Activities Schedules (Table 1 and Table 
2).
Once a rollover subject reports their first HAE attack they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  This 
treatment visit may be counted as a scheduled study visit, or as an acceptable extra study visit.  
For details on determining whether the second dose is counted as a scheduled or extra study visit, 
refer to Section 3.1.1.  
Regardless of when the second dose is administered, the following tests and assessments will be 
conducted pre-dose on the day it is administered:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)


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•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
The following tests and assessments will also be performed if the second dose occurs on a 
scheduled study visit for which they are required:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
12-Lead ECG (Section 6.7)
•
Quality of life assessments (Section 6.14)
•
Long-term prophylactic therapy continuation (Section 3.1.1) 
After the required pre-dose tests and assessments are completed:
•
Second dose of open-label DX-2930 (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.5
Visit 2 (Day 14 ±4 days); Dose 2 of DX-2930 for Non-Rollover Subjects
On Day 14, the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:


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•
Administer DX-2930 (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1)
•
AE collection (Section 6.16)
7.6
Continuation of Treatment Period: Visit 3 (Day 28 ±4 Days)
On Day 28, the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1).  For non-rollover subjects this dose represents Dose 3.  
At this visit, subjects have the option to self-administer at the investigational site. 
After administration of DX-2930, the following post-treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.7
Continuation of Treatment Period: Visit 4 (Day 42 ±4 Days)
On Day 42 the following procedures and assessments will be performed prior to DX-2930 
treatment:


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•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1).  For non-rollover subjects this dose represents Dose 4. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.8
Continuation of Treatment Period: Visit 5 (Day 56 ±4 Days)
On Day 56 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 5. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site.


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After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.9
Continuation of Treatment Period: Visits 6 and 7 (Days 70 and 84, All ±4 Days)
On Days 70 and 84 the following procedures and assessments will be performed prior to 
DX-2930 treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects these doses represent Dose 6 
and Dose 7. At this visit, subjects have the option to self-administer DX-2930 at the 
investigational site or the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.10
Continuation of Treatment Period: Visit 8 (Day 98 ±4 Days)
On Day 98 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8)
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)


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•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 8. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2) 
•
AE collection (Section 6.16)
7.11
Continuation of Treatment Period: Visit 9 (Day 112 ±4 Days)
On Day 112 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 9. At 
this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:


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•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.12
Continuation of Treatment Period: Visit 10 (Day 126 ±4 Days)
On Day 126 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 10. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.13
Continuation of Treatment Period: Visit 11 (Day 140 ±4 Days)
On Day 140 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)


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After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 11. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.14
Continuation of Treatment Period: Visit 12 (Day 154 ±4 Days)
On Day 154 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 12. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)


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7.15
Continuation of Treatment Period: Visit 13 (Day 168 ±4 Days)
On Day 168 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 13. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.16
Continuation of Treatment Period: Visit 14 (Day 182 ±4 Days)
On Day 182, the following procedures and assessments will be performed:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, and serum chemistry (Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Biomarker sample collection (6.8.1.6)
•
Anti-drug antibody sample collection (Section 6.11)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)


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•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 14. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2
•
AE collection (Section 6.16)
7.17
Continuation of Treatment Period: Visit 15 (Day 196 ±4 Days)
On Day 196 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 15. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)


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7.18
Continuation of Treatment Period: Visit 16 (Day 210 ±4 Days)
On Day 210 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 16. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 

AE collection (Section 6.16)
7.19
Continuation of Treatment Period: Visit 17 (Day 224 ±4 Days)
On Day 224 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Laboratory testing including hematology, coagulation, and serum chemistry (Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 17. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.


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After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.20
Continuation of Treatment Period: Visit 18 (Day 238 ±4 Days)
On Day 238 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 18. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.21
Continuation of Treatment Period: Visit 19 (Day 252 ±4 Days)
On Day 252 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)


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After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 19. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.22
Continuation of Treatment Period: Visit 20 (Day 266 ±4 Days)
On Day 266 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, and serum chemistry (Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Biomarker sample collection (6.8.1.6)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 20. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:


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•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2) 
•
AE collection (Section 6.16)
7.23
Continuation of Treatment Period: Visit 21 (Day 280 ±4 Days)
On Day 280 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 21. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.24
Continuation of Treatment Period: Visit 22 (Day 294 ±4 Days)
On Day 294 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:


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•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 22. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.25
Continuation of Treatment Period: Visit 23 (Day 308 ±4 Days)
On Day 308 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Laboratory testing including hematology, coagulation, and serum chemistry (Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 23. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.26
Continuation of Treatment Period: Visit 24 (Day 322 ±4 Days)
On Day 322 the following procedures and assessments will be performed prior to DX-2930 
treatment:


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Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 24. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.27
Continuation of Treatment Period: Visit 25 (Day 336 ±4 Days)
On Day 336 the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 25. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site or 
the subject’s home or other agreed upon location.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)


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•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.28
Continuation of Treatment Period: Visit 26 (Day 350 ±4 Days)
On Day 350, the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). At this visit, subjects have the option to self-administer 
DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
AE collection (Section 6.16)
7.29
Continuation of Treatment Period: Visit 27 (Day 364 ±4 Days)
On Day 364, the following procedures and assessments will be performed prior to DX-2930 
treatment:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, and serum chemistry (Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Biomarker sample collection (6.8.1.6)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)


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•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
After the preceding procedures and assessments are completed:
•
Administer DX-2930 (Section 5.1). For non-rollover subjects this dose represents Dose 27. 
At this visit, subjects have the option to self-administer DX-2930 at the investigational site.
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5) at 1 hour post-dose.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1) 
•
DX-2930 Self-administration and Subcutaneous Injection Survey (Section 6.15.2) 
•
AE collection (Section 6.16)
7.30
Continuation of Treatment Period: Visits 28 and 29 (Day 378 and 392 ±4 Days)
On Days 378 and 392, the following procedures and assessments will be performed prior to 
DX-2930 treatment:
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
After the preceding procedures and assessments are completed:
•
DX-2930 administration  (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs, including body temperature, HR, BP, and RR (Section 6.5) at 1 hour post-dose. 
No monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site.
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1)
•
AE collection (Section 6.16)
•
Site Check In Call


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7.31
Continuation of Treatment Period: On-Site Activities (Between Visit 30 and Visit 
66)
At Visit 30 through Visit 66 on-site visits will occur every 8 weeks, although dosing will 
continue at intervals of 14 ± 4 days. On-site activities will include the following:

Visit 30 (Day 406)

Visit 34 (Day 462)

Visit 38 (Day 518)

Visit 42 (Day 574)

Visit 46 (Day 630)

Visit 50 (Day 686)

Visit 54 (Day 742)

Visit 58 (Day 798)

Visit 62 (Day 854)

Visit 66 (Day 910)
At these visits, the following procedures and assessments will be performed prior to DX-2930 
treatment, per the Study Schedule of Activities:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8)
•
Vital signs, including body temperature, HR, BP, and RR – prior to dosing and 1 hour after 
dosing (recommended ± 15-minute window). Monitoring of vital signs will not be performed 
for subjects who elect to self-administer away from the investigative site at optional off-site 
visits (indicated non-shaded columns). (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Laboratory testing, including hematology, coagulation, serum chemistry, and urinalysis 
(urinalysis is performed as part of the clinical laboratory testing at Days 574, 742, 910/Visits 
42, 54, 66) (Section 6.8)
•
PK, PD, Anti-drug antibody, and Biomarker sample collection (Section 6.8, Section 6.9, 
Section 6.10 Section 6.11) – only at Visits 34, 42, 50, 58, and 66 during this time range
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
•
Quality of life assessments (Section 6.14)
•
AE-QoL
•
EQ-5D-5L
•
WPAI-GH


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•
HADS
•
SF-12
•
AECT
•
TSQM-9 – only at Visit 42 during this time range
After the preceding procedures and assessments are completed:
•
DX-2930 administration  (Section 5.1)
After administration of DX-2930, the following post treatment procedures and assessments will 
be performed:
•
Vital signs, including body temperature, HR, BP, and RR (Section x) at 1 hour post-dose. No 
monitoring of vital signs will be performed for subjects who elect to self-administer away 
from the investigational site. (Section 6.5)
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1)
•
DX-2930 Self-administration and Subcutaneous Injection Survey and Pre-filled Syringe 
Survey -- Collect subject's injection reports of their experience with DX-2930 self-
administration, subcutaneous administration, and prefilled syringe (if relevant) for all doses.
(Section 6.15.2)
•
AE collection (Section 6.16)
Monitoring during the periods between on-site visits is described below in Section 7.32.
7.32
Continuation of Treatment Period: Potential Off-Site Activities (Between Visit 31 
and Visit 65)
During the periods between the required on-site visits, subjects will have the option to self-
administer DX-2930 either at the investigational site or the subject’s home or other agreed upon 
location. For subjects who self-administer at home, site personnel will call within approximately 
3 days after the planned self-administration to ensure the administration occurred, to collect AEs, 
concomitant medications, and to ensure all attacks have been appropriately documented.
Potential off-site visits will include the following (ie, visits at 2-week intervals between the visits 
that are on-site visits):

Visits 31, 32, 33 (Days 420, 434, 448)

Visits 35, 36, 37 (Days 476, 490, 504)

Visits 39, 40, 41 (Days 532, 546, 560)

Visits 43, 44, 45 (Days 588, 602, 616)

Visits 47, 48, 49 (Days 644, 658, 672)


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
Visits 51, 52, 53 (Days 700, 714, 728)

Visits 55, 56, 57 (Days 756, 770, 784)

Visits 59, 60, 61 (Days 812, 826, 840)

Visits 63, 64, 65 (Days 868, 882, 896)
The assessments to be performed (regardless of whether the subject exercises the off-site option 
or not) will include the following, as shown on the Study Schedules of Events: 
•
DX-2930 administration  (Section 5.1)
•
HAE attack information (Section 6.4)
•
Concomitant therapy (Section 6.12)
•
DX-2930 Injection Report (Section 6.15.1)
•
AE collection (Section 6.16)
If the subject is off-site, the following will also be performed:
•
Site Check In Call
If the subject is on-site, the following will also be performed:
•
Vital signs including body temperature, HR, BP, and RR (Section 6.5) – prior to dosing and 
1 hour after dosing (recommended ± 15-minute window). Monitoring of vital signs will not 
be performed for subjects who elect to self-administer away from the investigative site at 
optional off-site visits (indicated non-shaded columns). (Section 6.5)
7.33
Completion of Treatment Period:  Visit 67 (Day 924 ±4 Days)
On Day 924, the following procedures and assessments will be performed. Note that DX-2930 
will not be administered during this visit:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Biomarker sample collection (Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)


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7.34
Follow-up Period:  Visit 68 (Day 938 ±4 Days)
On Day 938, all rollover and non-rollover subjects will receive a site check-in call.  During this 
call, study site personnel will collect information shown in the Study Schedule of Activities: 
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
AE collection (Section 6.16)
7.35
Final Follow-up Visit:  Visit 69 (Day 952 ±4 Days)
On Day 952, all rollover and non-rollover subjects will complete a final study visit at the 
investigative site, including the activities shown on the Study Schedule of Activities:
•
Pregnancy test, serum or urine (females of childbearing potential) (Section 6.8) 
•
Vital signs including body temperature, HR, BP and RR (Section 6.5)
•
Physical examination, including weight (Section 6.6)
•
12-Lead ECG (Section 6.7)
•
Laboratory testing including hematology, coagulation, serum chemistry and urinalysis 
(Section 6.8)
•
PK sample collection (Section 6.9)
•
PD sample collection (Section 6.10)
•
Anti-drug antibody sample collection (Section 6.11)
•
Biomarker sample collection (Section 6.8)
•
Concomitant therapy (Section 6.12)
•
HAE attack information (Section 6.4)
•
Quality of life assessments 
•
AE-QoL (Section 6.14) 
•
EQ-5D-5L (Section 6.14) 
•
WPAI-GH (Section 6.14) 
•
HADS (Section 6.14) 
•
SF-12 (Section 6.14) 
•
AECT (Section 6.14.6)
•
TSQM-9 (Section 6.14.7)
•
Global Impression of Treatment Response (Section 6.14.8)
•
AE collection (Section 6.16)
•
Exit Interview (Section 6.14.9)


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•
Study Discharge: Subjects will be discharged at this study visit. 
7.36
Early Termination 
Subjects who terminate early from the study will undergo (if possible) all of the assessments and 
procedures scheduled for Day 952.


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8.
QUALITY CONTROL AND ASSURANCE
The Sponsor and the Contract Research Organization (CRO) conducting trial management 
services, Rho, Inc., will implement a system of quality assurance that includes all elements 
described in this protocol. Within this system, SOPs from the Sponsor and CRO will be 
implemented to ensure that the clinical trial is conducted in compliance with regulatory 
requirements and Good Clinical Practices (GCP). Quality control will be applied to each stage of 
data handling to ensure that data are accurate, reliable and processed correctly. 
The site staff should assist in all aspects of audit/inspection.


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9.
DATA ANALYSIS / STATISTICAL METHODS
9.1
General Considerations
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, Cary, 
North Carolina, USA).
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. Where applicable, estimates from statistical model of least 
squares means, standard errors, and 95% confidence intervals for least squares means will be 
provided. Time-to-event data will be summarized using Kaplan-Meier estimates of the 25th, 50th 
(median), and 75th percentiles with associated two-sided 95% confidence intervals, as well as 
percentage of censored observations. Plots of the Kaplan-Meier curves and supporting data 
listings detailing each subject’s contribution to the analysis will be provided. 
Formal hypothesis testing will not be performed.  Any hypothesis testing will be exploratory in 
nature and resulting p-values will be considered descriptive.
9.2
Sample Size Determination
No formal sample size calculation was performed.  The sample size is not based on any 
statistical considerations.  This study is designed to evaluate the safety and efficacy of open-label 
treatment with DX-2930 in subjects who participated in Study DX-2930-03  (rollover subjects) 
and individuals who were not otherwise able to participate in Study DX-2930-03  (non-rollover 
subjects).
9.3
Method of Assigning Study Subjects to Treatment
Subjects meeting all eligibility criteria will be enrolled in the study and sequentially assigned a 
unique site-based identification number.
9.4
Analysis Populations
9.4.1
Safety Population
The Safety Population will include all subjects who received any study drug after entering Study 
DX-2930-04 (ie, any exposure to open-label DX-2930). Unless otherwise specified, summary 
tabulations conducted with the Safety Population will be presented by the subject’s study entry 
type (rollover or non-rollover) and overall.
9.4.2
Rollover Safety Population
The Rollover Safety Population is the subset of subjects who participated in Study DX-2930-03 
and received any study drug after entering Study DX-2930-04 (ie, any exposure to open-label 
DX-2930). Unless otherwise specified, summary tabulations conducted with the Rollover Safety 
Population will be presented by the subject’s prior treatment group from Study DX-2930-03 


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(DX-2930 300 mg every 2 weeks, DX-2930 300 mg every 4 weeks, DX-2930 150 mg every 
4 weeks, and Placebo).
9.4.3
Non-rollover Safety Population
The Non-rollover Safety Population is the subset of subjects who directly entered Study 
DX-2930-04 and received any study drug after entering Study DX-2930-04 (ie, any exposure to 
open-label DX-2930).  Unless otherwise specified, summary tabulations conducted with the 
Non-rollover Safety Population will be presented by subject’s prior type of LTP therapy prior to 
study entry (C1-INH, androgens, anti-fibrinolytics, and not on LTP)..
9.5
Population Description and Exposure
9.5.1
Subject Disposition
The numbers of subjects treated with study drug, completed the study and discontinued 
prematurely by reason will be summarized for each analysis population.
9.5.2
Demographics and Other Baseline Characteristics
Baseline and demographic variables will be summarized for each analysis population.
9.5.3
Medical History
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by system organ class (SOC) and preferred term (PT) for each analysis 
population.
9.5.4
Treatment Exposure and Compliance
Treatment compliance and the extent of exposure to study drug will be described by the 
percentage of planned doses received by the subject, total number of doses received by the 
subject, and the number and percentage of subjects that received at least 80% of planned doses, 
summarized for each analysis population.
9.5.5
Prior and Concomitant Medications
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD).  The number and percentage of subjects with prior or concomitant medications will be 
summarized by therapeutic class and preferred term for each analysis population.  A separate, 
similar table will be provided for the subset of concomitant medications classified as rescue 
medications.
9.6
Analysis of Efficacy
9.6.1
Time to the First Investigator-confirmed HAE Attack
Time to the first investigator-confirmed HAE attack will be analyzed using the Rollover Safety 
Population.


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Time to the first investigator-confirmed HAE attack (days) will be calculated from the date and 
time of the first open-label dose of DX-2930 to the date and time of the first investigator-
confirmed HAE attack after the first open-label dose.  Subjects who discontinue the study prior 
to experiencing their first on-study investigator-confirmed HAE attack will be censored at the 
date and time of study discontinuation.  Time to the first investigator-confirmed HAE attack will 
be summarized using Kaplan-Meier methods.
Multivariate and univariate Cox proportional hazards regression models will be employed to 
examine the impact of baseline covariates on the time to the first investigator-confirmed HAE 
attack, including but not limited to: baseline attack rate prior to entering Study DX-2930-03, the 
treatment group in Study DX-2930-03, the time since the last dose given in Study DX-2930-03, 
the time since the last HAE attack, and the rate of attacks during Study DX-2930-03. Results of 
this exploratory analysis will be summarized.  
9.6.2
Number of Investigator-confirmed HAE Attacks
The number of investigator-confirmed HAE attacks during the treatment period (Day 0 through 
Day 924) expressed as a monthly HAE attack rate, will be analyzed using each analysis 
population.
The treatment period investigator-confirmed HAE attack rate will be calculated for each subject 
as the number of investigator-confirmed HAE attacks occurring during the treatment period 
divided by the number of days the subject contributed to the treatment period multiplied by 
28 days.  
The baseline investigator-confirmed HAE attack rate will be calculated for each subject as the 
number of investigator-confirmed HAE attacks occurring during the pretreatment period for 
rollover subjects or historical reporting period for non-rollover subjects divided by the number of 
days the subject contributed to the pretreatment period for rollover subjects or historical 
reporting period for non-rollovers multiplied by 28 days.
The baseline, treatment period, and treatment period change from baseline in the investigator-
confirmed HAE attack rate will be summarized for each analysis population. The summary will 
include the total number of investigator-confirmed HAE attacks reported during each period and 
subject-time in months that each subject contributed to each period. Figures will be created for 
each analysis population plotting the on-study investigator-confirmed HAE attacks reported 
during the treatment period relative to Day 0 for each subject.
In addition, the number of investigator-confirmed HAE attacks per month (defined as 28 days) 
will be summarized descriptively by month (per 28 day interval) for each analysis population. 
The summary will include the number, change from baseline, and percent change from baseline 
of investigator-confirmed HAE attacks. Investigator-confirmed HAE attacks will be grouped into 
28-day intervals using the start date of the HAE attack. The date of the first exposure to study 
drug in this study will be used as the start of the first interval and end of the interval will be the 
date of first exposure to study drug in this study plus 28 days. Each successive interval will start 
the last day of the prior interval plus 1 day and end 28 days later. 


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Similar summary tables will be presented for the following efficacy endpoints for each analysis 
population:
•
Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period.
•
Number of moderate or severe investigator-confirmed HAE attacks during the treatment 
period.
•
Number of high-morbidity investigator-confirmed HAE attacks during the treatment period; 
a high-morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation 
< 24 hours), hemodynamically significant (systolic blood pressure < 90, requires IV 
hydration, or associated with syncope or near-syncope) or laryngeal.
9.7
Analysis of Safety
9.7.1
Adverse Events
Adverse events will be coded using the MedDRA coding dictionary.  Separate summaries will be 
presented for each analysis population.
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not.  If a determination cannot be made using the non-missing 
date parts as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.  
Related AEs are AEs classified as related to study drug by the investigator.  Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator.
For this analysis, AEs will be classified to one of two analysis periods:
•
Treatment Period AEs will include all AEs starting at or after the first exposure to open-label 
DX-2930 in this study to those starting before or at the subject’s last visit date during the 
treatment period in this study (AEs starting at or after treatment on Day 0 to the Day 924 
visit). 
•
Follow-up Period AEs will include all AEs starting at or after the subject’s last visit date of 
the treatment period in this study (AEs starting after the Day 924 visit). 


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For AEs with partial onset times, non-missing date parts will be used to determine if the AE falls 
within the period. If a determination cannot be made using the non-missing date parts as to if the 
AE falls within the period, the AE will be conservatively counted as a treatment-period AE. 
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE,  
any severe AE,  any related severe AE, and any investigator-reported AESI, as well as the total 
number of events for each category will be summarized for each analysis period.  The number of 
deaths due to an AE, hospitalization due to an AE and study discontinuation due to an AE will be 
summarized for each analysis period. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC, and PT for each analysis period. This tabulation will be repeated for 
related AEs, SAEs, related SAEs, severe AEs, related severe AEs, and investigator-reported 
AESI for treatment period and follow-up period AEs. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by PT for treatment period AEs only. This tabulation will be repeated for related 
AEs and serious AEs for treatment period AEs. 
All AEs will be provided in subject listings. Listings will be presented separately for each 
analysis period.  In addition, subject listings of AEs causing discontinuation of study medication, 
AEs leading to death, SAEs, related AEs, severe AEs, and AEs of special interest (AESIs) will 
be produced. 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions and 
disordered coagulation (hypercoagulability events and bleeding events).  Standardized MedDRA 
Queries (SMQ) for each AESI will be performed using the study data. The number and 
percentage of subjects with an AESI, as well as the total number of AESIs, will be summarized 
by SOC and PT for each analysis period. Separate summary tables will be created for each AESI 
and for those events with the SMQs classified as related, serious, related serious, severe, and 
related severe.  A listing detailing the PT within the SMQ will be provided.
9.7.2
Laboratory Test Results
Laboratory test results will be summarized using the Safety Population.
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For rollover 
subjects previously exposed to DX-2930, baseline is the last non-missing value prior to first exposure 
to study drug in Study DX-2930-03.        
Actual values and change from baseline clinical laboratory tests will be summarized by study 
visit. If more than one laboratory result is reported per study visit per parameter, the last non-missing 
result will be selected for analysis.
Laboratory test results will be classified according to the reference ranges and clinical significance as 
determined by the investigator. The number of subjects with a non-missing result, and the number 
and percentage of subjects with a clinically significant result less than the lower limit of normal, non-
clinically significant result less than the lower limit of normal, within the normal range, non-


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clinically significant result more than the upper limit of normal, and clinically significant result more 
than the upper limit of normal will be summarized by study visit. If more than one laboratory result is 
reported per study visit per parameter, the result yielding the most severe classification will be 
selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study visit per parameter, the result yielding the 
most severe classification will be selected for analysis. 
Subjects with clinically significant abnormal laboratory test results will be listed.  This listing 
will include all results of the laboratory parameter that was abnormal and determined to be 
clinically significant by the investigator for a subject across study visit to identify any trends.
9.7.3
Vital Signs
Vital signs will be summarized using the Safety Population.
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For 
rollover subjects previously exposed to DX-2930, baseline is the last non-missing value prior to 
first exposure to study drug in Study DX-2930-03.
Actual values and changes from baseline in vital signs will be summarized by study visit and 
study time point. All vital sign data will be presented in subject listings.
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage of 
subjects with a non-clinically significant result and clinically significant result will be summarized by 
study visit and study time point. If more than one vital sign result is reported per study visit and study 
time point per parameter, the result yielding the most severe classification will be selected for 
analysis. 
Subjects with clinically significant vital sign values will be listed.  This listing will include all results 
of the vital sign parameter that was determined by the investigator to be clinically significant for a 
subject across study time points to identify any trends.
9.7.4
Electrocardiography
Electrocardiography results will be summarized using the Safety Population.
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG no performed, will be summarized by study 
visit. Subjects with clinically significant ECG results will be listed.  This listing will include all 
results for a subject across study time points to identify any trends.
9.8
Other Analyses
Additional analyses of pharmacokinetic (PK), pharmacodynamic (PD), biomarker data, and 
potential effect of ADA on PK, PD and biomarker will be described in a separate PK/PD report.


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Additional analysis of quality of life (QoL) data will be described in a separate QoL report. 
9.8.1
Analysis of Pharmacokinetic Data
Plasma concentrations of DX-2930 will be summarized by nominal PK sampling time using the 
Safety Population. 
9.8.2
Analysis of Pharmacodynamic Data
Plasma kallikrein activity will be summarized by nominal PD sampling time using the Safety 
Population.
9.8.3
Analysis of Biomarker Data
Additional biomarkers will be summarized by nominal sampling time using the Safety 
Population.
9.8.4
Analysis of Immunogenicity Data
Blood samples will be collected and tested for the presence of anti-drug antibody. Endpoint titers 
and assessment of in-vitro neutralization will be reported for samples testing positive. The 
number and percentage of negative, positive, and/or with neutralizing antibodies antibody 
samples will be reported and will be summarized by study visit and overall using the Safety 
Population.
9.8.5
Analysis of Quality of Life Assessments
Quality of life assessments will be summarized using the Safety Population.
The number and percentage of subjects at each level of the EQ-5D-5L dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) will be summarized by study 
visit. In addition, the VAS score for the subject’s self-rated health will be summarized by study 
visit.  
The responses to the SF-12 for each item will be tabulated by study visit using the Safety 
Population.  In addition, Physical and Mental Health Composite Scores (PCS & MCS) will be 
computed using the scores of twelve questions and range from 0 to 100, where a zero score 
indicates the lowest level of health measured by the scales and 100 indicates the highest level of 
health.
Responses to the HADS for each item will be tabulated by study visit. In addition, continuous 
and categorical (0-7: normal, 8-10: mild, 11-14: moderate, 15-21: severe) total scores based on 
the items related to depression and anxiety, will be summarized by study visit.  Each item in the 
questionnaire is scored from 0-3, with total scores between 0-21 for either depression or anxiety.  
Scores for the entire scale (emotional distress) will also be presented.  Total score for the entire 
scale range from 0 to 42, with higher scores indicating more distress.
Responses to the WPAI-GH for each item will be summarized by study visit. In addition, four 
main scores in relation to general health will be summarized by study visit. Scores will be 
calculated as absenteeism (percentage work time missed due to health), presenteeism (percent 
impairment while working due to health), work productivity loss (percent overall work 


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impairment due to health), and activity impairment (percent activity impairment due to health). 
The scores are percentages, with higher values indicating greater percentage impairment. Only 
respondents who report being employed full-time or part-time will contribute data for 
absenteeism, presenteeism, and overall work productivity loss. All respondents contribute data 
for activity impairment. 
Responses to the AE-QoL for each item will be tabulated by study visit.  In addition, the domain 
scores (functioning, fatigue/mood, fears/shame, nutrition) and total score will be summarized by 
study visit. Each item in the questionnaire is scored from 0-4, with domain and total scores 
calculated using a linear transformation to a 0-100 scale.
The responses to the AECT for each item will be tabulated by study visit. In addition, total score 
will be computed using the scores of all questions.
The responses to the TSQM-9 for each item will be tabulated by study visit. In addition, total 
score will be computed using the scores of 9 questions and range from 0 to 100, where a zero 
score indicates the lowest level of treatment satisfaction and 100 indicates the highest level of 
treatment satisfaction.
Response to the Global Impression of Treatment Response question will be tabulated by study 
visit. 
9.8.6
Analysis of Experience with Study Drug Self-administration
For each study population, the responses to each item of the Self-administration and 
subcutaneous injection survey will be tabulated by study visit. 
The number and percentage of subjects who performed study drug administration via study staff 
administration in-clinic, self-administration in-clinic, and self-administration at home will be 
tabulated for each study population by study visit. 
The number and percentage of subjects who had ever performed study drug administration via 
study staff administration in-clinic, self-administration in-clinic, or self-administration at home, 
as well as the total number of injections in each category, will be tabulated for each study 
population. Additionally, the number and percentage of subjects who received 0, 1-5, 6-10, 11-
20, or >20 study staff administration in-clinic, self-administration in-clinic, or self-administration 
at home will be summarized for each study population.
9.8.7
Analysis of Subject Experience with Pre-filled Syringe Use (if Available)
For each study population, the responses to each item of the pre-filled syringe usage 
questionnaire will be tabulated by study visit.
9.8.8
Analysis of Subject Response to Rescue medication
For each study population, number and percentage of subjects receiving each type of rescue 
medication (icatibant [Firazyr®] and ecallantide [Kalbitor®]) will be summarized. In addition, the 
total number of doses they received will also be summarized by type of rescue medication.


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The duration of HAE attacks treated with rescue medication will be summarized using 
descriptive statistics (n, median, 25% and 75% quartiles, and range) by type of rescue medication 
and rescue medication-treated attack number. 
9.9
Statistical/Analytic Considerations
9.9.1
Interim Analyses and Data Monitoring
Interim analyses may be conducted to support administrative decisions and/or regulatory 
reporting when a reasonable number of subjects have completed 12 months of consecutive 
exposure to DX-2930 across the combined DX-2930-03 and DX-2930-04 studies, and only after 
database lock of Study DX-2930-03. 
An independent Data Safety Monitoring Board (DSMB) has been established to provide an 
ongoing, independent review and assessment of the safety data for Study DX-2930-03. While an 
independent DSMB is not currently planned for this study, summary safety data from Study DX-
2930-04 may be reviewed by the DSMB established for Study DX-2930-03 as part of the 
collection of safety information available on DX-2930.
9.9.2
Multiple Comparisons/Multiplicity
No adjustment for multiple comparisons will be performed.  Any statistical testing will be 
considered exploratory.
9.9.3
Handling of Missing Data
All available data will be included in the analysis.  No imputation of missing data will be 
performed.
9.9.4
Adjustment for Covariates
The impact of baseline covariates on the time to the first investigator-confirmed HAE attack will 
be explored to identify and assess the importance of potential prognostic factors.
9.9.5
Multicenter Studies
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis.
9.9.6
Subgroup Analyses
Subgroup analyses are planned for the number of investigator-confirmed HAE attacks during the 
treatment period and adverse events using the Safety Population. The following subgroups will 
be used:
•
Age Group (<18, 18 to <40, 40 to <65, ≥65 years)
•
Sex (Male, Female)
•
Race Group (White, Other)
•
Weight Group (<50, 50 to <75, 75 to <100, ≥100 kg)


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•
BMI Group (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2)
•
Baseline HAE Attack Rate (1 to <2, 2 to <3, ≥3 attacks/month)
•
HAE Type (Type I, Type II, Unspecified)
•
Geographic Region (US, Canada, Jordan, Europe)
•
DX-2930 Administration Type (Health Care Provider, Self-administration)
•
History of laryngeal HAE attacks (history of laryngeal attack, no history of laryngeal attack)
9.9.7
Sensitivity Analyses
The following sensitivity analyses will be performed on the number of investigator-confirmed 
HAE attacks during the treatment period for each analysis population to evaluate the robustness 
of the results. Data summaries will parallel those described for the number of investigator-
confirmed HAE attacks during the treatment period efficacy endpoint.  
1. The analysis will be repeated counting HAE attacks occurring on Day 14 after administration 
of study drug through Day 924, instead of Day 0 to Day 924.  For this analysis, the period of 
analysis would be a subset of the treatment period, defined as Day 14 to Day 924.
2. The analysis will be repeated counting HAE attacks occurring on Day 28 after administration 
of study drug through Day 924, instead of Day 0 to Day 924. For this analysis, the period of 
analysis would be a subset of the treatment period, defined as Day 28 to Day 924.
3. The analysis will be repeated using all subject reported HAE attacks instead of limiting the 
analysis to those attacks that were investigator-confirmed.


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10. STUDY ADMINISTRATIVE STRUCTURE
The study administration structure is provided in Table 3. 
Table 3
Study Administrative Structure
Sponsor Contact:
, MD
, Clinical Development
300 Shire Way, Lexington, MA 02421 USA
Phone: 
Global Medical Monitor: 
, MD
300 Shire Way, Lexington, MA 02421 USA
Phone: 
Study Monitoring (US):
Rho, Inc.
6330 Quadrangle Drive, Chapel Hill, NC 27517
Phone: 
Study Monitoring (Jordan)
Triumpharma
07 Bldg., Al-Yarooty St.
P.O. Box 2233, Amman
11941, Jordan
Phone: 
, 
Study Monitoring (Canada)
Red Maple Trials Incorporated
1081 Carling Avenue, Suite 707
Ottawa, Ontario, Canada, K1Y4G2
Phone: 
Study Monitoring (Europe)
Dyax Corp., an indirect, wholly owned subsidiary of 
Shire plc.
300 Shire Way, Lexington, MA 02421
Phone:
10.1
Institutional Review Board/ Research Ethics Board/Independent Ethics Committee
The protocol and all protocol amendments must be signed and dated by the investigator and 
approved in writing by the IRB/REB/IEC in accordance with GCP prior to implementation. In 
addition, the IRB/REB/IEC must approve the written informed consent form, any consent form 
updates, subject recruitment materials (eg, advertisements), and any written information to be 
provided to subjects prior to implementation. The investigator must provide an annual report to 
the IRB/REB/IEC on the progress of the study including number of subjects enrolled, 
discontinued, and SAEs. It is required that a yearly review of the protocol by the IRB/REB/IEC 
be documented in a letter from the IRB/REB/IEC. The investigator must provide notification to 
the IRB/REB/IEC of the completion, termination or discontinuation of the study.


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10.2
Ethical Conduct of the Study
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor and 
the investigator abide by the principles of the International Conference on Harmonisation (ICH) 
guidelines on GCP, applicable local regulatory requirements, and the Declaration of Helsinki 
(Version 2008). The clinical study also will be carried out in keeping with national and local 
legal requirements [in accordance with United States Investigational New Drug (IND) 
regulations (21 CFR 56)].
10.3
Subject Information and Consent
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
according to the regulatory and legal requirements of the participating country. As part of this 
procedure, the investigator must explain orally and in writing the nature, duration, and purpose 
of the study, and the action of the drug in such a manner that the study subject is aware of the 
potential risks, inconveniences, or AEs that may occur. The study subject should be informed 
that he/she is free to withdraw from the study at any time. He/she will receive all information 
that is required by federal regulations and ICH guidelines. Subjects who are under the age of 18 
(or lower if age of consent is less than 18 in a specific country) and whose legal guardian or 
caretaker has provided written informed consent will provide their assent to participate. The 
investigator or designee will provide the Sponsor with a copy of the IRB/REB/IEC-approved 
informed consent form prior to the start of the study.
10.4
Subject Confidentiality
The anonymity of participating subjects must be maintained. Subjects will be specified on study 
documents by their subject number, initial or birth date (if allowed based on local data protection 
regulations), not by name. Documents that identify the subject (eg, the signed informed consent 
document) must be maintained in confidence by the investigator.
The investigator agrees not to use or disclose protected health information other than as 
permitted or required by the subject authorization or as required by law.
10.5
Study Monitoring
The Sponsor (or designee) will conduct a study initiation visit to verify the qualifications of the 
investigator, inspect the facilities, and inform the investigator of responsibilities and procedures 
for ensuring adequate and correct documentation.
The investigator must prepare and maintain adequate and accurate records of all observations 
and other data pertinent to the clinical study for each study participant. Frequent communication 
between the clinical site and the Sponsor is essential to ensure that the safety of the study is 
monitored adequately. The investigator will make all appropriate safety assessments on an 
ongoing basis. The Medical Monitor may review safety information as it becomes available 
throughout the study.


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All aspects of the study will be carefully monitored with respect to GCP and SOPs for 
compliance with applicable government regulations. The Study Monitor will be an authorized 
individual designated by the Sponsor. The Study Monitor will have access to all records 
necessary to ensure integrity of the data and will periodically review the progress of the study 
with the investigator.
10.6
Case Report Forms and Study Records
The investigator will ensure the accuracy, completeness, and timeliness of the data reported to 
the Sponsor. Data collection processes and procedures will be reviewed and validated to ensure 
completeness, accuracy, reliability, and consistency. A complete audit trail will be maintained of 
all data changes. The investigator or designee will cooperate with the Sponsor’s representative(s) 
for the periodic review of study documents to ensure the accuracy and completeness of the data 
capture system at each scheduled monitoring visit.
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the clinical sites by means of 
electronic or manual queries.
The investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE and concomitant medication reporting, raw data collection forms, 
etc.) designed to record all observations and other pertinent data for each subject receiving 
randomized study drug.
The investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB/REB/IEC to have direct access to all documents pertaining to 
the study.
A Trial Master File will be maintained by the Sponsor (or designee). All documents and other 
materials that pertain to the conduct of the trial quality of the data, and compliance with GCPs 
will be collected in the Trial Master File.
10.7
Data Safety Monitoring Board
An independent Data Safety Monitoring Board (DSMB) has been established to provide 
ongoing, independent review and assessment of the safety data for Study DX-2930-03. While an 
independent DSMB is not currently planned for this study, summary safety data from Study DX-
2930-04 may be reviewed by the DSMB established for Study DX-2930-03 as part of the 
collection of safety information available on DX-2930. 
The DSMB will adhere to a prospectively determined Charter, which will be written by the 
Sponsor and approved by the DSMB. The Charter will define the responsibilities of the DSMB 
and Sponsor, the number and timing of the DSMB meetings, the conduct of the meetings, and 
the data sets to be reviewed by the DSMB. Further details regarding the DSMB can be found in 
the DSMB charter.


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10.8
Protocol Violations/Deviations
The investigator will be instructed not to deviate from the protocol, except where necessary to 
eliminate an immediate hazard to study participants. Should other unexpected circumstances 
arise that will require deviation from protocol-specific procedures, the investigator should 
contact their Sponsor representative to discuss the appropriate course of action. 
The investigator should document all protocol deviations/violations in the subject’s eCRF and 
source documents or the Investigator Site File if appropriate. In the event of a significant 
deviation/violation, the investigator should notify the Sponsor representative. Significant 
deviations/violations include, but are not limited to those that increase the health risk to the 
subject, or confound interpretation of primary study assessments. The investigator will promptly 
report all changes in research activity and all unanticipated problems involving risks to human 
subjects or others to his or her IRB/REB/IEC.
10.9
Premature Closure of the Study
If the Sponsor, investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated overall or at a specific site after appropriate consultation between 
the Sponsor and the investigator(s). In addition, a decision on the part of the Sponsor to stop the 
study, or to suspend or discontinue development of the investigational product may be made at 
any time. Conditions that may warrant termination of the study or site include, but are not limited 
to, the following:
•
The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in 
the study
•
Failure of the investigator to comply with pertinent global regulations
•
Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities
•
Insufficient adherence by the investigator to protocol requirements
10.10 Access to Source Documentation and On-Site Audits
Regulatory agencies may request access to all study records, including source documents, for 
inspection and copying, in keeping with country regulations. The investigator should 
immediately notify the Sponsor representative of any announced or unannounced regulatory 
agency inspections. An auditing inspection may also be conducted by the Sponsor representative 
or designee. Any aspect of the trial may be subject to audit by the Sponsor and/or inspection by 
regulatory authorities or the IRB/REB/IEC. Such audits/inspections may take place at the 
Sponsor’s site(s), the CRO, or at the clinical sites, including laboratories, pharmacies and any 
other facilities used for the study. 


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The investigator will be responsible for the accuracy of the data entered in the eCRF. The 
investigator will permit the designated Sponsor representatives and regulatory bodies to have 
direct access to the source documents to verify data represented in the eCRF.
10.11 Data Generation and Analysis
This study will be performed in accordance with regulatory requirements outlined in Food and 
Drug Administration (FDA) 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, 21 CFR Part 312 
and 21 CFR Part 11 as well as the ICH GCP E6 Guidelines. The study monitors will meet with 
the investigators and staff shortly before the start of the trial to review the procedures for study 
conduct and documentation. During the study, the monitors will visit the sites to verify record 
keeping and adherence to the protocol. For this study, eCRFs will be used. The monitors will 
conduct 100% source document verification by comparing the eCRFs with the source documents 
to ensure accuracy and consistency. Edit check programs, other forms of electronic validation, 
manual listings and a query process will be executed to verify the accuracy of the database. The 
EDC system will maintain a full audit trail of electronic data changes. Access to all source 
documentation will be made available for monitoring and audit purposes.
10.12 Retention of Data
All source documents (eg, informed consent forms, laboratory reports, progress notes, medical 
histories, physical and diagnostic findings, diagnosis and pharmacy records, and DX-2930 
dispensing/disposition records) that support data in the eCRFs of each study subject must be 
retained in the files of the responsible investigator.
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the DX-2930. However, these documents 
should be retained for a longer period if required by the applicable legal requirements.
If the responsible investigator retires, relocates or for any other reason withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor representative must be notified in writing of the name and 
address of the new custodian, prior to the transfer.
10.13 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the Sponsor. The 
following information is collected: any significant payments from the Sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the Sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).


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10.14 Publication and Disclosure Policy
All information concerning DX-2930, Sponsor operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information, supplied to the 
investigator by a Sponsor representative and not previously published, is considered confidential 
and remains the sole property of the Sponsor. The investigator must agree to use this information 
only to accomplish this study, and must not use it for other purposes without the Sponsor’s 
advanced written consent. A description of this clinical study may also be available on the 
externally facing public websites and registries. A summary of the study results may be 
potentially disclosed as per local and country specific requirements.
The information developed in this study will be used by the Sponsor in connection with the 
continued development of DX-2930 and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. To permit the information derived from the 
clinical studies to be used, the investigator is obligated to provide the Sponsor with all data 
obtained in the study.


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11. REFERENCE LIST
Bennett, G & Craig, T 2015. Hereditary angioedema with a focus on the child. Allergy Asthma 
Proc, 36, 70-3.
Bharmal, M, Payne, K, Atkinson, MJ, Desrosiers, M-P, Morisky, DE & Gemmen, E 2009. 
Validation of an abbreviated Treatment Satisfaction Questionnaire for Medication 
(TSQM-9) among patients on antihypertensive medications. Health and Quality of Life 
Outcomes, 7, 36.
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deficiency. Arch Intern Med, 163, 1229-35.
Bork, K, Hardt, J & Witzke, G 2012. Fatal laryngeal attacks and mortality in hereditary 
angioedema due to C1-INH deficiency. J Allergy Clin Immunol, 130, 692-7.
Bork, K, Meng, G, Staubach, P & Hardt, J 2006. Hereditary angioedema: new findings 
concerning symptoms, affected organs, and course. Am J Med, 119, 267-74.
Bork, K, Siedlecki, K, Bosch, S, Schopf, RE & Kreuz, W 2000. Asphyxiation by laryngeal 
edema in patients with hereditary angioedema. Mayo Clin Proc, 75, 349-54.
Bygum, A 2009. Hereditary angio-oedema in Denmark: a nationwide survey. The British journal 
of dermatology, 161, 1153-8.
Craig, T, Aygoren-Pursun, E, Bork, K, Bowen, T, Boysen, H, Farkas, H, Grumach, A, Katelaris, 
CH, Lockey, R, Longhurst, H, Lumry, W, Magerl, M, Martinez-Saguer, I, Ritchie, B, 
Nast, A, Pawankar, R, Zuraw, B & Maurer, M 2012. WAO Guideline for the 
Management of Hereditary Angioedema. World Allergy Organ J, 5, 182-99.
Davis, AE, 3rd 2006. Mechanism of angioedema in first complement component inhibitor 
deficiency. Immunology and allergy clinics of North America, 26, 633-51.
Farkas, H 2010. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma 
Clin Immunol, 6, 18.
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Hereditary angioedema in the German-speaking region. Hautarzt, 49, 114-22.
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Kaplan, AP & Joseph, K 2010. The bradykinin-forming cascade and its role in hereditary 
angioedema. Ann Allergy Asthma Immunol, 104, 193-204.
Kenniston, JA, Faucette, RR, Martik, D, Comeau, SR, Lindberg, AP, Kopacz, KJ, Conley, GP, 
Chen, J, Viswanathan, M, Kastrapeli, N, Cosic, J, Mason, S, Dileo, M, Abendroth, J, 
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Reilly, MC, Zbrozek, AS & Dukes, EM 1993. The validity and reproducibility of a work 
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Staubach, P & Maurer, M 2014. Development and validation of the Urticaria Control 
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Weller, K, Groffik, A, Magerl, M, Tohme, N, Martus, P, Krause, K, Metz, M, Staubach, P & 
Maurer, M 2012. Development and construct validation of the angioedema quality of life 
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Zuraw, BL 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.
Zuraw, BL, Bernstein, JA, Lang, DM, Craig, T, Dreyfus, D, Hsieh, F, Khan, D, Sheikh, J, 
Weldon, D, Bernstein, DI, Blessing-Moore, J, Cox, L, Nicklas, RA, Oppenheimer, J, 
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12. APPENDICES
Appendix 1
Protocol History
Appendix 2
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Tables 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infection Diseases)
Appendix 3
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Tables 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infection Diseases)
Appendix 4
HAE Attack Assessment and Reporting Procedures (HAARP)
Appendix 5
Summary of Pivotal Study DX-2930-03 in Subjects with HAE


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APPENDIX 1
Protocol History
Amendment Summary and Rationale
Amendment 1 to Protocol DX-2930-04 expanded upon the scope of the original protocol. Key 
revisions included extension of the study from 6 months to approximately 1 year, a 
corresponding increase in the number of study drug doses a subject may receive, allowance for 
subjects to elect self-administration both at and away from the site after completion and 
understanding of training, addition of 3 tertiary objectives, and revision of statistical 
methodology to accommodate changes in efficacy and other endpoints to allow for a more robust 
analysis.
Amendment 2 provided a number of clarifications and corrections. 
Noteworthy changes to the protocol are captured in the tables below. Additional minor revisions 
in grammar, spelling, punctuation, and format have been made for clarity and are not reflected in 
the summary of changes.
Document
Date
Global/Country/Site Specific
Original Protocol
Amendment 1.0
Amendment 2.0
14 December 2015
27 June 2016
20 Jan 2017
Global
Global
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
27 June 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
Administrative updates related to changes in parties responsible for the study (eg, 
Sponsor, Sponsor Contact/Medical Director, and Medical Monitor) were made to 
reflect current information.
Title page, Protocol 
Signature Page, Section 10 
Study Administrative 
Structure
Study location was updated to reflect study sites planned across regions rather 
than individual countries.
Synopsis Study Location
The tertiary objective to evaluate the effect of DX-2930 on health-related quality 
of life (QoL) was rephrased for clarity.
Synopsis Tertiary 
Objectives and Section 2.3 
Tertiary Objectives
The tertiary objective to characterize the Pharmacokinetic (PK) and 
Pharmacodynamic (PD) profile of DX-2930 was clarified to indicate 
administration would be subcutaneous.
Synopsis Tertiary 
Objectives and Section 2.3 
Tertiary Objectives
Three additional tertiary objectives were added to obtain more comprehensive 
information:

To evaluate safety and efficacy in the non-rollover population of 
switching from long-term prophylactic (LTP) treatment to DX-2930

To evaluate breakthrough attack characteristics while receiving DX-2930 
compared to historical baseline
Synopsis Tertiary 
Objectives and Section 2.3 
Tertiary Objectives


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Amendment Number
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Amendment Date
27 June 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change

To evaluate subject experience with self-administration of DX-2930 
including ease of SC administration of DX-2930
The number of non-rollover subjects allowed in DX-2930-04 was increased to at 
least 50 subjects with up to a maximum of 100 subjects.
Synopsis Study Design, 
Section 3.1.1 Overview
The number of non-rollover subjects was increased from at least 50 subjects up to 
a maximum of 100 subjects. Enrollment of subjects 12 to 17 years age was revised 
to be at least 15 including the estimated 10 rollover subjects from Study DX-2930-
03.  Therefore, the total enrollment for the study was updated to be at least 150, 
but not more than 250.
Synopsis Study Population 
and Section 4.1 Study 
Population
Revised to allow non-rollover subjects to continue long-term prophylactic HAE 
therapy with C1-INH, androgens or anti-fibrinolytics, for 2 weeks; initiation of 
tapering and discontinuation of LTP must occur within 3 weeks of receiving the 
first dose of DX-2930.
Synopsis Study Design, 
Section 3.1.1 Overview
Clarified that rollover subjects who experience their first attack outside the 
window of accepted scheduled visits are allowed to have an extra (unscheduled) 
study visit.
Synopsis Treatment 
Period, Section 3.1.1 
Overview
The study has been extended in duration from 6 months to approximately one year 
and subsequently the number of doses of study drug a subject may receive has 
been increased. 
Synopsis Duration of 
Treatment and Duration of 
Study for Individual 
Subjects, Study Activities 
Schedule
The study was expanded to allow subjects to self-administer doses of DX-2930 
without supervision after receiving the first 2 doses of DX-2930 at the study site.  
Subjects must be considered suitable candidates; receive training; confirm 
understanding; and record specific information regarding subcutaneous 
administration and experience with self-administration.  Subjects who elect to self-
administer investigational product will be provided with supplies and be instructed 
on investigational product transport, storage, treatment compliance, and retention 
of all used and unused product vials for drug accountability purposes. Written 
instructions on DX-2930 handling and self-administration procedures will be 
provided to trained subjects prior to initiating self-administration.  Vital signs will 
not be monitored for doses self-administered away from the investigational site.  
Synopsis Self-
Administration, Section 
3.1.1


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Amendment Number
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Amendment Date
27 June 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
Since no data on embryo-fetal development toxicity are available for DX-2930, 
the clinical trial facilitation group’s (CTFG) provided recommendations related to 
contraception and pregnancy testing.  The inclusion criterion for contraception 
requirements was modified to emphasize the use of highly effective contraceptive 
measures and details for allowances (including stable estrogen doses) during 
treatment and until the end of relevant systemic exposure for women of 
childbearing potential. It was also clarified that the use of a male condom with or 
without spermicide or cervical cap, diaphragm, or sponge with spermicide or a 
combination (double-barrier methods) is not considered highly effective.  
Additional pregnancy tests (urine or serum) were also added for monitoring of 
pregnancy during treatment.
Synopsis Criteria for 
Inclusion, Section 4.2
Management of acute attacks was clarified to indicate that administration of the 
investigational product and study procedures will continue without alteration to 
the protocol-specified study schedule, even if the subject has HAE symptoms or 
receives treatment for an HAE attack.
Synopsis, Management of 
Acute Attacks, Section 
5.4.1.1
Additional information was added to the study collection of data for HAE attacks 
to obtain more comprehensive information.
Section 6.4
Efficacy endpoints were revised from mean rates to number of attacks. 
Synopsis Statistical 
Methodology, Section 
9.6.2
Where appropriate, “Dyax” was replaced with the generic term of “the Sponsor.”
Entire protocol Sections 1-
10
A section on management of HAE attacks was added to Study Treatment(s).
Synopsis Management of 
Acute Attacks, Section 
5.4.1.1
The study has been extended to incorporate an additional 6 months of treatment 
with DX-2930.  Therefore the Study Activities Schedule has been revised to 
accommodate study assessments at dosing Visits 14-26.  Follow-up visits 
(following end of treatment) are now occurring at Days 264, 378, and 392 (Visits 
27, 28, and 29).
Study Activities Table, 
Section 7
The exclusion criterion prohibiting dosing with an investigational drug or 
exposure to an investigational device with 4 weeks prior to screening was clarified 
to not include DX-2930 or other HAE therapies.
Synopsis Exclusion 
Criteria, Section 4.3
The analysis population was clarified and is based on subjects who receive any 
exposure to DX-2930 in this study.
Synopsis Analysis 
Populations, Section 9.4
Data analysis and statistical methodology was revised to accommodate changes in 
efficacy or other study endpoints and to allow for more robust analyses.  
Synopsis Statistical 
Methodology  , Section 9.6
An interim analysis was added and will be conducted when at least 35 subjects 
complete 12 months of DX-2930 exposure.
Synopsis Interim Analysis 
and Data Monitoring, 
Section 9.9.1


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Amendment Number
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Amendment Date
27 June 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
The efficacy evaluation period was updated to begin at Day 0 instead of Day 14 to 
be consistent with the intent-to-treat analysis principle.
Synopsis Statistical 
Methodology, Section 
9.6.2
Quality of life assessments were revised and expanded to include EQ-5D-5L, SF-
12, HADS, WPAI-GH and AE-QoL.
Synopsis Quality of Life 
Assessments, Section 6.14
An injection report and self-administration and SC injection survey were added to 
the study activities schedule and study procedures.
Synopsis DX-2930 
Injection Report and Self-
Administration and 
Subcutaneous Injection 
Survey, Section 6.15
Details on collection of prior medications were added to indicate documentation 
should extend to 4 weeks prior to study screening for non-rollover subjects.
Section 5.4
Information on packaging and labeling was expanded to detail the supplies for 
self-administration.
Section 5.7
Clarifying language was added to subject information and consent to indicate that 
subjects under 18 years will provide their assent to participate in the study if their 
legal guardian or caretaker has provided written informed consent.
Section 10.3 Subject 
Information and Consent
A new section was added for a Data Safety Monitoring Board (DSMB) who will 
provide an independent review of safety
Section 10.7 Data Safety 
Monitoring Board
To ensure subject safety, information on premature closure of the study was added 
to indicate some examples of conditions under which the study may be terminated 
overall or at a specific site after consultation between the Sponsor and 
investigators.
Section 10.9 Premature 
Closures of the Study
Financial disclosure language was updated to be consistent with 21 CFR 54 2(b) 
(1998).
Section 10.13 Financial 
Disclosure
Study Results/Publication Policy was updated to include language regarding 
posting of appropriate study information on applicable websites by the Sponsor. 
Additional detail on publication and disclosure of study information was added to 
indicate potential for public information.
Section 10.14 Publication 
and Disclosure Policy
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
20 Jan 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Updated administrative information to reflect current contact information, 
including contact information for the 24-Hour Global Medical Monitor and 
Title Page, Section 
6.16.5.5, Section 10


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Amendment Number
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Amendment Date
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Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Back-Up Global Medical Monitor and Sponsor Contact.
Included clarifying note that female rollover subjects (those who previously 
participated in Study DX-2930-03) of childbearing potential may continue to use 
the effective birth control method used during Study DX-2930-03. 
Synopsis
Introduced the international nonproprietary name “lanadelumab.”
Section 4.2
Clarified that sites will call subjects within approximately 3 days of planned off-
site self-administrations.
Synopsis, Section 5.1
Clarified that adolescent subjects should complete the WPAI-GH questionnaire 
and use the term “school” instead of “work” when filling out this questionnaire.  
These data will be analyzed separately.
Synopsis, Section 4.1, 
Section 5.1, Section 5.6
Refined language on interim analyses options to allow for interim analyses to be 
performed as appropriate for regulatory reporting and/or internal administrative 
decisions.
Section 6.14.3
The following editorial changes were made to remove inconsistencies in the text and to ensure all agreed 
changes from Amendment 1 and administrative letters are accurately presented across all sections
Removed the duplicate Study Activities Schedule from Appendix 1 and changed 
in-text references/linking to the Study Activities Schedule from Appendix 1, to 
ensure a single location for the Study Activities Schedule.
Entire protocol
Corrected the numbers in Figure 1 to correctly present the length of treatment 
period.
Figure 1
Corrected text regarding the treatment period duration: the treatment period is 
364 days, with the last dose of study drug administered on Day 350.
Synopsis, entire protocol
Added text from Section 3.1.1. to the synopsis for clarity; specifically, that the 3rd
dose must be administered at the next pre-defined study visit according to the 
Study Activities Schedule.
Synopsis
Clarified that subjects in Study DX-2930-03 can be consented for enrollment in 
Study DX-2930-04 on or after Day 168 of Study DX-2930-03. 
Synopsis, Table 1  
(footnote “5”), Section 
3.1.1, Section 6.1,Section 
7.2
Revised text in Section 3.1.1 to match correct text in Synopsis, including text 
regarding standard of care treatment for subjects who experience an acute attack 
of HAE during the study.
Synopsis, Section 3.1.1
Updated wording regarding the enrollment number for non-rollover subjects from 
“up to a maximum of 100” to “approximately 100” in total.
Synopsis, Section 3.1.1, 
Section 4.1
Corrected text regarding the follow-up period: the follow-up period is 4 weeks 
from the last visit of the protocol-defined treatment period. Removed inconsistent 
text that erroneously mentioned an 8-week follow up period.
Synopsis, 
Removed text indicating that the Sponsor would provide ancillary supplies to 
sites since the sites are responsible for sourcing them.
Section 3.1.1, Section 3.4, 
and Section 5.2
Clarified text to align with Study Activities Schedule; specifically, subject 
surveys on their experience with SC and self-administration injections of DX-
Section 5.7


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Amendment Number
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Amendment Date
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Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
2930 are to be completed by the subject during the study.
Clarified text to align with Study Activities Schedule; specifically, that vital signs 
will be monitored both prior to dosing and at 1 hour post-dosing when dosing 
occurs at the investigational site, with a ±15 minutes window for all vital signs. 
Vital signs are not monitored when subjects elect to self-administer study drug 
away from the site.
Section 6.5, Section 7 
itemization per visit
Clarified text to align with Study Activities Schedule; specifically, that weight is 
collected during each physical exam.
Table 1, Section 6.6, 
Section 7
Clarified text to align with Study Activities Schedule; specifically, that height is 
only collected at the Screening visit.
Table 1, Section 6.6, 
Section 7.1
Clarified text to align with Study Activities Schedule; specifically, that 
pregnancy tests performed on Day 0 must be urine-based to confirm eligibility 
prior to dosing while subsequent pregnancy tests can be urine or serum-based.
Section 6.8.1.5
Removed outdated contact information from safety reporting text.
Section 6.16.5.5
Removed remnant text regarding the requirement to complete a 2-week wash-out 
period before entering the treatment period for non-rollover subjects on LTP for 
HAE. Washout period does not exist for non-rollover subjects.
Section 7.1
Removed remnant text regarding the requirement for urinalysis for Visits 14, 17, 
20, and 23. Urinalysis is not required at these visits.
Section 7.16, Section 
7.19, Section 7.22, and 
Section 7.25
Removed text indicating a subject could self-administer study drug at their home 
or other agreed upon location and that no monitoring of vital signs will be 
performed for Visit 17 since this is a mandated investigational site visit.
Section 7.19
Removed safety analysis category called “pretreatment group” since a 
pretreatment period does not exist in this study.
Section 9.7.1


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APPENDIX 2
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
(Modified) (US National Institutes of Health; National Institute of 
Allergy and Infectious Diseases)


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials.  This toxicity table is not comprehensive and 
should not be applied directly to all trials.   
  
When selecting a toxicity table, the following are some of the items that must be taken into 
consideration: 
  
• 
The population being studied  
o 
Does the clinical trial evaluate healthy subjects, subjects with a particular disease 
or condition?  
• 
The stage of test article development  
o 
Is the clinical trial a Phase I, II, III or IV? 
• 
The type of test article  
o 
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent?  
• 
The prior human and preclinical experience with the test article 
o 
Are there any specific findings that require adjustment of the toxicity table?  
  
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal 
values at the single site. Multi-center clinical trials should reconcile among their laboratory normal 
values when evaluating a healthy volunteer population. 
  
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when 
selecting or developing a toxicity table for a DMID-sponsored trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to 
estimate grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to 
moderate 
limitation 
in 
activity - some assistance may be needed; no or minimal 
medical intervention/therapy required 
GRADE 3 
Severe  
 
Marked limitation in activity, some 
assistance usually required; medical intervention/therapy 
required, hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme 
limitation 
in 
activity, 
significant 
assistance 
required; 
significant 
medical 
intervention/therapy required, hospitalization or hospice 
care probable 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening 
include, but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, 
disseminated intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, 
severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s 
Common Toxicity Criteria (CTC), and World Health Organization (WHO)) have 
been adapted for use by the Division of Microbiology and Infectious Diseases 
(DMID) and modified to better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to 
the “Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
HEMATOLOGY 
 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hemoglobin 
 
9.5 - 10.5 gm/dL 
 
8.0  - 9.4gm/dL 
 
 6.5 - 7.9 gm/dL 
 
< 6.5 gm/dL 
 
Absolute Neutrophil Count 
 
1000-1500/mm3 
 
750-999/mm3 
 
500-749/mm3 
 
<500/mm3 
 
Platelets 
 
75,000-
99,999/mm3 
 
50,000-
74,999/mm3 
 
20,000-49,999/mm3 
 
<20,000/mm3 
WBCs  
11,000-13,000/ 
mm3 
13,000- 
15,000 /mm3 
15,000- 
30,000/mm3 
>30,000 or 
<1,000 /mm3 
% Polymorphonuclear 
Leucocytes + Band Cells 
 > 80% 
90 – 95% 
>95% 
---------- 
 
 
Abnormal 
Fibrinogen 
Low: 
100-200 mg/dL  
 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL  
 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
 
    ---------- 
Fibrinogen 
associated with 
gross bleeding or 
with 
disseminated 
coagulation 
 
Fibrin Split Product 
 
20-40 mcg/ml 
 
41-50 mcg/ml 
 
51-60 mcg/ml 
 
> 60 mcg/ml 
 
Prothrombin  
Time (PT) 
 
1.01 - 1.25 x ULN 
 
1.26-1.5 x ULN 
 
1.51 -3.0 x ULN 
 
>3 x ULN 
 
Activated Partial 
Thromboplastin (APPT) 
 
1.01 -1.66 x ULN 
 
1.67 - 2.33 x 
ULN 
 
2.34 - 3 x ULN 
 
> 3 x ULN 
 
Methemoglobin 
 
5.0 - 9.9 % 
 
10.0 - 14.9 % 
 
15.0 - 19.9% 
 
> 20.0 % 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CHEMISTRIES 
   
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hyponatremia 
 
130-135 mEq/L 
 
 123-129 
mEq/L 
 
116-122 mEq/L 
 
< 116 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypernatremia 
 
146-150 mEq/L 
 
151-157 mEq/L 
 
158-165 mEq/L 
 
> 165 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypokalemia 
 
3.0 - 3.4 mEq/L 
 
2.5 - 2.9 mEq/L 
 
2.0 - 2.4 mEq/L  
or intensive 
replacement 
therapy or 
hospitalization 
required 
 
< 2.0 mEq/L or 
abnormal 
potassium with 
 paresis, ileus or 
life-threatening 
arrhythmia 
 
Hyperkalemia 
 
5.6 - 6.0 mEq/L 
 
6.1 - 6.5 mEq/L 
 
6.6 - 7.0 mEq/l 
 
> 7.0 mEq/L 
or abnormal 
potassium  with 
life-threatening 
arrhythmia 
 
Hypoglycemia 
 
55-64 mg/dL 
 
40-54 mg/dL 
 
30-39 mg/dL 
 
<30 mg/dL or 
abnormal glucose 
with mental 
status changes or 
coma 
 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
 
116 - 160 mg/dL 
 
161- 250 
mg/dL 
 
251 - 500 mg/dL 
 
> 500 mg/dL or 
abnormal glucose 
with ketoacidosis 
 or seizures 
 
Hypocalcemia 
(corrected for albumin) 
 
8.4 - 7.8 mg/dL 
 
7.7 - 7.0 mg/dL 
 
6.9 - 6.1 mg/dL 
 
< 6.1 mg/dL 
or abnormal 
calcium with life 
threatening 
arrhythmia or 
tetany 
 
 
 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
CHEMISTRIES (continued) 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hypercalcemia 
(correct for albumin) 
 
10.6 - 11.5 mg/dL 
 
11.6 - 12.5 
mg/dL 
 
12.6 - 13.5 mg/dL 
 
> 13.5 mg/dL or 
abnormal calcium 
with life 
threatening 
arrhythmia 
 
Hypomagnesemia 
 
1.4 - 1.2 mEq/L 
 
1.1 - 0.9 mEq/L 
 
0.8 - 0.6 mEq/L 
 
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
 
Hypophosphatemia 
 
2.0 - 2.4 mg/dL 
 
1.5 -1.9 mg/dL 
or 
replacement Rx 
required 
 
1.0 -1.4 mg/dL  
intensive therapy  
or 
hospitalization 
required 
 
< 1.0 mg/dL or 
abnormal 
phosphate with 
life-threatening 
arrhythmia 
 
Hyperbilirubinemia (when 
accompanied by any increase 
in other liver function test) 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x 
ULN 
 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
 
Hyperbilirubinemia (when 
other liver function are in the  
normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x 
ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
 
BUN 
 
1.25 - 2.5 x ULN 
 
2.6 - 5 x ULN 
 
5.1 - 10 x ULN 
 
> 10 x ULN 
Hyperuricemia (uric acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
 
 
 
Creatinine 
 
1.1 - 1.5 x ULN  
 
1.6 - 3.0 x ULN 
 
3.1 - 6 x ULN 
 
> 6 x ULN or 
dialysis required 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ENZYMES 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
AST (SGOT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
ALT (SGPT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
GGT 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
Alkaline Phosphatase 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
Amylase 
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
Lipase  
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
 
 
URINALYSIS 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Proteinuria 
 
1+ 
 or  
200 mg - 1 gm 
loss/day 
 
2-3+  
or  
1- 2 gm 
loss/day 
 
4+ 
 or  
2-3.5 gm loss/day 
 
nephrotic 
syndrome  
or 
> 3.5 gm loss/day 
Hematuria 
 
microscopic only 
<10 rbc/hpf 
 
gross, no clots 
>10 rbc/hpf 
 
gross, with or 
without clots, OR 
red blood cell casts 
 
obstructive or 
required 
transfusion 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CARDIOVASCULAR 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cardiac Rhythm 
 
 
 
asymptomatic, 
transient signs, 
no 
Rx required 
 
recurrent/persistent; 
symptomatic Rx 
required 
 
unstable 
dysrythmia; 
hospitalization 
and treatment 
required 
 
Hypertension 
 
transient increase 
> 20 mm/Hg; no 
treatment 
 
recurrent, 
chronic 
increase 
 > 20mm/Hg. 
/treatment 
required 
 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
 
end organ 
damage or 
hospitalization 
required 
 
Hypotension 
 
transient 
orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
 
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable 
with oral fluid 
treatment 
 
requires IV fluids; 
no hospitalization 
required 
 
mean arterial 
pressure  
<60mm/ Hg or 
end organ 
damage or shock;   
requires 
hospitalization 
and vasopressor 
treatment 
 
Pericarditis 
 
minimal effusion 
 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
 
symptomatic 
effusion; pain; 
EKG changes 
 
tamponade; 
pericardiocentesis 
or surgery 
required 
 
Hemorrhage, Blood Loss 
 
microscopic/occult 
 
mild, no 
transfusion 
 
gross blood loss; 
1-2 units transfused 
 
massive blood 
loss; > 3 units 
transfused 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
RESPIRATORY 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cough  
 
transient- no 
treatment 
 
persistent 
cough; 
treatment 
responsive 
 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
 
Bronchospasm, Acute 
 
transient; no 
treatment; 
70% - 80% FEV1  
of peak flow 
 
requires 
treatment; 
normalizes with 
bronchodilator; 
FEV1 50% - 
70% 
(of peak flow) 
 
no normalization 
with 
bronchodilator; 
FEV1 25% - 50% 
of peak flow; or  
retractions present 
 
cyanosis: FEV1 
< 25% 
of peak flow or 
intubation 
necessary 
Dyspnea 
 
dyspnea on 
exertion 
dyspnea with 
normal activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
GASTROINTESTINAL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Nausea 
 
mild or transient; 
maintains 
reasonable intake 
 
moderate 
discomfort; 
intake 
decreased 
significantly; 
some activity 
limited 
 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
 
Vomiting 
 
1 episode in 24 
hours 
2-5 episodes in 
24 hours 
>6 episodes in 24 
hours or needing 
IV fluids 
 
 
 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral 
nutrition 
 
Constipation 
 
requiring stool 
softener or dietary 
modification 
requiring 
laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
 
obstruction or 
toxic megacolon 
 
Diarrhea 
 
mild or transient; 
3-4 loose 
stools/day or mild 
diarrhea last < 1 
week 
 
moderate or 
persistent; 5-7 
loose stools/day 
or diarrhea 
lasting >1 week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
 
 
hypotensive 
shock or 
physiologic 
consequences 
requiring 
hospitalization   
 
Oral Discomfort/Dysphagia 
 
mild discomfort; 
no difficulty 
swallowing 
 
some limits on 
eating/drinking 
 
eating/talking very 
limited; unable to 
swallow solid 
foods 
 
unable to drink 
fluids; requires 
IV fluids 
 
 
Shire
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
NEUROLOGICAL 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Neuro-Cerebellar 
 
slight 
incoordination 
dysdiadochokinesis 
 
intention 
tremor, 
dysmetria, 
slurred speech; 
nystagmus 
 
locomotor ataxia 
 
incapacitated 
 
Psychiatric 
 
mild anxiety or 
depression 
 
moderate 
anxiety or 
depression; 
therapy 
required; 
change in 
normal routine 
 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
 
acute psychosis 
requiring 
hospitalization;  
or suicidal 
gesture/attempt 
or hallucinations 
 
Muscle Strength 
 
subjective 
weakness 
no objective 
symptoms/ signs 
 
mild objective  
signs/symptoms 
no decrease in 
function 
 
objective weakness 
function limited 
 
paralysis 
Paresthesia (burning, tingling, 
etc.) 
mild discomfort; 
no treatment  
required 
moderate 
discomfort; 
non-narcotic 
analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision 
and/or hearing 
moderate 
impairment 
(mod decreased 
sensation, e.g., 
vibratory, 
pinprick, 
hot/cold to 
ankles) and/or 
joint position or 
mild 
impairment that 
is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod degree 
in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs 
and trunk; 
paralysis;  or 
seizures 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
MUSCULOSKELATEL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Arthralgia 
(joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics 
and/or pain 
interfering with 
function but not 
with activities 
of daily living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain 
with 
inflammation, 
erythema or 
joint swelling – 
interfering with 
function, but 
not with 
activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of  
activity 
muscle 
tenderness (at 
other than 
injection site) 
or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shire
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Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
Page 138


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
SKIN 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, 
dry 
desquamation 
vesiculation or 
moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, 
mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected 
Stevens-Johnson 
or  necrosis 
requiring surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate 
itching at 
injection 
extremity 
itching over entire 
body 
 
 
 
 
SYSTEMIC 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Allergic Reaction 
 
pruritus without 
rash 
 
localized 
urticaria 
 
generalized 
urticaria; 
angioedema 
 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, 
moderate; 
treatment 
required 
severe; responds to 
initial narcotic 
therapy 
intractable; 
requires repeated 
narcotic therapy 
 
Fever: oral 
 
37.7 - 38.5 C or  
100.0 - 101.5 F 
 
38.6 - 39.5 C or 
101.6 - 102.9 F 
 
39.6 - 40.5 C or 
103 - 105 F 
 
> 40 C or 
> 105 F 
 
Fatigue 
 
normal activity 
reduced < 48 hours 
 
 normal activity 
decreased 25- 
50% > 48 hours 
 
normal activity 
decreased > 50% 
can’t work 
 
unable to care for 
self 
 
 
 
 
 
 
 
 
 
 
Shire
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Clinical Trial Protocol Amendment 3
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APPENDIX 3
National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (Modified) (US National Institutes of Health; National 
Institute of Allergy and Infectious Diseases


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 
 
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials.  This toxicity table is not comprehensive and should 
not be applied directly to all trials.   
  
When selecting a toxicity table, the following are some of the items that must be taken into consideration: 
  
• 
The population being studied  
o 
Does the clinical trial evaluate healthy subjects, subjects with a particular disease or 
condition?  
• 
The stage of test article development  
o 
Is the clinical trial a Phase I (is it for the fisrt time in human subjects?) , II, III or IV? 
• 
The type of test article  
o 
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent?  
• 
The prior human and preclinical experience with the test article 
o 
Are there any specific findings that require adjustment of the toxicity table?  
o 
Has it been approved for this indication in adult population? 
  
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal values at the 
single site. Multi-center clinical trials should reconcile among their laboratory normal values when 
evaluating a healthy volunteer population. 
  
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when selecting 
or developing a toxicity table for a DMID-sponsored trial. 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Trial Protocol Amendment 3
DX-2930-04
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to moderate limitation in activity - 
some assistance may be needed; no or minimal medical 
intervention/therapy required 
GRADE 3 
Severe  
 
Marked 
limitation 
in 
activity, 
some 
assistance usually required; medical intervention/therapy required, 
hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme limitation in activity, significant 
assistance required; significant 
medical 
intervention/therapy 
required, hospitalization or hospice care probable 
GRADE 5                              Death 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening include, 
but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria (CTC), and World Health Organization (WHO)) have been adapted for 
use by the Division of Microbiology and Infectious Diseases (DMID) and modified to 
better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
Shire
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DX-2930-04
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 
(Selected Values for children less than or equal  
to 3 months of age – does not apply for preterm infants)  
 
 
For all parameters not listed on this table, please refer 
 to the DMID Toxicity Table for children > 3 months of age. 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin 
1-7 days old 
13.0-14.0 gm/dL 
12.0-12.9 gm/dL 
<12 gm/dL 
Cardiac Failure  
secondary to Anemia 
8-21 days old 
12.0-13.0 gm/dL 
10.0-11.9 gm/dL 
<10.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
22-35 days old 
9.5-10.5 gm/dL 
8.0-9.4 gm/dL 
<8.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
36-60 days old 
8.5-9.4 gm/dL 
7.0-8.4 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
61-90 days old 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
Abs Neutrophil Ct 
1 day old 
5000-7000/mm3 
3000-4999/mm3 
1500-2999/mm3 
<1500/mm3 
2-6 days old 
1750-2500/mm3 
1250-1749/mm3 
750-1249/mm3 
<750/mm3 
7-60 days old 
1200-1800/mm3 
900-1199/mm3 
500-899/mm3 
<500/mm3 
61-90 days old 
750-1200/mm3 
400-749/mm3 
250-399/mm3 
<250/mm3 
Bilirubin (Fractionated bilirubin test must be preformed when total bilirubin is elevated) 
<7 days old 
. 
20-25mg/dL 
26-30 mg/dL 
>30 mg/dL 
7-60 days old 
1.1-1.9xN 
2.0-2.9Xn 
3.0-7.5xN 
>7.5xN 
61-90 days old 
1.1-1.9xN 
2.0-2.9xN 
3.0-7.5xN 
>7.5xN 
 
Shire
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
(Selected Values for children less than or equal  
to 3 months of age)  
 
 
HEMATOLOGY (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Creatinine 
<7 days old 
1.0-1.7 mg/dL 
1.8-2.4 mg/dL 
2.5-3.0 mg/dL 
>3.0 mg/dL 
7-60 days old 
0.5-0.9 mg/dL 
1.0-1.4 mg/dL 
1.5-2.0 mg/dL 
>2.0 mg/dL 
61-90 days old 
0.6-0.8 mg/dL 
0.9-1.1 mg/dL 
1.2-1.5 mg/dL 
>1.5 mg/dL 
Cr Clearance 
<7 days old 
35-40 ml/min 
30-34 ml/min 
25-29 ml/min 
<25 ml/min 
7-60 days old 
45-50 ml/min 
40-44 ml/min 
35-39 ml/min 
<35 ml/min 
61-90 days old 
60-75 ml/min 
50-59 ml/min 
35-49 ml/min 
<35 ml/min 
Hypocalcemia 
<7 days old 
6.5–6.9 mEq/L 
6.0-6.4 mEq/L 
5.5-5.9 mEq/L 
<5.5 mEq/L 
7-60 days old 
7.6-8.0 mEq/L 
7.0-7.5 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
61-90 days old 
7.8-8.4 mEq/L 
7.0-7.7 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
Hypercalcemia 
<7 days old 
12.0-12.4 mEq/L 
12.5-12.9 mEq/L 
13.0-13.5 mEq/L 
>13.5 mEq/L 
7-60 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
61-90 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 
 (Greater than 3 months of age) 
 
LOCAL REACTIONS 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Induration 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Erythema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Edema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Rash at Injection Site 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Pruritus 
Slight itching at 
injection site 
Moderate itching at 
injection extremity 
Itching at injection 
extremity and other 
sites 
Itching over entire 
body 
 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin for 
children greater than 
months and less than 
2 years of age 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Hemoglobin for 
children greater that 2 
years of age 
10-10.9 gm/dL 
7.0-9.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Absolute Neutrophil 
Count 
750-1200/mm3  
400-749/mm3 
250-399/mm3 
<250/mm3 
Platelets 
------- 
50,000-75,000/mm3 
25,000-49,999/mm3 
<25,000/mm3 
Prothrombin Time 
(PT) 
1.1-1.2 x ULN 
1.3 -1.5 x ULN 
1.6 -3.0 x ULN 
>3.0 x ULN 
Partial 
Thromboplastin Time 
(PTT) 
1.1-1.6 x ULN 
1.7-2.3 x ULN 
2.4 -3.0 x ULN 
>3.0 x ULN 
Shire
CONFIDENTIAL
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
Page 145


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (Greater than 3 months of age)  
 
GASTROINTESTINAL  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Bilirubin (when 
accompanied by any 
increase in other liver 
function test) 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x ULN 
 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
Bilirubin (when other 
liver function are in 
the  normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
AST (SGOT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
ALT (SGPT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
GGT 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
Pancreatic Amylase 
1.1-1.4 x ULN 
1.5-1.9 x ULN 
2.0-3.0 x ULN 
>3.0 x ULN 
Uric Acid 
7.5-9.9mg/dL 
10-12.4 mg/dL 
12.5-15.0 mg/dL 
>15.0 mg/dL 
CPK 
See Neuromuscular Toxicity 
Appetite 
----------------- 
Decreased appetite 
Appetite very 
decreased, no solid 
food taken 
No solid or liquid taken  
Abdominal Pain 
Mild 
Moderate-  
No Treatment Needed 
Moderate-  
Treatment Needed 
Severe-  
Hospitalized for treatment 
Diarrhea 
Slight change in 
consistency and/or 
frequency of stools 
Liquid stools 
Liquid stools greater 
that 4x the amount or 
number normal for 
this child 
Liquid stools greater than 8x 
the amount or number 
normal for this child  
 
Shire
CONFIDENTIAL
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
Page 146


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (Greater than 3 months of age)  
 
GASTROINTESTINAL (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Constipation 
Slight change in the 
consistency/frequency 
of stool 
Hard, dry stools with 
a change in frequency 
Abdominal pain 
Distention and 
Vomiting 
Nausea 
Mild 
Moderate-  
Decreased oral intake 
Severe-Little  
oral intake 
Unable to ingest food  
or fluid for more than 
24 hours 
Vomiting 
1 episode/day 
2-3 episodes  
per day 
4-6 episodes per day  
Greater than 6 episodes 
per day or Intractable 
Vomiting 
Shire
CONFIDENTIAL
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
Page 147


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (Greater than 3 months of age)  
 
ELECTROLYTES 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
CREATININE  
3 Months -2 Years of 
age  
0.6-0.8 x ULN 
0.9-1.1 x ULN 
1.2-1.5 x ULN 
>1.5 x ULN 
2 Years- 12 Years of 
age 
0.7-1.0 x ULN 
1.1-1.6 x ULN 
1.7-2.0 x ULN 
>2.0 x ULN 
Greater than  
12 Years of age 
1.0-1.7 x ULN 
1.8-2.4 x ULN 
2.5-3.5 x ULN 
>3.5 x ULN 
 
Shire
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Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
Page 148


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (Greater than 3 months of age)  
 
ELECTROLYTES  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hypernatremia 
 
<145-149 mEq/L 
150-155 mEq/L 
>155 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyponatremia 
 
130-135 mEq/L 
129-124 mEq/L 
<124 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyperkalemia 
5.0-5.9 mEq/L 
6.0-6.4 mEq/L 
6.5-7.0 mEq/L 
>7.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythamia 
Hypokalemia 
3.0-3-5 mEq/L 
2.5-2.9 mEq/L 
2.0-2.4 mEq/L 
<2.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythmia 
Hypercalcemia 
10.5-11.2mg/dL 
11.3-11.9 mg/dL 
12.0-12.9 mg/dL 
>13.0 mg/dL 
Hypocalcemia 
7.8-8.4 mg/dL 
7.0-7.7 mg/dL 
6.0-6.9 mg/dL 
<6.0 mg/dL 
Hypomagnesemia 
1.2-1.4 mEq/L 
0.9-1.1 mEq/L 
0.6-0.8 mEq/L 
<0.6 mEq/L or 
abnormal magnesium 
AND cardiac 
arrhythmia 
Hypoglycemia 
55-65 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose 
AND mental status 
changes 
Hyperglycemia 
116-159 mg/dL 
160-249 mg/dL 
250-400 mg/dL 
>400 mg/dL or 
ketoacidosis 
Proteinuria 
Tr-1+  
or 
 <150 mg/day 
2+  
or 
150-499 mg/day 
3+  
or  
500-1000 mg/day 
4+ 
 or 
 Nephrotic syndrome 
>1000 mg/day 
Hematuria 
Microscopic <25 
Microscopic >25 
 
Gross hematuria 
Shire
CONFIDENTIAL
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
Page 149


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 
cells/hpf 
cells/hpf 
 
Shire
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Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
Page 150


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 
 (Greater than 3 months of age) 
 
CENTRAL NERVOUS SYSTEM (CNS) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Generalized CNS 
Symptoms 
 
 
Dizziness 
Hypotonic, 
hyporesponsive 
episodes;   
Seizures; 
Apnea/Bradycardia; 
Inconsolable crying > 
3 hrs; 
Headache  
Mild 
Moderate, Responds 
to non-narcotic 
analgesia 
Moderate to Severe,  
Responds to narcotic 
analgesia 
Intractable 
Level of Activity 
 
Slightly irritable OR 
slightly subdued 
Very irritable OR 
Lethargic 
Inconsolable OR 
Obtunded 
Visual 
 
Blurriness, diplopia, 
or horizontal 
nystagmus of < 1 
hour duration, with 
spontaneous 
resolution 
More than 1 episode 
of Grade 2 
symptoms per week, 
or an episode of 
Grade 2 symptoms 
lasting more than  
1 hour with 
spontaneous 
resolution by 4 
hours or vertical 
nystagmus 
Decrease in visual 
acuity, visual field 
deficit, or oculogyric 
crisis  
Myelopathy 
 
None 
None 
Myelopathic/spinal 
cord symptoms, such 
as: pyramidal tract 
weakness and 
disinhibition, sensory 
level, loss of 
proprioception, 
bladder/bowel 
dysfunction 
Shire
CONFIDENTIAL
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
Page 151


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 
(Greater than 3 months of age) 
 
PERIPHERAL NERVOUS SYSTEM  
PARAMETER 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Neuropathy/  
Lower Motor 
Neuropathy 
 
Mild transient  
Paresthesia only 
Persistent or 
progressive 
paresthesias, burning 
sensation in feet, or 
mild dysesthesia; no 
weakness; mild to 
moderate deep 
tendon reflex 
changes; no sensory 
loss 
Onset of significant 
weakness, decrease or 
loss of DTRs, sensory 
loss in "stocking 
glove" distribution, 
radicular sensory loss, 
multiple cranial nerve 
involvement; bladder 
or bowel dysfunction, 
fasciculations, 
respiratory 
embarrassment from 
chest wall weakness. 
Myopathy or 
Neuromuscular 
Junction Impairment 
Normal or mild 
 (<2 x ULN) CPK 
elevation 
Mild proximal 
weakness and/or 
atrophy not affecting 
gross motor function. 
Mild myalgias, +/- 
mild CPK elevation 
(<2 x ULN)  
Proximal muscle 
weakness and/or 
atrophy affecting 
motor function +/- 
CPK elevation; or 
severe myalgias with 
CPK >2 x ULN;  
Onset of myasthenia-
like symptoms 
(fatigable weakness 
with external, variable 
ophthalmoplegia 
and/or ptosis), or 
neuromuscular 
junction blockade 
(acute paralysis) 
symptoms 
 
Shire
CONFIDENTIAL
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
Page 152


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 
 (Greater than 3 months of age)  
 
OTHER  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Allergy 
Pruritus without Rash 
Pruritic Rash 
Mild Urticaria 
Severe Urticaria  
Anaphylaxis, 
Angioedema 
Drug Fever (Rectal) 
. 
38.5-40C 
101.3 – 104.0F 
Greater than 40.0C 
Greater than 104.0F 
Sustained Fever:  
Equal or greater than 
40C (104.0F) for 
longer than 5 days 
Cutaneous 
Localized rash 
Diffuse 
maculopapular 
Rash 
Generalized urticaria 
Stevens-Johnson 
Syndrome or Erythema 
multiforme 
Stomatitis 
Mild discomfort 
Painful, difficulty 
swallowing, but able 
to eat and drink  
Painful: unable to 
swallow solids 
Painful:  unable to 
swallow liquids; 
requires IV fluids 
Clinical symptoms 
not otherwise 
specified in this table 
No therapy; monitor 
condition 
May require minimal 
intervention and 
monitoring 
Requires medical care 
and possible 
hospitalization 
Requires active 
medical intervention, 
hospitalization, or 
hospice care 
Laboratory values not 
otherwise specified in 
this table 
Abnormal, but 
requiring no 
immediate 
intervention; follow 
Sufficiently abnormal 
to require evaluation 
as to causality and 
perhaps mild 
therapeutic 
intervention, but not 
of sufficient severity 
to warrant immediate 
changes in study drug 
Sufficiently severe to 
require evaluation 
and treatment, 
including at least 
temporary suspension 
of study drug 
Life-threatening 
severity; Requires 
immediate evaluation, 
treatment, and usually 
hospitalization; Study 
drug must be stopped 
immediately and 
should not be restarted 
until the abnormality is 
clearly felt to be 
caused by some other 
mechanism that study 
drug 
 
 
 
Shire
CONFIDENTIAL
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
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Shire
CONFIDENTIAL
Page 154
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
APPENDIX 4
HAE Attack Assessment and Reporting Procedures (HAARP)


DX-2930
HAE Attack Assessment and Reporting Procedures (HAARP)
29 June 2017
Confidential
Page 1 of 8
Shire
HAE Attack Assessment and Reporting Procedures
(HAARP)
Title:
HAE Attack Assessment and Reporting Procedures (HAARP)
Product Name:
DX-2930
Indication:
Prevention of angioedema attacks in patients with HAE
Sponsor:
Dyax Corp. (an indirect, wholly owned subsidiary of Shire plc.)
300 Shire Way, Lexington, MA 02421
Original Date (v1.0):
Version 2.0:
14 September 2015
29 June 2017
Confidentiality Statement
This document is the property of Dyax Corp, an indirect, wholly owned subsidiary of Shire plc. The
information in this document contains trade secrets and commercial information that are privileged or
confidential and may not be disclosed without the express written permission of Dyax unless required by federal
or state law or regulations. Any person to whom the information is disclosed must be informed that the
information is privileged or confidential and may not be further disclosed by them. These restrictions on
disclosure will apply equally to all future information supplied to you that is indicated as privileged or
confidential.
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TABLE OF CONTENTS
1
PURPOSE..........................................................................................................................3
2
DEFINITION OF AN ATTACK.......................................................................................3
3
REPORTING AND ASSESSMENT OF ATTACK DATA..............................................3
3.1
Subject-Reported Symptoms ...................................................................................4
3.1.1
Attack Information.........................................................................................4
3.1.2
Worsening Symptoms....................................................................................5
3.1.3
Subject Training.............................................................................................5
3.1.4
Reporting Multiple Attacks............................................................................5
3.1.5
Caregiver Report............................................................................................5
3.1.6
Subject Contact with Sites .............................................................................5
3.2
Site Contact with the Subject...................................................................................5
3.2.1
Review of subject report of symptoms ..........................................................6
3.2.2
Documenting a Reported Attack....................................................................6
3.2.3
Site Training...................................................................................................7
3.3
HAE attacks as Adverse Events...............................................................................7
4
INVESTIGATOR ATTACK ASSESSMENT...................................................................8
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1
PURPOSE
This document applies to clinical trials that involve investigator adjudication/assessment of 
angioedema attacks. The purpose of this document is to provide a definition of an HAE 
attack and to define a standardized set of procedures for the reporting and assessment of 
events reported by subjects to determine whether those events are true HAE attacks.
2
DEFINITION OF AN ATTACK
To be confirmed as an HAE attack, the event must have symptoms or signs consistent with 
an attack in at least one of the following locations:
•
Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region
•
Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea
•
Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx
Despite the presence of these symptoms, the investigator may still determine clinically that 
the event did not represent an HAE attack if there are features that strongly refute such a 
diagnosis. For example, the reported event is accompanied by symptoms that are not 
consistent with an attack (e.g., urticaria), the reported event persists well beyond the typical 
time course of an attack (e.g., greater than 7 days), or there is a likely alternate etiology for 
the event (e.g., the subject’s abdominal symptoms are attributable to a viral gastroenteritis 
outbreak in the household).
To be counted as a unique attack distinct from their previous attack, the new symptoms must 
occur at least 24 hours after resolution of the prior attack’s symptoms.
Attack resolution is defined as the subject no longer having symptoms of the attack. 
Prodromal symptoms by themselves are not considered an attack.
Patient report of use of acute HAE attack treatment for an attack by itself is not confirmation 
that an attack occurred.
3
REPORTING AND ASSESSMENT OF ATTACK DATA
At screening for applicable clinical trials, subject HAE attack history will be collected by the 
site for entry into the clinical database. Information collected will include any prior history of 
laryngeal attacks, attack frequency, average severity, predominant location(s), average 
duration, acute attack therapy use, and history of long-term prophylaxis.
During the relevant study periods, as defined in the applicable study protocol, subjects (or 
caregivers, for subjects < 18 years old) will be instructed to contact the site within 72 hours 
of the start of symptoms of an attack. In the situation that a subject is incapacitated and is
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unable to contact the site, a family member or other individual with detailed knowledge of 
the event can provide the information. If desired by the subject, memory aids may be 
provided to assist in tracking any HAE attacks subject’s experience. Any tools or devices the 
subject uses to track this information are not intended to serve as source documents for the 
study.
Site personnel will review the information provided by the subject or caregiver and solicit 
additional information as necessary to document the attack. Information documented by the 
site will be considered source for the study.
A designated individual at the site (the collector) will contact the subject or caregiver on a 
regular basis as defined in the study protocol, regardless of whether or not the subject has 
reported any attacks, in order to solicit for any attacks that may have occurred but were not 
reported. In addition, during each study visit, site personnel will solicit for any new attack 
information that was not provided through previous contact with the subject or caregiver.
The Investigator or designee (the assessor) will review the attack information and evaluate if 
the event represents a confirmed HAE attack. If necessary for the evaluation, the investigator 
or designee may contact the subject to receive additional information.
3.1
Subject-ReportedSymptoms
Subjects and caregivers can use any existing methods by which they track information about 
their attacks, or, if requested, memory aids can be provided by the study site. However, 
subjects (or a caregiver) will need to track attacks in such a way as to be able to contact the 
study site as soon as possible, but not later than 72 hours (3 full days) after the first 
symptoms appear, to report the information.
3.1.1
Attack Information
The following information should be provided by the subject (or caregiver) at the time they 
are reporting an attack to the site:
•
Date and time symptoms of an attack were first experienced
•
Description of symptoms experienced, including location(s)
•
Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits
•
Any medications used to treat the attack
•
If the attack resolved, date and time the subject was no longer experiencing symptoms
Subjects do not have to wait for their symptoms to completely resolve to report an attack. 
Information about ongoing symptoms can be obtained by the site during the check-in call 
and/ or at a scheduled study visit. Subjects should not withhold or delay any treatment they 
would normally receive to treat their attack in order contact the site.
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3.1.2
Worsening Symptoms
The site may request the subject call them back if they experience worsening symptoms
and/ or new symptoms for a reported attack. Otherwise, the new information will be captured 
during the next check-in call or scheduled study visit. Subjects may contact the site on their 
own to provide information about any worsening symptoms.
3.1.3
Subject Training
During screening, site personnel will train subjects on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide. The 
patient will confirm their understanding of what is required of them for reporting attacks to 
the site. Sites will assess the subject’s compliance with the reporting requirements 
throughout the study and may retrain the subject if necessary in order to maintain the 
integrity of the data provided to the site.
3.1.4
Reporting Multiple Attacks
If a subject experiences symptoms they attribute to more than one unique attack they can 
report this as multiple attacks to the site. Based on the definition of an attack as stated in 
Section 2, it will be the determination of the investigator or designee as to whether events 
reported as being separate are confirmed as separate attacks or not.
3.1.5
Caregiver Report
During screening, site personnel will train subject caregivers (if applicable) on identifying 
symptoms of an attack, the requirements for reporting attacks and the information they will 
be expected to provide. The caregiver will confirm their understanding of what is required of 
them for reporting attacks to the site. Sites will assess the caregiver’s compliance with the 
reporting requirements throughout the study and may retrain the caregiver if necessary in 
order to maintain the integrity of the data provided to the site.
3.1.6
Subject Contact with Sites
Site personnel will establish a recommended method and time window for each subject to 
contact the site to report any symptoms of an attack. Sites will establish a primary contact 
person and, if possible, a back-up person, with contact information. Back-up plans, including 
call backs and/ or use of back-up contacts, should be established in case the subject is unable 
to reach someone at the site.
3.2
Site Contact with the Subject
Sites will establish a recommended day and time window for check-in calls between study 
visits, as outlined in the study protocol. The date and time for check-ins can be modified 
based on when the last contact with the subject was made. When the site is contacted by a 
subject reporting symptoms of an attack the site should make sure they have the ability to 
record the information provided in a complete and accurate way. Back-up plans should be
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established in case the subject misses a call from the site. A study schedule for each subject’s 
on-site visits will be provided to the subject by the site.
3.2.1
Review of subject report of symptoms
During contact with the subject, whether subject-initiated or a regular check-in, site 
personnel should ask the subject to provide them information about new or ongoing HAE 
attacks experienced.
The site will try to obtain all information necessary to document the attack completely. 
Missing information may impact the assessment of any attack and should be avoided 
whenever possible.
3.2.2
Documenting a Reported Attack
Complete and accurate documentation of each reported attack is important to making an 
Investigator assessment of the attack. The site should document the following information 
about each attack reported by the subject or caregiver:
•
Date and time of contact with the subject
•
Date and time the subject first experienced symptoms
•
Description of symptoms experienced, including location(s)
•
Impact on activity and whether any assistance was required
•
If the attack has resolved or is ongoing. If the attack has resolved, the date and time the 
subject was no longer experiencing any symptoms of the attack
•
Names of any medications used to treat the attack including HAE acute therapy or other 
non-HAE treatments
•
If hospitalization occurred
•
If a trip to the emergency department occurred
Additional probing questions about what the subject experienced to determine:
•
If the subject only experienced prodromal symptoms
•
If the subject experienced anything different than their typical attack
•
If there were any possible alternative etiologies of the symptoms. For example, a viral 
gastroenteritis outbreak in the household could explain abdominal symptoms
The overall severity of the subject’s attack will be determined by the site using the following 
definitions:
-
Mild: Transient or mild discomfort
-
Moderate: Mild to moderate limitation in activity - some assistance needed
-
Severe: Marked limitation in activity, assistance required
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The site will also document the date and time of investigator or designee review, the official 
designation of the event as an attack or not, and if applicable, the reason why an event is not 
considered an attack.
All reported attacks will be entered by site personnel into the electronic case report form 
(eCRF).
3.2.3
Site Training
Site personnel responsible for collecting attack information about subject HAE attacks will 
need to pass a “Collector” training assessment covering the following:
•
definition of an HAE attack
•
requirements of subjects and caretakers for reporting attacks
•
reporting worsening symptoms and multiple attacks
•
information to be collected from subjects and caregivers as well as the additional probing 
questions to gather context for the attack information provided
•
assessment of attack severity
•
entry of the attack data into the eCRF
•
reporting HAE attacks as adverse events
•
requirements for Investigator assessment of attacks
Trainings will be conducted prior to sites screening subjects. Trainings will be documented 
in the Trial Master File. Investigators and designees will be trained on these procedures as 
well and must pass an “Assessor” training in order to officially assess attacks for this study.
All responsible persons involved in the collection of information from subjects or assessing 
attacks must be listed on FDA Form 1572.
3.3
HAE attacks as Adverse Events
At the time of each contact and scheduled study visit, site personnel will ask if the subject 
experienced any adverse events or changes to the medications they are taking.
HAE attacks will be captured as AEs. All AEs, regardless of seriousness, severity, or causal 
relationship to study drug, will be recorded on the AE page of the eCRF.
Any AE reported to the site meeting criteria for a serious adverse event must be reported to 
Dyax using the SAE Reporting Form in the EDC system within 24 hours of becoming aware 
of the event. For all serious adverse events that are reported as HAE attacks, the Principal 
Investigator or physician designee will review the event within 24 hours of initial notification 
and, in accordance with HAARP, evaluate if it represented a confirmed HAE attack.
For all non-serious AEs that are reported as HAE attacks, the Principal Investigator or 
physician designee will review the event within 3 days of initial notification and, in 
accordance with HAARP, evaluate if it represented a confirmed HAE attack. If necessary for 
the evaluation, the Investigator or designee may contact the subject for additional
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information. Any subject-reported attack not confirmed by the Investigator must have an 
alternate AE diagnosis recorded.  All subject-reported and Investigator-confirmed HAE 
attacks will be recorded in the eCRF.
4
INVESTIGATOR ATTACK ASSESSMENT
The Principal Investigator for a study site may identify a physician designee to assess patient 
symptom information and make attack determinations. Sites should be limited to two 
individuals responsible for assessing attacks, one of them being the Principal Investigator. 
Assessors must be experienced with HAE and familiar with the study subject’s disease 
history.
The assessor must review the information and determine whether the event is an actual attack 
or not. If needed, the assessor can contact the subject and/or caregiver to clarify information 
or ask for any additional detail. The determination will be documented along with the date 
and time the determination was made. Any event deemed not an attack must be accompanied 
by an explanation and alternative diagnosis by the assessor.
When reviewing subject information, the assessor will follow the definitions of an attack as 
outlined in these procedures and, taking all available information about the event into 
consideration, will determine if it is a confirmed attack. The assessment of the attack is the 
Investigator or designee’s own, and not the opinion of the subject, the subject’s caregiver or 
any other site personnel. Assessors may consult with one another about a particular subject’s 
attack but only one assessor makes the documented determination. It is possible for both the 
Principal Investigator and physician designee to assess different attacks for the same subject.
Page 162


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Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
APPENDIX 5
Summary of Pivotal Study DX-2930-03 in Subjects with HAE
The proposed pivotal clinical study (Study DX-2930-03) is entitled “HELP Study®: A 
Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to 
Evaluate DX-2930 For Long-Term Prophylaxis Against Acute Attacks of Hereditary 
Angioedema (HAE).” This study will be a multi-center, double-blind, randomized, placebo-
controlled parallel-arm study evaluating the efficacy of DX-2930 in preventing acute 
angioedema attacks in patients with Type I or Type II HAE. The double-blind study is planned to 
be followed by the study described in the present protocol, an open-label extension (OLE) study 
(DX-2930-04).
The primary objective of Study DX-2930-03 is to evaluate the efficacy of DX-2930 in 
preventing HAE attacks. The secondary objective is to evaluate the safety of repeated SC 
administrations of DX-2930. The tertiary objectives are to evaluate the pharmacodynamic effects 
of chronically administered DX-2930; to assess the immunogenicity of chronically administered 
DX-2930; to evaluate the pharmacokinetics of chronically administered DX-2930; and to 
evaluate the effect of DX-2930 upon quality of life assessments.
Subjects aged 12 years and over with a documented diagnosis of Type I or Type II HAE who 
experience at least 1 attack per 4 weeks will be eligible for the study. Up to 120 subjects are 
planned for enrollment across approximately 60 sites in the United States, Canada, Italy, 
Germany, United Kingdom and Jordan.
Following informed consent, subjects will undergo screening assessments.  Subjects who are on 
long-term prophylactic therapy for HAE are required to undergo a minimum 2 week washout 
period prior to the start of the run-in period.  Subjects who are either not on long-term 
prophylactic therapy for HAE, or have completed the required washout period will enter a run-in 
period of 4 weeks to determine the baseline HAE attack rate. The run-in period may be extended 
to 8 weeks if the minimum baseline attack rate is not achieved in the first 4 weeks. HAE subjects 
will then be randomized 2:1 to receive repeated subcutaneous (SC) administrations of DX-2930 
or placebo in a double-blind fashion.  Subjects who are randomized to DX-2930 will be assigned 
in a 1:1:1 ratio to one of three dose regimens: 300 mg every 2 weeks, 300 mg every 4 weeks or 
150 mg every 4 weeks.  Each subject will undergo a treatment period consisting of 13 doses of 
blinded study drug, for a period of 26 weeks from the date of first dose on Day 0 through Day 
182.
Subjects may consent to rollover into the OLE study (present protocol DX-2930-04) upon 
completion of their participation in the double-blind treatment period.
The primary endpoint will be to compare the number of investigator-confirmed HAE attacks 
observed in each DX-2930 treatment arm to that in the placebo arm during the efficacy 
assessment period (Day 0 through Day 182).
Figure 2 shows a schematic of the double-blind, pivotal study.


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DX-2930-04
29 June 2017
Figure 2
Overview of the Design of Pivotal Study DX-2930-03
Dose Rationale for Double-Blind, Pivotal Study DX-2930-03
The dose rationale is based on the pharmacodynamic bioactivity, PK, safety, and efficacy of DX-
2930 from the Phase 1 clinical studies and nonclinical studies. Together, these attributes provide 
the rationale for the selected doses and regimens to achieve drug levels likely to prevent a 
majority of HAE attacks. Based on these considerations, 300 mg every 2 weeks, 300 mg every 
4 weeks, and 150 mg every 4 weeks were identified as the dosing regimens for evaluation,
The 3 proposed dose-regimen combinations provide a 6-fold range of steady-state trough 
concentrations and leverage both the biomarker and efficacy data generated in Study 
DX-2930-02.  Evaluation of the DX-2930 plasma concentrations at the time of attacks reported 
by DX-2930 treated subjects in DX-2930-02 suggests that the 3 planned dosing regimens will 
provide a meaningful range of clinical response while avoiding non-therapeutic or super-
therapeutic doses and regimens.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
NCT Number:   
NCT02741596 
 
Study Title:  
HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long- 
Term Safety and Efficacy of DX-2930 for Prevention Against Acute 
Attacks of Hereditary Angioedema (HAE) 
 
 
Study Number:  
DX-2930-04 
 
 
SAP Version and Date:   
Original: 10 December 2019 
PK/PD Statistical Analysis Plan: 29 January 2020 
PRO Report HELP Study Extension: 24 March 2020 


 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
HELP Study ExtensionTM: An Open-Label Study to Evaluate the 
Long-Term Safety and Efficacy of DX-2930 for Prevention 
Against Acute Attacks of Hereditary Angioedema (HAE) 
Protocol Number: 
DX-2930-04 
Protocol Version/Date: 
Amendment 3.0 29 June 2017  
Indication: 
Prevention of angioedema attacks in subjects with HAE 
Study Phase 
III 
SAP Analysis Type 
Final 
SAP Version/Date 
10 December 2019 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is the proprietary and confidential property of Dyax Corp., an indirect, 
wholly owned subsidiary of Takeda 


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DX-2930-04 Statistical Analysis Plan 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF IN-TEXT TABLES ..........................................................................................................6 
1. LIST OF ABBREVIATIONS .....................................................................................................7 
2. INTRODUCTION ......................................................................................................................9 
2.1 
Purpose of the Statistical Analysis Plan ...........................................................................9 
2.2 
Background ......................................................................................................................9 
2.3 
Study Rationale ................................................................................................................9 
3. STUDY OBJECTIVES .............................................................................................................10 
3.1 
Primary Objectives .........................................................................................................10 
3.2 
Secondary Objectives .....................................................................................................10 
3.3 
Tertiary Objectives .........................................................................................................10 
4. STUDY DESIGN ......................................................................................................................11 
4.1 
General Description ........................................................................................................11 
4.2 
Discussion of Study Design, Including the Choice of Control Group ...........................14 
4.3 
Sample Size Determination ............................................................................................15 
5. EFFICACY AND SAFETY ENDPOINTS ..............................................................................16 
5.1 
Efficacy Endpoints .........................................................................................................16 
5.2 
Safety Endpoints ............................................................................................................16 
5.3 
Other Endpoints ..............................................................................................................16 
6. EFFICACY AND SAFETY VARIABLES ..............................................................................17 
6.1 
Study Activities Schedule ..............................................................................................17 
6.2 
Efficacy Assessments .....................................................................................................17 
6.3 
Safety Assessments ........................................................................................................19 
6.3.1 Adverse Events ..........................................................................................................19 
6.3.1.1 
Adverse Events of Special Interest .........................................................20 
6.3.2 Vital Signs .................................................................................................................20 
6.3.3 Physical Examination ................................................................................................20 
6.3.4 Electrocardiogram (ECG) ..........................................................................................21 
6.3.5 Clinical Laboratories .................................................................................................21 
6.3.5.1 
Hematology ............................................................................................21 
6.3.5.2 
Coagulation ............................................................................................21 
6.3.5.3 
Chemistry ...............................................................................................22 
6.3.5.4 
Urinalysis ...............................................................................................22 
6.3.5.5 
Pregnancy Test .......................................................................................22 
6.3.5.6 
Assays .....................................................................................................22 


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6.3.6 Prior and Concomitant Therapies ..............................................................................23 
6.4 
Other Assessments .........................................................................................................23 
6.4.1 Pharmacokinetic Assessment ....................................................................................23 
6.4.2 Pharmacodynamic Assessment .................................................................................23 
6.4.3 Plasma Anti-Drug Antibody Testing .........................................................................23 
6.4.4 Quality of Life Assessments ......................................................................................23 
6.4.4.1 
AE-QoL ..................................................................................................23 
6.4.4.2 
EQ-5D-5L ...............................................................................................24 
6.4.4.3 
WPAI-GH ...............................................................................................24 
6.4.4.4 
HADS .....................................................................................................24 
6.4.4.5 
SF-12v2 ..................................................................................................24 
6.4.4.6 
Angioedema Control Test (AECT) ........................................................25 
6.4.4.7 
Treatment Satisfaction Questionnaire for Medication (TSQM-9) .........25 
6.4.4.8 
Subject’s and Investigator’s Global Impression of Change ...................25 
6.4.5 DX-2930 Injection Report and Self-Administration and Subcutaneous 
Injection Survey .........................................................................................................25 
7. STATISTICAL ANALYSIS .....................................................................................................26 
7.1 
General Methodology .....................................................................................................26 
7.2 
Analysis Populations ......................................................................................................26 
7.2.1 Safety Population .......................................................................................................27 
7.2.2 Rollover Safety Population ........................................................................................27 
7.2.3 Non-Rollover Safety Population ...............................................................................27 
7.3 
Subject Disposition ........................................................................................................27 
7.4 
Protocol Deviations ........................................................................................................27 
7.5 
Demographic and Other Baseline Characteristics ..........................................................28 
7.6 
Medical History ..............................................................................................................29 
7.7 
Treatment Compliance and Extent of Exposure ............................................................29 
7.8 
Analysis of Efficacy .......................................................................................................29 
7.8.1 Primary Efficacy Analysis .........................................................................................29 
7.8.2 Secondary Efficacy Analyses ....................................................................................30 
7.8.3 Exploratory Efficacy Analyses ..................................................................................34 
7.8.4 Rescue Medication Use .............................................................................................37 
7.8.5 Supportive Treatment Use .........................................................................................37 
7.8.6 Trigger .......................................................................................................................37 
7.9 
Analysis of Safety ..........................................................................................................37 
7.9.1 Adverse Events ..........................................................................................................38 
7.9.2 Clinical Laboratory Evaluation .................................................................................42 
7.9.3 Vital Signs .................................................................................................................46 


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7.9.4 Electrocardiography ..................................................................................................46 
7.9.5 Physical Examinations ...............................................................................................46 
7.9.6 Prior and Concomitant Medications ..........................................................................47 
7.10 Other Analyses ...............................................................................................................47 
7.10.1 Analysis of Pharmacokinetic Data ............................................................................47 
7.10.2 Analysis of Pharmacodynamic Data .........................................................................47 
7.10.3 Analysis of Immunogenicity Data .............................................................................47 
7.10.4 Analysis of Quality of Life Data ...............................................................................48 
7.10.5 Analysis of Study Drug Self-Administration ............................................................48 
7.10.6 Summary of Angioedema Control Test (AECT) by Study Visit ..............................49 
7.10.7 Summary of Treatment Satisfaction Questionnaire for Medication (TSQM-
9) by Study Visit ........................................................................................................49 
7.10.8 Summary of Subject’s Global Impression of Change ...............................................49 
7.10.9 Summary of Investigator’s Global Impression of Change ........................................50 
8. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ................51 
8.1 
Changes in the Conduct of the Study .............................................................................51 
8.2 
Change from the Analyses Planned in the Protocol .......................................................51 
8.2.1 Cox Proportional Hazard Model ...............................................................................51 
8.2.2 Drug Interruption .......................................................................................................51 
8.2.3 Self-Administration Subgroup ...................................................................................51 
9. STATISTICAL/ANALYTIC ISSUES .....................................................................................52 
9.1 
Adjustment for covariates ..............................................................................................52 
9.2 
Handling of Dropouts or Missing Data ..........................................................................52 
9.3 
Interim Analysis and Data Monitoring ...........................................................................52 
9.4 
Multicenter Studies ........................................................................................................52 
9.5 
Multiple Comparisons/Multiplicity ................................................................................52 
9.6 
Examination of Subgroups .............................................................................................52 
9.7 
Sensitivity Analyses .......................................................................................................53 
9.7.1 Steady State Analyses ................................................................................................53 
9.7.2 Analyses on Number of All HAE Attacks ................................................................54 
9.7.3 Analyses Excluding Subjects Without Confirmed Type I or Type II HAE ..............54 
10. 
APPENDICIES ..............................................................................................................56 
Appendix 1. 
List of Statistical Outputs .......................................................................56 
Appendix 1.1 
List of Planned Tables ............................................................................56 
Appendix 1.2 
List of Planned Figures ..........................................................................76 
Appendix 1.3 
List of Planned Listings ..........................................................................78 
Appendix 2. 
Definitions and Programming Conventions ...........................................79 
Appendix 2.1 
Age .........................................................................................................79 


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Appendix 2.2 
BMI ........................................................................................................79 
Appendix 2.3 
Study Day ...............................................................................................79 
Appendix 2.4 
Duration of Events .................................................................................79 
Appendix 2.5 
Algorithm to Identify LTP Use at Baseline ...........................................79 
Appendix 2.6 
Definition of Unique Subject ID ............................................................80 
Appendix 2.7 
Analysis Periods .....................................................................................80 
Appendix 2.7.1 
Pretreatment Period ................................................................................80 
Appendix 2.7.2 
Treatment Period ....................................................................................80 
Appendix 2.7.3 
Handling of Subjects with Extended Drug Interruption(s) ....................81 
Appendix 2.7.4 
Follow-up Period ....................................................................................83 
Appendix 2.8 
Handling of HAE Attack Data ...............................................................84 
Appendix 2.8.1 
Imputing Missing Start or End Date and Time for HAE Attacks ..........84 
Appendix 2.8.2 
Unique HAE Attacks ..............................................................................85 
Appendix 2.8.3 
HAE Attack Duration .............................................................................85 
Appendix 2.8.4 
Investigator-confirmed HAE Attacks Requiring Acute Therapy ...........85 
Appendix 2.8.5 
Moderate and Severe Investigator-confirmed HAE Attacks ..................85 
Appendix 2.8.6 
HAE Attack Severity ..............................................................................85 
Appendix 2.9 
HAE Attack Rate ....................................................................................86 
Appendix 2.9.1 
Baseline HAE Attack Rate .....................................................................86 
Appendix 2.9.2 
Treatment Period HAE Attack Rate .......................................................86 
Appendix 2.9.3 
Time to First HAE Attack ......................................................................86 
Appendix 2.10 
Adverse Events .......................................................................................86 
Appendix 2.10.1 Treatment-emergent Adverse Events .....................................................86 
Appendix 2.10.2 Related Adverse Events .........................................................................87 
Appendix 2.10.3 Severe Adverse Events ...........................................................................87 
Appendix 2.10.4 Investigator-reported AESI ....................................................................87 
Appendix 2.10.5 Injection Site Reaction AEs ...................................................................87 
Appendix 2.11 
Non-standard Laboratory Results ...........................................................88 
Appendix 2.12 
Clinical Significance Attributions for Laboratory Results .....................88 
Appendix 2.13 
Angioedema Quality of Life ..................................................................89 
Appendix 2.14 
WAPI-GH ...............................................................................................90 
Appendix 2.15 
HADS .....................................................................................................91 
Appendix 2.16 
Study Activity Schedules .......................................................................92 
Appendix 2.16.1 Study Activity Schedule – Day -28 through Day 365 from 
Amendment 3.0 ......................................................................................92 
Appendix 2.16.2 Study Activities Schedule for Day 366 through Day 952 ......................96 
11. 
REFERENCES .............................................................................................................100 


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LIST OF IN-TEXT TABLES 
Table 1 
Defining Treatment Months for Non-Rollover Subjects ......................................32 
Table 2 
Adverse Event Tabulations by Analysis Population and Stage ............................41 
Table 3 
Lab Parameter Criteria Categories ........................................................................45 
Table 4 
List of Analyses during the Treatment Period and Steady State Period ...............54 
Table 5 
List of Analyses Excluding Subjects without Confirmed Type I or Type II 
HAE ......................................................................................................................55 
Table 6 
LTP Prior to Study Enrollment .............................................................................79 
Table 7 
LTP Subgroup .......................................................................................................80 
Table 8 
SMQs Used to Identify AESI ...............................................................................87 
Table 9 
Convention for Converting Non-Standard Laboratory Results ............................88 
 
 


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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AE-QoL 
Angioedema Quality of Life Questionnaire 
AESI  
Adverse event of special interest 
aPTT 
Activated partial thromboplastin time 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
C1-INH 
C1 esterase inhibitor 
CSR 
Clinical study report 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eDISH 
evaluation of Drug-Induced Serious Hepatotoxicity 
EQ-5D-5L 
EuroQoL 5-Dimensional 5-Level Measure 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
HAARP 
HAE Attack Assessment and Reporting Procedures 
HADS 
Hospital Anxiety and Depression Scale 
HAE 
Hereditary angioedema  
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
IP 
Investigational product 
IRB 
Institutional review board 


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Abbreviation 
Definition 
IV 
Intravenous 
KM 
Kaplan-Meier 
LTP 
Long-term prophylaxis 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS & MCS 
Physical and Mental Health Composite Scores 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
QoL 
Quality of life 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SF-12 
12-Item Short Form Survey 
SMQ 
Standardized MedDRA Queries 
SOC 
System organ class 
VAS 
Visual analog scale 
WHO-DD 
World Health Organization-Drug Dictionary 
WPAI-GH 
Work Productivity and Activity Impairment Questionnaire: General Health 
 


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2. 
INTRODUCTION 
2.1 
Purpose of the Statistical Analysis Plan 
This statistical analysis plan (SAP) is being developed after review of the DX-2930-04 protocol 
amendment 3.0, but before the final database lock. This SAP contains detailed information to aid 
in the implementation of the statistical analysis and reporting of the study data for use in the final 
clinical study report (CSR) and publication. This SAP is being written with due consideration of 
the recommendations outlined in the most recent International Conference on Harmonisation 
(ICH) E9 Guideline, entitled Guidance for Industry: Statistical Principles for Clinical Trials, and 
the most recent ICH E3 Guideline, entitled Guidance for Industry: Structure and Content of 
Clinical Study Reports. 
This SAP describes the analysis sets that will be used for analysis, as well as subject 
characteristics, efficacy, safety, pharmacokinetic (PK), pharmacodynamic (PD), 
immunogenicity, and quality of life (QoL) parameters. The details of the specific statistical 
methods as stated in the protocol will be provided and any changes from the protocol-specified 
analyses will be documented in the SAP prior to the database lock. If additional analyses are 
required to supplement the planned analyses described in this SAP after the database lock, they 
may be completed and will be described in the final CSR. Table, figure, and listing specifications 
are provided in separate documents. 
The DX-2930-04 protocol amendment 3.0 was finalized on 29JUN2017. The purpose of this 
amendment was to add new objectives and related measurements, QoL endpoints, and extend the 
study from 12 months to 30 months to continue to obtain data important for the assessment of 
DX-2930 (ie, safety and efficacy data).  
2.2 
Background 
DX-2930-04 is an open-label, long term safety and efficacy extension study of DX-2930-03, to 
evaluate the investigational medicinal product (IMP), DX-2930, in preventing acute angioedema 
attacks in subjects with Type I or Type II hereditary angioedema (HAE). Details of the study 
design, rationale, and procedures are documented in Protocol DX-2930-04 Amendment 3.0. 
2.3 
Study Rationale 
DX-2930 is a fully human IgG1 recombinant monoclonal antibody that binds specifically to 
active plasma kallikrein. DX-2930 is being developed for prophylactic treatment of angioedema 
attacks in subjects with HAE, a serious and life-threatening disease. 


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3. 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
To evaluate the long-term safety of repeated subcutaneous (SC) administrations of DX-2930 
3.2 
Secondary Objectives 
• To evaluate the long-term efficacy of DX-2930 in preventing HAE attacks 
• To characterize the outer bounds of dosing frequency for DX-2930 
3.3 
Tertiary Objectives 
• To assess the immunogenicity of chronically administered DX-2930 
• To evaluate the effect of DX-2930 on health-related QoL 
• To characterize the PK and PD profile of SC administration of DX-2930 
• To evaluate safety and efficacy in the non-rollover population of switching from 
long-term prophylactic (LTP) treatment to DX-2930 
• To evaluate breakthrough attack characteristics while receiving DX-2930 compared with 
historical baseline breakthrough attack characteristics 
• To evaluate subject experience with self-administration of DX-2930, including ease of 
SC administration of DX-2930  
• To assess the clinical response of rescue medications for the treatment of acute 
angioedema attacks while on DX-2930 therapy (applicable for subjects ≥18 years of age) 
• To assess treatment satisfaction 
• To assess global impression of treatment response 
• To assess control of angioedema 
 
The following objectives included in Amendment 3.0 will not be evaluated for the final CSR due 
to data unavailability at the time of the analysis: 
• To evaluate subject experience and ease of use of the prefilled syringe, if available 


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4. 
STUDY DESIGN 
4.1 
General Description 
DX-2930-04 is an open-label, long-term safety and efficacy extension study of DX-2930-03, to 
evaluate the IMP, DX-2930, in preventing acute angioedema attacks in subjects with Type I or 
Type II HAE. Figure 1 in the protocol shows a schematic of DX-2930-04. 
Two types of subjects will be enrolled into this study: 
• Subjects who roll over from the DX-2930-03 study 
• Subjects who are non-rollover (ie, were not participants in DX-2930-03) 
Rollover Subjects 
Rollover subjects are subjects who complete the double-blind treatment period at Day 182 of the 
DX-2930-03 study and consent to enter DX-2930-04. Subjects who discontinue from 
DX-2930-03 after enrollment are not eligible to enroll in DX-2930-04. 
Subjects should be asked about their interest in the DX-2930-04 study after enrollment into 
DX-2930-03 to anticipate enrollment and preparedness for DX-2930-04. Willing subjects must 
sign informed consent for DX-2930-04 after Day 168 of study DX-2930-03 and no later than the 
final DX-2930-03 Day 182 treatment period study visit. 
The first DX-2930-04 visit for rollover subjects (Day 0) occurs on the same day as the DX-2930-
03 Day 182 study visit. Rollover subjects will complete all DX-2930-03 final study assessments 
(Day 182), at which time they will be discharged from that study. No assessments conducted 
between the DX-2930-03 Day 182 study visit and the first DX-2930-04 visit (Day 0) will be 
duplicated.  
All subjects, caregivers, investigators, and study site personnel will remain blinded to the 
DX-2930-03 treatment assignment until the conclusion of the DX-2930-04 study. 
Non-rollover subjects 
At least 50 subjects (to approximately 100) who were not participants in the DX-2930-03 study 
will be permitted to enroll if they meet the eligibility requirements. Subjects who screen fail out 
of DX-2930-03 for not meeting the minimum attack requirements during the run-in period must 
wait until enrollment for the double-blind study has ended before they can screen for DX-2930-
04. The Sponsor may ease this restriction based on the enrollment rate observed in DX-2930-03. 
Subjects who are still in the run-in period for DX-2930-03 when enrollment for that study closes, 
as well as subjects on prior LTP who screen fail out of DX-2930-03 due to an inability to wash 
out of their LTP, may screen for DX-2930-04 following discussion with the Sponsor’s Medical 
Monitor. 


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Screening Period: 
Rollover subjects 
There is no screening period for rollover subjects. 
Non-rollover subjects 
Non-rollover subjects must provide informed consent and have screening assessments completed 
within 4 weeks prior to their first open-label dose. Screened non-rollover subjects (adults and 
adolescents) who are on LTP with C1 esterase inhibitor (C1-INH) therapy for HAE can continue 
their current LTP until Day 8 (or Day 15), such that subjects will have received 2 (or 4) doses of 
C1-INH. A similar tapering schedule is recommended for subjects on attenuated androgens (eg, 
danazol) or anti-fibrinolytics (eg, tranexamic acid). However, the taper can be prolonged by an 
additional week as long as androgen or anti-fibrinolytic therapy is stopped within 3 weeks of 
receiving the first dose of DX-2930. 
Treatment Period: 
Rollover Subjects 
Following informed consent and pre-dose assessments, rollover subjects will receive a single 
open-label dose of DX-2930 administered SC on Day 0. Subjects will not receive any additional 
DX-2930 doses until their first reported and investigator-confirmed HAE attack.  As such, the 
total number of doses within the treatment period will vary by rollover subject. 
The duration of time between the first open-label dose and first reported HAE attack will vary by 
rollover subject. All rollover subjects must adhere to the Study Activities Schedules (Appendix 
2.16) for the entire duration of the study. However, until a rollover subject reports their first 
HAE attack, only scheduled study visits where the following tests and assessments are performed 
must be conducted at the investigative site: pregnancy testing, clinical laboratory testing, 
physical examination, 12-lead electrocardiogram (ECG), QoL, PK, PD, and anti-drug antibody 
(ADA) sample collection. All other scheduled study visits may be conducted via site check-in 
calls to collect information on adverse events (AEs), concomitant therapy, and HAE attack data. 
See the Study Activities Schedules (Appendix 2.16) to determine which visits must be conducted 
at the study site. 
Once a rollover subject reports their first HAE attack, they will present to the investigative site 
for their second open-label dose of DX-2930 as quickly as subject and site schedules allow.  If 
the second dose is to be administered within the accepted ± 4-day window around a scheduled 
study visit, this treatment visit will represent that scheduled visit. If that scheduled visit has 
already occurred, the day of the visit will be considered an acceptable extra study visit. 
In the event that the second dose is to be administered outside of the accepted ±4 day window 
around a scheduled visit, the day of the visit will be considered an acceptable extra study visit 
(ie, this visit will not replace any scheduled visit). 


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Regardless of the study day, at the visit in which the second open-label dose of DX-2930 is 
administered, the subject will undergo pre-dose assessments for vital signs, physical 
examination, clinical laboratory testing, and blood sampling for PK, PD, and ADA assessments. 
Vital signs will be obtained at 1 hour post-dosing. As with all study visits, information will be 
collected on AEs, concomitant therapy, and HAE attack data. 
For the purpose of efficacy and safety analyses defined in this SAP, the treatment period for 
rollover subjects is further divided into two stages: The Dose-and-wait stage and Regular Dosing 
stage. The Dose-and-wait stage starts on the day of first study drug administration, or Day 0, and 
ends right before the date/time of the second dose. The Regular Dosing stage starts on the 
date/time of second dose and runs through the end of treatment period. For a detailed definition 
on these two stages, refer to Appendix 2.7.2.1 and Appendix 2.7.2.2. 
Non-rollover Subjects 
Once all screening assessments have been completed and eligibility confirmed, non-rollover 
subjects will arrive at the study site and, following pre-dose assessments, receive an open-label 
dose of 300 mg DX-2930 administered SC on Day 0. Non-rollover subjects will continue to 
receive SC administrations of open-label 300 mg DX-2930 every 2 weeks throughout the 
duration of the treatment period. Screened non-rollover subjects (adults and adolescents) who are 
on LTP with C1 esterase inhibitor (C1-INH) therapy, attenuated androgens (eg, danzol), or anti-
fibrinolytics (eg, tranexamic acid) for HAE can continue their current LTP until as late as Day 
21. 
For the purpose of safety analyses defined in this SAP, the treatment period for non-rollover 
subjects are further divided into two stages: The Tapering stage and Non-tapering stage. The 
Tapering stage starts on the day of first study drug administration, or Day 0, and ends at the last 
date/time of LTP use. The Non-tapering stage starts right after last date/time of LTP use and runs 
through the end of the treatment period. For a detailed definition on these two stages, refer to 
Appendix 2.7.2.3 and Appendix 2.7.2.4. 
All Subjects: 
For all subjects, subsequent doses after the second dose require a minimum of 10 days and 
maximum of 18 days between administrations, and should fall within the accepted ± 4 day 
window around study visits. 
After the second DX-2930 dose is given, either within the study window (±4 days) or at an 
acceptable extra study visit, the 3rd dose must be administered at the next pre-defined study visit 
according to the Study Activities Schedules (Appendix 2.16). 
Regardless of when a subject’s first HAE attack occurs, there will be a minimum of 10 days 
between their first open-label dose and their second open-label dose. Following their second 
open-label dose, subjects will continue to receive repeated SC administrations of open-label DX- 
2930 every 2 weeks for the remaining duration of the treatment period. The treatment period will 
last approximately 30 months from the date of the first open label dose. The number of doses 


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administered during this period will vary by subject based on the date of each subject’s second 
dose. The Day 910 study visit is the last visit at which a dose may be administered. 
Self-Administration 
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with the 
physical and mental capability of learning and willingness to be trained) may be allowed to self-
administer treatment. Subjects must complete appropriate training by the investigator or designee 
and have their understanding of the procedures confirmed by the investigator or designee. 
Subjects are allowed to initiate self-administration after receiving the first 2 doses of DX-2930 at 
the study site. Once initiated, subjects may self-administer subsequent doses of DX-2930 at the 
investigational site (when visits are scheduled study site visits), the subject’s home, or other 
agreed upon location (when the study permits off-site dosing). See Study Activities Schedules in 
Appendix 2.16 for details. Adolescent subjects self-administering DX-2930 will be supervised 
by a parent/legal guardian/caregiver. Alternatively, a parent/legal guardian/caregiver, after 
completing appropriate training, will be allowed to administer the investigational product to an 
adolescent without study site personnel supervision. Site personnel will call subjects after the 
planned self-administration to ensure the administration occurred, to collect AEs and 
concomitant medications, and to ensure all attacks have been appropriately documented.  No 
monitoring of vital signs will be performed for subjects who elect to self-administer at home. 
Follow-up Period: 
After completion of the treatment period, all subjects will undergo safety evaluations during a 4-
week follow-up period.  
Modifications to Open-Label Dosing 
If at any time an important dose-related safety signal is identified either from this study or DX-
2930-03, the Sponsor may decide to switch the enrolled subjects who have not yet completed the 
treatment period and any subsequent subjects to receive a different open-label dose and/or 
frequency. 
In addition, based on the results of the DX-2930-03 study, the Sponsor may switch to a different 
dose and/or frequency. 
4.2 
Discussion of Study Design, Including the Choice of Control Group 
This study is an open-label, long-term safety and efficacy extension study of DX-2930-03, to 
evaluate the IMP, DX-2930, in preventing acute angioedema attacks in subjects with Type I or 
Type II HAE. The following is a discussion of the rationale behind the design of the trial. 
• Primary endpoint selection: The objective of this study is to evaluate the long-term safety 
of repeated SC administrations of DX-2930. Safety endpoints include AEs, clinical 
laboratory results, vital signs, and electrocardiography. 


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• Dose selection: The dose selected for the open-label extension (300 mg every 2 weeks) is 
anticipated to be effective and safe as determined in the pivotal, double-blind DX-2930-03 
trial. If at any time an important dose-related safety signal is identified either from this study 
or DX-2930-03, the Sponsor may decide to switch the enrolled subjects who have not yet 
completed the treatment period and any subsequent subjects to receive a different open-label 
DX-2930 dose and/or frequency. Additionally, based on the efficacy results of the DX-2930-
03 study, the Sponsor may switch to a different dose and/or frequency. 
• Control group selection: This is an open-label extension study that does not include any 
control groups. 
• Study population: Subjects 12 years of age and older with a confirmed diagnosis of HAE 
(Type I or II) who have a historical baseline HAE attack rate of at least 1 per 12 weeks. 
• Baseline symptom severity: To be eligible to participate in the study, subjects had to have a 
historical baseline HAE attack rate of at least 1 per 12 weeks.  
• Stratified randomization: There is no randomization for this study. 
• Safety monitoring: AEs, clinical laboratory results, vital signs, and ECG recordings will be 
monitored throughout the study. 
4.3 
Sample Size Determination 
No formal sample size calculation was performed. The sample size is not based on any statistical 
considerations. This study is designed to evaluate the safety and efficacy of open-label treatment 
with DX-2930 in subjects who participated in DX-2930-03 (rollover subjects) and individuals 
who were not otherwise able to participate in DX-2930-03 (non-rollover subjects). 
 


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5. 
EFFICACY AND SAFETY ENDPOINTS 
5.1 
Efficacy Endpoints 
• Time from first open-label study dose to the first investigator-confirmed HAE attack for 
rollover subjects  
• Number of investigator-confirmed HAE attacks during the treatment period  
• Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period  
• Number of moderate or severe HAE attacks during the treatment period  
• Number of high-morbidity HAE attacks during the treatment period; a high-morbidity HAE 
attack is defined as any attack that has at least one of the following characteristics: severe in 
intensity, results in hospitalization (except hospitalization for observation < 24 hours), 
hemodynamically significant (systolic blood pressure < 90, requires intravenous [IV]  
hydration, or associated with syncope or near-syncope) or laryngeal angioedema. 
5.2 
Safety Endpoints 
The safety and tolerability of DX-2930 will be evaluated through the assessment of AEs, clinical 
laboratory testing, vital sign measurements, ECG recordings, and concomitant medications. 
5.3 
Other Endpoints 
Additional endpoints of interest in this study are the plasma concentration of DX-2930, PD 
biomarker assays, ADAs, and QoL data as collected with the EuroQoL Group 5-Dimension 
(EQ5D) Questionnaire, the Angioedema Quality of Life (AE-QoL) Questionnaire, 12 Item Short 
Form v2 Health Survey (SF-12v2)., Hospital Anxiety and Depression Scale (HADS), Work 
Productivity and Activity Impairment – General Health (WPAI-GH) Questionnaire, Angioedema 
Control Test (AECT), Treatment Satisfaction Questionnaire for Medication (TSQM-9), Subjects’ 
and Investigators’ Global Impression of Treatment Response,  the DX-2930 injection report, and 
the DX-2930 self-administration and SC injection survey. 


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6. 
EFFICACY AND SAFETY VARIABLES 
6.1 
Study Activities Schedule 
Please refer to Appendix 2.16 for details of assessments performed at each visit. 
6.2 
Efficacy Assessments 
The collection, reporting, and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP). Study site personnel will be 
trained on HAARP prior to screening and enrolling subjects at their site. 
Study site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks, and the information they will be expected to provide. The 
subject (and caregiver) will confirm their understanding of what is required of them for reporting 
attacks to the site. 
At screening, HAE attack history will be collected for non-rollover subjects. Information 
collected will include any prior history of laryngeal attacks, attack frequency, average severity, 
predominant attack location(s), triggers, average duration, acute attack therapy use, and history 
of LTP (including duration of LTP, medication(s) and dose used for LTP, and frequency of 
attacks while receiving LTP). If available, information will also be collected on HAE diagnosis 
(year of confirmation, how many years after onset of symptoms diagnosis was confirmed, or 
whether the subject was misdiagnosed). 
During the study, subjects (or caregivers) will be instructed to notify and report details to the 
study site within 72 hours of the onset of an attack. This includes the first attack experienced by 
rollover subjects following their first open-label dose. In the situation that a subject is 
incapacitated following an attack, this information can be provided to the site by a family 
member or other individual with detailed knowledge of the event. If desired by the subject, 
memory aids can be provided to assist in tracking any HAE attacks experienced. 
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack: 
• Date and time symptoms of an attack were first experienced 
• Description of symptoms experienced, including location(s) 
• Impact on activity (work, school, social interactions) and whether any assistance or medical 
intervention was required, including hospitalizations, additional laboratory tests, or 
emergency department visits 
• Any medications used to treat the attack (both prescription and over the counter) 
• If the attack resolved, date and time the subject was no longer experiencing symptoms 
Site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP.  


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For rollover subjects, study site personnel will contact rollover subjects approximately every 
7 days following the first open-label dose until the subject has received their second open-label 
dose. This is to ensure accurate reporting for any HAE attacks not already reported by the subject 
as required within 72 hours. During each study visit, study site personnel will solicit any new 
HAE attack information that was not already provided to the site. 
In this study, HAE attacks will be captured as AEs. All AEs, regardless of seriousness, severity, 
or causal relationship to DX-2930, will be recorded on the AE page of the electronic case report 
form (eCRF). Any AE reported to the site meeting criteria for a serious adverse event (SAE) 
must be reported to the Sponsor using the SAE Reporting Form in the electronic data capture 
(EDC) system within 24 hours of becoming aware of the event. For all SAEs that are reported as 
HAE attacks, the investigator or physician designee will review the event within 24 hours of 
initial notification and, in accordance with HAARP, evaluate whether it represented a confirmed 
HAE attack. For all non-serious AEs that are reported as HAE attacks, the investigator or 
physician designee will review the event within 3 days of initial notification and, in accordance 
with HAARP, evaluate whether it represented a confirmed HAE attack. If necessary for the 
evaluation, the investigator or designee may contact the subject to receive additional information. 
Any subject-reported attack not confirmed by the investigator or physician designee must have 
an alternate AE diagnosis recorded. All subject-reported and investigator/physician designee-
confirmed HAE attacks will be recorded in the eCRF. 
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured. 
To be confirmed as an HAE attack, the event must have symptoms or signs consistent with an 
attack in at least one of the following locations:  
• Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region. 
• Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea. 
• Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx. 
Despite the presence of these symptoms, the investigator or physician designee may still 
clinically determine that the event did not represent an attack if there are features that strongly 
refute such a diagnosis. For example, if the reported event is accompanied by symptoms that are 
not consistent with an HAE attack (eg, urticaria), the reported event persists well beyond the 
typical time course of an HAE attack, or there is a likely alternate etiology for the event (eg, the 
subject’s abdominal symptoms are attributable to a viral gastroenteritis outbreak in the 
household). 
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms. 


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6.3 
Safety Assessments 
6.3.1 
Adverse Events 
AEs will be collected from the signing of the informed consent through the last study visit. For a 
detailed definition of AEs, SAEs, severity of AEs, and relatedness of AEs and SAEs, please refer 
to the protocol. 
An AE is treatment-emergent if the onset time is after first administration of open-label DX-2930 
through the final follow-up visit or, in the event that onset time precedes first DX-2930 
administration, the AE increases in severity during the open-label treatment period. If onset date 
and times are missing, then the AE will be classified as being treatment-emergent unless there 
are partial dates and times that clearly demonstrate that the AE occurred prior to first DX-2930 
administration. 
For rollover subjects, any AE that started during the subject’s participation in DX-2930-03 and 
was ongoing at the time of the first open-label dose in DX-2930-04 will not be counted as an AE 
in DX-2930-04 unless that event has worsened in severity or frequency following the first 
open-label dose. AEs that started during subject participation in DX-2930-03, resolved following 
the first open-label dose in DX-2930-04, and then subsequently reappeared in DX-2930-04 will 
be counted as a new treatment-emergent AE in DX-2930-04. 
In this study, the severity of AEs will be assessed according to Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table, Draft, November 2007 (US National 
Institutes of Health: National Institute of Allergy and Infectious Diseases) (See Appendix 2 in 
the protocol) and the DMID Pediatric Toxicity Table, Draft, November 2007 (US National 
Institutes of Health: National Institute of Allergy and Infectious Diseases) (See Appendix 3 in 
the protocol). For abnormalities not specifically found in the Toxicity Tables, the following 
general scale will be used to estimate grade of severity: 
• GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required 
• GRADE 2 (Moderate): Mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required 
• GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible  
• GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
Any treatment-emergent ECG abnormality that is considered by the investigator as clinically 
significant and requiring intervention/therapy will be assessed as a severe AE. 
The causal relationship between DX-2930 and the AE will be assessed using the following 
categories: 


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Not Related: Factors consistent with an assessment of Not Related include: 
• Temporal relationship is lacking (ie, the event did not occur within a reasonable 
time frame following administration of DX-2930); or 
• Other causative factors more likely explain the event (eg, a pre-existing condition, 
other concomitant treatments). 
Related: Factors consistent with an assessment of Related include: 
• There is a positive temporal relationship (ie, the event occurred within a 
reasonable time frame following administration of DX-2930); or 
• The AE is more likely explained by administration of DX-2930 than by another 
cause (ie, the AE shows a pattern consistent with previous knowledge of 
DX-2930 or the class of DX-2930). 
Clinical significance of individual AEs will be determined by the investigator, with discussion 
with the Medical Monitor as appropriate. 
6.3.1.1 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Investigators will report all AESI to the Sponsor, regardless of causality, using the same 
timelines as described for SAE reporting. For a detailed description on the tracking of AESI 
during the study, refer to Protocol section 6.16.1.6. 
6.3.2 
Vital Signs 
Vital signs will be assessed by the investigator or his/her qualified designee according to the 
Study Activities Schedules (Appendix 2.16) unless the subject has qualified and elected to self-
administer away from the investigational site for that visit. Routine vital sign assessments will be 
taken with the subject in the sitting or supine position after 5 minutes at rest and will include 
body temperature, heart rate, blood pressure, and respiratory rate. Blood pressure should be 
determined using the same arm and the same equipment for each assessment. For subjects who 
roll over from DX-2930-03, vital signs taken during the final study visit in DX-2930 will serve 
as the Day 0 pre-dose vital signs in this study and will not be duplicated. 
6.3.3 
Physical Examination 
A physical examination including height, weight, and calculation of body mass index (BMI) will 
be performed by the investigator or his/her qualified designee according to the Study Activities 
Schedules (Appendix 2.16). The physical examination will be performed in accordance with 
standards at the site. 
For subjects who roll over from DX-2930-03, the physical exam taken during the final study visit 
in DX-2930-03 will serve as the Day 0 pre-dose physical exam in this study and will not be 
duplicated. 


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6.3.4 
Electrocardiogram (ECG) 
A standard 12-lead ECG (single recording) will be performed according to the Study Activities 
Schedules (Appendix 2.16). The date and time of each ECG and its results will be documented in 
the source documents and eCRF. ECGs will be sent to a central reading vendor for assessment. 
For subjects who roll over from DX-2930-03, the ECG taken during the final study visit in DX-
2930-03 will serve as the Day 0 pre-dose ECG in this study and will not be duplicated. 
6.3.5 
Clinical Laboratories 
Laboratory testing will be performed according to the Study Activities Schedules (Appendix 
2.16). 
Laboratory testing includes general safety parameters (hematology, coagulation, urinalysis, and 
serum chemistry), pregnancy tests (in females of childbearing potential), C1-INH functional 
assay, C4 assay, C1q assay, PK sampling, PD sampling, and plasma ADA testing. All laboratory 
tests will be performed using established and validated methods. 
When multiple sample collection types are performed at the same assessment time point, the 
samples will be drawn in the following order (depending on what sample types are to be 
collected at that time point): laboratory safety samples (hematology, coagulation, serum 
chemistry), C1-INH, C4, C1q, PK, ADAs, PD. Aliquots from the PK, PD, and ADA samples 
may be retained as back-up for additional parameter testing if necessary. Subjects will be in a 
seated or supine position during blood collection. The total blood draw for each rollover subject 
will be approximately 269.8 mL. The total blood draw for each non-rollover subject will be 
approximately 283 mL. For rollover subjects, testing performed on samples collected during the 
final study visit in DX-2930-03 will serve as the Day 0 pre-dose laboratory testing in this study 
and will not be duplicated. 
6.3.5.1 
Hematology 
The following hematology assessments will be made: 
• Hemoglobin 
• Hematocrit 
• Red blood cell count 
• White blood cell count with differential 
• Mean corpuscular volume  
• Mean corpuscular hemoglobin  
• Mean corpuscular hemoglobin concentration  
• Absolute platelet count 
6.3.5.2 
Coagulation 
The following coagulation assessments will be made: 
• Prothrombin time  
• Activated partial thromboplastin time  
• International Normalized Ratio 


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6.3.5.3 
Chemistry 
The following chemistry assessments will be made: 
• Albumin 
• Alkaline phosphatase 
• Alanine aminotransferase (ALT; SGPT) 
• Aspartate aminotransferase (AST; SGOT) 
• Bilirubin (total and direct) 
• Blood urea nitrogen 
• Calcium 
• Carbon dioxide 
• Chloride 
• Creatinine 
• Creatine phosphokinase 
• Glucose 
• Phosphate 
• Magnesium 
• Potassium 
• Sodium 
• Total protein 
• Uric acid 
6.3.5.4 
Urinalysis 
The following urinalysis assessments will be made: 
• Bilirubin 
• Glucose 
• Ketones 
• Blood  
• Nitrite 
• pH 
• Protein 
• Specific gravity 
• Microscopy (if indicated by macroscopic findings) 
6.3.5.5 
Pregnancy Test 
Pregnancy tests will be either serum or urine based. 
6.3.5.6 
Assays 
Results of a C1-INH functional assay are required for eligibility assessment. Samples will be 
drawn at the screening visit unless they were previously drawn in Study DX-2930-02 or Study 
DX-2930-03. Results of a C4 assay may also be required for eligibility assessment. The C4 
sample will be drawn at the same time as the C1-INH sample is drawn during the screening visit 
unless previously drawn in Study DX-2930-02 or Study DX-2930-03.  Results of the C1-INH 


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and C4 assays from Study DX-2930-02 or Study DX-2930-03 may be used to confirm diagnosis 
in this study. Subjects may be retested if results are incongruent with clinical history or believed 
by the investigator to be confounded by recent LTP use. 
Results of a C1q assay may be further required for eligibility assessment. Any subject who 
requires C1-INH and C4 assay results for diagnostic confirmation in this study will have C1q 
assay results obtained as well. The C1q sample will be drawn at the same time as the C1 and C4 
sample is drawn during the screening visit. 
6.3.6 
Prior and Concomitant Therapies 
The Sponsor representatives and investigator at the site conducting the trial will review and 
evaluate prior (4 weeks prior to study screening) and concomitant medication usage on an 
ongoing basis. For subjects not rolling over from DX-2930-03, all prescription and over-the-
counter medications, herbals, and supplements that are being taken or have been taken by 
subjects from the time of screening through the duration of the study will be regarded as 
concomitant medications and must be documented on the source document and eCRF following 
informed consent. For subjects rolling over from DX-2930-03, concomitant therapy use will be 
carried forward from that study and will continue to be collected through the duration of the 
study. 
6.4 
Other Assessments 
6.4.1 
Pharmacokinetic Assessment 
Blood samples for the measurement of plasma DX-2930 concentration will be obtained as 
specified in the Study Activities Schedules (Appendix 2.16). 
6.4.2 
Pharmacodynamic Assessment 
To evaluate the PD effects of DX-2930-03 on plasma kallikrein activity, blood samples will be 
obtained as specified in the Study Activities Schedules (Appendix 2.16). 
6.4.3 
Plasma Anti-Drug Antibody Testing 
Plasma samples for testing for formation of antibodies to DX-2930 will be obtained as specified 
in the Study Activities Schedules (Appendix 2.16). 
6.4.4 
Quality of Life Assessments 
Quality of life assessments will be conducted using the AE-QoL, EQ-5D-5L, WPAI-GH, HADS, 
AECT, TSQM-9, Subject’s and Investigator’s Global Impression of Change and SF-12v2. See 
Study Activities Schedules (Appendix 2.16) for timing of assessments. For subjects who rollover 
from DX-2930-03, QoL assessments obtained during the final study visit in DX-2930-03 will 
serve as the Day 0 pre-dose QoL assessments in the current study and will not be duplicated.   
6.4.4.1 
AE-QoL 
The AE-QoL is a self-administered, symptom-specific tool developed and validated to assess 
QoL impairment in recurrent angioedema subjects (Weller et al. 2012). The AE-QoL consists of 


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17 questions covering four domains/dimensions (functioning, fatigue/mood, fear/shame, 
nutrition). Each of the 17 items has a five-point Likert-type response scale ranging from 1 
(Never) to 5 (Very Often). The AE-QoL is scored to produce a score for each domain and a total 
score ranging from 0 to 100, with higher scores indicating stronger impairment. It takes 
approximately 5 minutes to complete the AE-QoL. Details of how to compute scores for the 
domains and the total score are included in Appendix 2.13. 
6.4.4.2 
EQ-5D-5L 
The EQ-5D-5L is a self-administered standardized measure of health status comprising a 
descriptive system and a visual analogue scale (VAS). The descriptive system consists of five 
health-related QoL dimensions (ie, mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Each dimension is rated on a 5-point response scale (5 levels) indicating 
severity of problems, where 1 is “no problems” and 5 is “extreme problems”. The EQ-5D VAS is 
a measure of overall self-rated health status on a 20-cm vertical VAS with endpoints labelled 
“the best health you can imagine” and “the worst health you can imagine”. The VAS ranges from 
0 to 100, with higher scores indicative of better overall health. 
6.4.4.3 
WPAI-GH 
The WPAI-GH is a 6-item instrument assessing work and activity impairment due to health 
problems during the past 7 days. The instrument elicits four main scores in relation to general 
health specifically: absenteeism (the percentage of work time missed because of one's health in 
the past 7 days), presenteeism (the percentage of impairment experienced while at work in the 
past 7 days because of one's health), overall work productivity loss (an overall impairment 
estimate that is a combination of absenteeism and presenteeism), and activity impairment (the 
percentage of impairment in daily activities because of one's health in the past 7 days) (Reilly et 
al. 1993). 
6.4.4.4 
HADS 
The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale to detect states of 
depression, anxiety, and emotional distress amongst subjects who were being treated for a 
variety of clinical problems (Zigmond and Snaith 1983). The scale has a total of 14 items. Seven 
of the items relate to anxiety and seven relate to depression. The responses are scored on a scale 
of 0–3 (3 indicates higher symptom frequencies). Scores for each subscale (anxiety and 
depression) range from 0 to 21 with scores categorized as follows: normal 0–7, mild 8–10, 
moderate 11–14, and severe 15–21. Scores for the entire scale (emotional distress) range from 0 
to 42, with higher scores indicating more distress. This scale reflects how a subject has been 
feeling during the past week. 
6.4.4.5 
SF-12v2 
The SF-12v2 Health Survey is a reliable and valid generic measure of functional health and 
wellbeing. The SF-12v2 consists of 12 questions, all selected from the SF-36 Health Survey 
(Ware et al. 1996). The SF-12v2 yields eight health domains (physical functioning, role physical, 
bodily pain, general health, vitality, social functioning, role emotional, and mental health). 
Physical and Mental Health Composite Scores (PCS & MCS) can be computed using the scores 
of 12 questions and range from 0 to 100, where a zero score indicates the lowest level of health 


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measured by the scales and 100 indicates the highest level of health. The standard form of the 
instrument asks patients to reply to questions according to how they have felt over the last 4 
weeks. 
6.4.4.6 
Angioedema Control Test (AECT) 
The Angioedema Control Test (AECT) is a patient reported outcome measure. The concept of 
the AECT is comparable to those of the well-established Asthma Control Test (ACT) and 
Urticaria Control Test (UCT) (Nathan et al. 2004; Weller et al. 2014). The AECT could be used 
to assess control of angioedema among patients with recurrent angioedema (including hereditary 
angioedema) and to aid treatment decisions. The AECT consists of up to 10 questions. Each 
question has 5 answer options (verbal rating scale) that are scored from 0 to 4 points, which 
ultimately comprise the total AECT score. 
6.4.4.7 
Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
The TSQM-9 is a validated 9-item questionnaire developed to measure subjects’ satisfaction 
with their medication and includes three scale scores: effectiveness, convenience, and global 
satisfaction (Bharmal et al. 2009). Scale scores for each of the 3 scales, as well as a combined 
score are calculated separately. Scores are transformed to a 0 to 100 scale, where higher scores 
indicate greater treatment satisfaction. The TSQM-9 has been applied in clinical studies in 
several chronic conditions. 
6.4.4.8 
Subject’s and Investigator’s Global Impression of Change 
The subjects’ and investigators’ global impression of treatment response will be assessed using a 
one-item question. The item will assess overall perception of treatment response. Assessment 
will be performed separately by the subject and investigator. The subjects and investigators will 
be asked to think of “today” while rating the question (or an appropriate translation, as 
applicable): “Overall, how would you rate your response to the study medication?” There will be 
five response options; namely, poor; fair; good; very good, excellent. 
6.4.5 
DX-2930 Injection Report and Self-Administration and Subcutaneous Injection 
Survey 
Assessments of subject experience with self-administration and SC injections of DX-2930 will 
be conducted. 
After receiving appropriate training, to include retention of all used and unused vials of IMP for 
drug accountability, subjects are allowed to self-administer DX-2930 after receiving the first 2 
doses of DX-2930 at the study site. Subjects who choose to self-administer or have a parent/legal 
guardian/caregiver administer DX-2930 must complete an assessment of their experience with 
self-administration and SC injection for each dose received. Study personnel will document the 
subject’s responses in the subject’s medical record and eCRF. 


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7. 
STATISTICAL ANALYSIS 
7.1 
 General Methodology 
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, Cary, 
North Carolina, USA). Separate analytic plans will be developed to support analysis of PK data 
and quality of life data. 
All data listings will be sorted by rollover status, prior treatment group for roll-over subjects and 
LTP therapy for non-rollover subjects, site, and subject number, and will include the subject’s 
age, sex, and race.  
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation, minimum, and maximum 
values will be presented. Where applicable, estimates from statistical model of least squares 
means, treatment differences, standard errors, p-values, and 95% confidence intervals for least 
squares mean treatment differences will be provided. The time to the first investigator-confirmed 
HAE attack will be summarized using Kaplan-Meier methods for the 03 study treatment groups, 
and DX-2930 total groups combined. Kaplan-Meier estimates of the 10th, 20th, 25th, 30th, 40th, 
50th (median), and 75th percentiles with associated 2-sided 95% confidence intervals for the 
median, as well as percentage of censored observations and the number of events, will be 
presented. The number and percentage of subjects, as estimated using the Kaplan-Meier method, 
with the first HAE attack by 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, and 8 weeks are 
presented for each group. Plots of the KM curves and supporting data listings detailing each 
subject’s contribution to the analysis will be provided.  
No formal statistical hypothesis testing will be performed. All p-values will be considered 
descriptive. 
For the summary statistics of all numerical variables unless otherwise specified, minimum and 
maximum will be displayed to the same level of precision as the data collected. Mean and 
median will be displayed to one level of precision greater than the data collected. Standard 
deviation will be displayed to two levels of precision greater than the data collected. P-values 
will be rounded to 3 decimal places, p-values <0.0005 will be displayed as <0.001. 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts. The denominator for all percentages will be the number 
of subjects for that treatment group within the population of interest, unless otherwise specified. 
See Appendix 2 for detailed descriptions of analysis definitions and programming conventions. 
7.2 
 Analysis Populations 
The analysis populations will be defined as follows:  


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7.2.1 
Safety Population 
The Safety Population will include all subjects who received any study drug after entering the 
DX-2930-04 study (ie, any exposure to open-label DX-2930). Unless otherwise specified, 
summary tabulations conducted with the Safety Population will be presented by the subject’s 
study entry type (rollover or non-rollover) and overall.  
7.2.2 
Rollover Safety Population 
The Rollover Safety Population is the subset of subjects who participated in the DX-2930-03 
study and received any study drug after entering the DX-2930-04 study (ie, any exposure to 
open-label DX-2930). Unless otherwise specified, summary tabulations conducted with the 
Rollover Safety Population will be presented by the subject’s prior treatment group from the 
DX-2930-03 study (Placebo, DX-2930 150 mg every 4 weeks, DX-2930 300 mg every 4 weeks, 
DX-2930 300 mg every 2 weeks). 
7.2.3 
Non-Rollover Safety Population 
The Non-rollover Safety Population is the subset of subjects who entered the DX-2930-04 study 
directly and received any study drug after entering the DX-2930-04 study (ie, any exposure to 
open-label DX-2930). Unless otherwise specified, summary tabulations conducted with the 
Non-rollover Safety Population will be presented by subject’s prior type of LTP therapy prior to 
study entry (No LTP Use, C1-INH only, Oral Therapy, and C1-INH and Oral Therapy). The 
purpose of subdividing the Non-rollover Safety Population based on the subjects’ prior type of 
LTP therapy is to explore the impact of prior LTP on transitioning to the new treatment. 
7.3 
Subject Disposition 
The number of subjects with informed consent, treated with study drug, completed study, 
completed study or transitioned to commercial product, and discontinued prematurely by reason, 
including subjects transitioned to commercial product, will be summarized for each analysis 
population. Within each analysis population, these categories will be presented by prior DX-
2930-03 treatment group for rollover subjects, LTP therapy prior to study entry for non-rollover 
subjects, and overall. Listings of all disposition data will be provided. 
7.4 
Protocol Deviations 
Protocol deviations will be collected at both the site and subject level.  
Deviations at the site level will be applied to all subjects who were enrolled at that site at the 
time of the deviation. Deviation types for site-level deviations are use of incorrect equipment, 
use of incorrect forms, use of expired laboratory samples, use of equipment with expired 
maintenance, study procedure completed by non-authorized personnel, site personnel did not 
complete training prior to completing study procedure, amendment implementation without 
approval/notification of institutional review board/ethics committee (IRB/EC), temperature 
excursion, investigational product (IP), and other.  


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Deviation types for subject-level deviations are eligibility criteria, informed consent/assent/ 
HIPAA, concomitant medication, investigational product, study visit (missed/out of window), 
study procedure (missed/out of window), site personnel/assessor error safety reporting, IRB/EC 
reporting, EQ-5D, Angioedema Quality of Life, lab collection, and other (not otherwise defined). 
Summary tables of protocol deviations by rollover status and overall will be provided for the 
Safety Population. All protocol deviations will be included in a subject listing.  
7.5 
Demographic and Other Baseline Characteristics 
Baseline and demographic variables will be descriptively summarized for each analysis 
population.  
Demographic variables to be presented include the following:  
- age (years), 
- age group (<18, 18 to <40, 40 to <65, ≥65 years),  
- sex (male, female), 
- ethnicity (Hispanic, Non-Hispanic, Not Reported, Unknown),  
- race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian 
or Other Pacific Islander, White, Multiple, and Other), 
- race group (White, Other), 
- geographical region (US, Canada, Europe, and Jordan), 
- height (cm), 
- weight (kg), 
- weight group (<50, 50 to <75, 75 to <100, ≥100 kg),  
- BMI (kg/m2), 
- BMI group for subjects ≥ 18 years of age (Underweight: <18.5, Normal: 18.5 to <25, 
Overweight: 25 to <30, Obese: ≥30 kg/m2) , 
- BMI percentile group for subjects < 18 years of age (Underweight: < 5th percentile, Healthy or 
Overweight: 5th – 95th percentile, Obese: ≥ 95th percentile), 
- long term prophylactic (LTP) therapy use (C1-INH, Androgens, Anti-fibrinolytics, or not on 
LTP), 
- type of LTP therapy (C1-INH, Oral Therapy, C1-INH and Oral Therapy, not on LTP) 
For rollover subjects, the LTP presented is the LTP used prior to randomization into the DX-
2930-03 study. 
A separate table will be created for HAE history and will include age at onset of angioedema 
symptoms, HAE type (Type I, Type II, Unspecified), history of laryngeal attacks, primary attack 
locations, number of attacks in the last 1, 3, and 12 months, and baseline HAE attack rate 
(attacks/4 weeks) (refer to Appendix 2.9.1 for a definition of the baseline HAE attack rate). All 
baseline and demographic data will be presented in subject listings. 
In order to explore the demographics of those subjects who self-administer the study drug, an 
additional table will be included that presents demographics for the subgroup of administration 
types (subjects with > 80% self-administration, subjects with > 80% administration by study 
staff in-clinic, and subjects with < 80% self-administration and < 80% administration by study 
staff in-clinic). 


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7.6 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 20.0 and summarized by system organ class (SOC) and preferred term (PT) for each 
analysis population. Tabulations will be presented sorted by SOC in alphabetical order and by 
PT within each SOC by descending frequency of the overall population. Medical History events 
reported in the DX-2930-03 study are included for rollover subjects. All medical history will be 
presented in subject listings.  
7.7 
Treatment Compliance and Extent of Exposure 
All planned study drug administrations will be recorded in the eCRF, including whether the 
injection was given by study staff in clinic, self-administered in clinic, or self-administered at 
home; whether a full, partial, or no dose was given; date and time of dose; and location of the 
injection.  
Because of the Dose-and-wait stage of the treatment period for rollover subjects, the number of 
planned doses is defined as the number of doses a subject is scheduled to receive during the 
Regular Dosing stage (refer to Appendix 2.7.2.2 for a definition of the regular dosing stage) plus 
1 (to include the initial dose of study drug on the DX-2930-04 study). Treatment compliance will 
be described by the percentage of planned doses received by the subject, total number of doses 
received by the subject, and the number and percentage of subjects that received at least 80% of 
planned doses, summarized for each analysis population.  
For each analysis population, exposure to the study treatment will be summarized using total 
dose (the total number of mg of DX-2930 a subject receives on the DX-2930-04 study), time on 
study (exposure duration during the treatment period), exposure duration excluding drug 
interruption (efficacy), exposure duration excluding drug interruption (safety).Duration of 
participation categorized by <1 month, 1-<3 months, 3-<6 months, 6-<12 months, 12-<18 
months, 18 - <24 months, and 24-<33 months; or ≥ 6 months, ≥9 months,  ≥ 12 months, ≥18 
months, ≥ 24 months, and ≥ 30 months will be provided for the exposure duration during the 
treatment period. Summaries will also be provided for each analysis population of the total 
number of doses received, percentage of injections that were self-administered at home, self-
administered in the clinic, and administered by the study staff in-clinic. Listings of study 
administrations by subject will also be provided. 
A listing of subjects with drug interruption will be provided. 
7.8 
Analysis of Efficacy 
All efficacy analyses will be performed separately on the Safety Population, Rollover Safety 
Population and Non-Rollover Safety Population.  
7.8.1 
Primary Efficacy Analysis 
The primary objective for this study is safety.  All efficacy endpoints are secondary. 


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7.8.2 
Secondary Efficacy Analyses 
There are 5 secondary efficacy endpoints for this study: 
• Time from first open-label study dose to the first investigator-confirmed HAE attack for 
rollover subjects 
• Number of investigator-confirmed HAE attacks during the treatment period  
• Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period  
• Number of moderate or severe investigator-confirmed HAE attacks during the treatment 
period  
• Number of high-morbidity investigator-confirmed HAE attacks during the treatment 
period  
Time to first investigator-confirmed HAE attack 
Time to the first investigator-confirmed HAE attack will be analyzed using the Rollover Safety 
Population.  
These data will be used to explore the potential "outer bounds" of dosing frequency against a 
background of prior exposure to DX-2930 from Study DX-2930-03. A KM plot of time to first 
investigator-confirmed HAE attack will be produced by the prior treatment group from Study 
DX-2930-03. Additionally, a similar plot will be presented for only the first 8 weeks in the DX-
2930-04 study. Additionally, a KM plot of time to first investigator-confirmed HAE attack will 
be produced for the DX-2930 total group and placebo group, and another KM plot will present 
the DX-2930 total group and placebo group for the first 8 weeks. If a subject has not had an 
attack, the subject will be censored at the earlier of the early discontinuation date, database cut 
date, or Day 924 visit of the DX-2930-04 study. Subjects who received the second dose of study 
drug prior to the first attack will be censored at the date of their second dose of study drug. Each 
subject’s censoring status and time to event will be provided in a listing. Details on the 
calculation of time to first investigator-confirmed HAE attack can be found in Appendix 2.9.3. 
In addition, the impact of baseline covariates on the time to the first investigator-confirmed HAE 
attack will be examined using Cox proportional hazards regression models. A Cox proportional 
hazards model will be conducted using DX-2930 concentration level at Day 0 of the DX-2930-
04 study prior to the first dose of the study drug as the independent variable and time to first 
HAE attack as the dependent variable. Additional Cox PH models will be run using age group, 
weight group, BMI group , sex, race group, baseline HAE attack rate group, HAE type, 
geographic region, and history of laryngeal attacks as independent variables adjusting for DX-
2930 concentration level at Day 0 in the DX-2930-04 study with time to first HAE attack as the 
dependent variable. Additional models may be considered as appropriate. Results of this 
exploratory analysis will be summarized and will include hazard ratios, corresponding 95% 
confidence intervals and p-values for each factor. 


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Number of investigator-confirmed HAE attacks 
The number of investigator-confirmed HAE attacks during the treatment period (Day 0 through 
the end of treatment period ), expressed as a monthly HAE attack rate, will be summarized for 
each analysis population. For non-rollover subjects, the monthly attack rate will be reported for 
the entire treatment period. For rollover subjects, the monthly attack rate will be reported for the 
Regular Dosing stage of the treatment period (refer to Appendix 2.7.2.2 for a definition of the 
Regular Dosing stage).  
Detailed information on calculating the baseline HAE attack rate and the HAE attack rate during 
the treatment period can be found in Appendix 2.9.1 and Appendix 2.9.2 respectively. 
For the Rollover Safety Population, the following will be summarized: the baseline investigator-
confirmed HAE attack rate per month (DX-2930-03 run-in period monthly investigator-
confirmed HAE attack rate), DX-2930-03 treatment period investigator-confirmed HAE attack 
rate per month, the Regular Dosing stage investigator-confirmed HAE attack rate per month, the 
Regular Dosing stage investigator-confirmed HAE attack rate change from the monthly attack 
rate in the DX-2930-03 run-in period, the Regular Dosing stage investigator confirmed HAE 
attack rate change from the monthly attack rate in the DX-2930-03 treatment period, the percent 
change of the Regular Dosing stage investigator-confirmed HAE attack rate from the run-in 
period attack rate in the DX-2930-03 treatment period , and the percent change of the Regular 
Dosing stage investigator-confirmed HAE attack rate from the monthly attack rate in the DX-
2930-03 treatment period.   
An additional table for the Rollover Safety Population will be added that categorizes rollover 
subjects by their prior LTP and the following will be summarized: the historical HAE attack rate 
(HAE attack rate as reported in the last 3 months in the HAE history Appendix 2.9.1), the 
Regular Dosing stage investigator-confirmed HAE attack rate per month, the Regular Dosing 
stage investigator-confirmed HAE attack rate change from the historical monthly attack rate,  
and the percent change of the Regular Dosing stage investigator-confirmed HAE attack rate from 
the historical attack rate. 
For the Non-rollover Safety Population, the baseline HAE attack rate for non-rollover subjects 
are derived from the number of attacks reported in the last 3 months in the HAE history 
(Appendix 2.9.1). The following will be summarized for the Non-Rollover Safety population: the 
baseline investigator-confirmed HAE attack rate per month, the treatment period investigator-
confirmed HAE attack rate per month, and the treatment period investigator-confirmed HAE 
attack rate change from baseline.  
Pooled results for the Rollover Safety Population and Non-Rollover Safety Population will be 
presented for the Safety Population. The summaries will include the total number of investigator-
confirmed HAE attacks reported during each period, total subject-time in months that each 
subject contributed to each period, summary statistics for the baseline investigator-confirmed 
HAE attack rate per month, the treatment period (Regular Dosing stage for rollover subjects) 
investigator-confirmed HAE attack rate per month, and the treatment period (Regular Dosing 
stage) investigator-confirmed HAE attack rate change and percent change from baseline. Figures 
will be created for each analysis population plotting the on-study investigator-confirmed HAE 


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attacks reported during the treatment period by prior LTP use for the Non-Rollover Safety 
Population and the Regular Dosing stage by prior treatment in the DX-2930-03 study for the 
Rollover Safety Population for each subject (ie, birds on a wire plots). A graph showing results 
in the Safety Population by pooling results from rollover subjects and non-rollover subjects. All 
subjects with less than 50% reduction in HAE attacks from the run-in period to the treatment 
period will be presented in a listing which include the unique subject id, age, sex, race, weight, 
weight group, timepoints of anti-drug antibody testing, confirmation of anti-drug antibody 
testing, time point of test for neutralizing antibody,  result of test for neutralizing anti-body, 
baseline attack rate, attack rate during the treatment period (regular dosing stage for rollover 
subjects), treatment period percent change from baseline, steady state treatment period percent 
change from baseline. 
In addition, the number of investigator-confirmed HAE attacks per month (defined as 28 days) 
will be summarized descriptively by study month (per 28-day interval) for each study population.    
The summary will include baseline number of attacks, the number, change from baseline, and 
percentage change from baseline of investigator-confirmed HAE attacks for each study month.  
For the Rollover Safety Population, investigator-confirmed HAE attack per month for each study 
month will be summarized for the Regular Dosing stage. A bar chart representing the number of 
attacks per month during the Regular Dosing stage and a separate bar chart presenting the 
percent change from the DX-2930-03 treatment period attack rate for each study month during 
the Regular Dosing stage will be presented. An additional bar chart presenting the percent 
change from baseline, the DX-2930-03 run-in period will be presented for each study month 
during the Regular Dosing stage. 
For the Non-rollover Safety Population, the number of investigator-confirmed HAE attacks per 
month will be grouped into 28-day intervals using the start date of the HAE attack using Table 1 
below.   
For the Safety Population, investigator-confirmed HAE attack per month for each study month 
will be presented for the Safety Population, pooling results from Rollover Safety Population and 
Non-rollover Safety Population. In this summary, for Rollover Safety Population, the DX-2930-
03 study baseline HAE attack rate will be used as the baseline. 
Table 1 Defining Treatment Months for Non-Rollover Subjects 
Visit 
Month 
Study Day 
3 
1 
0-27 
5 
2 
28-55 
7 
3 
56-83 
9 
4 
84-111 
11 
5 
112-139 
13 
6 
140-167 
15 
7 
168-195 
17 
8 
196-223 
19 
9 
224-251 
21 
10 
252-279 


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Table 1 Defining Treatment Months for Non-Rollover Subjects 
Visit 
Month 
Study Day 
23 
11 
280-307 
25 
12 
308-335 
27 
13 
336-363 
29 
14 
364-391 
31 
15 
392-419 
33 
16 
420-447 
35 
17 
448-475 
37 
18 
476-503 
39 
19 
504-531 
41 
20 
532-559 
43 
21 
560-587 
45 
22 
588-615 
47 
23 
616-643 
49 
24 
644-671 
51 
25 
672-699 
53 
26 
700-727 
55 
27 
728-755 
57 
28 
756-783 
59 
29 
734-811 
61 
30 
812-839 
63 
31 
840-867 
65 
32 
868-895 
67 (End of Treatment Period) 
33 
896-924 
68 (Follow-up 1) 
- 
925-938 
69 (Follow-up 2; End of 
Study; Early Termination) 
- 
939-952 
 
For the Safety Population, the baseline investigator-confirmed HAE attack rate, treatment period 
(Regular Dosing Stage for rollover subjects) investigator-confirmed HAE attack rate, and 
treatment period (Regular Dosing Stage for rollover subjects) change from baseline on 
investigator-confirmed HAE attack rate will be summarized by the percentage of self-
administration during the study. Subjects will be subgrouped by the percentage of self-
administration during the treatment period: 
Predominant Self-administration: greater than or equal to 80% self-administration 
Predominant HCP-administration: greater than or equal to 80% administration by study staff in-
clinic 
Mixed administration: less than 80% self-administration and less than 80% administration by 
study staff in-clinic 


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All HAE attacks will be presented in a listing. All laryngeal HAE attacks will be presented in a 
listing.   
Number of investigator-confirmed HAE attacks requiring acute treatment during the treatment 
period 
This endpoint will be analyzed using the same methods as for the overall number of investigator-
confirmed HAE attacks with the exception of the monthly line graphs. The listing of HAE 
attacks will include the specific acute treatments given during the attack. 
Number of moderate or severe investigator-confirmed HAE attack 
The severity of the HAE attack will be determined by the investigator. See Appendix 2.8.6 for 
details. The number of moderate or severe investigator-confirmed HAE attacks will be presented 
using the methods for the overall number of investigator-confirmed HAE attacks with the 
exception of the monthly line graphs.  The listing of HAE attacks will include severity. 
Number of high-morbidity investigator-confirmed HAE attacks during the treatment period 
A high-morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation < 24 
hours), hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal edema. This endpoint will be analyzed 
using the methods for the overall number of investigator-confirmed HAE attacks with the 
exception of the monthly line graphs.  The listing of HAE attacks will include a high morbidity 
flag. 
7.8.3 
Exploratory Efficacy Analyses 
Number and percentage of subjects that are attack-free during the treatment period 
The number and percentage of subjects who are attack-free for 3 months or 6 months or for the 
entire treatment period (Regular Dosing stage for the Rollover Safety Population) will be 
summarized for each analysis population.  
In addition, the number and percentage of subjects who are attack-free for 6 months during each 
of the 6 month intervals (0- <6 months, 6- <12 months, 12- <18 months, 18-<24 months, and 24-
<30 months) for the treatment period (regular Dosing Stage for the Rollover Safety Population) 
will be summarized.  Also, the number and percentage of subjects who are attack-free for 4  
months during each of the 4 month intervals (0-<4 months, 4-<8 months, 8-<12months, 12-<16 
months, 16-<20 months, 20-<24 months, 24-<28 months, and 28-<32 months) for the treatment 
period (regular Dosing Stage for the Rollover Safety Population) will be summarized. 
Subjects who have not completed the full interval but are attack-free for the time observed, will 
be counted as attack-free for the full interval in the analysis.  


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Percentage of HAE attack-free days 
The percentage of HAE attack-free days will be summarized for each analysis population. An 
attack-free day is defined as a calendar day with no investigator-confirmed HAE attacks.  
For the Non-Rollover Safety Population, the percentage of HAE attack-free days will be 
calculated by counting the number of days in the treatment period without an HAE attack and 
dividing by the number of days the subject spends in the treatment period. For the Rollover 
Safety Population, the percentage of HAE attack-free days will be calculated by counting the 
number of days in the Regular Dosing stage of the treatment period without an HAE attack and 
dividing by the number of days the subject spends in the regular dosing stage of the treatment 
period. For the Safety Population, pooled results in the Non-Rollover Safety Population and the 
Rollover Safety Population will be presented. Summaries of the percentage of HAE attack-free 
days will be provided by treatment group in the DX-2930-03 study for the rollover subjects and 
by prior LTP use for the non-rollover subjects for overall treatment period for non-rollover 
subjects and the Regular Dosing stage of the treatment period for the rollover subjects.  
Summary of attack-free period 
For each subject, the mean duration of an attack-free period will be derived by taking the average 
of the attack-free periods for the subject. Summary of the mean attack-free period will be 
provided for the Safety Population, Rollover Safety Population, and the Non-Rollover Safety 
Population. In this analysis, an attack-free day is defined as a calendar day with no investigator-
confirmed HAE attack.  An attack-free period is defined as a continuous number of days without 
any investigator-confirmed HAE attacks.  For the Rollover Safety Population, the summary of 
mean attack-free periods will be described during the regular dosing stage of the treatment 
period. 
For each subject, the longest duration of an attack-free period will be derived by taking the 
longest duration of the attack-free periods for the subject. Summary of the longest attack-free 
period will be provided for the Safety Population, Rollover Safety Population, and the Non-
Rollover Safety Population.  For the Rollover Safety Population, the summary of longest attack-
free periods will be described during the regular dosing stage of the treatment period. 
Additionally, a categorical summary for the longest duration of an attack-free period will be 
presented.  The number and percentage of subjects with the longest duration that are within the 
categories of 0 to < 3 months, 3 to < 6 months, 6 to < 9 months, 9 to < 12 months, and > 12 
months will be summarized. 
Achievement of a pre-specified reduction from baseline in the investigator-confirmed HAE attack 
rate (ie, responder analysis)  
Achievement of a pre-specified reduction from baseline in the investigator-confirmed HAE 
attack rate will be analyzed for each analysis population. There will be five classes of responders 
based on pre-specified percentage reduction in the investigator-confirmed HAE attack rate from 
the baseline attack rate: 50% or more reduction, 60% or more reduction, 70% or more reduction, 
80% or more reduction and 90% or more reduction. For each subject, a treatment period HAE 


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attack rate baseline HAE attack rate will be calculated. See Section 10.2.9 for details. The 
percentage reduction will be calculated as the baseline HAE attack rate minus the treatment 
period (regular dosing stage for rollover subjects) HAE attack rate divided by the baseline HAE 
attack rate. Summary statistics will be presented for each of the five classes of responders by 
treatment. The five classes of responders are nested within each other and not mutually 
exclusive. 
The Non-rollover Safety Population subjects with 0 baseline attack rate will be excluded from 
this analysis.  
Achievement of <1 investigator-confirmed HAE attacks per month during the treatment period 
(regular dosing stage for rollover subjects) 
The number and percentage of subjects who had less than 1 investigator-confirmed HAE attack 
per month will be presented for each analysis population.   
Characteristics of investigator-confirmed HAE attacks, including attack duration, severity, 
location, trigger, and medication use during the treatment period 
For each analysis population, attack characteristics at the subject level and event level, as 
described below, will be summarized for the treatment period for non-rollover subjects and the 
Regular Dosing stage for rollover subjects. 
Subject level HAE attack characteristics 
HAE Attack Duration 
For each subject, the mean duration of all investigator-confirmed HAE attacks will be calculated 
in hours and summarized. See Appendix 2.8 for details on handling HAE attack data. The 
subject-level average attack duration will be categorized into 12 hour intervals and tabulated by 
category (<12 hours, 12-24 hours, >24-48 hours, and >48 hours).   
HAE Attack Severity 
For each subject, the mean and maximum severity of all investigator-confirmed HAE attacks will 
be calculated using a numerical rating and summarized. See Appendix 2.8.6 for details. The 
number and percentage of subjects will be tabulated by maximum attack severity (no attacks, 
mild, moderate, and severe).   
Event level HAE attack characteristics 
HAE Attack Location 
The number and percentage of subjects with attacks, as well as the total number of attacks, will 
be tabulated by the primary attack location (peripheral, abdominal, and laryngeal) as determined 
by the investigator. Additionally, the attack location will be re-classified and summarized with 
an emphasis on laryngeal attacks. In this summary, an attack with either the primary or 


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secondary location(s) identified as laryngeal will be considered as a laryngeal attack; otherwise 
attacks will be classified by their reported primary attack location.   
7.8.4 
Rescue Medication Use 
The number and percentage of subjects with rescue medication use for an HAE attack, as well as 
the number of rescue medications, will be tabulated by rescue medication by type (ecallantide, 
icatibant, nano-filtered C1-INH, plasma-derived C1-INH, recombinant C1-INH, fresh frozen 
plasma, and other) as reported in the AE CRF.  
7.8.5 
Supportive Treatment Use 
The number and percentage of subjects with supportive treatment use for an HAE attack, as well 
as the number of events, will be tabulated by supportive treatment by type (IV fluids, pain 
medication, oxygen, anti-emetic, and other) as reported in the AE CRF.  
7.8.6 
Trigger 
The number and percentage of subjects with trigger for an HAE attack, as well as the number of 
triggers, will be tabulated by type of triggers as reported in the AE CRF.   
The subject-level and event-level HAE characteristics analyses will be repeated for the safety 
population for the primary endpoints in subgroups of subjects with ≤50% reduction in attack-rate 
from baseline and subjects with > 50% reduction in attack-rate from baseline. Subjects with 0 
baseline attack rate will be excluded from this analysis. 
Rescue Medication Use  
A summary of the number of HAE attacks by type and number of rescue medication uses will be 
calculated for the Safety Population.  The summary will present the overall number of HAE 
attacks, and number of HAE attacks by number of rescue medication uses (no rescue medication 
use, 1 rescue medication use, or more than 1 rescue medication use). The attacks that required 
rescue medication use will be further summarized by type of rescue medication (C1-INH, 
icatibant, other, or a mixture of rescue medications) and number of rescue medication uses (1 
rescue medication or more than 1 rescue medication).  
An additional table will be created for an event level summary of duration (hours) of 
investigator-confirmed HAE attacks by severity, location, and rescue medication use for the 
Safety Population.  Investigator-confirmed HAE attacks will be classified by severity (Mild, 
Moderate, Severe) and rescue medication use (No rescue medication use, C1-INH, icatibant, 
other) or by location (Laryngeal, Abdominal, Peripheral) and rescue medication use. Duration of 
HAE attacks will then be summarized for each subset of the attacks using summary statistics.  
7.9 
Analysis of Safety 
All safety analyses will be performed separately on the Safety Population, Rollover Safety 
Population, and Non-Rollover Safety Population, unless otherwise specified.   No inferential 
statistics are planned. 


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7.9.1 
Adverse Events 
AEs will be coded using the MedDRA coding dictionary version 20.0.  
The analyses described in this section will be based on treatment-emergent AEs, referred to 
simply as AEs in this section for brevity. The definition of treatment-emergent AEs can be found 
in Appendix 2.10.1.  
Related AEs are AEs classified as related to study drug by the investigator.  Severe AEs are AEs 
classified as severe (GRADE 3) or life-threatening (GRADE 4) by the investigator. 
For this analysis, AEs will be classified to one of two analysis periods: 
Treatment Period AEs will include all AEs starting at or after the first exposure to open-label 
DX-2930 in the current study to those starting before or at the subject’s last visit date during the 
treatment period in the current study (AEs starting at or after treatment on Day 0 but before or at 
the end of treatment period). 
Follow-up Period AEs will include all AEs starting at or after the subject’s last visit date of the 
treatment period in the current study (AEs starting after the Day 924 visit, the last visit during the 
treatment period). For AEs with partial onset times, non-missing date parts will be used to 
determine whether the AE falls within the period. If a determination cannot be made using the 
non-missing date parts, the AE will be conservatively counted as a treatment-period AE. Follow-
up period AEs will be presented in listings. 
For each analysis of the Rollover Safety Population, the AEs will be presented for the treatment 
period,  and the Dose-and-wait stage and the Regular Dosing stage of the treatment period (refer 
to Appendix 2.7.2.1 for a definition of the Dose-and-wait stage and Appendix 2.7.2.2 for a 
definition of the Regular Dosing stage) unless otherwise specified. For each analysis of the Non-
rollover Safety Population, the AEs will be presented for the treatment period and the Tapering 
stage and Non-tapering stage of the treatment period (refer to Appendix 2.7.2.3 for a definition 
of the Tapering stage and Appendix 2.7.2.4 for a definition of the Non-tapering stage of the 
treatment period) unless otherwise specified. For each analysis of the Safety Population, pooled 
results from the Rollover Safety Population and Non-rollover Population will be presented for 
the treatment period. 
For each study population and each treatment stage, the total subject-time in years, average 
subject-time (years), total number of doses across all subjects, and average number of doses for 
each subject will  be presented for the summary AE tables, as well as  the number and percentage 
of subjects with any AE, any related AE, any SAE, any related SAE, any severe AE, any related 
severe AE, and any investigator-reported AESI, as well as the total number of events for each 
category, will be summarized for the treatment period.   The number of deaths due to an AE, 
hospitalizations due to an AE, and study discontinuations due to an AE will be summarized for 
the treatment period.  
For each analysis population, the number and percentage of subjects with an AE, as well as the 
total number of AEs, will be summarized by SOC and PT for the treatment period. This 


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tabulation will be repeated for related AEs, SAEs, related SAEs, severe AEs, and related severe 
AEs for treatment period AEs. Tabulations will be presented sorted by SOC in alphabetical order 
and by PT within each SOC by descending frequency in the total column of the Safety 
Population. 
For each analysis population, the number and percentage of subjects with an AE will be 
summarized by maximum severity, SOC, and PT for the treatment period. Subjects will be 
counted once per SOC and once per PT at the maximum severity. Tabulations will be presented 
sorted by SOC in alphabetical order and by PT within each SOC by descending frequency in the 
total column of the Safety Population. 
For each analysis population, the number of AEs will be summarized by severity, SOC, and PT 
for the treatment period. Tabulations will be presented sorted by SOC in alphabetical order and 
by PT within each SOC by descending frequency in the total column of the Safety Population. 
For each analysis population, the number and percentage of subjects with an AE, as well as the 
total number of AEs, will be summarized by PT for treatment period AEs only. This tabulation 
will be repeated for related AEs and severe AEs for treatment period AEs for each study 
population. 
All AEs will be provided in subject listings. In addition, subject listings of AEs causing 
discontinuation of study medication, AEs leading to death, SAEs, related AEs, severe AEs, and 
AESIs will be produced. 
Adverse Events of Special Interest (AESI) 
Adverse events of special interest AESIs for this study are hypersensitivity reactions and 
disordered coagulation (hypercoagulability events and bleeding events).  Investigators are 
required to document any potential AESIs on the CRF page, and notify the sponsor within 24 
hours. In addition to investigator-reported AESIs, standardized MedDRA Queries (SMQ) for 
each AESI category will be performed using the study data.  
Summaries of AESIs will be presented for the treatment period for the Safety Population, for the 
treatment period and regular dosing stage of the treatment period for the Rollover Safety 
Population, and for the treatment period and Tapering stage of the Non-Rollover Safety 
Population. 
Investigator-reported AESIs and SMQ-defined AESIs will be summarized separately, as shown 
below: 
Summary of AESI: For each analysis population, the number and percentage of subjects with 
any AESI, any related AESI, any severe AESI, any related severe AESI, any serious AESI, and 
any related serious AESI, as well as the total number of events for each category, will be 
summarized. The number of deaths due to an AESI, hospitalization due to an AESI and study 
discontinuation due to an AESI will be summarized for each analysis period.   


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AESIs by SOC and PT: For each analysis population, the number and percentage of subjects 
with an AESI, as well as the total number of AESIs, will be summarized by SOC and PT for 
each analysis period. This tabulation will be repeated for related AESIs for the treatment period. 
Tabulations will be presented sorted by SOC in alphabetical order and by PT within each SOC 
by descending frequency in the overall DX-2930 group and then the placebo group.  
Related AESIs by SOC and PT: For each analysis population, the number and percentage of 
subjects with a related AESI, as well as the total number of related AESIs, will be summarized 
for each treatment group and overall DX-2930 by SOC and PT for the treatment period. 
Tabulations will be presented sorted by SOC in alphabetical order and by PT within each SOC 
by descending frequency in the rollover subjects and then in the non-rollover subjects.  
SMQ-defined hypersensitivity AESIs during the treatment period include several different terms 
describing injection site reactions. The Data Monitoring Committee (DMC) pointed out that 
including these terms in the tabulation could detract from the focus on systemic AESIs. 
Therefore, tables on SMQ-defined hypersensitivity AESIs during the treatment period will be 
summarized in two ways: a display with all injection site reaction terms (PTs containing 
‘Injection site,’ ‘Administration site,’ or ‘Application site’) included, and a display with all 
injection site reaction terms excluded. Additionally, HAE preferred terms will be removed from 
SMQ-defined hypersensitivity summaries. 
A listing of investigator-reported AESIs will be provided.  
Injection Site Reactions (ISR) 
ISR AEs were not predefined in the protocol, but instead are identified using the algorithm 
detailed in Appendix 2.10.5 based on the spontaneous reporting of adverse events.  
The number and percentage of subjects with any ISR AE, any related ISR AE, any severe ISR 
AE, any related severe ISR AE, any ISR SAE, and any related ISR SAE, as well as the total 
number of events for each category, will be summarized for each analysis population. The 
number of deaths due to an ISR AE, hospitalization due to an ISR AE, and study discontinuation 
due to an ISR AE will be summarized for each analysis population.  
The number and percentage of subjects with an ISR AE, as well as the total number of ISR AEs, 
will be summarized for each analysis population by SOC, and PT for the treatment period. The 
number and percentage of subjects with an ISR AE will be summarized for each analysis 
population by SOC, PT, and maximum severity for the treatment period.  Tabulations will be 
presented sorted by SOC in alphabetical order and by PT within each SOC by descending 
frequency in the rollover subjects, then non-rollover subjects.  
For each analysis population, the number ISR AEs will be summarized by severity, SOC, and PT 
for the treatment period. Tabulations will be presented sorted by SOC in alphabetical order and 
by PT within each SOC by descending frequency in the total column of the Safety Population. 


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The number of injections, number of injection site reactions, and the percent of injections with 
ISR AEs will be summarized by the administration type of the injection and location of the 
injection. 
The duration of ISR AEs overall and by PT will be summarized numerically (summary statistics) 
and categorically (0 - 0.5 hour, >0.5 - 1 hour, >1- 12 hours, >12 – 24 hours, ≤1 day – unclear, >1 
– 14 days, and >14 days). Definition of the duration of ISR is provided in Appendix 2.10.5.1.   
A Listing of ISR AEs during the treatment period will be provided. 
A listing detailing the PT within the SMQ will be provided.  
Table 2 provides a summary of the AE tabulations by analysis population and stage as described 
in this section. 
Table 2 Adverse Event Tabulations by Analysis Population and Stage 
 
Safety 
Population
* 
Rollover Safety Population 
Non-rollover Safety Population 
 
 
 
 
Treatment 
Period 
Dose-and-
Wait 
Stage 
Regular-
Dosing 
Stage 
Treatment 
Period 
Tapering 
Stage 
Non-
Tapering 
Stage 
Treatment 
Period 
AE summary 
x 
x 
x 
x 
x 
x 
x 
AE by SOC and PT 
x 
x 
x 
x 
x 
x 
x 
AE by PT 
x 
x 
x 
x 
x 
x 
 
Related AE by SOC and PT 
x 
x 
x 
x 
x 
x 
x 
Related AE by PT 
x 
x 
x 
x 
x 
x 
 
Severe AE by SOC and PT 
x 
x 
x 
x 
x 
x 
x 
Related Severe AE by SOC and 
PT 
x 
x 
x 
x 
x 
x 
x 
SAE by SOC and PT 
x 
x 
x 
x 
x 
x 
x 
SAE by PT 
x 
x 
x 
x 
x 
x 
 
Related SAE by SOC and PT  
x 
x 
x 
x 
x 
x 
x 
AE by max severity, SOC, and 
PT (subject level) 
x 
x 
x 
x 
x 
x 
x 
AE by severity, SOC, and PT 
(event level) 
x 
x 
x 
x 
x 
x 
x 
Summary 
of 
Investigator-
reported AESI 
x 
x 
x 
x 
x 
x 
x 
Investigator-reported AESI by 
SOC and PT 
x 
x 
x 
x 
x 
x 
x 
Related 
Investigator-reported 
AESI by SOC and PT 
x 
x 
x 
x 
x 
x 
x 
SMQ-defined AESI by SOC and 
PT 
x 
x 
x 
x 
x 
x 
x 
Related SMQ-defined AESI by 
SOC and PT 
x 
x 
x 
x 
x 
x 
x 
Summary of ISR AEs 
x 
x 
x 
x 
x 
x 
x 
ISR AEs by SOC and PT 
x 
x 
x 
x 
x 
x 
x 


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Table 2 Adverse Event Tabulations by Analysis Population and Stage 
 
Safety 
Population
* 
Rollover Safety Population 
Non-rollover Safety Population 
 
 
 
ISR AEs by Max Severity, SOC, 
and PT (subject level) 
x 
x 
x 
x 
x 
x 
x 
ISR AEs by Severity, SOC, and 
PT (event level) 
x 
x 
x 
x 
x 
x 
x 
Number and duration of ISR 
AEs 
x 
x 
x 
x 
x 
x 
x 
AE = adverse event; AESI = AE of special interest; PT = preferred term; SOC = system organ class 
*Summary in the Safety Population will be presented for the overall treatment period 
In this study, the efficacy endpoints are based on AEs. If DX-2930 is efficacious, it will result in 
a systematic difference in the incidence of AEs by treatment group which will complicate the 
interpretation of the safety results. Thus, the collection of tabulations described above and 
summarized in Table 2 (with the exception of the analyses of AESI and ISR)will be produced for 
2 mutually exclusive subgroups of AEs based on whether the AE was identified in EDC as a 
subject-reported HAE attack, and defined as follows: 
Non-HAE Attack Reported AEs will include the subset of AEs identified in EDC as not a 
reported HAE attack. Essentially, this will be all AEs excluding HAE attack reported events. 
HAE Attack Reported AEs will include the subset of AEs identified in EDC as a reported HAE 
attack. Note that this includes investigator-confirmed HAE attacks; all investigator-confirmed 
HAE attacks will be coded to the PT of HAE. 
7.9.2 
Clinical Laboratory Evaluation 
Laboratory test results will be summarized by panel type (hematology, coagulation, chemistry, 
urinalysis) using the Safety Population. Laboratory test results will be presented in conventional 
units.  
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For 
rollover subjects previously exposed to DX-2930, baseline is the last non-missing value prior to 
first exposure to study drug in the DX-2930-03 study. 
Actual values and change from baseline clinical laboratory tests will be summarized by study 
visit. If more than one laboratory result is reported per study visit per parameter, the last non-
missing result will be selected for analysis. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator.  See Appendix 2.12 for details on handling 
clinical significance attribution for lab values.  The number of subjects with a non-missing result, 
and the number and percentage of subjects with a clinically significant result below the lower 
limit of normal, clinically non-significant result below the lower limit of normal, within the 
normal range, clinically non-significant result above the upper limit of normal, and clinically 
significant result above the upper limit of normal will be summarized by study visit. If more than 
one laboratory result is reported per study visit per parameter, the result yielding the most severe 


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classification will be selected for analysis.  In the event of a tie, the earlier measurement will be 
used. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study visit per parameter, the result yielding the 
most severe classification will be selected for analysis. 
Subjects with clinically significant abnormal laboratory test results will be listed by panel type. 
This listing will include all results of the laboratory parameter that was abnormal and determined 
to be clinically significant by the investigator for a subject across study visits to identify any 
trends. Subjects whose lab profile that may need further examination will be identified by the 
study physician. A line plot or related analysis will be generated. 
Additional Lab Analyses 
For the Safety Population, additional analyses will be conducted on liver function tests using the 
highest pre-treatment and highest treatment period measurements.   The number and percentage 
of subjects with highest results falling into the categories of normal, 1-<3 x the upper limit of 
normal, 3-5 x the upper limit of normal, and greater than 5 x the upper limit of normal on the 
liver function tests for ALT and AST will be summarized for all pre-treatment measurements and 
treatment period measurements.  Total bilirubin will be summarized by the number and 
percentage of subjects with highest results fall into the categories of <  2x the upper limit of 
normal (ULN)  and > 2 x the upper limit of normal for all pre-treatment measurements and 
treatment period measurements. .  
Hepatic profiles that plot the individual levels of ALT, AST, and total bilirubin will be further 
created for subjects identified by the study physician. A line plot or related analysis will be 
generated. As of last subject last visit date, or 31OCT2019, subjects identified as having elevated 
LFT results are: 
03 study: 
    Discontinued – no further update 
    Ongoing  
    Ongoing  
    Ongoing  
04 study 
   Discontinued  
   Discontinued  
   Ongoing  
   Ongoing  


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   Ongoing  
   Discontinued 
   Ongoing   
   Discontinued  
   Ongoing 
   Ongoing 
Additionally, for the Safety Population, a shift table summarizing the shift in categories from 
highest pre-treatment measurements to the highest treatment period measurements will be 
created for the liver function tests including ALT, AST, and total bilirubin. For ALT and AST, 
the categories were normal, 1-<3 x the upper limit of normal, 3-5 x the upper limit of normal, 
and greater than 5 x the upper limit of normal; for total bilirubin the categories were normal, <  
2.0 x the upper limit of normal and > 2.0 x the upper limit of normal. Also, for the Safety 
Population, shift tables will be presented for hematology, chemistry, and coagulation using the 
categories defined in Table 3. 
An eDISH graph (Paul B. Watkins, 2011) plotting the highest total bilirubin vs. highest ALT in 
multiples of ULN during the treatment period will be produced. Subject IDs for the subjects not 
in the area of ≤3 x ULN for ALT and ≤2 x ULN for total bilirubin will be shown in the graph. 
Additional lab parameters may be evaluated as identified by the study physician.  All laboratory 
data will be provided in subject listings by panel type. 


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Table 3 Lab Parameter Criteria Categories 
Parameter 
Criteria Categories 
Liver Function Tests 
ALT (U/L) 
Normal 
1-3 x ULN 
3-5 x ULN 
> 5 x ULN 
AST (U/L) 
Normal 
1-3 x ULN 
3-5 x ULN 
> 5 x ULN 
Total Bilirubin (mg/dL) 
Normal 
≤2.0 x ULN 
> 2.0 x ULN 
- 
Chemistry 
Albumin (g/dL) 
Low (< 0.6 x LLN) 
Normal (≥ 0.6 x LLN) 
- 
- 
Creatinine (mg/dL) 
Normal (≤ 1.5 x ULN) 
High (>1.5 x ULN) 
- 
- 
Glucose (mg/dL) 
Low (< 0.6 x LLN) 
Normal (0.6 x LLN - 3.5 x ULN) 
High (>3.5 x ULN) 
- 
Potassium (mEq/L) 
Low (< 0.85 x LLN) 
Normal (0.85 x LLN - 1.2 x ULN) 
High (>1.2 x ULN) 
- 
Urea Nitrogen (mg/dL) 
Normal (≤ 3.0 x ULN) 
High (> 3.0 x ULN) 
- 
- 
Hematology 
Eosinophils/Leukocytes 
Normal (≤4.0  x ULN) 
> 4.0 x ULN 
- 
- 
Hematocrit 
Low (<0.6 x LLN) 
Normal (0.6 x LLN - 1.3 x ULN)             High (>1.3 x ULN)     - 
Hemoglobin (g/dL)                                               Low (<0.6 x LLN) 
Normal (0.6 x LLN - 1.3 x ULN) 
High (>1.3 x ULN)     - 
Leukocytes (10^3/uL) 
Low (<0.5 x LLN) 
Normal (0.5 x LLN - 2.0 x ULN) 
High (>1.3 x ULN) 
- 
Neutrophils (10^3/uL) 
Low (<0.5 x LLN) 
Normal (≥0.5 x LLN) 
- 
- 
Platelets (10^3/uL) 
Low (<0.4 x LLN) 
Normal (0.4 x LLN - 2.0 x ULN)             High (>2.0 x ULN)   
- 
Coagulation 
Activated Partial Thromboplastin Time (sec) 
≤ 1.5 x ULN 
> 1.5 X ULN                                            - 
- 
Prothrombin Intl. Normalized Ratio 
≤ 2 x ULN                               > 2 x ULN                                              
- 
- 
Prothrombin Time (sec) 
≤ 1.5 x ULN                            > 1.5 x ULN 
- 
- 
 


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7.9.3 
Vital Signs 
Vital signs will be summarized using the Safety Population.  Note that vital signs will not be 
monitored for subjects who self-administer study drug at optional off-site visits. 
Baseline is defined as the last non-missing value prior to the first exposure to DX-2930. For 
rollover subjects previously exposed to DX-2930, baseline is the last non-missing value prior to 
first exposure to study drug in the DX-2930-03 study. 
Actual values and changes from baseline in vital signs will be summarized by study visit and 
study time point (pre-dose and 1 hour post-dose at dosing visits).  In addition the change from 
pre-dose value (1 hour post-dose value minus pre-dose value) will be summarized for each study 
visit.  All vital sign data will be presented in subject listings. 
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage 
of subjects with a clinically non-significant result and clinically significant result will be 
summarized by study visit and study time point. If more than one vital sign result is reported per 
study visit and study time point per parameter, the result yielding the most severe classification 
will be selected for analysis. 
Subjects with clinically significant vital sign values will be listed. This listing will include all 
results of the vital sign parameter that was determined by the investigator to be clinically 
significant for a subject across study visits and time points to identify any trends. 
All vital sign data will be provided in subject listings. 
7.9.4 
Electrocardiography 
ECG results will be summarized using the Safety Population. 
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG not performed, will be summarized by study 
visit. Subjects with clinically significant ECG results will be listed. This listing will include all 
results for a subject across study visits to identify any trends. 
All ECG data will be provided in subject listings. 
7.9.5 
Physical Examinations 
Physical examinations will be summarized using the Safety Population.   
Physical examination findings by body system will be classified as normal, abnormal not 
clinically significant, abnormal clinically significant, or not performed by the investigator, and 
will be summarized by study visit. Subjects with clinically significant abnormal physical 
examination findings will be listed. This listing will include all results of the body system that 
was determined by the investigator to be clinically significant for a subject across study visits to 
identify any trends. 


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All physical examination findings will be provided in subject listings. 
7.9.6 
Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) version 2015, Q3. 
Prior medications are defined as medications with start and stop times at or prior to the time of 
study drug administration for non-rollover subjects. There will be no prior medications for 
rollover subjects.  
Concomitant medications are defined as medications with a start time after the time of study 
drug administration or medications with a start time prior to study drug administration but 
continuing after treatment.  
For medications with partial onset times, non-missing date parts will be used to determine 
whether the medication is concomitant or prior medication. If a determination cannot be made 
using the non-missing date parts as to when the medication occurred relative to study drug 
administration, then the medication will be classified as concomitant.  
The number and percentage of subjects with prior or concomitant medications will be 
summarized by therapeutic class and preferred term for each analysis population. A separate, 
similar table will be provided for the subset of concomitant medications classified as rescue 
medications. All medications will be presented in subject listings. 
7.10 
Other Analyses 
Additional analyses of PK and PD data will be described in a separate PK/PD report. 
Additional analysis of QoL data will be described in a separate QoL report.  
7.10.1 
Analysis of Pharmacokinetic Data 
Plasma concentrations of DX-2930 will be summarized by nominal PK sampling time and listed 
by subject using the Safety Population. 
Plasma concentrations reported as BLQ (below the limit of quantification) of the assay will be 
reported as zero in the data listings, and BLQ concentrations are treated as zero in the calculation 
of summary statistics. 
7.10.2 
Analysis of Pharmacodynamic Data 
Plasma kallikrein activity will be summarized by nominal PD sampling time and listed by 
subject using the Safety Population. 
7.10.3 
Analysis of Immunogenicity Data 
The number and percentage of ADA-positive results will be summarized by study visit and 
overall and listed by subject using the Safety Population. 


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7.10.4 
Analysis of Quality of Life Data 
Quality of life assessments will be summarized using the Safety Population.  The number and 
percentage of subjects at each level of the EQ-5D-5L dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression) will be presented by study visit. In addition, 
the VAS score for the subject’s self-rated health will be summarized by study visit.   
The responses to the SF-12 for each item will be tabulated by study visit. In addition, PCS & 
MCS will be computed using the scores of 12 questions and range from 0 to 100, where a zero 
score indicates the lowest level of health measured by the scales and 100 indicates the highest 
level of health. 
Responses to the HADS for each item will be tabulated by study visit. In addition, continuous 
and categorical (0-7, normal; 8-10, mild; 11-14, moderate; 15-21, severe) total scores based on 
the items related to depression and anxiety will be summarized by study visit. Each item in the 
questionnaire is scored from 0 to 3, with total scores between 0 and 21 for either depression or 
anxiety. Scores for the entire scale (emotional distress) will also be presented. The total score for 
the entire scale ranges from 0 to 42, with higher scores indicating more distress. 
Responses to the WPAI-GH for each item will be summarized by study visit. In addition, four 
main scores in relation to general health will be summarized by study visit. Scores will be 
calculated as absenteeism (percentage of work time missed due to health), presenteeism 
(percentage impairment while working due to health), work productivity loss (percentage overall 
work impairment due to health), and activity impairment (percentage activity impairment due to 
health). The scores are percentages with higher values indicating greater percentage impairment. 
Only respondents who report being full-time or part-time employed provide data for 
absenteeism, presenteeism, and overall work productivity loss. All respondents provide data for 
activity impairment. 
The responses to the AE-QoL for each item will be tabulated by study visit. In addition, the 
domain scores (functioning, fatigue/mood, fears/shame, nutrition) and total score will be 
summarized by study visit. Each item in the questionnaire is scored from 0 to 4, with domain and 
total scores calculated using a linear transformation to a 0 to 100 scale.  See details in Appendix 
2.13. 
All QoL data will be provided in subject listings and a separate analysis plan will be developed 
for QoL data. 
7.10.5 
Analysis of Study Drug Self-Administration 
For each analysis population, the responses to the self-administration and subcutaneous injection 
survey for each item will be tabulated by study visit.  
The number and percentage of subjects who performed study drug administration as well as the 
total number of injections that were administered via study staff administration in-clinic, self-
administration in-clinic, and self-administration at home will be tabulated for the safety 
population, rollover safety population, and non-rollover safety population overall and by study 
visit.   


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For each analysis population, summary statistics for the total number of doses received, 
percentage of doses self-administered at home, percentage of doses self-administered in clinic, 
and percentage of doses administered by study staff in clinic will be presented.   
The number and percentage of subjects who had ever performed study drug administration as 
well as the total number of injections administered via study staff administration in-clinic, self-
administration in-clinic, or self-administration at home, as well as the total number of injections 
in each category, will be tabulated for the safety population, rollover safety population, and non-
rollover safety population. Additionally, the number and percentage of subjects who received 0, 
1 to 5, 6 to 10, 11 to 20, or >20 self-administration in-clinic, or self-administration at home will 
be summarized for each analysis population. The number and percentage of subjects who 
received greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, 
greater than or equal to 80%, greater than or equal to 90% of their doses by the study staff in-
clinic will be summarized for the Safety Population. 
The number and percentage of study drug administrations whose duration was 0 to 10 seconds, 
11 to 20 seconds, 21 to 30 seconds, 31 to 60 seconds, greater than 1 minute to less than or equal 
to 2 minutes, greater than 1 minute to less than or equal to 3 minutes, greater than 3 minutes to 
less than or equal to 4 minutes, greater than 4 minutes to less than or equal to five minutes, and 
greater than 5 minutes will be summarized for each dose that was self-administered at home, 
self-administered in-clinic, administered by the study staff in-clinic, and overall. 
7.10.6 
Summary of Angioedema Control Test (AECT) by Study Visit  
AECT results will be summarized for the safety population. Number and percentage of subjects 
in each respond category will be summarized by study visit. 
All AECT data will be provided in subject listings. 
7.10.7 
Summary of Treatment Satisfaction Questionnaire for Medication (TSQM-9) by 
Study Visit  
A summary of TSQM-9 results will be provided for the safety population. Number and 
percentage of subjects in each respond category will be summarized by study visit. 
All TSQM-9 data will be provided in subject listings. 
7.10.8 
Summary of Subject’s Global Impression of Change 
A summary of subject’s global impression of changed will be provided for the safety population. 
Number and percentage of subjects in each respond category will be summarized by study visit. 
All subjects’ global impression of change data will be provided in subject listings. 


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7.10.9 
 Summary of Investigator’s Global Impression of Change 
A summary of investigator’s global impression of changed will be provided for the safety 
population. Number and percentage of subjects in each respond category will be summarized by 
study visit. 
All investigators’ global impression of change data will be provided in subject listings. 


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8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
8.1 
Changes in the Conduct of the Study 
There was no change in the conduct of the study. 
8.2 
Change from the Analyses Planned in the Protocol 
8.2.1 
Cox Proportional Hazard Model 
Instead of a multivariate analysis, univariate cox-proportional hazard models will be conducted 
controlling for DX-2930 concentration at Day 0 of the DX-2930-04 study in order to explore the 
factors which impact the time to first HAE attack for the Rollover Safety Population. 
8.2.2 
Drug Interruption 
A subset of subjects missed consecutive doses due to safety concerns. In order to handle the 
safety and efficacy data in these subjects appropriately, the definition of drug interruption, and 
data handling approach for drug interruptions were added in the section Appendix 2.7.3. 
8.2.3 
Self-Administration Subgroup 
Instead of presenting the self-administration subgroup as ever self-administered vs. never self-
administered, the subgroup is now defined as subjects with >80% self-Administration, > 80% 
administration by study staff in-clinic, and mixed administration (< 80% Self-Administration and 
< 80% Administration by Study Staff in-clinic). 


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9. 
STATISTICAL/ANALYTIC ISSUES 
9.1 
Adjustment for covariates 
Univariate Cox proportional hazards regression models will be employed to examine the impact 
of baseline covariates on the time to the first investigator-confirmed HAE attack controlling for 
DX-2930 concentration at Day 0 in the DX-2930-04 study. Results of this exploratory analysis 
will be summarized and will include hazard ratios and the corresponding 95% confidence 
intervals. 
9.2 
Handling of Dropouts or Missing Data 
All available data for investigator-confirmed HAE attacks will be included in the analysis. The 
HAE attack rate will be normalized to 28 days using all available data. 
9.3 
Interim Analysis and Data Monitoring 
Two formal interim analyses were conducted after database lock of the DX-2930-03 study. The 
interim analyses were defined within the statistical analysis plans for the respective interim 
analyses. 
An independent DMC has been established to provide ongoing, independent review and 
assessment of the safety data for the DX-2930-03 study. An independent DMC has looked at 
data from DX-2930-04 3 times and additional reviews may be scheduled by the DMC 
established for the DX-2930-03 study as part of the collection of safety information available on 
DX-2930. 
9.4 
Multicenter Studies 
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis. 
9.5 
Multiple Comparisons/Multiplicity 
All p-values will be considered descriptive. No adjustments for multiple comparisons will be 
made. 
9.6 
Examination of Subgroups  
Subgroup analyses are planned for the time to first HAE attack in Rollover Safety Population, 
number of investigator-confirmed HAE attacks during the treatment period and adverse events 
(non-HAE attack treatment period AEs, related AEs, and severe AEs) using the Safety 
Population. Any p-values that are presented will be descriptive.  
The following subgroups will be used: 
• Age Group (<18, 18 to <40, 40 to <65, ≥65 years) 


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• Sex (Male, Female) 
• Race Group (White, Other) 
• Weight Group (<50, 50 to <75, 75 to <100, ≥100 kg) 
• BMI Group (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2) 
• Baseline HAE Attack Rate Group (1 to <2, 2 to <3, ≥3 attacks/month) 
• HAE Type (Type I, Type II, Unspecified) 
• Geographic Region (US, Canada, Jordan, Europe) 
• DX-2930 Administration Type (>80% Self-Administration, > 80% Administration by 
Study Staff in-clinic, Mixed Administration (< 80% Self-Administration and < 80% 
Administration by Study Staff in-clinic) 
• History of Laryngeal Attack (history of laryngeal attack, no history of laryngeal attack) 
• 
Type of Long-term Prophylactic Therapy Prior to Study Enrollment (C1-INH, Oral Therapy, 
C1-INH and Oral Therapy, Not on LTP) (for the Safety Population and Rollover Safety 
Population ONLY) 
 
For the time to event subgroup analysis, the DX-2930 administration type will not be included 
because subjects only receive one dose.  Data analyses and summaries will parallel those 
described for the primary analysis of the efficacy endpoints and the primary analysis of the 
adverse events. 
9.7 
Sensitivity Analyses 
9.7.1 
Steady State Analyses 
The following sensitivity analyses will be performed to evaluate the robustness of the results. 
Data summaries will parallel those described for the number of investigator-confirmed HAE 
attacks during the treatment period.   
The analyses in Table 4 will be repeated for events occurring during the Steady State Period on 
Day 70 after administration of study drug through the end of Treatment Period, instead of Day 0 
to the end of Treatment Period for non-rollover subjects and the Regular Dosing Stage for 
rollover subjects. For these analyses, the analysis period would be a subset of the treatment 
period (Regular Dosing Stage for non-rollover subjects), defined as Day 70 to the end of 
treatment period. 


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Table 4 List of Analyses during the Treatment Period and Steady State Period 
 
Treatment Period 
(Regular Dosing Stage for 
Rollover Subjects) 
Steady State Period (Day 70 
through the end of treatment 
period) 
Number of Investigator-confirmed 
(IC) HAE attacks 
x 
x 
Number of IC HAE attacks 
requiring acute treatment 
x 
x 
Number of moderate or severe 
investigator-confirmed HAE attacks 
x 
x 
Number of high-morbidity 
investigator confirmed attacks 
x 
x 
Number and percentage of subjects 
that are attack-free 
x 
x 
Percentage of attack-free days 
x 
x 
Summary of attack-free period 
x 
x 
Achievement of a pre-specified 
reduction from baseline in the 
investigator confirmed HAE attack 
rate 
x 
x 
Achievement of <1 IC HAE attack 
per month 
x 
x 
Subject level attack characteristics 
x 
x 
Event level attack characteristics 
x 
x 
 
9.7.2 
Analyses on Number of All HAE Attacks 
The efficacy endpoint analysis on the number of investigator-confirmed HAE attacks during the 
treatment period will be repeated using all subject-reported HAE attacks instead of the analysis 
to only those attacks that were investigator-confirmed. 
9.7.3 
Analyses Excluding Subjects Without Confirmed Type I or Type II HAE 
Subjects
 and 
 were listed as having a major protocol deviation because 
they did not have Type I or Type II HAE confirmed by C1 INH and C4 measurements.  
Sensitivity analyses will be performed on the following tables in Table 5 excluding subjects
and
in order to evaluate the robustness of the efficacy results. 


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Table 5 List of Analyses Excluding Subjects without Confirmed Type I or Type II HAE 
 
Safety Population 
Safety Population Excluding 
subjects without confirmed Type I 
or Type II HAE 
Number of Investigator-confirmed 
(IC) HAE attacks during the 
Treatment Period 
x 
x 
Number of IC HAE attacks during 
Day 70 to the End of Treatment 
Period 
x 
x 
Subject Level Characteristics of IC 
HAE attacks during the Treatment 
Period 
x 
x 
Subject Level Characteristics of IC 
HAE attacks during Day 70 to the 
End of the Treatment Period 
x 
x 
Event Level Characteristics of IC 
HAE attacks during the Treatment 
Period 
x 
x 
Event Level Characteristics of IC 
HAE attacks during Day 70 to the 
End of the Treatment Period 
x 
x 
Number and Percentage of Subjects 
that are Attack-free during the 
Treatment Period 
x 
x 
Number and Percentage of Subjects 
that are Attack-free during Day 70 
to the End of the Treatment Period 
x 
x 
Responder Analysis using IC HAE 
attacks during the Treatment Period 
vs. baseline by responder threshold 
during the Treatment Period 
x 
x 
Responder Analysis using IC HAE 
attacks during Day 70 to the End of 
the Treatment Period vs. baseline by 
responder threshold during the 
Treatment Period 
x 
x 


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10. APPENDICIES 
Appendix 1. List of Statistical Outputs 
Appendix 1.1 
List of Planned Tables 
Table No. 
Title 
14.1.1.1 
Analysis Population – All Subjects 
14.1.1.2 
Analysis Populations by Site – All Subjects 
14.1.2.1 
Subject Disposition – Safety Population 
14.1.2.2 
Subject Disposition – Rollover Safety Population 
14.1.2.3 
Subject Disposition – Non-Rollover Safety Population 
14.1.3.1 
Demographics and Baseline Characteristics – Safety Population 
14.1.3.2 
Demographics and Baseline Characteristics – Rollover Safety Population 
14.1.3.3 
Demographics and Baseline Characteristics – Non-Rollover Safety Population 
14.1.3.4 
Demographics and Baseline Characteristics by Administration Type – Safety Population 
14.1.3.5 
Demographics and Baseline Characteristics by Administration – Rollover Safety Population 
14.1.3.6 
Demographics and Baseline Characteristics by Administration – Non-Rollover Safety 
Population 
14.1.4.1 
Baseline HAE Attack History – Safety Population 
14.1.4.2 
Baseline HAE Attack History – Rollover Safety Population 
14.1.4.3 
Baseline HAE Attack History – Non-Rollover Safety Population 
14.1.5.1 
Medical History by System Organ Class, and Preferred Term – Safety Population 
14.1.5.2 
Medical History by System Organ Class, and Preferred Term – Rollover Safety Population 
14.1.5.3 
Medical History by System Organ Class, and Preferred Term – Non-Rollover Safety 
Population 
14.1.6.1 
Prior Medications – Non-Rollover Safety Population 
14.1.6.2.1 
Concomitant Medications and Therapies (Excluding Medications taken for an HAE Attack) – 
Safety Population 
14.1.6.2.2 
Concomitant Medications and Therapies (Excluding Medications taken for an HAE Attack)– 
Rollover Safety Population 
14.1.6.2.3 
Concomitant Medications and Therapies (Excluding Medications taken for an HAE Attack) 
by Treatment Group – Non-Rollover Safety Population 
14.1.6.3.1 
Concomitant Medications taken for an HAE Attack (Rescue Medications) – Safety 
Population  
14.1.6.3.2 
Concomitant Medications taken for an HAE Attack (Rescue Medications) – Rollover Safety 
Population 
14.1.6.3.3 
Concomitant Medications taken for an HAE Attack (Rescue Medications) – Non-Rollover 
Safety Population 
14.1.7.1 
Summary of Protocol Deviation Type – Safety Population 
14.1.8.1.1 
Treatment Compliance– Safety Population 
14.1.8.1.2 
Treatment Compliance– Rollover Safety Population 
14.1.8.1.3 
Treatment Compliance– Non-Rollover Safety Population 


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Table No. 
Title 
14.1.8.2.1 
Study Drug Exposure – Safety Population 
14.1.8.2.2 
Study Drug Exposure – Rollover Safety Population 
14.1.8.2.3 
Study Drug Exposure – Non-Rollover Safety Population 
14.1.8.2.4 
Listing of Study Drug Exposure for Subjects with Study Drug Interruption – Safety 
Population 
14.1.8.3.1 
Summary of Study Drug Administration – Safety Population 
14.1.8.3.2 
Summary of Study Drug Administration –Rollover Safety Population 
14.1.8.3.3 
Summary of Study Drug Administration – Non-Rollover Safety Population 
14.1.9.1 
Summary of Study Drug Administration Duration by Administration Type – Safety 
Population 
14.1.9.2 
Percentage of Self-administration and Administration by Study-staff in Clinic – Safety 
Population 
14.2.1.1.1 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period – Rollover 
Safety Population 
14.2.1.1.2 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by Age 
Group – Rollover Safety Population 
14.2.1.1.3 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by Sex – 
Rollover Safety Population 
14.2.1.1.4 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by Race 
Group – Rollover Safety Population 
14.2.1.1.5 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by Weight 
Group – Rollover Safety Population 
14.2.1.1.6 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by BMI 
Group – Rollover Safety Population 
14.2.1.1.7 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by Baseline 
HAE Attack Rate Group – Rollover Safety Population 
14.2.1.1.8 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by HAE 
Type – Rollover Safety Population 
14.2.1.1.9 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by 
Geographic Region – Rollover Safety Population 
14.2.1.1.10 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by History 
Laryngeal Attack – Rollover Safety Population 
14.2.1.1.11 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by Prior 
Long-term Prophylactic Therapy – Rollover Safety Population 
14.2.1.1.12 
Cox Proportional Hazard Regression of Time to First Investigator-Confirmed HAE Attack 
During the Treatment Period – Rollover Safety Population 
14.2.2.1 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) – Safety Population 
14.2.2.2 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period – Rollover Safety Population 
14.2.2.3 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period – Non-
Rollover Safety Population 
14.2.2.4 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) by Age Group– Safety Population 


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Table No. 
Title 
14.2.2.5 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by Age Group – Rollover Safety Population 
14.2.2.6 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by Age Group 
– Non-Rollover Safety Population 
14.2.2.7 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) by Sex – Safety Population 
14.2.2.8 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by Sex – Rollover Safety Population 
14.2.2.9 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by Sex – Non-
Rollover Safety Population 
14.2.2.10 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) by Race Group– Safety Population 
14.2.2.11 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by Race Group – Rollover Safety Population 
14.2.2.12 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by Race 
Group – Non-Rollover Safety Population 
14.2.2.13 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by Weight 
Group – Safety Population 
14.2.2.14 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by Weight Group – Rollover Safety Population 
14.2.2.15 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by Weight 
Group – Non-Rollover Safety Population 
14.2.2.16 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) by BMI Group– Safety Population 
14.2.2.17 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by BMI Group – Rollover Safety Population 
14.2.2.18 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by BMI 
Group – Non-Rollover Safety Population 
14.2.2.19 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) by Baseline HAE Attack Rate Group – Safety 
Population 
14.2.2.20 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by Baseline HAE Attack Rate Group– Rollover Safety Population 
14.2.2.21 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by Baseline 
HAE Attack Rate Group– Non-Rollover Safety Population 
14.2.2.22 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) by HAE Type – Safety Population 
14.2.2.23 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by HAE Type 
– Rollover Safety Population 
14.2.2.24 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by HAE Type – Non-Rollover Safety Population 
14.2.2.25 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) by Geographic Region – Safety Population 
14.2.2.26 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by 
Geographic Region – Rollover Safety Population 


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Table No. 
Title 
14.2.2.27 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by Geographic Region – Non-Rollover Safety Population 
14.2.2.28 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) by DX-2930 Administration Type – Safety Population 
14.2.2.29 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by DX-2930 Administration Type – Rollover Safety Population 
14.2.2.30 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period by DX-2930 
Administration Type – Non-Rollover Safety Population 
14.2.2.31 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) by History of Laryngeal Attack – Safety Population 
14.2.2.32 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by History of Laryngeal Attack – Rollover Safety Population 
14.2.2.33 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period   by History of 
Laryngeal Attack – Non-Rollover Safety Population 
14.2.2.34 
Number of Investigator-Confirmed HAE Attacks by Month During the Treatment Period 
(Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.2.35 
Number of Investigator-Confirmed HAE Attacks by Month During the Regular Dosing Stage 
of the Treatment Period – Rollover Safety Population 
14.2.2.36 
Number of Investigator-Confirmed HAE Attacks by Month During the Treatment Period – 
Non-Rollover Safety Population 
14.2.2.37 
Number of Investigator-Confirmed HAE Attacks During Day 70 to the End of the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.2.38 
Number of Investigator-Confirmed HAE Attacks During Day 70 of the Regular Dosing Stage 
through the End of the Treatment Period – Rollover Safety Population 
14.2.2.39 
Number of Investigator-Confirmed HAE Attacks During Day 70 to the End of the Treatment 
Period – Non-rollover Safety Population 
14.2.2.40 
Number of Investigator-Confirmed HAE Attacks during the Treatment Period by Percentage 
of Self-Administration (Regular Dosing Stage for Rollover Subjects)  – Safety Population 
14.2.2.41 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by Prior Long-Term Prophylaxis – Safety Population 
14.2.2.42 
Number of Investigator-Confirmed HAE Attacks During the Regular Dosing Stage of the 
Treatment Period by Prior Long-Term Prophylaxis – Rollover Safety Population 
14.2.3.1 
Number of Investigator-confirmed HAE Attacks Requiring Acute Treatment During the 
Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.3.2 
Number of Investigator-confirmed HAE Attacks Requiring Acute Treatment During the 
Regular Dosing Stage of the Treatment Period – Rollover Safety Population 
14.2.3.3 
Number of Investigator-confirmed HAE Attacks Requiring Acute Treatment During the 
Treatment Period – Non-Rollover Safety Population 
14.2.3.4 
Number of Investigator-confirmed HAE Attacks Requiring Acute Treatment by Month 
During the Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety 
Population 
14.2.3.5 
Number of Investigator-confirmed HAE Attacks Requiring Acute Treatment by Month 
During the Regular Dosing Stage of the Treatment Period – Rollover Safety Population 


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Table No. 
Title 
14.2.3.6 
Number of Investigator-confirmed HAE Attacks Requiring Acute Treatment by Month 
During the Treatment Period – Non-Rollover Safety Population 
14.2.3.7 
Number of Investigator-Confirmed HAE Attacks Requiring Acute Treatment During Day 70 
to the End of the Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety 
Population 
14.2.3.8 
Number of Investigator-Confirmed HAE Attacks Requiring Acute Treatment During Day 70 
of the Regular Dosing Stage through the End of the Treatment Period – Rollover Safety 
Population 
14.2.3.9 
Number of Investigator-Confirmed HAE Attacks Requiring Acute Treatment During Day 70 
to the End of the Treatment Period – Non-rollover Safety Population 
14.2.4.1 
Number of Moderate or Severe Investigator-confirmed HAE Attacks During the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.4.2 
Number of Moderate or Severe Investigator-confirmed HAE Attacks During the Regular 
Dosing Stage of the Treatment Period – Rollover Safety Population 
14.2.4.3 
Number of Moderate or Severe Investigator-confirmed HAE Attacks During the Treatment 
Period – Non-Rollover Safety Population 
14.2.4.4 
Number of Moderate or Severe Investigator-confirmed HAE Attacks by Month During the 
Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.4.5 
Number of Moderate or Severe Investigator-confirmed HAE Attacks by Month During the 
Regular Dosing Stage of the Treatment Period – Rollover Safety Population 
14.2.4.6 
Number of Moderate or Severe Investigator-confirmed HAE Attacks by Month During the 
Treatment Period – Non-Rollover Safety Population 
14.2.4.7 
Number of Moderate or Severe Investigator-Confirmed HAE Attacks During Day 70 to the 
End of the Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety 
Population 
14.2.4.8 
Number of Moderate or Severe Investigator-Confirmed HAE Attacks During Day 70 of the 
Regular Dosing Stage through the End of the Treatment Period – Rollover Safety Population 
14.2.4.9 
Number of Moderate or Severe Investigator-Confirmed HAE Attacks During Day 70 to the 
End of the Treatment Period – Non-rollover Safety Population 
14.2.5.1 
Number of High-Morbidity Investigator-confirmed HAE Attacks During the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.5.2 
Number of High-Morbidity Investigator-confirmed HAE Attacks During the Regular Dosing 
Stage of the Treatment Period – Rollover Safety Population 
14.2.5.3 
Number of High-Morbidity Investigator-confirmed HAE Attacks During the Treatment 
Period – Non-Rollover Safety Population 
14.2.5.4 
Number of High-Morbidity Investigator-confirmed HAE Attacks by Month During the 
Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.5.5 
Number of High-Morbidity Investigator-confirmed HAE Attacks by Month During the 
Regular Dosing Stage of the Treatment Period – Rollover Safety Population 
14.2.5.6 
Number of High-Morbidity Investigator-Confirmed HAE Attacks by Month during the 
Treatment Period – Non-Rollover Safety Population 
14.2.5.7 
Number of High-Morbidity Investigator-Confirmed HAE Attacks During Day 70 to the End 
of the Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.5.8 
Number of High-Morbidity Investigator-Confirmed HAE Attacks During Day 70 of the 
Regular Dosing Stage through the End of the Treatment Period – Rollover Safety Population 


Shire 
CONFIDENTIAL 
Page 61 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.2.5.9 
Number of High-Morbidity Investigator-Confirmed HAE Attacks During Day 70 to the End 
of the Treatment Period – Non-rollover Safety Population 
14.2.6.1 
Number of All HAE Attacks During the Treatment Period (Regular Dosing Stage for 
Rollover Subjects) – Safety Population 
14.2.6.2 
Number of All HAE Attacks During the Regular Dosing Stage of the Treatment Period – 
Rollover Safety Population 
14.2.6.3 
Number of All HAE Attacks During the Treatment Period – Non-Rollover Safety Population 
14.2.7.1 
Number of All HAE Attacks During Day 70 to the End of the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) – Safety Population 
14.2.7.2 
Number of All HAE Attacks During Day 70 of the Regular Dosing Stage through the End of 
the Treatment Period – Rollover Safety Population 
14.2.7.3 
Number of All HAE Attacks During Day 70 to the End of the Treatment Period – Non-
Rollover Safety Population 
14.2.8.1 
Subject Level Characteristics of Investigator-confirmed HAE attacks during the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.8.2 
Subject Level Characteristics of Investigator-confirmed HAE attacks during the Treatment 
Period – Rollover Safety Population 
14.2.8.3 
Subject Level Characteristics of Investigator-confirmed HAE attacks during the Treatment 
Period – Non-Rollover Safety Population 
14.2.8.4 
Event Level Characteristics of Investigator-confirmed HAE attacks during the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.8.5 
Event Level Characteristics of Investigator-confirmed HAE attacks during the Treatment 
Period – Rollover Safety Population 
14.2.8.6 
Event Level Characteristics of Investigator-confirmed HAE attacks during the Treatment 
Period – Non-Rollover Safety Population 
14.2.8.7 
Subject Level Characteristics of Investigator-confirmed HAE Attacks during the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) by Percent Reduction 
14.2.8.8 
Event Level Characteristics of Investigator-confirmed HAE Attacks during the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) by Percent Reduction 
14.2.9.1 
 Subject Level Characteristics of Investigator-confirmed HAE Attacks during Day 70 to the 
End the Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.9.2 
 Subject Level Characteristics of Investigator-confirmed HAE Attacks during Day 70 of the 
Regular Dosing Stage to the End the Treatment Period – Rollover Safety Population 
14.2.9.3 
 Subject Level Characteristics of Investigator-confirmed HAE Attacks during Day 70 to the 
End the Treatment Period – Non-Rollover Safety Population 
14.2.9.4 
Event Level Characteristics of Investigator-confirmed HAE Attacks during Day 70 to the 
End the Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.9.5 
Event Level Characteristics of Investigator-confirmed HAE Attacks during Day 70 of the 
Regular Dosing Stage to the End the Treatment Period – Rollover Safety Population 
14.2.9.6 
Event Level Characteristics of Investigator-confirmed HAE Attacks during Day 70 to the 
End the Treatment Period – Non-Rollover Safety Population 
14.2.10.1 
Subject Level Characteristics of All HAE attacks during the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) – Safety Population 
14.2.10.2 
Subject Level Characteristics of All HAE attacks during the Treatment Period – Rollover 
Safety Population 


Shire 
CONFIDENTIAL 
Page 62 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.2.10.3 
Subject Level Characteristics of All HAE attacks during the Treatment Period – Non-
Rollover Safety Population 
14.2.10.4 
Event Level Characteristics of All HAE attacks during the Treatment Period (Regular Dosing 
Stage for Rollover Subjects) – Safety Population 
14.2.10.5 
Event Level Characteristics of All HAE attacks during the Regular Dosing Stage of the 
Treatment Period – Rollover Safety Population 
14.2.10.6 
Event Level Characteristics of All HAE attacks during the Treatment Period – Non-Rollover 
Safety Population 
14.2.11.1 
Number and Percentage of Subjects that are Attack-Free during the Treatment Period 
(Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.11.2 
Number and Percentage of Subjects that are Attack-Free during the Regular Dosing Stage of 
the Treatment Period – Rollover Safety Population 
14.2.11.3 
Number and Percentage of Subjects that are Attack-Free during the Treatment Period – Non-
Rollover Safety Population 
14.2.12.1 
Number and Percentage of Subjects that are Attack-Free during Day 70 to the End the 
Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.12.2 
Number and Percentage of Subjects that are Attack-Free during Day 70 of the Regular 
Dosing Stage through the End of Treatment Period – Rollover Safety Population 
14.2.12.3 
Number and Percentage of Subjects that are Attack-Free during Day 70 to the End the 
Treatment Period – Non-Rollover Safety Population 
14.2.12.4 
Summary of Percentage and Number of Attack-Free Days by Month during the Treatment 
Period (Regular Dosing Stage for Rollover Subjects)– Safety Population 
14.2.12.5 
Summary of Percentage and Number of Attack-Free Days by Month during the Regular 
Dosing Stage of the Treatment Period – Rollover Safety Population 
14.2.12.6 
Summary of Percentage and Number of Attack-Free Days by Month during the Treatment 
Period – Non-Rollover Safety Population 
14.2.13.1 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
vs. Baseline by Responder Threshold during the Treatment Period (Regular Dosing Stage for 
Rollover Subjects) – Safety Population 
14.2.13.2 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
vs. Baseline by Responder Threshold during the Regular Dosing Stage of the Treatment 
Period – Rollover Safety Population 
14.2.13.3 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
vs. Baseline by Responder Threshold during the Treatment Period – Non-Rollover Safety 
Population 
14.2.13.4 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
vs. Baseline by Responder Threshold during Day 70 to the End the Treatment Period 
(Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.13.5 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
vs. Baseline by Responder Threshold during Day 70 of the Regular Dosing Stage through the 
End of Treatment Period – Rollover Safety Population 
14.2.13.6 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
vs. Baseline by Responder Threshold during Day 70 to the End the Treatment Period – Non-
Rollover Safety Population 


Shire 
CONFIDENTIAL 
Page 63 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.2.14.1 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, 6 
Months, 9 Months, or until the End of Treatment Period during the Treatment Period 
(Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.14.2 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, 6 
Months, 9 Months or until the End of Treatment Period during the Regular Dosing Stage of 
the Treatment Period – Rollover Safety Population 
14.2.14.3 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, 6 
Months, or until the End of Treatment Period during the Treatment Period – Non-Rollover 
Safety Population 
14.2.14.4 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, 6 
Months, 9 Months or until the End of Treatment Period during Day 70 to the End the 
Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.14.5 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, 6 
Months, 9 Months, or until the End of Treatment Period during Day 70 of the Regular Dosing 
Stage through the End of Treatment Period – Rollover Safety Population 
14.2.14.6 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, 6 
Months, 9 Months, or until the End of Treatment Period during Day 70 to the End the 
Treatment Period – Non-Rollover Safety Population 
14.2.15.1 
Achievement of <1 Investigator-Confirmed HAE Attack per Month during the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.15.2 
Achievement of <1 Investigator-Confirmed HAE Attack per Month during the Regular 
Dosing Stage of the Treatment Period – Rollover Safety Population 
14.2.15.3 
Achievement of <1 Investigator-Confirmed HAE Attack per Month during the Treatment 
Period – Non-Rollover Safety Population 
14.2.15.4 
Achievement of <1 Investigator-Confirmed HAE Attack per Month during Day 70 to the End 
the Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.15.5 
Achievement of <1 Investigator-Confirmed HAE Attack per Month during Day 70 of the 
Regular Dosing Stage through the End of Treatment Period – Rollover Safety Population 
14.2.15.6 
Achievement of <1 Investigator-Confirmed HAE Attack per Month during Day 70 to the End 
the Treatment Period – Non-Rollover Safety Population 
14.2.16.1 
Summary of Number of HAE Attacks by Type of Rescue Medication – Safety Population 
142.16.2 
Subject Level Summary of Mean Duration (hours) of HAE Attacks by Rescue Medication 
Use, Severity, and Location – Safety Population 
14.2.17.1 
Subject Listing of Efficacy Parameters- Part 1 – Safety Population 
14.2.17.2 
Subject Listing of Efficacy Parameters- Part 2 – Safety Population 
14.2.17.3 
Listing of Laryngeal HAE Attacks – Safety Population 
14.2.17.4 
Listing of Subjects with Less than 50% Reduction in HAE Attack Rate – Safety Population 
14.2.18.1 
Plasma Concentrations of DX-2930 by Study Visit – Safety Population 
14.2.18.2 
Plasma Kallikrein Activity Measured by %cHMWK by Study Visit – Safety Population 
14.2.19.1 
Summary of EQ-5D-DL Dimensions and VAS Study Visit – Safety Population 
14.2.19.2 
Summary of SF-12 by Study Visit – Safety Population 
14.2.19.3 
Summary of HADS by Study Visit – Safety Population 
14.2.19.4 
Summary of WPAI-GH by Study Visit – Safety Population 


Shire 
CONFIDENTIAL 
Page 64 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.2.19.5 
Summary of Angioedema Quality of Life Items, Domains and Total Score by Study Visit – 
Safety Population 
14.2.19.6 
Summary of Angioedema Control Test (AECT) by Study Visit – Safety Population 
14.2.19.7 
Summary of Treatment Satisfaction Questionnaire for Medication (TSQM-9) by Study Visit 
– Safety Population 
14.2.19.8 
Summary of Subject’s Global Impression of Change – Safety Population 
14.2.19.9 
Summary of Investigator’s Global Impression of Change – Safety Population 
14.2.20.1 
Percentage of Study Drug Administration Type – Safety Population 
14.2.20.2 
Percentage of Study Drug Administration Type – Rollover Safety Population 
14.2.20.3 
Percentage of Study Drug Administration Type – Non-Rollover Safety Population 
14.2.20.4 
Summary of Self-Administration and Subcutaneous Injection Survey – Safety Population 
14.2.20.5 
Summary of Self-Administration and Subcutaneous Injection Survey – Rollover Safety 
Population 
14.2.20.6 
Summary of Self-Administration and Subcutaneous Injection Survey – Non-Rollover Safety 
Population 
14. 2.20.7 
Summary of Study Drug Administration by Visit -Safety Population 
14. 2.20.8 
Summary of Study Drug Administration by Visit -Rollover Safety Population 
14. 2.20.9 
Summary of Study Drug Administration by Visit -Non-Rollover Safety Population 
14.2.20.10 
Study Drug Self-Administration Categories -Safety Population 
14. 2.20.11 
Study Drug Self-Administration Categories -Rollover Safety Population 
14.2.20.12 
Study Drug Self-Administration Categories -Non-Rollover Safety Population 
14.2.21.1 
Number of Investigator-Confirmed HAE Attacks During the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) – Safety Population excluding subjects 
and 
14.2.21.2 
Number of Investigator-Confirmed HAE Attacks During Day 70 to the End of the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) – Safety Population excluding subjects 
 and 
 
14.2.21.3 
Subject Level Characteristics of Investigator-confirmed HAE attacks during the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) – Safety Population excluding subjects 
and
14.2.21.4 
Event Level Characteristics of Investigator-confirmed HAE attacks during the Treatment 
Period (Regular Dosing Stage for Rollover Subjects) – Safety Population excluding subjects 
 and 
14.2.21.5 
Subject Level Characteristics of Investigator-confirmed HAE Attacks during Day 70 to the 
End the Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
excluding subjects 
 and 
 
14.2.21.6 
Event Level Characteristics of Investigator-confirmed HAE Attacks during Day 70 to the 
End the Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
excluding subjects 
 and 
 
14.2.21.7 
Number and Percentage of Subjects that are Attack-Free during the Treatment Period 
(Regular Dosing Stage for Rollover Subjects) – Safety Population excluding subjects 
and


Shire 
CONFIDENTIAL 
Page 65 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.2.21.8 
Number and Percentage of Subjects that are Attack-Free during Day 70 to the End the 
Treatment Period (Regular Dosing Stage for Rollover Subjects) – Safety Population 
excluding subjects 
and 
 
14.2.21.9 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
vs. Baseline by Responder Threshold during the Treatment Period (Regular Dosing Stage for 
Rollover Subjects) – Safety Population excluding subjects 
and 
14.2.21.10 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
vs. Baseline by Responder Threshold during Day 70 to the End the Treatment Period 
(Regular Dosing Stage for Rollover Subjects) – Safety Population excluding subjects
 and
 
14.3.1.1.1 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period – Safety Population 
14.3.1.1.2 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Age Group – Safety Population 
14.3.1.1.3 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Sex – Safety Population 
14.3.1.1.4 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Race Group – Safety Population 
14.3.1.1.5 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Weight Group – Safety Population 
14.3.1.1.6 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by BMI Group – Safety Population 
14.3.1.1.7 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Baseline HAE Attack Rate Group – Safety Population 
14.3.1.1.8 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by HAE Type – Safety Population 
14.3.1.1.9 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Geographic Region – Safety Population 
14.3.1.1.10 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by DX2930 Administration Type – Safety Population 
14.3.1.1.11 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by History of Laryngeal Attack – Safety Population 
14.3.1.1.12 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Prior Long-Term Prophylaxis – Safety Population 
14.1.1.13 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period – Rollover Safety Population 
14.3.1.1.14 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period – Non-Rollover Safety Population 
14.3.1.2.1.1 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by System Organ Class, and Preferred Term – Safety Population 
14.3.1.2.1.2 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by System Organ Class, and Preferred Term – Rollover Safety Population 
14.3.1.2.1.3 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by System Organ Class, and Preferred Term – Non-Rollover Safety 
Population 


Shire 
CONFIDENTIAL 
Page 66 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.1.2.2.1 
Treatment-Emergent Adverse Events during the Treatment Period by Preferred Term – 
Safety Population 
14.3.1.2.2.2 
Treatment-Emergent Adverse Events during the Treatment Period by Preferred Term – 
Rollover Safety Population 
14.3.1.2.2.3 
Treatment-Emergent Adverse Events during the Treatment Period by Preferred Term – Non-
Rollover Safety Population 
14.3.1.2.3 
Treatment-Emergent Adverse Events during the Treatment Period by Age Group, System 
Organ Class and Preferred Term – Safety Population 
14.3.1.2.4 
Treatment-Emergent Adverse Events during the Treatment Period by Sex, System Organ 
Class and Preferred Term – Safety Population 
14.3.1.2.5 
Treatment-Emergent Adverse Events during the Treatment Period by Race Group, System 
Organ Class and Preferred Term – Safety Population 
14.3.1.2.6 
Treatment-Emergent Adverse Events during the Treatment Period by Weight Group, System 
Organ Class and Preferred Term – Safety Population 
14.3.1.2.7 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by BMI Group, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.2.8 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by Baseline HAE Attack Rate Group, System Organ Class and Preferred 
Term – Safety Population 
14.3.1.2.9 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by HAE Type, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.2.10 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by Geographic Region, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.2.11 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by DX-2930 Administration Type, System Organ Class and Preferred Term 
– Safety Population 
14.3.1.2.12 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by History of Laryngeal Attack, System Organ Class and Preferred Term – 
Safety Population 
14.3.1.2.13 
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by Prior Long-Term Prophylaxis, System Organ Class, and Preferred Term 
– Safety Population 
14.3.1.3.1 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by Treatment Group, System Organ Class, Preferred Term, and Maximum 
Severity – Safety Population 
14.3.1.3.2 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by Treatment Group, System Organ Class, Preferred Term, and Maximum 
Severity – Rollover Safety Population 
14.3.1. 3.3 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by Treatment Group, System Organ Class, Preferred Term, and Maximum 
Severity – Non-Rollover Safety Population 
14.3.1.3.4 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by Treatment Group, System Organ Class, Preferred Term, and Severity – 
Safety Population 


Shire 
CONFIDENTIAL 
Page 67 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.1.3.5 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by Treatment Group, System Organ Class, Preferred Term, and Severity – 
Rollover Safety Population 
14.3.1.3.6 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period by Treatment Group, System Organ Class, Preferred Term, and Severity – 
Non-Rollover Safety Population 
14.3.1.4.1.1 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by System Organ Class, and Preferred Term – Safety Population 
14.3.1.4.1.2 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by System Organ Class, and Preferred Term – Rollover Safety 
Population 
14.3.1.4.1.3 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by System Organ Class, and Preferred Term – Non-Rollover 
Safety Population 
14.3.1.4.2.1 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Preferred Term – Safety Population 
14.3.1.4.2.2 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Preferred Term – Rollover Safety Population 
14.3.1.4.2.3 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Preferred Term – Non-Rollover Safety Population 
14.3.1.4.3 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Age Group, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.4.4 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Sex, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.4.5 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Race Group, System Organ Class and Preferred Term – 
Safety Population 
14.3.1.4.6 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Weight Group, System Organ Class and Preferred Term – 
Safety Population 
14.3.1.4.7 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by BMI Group, System Organ Class and Preferred Term – 
Safety Population 
14.3.1.4.8  
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Baseline HAE Attack Rate Group, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.4.9 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by HAE Type, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.4.10 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Geographic Region, System Organ Class and Preferred Term 
– Safety Population 
14.3.1.4.11 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by History of Laryngeal Attacks, System Organ Class and 
Preferred Term –Safety Population 


Shire 
CONFIDENTIAL 
Page 68 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.1.4.12 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by DX-2930 Administration Type, System Organ Class and 
Preferred Term –Safety Population 
14.3.1.4.13 
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Prior Long-Term Prophylaxis, System Organ Class and 
Preferred Term –Safety Population 
14.3.1.5.1.1 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by System Organ Class, and Preferred Term – Safety Population 
14.3.1.5.1.2 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by System Organ Class, and Preferred Term – Rollover Safety 
Population 
14.3.1.5.1.3 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by System Organ Class, and Preferred Term – Non-Rollover 
Safety Population 
14.3.1.5.2.1 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Preferred Term – Safety Population 
14.3.1.5.2.2 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Preferred Term – Rollover Safety Population 
14.3.1.5.2.3 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Preferred Term – Non-Rollover Safety Population 
14.3.1.5.3 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Age Group, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.5.4 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Sex, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.5.5 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Race Group, System Organ Class and Preferred Term – 
Safety Population 
14.3.1.5.6 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Weight Group, System Organ Class and Preferred Term – 
Safety Population 
14.3.1.5.7 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by BMI Group, System Organ Class and Preferred Term – 
Safety Population 
14.3.1.5.8 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Baseline HAE Attack Rate Group, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.5.9 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by HAE Type, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.5.10 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Geographic Region, System Organ Class and Preferred Term 
– Safety Population 
14.3.1.5.11 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by History of Laryngeal Attacks, System Organ Class and 
Preferred Term – Safety Population 


Shire 
CONFIDENTIAL 
Page 69 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.1.5.12 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by DX-2930 Administration Type, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.5.13 
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period by Prior Long-Term Prophylaxis, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.6.1.1 
Related Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported 
Events) during the Treatment Period by System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.6.1.2 
Related Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported 
Events) during the Treatment Period by System Organ Class, and Preferred Term – Rollover 
Safety Population 
14.3.1.6.1.3 
Related Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported 
Events) during the Treatment Period by System Organ Class, and Preferred Term – Non-
Rollover Safety Population 
14.3.1.7.1.1 
Serious Treatment-Emergent Adverse Events during the Treatment Period by System Organ 
Class, and Preferred Term – Safety Population 
14.3.1.7.1.2 
Serious Treatment-Emergent Adverse Events during the Treatment Period by System Organ 
Class, and Preferred Term – Rollover Safety Population 
14.3.1.7.1.3 
Serious Treatment-Emergent Adverse Events during the Treatment Period by System Organ 
Class, and Preferred Term – Non-Rollover Safety Population 
14.3.1.8.1.1 
Related Serious Treatment-Emergent Adverse Events during the Treatment Period by System 
Organ Class, and Preferred Term – Safety Population 
14.3.1.8.1.2 
Related Serious Treatment-Emergent Adverse Events during the Treatment Period by System 
Organ Class, and Preferred Term – Rollover Safety Population 
14.3.1.8.1.3 
Related Serious Treatment-Emergent Adverse Events during the Treatment Period by System 
Organ Class, and Preferred Term – Non-Rollover Safety Population 
14.3.1.9.1.1 
Summary of Treatment-Emergent HAE Attack Reported Adverse Events during the 
Treatment Period – Safety Population 
14.3.1.9.1.2 
Summary of Treatment-Emergent HAE Attack Reported Adverse Events during the 
Treatment Period – Rollover Safety Population 
14.3.1.9.1.3 
Summary of Treatment-Emergent HAE Attack Reported Adverse Events during the 
Treatment Period – Non-Rollover Safety Population 
14.3.1.9.2.1 
Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment Period by 
System Organ Class, and Preferred Term – Safety Population 
14.3.1.9.2.2 
Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment Period by 
System Organ Class, and Preferred Term – Rollover Safety Population 
14.3.1.9.2.3 
Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment Period by 
System Organ Class, and Preferred Term – Non-Rollover Safety Population 
14.3.1.9.3.1 
Related Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period by System Organ Class, and Preferred Term – Safety Population 
14.3.1.9.3.2 
Related Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period by System Organ Class, and Preferred Term – Rollover Safety Population 
14.3.1.9.3.3 
Related Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period by System Organ Class, and Preferred Term – Non-Rollover Safety Population 


Shire 
CONFIDENTIAL 
Page 70 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.1.9.4.1 
Severe Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period (Day 0 to Day 364) by, System Organ Class, and Preferred Term – Safety Population 
14.3.1.9.4.2 
Severe Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period (Day 0 to Day 364) by, System Organ Class, and Preferred Term – Rollover Safety 
Population 
14.3.1.9.4.3 
Severe Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period (Day 0 to Day 364) by, System Organ Class, and Preferred Term – Non-Rollover 
Safety Population 
14.3.1.9.5.1 
Related Severe Treatment-Emergent HAE Attack Reported Adverse Events during the 
Treatment Period System Organ Class, and Preferred Term – Safety Population 
14.3.1.9.5.2 
Related Severe Treatment-Emergent HAE Attack Reported Adverse Events during the 
Treatment Period System Organ Class, and Preferred Term – Rollover Safety Population 
14.3.1.9.5.3 
Related Severe Treatment-Emergent HAE Attack Reported Adverse Events during the 
Treatment Period System Organ Class, and Preferred Term – Non-Rollover Safety 
Population 
14.3.1.9.6.1 
Serious Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period System Organ Class, and Preferred Term – Safety Population 
14.3.1.9.6.2 
Serious Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period System Organ Class, and Preferred Term – Rollover Safety Population 
14.3.1.9.6.3 
Serious Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period System Organ Class, and Preferred Term – Non-Rollover Safety Population 
14.3.1.9.7.1 
Related Serious Treatment-Emergent HAE Attack Reported Adverse Events during the 
Treatment Period, System Organ Class, and Preferred Term – Safety Population 
14.3.1.9.7.2 
Related Serious Treatment-Emergent HAE Attack Reported Adverse Events during the 
Treatment Period, System Organ Class, and Preferred Term – Rollover Safety Population 
14.3.1.9.7.3 
Related Serious Treatment-Emergent HAE Attack Reported Adverse Events during the 
Treatment Period, System Organ Class, and Preferred Term – Non-Rollover Safety 
Population 
14.3.1.10.1.1 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity 
(Excluding HAE Attacks) during the Treatment Period – Safety Population 
14.3.1.10.1.2 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity 
(Excluding HAE Attacks) during the Treatment Period – Rollover Safety Population 
14.3.1.10.1.3 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity 
(Excluding HAE Attacks) during the Treatment Period – Non-Rollover Safety Population 
14.3.1.10.2.1 
Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding HAE 
Attacks) during the Treatment Period by System Organ Class and Preferred Term – Safety 
Population 
14.3.1.10.2.2 
Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding HAE 
Attacks) during the Treatment Period by System Organ Class and Preferred Term – Rollover 
Safety Population 
14.3.1.10.2.3 
Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding HAE 
Attacks) during the Treatment Period by System Organ Class and Preferred Term – Non-
Rollover Safety Population 
14.3.1.10.3.1 
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding 
HAE Attacks) during the Treatment Period by System Organ Class and Preferred Term – 
Safety Population  


Shire 
CONFIDENTIAL 
Page 71 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.1.10.3.2 
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding 
HAE Attacks) during the Treatment Period by System Organ Class and Preferred Term – 
Rollover Safety Population  
14.3.1.10.3.3 
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding 
HAE Attacks) during the Treatment Period by System Organ Class and Preferred Term – 
Non-Rollover Safety Population  
14.4.1.10.4.1 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity during 
the Treatment Period (Excluding HAE Attacks and ISR)– Safety Population 
14.4.1.10.4.2 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity during 
the Treatment Period (Excluding HAE Attacks and ISR)– Rollover Safety Population 
14.4.1.10.4.3 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity during 
the Treatment Period (Excluding HAE Attacks and ISR)– Non-Rollover Safety Population 
14.3.1.10.5.1 
Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity during the Treatment 
Period by System Organ Class and Preferred Term (Excluding HAE Attacks and ISR)– 
Safety Population 
14.3.1.10.5.2 
Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity during the Treatment 
Period by System Organ Class and Preferred Term (Excluding HAE Attacks and ISR) – 
Rollover Safety Population 
14.3.1.10.5.3 
Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity during the Treatment 
Period by System Organ Class and Preferred Term (Excluding HAE Attacks and ISR) – Non-
Rollover Safety Population 
14.3.1.10.6.1 
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity during the 
Treatment Period by System Organ Class and Preferred Term (Excluding HAE Attacks and 
ISR)– Safety Population 
14.3.1.10.6.2 
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity during the 
Treatment Period by System Organ Class and Preferred Term (Excluding HAE Attacks and 
ISR) – Rollover Safety Population 
14.3.1.10.6.3 
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity during the 
Treatment Period by System Organ Class and Preferred Term (Excluding HAE Attacks and 
ISR) – Non-Rollover Safety Population 
14.3.1.11.1.1 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Bleeding during the 
Treatment Period – Safety Population 
14.3.1.11.1.2 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Bleeding during the 
Treatment Period – Rollover Safety Population 
14.3.1.11.1.3 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Bleeding during the 
Treatment Period – Non-Rollover Safety Population 
14.3.1.11.2.1 
Treatment-Emergent Adverse Events of SMQ-Defined Bleeding during the Treatment Period 
by System Organ Class and Preferred Term – Safety Population 
14.3.1.11.2.2 
Treatment-Emergent Adverse Events of SMQ-Defined Bleeding during the Treatment Period 
by System Organ Class and Preferred Term – Rollover Safety Population 
14.3.1.11.2.3 
Treatment-Emergent Adverse Events of SMQ-Defined Bleeding during the Treatment Period 
by System Organ Class and Preferred Term – Non-Rollover Safety Population 
14.3.1.11.3.1 
Related Treatment-Emergent Adverse Events of SMQ-Defined Bleeding (SMQ-Defined) 
during the Treatment Period by System Organ Class and Preferred Term – Safety Population 
14.3.1.11.3.2 
Related Treatment-Emergent Adverse Events of SMQ-Defined Bleeding during the 
Treatment Period by System Organ Class and Preferred Term – Rollover Safety Population 


Shire 
CONFIDENTIAL 
Page 72 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.1.11.3.3 
Related Treatment-Emergent Adverse Events of SMQ-Defined Bleeding during the 
Treatment Period by System Organ Class and Preferred Term – Non-Rollover Safety 
Population 
14.3.1.12.1.1 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable during 
the Treatment– Safety Population 
14.3.1.12.1.2 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable during 
the Treatment– Rollover Safety Population 
14.3.1.12.1.3 
Summary of Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable during 
the Treatment– Non-Rollover Safety Population 
14.3.1.12.2.1 
Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable during the 
Treatment Period by System Organ Class and Preferred Term – Safety Population 
14.3.1.12.2.2 
Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable during the 
Treatment Period by System Organ Class and Preferred Term – Rollover Safety Population 
14.3.1.12.2.3 
Treatment-Emergent Adverse Events of Hypercoagulable during the Treatment Period  by 
System Organ Class and Preferred Term – Non-Rollover Safety Population 
14.3.1.12.3.1 
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable during the 
Treatment Period by System Organ Class and Preferred Term – Safety Population  
14.3.1.12.3.2 
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable during the 
Treatment Period by System Organ Class and Preferred Term – Rollover Safety Population  
14.3.1.12.3.3 
Related Treatment-Emergent Adverse Events of SMQ-Defined during the Treatment Period 
by System Organ Class and Preferred Term – Non-Rollover Safety Population  
14.3.1.13.1.1 
Summary of Treatment-Emergent Adverse Events of Investigator-Reported AESI during the 
Treatment Period – Safety Population 
14.3.1.13.1.2 
Summary of Treatment-Emergent Adverse Events of Investigator-Reported AESI during the 
Treatment Period – Rollover Safety Population 
14.3.1.13.1.3 
Summary of Treatment-Emergent Adverse Events of Investigator-Reported AESI during the 
Treatment Period – Non-Rollover Safety Population 
14.3.1.13.2.1 
Treatment-Emergent Adverse Events of Investigator-Reported AESI during the Treatment 
Period by System Organ Class and Preferred Term – Safety Population 
14.3.1.13.2.2 
Treatment-Emergent Adverse Events of Investigator-Reported AESI during the Treatment 
Period by System Organ Class and Preferred Term – Rollover Safety Population 
14.3.1.13.2.3 
Treatment-Emergent Adverse Events of Investigator-Reported AESI during the Treatment 
Period by System Organ Class and Preferred Term – Non-Rollover Safety Population 
14.3.1.13.3.1 
Related Treatment-Emergent Adverse Events of Investigator-Reported AESI during the 
Treatment Period by System Organ Class and Preferred Term – Safety Population  
14.3.1.13.3.2 
Related Treatment-Emergent Adverse Events of Investigator-Reported AESI during the 
Treatment Period by System Organ Class and Preferred Term –Rollover Safety Population  
14.3.1.13.3.3 
Related Treatment-Emergent Adverse Events of Investigator-Reported AESI during the 
Treatment Period by System Organ Class and Preferred Term – Non-Rollover Safety 
Population  
14.3.1.14.1.1 
Summary of Treatment Emergent Adverse Events of Injection Site Reaction during the 
Treatment Period – Safety Population 
14.3.1.14.1.2 
Summary of Treatment Emergent Adverse Events of Injection Site Reaction during the 
Treatment Period – Rollover Safety Population 


Shire 
CONFIDENTIAL 
Page 73 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.1.14.1.3 
Summary of Treatment Emergent Adverse Events of Injection Site Reaction during the 
Treatment Period – Non-Rollover Safety Population 
14.3.1.14.2.1 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period 
by System Organ Class and Preferred Term – Safety Population 
14.3.1.14.2.2 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period 
by System Organ Class and Preferred Term – Rollover Safety Population 
14.3.1.14.2.3 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period 
by System Organ Class and Preferred Term – Non-Rollover Safety Population 
14.3.1.14.3.1 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period 
by Treatment Group, System Organ Class, Preferred Term, and Maximum Severity – Safety 
Population 
14.3.1.14.3.2 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period 
by Treatment Group, System Organ Class, Preferred Term, and Maximum Severity – 
Rollover Safety Population 
14.3.1.14.3.3 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period 
by Treatment Group, System Organ Class, Preferred Term, and Maximum Severity – Non-
Rollover Safety Population 
14.3.1.14.3.4 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period 
by Treatment Group, System Organ Class, Preferred Term, and Severity – Safety Population 
14.3.1.14.3.5 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period 
by Treatment Group, System Organ Class, Preferred Term, and Severity – Rollover Safety 
Population 
14.3.1.14.3.6 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period 
by Treatment Group, System Organ Class, Preferred Term, and Severity – Non-Rollover 
Safety Population 
14.3.1.14.4.1 
Summary on Duration of Injection Site Reaction Treatment Emergent Adverse Events during 
the Treatment Period – Safety Population 
14.3.1.14.4.2 
Summary on Duration of Injection Site Reaction Treatment Emergent Adverse Events during 
the Treatment Period – Rollover Safety Population 
14.3.1.14.4.3 
Summary on Duration of Injection Site Reaction Treatment Emergent Adverse Events during 
the Treatment Period – Non-Rollover Safety Population 
14.3.1.14.5.1 
Summary on Injection Site Reaction Treatment Emergent Adverse Events during the 
Treatment Period by administration type and preferred term– Safety Population 
14.3.1.14.5.2 
Summary on Injection Site Reaction Treatment Emergent Adverse Events during the 
Treatment Period by Administration type and preferred term – Rollover Safety Population 
14.3.1.14.5.3 
Summary on Injection Site Reaction Treatment Emergent Adverse Events during the 
Treatment Period by Administration type and preferred term – Non-Rollover Safety 
Population 
14.3.1.14.5.4 
Summary on Injection Site Reaction Treatment Emergent Adverse Events during the 
Treatment Period by Administration Location and Preferred Term – Safety Population 
14.3.1.14.5.5 
Summary on Injection Site Reaction Treatment Emergent Adverse Events during the 
Treatment Period by Administration Location and Preferred Term – Rollover Safety 
Population 
14.3.1.14.5.6 
Summary on Injection Site Reaction Treatment Emergent Adverse Events during the 
Treatment Period by Administration Location and Preferred Term – Non-Rollover Safety 
Population 


Shire 
CONFIDENTIAL 
Page 74 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.2.1 
Listing of Adverse Events Resulting in Death – All Subjects 
14.3.2.2 
Listing of Serious Adverse Events – All Subjects 
14.3.2.3 
Listing of Adverse Events Resulting in Study Drug Interrupted or Withdrawn – All Subjects 
14.3.2.4 
Listing of Related Adverse Events During the Treatment Period– All Subjects 
14.3.2.5 
Listing of Severe Adverse Events During the Treatment Period – All Subjects 
14.3.2.6 
Listing of Hypersensitivity Adverse Events During the Treatment Period (Excluding HAE 
Attacks) – All Subjects 
14.3.2.7 
Listing of Bleeding Adverse Events During the Treatment Period – All Subjects 
14.3.2.8 
Listing of Hypercoagulable Adverse Events During the Treatment Period – All Subjects 
14.3.2.9 
Listing of Investigator-reported AESI During the Treatment Period- All Subjects 
14.3.2.10 
Listing of Follow-up Period Adverse Events – All Subjects 
14.3.2.11 
Listing of Injection Site Reaction Adverse Events During the Treatment Period 
14.3.3 
No statistical table will be generated.  Numbering reserved for SAE narratives per ICH. 
14.3.4.1.1 
Actual Values and Change from Baseline in Hematology Results by Study Visit – Safety 
Population 
14.3.4.1.2 
Categorical Hematology Results by Study Visit – Safety Population 
14.3.4.1.3 
Listing of Clinically Significant Abnormal Hematology Results – Safety Population 
14.3.4.1.4 
Shift Table of Highest Hematology Results – Safety Population 
14.3.4.1.5 
 Highest Hematology Results – Safety Population 
14.3.4.2.1 
Actual Values and Change from Baseline in Coagulation Results by Study Visit – Safety 
Population 
14.3.4.2.2 
Categorical Coagulation Results by Study Visit – Safety Population 
14.3.4.2.3 
Listing of Clinically Significant Abnormal Coagulation Results – Safety Population 
14.3.4.2.4 
Shift Table of Highest Coagulation Results – Safety Population 
14.3.4.2.5 
Highest Coagulation Results – Safety Population 
14.3.4.3.1 
Actual Values and Change from Baseline in Chemistry Results by Study Visit – Safety 
Population 
14.3.4.3.2 
Categorical Chemistry Results by Study Visit – Safety Population 
14.3.4.3.3 
Listing of Clinically Significant Abnormal Chemistry Results – Safety Population 
14.3.4.3.4 
Highest Liver Function Tests by Study Period – Safety Population 
14.3.4.3.5 
Shift Table of Highest Liver Function Tests- Safety Population 
14.3.4.3.6 
Shift Table of Highest Chemistry Results – Safety Population 
14.3.4.3.7 
Highest Chemistry Results – Safety Population 
14.3.4.4.1 
Actual Values and Change from Baseline in Urinalysis Results by Study Visit – Safety 
Population 
14.3.4.4.2 
Categorical Urinalysis Results by Study Visit – Safety Population 
14.3.4.4.3 
Listing of Clinically Significant Abnormal Urinalysis Results – Safety Population 
14.3.4.5.1 
Actual Values and Change from Baseline in Vital Signs Study Visit and Study Time Point – 
Safety Population 
14.3.4.5.2 
Categorical Vital Signs Results by Study Visit and Study Time Point – Safety Population 


Shire 
CONFIDENTIAL 
Page 75 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Table No. 
Title 
14.3.4.5.3 
Listing of Clinically Significant Vital Signs – Safety Population 
14.3.4.6.1 
Categorical Electrocardiogram Results by Study Visit – Safety Population 
14.3.4.6.2 
Listing of Clinically Significant Electrocardiogram Results – Safety Population 
14.3.4.7.1 
Categorical Physical Examination Findings by Study Visit – Safety Population  
14.3.4.7.2 
Listing of Clinically Significant Physical Examination Findings – Safety Population 
14.3.4.8.1 
Immunogenicity by Study Visit – Safety Population 
14.3.4.8.2 
Listing of Positive Immunogenicity Results – Safety Population 


Shire 
CONFIDENTIAL 
Page 76 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Appendix 1.2 
List of Planned Figures 
Figure No. 
Title 
14.2.1.1 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by DX-2930 
Exposure in the DX-2930-03 Study – Rollover Safety Population 
14.2.1.2 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by DX-2930 
Exposure in the DX-2930-03 Study (First 8 Weeks)– Rollover Safety Population 
14.2.1.3 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by DX-2930 
Exposure in the DX-2930-03 Study (Total DX-2930 vs. Placebo)– Rollover Safety Population 
14.2.1.4 
Time to First Investigator-Confirmed HAE Attack During the Treatment Period by DX-2930 
Exposure in the DX-2930-03 Study (First 8 Weeks, Total DX-2930 vs. Placebo)– Rollover 
Safety Population 
14.2.2.1.1 
Investigator-confirmed HAE Attacks during the Treatment Period (Regular Dosing Stage for 
Rollover Subjects) for Each Subject– Safety Population 
14.2.2.1.2 
Investigator-confirmed HAE Attacks during the Regular Dosing Stage of the Treatment Period 
– Rollover Safety Population 
14.2.2.1.3 
Investigator-confirmed HAE Attacks during the Treatment Period – Non-Rollover Safety 
Population 
14.2.2.2.1 
All HAE Attacks during the Treatment Period (Regular Dosing Stage for Rollover Subjects)– 
Safety Population 
14.2.2.2.2 
All HAE Attacks during the Regular Dosing Stage of the Treatment Period– Rollover Safety 
Population 
14.2.2.2.3 
All HAE Attacks during the Treatment Period – Non-Rollover Safety Population 
14.2.3.1.1 
Investigator-confirmed HAE Attacks Requiring Acute Treatment during the Treatment Period 
(Regular Dosing Stage for Rollover Subjects)– Safety Population 
14.2.3.1.2 
Investigator-confirmed HAE Attacks Requiring Acute Treatment during the Regular Dosing 
Stage of the Treatment Period –Rollover Safety Population 
14.2.3.1.3 
Investigator-confirmed HAE Attacks Requiring Acute Treatment during the Treatment Period– 
Non-Rollover Safety Population 
14.2.4.1.1 
Moderate and Severe Investigator-confirmed HAE Attacks during the Treatment Period 
(Regular Dosing Stage for Rollover Subjects)– Safety Population 
14.2.4.1.2 
Moderate and Severe Investigator-confirmed HAE Attacks during the Regular Dosing Stage of 
the Treatment Period– Rollover Safety Population 
14.2.4.1.3 
Moderate and Severe Investigator-confirmed HAE Attacks during the Treatment Period– Non-
Rollover Safety Population 
14.2.5.1.1 
High-morbidity Investigator-confirmed HAE Attacks during the Treatment Period (Regular 
Dosing Stage for Rollover Subjects) – Safety Population 
14.2.5.1.2 
High-morbidity Investigator-confirmed HAE Attacks during the Regular Dosing Stage of the 
Treatment Period– Rollover Safety Population 
14.2.5.1.3 
High-morbidity Investigator-confirmed HAE Attacks during the Treatment Period – Non-
Rollover Safety Population 
14.2.6.1.1 
Mean Number of Investigator-confirmed HAE Attacks per Month During the Treatment Period 
(Regular Dosing Stage for Rollover Subjects) for Each Study Month – Safety Population 
14.2.6.1.2 
Mean Number of Investigator-confirmed HAE Attacks per Month During the Regular Dosing 
Stage of the Treatment Period for Each Study Month – Rollover Safety Population 


Shire 
CONFIDENTIAL 
Page 77 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Figure No. 
Title 
14.2.6.1.3 
Mean Number of Investigator-confirmed HAE Attacks per Month During the Treatment Period 
for Each Study Month – Non-Rollover Safety Population 
14.2.7.1.1 
Mean Percent Change in Monthly Attack Rate from Baseline During the Treatment Period 
(Regular Dosing Stage for Rollover Subjects) – Safety Population 
14.2.7.1.2 
Mean Percent Change in Monthly Attack Rate from Baseline During the Regular Dosing Stage 
of the Treatment Period – Rollover Safety Population 
14.2.7.1.3 
Mean Percent Change in Monthly Attack Rate from DX-2930-03 Treatment Period During the 
Regular Dosing Stage of the Treatment Period – Rollover Safety Population 
14.2.7.1.4 
Mean Percent Change in Monthly Attack Rate from Baseline During the Treatment– Non-
rollover Safety Population 
14.2.8.1 
Plot of Mean DX-2930 Concentration Over Time – PK Population 
14.3.4.3.4 
Highest ALT/Total Bilirubin During the Treatment Period – Safety Population 
14.3.5.x 
Hepatic Profile for Subjects Identified by Study Physician  
 


Shire 
CONFIDENTIAL 
Page 78 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Appendix 1.3 
List of Planned Listings 
Listing No. 
Title 
16.2.1 
Disposition 
16.2.2 
Protocol Deviations 
16.2.3.1 
Analysis Populations 
16.2.3.2 
Inclusion and Exclusion Criteria 
16.2.4.1 
Demographics  
16.2.4.2 
Baseline Disease Characteristics 
16.2.4.3 
Medical History 
16.2.4.4 
Prior and Concomitant Medications 
16.2.5.1 
Study Drug Administration 
16.2.5.2 
Treatment Compliance and Exposure 
16.2.6.1 
HAE Attacks 
16.2.6.2 
Plasma Concentration of DX-2930 
16.2.6.3 
Kallikrein Activity 
16.2.6.4 
EQ5D 
16.2.6.5 
SF-12 
16.2.6.6 
HADS 
16.2.6.7 
WPAI-GH 
16.2.6.8 
Angioedema Quality of Life 
16.2.6.9 
Angioedema Control Test (AECT)  
16.2.6.10 
Summary of Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
16.2.6.11 
Subject and Investigator Global Impression of Change  
16.2.7 
Adverse Events 
16.2.8.1 
Hematology Values 
16.2.8.2 
Coagulation Values 
16.2.8.3 
Chemistry Values 
16.2.8.4 
Urinalysis Values 
16.2.8.5 
Vital Signs 
16.2.8.6 
ECGs 
16.2.8.7 
Immunogenicity 
16.2.8.8 
Physical Examinations 


Shire 
CONFIDENTIAL 
Page 79 
DX-2930-04 Statistical Analysis Plan 
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Appendix 2. Definitions and Programming Conventions 
Appendix 2.1 
Age 
Age will be calculated as the date of birth minus the date of informed consent of the DX-2930-04 
study, truncated to years. 
Appendix 2.2 
BMI 
BMI will be calculated as: 
 
Appendix 2.3 
Study Day 
The study day is calculated as start or stop date – date of first dose + 1 for dates on or after first 
dose, or start or stop date – date of first dose for dates prior to first dose. 
Appendix 2.4 
Duration of Events 
The duration of an event is calculated as stop date/time – start date/time if time is not missing, 
and stop date – start date + 1 if either the start or stop time is missing. 
Appendix 2.5 
Algorithm to Identify LTP Use at Baseline 
The LTP (C1-INH, Androgens, or Anti-fibrinolytics) treatment a subject was on prior to study 
enrollment will be determined by applying the algorithm presented in Table 6 to prior 
medications (i.e., medications with start and stop date prior to study enrollment) reported for that 
subject that lasted for ≥4 days.  
Table 6 LTP Prior to Study Enrollment 
LTP 
Algorithm to Identify Medications 
C1-INH 
ATC level 4 in (‘B06AC’) and preferred drug term not in (‘icatibant’, 
‘ecallantide’, ‘icatibant acetate’) 
Androgens 
ATC level 4 in (‘G03BA’, ‘G03BB’, ‘A14AA’) or preferred drug term 
in (‘danazol’, ‘oxandrolone’)  
Anti-fibrinolytics 
ATC level 4 in (‘B02AA’, ‘B02AB’) 
 
Subjects will be further classified into four LTP subgroups, based on the LTP use prior to study 
enrollment. Table 7 provides the algorithm to classify subjects by type of LTP use prior to study 
enrollment. 


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Table 7 LTP Subgroup 
LTP Subgroup 
Subject 
C1-INH 
Subjects who took only C1-INH as LTP 
Oral Therapy 
Subjects who took either Androgens and/or Anti-fibrinolytics as LTP 
but not C1-INH   
C1-INH and Oral Therapy 
Subjects who took C1-INH and androgens and/or anti-fibrinolytics as 
LTP   
Not on LTP  
Subjects who didn’t take any LTP medications prior to study 
randomization 
 
Appendix 2.6 
Definition of Unique Subject ID 
The unique subject id consists of the study number of the first DX-2930 study in which a subject 
participated and is followed by the subject id from the first DX-2930 in which a subject 
participated. 
Appendix 2.7 
Analysis Periods 
Appendix 2.7.1 
Pretreatment Period 
The pretreatment period is defined for non-rollover subjects as the interval of time that starts at 
the date/time informed consent is signed and ends prior to the date/time of first exposure to study 
drug (Day 0 visit).   
[date/time of informed consent, date/time of first exposure to study drug) 
The Pretreatment Period is not defined for rollover subjects.  
Appendix 2.7.2 
Treatment Period 
The treatment period is defined as the interval of time that starts on the date/time of first 
exposure to study drug (Day 0 visit) and ends on the earliest of the 2 following dates (1) date of 
study discontinuation or (2) Day 924 visit date. There are two types of subjects in this study, the 
rollover subjects and the non-rollover subjects. The treatment period is split into two different 
stages for the rollover subjects- the dose-and-wait stage and the regular dosing stage. For the 
non-rollover subjects, the treatment period is split into two different stages, the tapering stage 
and the non-tapering stage. 
The treatment period is defined as: 
[date/time of first exposure to study drug, date of Day 924 visit or treatment discontinuation] 


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Appendix 2.7.2.1 
Dose-and-Wait Stage for Rollover Subjects 
The dose-and-wait stage of the treatment period for the rollover subjects is defined as the interval 
of time that starts on the date/time of first study exposure to study drug (Day 0 visit) and ends on 
the date/time the subject receives the second dose of study drug after the first HAE attack (or the 
date of treatment discontinuation, if earlier). 
[date/time of first exposure to study drug, date/time of the second dose) 
Appendix 2.7.2.2 
Regular Dosing Stage for Rollover Subjects 
The regular dosing stage for rollover subjects is defined as the interval of time that starts on the 
date/time of the second dose of the study drug and ends on the earliest of the date of study 
discontinuation or Day 924 visit date. 
[date/time of the second dose, date of Day 924 visit or treatment discontinuation] 
For rollover subjects, the Day 70 analyses will be performed for the time period start on the Day 
70 of the regular dosing stage and ends on the end of regular dosing stage. 
For re-enrolled rollover subjects, their regular dosing stage is defined as the interval of time that 
starts on the date/time of the second dose of the study drug and ends on the earliest of the date of 
study discontinuation or Day 924 visit date, excluding the time period between Day 364 visit 
(under protocol amendment 2.0) and the visit they re-enroll into the study. 
For re-enrolled rollover subjects, the Day 70 analyses will be performed for the time period of 
regular dosing stage, excluding the first 69 days from both the first and second enrollments. 
Appendix 2.7.2.3 
Tapering Stage for Non-rollover Subjects 
The tapering stage for the non-rollover subjects is defined as the interval of time that starts on the 
date/time of the first exposure to study drug (Day 0 visit) and ends on the date/time of the last 
dose of long-term prophylactic therapy on the DX-2930-04 study. 
[date/time of first exposure to study drug, date/time of last LTP use] 
Appendix 2.7.2.4 
Non-Tapering Stage for Non-rollover Subjects 
The non-tapering stage for non-rollover subjects is defined as the interval of time that starts on 
the date/time of the last dose of long-term prophylactic therapy to the earliest of the date of the 
early study discontinuation date or Day 924 visit. 
(date/time of last LTP use, date of Day 924 visit or treatment discontinuation] 
Appendix 2.7.3 
Handling of Subjects with Extended Drug Interruption(s) 
During this long term safety study, a subset of subjects had drug interruption(s) due to safety 
concerns such as pregnancy or elevated liver enzymes.  For subjects with an extended drug 
interruption, which is defined as missing >3 consecutive study medication doses prior to the 
earlier of Day 924 visit date or early study discontinuation date, the time period and the 


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corresponding efficacy and safety events during the presumed low drug exposure drug 
interruption period will be excluded from safety and efficacy analyses. 
Drug Interruption Period Considerations 
• Drug interruption period for efficacy analyses impact on efficacy endpoints of HAE 
attacks. 
• Drug interruption period for safety analyses impact on safety endpoints of AEs (including 
HAE AEs), laboratory measurements, vital signs, ECG, and immunogenicity. 
• For efficacy analyses, the time period of 28 days after the last study medication dose 
prior to drug interruption will not be included in the efficacy drug interruption period. 
This is because the dosing frequency for the lanadelumab treatment can be once every 4 
weeks. 
• For safety analyses on HAE attacks, time period of 70 days after the last study 
medication dose prior to drug interruption will not be included in the safety drug 
interruption period. This is because the half-life of lanadelumab is around 14 days, and 70 
days would be 5 half-lives after the last dose prior to drug interruption. 
• For the final CSR, all of the drug interruptions were approved by the Sponsor and the 
investigator. Therefore, these subjects are considered as compliant during the drug 
interruption.  The expected number of doses for these subjects will be calculated as the 
total number of expected doses during the treatment period minus doses missed during 
the drug interruption. 
• The gap in study medication use for the subjects who completed the Protocol 
Amendment 2.0 and later re-enrolled in the Protocol Amendment 3.0 is not considered as 
a drug interruption. 
Existence of Drug Interruption Period 
• For efficacy analyses, the existence of drug interruption period is determined by 
comparing the dates of 1) Date of last study medication prior to drug interruption + 29 
days, 2) day 924 visit date, and 3) early study discontinuation date. If date 1) is on or 
after the earlier of date 2) and 3), then there will be no drug interruption period defined 
for efficacy analyses. 
• For safety analyses, the existence of drug interruption period is determined by comparing 
the dates of 1) Date of last study medication prior to drug interruption + 71 days, 2) day 
924 visit date, and 3) early study discontinuation date. If date 1) is on or after the earlier 
of date 2) and 3), then there will be NO drug interruption period defined for safety 
analyses. 
Start Date of Drug Interruption Period 
When a drug interruption period exists, derive the start date of drug interruption as: 
• For efficacy Analyses, the start date of the drug interruption is defined as date last study 
medication prior to drug interruption + 29 days. 


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• For safety Analyses, the start date of the drug interruption is defined as date last study 
medication prior to drug interruption + 71 days. 
End Date of Drug Interruption Period 
For both efficacy and safety analyses, the end date of drug interruption period is defined as the 
earlier of the first dose after drug interruption -1, Day 924 visit date, or early study drug 
discontinuation date. If a subject didn’t receive additional study drug after the drug interruption, 
then the end date of drug interruption period is defined as the earlier of Day 924 visit date or 
early study drug discontinuation date.  
Duration of Drug Interruption 
• For efficacy analyses, the duration of drug interruption will be derived as: 
End date of drug interruption period – Start date of drug interruption period (efficacy) + 1 
• For efficacy analyses, the duration of drug interruption will be derived as: 
End date of drug interruption period – Start date of drug interruption period (safety) + 1 
Duration of Exposure Excluding Drug Interruption Period 
• For efficacy analyses, the duration of exposure excluding drug interruption period will be 
derived as: 
Treatment Period duration – Drug interruption period duration for efficacy 
• For safety analyses, the duration of exposure excluding drug interruption period will be 
derived as: 
  
Treatment Period duration – Drug interruption period duration for safety  
Appendix 2.7.4 
Follow-up Period 
There were subjects who completed the study under protocol amendment 2.0, and re-enrolled 
into the study after the approval of Amendment 3.0. Therefore, for these subjects, there are two 
follow-up periods. 
• The follow up period 1 is defined as the interval of time that starts on the date of 
the Day 364 visit (per protocol amendment 2.0) + 1 and ends on the date of re-
enrollment.  
[date of Day 364 visit + 1, date of re-enrollment -1] 
• The follow-up period 2 is defined as the interval of time that starts on the date of 
the Day 924 visit (or treatment discontinuation) + 1 and ends on the date of the 
subject’s last date of contact for the study.  
• [date of Day 924 visit or treatment discontinuation + 1, date of last study contact] 


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For all other subjects, the follow-up period is defined as the interval of time that starts on the 
date of the Day 924 visit (or treatment discontinuation) + 1 and ends on the date of the subject’s 
last date of contact for the study.  
[date of Day 924 visit or treatment discontinuation + 1, date of last study contact] 
Appendix 2.8 
Handling of HAE Attack Data 
The following rules apply to the handling of HAE attack data for efficacy analyses only. HAE 
attacks starting prior to the run-in period are not processed by these rules. For safety analyses, 
HAE attacks will be analyzed as reported. 
Appendix 2.8.1 
Imputing Missing Start or End Date and Time for HAE Attacks 
In general, missing start time will be imputed as 0:00 and missing end time will be imputed as 
23:59. However, the following rules will be applied for the attacks satisfying the corresponding 
conditions, in order to conservatively classify the attacks as separate, distinct attacks with at least 
24 hours in-between: 
• For HAE attacks with a missing start time and a non-missing start date one calendar day 
after the end date of the previous attack, the start time will be imputed using the end time 
of the previous HAE attack to ensure there are 24 hours in between the two attacks.  
• For HAE attacks with a missing start time and a non-missing end date/time within 24 
hours from the end date/time of the previous attack, the attack should be considered as 
one attack with the previous attack (see Appendix 2.8.2 for details on combining HAE 
attacks)  
• For HAE attacks with missing end time and a non-missing end date one calendar day 
before the start date of the next attack, the end time will be imputed as the start time of 
the next HAE attack to ensure there are 24 hours in between the two attacks.  
• For HAE attacks with a missing end time and non-missing start date/time within 24 hours 
from the start date/time of the next attack, the attack should be considered as one attack 
with the next attack (see Appendix 2.8.2 for details on combining HAE attacks)  
For HAE attacks with a non-missing start date and time and a missing stop date and time: 
• If the event is not indicated as ongoing, the stop date and time will be imputed as start 
date and time + 48 hours or 24 hours before the start date and time of the next attack, 
whichever is earlier. 
• If the event is indicated as ongoing, the stop date and time will be imputed as the earlier 
of the following two date and time: 
 Start date and time + 48 hours or study completion date and the stop time of 
23:59, whichever is later. 


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 24 hours before the start date and time of the next attack. 
Appendix 2.8.2 
Unique HAE Attacks 
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.   
Specifically, there must be at least 24 hours between the stop date/ time of the first event and the 
start date/time of the next event, for the attacks to be considered distinct. If there is less than 24 
hours between the stop date/time of the first event and the start date/time of the next event, the 
events will be counted as one attack.  
When two or more attacks are combined for efficacy analysis, the parameters of the attacks will 
be conservatively chosen. The start date and time of the combined attack will take the earliest 
start date and time from the individual attacks; and the end date and time of the combined attack 
will take the latest end date and time of the individual attacks. The severity of the combined 
attack will take the highest severity from the individual attacks. The primary location of the 
combined attack will be determined by the primary location of the individual attacks, and by 
following the hierarchy of laryngeal attack, abdominal attack, and peripheral attack. One primary 
location will be taken; and all the other primary location(s) and secondary locations will be 
considered as secondary location for the combined attack. The rescue medications and 
supportive treatment for the combined attack will include all the records from individual attacks. 
Also, the combined attack will be considered as an investigator-confirmed attack if any of the 
individual attack being combined is an investigator-confirmed attack.  
Appendix 2.8.3 
HAE Attack Duration 
The duration of an HAE attack is calculated as stop date/time – start date/time.  
Appendix 2.8.4 
Investigator-confirmed HAE Attacks Requiring Acute Therapy 
Investigator-confirmed HAE attacks requiring acute therapy are those attacks identified as 
‘treated for HAE attack with acute therapy’ on the CRF.  
Appendix 2.8.5 
Moderate and Severe Investigator-confirmed HAE Attacks  
Moderate and severe investigator-confirmed HAE attacks are those attacks that were classified as 
of moderate or severe according to the HAARP defined severity and reported as such on the 
CRF. 
Appendix 2.8.6 
HAE Attack Severity 
The overall severity of the subject’s attack was to be determined by the investigator using the 
following definitions provided as part of HAARP: 
- Mild: Transient or mild discomfort  
- Moderate: Mild to moderate limitation in activity - some assistance needed 


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- Severe: Marked limitation in activity, assistance required 
The average attack severity will be calculated per subject by attributing a numeric value to each 
severity as follows: 1=Mild, 2=Moderate, and 3=Severe. Higher values will indicate more severe 
attacks, while lower values will indicate less severe attacks. 
Appendix 2.9 
HAE Attack Rate 
Appendix 2.9.1 
Baseline HAE Attack Rate 
The baseline investigator-confirmed HAE attack rate will be calculated for each subject as the 
number of investigator-confirmed HAE attacks occurring during the run-in period of DX2930-03 
for rollover subjects or historical reporting period 3 month prior to the study enrollment for non-
rollover subjects divided by the number of days in 3 month (90 days) and multiplied by 28 days.  
Appendix 2.9.2 
Treatment Period HAE Attack Rate 
The treatment period investigator-confirmed HAE attack rate will be calculated for each subject 
as the number of investigator-confirmed HAE attacks occurring during the treatment period 
divided by the number of days the subject contributed to the treatment period multiplied by 
28 days. For rollover subjects, the HAE attack rate for the regular dosing stage of the treatment 
period is calculated for each subject as the number of investigator-confirmed HAE attacks 
occurring during the regular dosing stage of the treatment period divided by the number of days 
the subject contributed to the regular dosing stage of the treatment period multiplied by 28 days. 
Appendix 2.9.3 
Time to First HAE Attack 
Time to the first investigator-confirmed HAE attack (days) will be calculated from the date and 
time of the first open-label dose of DX-2930 to the date and time of the first investigator-
confirmed HAE attack after the first open-label dose. Subjects who discontinue the study prior to 
experiencing their first on-study investigator-confirmed HAE attack will be censored at the date 
and time of study discontinuation. Subjects who do not experience an HAE attack will be 
censored at the earlier of the database cut date around 31AUG18 or the date of the Day 924 visit.   
Appendix 2.10 Adverse Events  
Appendix 2.10.1 Treatment-emergent Adverse Events 
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine 
whether the AE is treatment-emergent. If a determination cannot be made using the non-missing 
date parts as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.  


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Appendix 2.10.2 Related Adverse Events 
Related AEs are AEs classified as related to study drug by the investigator.  If the assessment by 
the investigator is missing, then the AE will be classified as related. 
Appendix 2.10.3 Severe Adverse Events 
Severe AEs are AEs classified as severe (grade 3) or life threatening (grade 4) by the investigator 
using DMID criteria.  If severity is missing, then the AE will be classified as severe. 
Appendix 2.10.4 Investigator-reported AESI  
An investigator-reported AESI is an adverse event identified by the investigator on the CRF as 
an adverse event of special interest.  
Appendix 2.10.4.1 
SMQ-Defined AESI 
The broad terms from MedDRA 20.0 SMQ will be used to identify an SMQ-defined AESI. 
Table 8 shows the SMQ’s used to identify AESI of hypersensitivity, hypercoagulable, and 
bleeding. 
Table 8 SMQs Used to Identify AESI 
AESI 
SMQ 
Hypersensitivity 
Hypersensitivity 
Hypercoagulable 
Embolic and thrombotic events, arterial 
Embolic and thrombotic events, venous 
Embolic and thrombotic events, vessel type unspecified and mixed 
arterial and venous 
Bleeding 
Haemorrhage laboratory terms 
Haemorrhage terms (excl laboratory terms) 
 
Appendix 2.10.5  Injection Site Reaction AEs 
Injection site reaction (ISR) AEs will be identified by adverse events with the preferred terms 
starting with ‘Injection site’, ‘Application site’, or ‘Administration site’.  
Appendix 2.10.5.1 
Duration of Injection Site Reaction AEs 
Duration of ISR AEs is calculated as "stop date/time – start date/time" for the ISR AEs with 
non-missing start and stop date/time.  


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The missing start or stop date/time for ISR AEs will not be imputed. ISR AEs with missing start 
or stop date/time will be excluded from the summary statistics analysis and reported as number 
missing in the continuous analysis of ISR AE duration. For the categorical analyses on ISR AE 
duration, the following rules will be applied: 
• ISR AE with non-missing start and stop date/time: duration of the AE will be calculated 
as ‘stop date/time – start date/time’ and mapped to a duration category. 
• ISR AE with non-missing start and stop dates and missing time: duration of the AE will 
be calculated as ‘stop date – start date +1’. If the calculated duration is 1 day, then the 
duration category for this AE is ≤ 1 day - unclear. If the calculated duration is greater 
than 1 day, then it will be mapped to a >1 Day category. 
• ISR AE with missing start or stop date: The ISR AE will be excluded from the 
categorical analyses on duration. 
 
Appendix 2.11  Non-standard Laboratory Results 
The non-standard laboratory results will be converted to numeric values using the rules shown in 
Table 9. 
Table 9 Convention for Converting Non-Standard Laboratory 
Results 
Non-Standard Lab Values 
 
Standardized Numeric Values 
<0.2 
Deduct 0.01 from the reference value. i.e., 0.19 
<0.1 
Deduct 0.01 from the reference value. i.e., 0.09 
>1.045 
Add 0.001 to the reference value. i.e. 1.046 
 
Appendix 2.12 Clinical Significance Attributions for Laboratory Results 
The EDC system design permitted attribution of clinical significance for all laboratory values, 
not just those that are outside of the reference range. Therefore, many data points have an 
attribution of clinical significance when none is expected.  
The laboratory results will be programmatically classified for analysis due to the database 
limitation using the following algorithm: 
1. Lab results within the reference range will be classified as Normal. 


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2. Lab results outside of the reference range will be classified as a) CS Low, b) NCS Low, 
c) NCS High, or d) CS High using a combination of the CS/NCS classification by the 
investigator and the Low/High classification based on the central lab reference range. 
For specified analyses, the highest pre-treatment lab value and the highest lab value during the 
treatment period will be used as well as the criteria presented in Table 3. 
Appendix 2.13 Angioedema Quality of Life 
Below are instructions for how to calculate AE-QoL domain scores and total score. 
AE-QoL is meant to be evaluated by determining its four individual domain scores (profile 
instrument), but it may also be used to determine a total score (index instrument). 
Each item answered by the subject scores between 0 and 4 points depending on the answer 
option chosen by the subject. The first answer option gets 0 points, the second option 1 point, the 
third option 2 points, etc. The AE-QoL domain scores and total score are calculated by using the 
following formula: 
(Sum of all completed items) / (maximum sum of all possible items)*100  
Computation 
of 
AE-QoL 
Total 
Score 
Example 
1: 
All 
items 
were 
completed 
(maximum 
possible 
sum: 
68 
points) 
Sum 
of 
all 
17 
completed 
items: 
41 
points. 
Total score = 100*(41/68) = 60 (out of a possible 100 points) 
Example 2: 2 items were not completed (maximum possible sum: 60 points).  
Sum 
of 
all 
15 
completed 
items: 
41 
points. 
Total score = 100*(41/60) = 68 (out of a possible 100 points) 
Computation 
of 
Domain 
Scores 
(Example: 
Fears/Shame) 
Example: 
Sum 
of 
all 
6 
completed 
items: 
14 
points  
Maximum 
possible 
sum: 
24 
points 
Domain Score = 100*(14/24) = 58 (out of a possible 100 points) 
Remarks 
Since only answered items are included in the computation (and the calculated domain and total 
scores are not raw scores but linear transformations to a 0-to-100 scale), missing items have little 
or no influence on the calculated scores. 
An AE-QoL domain score should not be calculated if more than one item is left unanswered in 
that domain. The AE-QoL total score should not be calculated if more than 25% of items 
(>4 items) are left unanswered. 
The lowest and highest possible domain and total scores are 0 and 100, respectively. 


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Appendix 2.14  WAPI-GH 
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, i.e., worse outcomes, as follows:  
Questions: 
1 = currently employed 
2 = hours missed due to health problems 
3 = hours missed other reasons 
4 = hours actually worked 
5 = degree health affected productivity while working 
6 = degree health affected regular activities 
Scores: 
Multiply scores by 100 to express in percentages. 
Percent work time missed due to health: Q2/(Q2+Q4) 
Percent impairment while working due to health: Q5/10 
Percent overall work impairment due to health: 
      Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4)))x(Q5/10)] 
Percent activity impairment due to health: Q6/10  
 


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Appendix 2.15  HADS 


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Appendix 2.16 Study Activity Schedules 
Appendix 2.16.1 Study Activity Schedule – Day -28 through Day 365 from Amendment 3.0 
Activities Occurring at 
 
Treatment Period ± 4 days for each visit                  = scheduled in-site visits for all subjects.  
  = potential subject-elected off-site activity and/or self-administration dosing. 
Non Rollover Visit 
Scra 
1 
 
2 
3 
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27  
Rollover Visit 
- 
Chkb 
Dose 
- 
1 
 
2 
3 
4 
5 6 7 8 9 10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
23 
24 
25 
26 27 
Day (± 4 days) 
-28 
0 
 
14 
28 c 42 56 70 84 98 112 126 140 154 168 182 196 210 224 
238 
252 
266 
280 
294 
308 
322 
336 
350 364 
Informed Consentd 
• 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Reviewe 
• 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Long-term prophylactic therapy cont’de 
• 
• 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DX-2390-04 Administrationf,g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(rollover subjects) h 
 
• 
 
•  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  • 
•  •  •  •  •  • 
(nonrollover subjects)e 
 
• 
 
•  •  • • • • • • • • • • • • • • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Demographic and Medical History  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testi (females)  
 
•i 
 
• 
• 
 •  
 •  •  •  •  
 
• 
 
 
• 
 
 
• 
 
 
 
•  
Vital Signsj 
• 
• 
 
• 
• • • • • • • • • • • • • • • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Physical Examk 
• 
• 
 
• 
• 
 •  
 •  
 
 •  •  
 
 
 
 
• 
 
 
 
 
 
 
• 
Clinical Laboratory Testingl 
• 
• 
 
• 
• 
 •  
 •  
 
 •  •  
 
• 
 
 
• 
 
 
• 
 
 
 
• 


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Activities Occurring at 
 
Treatment Period ± 4 days for each visit                  = scheduled in-site visits for all subjects.  
  = potential subject-elected off-site activity and/or self-administration dosing. 
Non Rollover Visit 
Scra 
1 
 
2 
3 
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27  
Rollover Visit 
- 
Chkb 
Dose 
- 
1 
 
2 
3 
4 
5 6 7 8 9 10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
23 
24 
25 
26 27 
Day (± 4 days) 
-28 
0 
 
14 
28 c 42 56 70 84 98 112 126 140 154 168 182 196 210 224 
238 
252 
266 
280 
294 
308 
322 
336 
350 364 
12-Lead ECGm 
• 
• 
 
 
 
 
 
 
 •  
 
 
 
 •  
 
 
 
 
• 
 
 
 
 
 
 
• 
Prior (4 wks) & Concomitant Therapy  
• 
• • • 
• • • • • • • • • • • • • • • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Adverse Events 
• 
• • • 
• • • • • • • • • • • • • • • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
HAE Attack Datan 
• 
• 
 
• 
• • • • • • • • • • • • • • • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Quality of Life 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE-QoL, EQ-5D-5L, WPAI-GH, 
HADS, SF-12 
 
• 
 
 
• 
 •  
 •  •  •  •  
 
• 
 
 
• 
 
 
• 
 
 
 
• 
 
AECT, TSQM v.II, 
Global Treatment Response 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•  
DX-2930 Injection Report 
• 
• 
 
• 
• • • • • • • • • • • • • • • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
DX-2930 Self-administration & SC 
Injection Survey 
 
• 
 
 
 
 
 
 
 •  
 
 
 
 •  
 
 
 
 
• 
 
 
 
 
 
• 
• 
PK, PD, ADA,o & Biomarkerp Sample 
collection 
 
• 
 
 
 
 
 
 
 •  
 
 
 
 •  
 
 
 
 
• 
 
 
 
 
 
 
• 
Abbreviations:  ADA = anti-drug antibody; AECT = Angioedema Control Test; AE-QOL = Angioedema Quality of Life; Chk = check-in; Cont’d = continued; 
ECG = Electrocardiogram; EQ-5D-5L = EuroQoL 5-Dimensional 5-Level; HADS = Hospital Anxiety and Depression Scale; PK = Pharmacokinetic; 
PD = Pharmacodynamic; Scr=screening visit; Scr=screening; SF-12 = Short Form-12; TSQM-vII; WPAI-GH = Work Productivity and Activity Impairment – General 
Health 


Shire 
CONFIDENTIAL 
Page 94 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Activities Occurring at 
 
Treatment Period ± 4 days for each visit                  = scheduled in-site visits for all subjects.  
  = potential subject-elected off-site activity and/or self-administration dosing. 
Non Rollover Visit 
Scra 
1 
 
2 
3 
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27  
Rollover Visit 
- 
Chkb 
Dose 
- 
1 
 
2 
3 
4 
5 6 7 8 9 10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
23 
24 
25 
26 27 
Day (± 4 days) 
-28 
0 
 
14 
28 c 42 56 70 84 98 112 126 140 154 168 182 196 210 224 
238 
252 
266 
280 
294 
308 
322 
336 
350 364 
a 
Screening visit is for nonrollover subjects only.  Screening visit can occur up to 28 days prior to first open-label dose. 
b 
Study site personnel will contact rollover subjects approximately every 7 days following the first dose of open-label DX-2930 to solicit for any HAE attacks not 
already reported.  Site check-in with rollover subjects will continue until the subject receives their second open label dose. 
c 
Day 28 is a site check-in call for all rollover and nonrollover subjects. 
d 
All subjects must sign informed consent before undergoing study procedures.  Nonrollover subjects have up to 28 days to sign informed consent.  Rollover 
subjects must sign informed consent for Study DX-2930-04 on or after Day 168 of Study DX-2930-03.  Day 182 of Study DX-2930-03 is also Day 0 of Study DX-
2930-04, and informed consent may be completed on this visit, if not already provided. 
e 
Screened nonrollover subjects (adults and adolescents) who are on LTP with C1-INH therapy for HAE or AAE can continue their current LTP until Day 8 (or Day 
15) such that subjects will have received 2 (or 4) doses of C1-INH.  For subjects who are on attenuated androgens (eg, danazol) or anti-fibrinolytics (eg, 
tranexamic acid), a similar tapering schedule is recommended. However, the taper can be prolonged by an additional week as long as androgen or anti-fibrinolytic 
therapy is stopped within 3 weeks of receiving the first dose of DX-2930. Since C1-INH therapy may alter the lab results of C1-INH assessments, the investigator's 
discretion in collaboration with Medical Monitor is advised for proper documentation of eligibility. 
f 
Doses are administered every 14 ± 4 days. All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a physical and mental capability 
of learning and willing to be trained) may be allowed to self-administer DX-2930 after (1) completing appropriate training by the investigator or designee, (2) 
confirming their understanding, and (3) receiving the first 2 doses of DX-2930 at the study site. Subjects are then allowed to initiate home self-administration and 
may elect to self-administer subsequent doses of DX-2930 at the investigational site. If the subject switches to the PFS, the subject should receive a refresher 
training focused on the PFS 
g 
Site personnel will call subjects within approximately 3 days of the planned self-administration to ensure the administration occurred, to collect AEs, concomitant 
medications, and to ensure all attacks have been appropriately documented. 
h 
Rollover subjects will not receive Dose 2 until they have experienced the first reported, investigator-confirmed attack. In addition, a minimum of 10 days is 
required between Dose 1 and Dose 2. If the second dose is to be administered within the accepted ±4 day window around a scheduled study visit, this treatment 
visit will represent that scheduled visit unless that scheduled visit has already occurred. If that scheduled visit has already occurred, or if the second dose is to be 
administered outside of the accepted ± 4 day window around a scheduled visit, this visit will not replace any scheduled visit and will thus represent an acceptable, 
extra study visit (ie, an unscheduled visit). Regardless, at the visit in which the second open-label dose of DX-2930 is administered, the subject will undergo pre-
dose assessments for vital signs, physical examination (performed in accordance with standards at the site), clinical laboratory testing, PK, PD, and anti-drug 
antibody. Vital signs will be obtained at 1 hour post-dosing. As with all study visits, information will be collected on adverse events, concomitant therapy, and 
HAE attack data. Following Dose 2, subjects will begin regular administrations every 2 weeks 
i 
The pregnancy test will only be conducted in females of childbearing potential.  Tests performed on Day 0 must be urine-based to confirm eligibility prior to first 


Shire 
CONFIDENTIAL 
Page 95 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Activities Occurring at 
 
Treatment Period ± 4 days for each visit                  = scheduled in-site visits for all subjects.  
  = potential subject-elected off-site activity and/or self-administration dosing. 
Non Rollover Visit 
Scra 
1 
 
2 
3 
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27  
Rollover Visit 
- 
Chkb 
Dose 
- 
1 
 
2 
3 
4 
5 6 7 8 9 10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
23 
24 
25 
26 27 
Day (± 4 days) 
-28 
0 
 
14 
28 c 42 56 70 84 98 112 126 140 154 168 182 196 210 224 
238 
252 
266 
280 
294 
308 
322 
336 
350 364 
dose. Tests performed at screening and on indicated visits can be serum or urine-based. 
j 
There is a recommended ± 15 minute window for all vital signs. Vital signs will be obtained prior to dosing and 1 hour after dosing. Monitoring of vital signs will 
not be performed for subjects who elect to self-administer away from the investigative site at optional off-site visits (indicated non-shaded columns). 
k 
Physical examinations, including weight, will be conducted for all rollover and nonrollover subjects according to the study activities schedule and in accordance 
with standards at the site.  In addition to the physical examinations specified in the study activities schedule, an additional physical examination (performed in 
accordance with standards at the site) will be conducted for rollover subjects prior to dosing on the day of their second open-label dose, at whatever study visit that 
occurs.  Height will be collected at the Screening visit only. 
l 
Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis (urinalysis does not need to be done as part of the clinical 
laboratory testing at Visits 14, 17, 20, and 23). Clinical laboratory testing will be conducted for all rollover and nonrollover subjects according to the study 
activities schedule. In addition to the testing specified in the study activities schedule, additional testing will be conducted for rollover subjects prior to dosing on 
the day of their second open-label dose, at whatever study visit that occurs. 
m 
In addition to the timepoints shown, ECG is to be performed when clinically indicated. 
n 
Historical HAE attack information will be collected at screening. During the study, subjects (or caregivers) are instructed to report details of the attack to the study 
site within 72 hours of the onset of the attack. During study visits, study site personnel will solicit for any new HAE attack information that has not already been 
reported to the site 
o 
PK, PD, and anti-drug antibody samples will be drawn for all rollover and nonrollover subjects at the visits shown.  An additional sample will be drawn for 
rollover subjects prior to dosing on the day of their second open-label dose, at whatever  
p 
Samples for C1-INH, C4, and C1q assays will be collected at screening, Visit 14, and Visit 26, as applicable. Samples need not be obtained at screening for 
eligibility assessment if they were already collected as part of Study DX-2930 02 or Study DX-2930-03study visit that occurs. 


Shire 
CONFIDENTIAL 
Page 96 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Appendix 2.16.2 Study Activities Schedule for Day 366 through Day 952 
Activities Occurring at 
Treatment Period ± 4 days for each visit 
Follow 
Up 
Period 
= scheduled in-site visits for all subjects.  
  = potential subject-elected off-site activity and/or self-administration dosing. 
Visit 
 
28 
29  
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
60 
61 
62 
63 
64 
65 
66 
67  
68 
69 
EOS 
ETa 
Day (± 4 days) 
378 
392 
406 
420 
434 
448 
462 
476 
490 
504 
518 
532 
546 
560 
574 
588 
602 
616 
630 
644 
658 
672 
686 
700 
714 
728 
742 
756 
770 
784 
798 
812 
826 
840 
854 
868 
882 
896 
910 
924 
938 
952 
DX-2930 Administrationb,c 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
 
 
Physical Examd 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
• 
 
• 
Pregnancy Teste (females)  
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
• 
 
• 
Vital Signsf 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Concomitant Therapy 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Adverse Events 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
HAE Attack Datag 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Clinical Laboratory Testingh 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
• 
 
• 
PK, PD Collection, ADA 
Testing & Biomarkersi 
 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
 
• 
• 
 
• 


Shire 
CONFIDENTIAL 
Page 97 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Activities Occurring at 
Treatment Period ± 4 days for each visit 
Follow 
Up 
Period 
= scheduled in-site visits for all subjects.  
  = potential subject-elected off-site activity and/or self-administration dosing. 
Visit 
 
28 
29  
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
60 
61 
62 
63 
64 
65 
66 
67  
68 
69 
EOS 
ETa 
Day (± 4 days) 
378 
392 
406 
420 
434 
448 
462 
476 
490 
504 
518 
532 
546 
560 
574 
588 
602 
616 
630 
644 
658 
672 
686 
700 
714 
728 
742 
756 
770 
784 
798 
812 
826 
840 
854 
868 
882 
896 
910 
924 
938 
952 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Quality of Life 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE-QoL, EQ-5D-5L, WPAI-
GH, HADS, SF-12 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
 
AECTj 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
 
TSQM vII 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
Global Treatment Response 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Exit Interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Site Check In Callk 
• 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
 
DX-2930 Injection Reportl 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
 
 
DX-2930 Self-administration & 
SC Injection Surveyl & Pre-filled 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
 


Shire 
CONFIDENTIAL 
Page 98 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Activities Occurring at 
Treatment Period ± 4 days for each visit 
Follow 
Up 
Period 
= scheduled in-site visits for all subjects.  
  = potential subject-elected off-site activity and/or self-administration dosing. 
Visit 
 
28 
29  
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
60 
61 
62 
63 
64 
65 
66 
67  
68 
69 
EOS 
ETa 
Day (± 4 days) 
378 
392 
406 
420 
434 
448 
462 
476 
490 
504 
518 
532 
546 
560 
574 
588 
602 
616 
630 
644 
658 
672 
686 
700 
714 
728 
742 
756 
770 
784 
798 
812 
826 
840 
854 
868 
882 
896 
910 
924 
938 
952 
Syringe Survey 
Discharge from Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Abbreviations: AECT=Angioedema Control Test; EOS = End of Study; ET = Early Termination; Treatment Satisfaction Questionnaire for Medication version II = 
TSQM vII  
NOTE: Although the first visit shown on this Schedule is at Day 378, this schedule covers the entire period following the end of the previous schedule. Certain 
assessments should be collected continuously throughout the study (for example, AEs) are collected continuously throughout the study 
a 
Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures at Visit 69, the final study visit. 
b 
Doses are administered every 14 ± 4 days 
c 
All subjects (adolescent or adult) who are considered suitable candidates (i.e., those with a physical and mental capability of learning and willing to be trained) may 
self-administer DX-2930 at all visits. (If the subject switches to the PFS, the subject should receive a refresher training focused on the PFS.) Subjects may 
administer at home or other agreed upon location (during off-site self-administration visits; non-shaded columns). Subjects can opt to be seen in clinic for this visit 
d 
Physical examinations, including weight, will be conducted for all rollover and nonrollover subjects according to the study activities schedule and in accordance 
with standards at the site 
e 
The pregnancy test will only be conducted in females of childbearing potential. Tests performed at screening and indicated visits can be serum or urine-based 
f 
There is a recommended ± 15-minute window for all vital signs. Vital signs will be obtained prior to dosing and 1 hour after dosing. Monitoring of vital signs will 
not be performed for subjects who elect to self-administer away from the investigative site at optional off-site visits (indicated non-shaded columns). 
g 
During the study, subjects (or caregivers) are instructed to document attack details on their HAE Attack Log. Subjects will review Attack Log and details of the 
attacks at the study site during their in-clinic assessments. During study visits, study site personnel will solicit for any new HAE attack information that has not 
already been reported to the site. Study site personnel will utilize the HAARP guidelines in order to confirm the HAE attack within 7 days. 


Shire 
CONFIDENTIAL 
Page 99 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
Activities Occurring at 
Treatment Period ± 4 days for each visit 
Follow 
Up 
Period 
= scheduled in-site visits for all subjects.  
  = potential subject-elected off-site activity and/or self-administration dosing. 
Visit 
 
28 
29  
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
60 
61 
62 
63 
64 
65 
66 
67  
68 
69 
EOS 
ETa 
Day (± 4 days) 
378 
392 
406 
420 
434 
448 
462 
476 
490 
504 
518 
532 
546 
560 
574 
588 
602 
616 
630 
644 
658 
672 
686 
700 
714 
728 
742 
756 
770 
784 
798 
812 
826 
840 
854 
868 
882 
896 
910 
924 
938 
952 
h 
Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis (urinalysis is performed as part of the clinical laboratory testing 
at Days 574, 742, 910, and 938/Visits 42, 54, 66, 68 
i 
Biomarker samples for C1-INH, C4, and C1q assays will be collected at Visits 34, 42, 50, 58, 67, and 69. 
j 
The AECT will be performed once its validated version is available 
k 
Site personnel will call subjects within approximately 3 days of the planned self-administration to ensure the administration occurred, to collect AEs, concomitant 
medications, and to ensure all attacks have been appropriately documented. 
l 
Collect subject's injection reports of their experience with DX-2930 self-administration, subcutaneous administration, and prefilled syringe (if relevant) for all 
doses. 
 
 


Shire 
CONFIDENTIAL 
Page 100 
DX-2930-04 Statistical Analysis Plan 
Lanadelumab (DX-2930; SHP643) 
 
10 December 2019 
 
 
11. REFERENCES 
Paul B. Watkins, M. D. (2011). Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH). 
Drug Safety, 34(3), 243-252. 
Reilly MC, Zbrozek AS, Dukes EM 1993. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics; 4(5): 353-65. 
Ware J Jr, Kosinski M, Keller SD 1996. A 12-Item Short-Form Health Survey: construction 
of scales and preliminary tests of reliability and validity. Med Care; 34(3): 220-33. 
Weller K, Groffik A, Magerl M, Tohme N, Martus P, Krause K, Metz M, Staubach P, 
Maurer M. Development and construct validation of the angioedema quality of life 
questionnaire. Allergy. 2012; 67(10): 1289-98. 
Zigmond AS, Snaith RP 1983. The hospital anxiety and depression scale. Acta Psychiatr 
Scand; 67(6): 361-70. 
 


 
 
 
 
PRO Report: DX-2930-04  
HELP STUDY EXTENSION™ 
1. TITLE PAGE 
Study Title: 
HELP Study Extension™: An Open-Label Study 
to Evaluate the Long-Term Safety and Efficacy of 
DX-2930 for Prevention Against Acute Attacks of 
Hereditary Angioedema (HAE): Final PRO 
Analysis 
Investigational Product Name: 
Lanadelumab (DX 2930 ; SHP643) 
Sponsor: 
Dyax Corp. (an indirect wholly owned subsidiary 
of Shire plc.) 300 Shire Way, Lexington, MA 
02421 USA 
Date of the Report: 
14 Nov 2017 
Interim 1 
 
15 Oct 2018 
Interim 2 
 
24 Mar 2020 
Final 
 
Confidentiality Statement 
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations.  This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire 


Shire 
CONFIDENTIAL 
Page 2 
Final PRO report 
Lanadelumab (DX2930 ; SHP463) 
24 March 2020 
 
2. TABLE OF CONTENTS 
1. 
TITLE PAGE ...........................................................................................................................1 
2. 
TABLE OF CONTENTS .........................................................................................................2 
LIST OF IN-TEXT TABLES ..........................................................................................................4 
LIST OF IN-TEXT FIGURES.........................................................................................................4 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................5 
4. 
EXECUTIVE SUMMARY .....................................................................................................6 
5. 
BACKGROUND .....................................................................................................................7 
6. 
OBJECTIVES ..........................................................................................................................8 
7. 
METHODS ..............................................................................................................................9 
7.1 
DX-2930-04 study .........................................................................................................9 
7.1.1 
Study design .........................................................................................................9 
7.1.2 
PRO data ............................................................................................................10 
7.2 
PRO instruments ..........................................................................................................12 
7.2.1 
Angioedema Quality of Life (AE-QoL) Questionnaire .....................................12 
7.2.2 
EuroQol 5-Dimensions-5 levels (EQ-5D-5L) ....................................................12 
7.2.3 
Work Productivity and Activity Impairment – General Health (WPAI-GH) 
Questionnaire .....................................................................................................13 
7.2.4 
Hospital Anxiety and Depression Scale (HADS) ..............................................13 
7.2.5 
12 Item Short Form v2 Health Survey (SF-12v2) .............................................13 
7.2.6 
Angioedema Control Test (AECT) ....................................................................14 
7.2.7 
Treatment Satisfaction Questionnaire for Medication version 9 (TSQM-9) .....14 
7.2.8 
Global Impression of Treatment Response ........................................................14 
7.3 
Analysis population .....................................................................................................14 
7.4 
General principles ........................................................................................................14 
7.4.1 
Description of variables .....................................................................................14 
7.4.2 
Level of significance ..........................................................................................14 
7.5 
Missing data handling ..................................................................................................15 
7.6 
Software .......................................................................................................................15 
7.7 
Analysis plan ................................................................................................................15 
8. 
RESULTS ..............................................................................................................................16 
8.1 
Description of AE-QoL scores over the study .............................................................16 
8.1.1 
Description of AE-QoL scores and change in AE-QoL scores in Rollover 
Safety Population ...............................................................................................16 
8.1.2 
Description of AE-QoL scores and change in AE-QoL scores in the Non-
Rollover Safety population ................................................................................17 
8.1.3 
Description of change in AE-QoL scores in the Rollover Safety population 
by treatment received during DX-2930-03 ........................................................18 


Shire 
CONFIDENTIAL 
Page 3 
Final PRO report 
Lanadelumab (DX2930 ; SHP463) 
24 March 2020 
 
8.2 
Description of other PRO scores over the study ..........................................................19 
8.2.1 
Description of PRO scores and change in PRO scores in Rollover Safety 
Population ..........................................................................................................19 
8.2.2 
Description of PRO scores and change in PRO scores in the Non-Rollover 
Safety population ...............................................................................................23 
8.2.3 
Description of change in PRO scores in the Rollover Safety population by 
treatment received during DX-2930-03 .............................................................26 
8.3 
Exploratory analysis of AE-QoL score changes in the Rollover Safety Population ...26 
8.4 
Responder analysis and empirical cumulative distribution functions..........................28 
9. 
DISCUSSION OF RESULTS ...............................................................................................29 
10. CONCLUSION ......................................................................................................................31 
11. REFERENCE LIST ...............................................................................................................32 
12. LIST OF APPENDICES ........................................................................................................35 
Appendix 1 
DX-2930-04 PRO Statistical Analysis Plan v1.0 10 December 2019 .....36 
Appendix 2 
DX-2930-04 Final Analyses of Patient-Reported Outcomes from 
                    Study Statistical Outputs v1.0 5 March 2020 ..........................................54 
 


Shire 
CONFIDENTIAL 
Page 4 
Final PRO report 
Lanadelumab (DX2930 ; SHP463) 
24 March 2020 
 
LIST OF IN-TEXT TABLES 
Table 1 
PROs recording schedule in Study DX-2930-04 ..................................................11 
Table 2 
Description of Change in AE-QoL Scores from Day 0 to the End of Study 
Visit for Rollover Subjects (Rollover Safety Population) ....................................19 
Table 3 
Fit statistics of the linear regressions conducted on the change in AE-QoL 
scores from Day 0 to end of study visit in the Rollover Safety population ..........27 
Table 4 
Results of the linear regressions on change in AE-QoL scores from Day 0 
to end of study visit in the Rollover Safety population ........................................28 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Schematic DX-2930-04 Study Design....................................................................9 
Figure 2 
Description of AE-QoL scores at each visit from Day 0 to end of study 
visit in the Rollover Safety population (N=109) ..................................................17 
Figure 3 
Description of AE-QoL scores at each visit from Day 0 to end of study 
visit in the Non-Rollover Safety population (N=103) ..........................................18 
Figure 4 
Description of HADS domain scores at each visit from Day 0 to end of 
study visit in the Rollover Safety population (N=109) .........................................20 
Figure 5 
Description of WPAI-GH scores at each visit from Day 0 to end of study 
visit in the Rollover Safety population (N=109) ..................................................21 
Figure 6 
Description of SF-12v2 Mental Components and Physical Component 
scores at each visit from Day 0 to end of study visit in the Rollover Safety 
population (N=109) ..............................................................................................22 
Figure 7 
Description of HADS domain scores at each visit from Day 0 to end of 
study visit in the Non-Rollover Safety population (N=103) ................................23 
Figure 8 
Description of WPAI scores at each visit from Day 0 to end of study visit 
in the Non-Rollover Safety population (N=103) ..................................................24 
Figure 9 
Description of SF-12v2 Mental Component and Physical Component 
scores at each visit from Day 0 to end of study visit in the Non-Rollover 
Safety population (N=103) ...................................................................................25 
 


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3. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AECT 
Angioedema Control Test 
AE-QoL 
Angioedema Quality of Life Questionnaire 
ACT 
Asthma Control Test 
C1-INH 
C1 Inhibitor 
CDF 
Cumulative distribution function 
EQ-5D-5L 
EuroQoL 5-Dimensional 5-Level Measure 
HAE 
Hereditary angioedema 
HADS 
Hospital Anxiety and Depression Scale 
HRQoL 
Health-Related Quality of Life 
MCID 
Minimal clinically important difference 
PRO 
Patient-reported outcome 
q2wks 
Every two weeks 
q4wks 
Every four weeks 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SEM 
Standard error of the mean 
SF-12v2 
12 Item Short Form v2 Health Survey 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
UCT 
Urticaria Control Test 


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4. EXECUTIVE SUMMARY 
These analyses of the patient-reported outcome (PRO) data collected in Study DX-2930-04 
generated data supporting the benefit of lanadelumab (DX-2930) in terms of patient-centered 
outcomes. Subjects previously treated with lanadelumab in Study DX-2930-03 maintained or 
further improved patient-centered outcomes. Subjects not treated with lanadelumab before Study 
DX-2930-04 experienced clear improvement in outcomes, such as health-related quality of life, 
functioning or work life. 
This report describes the results of the AE-QoL scores and other PROs (EQ-5D-5L, WPAI-GH, 
HADS, SF-12v2 and TSQM-9) until the end of Study DX-2930-04, an open-label, long-term 
safety and efficacy extension of Study DX-2930-03. These analyses also investigated change in 
PRO scores between baseline and end of study according to previous exposure to lanadelumab in 
Study DX-2930-03. The analyses were conducted using all the planned visits of the study until 
the end of the study. They were run in the Safety population that included 212 subjects, 109 in 
the Rollover Safety population (i.e. subjects who completed the double-blind treatment period at 
Day 182 of Study DX-2930-03) and 103 in the Non-Rollover Safety population (i.e. subjects 
who did not participate in Study DX-2930-03 and entered directly in Study DX-2930-04). 
Overall, improvements in all AE-QoL scores were observed between Day 0 and end of study 
visit of DX-2930-04 in both subjects who participated in Study DX-2930-03 (Rollover) and 
subjects who did not (Non-Rollover). Subjects not previously treated with lanadelumab (either 
Non-Rollover subjects, or Rollover subjects treated with placebo in Study DX-2930-03) showed 
a greater improvement in all AE-QoL domains in DX-2930-04 study than subjects who had been 
treated with lanadelumab in Study DX-2930-03, supporting the benefit of lanadelumab 
treatment. 
HADS Anxiety and Depression scores remained stable over the course of the study, with mean 
scores lower than 6, indicating normal levels of anxiety and depression in both Rollover and 
Non-rollover subjects. In the Rollover Safety population no changes in the EQ-5D-5L, WPAI-
GH and SF-12v2 scores were observed. Subjects who had not been previously treated with 
lanadelumab (either Non-Rollover patients, or Rollover subjects from the placebo group in DX-
2930-03) reported improvement in all PROs when initiating treatment with lanadelumab across 
the wide range of PRO analyses from Study DX-2930-04. 
In both the Rollover and Non-Rollover Safety populations, the TSQM-9 scores showed that the 
subjects were very satisfied with their treatment effectiveness, found their treatment convenient 
and were very satisfied with their medication. 
A few limitations were observed with the analyses of PRO data from Study DX-2930-04. 
Especially, the generic instruments showed little to no impairment at baseline making it difficult 
to show improvements during follow-up. In addition some PRO scores showed floor effects  
which may have impacted the ability to demonstrate improvement. 


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5. BACKGROUND 
Hereditary Angioedema (HAE) is a rare, long-term and potentially life-threatening genetic 
disease, characterized by the occurrence of transitory and recurrent subcutaneous and/or 
submucosal edemas resulting in swelling. It can affect the face, arms, legs, airway and 
gastrointestinal tract.(Zuraw 2008) Attacks, without treatment, typically occur every couple of 
weeks and last for a few days.(N.I.H. 2020) Consequences of attacks may be fatal, by 
asphyxiation, when swelling occurs in the larynx. Prevalence of HAE has been estimated 
between 10,000 to 1 and 150,000 persons, depending on authors.(Göring, Bork et al. 1998, 
Bygum 2009, Nordenfelt, Dawson et al. 2014) Disease is caused by a genetic deficiency (HAE 
type I) or dysfunction (type II) of the C1 inhibitor (C1-INH) protein.(Donaldson and Evans 
1963) This results in increased amounts of bradykinin which promotes swelling.(Nussberger, 
Cugno et al. 1998) 
Lanadelumab (DX-2930 or SHP643) is a fully human G subclass 1 (IgG1) recombinant 
monoclonal antibody that binds specifically to active plasma kallikrein and inhibits its 
proteolytic activity. Lanadelumab is being developed for routine prophylaxis to prevent 
angioedema attacks in patients with HAE. Plasma plays a critical role in the pathogenesis of 
HAE attacks (Davis 2006, Kaplan and Joseph 2010), being a regulator of the release of 
bradykinin, and being itself regulated by C1-INH proteins. Kallikrein is already the target of a 
previously FDA approved drug for the prevention of acute HAE attacks. (Thompson 2010, 
Kalbitor® 2015) 
Study DX-2930-04 was an open-label, long-term safety and efficacy extension of Study DX-
2930-03. Study DX-2930-04 was conducted in subjects with Type I or Type II HAE to evaluate 
the long-term safety and efficacy of the investigational product, lanadelumab, in preventing acute 
angioedema attacks. The primary objective of Study DX-2930-04 was to evaluate the long-term 
safety of repeated subcutaneous (SC) administrations of lanadelumab; the secondary objectives 
of the study were to evaluate the long-term efficacy of lanadelumab in preventing acute HAE 
attacks and to characterize the outer bounds of dosing frequency for lanadelumab. Two types of 
subjects were enrolled into this study:  
• Subjects who rolled over from Study DX-2930-03 
• Subjects who were non-rollovers (i.e., were not participants in Study DX-2930-03). 
 
Two interim analyses of the patient-reported outcomes (PROs) collected in Study DX-2930-04 
have been conducted. They described the PRO data collected during the first months of the 
study, providing early results on the benefit of lanadelumab on health-related quality of life 
(HRQoL) in subjects with Type I or Type II HAE. 
This final PRO report to Study DX-2930-04 provides an update to the observations made from 
the second interim analyses issued on 26 Feb 2019. This report provides long-term evidence of 
the impact of lanadelumab on HRQoL and other PROs including measures of health status, 
anxiety and depression, and work productivity/activity impairment due to health disability. 


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6. OBJECTIVES 
The objectives of the PRO analyses performed using the PRO data collected in Study DX-2930-
04 were: 
• To describe PRO scores over the course of the DX-2930-04 study separately for patients 
who participated in the DX-2930-03 study (‘Rollover patients’) and patients who did not 
participate in the DX-2930-03 study (‘Non-Rollover patients’): 
o Functioning, Fatigue/Mood, Fear/Shame, Nutrition as assessed by the AE-QoL 
o Work productivity and activity impairment, as assessed by the WPAI-GH 
o Anxiety and depression, as assessed by the HADS 
o Generic health-related quality of life, as assessed by the SF-12v2 
o Treatment satisfaction, as assessed by the TSQM-9 
o Health status, as assessed by EQ-5D-5L 
• To investigate change in PRO scores between baseline and end of study according to 
previous exposure to lanadelumab in Study DX-2930-03. 


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7. METHODS 
7.1 
DX-2930-04 study 
7.1.1 
Study design 
Study DX-2930-04 was an open-label, long term safety and efficacy extension of Study DX-
2930-03, to evaluate lanadelumab for prevention of acute angioedema attacks in subjects with 
Type I or Type II HAE. A schematic study design of Study DX-2930-04 is provided in Figure 1. 
Figure 1 
Schematic DX-2930-04 Study Design 
 
Two types of subjects were enrolled into this study: rollover and non-rollover subjects. Rollover 
subjects were subjects who completed the double-blind treatment period at Day 182 of Study 
DX-2930-03 and consented to enter Study DX-2930-04. They received a single open-label dose 
of lanadelumab administered SC on Day 0. Rollover subjects did not receive any additional 
lanadelumab doses until their first reported and investigator-confirmed HAE attack. They then 
continued to receive repeated SC administrations of open-label 300mg lanadelumab every 2 
weeks for the remaining duration of the treatment period.   


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Non-rollover subject did not participate to DX-2930-03 and are thus “naïve” of lanadelumab use. 
They received an open-label dose of 300 mg lanadelumab administered SC on Day 0, then 
continued to receive SC dose every 2 weeks throughout the duration of the treatment period. 
The study duration was planned to be 34 months (952 days), including a 1-month follow up 
period, after the treatment period. The study was expected to enroll at least 100 rollover subjects, 
and at least 50 (to approximately 100) non-rollovers, to achieve a total enrollment of at least 150 
(maximum of 250). 
Additional information on Study DX-2930-04 investigational plan is provided in the final CSR 
26 March 2020 in Section 9. 
7.1.2 
PRO data 
Subjects in Study DX-2930-04 were asked to complete the following PRO instruments at various 
timepoints: 
• Angioedema Quality of Life Questionnaire (AE-QoL) 
• EuroQoL 5-Dimensional 5-Level Measure (EQ-5D-5L) 
• Work Productivity and Activity Impairment – General Health (WPAI-GH) Questionnaire 
• Hospital Anxiety and Depression Scale (HADS) 
• Short Form v2 Health Survey 12 Item version 2 (SF-12v2) 
• Angioedema Control Test (AECT) 
• Treatment Satisfaction Questionnaire for Medication (TSQM-9)  
• Global Impression of Treatment Response  
The PRO assessment schedule is presented in Table 1. Of those PRO instruments, only the 
AE-QoL and EQ-5D-5L were administered in Study DX-2930-03. 
All PRO instruments are described below. 
 


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Table 1 
PROs recording schedule in Study DX-2930-04 
Day 
0 
28 
56 
98 
126 
154 
182 
224 
266 
308 
364 
406 
462 
518 
574 
630 
686 
742 
798 
854 
910 
9521 
AE-QoL2 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
EQ-5D-5L 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
WPAI-GH 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
HADS 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
SF-12 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
AECT3 
 
 
 
 
 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
TSQM3 
 
 
 
 
 
 
 
 
 
 
✓ 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
Global 
Impression of 
Treatment 
Response3 
 
 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
✓ 
1 Records at day 952 corresponds to the end of the study and of the 4-week follow-up period (Day 924 to 952) 
2 AE-QoL=Angioedema Quality of Life 
3 These patient reported outcomes (PRO) questionnaires were added in Protocol Amendment 3 
 
 


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7.2 
PRO instruments 
HRQoL, health status, anxiety and depression, and work productivity/activity impairment due to 
health disability were assessed using the Angioedema Quality of Life (AE-QoL) questionnaire, 
EuroQoL 5-Dimensional 5-Level (EQ-5D-5L) descriptive system and visual analogue scale 
(VAS), 12-Item Short Form Survey (SF-12v2), Hospital Anxiety and Depression Scale (HADS), 
and Work Productivity and Activity Impairment: General Health (WPAI-GH) questionnaire 
(only the AE-QoL and EQ-5D-5L were administered in Study DX-2930-03). 
The following patient reported outcome (PRO) questionnaires were added in Protocol 
Amendment 3: Treatment Satisfaction Questionnaire for Medication (TSQM-9), Global 
Impression of Treatment Response, and Angioedema Control Test (AECT). 
7.2.1 
Angioedema Quality of Life (AE-QoL) Questionnaire 
The AE-QoL is a self-administered instrument developed and validated to assess health-related 
quality of life (HRQoL) impairment in subjects with recurrent angioedema.(Weller, Groffik et al. 
2012) It consists of 17 items divided in 4 domains/dimensions: functioning, fatigue/mood, 
fear/shame, nutrition. Items are 5-point Likert-type response scales ranging from “Never” to 
“Very Often”, asking for patient ratings over the last four weeks. Scores for each domain and a 
total score can be obtained by taking the mean of the item scores within the scale (or mean item 
scores of all items, for the total score) and transforming it linearly on a 0-100 scale. The AE-QoL 
scores range between 0 to 100, with lower scores indicating lower impairment and higher scores 
indicating greater QoL impairment.  
A 6-point difference has been reported to be the minimal clinically important difference (MCID) 
for the AE-QoL total score. (Weller, Magerl et al. 2016) This value was used as threshold for 
PRO response in the PRO responder analyses, for all AE-QoL scores (in the absence of specific 
value for the domain scores). 
7.2.2 
EuroQol 5-Dimensions-5 levels (EQ-5D-5L) 
The EQ-5D-5L is a self-administered standardized measure of health status comprised of a 
descriptive system and a Visual Analogue Scale (VAS).(Herdman, Gudex et al. 2011) The 
descriptive systems assess five dimensions of health status: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression(Herdman, Gudex et al. 2011). Each dimension is rated 
on a 5-point scale to describe subject health for the current day, with 1 being “no problems” and 
5 “extreme problems”. An index score can be derived from the five items to calculate utilities. 
The index score ranges between 0 and 1, with 1 corresponding to a perfect health. The UK 
crosswalk value set was used to calculate the EQ-5D-5L index scores. 
Separately from the descriptive part, the VAS is a measure of overall self-rated health status. The 
subject assesses his or her health using a 20-cm vertical VAS, between “the best health you can 
imagine” and “the worst health you can imagine”. Scores ranges from 0 to 100, with a higher 
score indicating better health. 


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7.2.3 
Work Productivity and Activity Impairment – General Health (WPAI-GH) 
Questionnaire 
The WPAI-GH is a 6-item self-assessment of the effect of health problems on the subject’s 
ability to work and perform regular activities, during the past 7 days.(Reilly, Zbrozek et al. 1993) 
WPAI-GH scoring guidelines lead to the creation of the following scores: percent work time 
missed due to health, percent impairment while working due to health, percent overall work 
impairment due to health, and percent activity impairment due to health. Adolescent subjects 
were asked to complete the WPAI-GH and use the term “school” instead of “work” when 
completing the questionnaire. The scores are percentages with higher values indicating greater 
impairment and less work productivity. 
The MCID for the WPAI-GH has been suggested in other conditions to be 7.2 for absenteeism, 
11.1 for presenteeism, 9.8 for overall work productivity, and 14.3 for activity impairment.(Bolge, 
Doan et al. 2009) Based on these values, the following values were used as thresholds for PRO 
response in the PRO responder analyses: 7 for absenteeism, 11 for presenteeism, 10 for overall 
work productivity, and 14 for activity impairment. 
7.2.4 
Hospital Anxiety and Depression Scale (HADS) 
The HADS is a self-assessed scale developed to detect subjects states of depression, anxiety, and 
emotional distress.(Zigmond and Snaith 1983) From its 14 items, 7 relate to anxiety and 7 to 
depression during the past week. Responses are scored on a scale ranging from 0 to 3, with 3 
indicating the highest symptom frequency. For each domain, scores range from 0 to 21, and can 
be categorized as normal (0 to 7), mild (8 to 10), moderate (11 to 14), and severe (15 to 21). 
Additionally, a total score can be calculated from the full set of items, ranging from 0 to 42, with 
a higher score indicating more distress.  
The MCID has been estimated in other conditions to be in the range 1.5-2.5.(Puhan, Frey et al. 
2008, Chan, Friedman et al. 2016) Based on these values, a 2-point value was used as threshold 
for PRO response in the PRO responder analyses for the HADS scores. 
7.2.5 
12 Item Short Form v2 Health Survey (SF-12v2) 
The SF-12v2 is a validated instrument designed to measure functional health and well-being. It 
consists of 12 questions, divided into 8 health domains: physical functioning, role physical, 
bodily pain, general health, vitality, social functioning, role emotional, and mental health.(Ware 
Jr, Kosinski et al. 1996) Questions asked subjects about their health for the last 4 weeks. Physical 
and Mental Health Composite, as well as domain scores can be calculated. They range from 0 to 
100, with 0 indicating the lowest health level as measured by the scales and 100 the highest. 
Norm-based scores are obtained using t-scores based on a general US population mean of 50.0, 
with a standard deviation of 10.0, allowing direct comparisons to the US general population. 
The MCID has been estimated in other conditions to be in the range 4.9-5.2. (Schwab, Lafage et 
al. 2008, Skolasky, Maggard et al. 2015) Based on these values, a 5-point value was defined to 
be used as threshold for PRO response in the PRO responder analyses for the SF-12v2 scores. 


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7.2.6 
Angioedema Control Test (AECT) 
The AECT is a 4-question instrument designed to assess the control of angioedema among 
subjects with recurrent angioedema (including HAE). It asks the frequency of symptoms, impact 
on HRQoL, impact of unpredictability, and perceived disease control. This is a useful measure 
specially to drive treatment decisions. Its concept is similar to the previously developed and 
established Asthma Control Test (ACT) and Urticaria Control Test (UCT).(Nathan, Sorkness et 
al. 2004, Weller, Groffik et al. 2014) Questions have 5 answer options (verbal rating scale), 
scored from 0 to 4 points.  
7.2.7 
Treatment Satisfaction Questionnaire for Medication version 9 (TSQM-9) 
The TSQM-9 is a generic 9-item measure of treatment satisfaction that allows for comparison 
across medication types and subjects conditions.(Bharmal, Payne et al. 2009) It assesses the 
subject’s perception of treatment effectiveness, convenience, and global satisfaction during the 
last two to three weeks or when the treatment was last used. Scores for each of the 3 domains, as 
well as a combined score are calculated separately. Scores are transformed to a 0 to 100 scale, 
with a higher score indicating higher satisfaction with treatment. 
7.2.8 
Global Impression of Treatment Response 
The subjects’ and investigators’ global impression of treatment response is assessed, using a 
single question: “Overall, how would you rate your response to the study medication?”. 
Responses options are namely, about the actual day: “poor”, “fair”, “good”, “very good” and 
“excellent”. 
7.3 
Analysis population 
• Safety Population: all subjects included in the study 
• Rollover Safety Population: subjects who participated in DX-2930-03 study  
• Non-rollover Safety Population: subjects who entered DX-2930-04 study directly  
 
7.4 
General principles 
7.4.1 
Description of variables 
Continuous variables were described by their frequency, mean, standard deviation (SD), standard 
error of the mean (SEM), median, first and third quartiles, extreme values (minimum and 
maximum values), and number of missing values. 
Categorical variables were described by the frequency and percentage of each response choice, 
with missing data being included in the calculation of percentage. 
7.4.2 
Level of significance 
All p-values are considered descriptive. Their interpretation are performed using a level of 
significance set to 5% (two-sided test). No method to control for multiple testing was applied. 


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7.5 
Missing data handling 
For the score calculations, the missing items of the PRO questionnaires were handled as 
proposed by the authors of the questionnaires. 
No missing PRO assessment was imputed in the analyses. 
7.6 
Software 
Data analysis were performed using SAS version 9.4. 
7.7 
Analysis plan 
The detailed analysis plan is available in Appendix 1. The analyses conducted on the PRO data 
of the DX-2930-04 study are summarized below: 
• Description of AE-QoL scores over the study: description of the AE-QoL scores in the 
Rollover Safety population and in the Non-Rollover Safety population at each visit from 
Day 0 to end of study visit; description of change in AE-QoL scores from Day 0 to each 
scheduled visit in the Rollover Safety population and in the Non-Rollover Safety 
population; description of change in AE-QoL scores from Day 0 to each scheduled visit 
in the Rollover Safety population by treatment received during the DX-2930-03 study 
• Description of other PRO scores over the study: description of the EQ-5D-5L index 
score, WPAI-GH scores, HADS scores, SF-12v2 scores and TSQM-9 scores in the 
Rollover Safety population and in the Non-Rollover Safety population at each visit from 
Day 0 to end of study visit; description of change in these PRO scores from Day 0 to each 
scheduled visit in the Rollover Safety population and in the Non-Rollover Safety 
population; description of change in these PRO scores from Day 0 to each scheduled visit 
in the Rollover Safety population by treatment received during the DX-2930-03 study 
• Exploratory analysis of AE-QoL changes in scores: linear regressions with the change in 
AE-QoL score from Day 0 to the end of study visit as explained variable and the 
following explanatory variables: duration of ‘regular’ treatment period, AE-QoL score at 
baseline, AE-QoL score at baseline from the DX-2930-03 study, and treatment received 
in the DX-2930-03 study in the Rollover Safety population. 
• Responder analysis and empirical cumulative distribution functions (CDFs): description 
of percentage of responders (i.e. change in score above a predefined threshold) at each 
scheduled post-baseline visit in the Rollover Safety population overall, as well as 
according to treatment received in the DX-2930-03 study; description of percentage of 
responders at each scheduled post-baseline visit in the Non-Rollover Safety population; 
CDFs of the change in scores from Day 0 to the end of study visit in the Rollover Safety 
population and in the Non-Rollover Safety population. Scores considered for the analysis 
were the AE-QoL scores, the WPAI-GH scores, the HADS scores and the SF-12v2 
scores. 


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8. 
RESULTS 
8.1 
Description of AE-QoL scores over the study 
8.1.1 
Description of AE-QoL scores and change in AE-QoL scores in Rollover Safety 
Population 
Figure 2 shows the distribution of AE-QoL scores in the Rollover Safety population at each visit 
from Day 0 to end of study visit. Mean AE-QoL scores were systematically lower than 40 (on a 
scale ranging from 0 to 100) at all visits, indicating no to moderate impairment due to 
angioedema. The first quartile was 0 at several visits for all AE-QoL domain scores, indicating a 
floor effect: a number of subjects (at least 25%) reported the best possible status measured by the 
AE-QoL in terms of Fatigue/Mood, Functioning, Nutrition and even, for more recent visits, 
Fears/Shame. Mean AE-QoL domain and total scores decreased (indicating improvement) in the 
early follow-up (schematically from Day 0 to Day 56) before reaching a plateau. The 
Fears/Shame score was the AE-QoL domain score showing the greatest decrease (indicating 
improvement) between Day 0 and end of study visit, with a mean (SD) change of -12.87 (19.20). 
Other AE-QoL scores also showed improvement with mean changes from Day 0 to end of study 
visit of -7.39 (23.79) for the Fatigue/Mood score, -11.11 (24.27) for the Functioning score, -7.22 
(26.10) for the Nutrition score, and -10.18 (17.90) for the Total score. A full description of the 
AE-QoL scores is available in Appendix 1, Output 1. 
 
 


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Figure 2 
Description of AE-QoL scores at each visit from Day 0 to end of study visit in 
the Rollover Safety population (N=109) 
 
AE-QoL=Angioedema Quality of Life; EOS=end of study; ET=early termination; Follow-up 2=EOS visit/ET 
Legend: Box for each score: interquartile range (Q1-Q3); +: mean; —: median; bottom and top bars: observed minimum and maximum values 
Lower scores indicate lower impairment and higher scores indicate greater QoL impairment. 
Source: Appendix 2, Output 1, Table 1.1.1, Table 1.1.2, Table 1.1.3, Table 1.1.4, Table 1.1.5, Table 1.1.6, Table 1.1.7, Table 1.1.8, Table 1.1.9, 
Table 1.1.10, Table 1.1.11, Table 1.1.12, Table 1.1.13, Table 1.1.14, Table 1.1.15, Table 1.1.16, Table 1.1.17, Table 1.1.18, Table 1.1.19, 
Table 1.1.20, Table 1.1.21 and Table 1.1.22 
8.1.2 
Description of AE-QoL scores and change in AE-QoL scores in the Non-Rollover 
Safety population 
Figure 3 shows the distribution of AE-QoL scores in the Non-Rollover Safety population at each 
visit from Day 0 to end of study visit. AE-QoL scores went from markedly higher values, 
distributed around means (SD) of 36.62 (22.56) for Fatigue/Mood, 46.24 (22.95) for Fear/Shame, 
36.89 (27.21) for functioning, 30.45 (26.60) for Nutrition and 39.31 (20.46) for the Total score at 
Day 0, to lower values distributed around means between 8 and 30 (on a scale ranging from 0 to 
100) depending on the scores and the visits. The greatest decrease in AE-QoL domain and total 
scores was mostly observed between Day 0 and Day 28 (or Day 56, for Fear/Shame). The 
Functioning score was the AE-QoL domain showing the greatest decrease (indicating 
improvement) between Day 0 and end of study visit, with a mean (SD) change of -26.16 (27.71). 
Other AE-QoL scores also showed  improvement over the follow-up, with mean changes from 


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Day 0 to end of study visit of -22.22 (24.31) for Fears/Shame, -11.60 (25.83) for 
Fatigue/Mood, -18.28 (24.35) for Nutrition, and -19.53 (21.31) for the Total score. Again, the 
first quartile was 0 at several visits for all AE-QoL domain scores, indicating a floor effect for 
these measures; a number of subjects (at least 25%) reported the best possible status measured by 
the AE-QoL in terms of Fatigue/Mood, Fear/Shame, Functioning, and Nutrition. Full AE-QoL 
domain and total score descriptions are available in Appendix 2, Output 2. 
Figure 3 
Description of AE-QoL scores at each visit from Day 0 to end of study visit in 
the Non-Rollover Safety population (N=103) 
 
AE-QoL=Angioedema Quality of Life; EOS=end of study; ET=early termination; Follow-up 2=EOS visit/ET 
Legend: Box for each score: interquartile range (Q1-Q3); +: mean; —: median; bottom and top bars: observed minimum and maximum values  
Lower scores indicate lower impairment and higher scores indicate greater QoL impairment. 
Source: Appendix 2, Output 2, Table 2.1.1, Table 2.1.2, Table 2.1.3, Table 2.1.4, Table 2.1.5, Table 2.1.6, Table 2.1.7, Table 2.1.8, Table 2.1.9, 
Table 2.1.10, Table 2.1.11, Table 2.1.12, Table 2.1.13, Table 2.1.14, Table 2.1.15, Table 2.1.16, Table 2.1.17, Table 2.1.18, Table 2.1.19, 
Table  2.1.20, Table 2.1.21 and Table 2.1.22 
8.1.3 
Description of change in AE-QoL scores in the Rollover Safety population by 
treatment received during DX-2930-03 
Table 2 describes the change in AE-QoL scores from Day 0 to the end of study visit in the 
Rollover Safety Population according to the treatment previously received in the DX-2930-03 
trial. Mean change between Day 0 and end of study visit showed greater improvement for 


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subjects previously treated with placebo than for subjects previously treated with lanadelumab in 
all AE-QoL scores. Full results are available in Appendix 2, Output 3. 
Table 2 
Description of Change in AE-QoL Scores from Day 0 to the End of Study Visit 
for Rollover Subjects (Rollover Safety Population) 
 
Double-Blind Actual Treatment 
 
Variable 
Placebo 
N=32 
DX-2930 150 mg 
every 4 weeks 
N=22 
DX-2930 300 mg 
every 4 weeks 
N=21 
DX-2930 300 mg 
every 2 weeks 
N=22 
Rollover Safety 
Population 
N=97 
AE-QoL 
Fatigue/Mood Score 
 
 
 
 
 
    n (missing) 
   30 (2) 
   19 (3) 
   20 (1) 
   21 (1) 
   90 (7) 
    Mean (SD) 
  -15.50 (25.06)    -8.16 
(23.35) 
   -4.50 (15.30)     2.14 (26.30)    -7.39 
(23.79) 
 
 
 
 
 
 
AE-QoL Fears/Shame 
Score 
 
 
 
 
 
    n (missing) 
   30 (2) 
   19 (3) 
   20 (1) 
   21 (1) 
   90 (7) 
    Mean (SD) 
  -20.00 (17.21)    -7.02 
(20.41) 
   -9.17 (18.37)   -11.51 (19.76)   -12.87 
(19.20) 
 
 
 
 
 
 
AE-QoL Functioning 
Score 
 
 
 
 
 
    n (missing) 
   30 (2) 
   19 (3) 
   20 (1) 
   21 (1) 
   90 (7) 
    Mean (SD) 
  -30.63 (22.10)    -1.32 
(15.11) 
   -5.31 (10.19)     2.38 (26.84)   -11.11 
(24.27) 
 
 
 
 
 
 
AE-QoL 
Nutrition 
Score 
 
 
 
 
 
    n (missing) 
   30 (2) 
   19 (3) 
   20 (1) 
   21 (1) 
   90 (7) 
    Mean (SD) 
  -25.42 (25.95)     2.63 
(14.78) 
    1.25 (18.98)     1.79 (27.75)    -7.22 
(26.10) 
 
 
 
 
 
 
AE-QoL Total Score 
 
 
 
 
 
    n (missing) 
   30 (2) 
   19 (3) 
   20 (1) 
   21 (1) 
   90 (7) 
    Mean (SD) 
  -21.81 (17.96)    -4.88 
(16.09) 
   -5.66 (10.17)    -2.66 (17.82)   -10.18 
(17.90) 
 
 
 
 
 
 
AE-QoL=Angioedema Quality of Life Questionnaire 
Negative values indicate improvement and positive values indicate worsening 
Source: Appendix 2, Output 3, Table 3.1 
8.2 
Description of other PRO scores over the study 
8.2.1 
Description of PRO scores and change in PRO scores in Rollover Safety 
Population 
Figure 4 shows the distribution of HADS domain scores in the Rollover Safety population at 
each visit from Day 0 to end of study visit. HADS Anxiety and Depression scores remained 
stable over the course of the study, with mean scores lower than 6, indicating normal levels of 
anxiety and depression. A full description of the HADS scores is available in Appendix 2, 
Output 4. 


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Figure 4 
Description of HADS domain scores at each visit from Day 0 to end of study 
visit in the Rollover Safety population (N=109) 
 
HADS=Hospital Anxiety and Depression Scale; EOS=end of study; ET=early termination; Follow-up 2=EOS visit/ET 
Legend: Box for each score: interquartile range (Q1-Q3); +: mean; —: median; bottom and top bars: observed minimum and maximum values 
0-7: normal anxiety/depression; 8-10: mild anxiety/depression; 11-14: moderate anxiety/depression; 15-21: severe anxiety/depression 
Source: Appendix 2, Output 4, Table 4.1.1, Table 4.1.2, Table 4.1.3, Table 4.1.4, Table 4.1.5, Table 4.1.6, Table 4.1.7, Table 4.1.8, Table 4.1.9, 
Table 4.1.10, Table 4.1.11, Table 4.1.12, Table 4.1.13, Table 4.1.14, Table 4.1.15, Table 4.1.16, Table 4.1.17, Table 4.1.18, Table 4.1.19, 
Table 4.1.20, Table 4.1.21 and Table 4.1.22 
Figure 5 shows the distribution of WPAI-GH domain scores in the Rollover Safety population at 
each visit from Day 0 to end of study visit. WPAI-GH domain scores remained stable over the 
follow-up, with mean percent activity impairment due to health between 17.76 (22.06) and 26.44 
(30.94); mean percent impairment while working due to health between 9.62 (14.93) and 18.82 
(26.46); mean percent overall work impairment due to health between 11.10 (18.27) and 21.19 
(29.27); and mean Percent work time missed due to health between 1.57 (6.66) and 6.84 (19.40). 
All scores showed a clear floor effect with several subjects reporting the smallest possible impact 
on productivity at all visits. A full description of the WPAI-GH is available in Appendix 2, 
Output 4. 
 


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Figure 5 
Description of WPAI-GH scores at each visit from Day 0 to end of study visit in 
the Rollover Safety population (N=109) 
 
WPAI-GH=Work and Productivity Activity Impairment – General Health questionnaire; EOS=end of study; ET=early termination; Follow-up 
2=EOS visit/ET 
Legend: Box for each score: interquartile range (Q1-Q3); +: mean; —: median; bottom and top bars: observed minimum and maximum values 
Higher values indicate greater impairment and less work productivity 
Source: Appendix 2, Output 4, Table 4.1.1, Table 4.1.2, Table 4.1.3, Table 4.1.4, Table 4.1.5, Table 4.1.6, Table 4.1.7, Table 4.1.8, Table 4.1.9, 
Table 4.1.10, Table 4.1.11, Table 4.1.12, Table 4.1.13, Table 4.1.14, Table 4.1.15, Table 4.1.16, Table 4.1.17, Table 4.1.18, Table 4.1.19, 
Table 4.1.20, Table 4.1.21 and Table 4.1.22 
Figure 6 shows the distribution of the SF-12v2 Mental and Physical Component scores in the 
Rollover Safety population at each visit from Day 0 to end of study visit. SF-12v2 Mental 
Component score (MCS) and Physical Component score (PCS) remained stable over the course 
of the study, with mean scores between 48.65 (10.08) and 51.15 (9.82) for the MCS score and 
between 48.84 (10.31) and 52.04 (8.81) for the PCS score. All the SF-12v2 scores were stable 
over the course of the study, except the General Health score that showed a slight increase from 
65.19 (24.59) at Day 0 to 71.17 (25.33) at the end of study visit. A full description of the SF-
12v2 scores is available in Appendix 2, Output 4. 


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Figure 6 
Description of SF-12v2 Mental Components and Physical Component scores at 
each visit from Day 0 to end of study visit in the Rollover Safety population 
(N=109) 
 
SF-12v2=12 Item Short Form v2 Health Survey; EOS=end of study; ET=early termination; Follow-up 2=EOS visit/ET 
Legend: Box for each score: interquartile range (Q1-Q3); +: mean; —: median; bottom and top bars: observed minimum and maximum values 
0 indicates the lowest health level as measured by the scales and 100 the highest 
Source: Appendix 2, Output 4, Table 4.1.1, Table 4.1.2, Table 4.1.3, Table 4.1.4, Table 4.1.5, Table 4.1.6, Table 4.1.7, Table 4.1.8, Table 4.1.9, 
Table 4.1.10, Table 4.1.11, Table 4.1.12, Table 4.1.13, Table 4.1.14, Table 4.1.15, Table 4.1.16, Table 4.1.17, Table 4.1.18, Table 4.1.19, 
Table 4.1.20, Table 4.1.21 and Table 4.1.22 
EQ-5D-5L was completed by the Rollover Safety population at each visit from Day 0 to end of 
study visit. Mean (± SD) EQ-5D-5L index score was 0.85 (±0.19) at Day 0 in the Rollover 
Safety population. It was stable over the study, going slightly up to 0.87 (±0.17) at Day 742 and 
down to 0.83 (±0.22) at Day 364. Mean (± SD) EQ-5D-5L at end of study visit was 0.86 (±0.18) 
(data not shown, see Appendix 2, Output 4). 
The TSQM-9 was completed by the subjects at Day 364, Day 574 and end of study visit only. 
Mean (±SD) Effectiveness score fluctuated between 90.30 (±18.17) and 94.26 (±10.87) 
indicating that Rollover subjects were very satisfied with their treatment effectiveness. Mean 
(±SD) Convenience score fluctuated between 83.92 (±15.70) and 86.48 (±17.69) indicating 
subjects reported their treatment was convenient. Mean (±SD) Satisfaction score ranged from 


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87.97 (±15.14) to 91.51 (±13.54) indicating that subjects were very satisfied with their 
medication. A full description of the TSQM-9 scores is available in Appendix 2, Output 4. 
8.2.2 
Description of PRO scores and change in PRO scores in the Non-Rollover Safety 
population 
Figure 7 shows the distribution of HADS domain scores in the Non-Rollover Safety population 
at each visit from Day 0 to end of study visit. The mean (SD) HADS Anxiety score was 7.10 
(4.06) at Day 0, indicating normal to mild anxiety. The mean HADS Depression score was 3.48 
(3.09) at Day 0, indicating normal depression. At each post-baseline visit, mean HADS Anxiety 
scores and mean HADS Depression scores were lower than 6 on a scale ranging from 0 to 21, 
indicating normal anxiety and normal depression. A full description of HADS scores is available 
in Appendix 2, Output 5. 
Figure 7 
Description of HADS domain scores at each visit from Day 0 to end of study 
visit in the Non-Rollover Safety population (N=103) 
 
HADS=Hospital Anxiety and Depression Scale; EOS=end of study; ET=early termination; Follow-up 2=EOS visit/ET 
Legend: Box for each score: interquartile range (Q1-Q3); +: mean; —: median; bottom and top bars: observed minimum and maximum values  
0-7: normal anxiety/depression; 8-10: mild anxiety/depression; 11-14: moderate anxiety/depression; 15-21: severe anxiety/depression 
Source: Appendix 2, Output 5, Table 5.1.1, Table 5.1.2, Table 5.1.3, Table 5.1.4, Table 5.1.5, Table 5.1.6, Table 5.1.7, Table 5.1.8, Table 5.1.9, 
Table 5.1.10, Table 5.1.11, Table 5.1.12, Table 5.1.13, Table 5.1.14, Table 5.1.15, Table 5.1.16, Table 5.1.17, Table 5.1.18, Table 5.1.19, 
Table 5.1.20, Table 5.1.21 and Table 5.1.22 


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Figure 8 shows the distribution of WPAI-GH domain scores in the Non-Rollover Safety 
population at each visit from Day 0 to end of study visit. Mean (SD) Percent activity impairment 
due to health score was 30.52 (27.29) at Day 0 and between 14.81 (22.06) and 24.18 (30.88) at 
each post-baseline visit. Mean (SD) Percent impairment while working due to health was 22.38 
(23.12) at Day 0 and mean (SD) Percent overall work impairment due to health was 24.90 
(25.62) at Day 0; these scores were between 9 and 21 at each post-baseline visit. Mean (SD) 
Percent work time missed due to health was below 7 at each visit. Full WPAI-GH score 
descriptions are available in Appendix 2, Output 5. 
Figure 8 
Description of WPAI scores at each visit from Day 0 to end of study visit in the 
Non-Rollover Safety population (N=103) 
 
WPAI-GH=Work and Productivity Activity Impairment – General Health questionnaire; EOS=end of study; ET=early termination; Follow-up 
2=EOS visit/ET 
Legend: Box for each score: interquartile range (Q1-Q3); +: mean; —: median; bottom and top bars: observed minimum and maximum values  
Higher values indicate greater impairment and less work productivity 
Source: Appendix 2, Output 5, Table 5.1.1, Table 5.1.2, Table 5.1.3, Table 5.1.4, Table 5.1.5, Table 5.1.6, Table 5.1.7, Table 5.1.8, Table 5.1.9, 
Table 5.1.10, Table 5.1.11, Table 5.1.12, Table 5.1.13, Table 5.1.14, Table 5.1.15, Table 5.1.16, Table 5.1.17, Table 5.1.18, Table 5.1.19, 
Table 5.1.20, Table 5.1.21 and Table 5.1.22 
Figure 9 shows the distribution of the SF-12v2 Mental and Physical Component scores in the 
Non-Rollover Safety population at each visit from Day 0 to end of study visit. SF-12v2 Mental 
Component scores and Physical Component scores increased slightly (i.e. improvement) at the 


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first post-Baseline visit and then remained stable over the course of the study, with mean (SD) 
scores ranging from 50.14 (8.88) to 53.27 (8.76) for the Mental Component score and 47.13 
(8.62) to 53.77 (5.80) for the Physical Component score. All SF-12v2 domain scores were stable 
over the course of the study. A full description of the SF-12v2 scores is available in Appendix 2, 
Output 5. 
Figure 9 
Description of SF-12v2 Mental Component and Physical Component scores at 
each visit from Day 0 to end of study visit in the Non-Rollover Safety population 
(N=103) 
 
SF-12v2=12 Item Short Form v2 Health Survey; EOS=end of study; ET=early termination; Follow-up 2=EOS visit/ET 
Legend: Box for each score: interquartile range (Q1-Q3); +: mean; —: median; bottom and top bars: observed minimum and maximum values 
0 indicates the lowest health level as measured by the scales and 100 the highest 
Source: Appendix 2, Output 5, Table 5.1.1, Table 5.1.2, Table 5.1.3, Table 5.1.4, Table 5.1.5, Table 5.1.6, Table 5.1.7, Table 5.1.8, Table 5.1.9, 
Table 5.1.10, Table 5.1.11, Table 5.1.12, Table 5.1.13, Table 5.1.14, Table 5.1.15, Table 5.1.16, Table 5.1.17, Table 5.1.18, Table 5.1.19, 
Table 5.1.20, Table 5.1.21 and Table 5.1.22 
EQ-5D-5L was completed by the Non-Rollover Safety population at each visit from Day 0 to 
end of study visit. Mean (± SD) EQ-5D-5L index score was 0.85 (±0.16) at Day 0 in the Non-
Rollover Safety population. It very slightly increased to 0.89 (±0.15) at end of study visit (data 
not shown, see Appendix 2, Output 5). 


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The TSQM-9 was completed by the subjects at Day 364, Day 574 and end of study visit only. 
Mean (±SD) Effectiveness score fluctuated between 90.29 (±15.15) and 91.70 (±14.68) 
indicating that Non-Rollover subjects were very satisfied with their treatment effectiveness. 
Mean (±SD) Convenience score fluctuated between 81.14 (±17.59) and 83.46 (±16.81) 
indicating subjects reported their treatment was convenient. Mean (±SD) Satisfaction score 
ranged from 87.68 (±13.93) to 89.00 (±16.75) indicating that subjects were very satisfied with 
their medication. A full description of the TSQM-9 scores is available in Appendix 2, Output 5. 
8.2.3 
Description of change in PRO scores in the Rollover Safety population by 
treatment received during DX-2930-03 
Mean change in PRO scores were described in the Rollover Safety Population from Day 0 to end 
of study visit according to the treatment previously received in the DX-2930-03 trial.  
Mean change between Day 0 and end of study visit showed greater improvement for subjects 
previously treated with placebo than for subjects previously treated with lanadelumab in WPAI-
GH scores and SF-12v2 Mental Component and Physical Component scores. Mean changes in 
HADS and EQ-5D-5L scores were similar regardless of the treatment received during Study DX-
2930-03. Full results are available in Appendix 2, Output 6. 
8.3 
Exploratory analysis of AE-QoL score changes in the Rollover Safety Population 
Linear regressions were conducted with the change in AE-QoL scores from Day 0 to end of 
study visit as explained variable, and the following explanatory variables: duration of ‘regular’ 
treatment period, AE-QoL score at baseline, treatment received in the DX-2930-03 study and 
baseline AE-QoL score in the DX-2930-03 study, in the Rollover Safety population. Detailed 
results are available in Appendix 2, Output 7. 
Table 3 presents the percentage of variance (R²) explained by the linear regressions conducted on 
the change in each AE-QoL score from Day 0 to end of study visit in the Rollover Safety 
population.  
The linear regressions explained respectively 34%, 35%, 57%, 36% and 41% of the variance of 
the change from Day 0 to end of study visit in the AE-QoL Fatigue/Mood, Fear/Shame, 
Functioning, Nutrition and Total scores, respectively. 


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Table 3 
Fit statistics of the linear regressions conducted on the change in AE-QoL 
scores from Day 0 to end of study visit in the Rollover Safety population 
Score 
Model with change in 
score from Day 0 to 
end of study visit 
N 
R² 
AE-QoL Fatigue/Mood score 
90 
0.336 
AE-QoL Fears/Shame score 
90 
0.354 
AE-QoL Functioning 
89 
0.572 
AE-QoL Nutrition score 
90 
0.358 
AE-QoL Total score 
90 
0.413 
In bold, R²>0.020 
AE-QoL: Angioedema Quality of Life Questionnaire 
Source: Appendix 2, Output 7, Table 7.1.1, Table 7.1.2, Table 7.2.1, Table 7.2.2, Table 7.3.1, Table 7.3.2, Table 7.4.1, Table 7.4.2, Table 7.5.1 
and Table 7.5.2 
Table 4 presents the estimates obtained on the linear regressions on the change in AE-QoL 
scores from Day 0 to end of study visit in the Rollover Safety population; results are presented 
for all 5 models as their percentage of explained variance is greater than 15%. The only variable 
that was significant at the threshold of 5% in each model was the Baseline AE-QoL score. The 
negative parameter estimates indicated that the decrease in the AE-QoL scores (i.e. 
improvement) from Day 0 to end of study visit was slightly higher for subjects who had higher 
Baseline AE-QoL scores. The treatment received during Study DX-2930-03 was also significant 
at the threshold of 5% in the AE-QoL Nutrition score model. The positive parameter estimates 
for all DX-2930 groups indicated that the decrease in the AE-QoL Nutrition score (i.e. 
improvement) from Day 0 to end of study visit was lower for subjects previously treated with 
DX-2930 than for subjects previously treated with placebo. This was in line with the raw 
description of change in score (see 8.1.3). 


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Table 4 
Results of the linear regressions on change in AE-QoL scores from Day 0 to end 
of study visit in the Rollover Safety population 
 
 
 
 
 
Treatment received in DX-2930-
03 study (Reference: Placebo) 
Score 
Intercept 
Baseline 
score 
Baseline 
score in 
the DX-
2930-03 
study 
Regular 
treatment 
period 
duration 
(in 
months) 
DX-2930 
150 mg 
every 4 
weeks 
DX-2930 
300 mg 
every 2 
weeks 
DX-2930 
300 mg 
every 4 
weeks 
AE-QoL Fatigue/Mood score 
5.399 
-0.586 
0.223 
-0.190 
1.647 
4.516 
1.223 
Ae-QoL Fears/Shame score 
3.570 
-0.436 
0.118 
-0.427 
8.550 
3.023 
6.651 
AE-QoL Functioning score 
-8.436 
-0.581 
0.095 
-0.053 
13.234 
11.579 
10.619 
AE-QoL Nutrition score 
-16.569 
-0.400 
0.093 
0.150 
17.138 
17.449 
20.663 
AE-QoL Total score 
-2.764 
-0.440 
0.091 
-0.172 
10.094 
9.233 
9.098 
In bold, significant variables (p<0.05); for treatment received in DX-2930-03 study, p-values are in bold only if the omnibus p-value was 
significant in the model.  
AE-QoL: Angioedema Quality of Life Questionnaire 
Source: Appendix 2, Output 7, Table 7.1.4, Table 7.2.4, Table 7.3.4, Table 7.4.4 and Table 7.5.4 
8.4 
Responder analysis and empirical cumulative distribution functions 
The percentage of PRO responders between Day 0 and end of study visit was calculated for all 
PRO scores and CDFs of the change in all available scores between Day 0 and end of study visit 
were plotted (Appendix 2, Output 8). A subject was considered a PRO responder if the change in 
score was greater than a predefined threshold that was considered clinically meaningful. The 
thresholds used for these analyses were a 6-point change for all AE-QoL scores; a 2-point 
change for HADS scores; a 5-point change for SF-12v2 scores; and changes of 14, 11, 10 and 7 
points for the WPAI-GH Percent activity impairment, Percent impairment while working, 
Percent overall work impairment, and Percent work time missed scores respectively. CDFs and 
percentage of responders were also obtained for the Non-Rollover Safety population, i.e., 
subjects who were not previously treated with lanadelumab (see Appendix 2, Output 9). 
The CDFs showed a consistent greater improvement in AE-QoL scores from Day 0 to end of 
study visit for subjects previously treated with placebo in the Rollover Safety population. No 
clear pattern was observed in the CDFs of the WPAI-GH, HADS and SF-12v2 scores. A higher 
percentage of responders in AE-QoL scores between Day 0 and end of study visit was observed 
in the Non-Rollover Safety population than in the Rollover Safety population. The percentage of 
responders in HADS Depression and Total scores, the WPAI-GH scores and the SF-12v2 (except 
for the Role Physical score, the Vitality score, the Mental Health score, and the Mental 
Component score) was also higher in the Non-Rollover Safety population than in the Rollover 
Safety population. 
Full results and CDFs are provided in Appendix 2, Output 8 (for the Rollover Safety population) 
and Output 9 (for the Non-Rollover Safety population). 


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9. DISCUSSION OF RESULTS 
The analyses presented in this report aimed to describe the AE-QoL and other PRO scores ( EQ-
5D-5L, WPAI-GH, HADS, SF-12v2 and TSQM-9) until end of study visit of Study DX-2930-04 
and to investigate change in PRO scores between baseline and end of study according to 
previous exposure to lanadelumab in Study DX-2930-03. Study DX-2930-04 was an open-label, 
long term safety and efficacy extension of Study DX-2930-03, which aimed to evaluate 
lanadelumab for prevention of acute angioedema attacks in subjects with Type I or Type II HAE. 
Two types of subjects were enrolled in this study: Rollover subjects, who completed the double-
blind treatment period at Day 182 of Study DX-2930-03 and consented to enter Study DX-2930-
04, and Non-Rollover subjects who did not participate in Study DX-2930-03 and entered directly 
in Study DX-2930-04.  
Overall, improvements in all AE-QoL scores were observed between Day 0 and end of study 
visit of DX-2930-04 in both subjects who participated in Study DX-2930-03 (Rollover) and 
subjects who did not (Non-Rollover). Most of the improvement in AE-QoL scores was observed 
during the early follow-up (before Day 56). Subjects not previously treated with lanadelumab 
(either Non-Rollover subjects, or Rollover subjects treated with placebo in Study DX-2930-03) 
showed a greater improvement in all AE-QoL domains in DX-2930-04 study than subjects who 
had been treated with lanadelumab in Study DX-2930-03. This indicates a possible benefit due to 
treatment  with lanadelumab. The overall improvement in AE-QoL scores observed in the 
Rollover Safety population may have been mainly driven by the improvement in subjects who 
switched from placebo to lanadelumab in Study DX-2930-04. These subjects showed greater 
change in AE-QoL scores in Study DX-2930-04. An improvement was observed during Study 
DX-2930-04 in the AE-QoL Fears/Shame score in subjects who had received lanadelumab 
300mg in Study DX-2930-03, but not in all other AE-QoL domain scores (Functioning, Nutrition 
and Fatigue/Mood) in which scores were maintained from baseline to end of study visit as 
expected. This may explain why the AE-QoL Fears/Shame score was the AE-QoL domain of the 
Rollover Safety population showing the greatest improvement overall in Study DX-2930-04. A 
longer follow-up may be needed for subjects to perceive improvement in distal concepts such as 
Fears and Shame, compared to Fatigue or Functioning. The longer follow-up offered by the 
open-label extension may have allowed this benefit to be captured. 
HADS Anxiety and Depression scores remained stable over the course of the study, with mean 
scores lower than 6, indicating normal levels of anxiety and depression in subjects who 
participated in Study DX-2930-03 (Rollover). In the Non-Rollover Safety population, the mean 
HADS anxiety score was 7 at baseline indicating normal to mild anxiety and the mean HADS 
depression score was 3 indicating no depression. At each post-baseline visit, HADS Anxiety and 
Depression scores were lower than 6, indicating normal level of anxiety and depression over the 
course of the study in the Non-Rollover safety population. No change in productivity as 
measured by the WPAI-GH was observed in subjects who participated in Study DX-2930-03 
(Rollover) except for those who received placebo in Study DX-2930-03 as their WPAI-GH 
scores decreased slightly, indicating an improvement in work productivity and impairment for 
those patients. A slight improvement in productivity was observed in subjects who did not 
participate in Study DX-2930-03 (Non-Rollover) at the beginning of Study DX-2930-04 then the 
WPAI-GH scores stabilized. The SF-12v2 scores were stable in the Rollover Safety population 


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during Study DX-2930-04, and subjects previously treated with placebo showed a slight increase 
(i.e. improvement) in SF-12 Physical and Mental Component scores; SF-12v2 scores were stable 
in the Non-Rollover Safety population. No change in health status was seen in Rollover and 
Non-Rollover subjects, who already had good health status at Day 0 (mean score=0.85 in both 
populations) as measured by the EQ-5D-5L. 
The benefit of the treatment was seen in the level of TSQM-9 scores at Day 364, Day 574 and 
end of study visit in both the Rollover and Non-Rollover Safety populations, showing that the 
subjects were very satisfied with their treatment effectiveness (mean Effectiveness score > 90), 
found their treatment convenient (mean Convenience score > 81) and were very satisfied with 
their medication (mean Satisfaction score > 87). 
Linear regressions of change in AE-QoL scores in the regular treatment period in the Rollover 
Safety population showed that the baseline AE-QoL scores statistically significantly explained 
the change in all AE-QoL scores, with subjects having higher baseline AE-QoL scores (i.e. 
greater QoL impairment) in Study DX-2930-04 having a higher decrease in AE-QoL scores 
(indicating a higher improvement). The treatment received during the DX-2930-03 study also 
statistically significantly explained the change in AE-QoL Nutrition score, with a lower decrease 
in the AE-QoL Nutrition score (i.e. improvement) from Day 0 to end of study visit for subjects 
previously treated with DX-2930 than for subjects previously treated with placebo. This result 
was confirmed by the CDFs on the AE-QoL Nutrition score and also observed for the other AE-
QoL scores, as they showed a greater improvement from Day 0 to end of study visit for subjects 
previously treated with placebo in the Rollover Safety population. No clear pattern was observed 
for the other scores. The percentage of responders to change in PRO scores from Day 0 to end of 
study visit was higher in the Non-Rollover Safety population than in the Rollover Safety 
population except for the HADS Anxiety score, SF-12v2 Role Physical, Vitality, Mental Health 
and Mental Component scores. The highest difference in percentage of responders to change 
between Rollover and Non-Rollover Safety population was observed in the AE-QoL scores. 
These results consistently support the benefit of lanadelumab, as subjects who had not been 
previously treated by lanadelumab reported greater improvement in all PROs when they initiate a 
treatment with lanadelumab than subjects remaining on lanadelumab. 
A few limitations were observed in the analyses of PRO data from Study DX-2930-04. 
Especially, the generic instruments (EQ-5D-5L, HADS and SF-12v2) showed little to no 
impairment at baseline making it difficult to show improvements. In addition,,  some PRO scores 
showed floor effects that may have impacted the ability to demonstrate higher improvement 
during follow-up of Study DX-2930-04; a number of subjects (typically at least 25%) 
systematically reported the lowest possible score(s), preventing any further improvement in the 
corresponding concept to be demonstrated. 


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10. CONCLUSION 
These analyses of PRO data collected in Study DX-2930-04 showed improvements in all AE-
QoL scores between Day 0 and end of study visit of DX-2930-04 in both subjects who 
participated in Study DX-2930-03 (Rollover) and subjects who did not (Non-Rollover). Subjects 
not previously treated with lanadelumab (either Non-Rollover subjects, or Rollover subjects 
treated with placebo in Study DX-2930-03) showed a greater improvement in all AE-QoL 
domains in DX-2930-04 study than subjects who had been treated with lanadelumab in Study 
DX-2930-03, supporting the benefit of lanadelumab treatment. 
 


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11. REFERENCE LIST 
Bharmal, M., K. Payne, M. J. Atkinson, M.-P. Desrosiers, D. E. Morisky and E. Gemmen 
(2009). "Validation of an abbreviated Treatment Satisfaction Questionnaire for Medication 
(TSQM-9) among patients on antihypertensive medications." Health quality of life outcomes 
7(1): 36. 
Bolge, S. C., J. F. Doan, H. Kannan and R. W. Baran (2009). "Association of insomnia with 
quality of life, work productivity, and activity impairment." Quality of life Research 18(4): 415. 
Bygum, A. (2009). "Hereditary angiooedema in Denmark: a nationwide survey." British Journal 
of Dermatology 161(5): 1153-1158. 
Chan, K. S., L. A. Friedman, O. J. Bienvenu, V. D. Dinglas, B. H. Cuthbertson, R. Porter, C. 
Jones, R. O. Hopkins and D. M. Needham (2016). "Distribution-based estimates of minimal 
important difference for hospital anxiety and depression scale and impact of event scale-revised 
in survivors of acute respiratory failure." General hospital psychiatry 42: 32-35. 
Davis, A. E., 3rd (2006). "Mechanism of angioedema in first complement component inhibitor 
deficiency." Immunol Allergy Clin North Am 26(4): 633-651. 
Donaldson, V. H. and R. R. Evans (1963). "A biochemical abnormality in hereditary 
angioneurotic edema: absence of serum inhibitor of C′ 1-esterase." The American journal of 
medicine 35(1): 37-44. 
Göring, H., K. Bork, P. Späth, R. Bauer, A. Ziemer, H. Hintner and B. Wüthrich (1998). 
"Hereditary angioedema in the German-speaking region." Der Hautarzt Zeitschrift fur 
Dermatologie, Venerologie, und verwandte Gebiete 49(2): 114-122. 
Herdman, M., C. Gudex, A. Lloyd, M. Janssen, P. Kind, D. Parkin, G. Bonsel and X. Badia 
(2011). "Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-
5L)." Qual Life Res 20(10): 1727-1736. 
Kalbitor® (2015). Kalbitor® 2015. Package Insert. Burlington, MA: Dyax Corp. 
Kaplan, A. P. and K. Joseph (2010). "The bradykinin-forming cascade and its role in hereditary 
angioedema." Ann Allergy Asthma Immunol 104(3): 193-204. 
N.I.H. (2020). "Hereditary angioedema. Genetics Home Reference."   Retrieved 24 Jan 2020, 
from https://ghr.nlm.nih.gov/condition/hereditary-angioedema. 
Nathan, R. A., C. A. Sorkness, M. Kosinski, M. Schatz, J. T. Li, P. Marcus, J. J. Murray and T. 
B. Pendergraft (2004). "Development of the asthma control test: a survey for assessing asthma 
control." Journal of Allergy Clinical Immunology 113(1): 59-65. 


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Nordenfelt, P., S. Dawson, C.-F. Wahlgren, A. Lindfors, L. Mallbris and J. Bjorkander (2014). 
Quantifying the burden of disease and perceived health state in patients with hereditary 
angioedema in Sweden. Allergy and asthma proceedings, OceanSide Publications; 1999. 
Nussberger, J., M. Cugno, C. Amstutz, M. Cicardi, A. Pellacani and A. Agostoni (1998). 
"Plasma bradykinin in angio-oedema." The Lancet 351(9117): 1693-1697. 
Puhan, M. A., M. Frey, S. Büchi and H. J. Schünemann (2008). "The minimal important 
difference of the hospital anxiety and depression scale in patients with chronic obstructive 
pulmonary disease." Health quality of life outcomes 6(1): 46. 
Reilly, M. C., A. S. Zbrozek and E. M. Dukes (1993). "The validity and reproducibility of a 
work productivity and activity impairment instrument." Pharmacoeconomics 4(5): 353-365. 
Schwab, F. J., V. Lafage, J.-P. Farcy, K. H. Bridwell, S. Glassman and M. R. Shainline (2008). 
"Predicting outcome and complications in the surgical treatment of adult scoliosis." Spine 
33(20): 2243-2247. 
Skolasky, R. L., A. M. Maggard, D. Li, L. H. Riley III and S. T. Wegener (2015). "Health 
behavior change counseling in surgery for degenerative lumbar spinal stenosis. Part I: 
improvement in rehabilitation engagement and functional outcomes." Archives of physical 
medicine rehabilitation 96(7): 1200-1207. 
Thompson, C. A. (2010). FDA approves kallikrein inhibitor to treat hereditary angioedema, 
ASHP. 
Ware Jr, J. E., M. Kosinski and S. D. Keller (1996). "A 12-Item Short-Form Health Survey: 
construction of scales and preliminary tests of reliability and validity." Medical care 34(3): 220-
233. 
Weller, K., A. Groffik, M. K. Church, T. Hawro, K. Krause, M. Metz, P. Martus, T. B. Casale, P. 
Staubach and M. Maurer (2014). "Development and validation of the Urticaria Control Test: a 
patient-reported outcome instrument for assessing urticaria control." Journal of Allergy Clinical 
Immunology 133(5): 1365-1372. e1366. 
Weller, K., A. Groffik, M. Magerl, N. Tohme, P. Martus, K. Krause, M. Metz, P. Staubach and 
M. Maurer (2012). "Development and construct validation of the angioedema quality of life 
questionnaire." Allergy 67(10): 1289-1298. 
Weller, K., M. Magerl, A. Peveling Oberhag, P. Martus, P. Staubach and M. Maurer (2016). 
"The Angioedema Quality of Life Questionnaire (AE QoL)–assessment of sensitivity to change 
and minimal clinically important difference." Allergy 71(8): 1203-1209. 
Zigmond, A. S. and R. P. Snaith (1983). "The hospital anxiety and depression scale." Acta 
psychiatrica scandinavica 67(6): 361-370. 


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Zuraw, B. L. (2008). "Hereditary angioedema." New England Journal of Medicine 359(10): 
1027-1036. 
 


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12. LIST OF APPENDICES 


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Appendix 1 
DX-2930-04 PRO Statistical Analysis Plan v1.0 10 December 2019 


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Patient-reported Outcomes Statistical Analysis Plan
Phase 3
HELP Study Extension™: An Open-Label Study to Evaluate the Long-Term 
Safety and Efficacy of DX-2930 for Prevention of Acute Attacks of Hereditary 
Angioedema (HAE)
Protocol Identifier: DX-2930-04
Study Sponsor(s):
Dyax Corp., (an indirect, wholly-owned subsidiary of Shire plc) 300 
Shire Way, Lexington, MA 02421 USA
Author:
Protocol:
Amendment 3.0
29 June 2017
Drug:
Lanadelumab (TAK-743, formerly SHP643, formerly DX-2930)
SAP Type:
Assessment of Patient Reported Outcomes Data
SAP Version #:
Version 1.0
SAP Date:
10 December 2019
Status:
Final


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TABLE OF CONTENTS
1. BACKGROUND ..................................................................................................................5
2. OBJECTIVES ......................................................................................................................6
3. MATERIAL..........................................................................................................................7
3.1 DX2930-04 Study...........................................................................................................7
3.1.1 Study Design............................................................................................................7
3.1.2 PROs Data...............................................................................................................8
3.2 PRO Instruments ........................................................................................................10
3.2.1 AE-QoL .................................................................................................................10
3.2.2 EQ-5D-5L ..............................................................................................................10
3.2.3 WPAI-GH Questionnaire ....................................................................................10
3.2.4 HADS.....................................................................................................................11
3.2.5 SF-12v2 ..................................................................................................................11
3.2.6 AECT.....................................................................................................................11
3.2.7 TSQM-9.................................................................................................................12
3.2.8 Global Impression of Treatment Response........................................................12
4. GENERAL ANALYTICAL CONSIDERATIONS ........................................................13
4.1 Analysis Population.....................................................................................................13
4.2 General Principles.......................................................................................................13
4.2.1 Description of Variables.......................................................................................13
4.2.2 Level of Significance.............................................................................................13
4.3 Missing Data Handling ...............................................................................................13
4.4 Software .......................................................................................................................13
5. ANALYSIS PLAN .............................................................................................................14
5.1 Description of AE-QoL Scores over the Study.........................................................14
5.1.1 Description of AE-QoL Scores and Change in AE-QoL Score in Rollover 
Subjects.................................................................................................................14
5.1.2 Description of AE-QoL Scores and Change in Score in Non-rollover Subjects14
5.1.3 Description of Change in AE-QoL Score in Rollover Subjects by Treatment 
Received During DX-2930-03..............................................................................14
5.2 Description of Other PRO Scores over the Study....................................................14
5.2.1 Description of PRO Scores and Change in PRO Score in Rollover Subjects .14
5.2.2 Description of PRO Scores and Change in Score in Non-rollover Subjects ...15
5.2.3 Description of Change in PRO Score in Rollover Subjects by Treatment 
Received During DX-2930-03..............................................................................15
5.3 Exploratory Analysis of AE-QoL Changes in Scores ..............................................15
5.3.1 Exploratory Analysis of AE-QoL Score Changes in Rollover Subjects..........15
5.4 Responder Analysis and Empirical Cumulative Distribution Functions ..............16


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5.4.1 Responder Analysis and Cumulative Distribution Function in Rollover 
Subjects.................................................................................................................16
5.4.2 Responder Analysis and Cumulative Distribution Function in Non-rollover 
Subjects.................................................................................................................16
6. REFERENCES...................................................................................................................17
LIST OF IN-TEXT TABLES
Table 1. PROs recording Schedule in DX2390-04 Study .....................................................9
LIST OF IN-TEXT FIGURES
Figure 1. Schematic DX-2930-04 Study Design.....................................................................7


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ABBREVIATIONS
Abbreviation
Definition
AECT
Angioedema Control Test
AE-QoL
Angioedema Quality of Life Questionnaire
ACT
Asthma Control Test
CDF
Cumulative distribution function
EQ-5D-5L
EuroQoL 5-Dimensional 5-Level Measure
HAE
Hereditary angioedema
HADS
Hospital Anxiety and Depression Scale
MCID
Minimal clinically important difference
PRO
Patient-reported outcome
HRQoL
Health-related quality of life
PRO-SAP
Patient-reported outcomes-specific statistical analysis plan
SEM
Standard error of the mean
SF-12v2
12 Item Short Form v2 Health Survey
TSQM
Treatment Satisfaction Questionnaire for Medication
UCT
Urticaria Control Test
VAS
Visual Analogue Scale
WPAI-GH
Work Productivity and Activity Impairment – General Health


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1. BACKGROUND
The DX-2930-04 open-label study will be conducted in subjects with Type I or Type II 
hereditary angioedema (HAE) to evaluate the long-term safety and efficacy of DX-2930. The 
primary objective of the DX-2930-04 study is to evaluate the long-term safety of repeated 
subcutaneous (SC) administrations of DX-2930; the secondary objectives of the study are to 
evaluate the long-term efficacy of DX-2930 in preventing acute HAE attacks and to characterize 
the outer bounds of dosing frequency for DX-2930. The DX-2930-04 study is an open-label 
extension of the DX-2930-03 study.
Patient-reported outcomes (PROs) were assessed in the DX-2930-04 study to investigate tertiary 
objectives, namely: to evaluate the effect of DX-2930 on health-related quality of life (HRQoL), 
to assess treatment satisfaction, and to assess global impression of treatment response. PRO 
instruments collected in the study included the angioedema quality of life questionnaire (AE-
QOL), the 12-item short-form version 2 health survey (SF-12v2), the hospital anxiety and 
depression scale (HADS), the work productivity and activity impairment – general health 
(WPAI-GH) questionnaire, the angioedema control test (AECT), the treatment satisfaction 
questionnaire for medication – 9 items (TSQM-9), the EuroQol group 5 dimension-5 levels (EQ-
5D-5L) questionnaire, and a subject global impression of treatment response.
This PRO-specific statistical analysis plan (PRO-SAP) describes the statistical analyses to be 
performed on the PRO data collected in the DX-2930-04 study to address the PRO objectives of 
the study. This PRO-SAP is being developed after review of the DX-2930-04 protocol 
amendment 3.0, but before the final database cut.


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2. OBJECTIVES
The objectives of the PRO analyses performed using the PRO data collected in the DX-2390-04 
study will be:
•
To describe PRO scores over the course of the DX-2930-04 study separately for patients 
who participated in the DX-2930-03 study (“rollover patients”) and patients who did not 
participate in the DX-2930-03 study (“non-rollover patients”):
-
Functioning, fatigue/mood, fear/shame, nutrition as assessed by the AE-QOL
-
Work productivity and activity impairment, as assessed by the WPAI-GH
-
Anxiety and depression, as assessed by the HADS
-
Generic HRQoL, as assessed by the SF-12v2
-
Treatment satisfaction, as assessed by the TSQM-9
-
Health status, as assessed by EQ-5D-5L
•
To investigate change in PRO scores between baseline and end of study according to 
previous exposure to DX-2930 in the DX-2930-03 study


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3. MATERIAL
3.1 DX2930-04 Study
3.1.1 Study Design
DX-2930-04 is an open-label, long term safety and efficacy extension study of DX-2930-03, 
which aims to evaluate DX-2930 for prevention of acute angioedema attacks in subjects with 
Type I or Type II HAE. A schematic study design of the DX-2930-04 study is provided in Figure 
1.
Figure 1. Schematic DX-2930-04 Study Design
Two types of subjects were to be enrolled into this study: rollover and non-rollover subjects. 
Rollover subjects were subjects who completed the double-blind treatment period at Day 182 of 
the DX-2930-03 study and consented to enter the DX-2930-04 study. They received a single 
open-label dose of 300 mg DX-2930 administered SC on Day 0. Subjects did not receive any 
additional DX-2930 doses until their first reported and investigator-confirmed HAE attack. They 
then continued to receive repeated SC administrations of open-label 300mg DX-2930 every 2 
weeks for the remaining duration of the treatment period. 


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Non-rollover subject did not participate in the DX-2930-03 study. They received an open-label 
dose of 300 mg DX-2930 administered SC on Day 0, then continued to receive a 300 mg SC 
dose every 2 weeks throughout the duration of the treatment period.
The study duration was planned to be 34 months (952 days), including a 4-week follow up 
period, after the treatment period. The study was expected to enroll at least 100 rollover subjects, 
and at least 50 (to approximately 100) non-rollover subjects, to achieve a total enrollment of at 
least 150 (maximum of 250) subjects.
3.1.2 PROs Data
Subjects enrolled in the DX-2930-04 study were asked to complete the following PRO 
instruments:
•
AE-QoL
•
EQ-5D-5L
•
WPAI-GH Questionnaire
•
HADS
•
SF-12v2
•
AECT
•
TSQM-9
•
Global Impression of Treatment Response
The PRO assessment schedule is presented in Table 1. Of those PRO instruments, only the AE-
QOL and EQ-5D-5L were administered in the previous DX-2930-03 study.
All PRO instruments are described below.


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Table 1. PROs recording Schedule in DX2390-04 Study
Day
0
28
56
98
126
154
182
224
266
308
364
406
462
518
574
630
686
742
798
854
910
9521
AE-QoL
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
EQ-5D-5L
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
WPAI-GH
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
HADS
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
SF-12
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
AECT
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
TSQM
✓
✓
✓
Global Impression 
of Treatment 
Response
✓
✓
                                                            
1 Records at Day 952 correspond to the end of the study and of the 4-week follow-up period (Day 924 to 952)


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3.2 PRO Instruments
3.2.1 AE-QoL
The AE-QoL is a self-administered instrument developed to assess HRQoL impairment in 
subjects with recurrent angioedema. (Weller et al. 2012) It consists of 17 items divided into 4
domains: functioning, fatigue/mood, fear/shame, and nutrition. Items are scored in 5-point 
Likert-scales ranging from “Never” to “Very Often”, asking for patient ratings over the last four 
weeks. Scores for each domain and a total score can be obtained by taking the mean of the item 
scores within the scale (or mean item scores of all items, for the total score) and transforming it 
linearly on a 0-100 scale. The AE-QOL scores range between 0 to 100, with a higher score 
indicating greater QoL impairment. 
A 6-point difference has been reported to be the minimal clinically important difference (MCID) 
for the AE-QOL total score. (Weller et al. 2016) This value will be used as threshold for PRO 
response in the PRO responder analyses, for all AE-QOL scores (in the absence of specific value 
for the domain scores).
3.2.2 EQ-5D-5L
The EQ-5D-5L is a self-administered standardized measure of health status comprising a 
descriptive system and a Visual Analogue Scale (VAS). (Herdman et al. 2011) The descriptive 
systems assess five dimensions of health status: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. (Herdman et al. 2011) Each dimension is rated on a 5-
point scale to describe subject health for the current day, with 1 being “no problems” and 5 
“extreme problems”. An index score can be derived using “value sets” that reflect the 
preferences of a population between the various health states defined by the five items. The 
index score is a utility measure that ranges between 0 and 1, with 1 corresponding to a perfect 
health. The UK value set will be used to calculate the EQ-5D-5L index scores in this study.
Separately from the descriptive part, the VAS is a measure of overall self-rated health status. The 
subject assesses his or her health using a 20-cm vertical VAS, between “the best health you can 
imagine” and “the worst health you can imagine.” Scores ranges from 0 to 100, with a higher 
score indicating better health.
3.2.3 WPAI-GH Questionnaire
The WPAI-GH is a 6-item self-assessment of the effect of health problems on the subject’s 
ability to work and perform regular activities, during the past seven days. (Reilly et al. 1993)
WPAI-GH scoring guidelines lead to the creation of the following scores: percent work time 
missed due to health, percent impairment while working due to health, percent overall work 
impairment due to health, and percent activity impairment due to health.


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The MCID for the WPAI-GH has been suggested in other conditions to be 7.2 for absenteeism, 
11.1 for presenteeism, 9.8 for overall work productivity, and 14.3 for activity impairment. (Bolge 
et al. 2009) Based on these values, the following values will be used as threshold for PRO 
response in the PRO responder analyses: 7 for absenteeism, 11 for presenteeism, 10 for overall 
work productivity, and 14 for activity impairment.
3.2.4 HADS
The HADS is a self-assessed instrument developed to detect subjects states of depression, 
anxiety, and emotional distress. (Zigmond and Snaith 1983) From its 14 items, 7 relate to anxiety 
and 7 to depression during the past week. Responses are scored on a scale ranging from 0 to 3, 
with 3 indicating the highest symptom frequency. For each domain, scores range from 0 to 21, 
and can be categorized as normal (0 to 7), mild (8 to 10), moderate (11 to 14), and severe (15 to 
21). Additionally, a total score can be calculated from the full set of items, ranging from 0 to 42, 
with a higher score indicating more distress. 
The MCID has been estimated in other conditions to be in the range 1.5-2.5. (Chan et al. 2016;
Puhan et al. 2008) Based on these values, a 2-point value will be used as threshold for PRO 
response in the PRO responder analyses for the HADS scores.
3.2.5 SF-12v2
The SF-12v2 is a validated instrument designed to measure functional health and well-being. It 
consists of 12 question, divided into 8 health domains: physical functioning, role physical, bodily 
pain, general health, vitality, social functioning, role emotional, and mental health. (Ware Jr. et al. 
1996) Questions are asked of subjects regarding their health for the last 4 weeks. Physical and 
Mental Health Composite, as well as raw and norm-based domain scores can be calculated. All 
scores range from 0 to 100, with 0 indicating the lowest health level as measured by the scales 
and 100 the highest. Norm-based scores are obtained using t-scores based on a general US 
population mean of 50.0, with a standard deviation of 10.0, allowing direct comparisons to the 
US general population.
The MCID has been estimated in other conditions to be in the range 4.9-5.2. (Schwab et al. 2008;
Skolasky et al. 2015) Based on these values, a 5-point value will be used as threshold for PRO 
response in the PRO responder analyses for the SF-12v2 scores.
3.2.6 AECT
The AECT is a 10-question instrument designed to assess the control of angioedema among 
subjects with recurrent angioedema (including HAE). Only the four first items (frequency of 
symptoms, impact on HRQoL, impact of unpredictability, and perceived disease control) were 
used in the study. This is a useful measure specially to drive treatment decisions. Its concept is 


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similar to the previously developed and established Asthma Control Test (ACT) and Urticaria 
Control Test (UCT). (Nathan et al. 2004; Weller et al. 2014) Questions have 5 answer options 
(verbal rating scale), scored from 0 to 4 points. A total AECT score can be obtained from the ten 
items but will not be computed in this study as only four of them will be available.
3.2.7 TSQM-9
The TSQM-9 is a generic measure of treatment satisfaction that allows for comparison across 
medication types and subjects conditions. (Bharmal et al. 2009) It assesses the subject’s 
perception of treatment effectiveness, convenience, and global satisfaction during the last two to 
three weeks or when the treatment was last used. Scores for each of the 3 domains, as well as a 
combined score are calculated separately. Scores are transformed to a 0 to 100 scale, with a 
higher score indicating higher satisfaction with treatment.
3.2.8 Global Impression of Treatment Response
The subject global impression of treatment response is assessed using a single question: “Overall, 
how would you rate your response to the study medication?”. Responses options are namely, 
about the actual day: “poor”, “fair”, “good”, “very good,” and “excellent”.


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4. GENERAL ANALYTICAL CONSIDERATIONS
4.1 Analysis Population
The PRO analyses will be conducted in the Safety population, Rollover Safety population and 
Non-rollover Safety populations, as defined in the main statistical analysis plan of the DX-2930-
04 study.
4.2 General Principles
4.2.1 Description of Variables
Quantitative variables will be described by their frequency, mean, standard deviation (SD), 
standard error of the mean (SEM), median, first and third quartiles, extreme values (minimum 
and maximum values), and number of missing values.
Qualitative variables will be described by the frequency and percentage of each response choice, 
with missing data being included in the calculation of percentage.
4.2.2 Level of Significance
No formal statistical hypothesis testing will be performed. All p-values will be considered 
descriptive.
4.3 Missing Data Handling
For the score calculations, the missing items of the PRO questionnaires will be handled as 
proposed by the authors of the questionnaires.
No missing PRO assessment will be imputed in the analyses.
4.4 Software
Data analysis will be performed using SAS version 9.4 (SAS Institute; Cary, North Carolina, 
USA).


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5. ANALYSIS PLAN
5.1 Description of AE-QoL Scores over the Study
5.1.1 Description of AE-QoL Scores and Change in AE-QoL Score in Rollover Subjects
The AE-QoL scores will be described at baseline and all scheduled assessment visits in the 
rollover safety population. 
The change in AE-QoL scores from baseline (Day 0) to each scheduled AE-QoL assessment visit 
will be described in the rollover safety population. 
5.1.2 Description of AE-QoL Scores and Change in Score in Non-rollover Subjects
The AE-QoL scores will be described at baseline and all scheduled assessment visits in the non-
rollover safety population.
The change in AE-QoL scores from baseline (Day 0) to each scheduled assessment visit will be 
described in the non-rollover safety population.
5.1.3 Description of Change in AE-QoL Score in Rollover Subjects by Treatment Received 
During DX-2930-03
The change from baseline (Day 0, Dose 1) to the end-of-study visit will be described in the 
rollover safety population by treatment received in the DX-2930-03 study (placebo and each of 
the 3 DX-2930 treatment arms).
5.2 Description of Other PRO Scores over the Study
The analyses specified in this section will be applied to the following PRO scores:
•
EQ-5D-5L index score
•
WPAI-GH scores
•
HADS domain scores
•
SF-12v2 raw and norm-based domains and composites scores
•
TSQM domain scores
5.2.1 Description of PRO Scores and Change in PRO Score in Rollover Subjects
The PRO scores will be described at baseline and all scheduled assessment visits in the rollover 
safety population. 


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The change in PRO scores from baseline (Day 0) to each scheduled PRO assessment visit will be 
described in the rollover safety population. 
5.2.2 Description of PRO Scores and Change in Score in Non-rollover Subjects
The PRO scores will be described at baseline and all scheduled assessment visits in the non-
rollover safety population.
The change in PRO scores from baseline (Day 0) to each scheduled assessment visit will be 
described in the non-rollover safety population.
5.2.3 Description of Change in PRO Score in Rollover Subjects by Treatment Received 
During DX-2930-03
The change from baseline (Day 0, Dose 1) to the end-of-study visit will be described in the 
rollover safety population by treatment received in the DX-2930-03 study (placebo and each of 
the 3 DX-2930 treatment arms).
5.3 Exploratory Analysis of AE-QoL Changes in Scores
5.3.1 Exploratory Analysis of AE-QoL Score Changes in Rollover Subjects
This section describes exploratory explanatory analyses of the change in the AE-QoL domain 
and total scores over the treatment period and over the regular treatment period in rollover 
subjects. These changes may depend on various simple factors: baseline AE-QoL score, time of 
treatment exposure (eg, duration of “regular” treatment period), treatment received in the DX-
2930-03 study, and baseline AE-QoL score in the DX-2930-03 study. 
The change in AE-QoL scores from baseline (Day 0) to the end-of-study visit will be analyzed 
using linear regressions with the change in AE-QoL score as explained variable and the 
following explanatory variables: duration of “regular” treatment period, AE-QoL score at 
baseline, AE-QoL score at baseline from the DX-2930-03 study, and treatment received in the 
DX-2930-03 study.
The change in AE-QoL scores from the Dose 2 PRO visit to end-of-study visit will be analyzed 
using linear regressions with the change in AE-QoL score as explained variable and the 
following explanatory variables: duration of “regular” treatment period, AE-QoL score at 
baseline, AE-QoL score at baseline from the DX-2930-03 study, and treatment received in the 
DX-2930-03 study.
These analyses will be performed in the rollover safety population.


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5.4 Responder Analysis and Empirical Cumulative Distribution Functions
The analyses specified in this section will be applied to the following PRO scores that have a 
value at baseline (Day 0) of the study DX-2930-04, and predefined responder thresholds (see 
description of the instruments above):
•
AE-QoL domain and total scores
•
WPAI-GH scores
•
HADS domain scores
•
SF-12v2 domain and composites scores
5.4.1 Responder Analysis and Cumulative Distribution Function in Rollover Subjects
For each PRO score, subjects whose change in score from baseline (Day 0, Dose 1) to the end-
of-study visit is greater than the predefined responder threshold will be categorized as responders. 
The percentage of responders will be calculated in the rollover safety population overall, and 
according to the treatment received in DX-2930-03.
Empirical cumulative distribution functions (CDF) of the change in score between baseline (Day 
0, Dose 1) and the end-of-study visit will be plotted in the rollover safety population overall, and 
according to the treatment received in DX-2930-03.
5.4.2 Responder Analysis and Cumulative Distribution Function in Non-rollover Subjects
For each PRO score, subjects whose change in score from baseline (Day 0) to the end-of-study
visit is greater than the predefined responder threshold will be categorized as responders. The 
percentage of responders will be calculated in the non-rollover safety population.
Empirical cumulative distribution functions (CDF) of the change in score between baseline (Day 
0) and the end-of-study visit will be plotted in the non-rollover safety population.


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6. REFERENCES
Bharmal, M., Payne, K., Atkinson, M. J., Desrosiers, M.-P., Morisky, D. E., Gemmen, E. J. H. & 
outcomes, q. o. l. 2009. Validation of an abbreviated Treatment Satisfaction 
Questionnaire for Medication (TSQM-9) among patients on antihypertensive medications. 
7, 36.
Bolge, S. C., Doan, J. F., Kannan, H. & Baran, R. W. J. Q. o. l. R. 2009. Association of insomnia 
with quality of life, work productivity, and activity impairment. 18, 415.
Chan, K. S., Friedman, L. A., Bienvenu, O. J., Dinglas, V. D., Cuthbertson, B. H., Porter, R., 
Jones, C., Hopkins, R. O. & Needham, D. M. J. G. h. p. 2016. Distribution-based 
estimates of minimal important difference for hospital anxiety and depression scale and 
impact of event scale-revised in survivors of acute respiratory failure. 42, 32-35.
Herdman, M., Gudex, C., Lloyd, A., Janssen, M., Kind, P., Parkin, D., Bonsel, G. & Badia, X. 
2011. Development and preliminary testing of the new five-level version of EQ-5D (EQ-
5D-5L). Qual Life Res, 20, 1727-36.
Nathan, R. A., Sorkness, C. A., Kosinski, M., Schatz, M., Li, J. T., Marcus, P., Murray, J. J., 
Pendergraft, T. B. J. J. o. A. & Immunology, C. 2004. Development of the asthma control 
test: a survey for assessing asthma control. 113, 59-65.
Puhan, M. A., Frey, M., Büchi, S., Schünemann, H. J. J. H. & outcomes, q. o. l. 2008. The 
minimal important difference of the hospital anxiety and depression scale in patients with 
chronic obstructive pulmonary disease. 6, 46.
Reilly, M. C., Zbrozek, A. S. & Dukes, E. M. J. P. 1993. The validity and reproducibility of a 
work productivity and activity impairment instrument. 4, 353-365.
Schwab, F. J., Lafage, V., Farcy, J.-P., Bridwell, K. H., Glassman, S. & Shainline, M. R. J. S. 
2008. Predicting outcome and complications in the surgical treatment of adult scoliosis. 
33, 2243-2247.
Skolasky, R. L., Maggard, A. M., Li, D., Riley III, L. H., Wegener, S. T. J. A. o. p. m. & 
rehabilitation 2015. Health behavior change counseling in surgery for degenerative 
lumbar spinal stenosis. Part I: improvement in rehabilitation engagement and functional 
outcomes. 96, 1200-1207.
Ware Jr, J. E., Kosinski, M. & Keller, S. D. J. M. c. 1996. A 12-Item Short-Form Health Survey: 
construction of scales and preliminary tests of reliability and validity. 34, 220-233.
Weller, K., Groffik, A., Church, M. K., Hawro, T., Krause, K., Metz, M., Martus, P., Casale, T. 
B., Staubach, P., Maurer, M. J. J. o. A. & Immunology, C. 2014. Development and 
validation of the Urticaria Control Test: a patient-reported outcome instrument for 
assessing urticaria control. 133, 1365-1372. e6.
Weller, K., Groffik, A., Magerl, M., Tohme, N., Martus, P., Krause, K., Metz, M., Staubach, P. 
& Maurer, M. J. A. 2012. Development and construct validation of the angioedema 
quality of life questionnaire. 67, 1289-1298.
Weller, K., Magerl, M., Peveling-Oberhag, A., Martus, P., Staubach, P. & Maurer, M. J. A. 2016. 
The Angioedema Quality of Life Questionnaire (AE-QoL)–assessment of sensitivity to 
change and minimal clinically important difference. 71, 1203-1209.
Zigmond, A. S. & Snaith, R. P. J. A. p. s. 1983. The hospital anxiety and depression scale. 67, 
361-370.


Data Summarization Analysis Plan – Final (Part 3) 
Lanadelumab 
Takeda (Shire) 
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1 
TITLE PAGE 
 
 
 
 
 
Analysis Plan 
Pharmacokinetic, Pharmacodynamic, HAE and Anti-Drug Antibody 
Data Summarization of Lanadelumab in Study DX-2930-04  
Final Analysis (Part 3) 
 
Investigational Medicinal Product: 
Lanadelumab (SHP643, DX-2930) 
Study Number: 
DX-2930-04  
Sponsor: 
Takeda (Shire) 
Reference No.: 
SHIR-CSC-134 
Date of Analysis Plan: 
January 29, 2020 
Version: 
Final 
 
 
 


Data Summarization Analysis Plan- Final (Part 3) 
Takeda (Shire) 
2 
SIGNATlJRE PAGE 
Approval 
Lanadelumab 
Protocol DX-2930-04 
The undersigned have reviewed the planned PK, PD, HAE and ADA data summarization plan. 
Certara Strategic Consulting 
, PhD. FCP 
Certara Strategic Consulting 
CSC Confidential 
Page 2 
Date 
Date 
29-Jan-2020 


Data Summarization Analysis Plan - Final (Part 3) 
Takeda (Shire) 
2 
SIGNATURE PAGE (CONT'D) 
Sponsor Review and Approval 
Lanadelumab 
Protocol DX-2930-04 
The undersigned have reviewed the planned PK, PO, HAE and ADA data summarization plan. 
0
 Global Clinical Pharmacology & Pharmacokinetics 
Clinical Research & Development 
Takeda 
CSC Confidential 
Page 3 
29-Jan-2020 


Data Summarization Analysis Plan – Final (Part 3) 
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Takeda (Shire) 
Protocol DX-2930-04 
 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE ..................................................................................................................................... 1 
2 
SIGNATURE PAGE ......................................................................................................................... 2 
2 
SIGNATURE PAGE (CONT’D) ...................................................................................................... 3 
3 
TABLE OF CONTENTS .................................................................................................................. 4 
4 
LIST OF ABBREVIATIONS ........................................................................................................... 5 
5 
BACKGROUND ................................................................................................................................ 6 
6 
OBJECTIVES .................................................................................................................................... 6 
7 
OBJECTIVES .................................................................................................................................... 8 
8 
DATA HANDLING ........................................................................................................................... 8 
8.1 
Data Transfer .................................................................................................................................... 8 
8.2 
Variables........................................................................................................................................... 9 
8.3 
Subjects with Long Drug Interruptions .......................................................................................... 11 
9 
DATA SUMMARIZATION ........................................................................................................... 12 
9.1 
PK, PD, HAE and ADA Data Summarization ............................................................................... 12 
9.2 
PK, PD, ADA and HAE (Overlaid Information) ........................................................................... 14 
10 
FORMATTING ELEMENTS FOR TABLES, LISTINGS AND FIGURES ............................. 15 
11 
SOFTWARE .................................................................................................................................... 15 
12 
ELECTRONIC DATASETS .......................................................................................................... 15 
13 
QUALITY CONTROL ................................................................................................................... 16 
14 
ARCHIVING ................................................................................................................................... 16 
15 
REFERENCES ................................................................................................................................ 16 
16 
LIST OF TABLES, FIGURES AND LISTINGS.......................................................................... 17 
17 
TABLE AND FIGURE SHELLS ................................................................................................... 23 
 


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Protocol DX-2930-04 
 
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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
BLQ 
Below the limit of quantification 
cHMWK  
2-Chain of high molecular weight kininogen 
CSC 
Certara Strategic Consulting  
CV 
Coefficient of variability 
EDT 
Electronic data transmission 
HAE 
Hereditary angioedema 
NAb 
Neutralizing antibody 
OLE 
Open-label extension 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
QC 
Quality control 
SC 
Subcutaneous 
sFTP 
Secure file transfer protocol 
SOP 
Standard Operating Procedure 
 
 


Data Summarization Analysis Plan – Final (Part 3) 
Lanadelumab 
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Protocol DX-2930-04 
 
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5 
BACKGROUND 
Lanadelumab (SHP643, DX-2930) is a fully human IgG1 recombinant monoclonal antibody that binds 
specifically to active plasma kallikrein. Lanadelumab is approved for the prophylactic treatment of 
angioedema attacks in patients with hereditary angioedema (HAE), a serious and life-threatening disease. 
 
6 
OBJECTIVES 
Protocol DX-2930-04 is an open-label study to evaluate the long-term safety and efficacy of DX-2930 for 
prevention against acute attacks of Hereditary Angioedema (HAE) (HELP Study ExtensionTM). There are 
two types of subjects to be enrolled into this study: (1) Subjects who rollover from Study DX-2930-03; (2) 
Subjects who are non-rollovers (i.e., were not participants in Study DX-2930-03). 
 
For rollover subjects: Following informed consent and pre-dose assessments, rollover subjects will 
receive a single open-label dose of 300 mg SHP643 administered subcutaneously (SC) on Day 0. 
Subjects will not receive any additional SHP643 doses until their first reported, and investigator-
confirmed, HAE attack. As such, the total number of doses within the treatment period will vary 
between rollover subjects. The duration between the first open-label dose and first reported HAE 
attack will vary between rollover subjects. Once a rollover subject reports their first HAE attack 
they will present to the investigative site for their second open-label dose of SHP643 as quickly as 
subject and site schedules allow. If the second dose is to be administered within the accepted ±4 
day window around a scheduled study visit (i.e., Day 14, 28, 42, 56, 70, 84, 98…), this treatment 
visit will represent that scheduled visit. If that scheduled visit has already occurred, the day of the 
visit will be considered an acceptable, extra study visit (i.e., an unscheduled visit). Similarly, if the 
second dose is administered outside of the accepted ±4 day window around a scheduled visit, the 
day of the visit will be considered an acceptable extra unscheduled study visit, (i.e., this visit will 
not replace any scheduled visit). Following the second open-label dose, rollover subjects will 
continue to receive repeated SC administrations of open label 300 mg SHP643 every 2 weeks for 
the remaining duration of the treatment period per the scheduled dosing in the Study Activities 
Schedule. 
 
For non-rollover subjects: Following pre-dose assessments, non-rollover subjects will receive an 
open-label dose of 300 mg SHP643 administered SC on Day 0 and will continue to receive SC 
administrations of open-label 300 mg SHP643 every 2 weeks throughout the duration of the 
treatment period per the scheduled dosing in the Study Activities Schedule.  


Data Summarization Analysis Plan – Final (Part 3) 
Lanadelumab 
Takeda (Shire) 
Protocol DX-2930-04 
 
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Subjects were to be 12 years of age or older experiencing at least one attack per 12 weeks. The total 
enrolment is expected to be at least 150, but not more than 250 subjects with a documented diagnosis of 
Type I or Type II HAE.  
PK, PD, and anti-drug antibody (ADA) samples were drawn for all rollover and non-rollover. In addition to 
the schedule, an additional PK, PD and anti-drug antibody sample will be drawn for rollover subjects prior 
to dosing on the day of their second open-label dose, at whatever study visit that occurs.  An overview of 
the study design is presented in Figure 1.  
Figure 1.  
Overview of Study Design (Protocol DX-2930-04) 
 
The DX-2930-04 protocol amendment 3.0 was finalized on 29 Jun 2017. The purpose of this amendment 
was to add new objectives and related measurements, quality of life (QoL) endpoints,  and extend the study 
from 12 months to 30 months (Day 952) to continue to obtain data important for the assessment of SHP643 
(i.e., safety and efficacy data). 
 


Data Summarization Analysis Plan – Final (Part 3) 
Lanadelumab 
Takeda (Shire) 
Protocol DX-2930-04 
 
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7 
OBJECTIVES  
The specific objectives of this project are to summarize PK, PD, HAE attacks and ADA results.  In addition, 
potential correlation between PK, PD and HAE attacks (average monthly HAE attack) in study DX-2930-
04 will be explored.  
This analysis plan provides general guidance on the extent, scope for the data summarization of PK, PD, 
HAE and ADA results. However, due to the uncertainty of the nature of the data a priori, deviations from 
this plan may occur. Due to the blinded nature of the data, effort will take place upon data base 
lock/unblinding to understand the data structure and nature of various variable.  This analysis plan may be 
modified accordingly. These modifications/will be discussed with Shire before finalizing the data 
summarizations and will be noted in the footnotes of TFLs for full transparency with the scientific rationale.   
 
8 
DATA HANDLING 
8.1 
Data Transfer 
Electronic files from Shire will be transferred to Certara Strategic Consulting (CSC) via a Secure File 
Transfer Protocol (sFTP) site provided by Shire. Electronic Data Transmission (EDT) contact at Shire will 
be: 
, MPH, PhD 
 Global Clinical Pharmacology & Pharmacokinetics 
Clinical Research & Development 
Takeda 
Office: 
Mobile: 
Email:   
          
The following CSC designates will be the EDT contacts: 
 PhD, FCP 
Certara Strategic Consulting  
Montréal, Québec, Canada H3A 2W5 
Cell:
Email:
Data will be provided as .csv or SAS transport files by Shire.  
 
 


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Lanadelumab 
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Protocol DX-2930-04 
 
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8.2 
Variables 
The dataset to be used in the summarization steps (i.e. to produce tables, listings and figures for Study 
DX-2930-04) will include at a minimum the following variables: 
Subject Information 
 
Study (STUDY) 
 
Unique patient ID (USUBJID) 
 
Nominal time of sample or observation (NTIME in hours) 
 
Visit day of sample or observation (VISIT) 
 
Visit number of sample of observation (VISITNUM) 
 
Study day (DAY) 
 
Indicator if the subject is a rollover from study DX-2930-03 or non-rollover (ROLL) where rollover 
from DX-2930-03 = ROLL and non-rollover = NONROLL 
 
Treatment indicator (ARM) – should be “Lanadelumab 300 mg every 2 weeks” for all subjects 
 
For subjects rolling over from DX-2930-03, indicator of which arm of DX-2930-03 the subject 
participated in (ARM03): 
o Placebo 
o Lanadelumab 300 mg every 2 weeks 
o Lanadelumab 300 mg every 4 weeks 
o Lanadelumab 150 mg every 4 weeks 
 
Dose administered (DOSE) in mg presented without units 
 
Location of dose administered (EXLOC) – abdomen = 0 and upper arm = 1 and thigh =2 (where 
applicable) 
 
Subject age (AGE) 
 
Subject age category (AGECATG)  
o  ≥18 years (Adult) 
o <18 years (Pediatric) 
 
 


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Primary PK and PD variables 
 
Lanadelumab concentrations in ng/mL  
 
Baseline %2-chain high molecular weight kininogen by Western Blot using citrate samples 
(BLHMWK) in % units 
 
On treatment %2-chain high molecular weight kininogen by Western Blot using citrate samples 
(CHMWK) in % units 
 
Percent change from baseline %2-chain high molecular weight kininogen by Western Blot using 
citrate 
samples 
(PCFBHMWK) 
in 
% 
units 
calculated 
at 
[(CHMWK-
BLHMWK)/(BLHMWK)]*100% 
 
Anti-Drug Antibody (ADA) 
In addition, the dataset will include measures of immunogenicity. As ADA testing is typically performed in 
a staged fashion, only samples which test presumably positive in a screening assay are submitted to a 
confirmatory assay. Similarly, only samples which are positive in a confirmatory assay are submitted to a 
neutralizing assay test. Datasets will contain the following ADA measurements with the possible results: 
1. Screening assay (presumptive positive, negative or NA) 
2. Confirmatory assay (positive, negative or NA) 
3. Neutralizing assay (positive, negative or NA) 
4. ADA titer level (value or NA if the sample was not submitted for a confirmatory assay) 
5. Overall status (positive, negative or NA) 
ADA samples coded as NA (or similar coding) imply the sample was not tested due the previous assay step 
result being non-positive. 
The dataset for summarization will include whether a sample was positive or non-positive in the 
confirmatory assay (CONFIRM) 
The dataset for summarization will include whether a sample was positive or non-positive in the neutralizing 
assay (NANTBD) 
The dataset for summarization will include the titer of the confirmatory assay (TITRE). For subjects where 
at least two on treatment samples are positive in CONFIRM, the subject will include an indicator if the 
subject had persistently positive ADA (to be defined by Shire) or transient ADA (ADAPER). For subjects 
where at least two on treatment samples are positive in NANTBD assay, the subject will include an indicator 
if the subject had persistently positive ADA (to be defined by Shire) or transient ADA (NABPER) 


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Lanadelumab 
Takeda (Shire) 
Protocol DX-2930-04 
 
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HAE History at Baseline and On-Treatment 
 
Each investigator confirmed HAE attack (HAEATTACK) during the baseline (for non-rollover 
subjects) evaluation period and while on treatment (both rollover and non-rollover subject) 
 
Baseline number of HAE attacks over a 28-day period (THAERIN). NOTE: A month is defined as 
a 4 week period or 28 days;  
o Baseline for the rollover population is defined as the number of investigator-confirmed 
HAE attacks occurring during the run-in period of DX2930-03 divided by the total number 
of days in the run-in period multiplied by 28 days;  
o Baseline for the non-rollover population is defined as historical rate of HAE attacks in the 
last 3 months prior to screening divided by the number of days the subject contributed to 
the historical reporting period multiplied by 28 days. 
 
Monthly number of HAE attacks with lanadelumab (each month will be represented by a unique 
column (e.g. THAEMONTH1 to THAEMONTH13). NOTE:  A month is defined as a 4 week period 
or 28 days. 
 
Total number of HAE attacks on treatment (THAETRT) 
 
Number of attack free days from the last dose of study drug in DX-2930-03 to the first dose in DX-
2930-04 for rollover subjects (left blank for non-rollover subjects) 
 
Number of attack free days after the first dose (300 mg) for rollover subjects left blank for non-
rollover subjects) 
 
8.3 
Subjects with Long Drug Interruptions 
For subjects with extended drug interruptions (defined as missing ≥3 consecutive study medication doses), 
the time period and the corresponding PK, PD, ADA and efficacy (HAE) will be excluded from the analysis.  
A footnote indicating the numbers of subjects excluded will be included for each table and figure) 
 
 
 
 
 


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Protocol DX-2930-04 
 
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9 
DATA SUMMARIZATION 
9.1 
PK, PD, HAE and ADA Data Summarization 
Pharmacokinetics (Lanadelumab Concentrations) 
For rollover subjects, blood samples for the measurement of lanadelumab concentrations were collected 1) 
prior to receiving a single open-label dose of 300 mg on Day 0, 2) after reporting a first HAE attack (second 
open label dose), and 3) at pre-specified scheduled visits following initiation of the Q2W 300 mg 
regimen(Visit 8, 14, 20, 27, 34, 42, 50, 58, 66 and 67; corresponding to Days 98, 182, 266, 364, 462, 574, 
686, 798, 910 and 924). Mean (+SD) lanadelumab concentrations will be presented for 1) the first open-
label dose (day 0) by treatment assignment in study DX-2930-03, 2) for the second open-label dose at 
scheduled visits (±4 days) by treatment assignment in Study DX-2930-03.  In addition, mean (+SD) 
lanadelumab concentrations will be presented after combining the second open-label dose at scheduled visits 
(±4 days) and time following initiation of Q2W 300 mg regimen (Day 98, 182, 266, 364, 462, 574, 686, 
798, 910 and 924). A footnote will be added to determine if any of the second open-label doses were 
administered at scheduled visits (Day 98, 182, 266, 364, 462, 574, 686, 798, 910 and 924). 
For non-rollover subjects, blood samples for the measurement of SHP643 concentrations were collected at 
baseline (Day 0) and at pre-specified scheduled visits (Visit 8, 14, 20, 27, 34, 42, 50, 58, 66 and 67; 
corresponding to Days 98, 182, 266, 364, 462, 574, 686, 798, 910 and 924) following initiation of Q2W 300 
mg regimen.  For non-rollover subjects, mean (+SD) concentrations of lanadelumab vs. Time (Day 0, 98, 
182, 266, 364, 462, 574, 686, 798, 910 and 924) will be presented.  
In addition, all the above analyses will be presented overall, and by age group (adult and pediatric 
population). 
Individual data will be presented in tabular format by time (nominal visit day) and summarized with 
descriptive statistics (Arithmetic mean, standard deviation, arithmetic CV%, median, minimum and 
maximum).  Any unscheduled results will be reported in subject listings. 
Pharmacodynamics (cHMWK) 
PD samples were collected at similar timepoint as PK (refer to section above). In rollover subjects, mean 
(+SD) of cHMWK levels (bar charts) will be presented for 1) the first open-label dose (day 0) by treatment 
assignment in study DX-2930-03, 2) for the second open-label dose at scheduled visits (±4 days) by 
treatment assignment in Study DX-2930-03 and 3) after combining the second open-label dose at scheduled 
visits (±4 days) and time (Day 98, 182, 266, 364, 462, 574, 686, 798, 910 and 924) following initiation of 
Q2W 300 mg Regimen. 


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For non-rollover subjects, mean (+SD) of cHMWK levels (bar charts) vs. Time (Day 0, 98, 182, 266, 364, 
462, 574, 686, 798, 910 and 924) will be presented.  
A similar presentation will be used for the percent (%) change from baseline cHMWK. 
In addition, all the above analyses will be presented overall, and by age group (adult and pediatric 
population). 
Individual data of cHMWK (raw and percent change from baseline) will be presented in tabular format by 
time (nominal visit day) and summarized with descriptive statistics (Arithmetic mean, standard deviation, 
arithmetic CV%, median, minimum and maximum).  Any unscheduled results will be reported in subject 
listings. 
 
HAE Attacks 
The number of HAE attack by month with sample size will be presented for rollover and non-rollover 
subjects.  In addition, the rate of HAE attack by month will be presented for rollover and non-rollover 
subjects.   
For rollover subjects, the number of days without HAE attack will be summarized graphically and in tabular 
formats by treatment assignment in study DX-2930-03 (Placebo, 150 mg Q4W, 300 mg Q4W, and 150 mg 
Q2W). 
All the above analyses will be presented overall, and by age group (adult and pediatric population).  
Any unscheduled assay results will be reported in a subject listing. 
 
 
 


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9.2 
PK, PD, ADA and HAE (Overlaid Information) 
PK and PD Summary Figures 
In rollover subjects, mean (+SD) concentrations of lanadelumab and cHMWK values (overlaid) will be 
presented for 1) the first open-label dose (day 0) by treatment assignment in study DX-2930-03, 2) for the 
second open-label dose at scheduled visits (±4 days) by treatment assignment in Study DX-2930-03 and 3) 
after combining the second open-label dose at scheduled visits (±4 days) and time (Day 98, 182, 266, 364, 
462, 574, 686, 798, 910 and 924) following initiation of Q2W 300 mg regimen. For non-rollover subjects, 
mean (+SD) concentrations of lanadelumab and cHMWK values (overlaid) vs. Time (Day 0, 98, 182, 266, 
364, 462, 574, 686, 798, 910 and 924) will be presented.  
 
PK and ADA Summary Figures 
In rollover subjects, mean (+SD) concentrations of lanadelumab and ADA status (confirmed ADA positive 
and non-positive) will be presented for the first open-label dose (day 0) by treatment assignment in study 
DX-2930-03 and for the second open-label dose at scheduled visits (±4 days) by treatment assignment in 
Study DX-2930-03 using bar charts. In addition, individual concentrations of lanadelumab in confirmed 
ADA positive and non-positive subjects will be presented after combining the second open-label dose at 
scheduled visits (±4 days) and time (Day 98, 182, 266, 364, 462, 574, 686, 798, 910 and 924) following 
initiation of Q2W 300 mg regimen. 
In non-rollover subjects, individual concentrations of lanadelumab in confirmed ADA positive and non-
positive subjects will be presented vs. Time (Day 0, 98, 182, 266, 364, 462, 574, 686, 798, 910 and 924) 
will be presented. 
A similar presentation will be used for subjects with positive or non-positive neutralizing antibody (NAb). 
All the above analyses will be presented overall, and by age group (adult and pediatric population).  
 
PD and ADA Summary Figures 
A similar approach as described in “PK and ADA Summary Figures” will be used for PD and ADA figures. 
 
PK, PD and HAE Attack Summary Figures 
For rollover subjects, mean (+SD) lanadelumab concentrations vs. time following initiation of Q2W 300 
mg regimen and monthly HAE attack rate (Day 98, 182, 266, 364, 462, 574, 686, 798, 910 and 924) will 
presented. For non-rollover subjects, mean (+SD) lanadelumab concentrations vs. time following initiation 
of Q2W 300 mg regimen and monthly HAE attack rate (run-in, Day 98, 182, 266, 364, 462, 574, 686, 798, 


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910 and 924) will presented.  
In addition, a correlation figure for individual lanadelumab concentrations associated with the first open-
label dose (day 0) and days without HAE attack by treatment assignment in Study DX-2930-03 will 
presented for rollover subjects.  A similar analysis will be performed for the second open-label dose at 
scheduled visits (±4 days). 
A similar approach as described above will be used for mean (+SD) and cHMWK levels. 
 
PK, PD, and HAE Attack Individual Figures 
Individual profiles of PK, PD and HAE will be presented graphically to explore potential correlations.  
 
10 FORMATTING ELEMENTS FOR TABLES, LISTINGS AND FIGURES 
 
%2-Chain cHMWK will be abbreviated as cHMWK in plots 
 
Concentration vs. time plots (lanadelumab and/or cHMWK) will include a closed circle to represent 
the observation; sequential observations will be joined by a solid line. 
 
For descriptive figures and tables, where applicable, sample size will be noted either within the plot 
or as a caption/footnote associated with the plot 
 
Overlay plots of different observations types will be color coded such that closed circles and line 
colors are observation specific. 
 
Footnotes are not to be imbedded in images/plots and should be editable text outside of the 
embedded image 
11 SOFTWARE 
Dataset construction, exploration and figures will be performed using Phoenix NLME (Version 7.2 or 
higher), R® (Version 3.3.1 or higher) or SAS.  
 
12 ELECTRONIC DATASETS 
Consistent with FDA’s requirements, datasets used for data summarization will be submitted as a SAS 
transport files (*.xpt). A description of each data item will be provided in a define.pdf file. Any 
concentrations and/or subjects that have been excluded from the analysis will be flagged and maintained in 
the datasets. Data definition documentation (“define.pdf” file) of the datasets used for the population PK 
analysis will be provided.  The data definition documentation will include analysis-ready datasets used for 


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model development and validation in SAS transport file (*.xpt) format. A document describing the analysis-
ready datasets and variables will be provided (that is, define.pdf file).  
 
13 QUALITY CONTROL 
Quality control of datasets will include high quality data visualizations, data driven exploratory analysis 
(e.g. concentration-time profiles, dosing history plots, time after dose analysis, and graphical display of 
goodness of fit such as distribution of weighted residuals, etc.), descriptive statistics, and stratification of 
information and/or code review. Random checks of the output dataset will be performed against the raw 
data to check programming logic where complex imputations/derivations are involved. 
 
14 ARCHIVING 
The project documentation (documents, report, records, and data) will be retained in hardcopy for a period 
of 3 years following project completion at CSC (Montreal, Quebec, Canada). During these retention periods, 
electronic versions of project documentation will be retained on CSC servers, with access limited to 
personnel assigned to the project. After completion of the retention period, sponsor approval will be 
requested and documented before destruction of documents. 
 
15 REFERENCES 
1. Study Number: DX-2930-04. HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-
Term Safety and Efficacy of DX-2930 for Prevention Against Acute Attacks of Hereditary Angioedema 
(HAE) Amendment 3.0, 29 June 2017.  
 


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16 LIST OF TABLES, FIGURES AND LISTINGS 
1- SUMMARY FIGURES - PK, PD, ADA, and HAE 
Mean Concentration-Time Profiles of Lanadelumab  
Figure 14.1. 
Mean (+SD) Lanadelumab Concentrations Prior to the First Open-Label Dose (Day 0) 
by Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.2. 
Mean (+SD) Lanadelumab Concentrations Prior to the Second Open-Label Dose by 
Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.3. 
Individual Lanadelumab Concentrations vs. Time (Starting from the First or Second 
Open-Label Dose) by Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.4. 
Individual and Mean (+SD) Lanadelumab Concentrations vs. Time - Non-Rollover 
Subjects  
 
Mean Levels of cHMWK 
 
Figure 14.5. 
Mean (+SD) cHMWK Levels Prior to the First Open-Label Dose (Day 0) by Study DX-
2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.6. 
Mean (+SD) cHMWK Levels Prior to the Second Open-Label Dose by Study DX-2930-
03 Treatment Assignment - Rollover Subjects  
Figure 14.7. 
Individual cHMWK Levels vs. Time (Starting from the First or Second Open-Label 
Dose) by Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.8. 
Individual and Mean (+SD) cHMWK Levels vs. Time - Non-Rollover Subjects  
 
Mean cHMWK Values (% Change from Baseline) 
Figure 14.9. 
Mean (SD) Percent Change of cHMWK from Study 03 and Study 04 Baseline Levels 
Prior to the First Open-Label Dose (Day 0) by Study DX-2930-03 Treatment 
Assignment - Rollover Subjects  
Figure 14.10. 
Mean (SD) Percent Change of cHMWK from Study 03 and Study 04 Baseline Levels 
For Samples Drawn Prior to the Second Open-Label Dose by Study DX-2930-03 
Treatment Assignment - Rollover Subjects  
Figure 14.11. 
Individual Percent Change from Baseline Levels of cHMWK vs. Time (Starting from 
the First or Second Open-Label Dose) by Study DX-2930-03 Treatment Assignment - 
Rollover Subjects  
Figure 14.12. 
Individual and Mean (SD) Percent Change from Baseline Levels of cHMWK vs. Time 
- Non-Rollover Subjects  
 
 
 


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Summary of HAE Attacks over Time  
Figure 14.13. 
Number of Hereditary Angioedema Attacks by Month with Sample Size - Rollover 
Subjects  
Figure 14.14. 
Number of Hereditary Angioedema Attacks by Month with Sample Size- Non-Rollover 
Subjects  
 
Figure 14.15. 
Rates of Hereditary Angioedema Attacks by Month - Rollover Subjects  
Figure 14.16. 
Rates of Hereditary Angioedema Attacks by Month – Non-Rollover Subjects  
 
Figure 14.17. 
Mean (+SD) Hereditary Angioedema Attack Free Days After the First Open Label Dose 
by Study DX-2930-03 Treatment Assignment - Rollover Subjects   
 
2- SUMMARY FIGURES– PK, PD, ADA, and HAE (Overlaid) 
 
Summary PK and PD Figures  
Figure 14.18. 
Mean (+SD) Lanadelumab Concentrations and cHMWK Levels Prior to the First Open-
Label Dose (Day 0) by Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.19. 
Mean (+SD) Lanadelumab Concentrations and cHMWK Levels Prior to the Second 
Open-Label Dose by Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.20. 
Individual Lanadelumab Concentrations and cHMWK Levels vs. Time (Starting from 
the First or Second Open-Label Dose) - Rollover Subjects  
Figure 14.21. 
Individual and Mean (+SD) Lanadelumab Concentrations and cHMWK Levels vs. Time 
- Non-Rollover Subjects  
 
Summary PK and ADA Figures 
 
Figure 14.22. 
Mean (+SD) Lanadelumab Concentrations in Confirmed Anti-Drug Antibody Positive 
and Non-Positive Subjects Prior to the First Open-Label Dose (Day 0) by Study DX-
2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.23. 
Mean (+SD) Lanadelumab Concentrations in Confirmed Anti-Drug Antibody Positive 
and Non-Positive Subjects Prior to the Second Open-Label Dose by Study DX-2930-
03 Treatment Assignment - Rollover Subjects  
Figure 14.24. 
Individual Lanadelumab Concentrations vs. Time in Confirmed Anti-Drug Antibody 
Positive and Non-Positive Subjects (Starting from the First or Second Open-Label 
Dose) - Rollover Subjects  
Figure 14.25. 
Individual and Mean (+SD) Lanadelumab Concentrations vs. Time in Confirmed Anti-
Drug Antibody Positive and Non-Positive Subjects - Non-Rollover Subjects  
Figure 14.26. 
Mean (+SD) Lanadelumab Concentrations in Neutralizing Positive and Non-Positive 
Subjects Prior to the First Open-Label Dose (Day 0) by Study DX-2930-03 Treatment 
Assignment - Rollover Subjects  
Figure 14.27. 
Mean (+SD) Lanadelumab Concentrations in Neutralizing Positive and Non-Positive  


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Figure 14.28. 
Individual Lanadelumab Concentrations vs. Time in Neutralizing Positive and Non-
Positive Subjects (Starting from the First or Second Open-Label Dose) - Rollover 
Subjects  
Figure 14.29. 
Individual and Mean (+SD) Lanadelumab Concentrations vs. Time in Neutralizing 
Positive and Non-Positive Subjects - Non-Rollover Subjects  
 
Summary PD and ADA Figures 
Figure 14.30. 
Mean (+SD) cHMWK Levels in Confirmed Anti-Drug Antibody Positive and Non-
Positive Subjects Prior to the First Open-Label Dose (Day 0) by Study DX-2930-03 
Treatment Assignment - Rollover Subjects 
Figure 14.31. 
Mean (+SD) cHMWK Levels in Confirmed Anti-Drug Antibody Positive and Non-
Positive Subjects Prior to the Second Open-Label Dose by Study DX-2930-03 
Treatment Assignment - Rollover Subjects  
Figure 14.32. 
Individual cHMWK Levels vs. Time in Confirmed Anti-Drug Antibody Positive and 
Non-Positive Subjects (Starting from the First or Second Open-Label Dose) - Rollover 
Subjects  
Figure 14.33. 
Individual and Mean (+SD) cHMWK Levels vs. Time in Confirmed Anti-Drug 
Antibody Positive and Non-Positive Subjects - Non-Rollover Subjects  
Figure 14.34. 
Mean (+SD) cHMWK Levels in Neutralizing Positive and Non-Positive Subjects Prior 
to the First Open-Label Dose (Day 0) by Study DX-2930-03 Treatment Assignment - 
Rollover Subjects 
Figure 14.35. 
Mean (+SD) cHMWK Levels in Neutralizing Positive and Non-Positive Subjects Prior 
to the Second Open-Label Dose by Study DX-2930-03 Treatment Assignment - 
Rollover Subjects  
Figure 14.36. 
Individual cHMWK Levels vs. Time in Neutralizing Positive and Non-Positive 
Subjects (Starting from the First or Second Open-Label Dose) - Rollover Subjects  
Figure 14.37. 
Individual and Mean (+SD) cHMWK Levels vs. Time in Neutralizing Positive and 
Non-Positive Subjects - Non-Rollover Subjects  
 
 
Summary PK, PD and HAE Attacks Figures  
Figure 14.38. 
Individual Lanadelumab Concentrations and Monthly Hereditary Angioedema Attack 
Rates vs. Time From Initiation of the 300 mg every 2 weeks Regimen (Starting from 
the Second Open-Label Dose) - Rollover Subjects  
Figure 14.39. 
Individual Lanadelumab Concentrations and Monthly Hereditary Angioedema Attack 
Rates vs. Time From Initiation of the 300 mg every 2 weeks Regimen (Starting from 
the Second Open-Label Dose) - Non-Rollover Subjects  
 


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Figure 14.40. 
Individual cHMWK Levels and Monthly Hereditary Angioedema Attack Rates vs. 
Time From Initiation of the 300 mg every 2 weeks Regimen (Starting from the Second 
Open-Label Dose) - Rollover Subjects  
Figure 14.41. 
Individual cHMWK Levels and Monthly Hereditary Angioedema Attack Rates vs. 
Time From Initiation of the 300 mg every 2 weeks Regimen (Starting from the Second 
Open-Label Dose) - Non-Rollover Subjects  
Figure 14.42. 
Individual Lanadelumab Concentrations Prior to the First Open-Label Dose (Day 0) vs. 
Hereditary Angioedema Attack Free Days Prior to the Second Open-Label Dose by 
Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.43. 
Individual Lanadelumab Concentrations Prior to the Second Open-Label Dose vs. 
Hereditary Angioedema Attack Free Days Prior to the Second Open-Label Dose by 
Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.44. 
Individual cHMWK Levels Prior to the First Open-Label Dose (Day 0) vs. Hereditary 
Angioedema Attack Free Days Prior to the Second Open-Label Dose by Study DX-
2930-03 Treatment Assignment - Rollover Subjects  
Figure 14.45. 
Individual cHMWK Levels Prior to the Second Open-Label Dose vs. Hereditary 
Angioedema Attack Free Days Prior to the Second Open-Label Dose by Study DX-
2930-03 Treatment Assignment - Rollover Subjects  
 
 
Note: the above summary PK and PD/ADA/HAE Figures(14.1 to 14.45) will be presented overall and 
stratified by age categories (<18 and ≥ 18 years) 
 
 
 
 
 


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3- SUMMARY TABLES 
Summary Tables of Lanadelumab Concentrations 
Table 14.1. 
Descriptive Statistics of Lanadelumab Concentrations Prior to the First Open-Label 
Dose (Day 0) by Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Table 14.2. 
Descriptive Statistics of Lanadelumab Concentrations - Rollover Subjects  
Table 14.3. 
Descriptive Statistics of Lanadelumab Concentrations vs. Time - Non-Rollover Subjects 
 
Summary Tables of cHMWK Levels (%) 
Table 14.4. 
Descriptive Statistics of cHMWK Levels Prior to the First Open-Label Dose (Day 0) 
by Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Table 14.5. 
Descriptive Statistics of cHMWK Levels - Rollover Subjects  
Table 14.6. 
Descriptive Statistics of cHMWK Levels vs. Time - Non-Rollover Subjects  
 
Summary Tables of cHMWK Percent Change from Baseline Levels (%) 
Table 14.7. 
Descriptive Statistics of cHMWK Percent Change from Baseline Levels Prior to the 
First Open-Label Dose (Day 0) by Study DX-2930-03 Treatment Assignment - 
Rollover Subjects  
Table 14.8. 
Descriptive Statistics of cHMWK Percent Change from Baseline Levels - Rollover 
Subjects  
Table 14.9. 
Descriptive Statistics of cHMWK Percent Change from Baseline Levels vs. Time - 
Non-Rollover Subjects  
 
Summary Measurements Tables (ADA) 
Table 14.10. 
Descriptive Statistics of Confirmed Positive Anti-Drug Antibody Samples Prior to the 
First Open-Label Dose (Day 0) by Study DX-2930-03 Treatment Assignment - 
Rollover Subjects  
Table 14.11. 
Descriptive Statistics of Confirmed Positive Anti-Drug Antibody Samples Prior to the 
Second Open-Label Dose by Study DX-2930-03 Treatment Assignment - Rollover 
Subjects  
Table 14.12. 
Descriptive Statistics of All Confirmed Positive Anti-Drug Antibody Samples From 
Initiation of the 300 mg every 2 weeks Regimen (Starting from the Second Open-Label 
Dose) - Rollover Subjects  
Table 14.13. 
Descriptive Statistics of Confirmed Positive Anti-Drug Antibody Samples vs. Time - 
Non-Rollover Subjects  
 


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Table 14.14. 
Descriptive Statistics of Neutralizing Positive Samples Prior to the First Open-Label 
Dose (Day 0) by Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Table 14.15. 
Descriptive Statistics of Neutralizing Positive Samples Prior to the Second Open-Label 
Dose by Study DX-2930-03 Treatment Assignment - Rollover Subjects  
Table 14.16. 
Descriptive Statistics of All Neutralizing Positive Samples From Initiation of the 300 
mg every 2 weeks Regimen (Starting from the Second Open-Label Dose) - Rollover 
Subjects  
Table 14.17. 
Descriptive Statistics of Neutralizing Positive Samples vs. Time - Non-Rollover 
Subjects  
 
Summary Measurements Tables (HAE Attacks) 
Table 14.18. 
Summary of Time to First Hereditary Angioedema Attack (after First Open-Label 
Dose) by Study DX-2930-03 Treatment Assignment - Rollover Subjects   
Table 14.19. 
Summary of Hereditary Angioedema Attacks by Month, Total Number of Attacks on 
Treatment and Average Attack Rate - Rollover Subjects  
Table 14.20. 
Summary of Hereditary Angioedema Attacks by Month, Total Number of Attacks on 
Treatment and Average Attack Rate - Non-Rollover Subjects  
 
 
Note: the above summary PK, PD, ADA and HAE Tables(14.1 to 14.20) will be presented overall and 
stratified by age categories (<18 and ≥ 18 years) 
 
 
4- INDIVIDUAL PROFILES 
 
Individual PK, PD and Efficacy Figures 
Figure 16.1. 
Individual Lanadelumab Concentrations, cHMWK Levels and Hereditary Angioedema 
Attacks vs. Time  
Figure 16.2. 
Individual Lanadelumab Concentrations, Percent Change from Baseline cHMWK 
Levels and Hereditary Angioedema Attacks vs. Time   
 
Individual PK, ADA and Efficacy Figures 
Figure 16.3. 
Individual Lanadelumab Concentrations, Confirmed Anti-Drug Antibody and 
Hereditary Angioedema Attacks vs. Time   
Figure 16.4. 
Individual Lanadelumab Concentrations, Neutralizing Antibody and Hereditary 
Angioedema Attacks vs. Time  
 
5- LISTINGS OF INDIVIDUAL MEASUREMENTS 
 
Figure 16.5. 
Individual Pharmacokinetics, Pharmacodynamics (cHMWK), Anti-Drug Antibody 
Values and Hereditary Angioedema Attacks vs. Time   


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17 TABLE AND FIGURE SHELLS 
Figure 14.3. 
Individual Lanadelumab Concentrations vs. Time (Starting from the First Open-
Label Dose) by Study DX-2930-03 Treatment Assignment - Rollover Subjects 
(Overall)  
 
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly.  
 
 


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Figure 14.5. 
Mean (+SD) cHMWK Levels Prior to the First Open-Label Dose (Day 0) by Study 
DX-2930-03 Treatment Assignment - Rollover Subjects (Overall)  
 
 
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly.  
 
 


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Figure 14.9  
Mean (SD) Percent Change of cHMWK from Study 03 Baseline Levels Prior to 
the First Open-Label Dose (Day 0) by Study DX-2930-03 Treatment Assignment - 
Rollover Subjects (Overall)  
 
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly.  
 
 
 
 
 
 


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Figure 14.13. Number of Hereditary Angioedema Attacks by Month with Sample Size - 
Rollover Subjects (Overall)  
 
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly.  
 
 
 
 


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Figure 14.18. Mean (+SD) Lanadelumab Concentrations and cHMWK Levels Prior to the First 
Open-Label Dose (Day 0) by Study DX-2930-03 Treatment Assignment - 
Rollover Subjects (Overall)  
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly.  
 
 
 


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Figure 14.22. Mean (+SD) Lanadelumab Concentrations in Confirmed Anti-Drug Antibody 
Positive and Non-Positive Subjects Prior to the First Open-Label Dose (Day 0) by 
Study DX-2930-03 Treatment Assignment - Rollover Subjects (Overall)  
 
 
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly.  
 
 
 


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Figure 14.30. 
Mean (+SD) cHMWK Levels in Confirmed Anti-Drug Antibody Positive and 
Non-Positive Subjects Prior to the First Open-Label Dose (Day 0) by Study DX-
2930-03 Treatment Assignment - Rollover Subjects (Overall)  
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly.  
 
 
 
 
 


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Figure 14.38. Individual Lanadelumab Concentrations and Monthly Hereditary Angioedema 
Attack Rates vs. Time From Initiation of the 300 mg every 2 weeks Regimen 
(Starting from the Second Open-Label Dose) - Rollover Subjects (Overall)  
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly.  
 
 
 


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Figure 14.40 
Individual cHMWK Levels and Monthly Hereditary Angioedema Attack Rates vs. 
Time From Initiation of the 300 mg every 2 weeks Regimen (Starting from the 
Second Open-Label Dose) - Rollover Subjects (Overall)  
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly.  
 
 
 
 
 


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Summary Measurements Tables (PK, ADA, and HAE) 
Table 14.2 
Descriptive Statistics of Lanadelumab Concentrations Following Study Initiation and 
After the Second Open-Label Dose - Rollover Subjects (Overall)   
 
Lanadelumab 
(ng/mL) 
DAY 98  
WEEK 14  
(n=xx) 
DAY 182  
WEEK 26  
(n=xx) 
DAY 266  
WEEK 38  
(n=xx) 
DAY 364  
WEEK 52  
(n=xx) 
DAY …  
WEEK ...  
(n=…) 
Mean  
 
 
 
 
 
SD  
 
 
 
 
 
SE  
 
 
 
 
 
CV%  
 
 
 
 
 
GeoMean  
 
 
 
 
 
GeoCV%  
 
 
 
 
 
Median  
 
 
 
 
 
Min  
 
 
 
 
 
Max  
 
 
 
 
 
Note: similar tables will be used to summarize cHMWK raw and change from baseline concentrations 
 
 
Table 14.10 Descriptive Statistics of Confirmed Positive Anti-Drug Antibody Samples Prior to the 
First Open-Label Dose (Day 0) by Study DX-2930-03 Treatment Assignment - Rollover 
Subjects (Overall) 
Treatment 
Day 
Not Positive 
Positive 
Total 
Percent Positive 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Similar tables will be used to summarize positive NAb 
 


Data Summarization Analysis Plan – Final (Part 3) 
Lanadelumab 
Takeda (Shire) 
Protocol DX-2930-04 
 
CSC Confidential 
Page 33 
29-Jan-2020 
Table 14.19 
Summary of Hereditary Angioedema Attacks by Month, Total Number of 
Attacks on Treatment and Average Attack Rate - Rollover Subjects (Overall) 
Subject 
Treatment 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Total 
Description 
1 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Data Summarization Analysis Plan – Final (Part 3) 
Lanadelumab 
Takeda (Shire) 
Protocol DX-2930-04 
 
CSC Confidential 
Page 34 
29-Jan-2020 
Individual PK, PD (cHMWK) and Efficacy Figures 
Figure 16.11:  Individual Lanadelumab Concentration, PD (cHMWK) and HAE Attacks vs. Time by 
Treatment  
 
Subject X 
 
 
 


Data Summarization Analysis Plan – Final (Part 3) 
Lanadelumab 
Takeda (Shire) 
Protocol DX-2930-04 
 
CSC Confidential 
Page 35 
29-Jan-2020 
Listings of Individual Measurements 
Listing 16.1 
Individual Pharmacokinetics, Pharmacodynamics (cHMWK), Anti-Drug Antibody Values and Hereditary 
Angioedema Attacks vs. Time  
Subject Day Cohort Treatment 
Study 03 
Treatment 
Visit 
Age 
Category 
Lanadelumab 
(ng/mL) 
cHMWK 
(%) 
% CFB 
cHMWK (%) Confirm NAb Titer 
(ng/mL) 
HAE 
Attack 
1 
 
 
 
  
 
 
 
 
 
 
 
 
1 
 
 
 
  
 
 
 
 
 
 
 
 
1 
 
 
 
  
 
 
 
 
 
 
 
 
1 
 
 
 
  
 
 
 
 
 
 
 
 
1 
 
 
 
  
 
 
 
 
 
 
 
 
2 
 
 
 
  
 
 
 
 
 
 
 
 
2 
 
 
 
  
 
 
 
 
 
 
 
 
2 
 
 
 
  
 
 
 
 
 
 
 
 
2 
 
 
 
  
 
 
 
 
 
 
 
 
2 
 
 
 
  
 
 
 
 
 
 
 
 
2 
 
 
 
  
 
 
 
 
 
 
 
 
Confirm: Confirmatory ADA results; Nab: Neutralizing antibody result; NS: No sample