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)
Phase: PHASE3
Conditions: Hereditary Angioedema (HAE)
Sponsor: Shire

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 
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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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Final: 14 December 2015
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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 
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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 
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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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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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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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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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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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Clinical Trial Protocol: DX-2930-04 
 
27 June 2016 
 
 
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
 
Page 21 of 151

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Clinical Trial Protocol: DX-2930-04 
 
27 June 2016 
 
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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Clinical Trial Protocol: DX-2930-04 
 
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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. 
 
Confidential 
Page 1 of 8 
Dyax Corp. 
Page 142 of 151

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 
 
 
Confidential 
Page 2 of 8 
Dyax Corp. 
Page 143 of 151

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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HAE Attack Assessment and Reporting Procedures (HAARP) 
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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-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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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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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. 
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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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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
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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., 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 

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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
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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
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

Shire
CONFIDENTIAL
Page 7
Clinical Trial Protocol Amendment 2
DX-2930-04
20 Jan 2017
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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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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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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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
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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
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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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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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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Clinical Trial Protocol Amendment 2
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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 
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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 
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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 
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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. 
Study personnel will document the subject’s responses in the subjects’ medical record and eCRF. 

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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 
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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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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 
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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-
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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 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 
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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. 
Page 118

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 
 
 
 
 
 
 
Page 121

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 
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 
 
Page 142

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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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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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

Shire
CONFIDENTIAL
Page 3
Clinical Trial Protocol Amendment 3
DX-2930-04
29 June 2017
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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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 

Shire
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Clinical Trial Protocol Amendment 3
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29 June 2017
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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Clinical Trial Protocol Amendment 3
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29 June 2017
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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Clinical Trial Protocol Amendment 3
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29 June 2017
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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Clinical Trial Protocol Amendment 3
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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 
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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 
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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
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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.
Bork, K, Hardt, J, Schicketanz, KH & 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, 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.
Goring, HD, Bork, K, Spath, PJ, Bauer, R, Ziemer, A, Hintner, H & Wuthrich, B 1998. 
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, 
Kuzmic, P, Ladner, RC, Edwards, TE, Tenhoor, C, Adelman, BA, Nixon, AE & Sexton, 
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Lei, WT, Shyur, SD, Huang, LH, Kao, YH & Lo, CY 2011. Type I hereditary angioedema in 
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Nordenfelt, P, Dawson, S, Wahlgren, CF, Lindfors, A, Mallbris, L & Bjorkander, J 2014. 
Quantifying the burden of disease and perceived health state in patients with hereditary 
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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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Maurer, M 2012. Development and construct validation of the angioedema quality of life 
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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
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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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
20 Jan 2017
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
20 Jan 2017
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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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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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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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 
 
 
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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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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 
 
 
 
 
 
 
 
 
 
 
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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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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. 
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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 
 
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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 
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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
CONFIDENTIAL
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
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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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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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29 June 2017
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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.
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Clinical Trial Protocol Amendment 3
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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.

Shire
CONFIDENTIAL
Page 164
Clinical Trial Protocol Amendment 3
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.