Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial to Evaluate the Efficacy and Safety of 3 Dose Levels of KVD824, an Oral Plasma Kallikrein Inhibitor, for Long-Term Prophylactic Treatment of Hereditary Angioedema Type I or II
Phase: PHASE2
Conditions: Angioedema, Hereditary, Types I and II
Sponsor: KalVista Pharmaceuticals, Ltd.

 
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CLINICAL TRIAL PROTOCOL 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial to Evaluate the Efficacy and Safety 
of Three Dose Levels of KVD824, an Oral Plasma Kallikrein Inhibitor, for Long-Term Prophylactic 
Treatment of Hereditary Angioedema Type I or II 
 
Protocol Number: 
KVD824-201 
 
Protocol Name 
KOMPLETE 
 
Compound: 
KVD824 (300 mg Modified-Release Tablet) 
 
Trial Phase: 
2 
 
Sponsor: 
KalVista Pharmaceuticals, Ltd.  
Porton Science Park 
Bybrook Road  
Porton Down  
Salisbury, SP4 0BF  
United Kingdom 
 
IND Number: 
152196 
 
EudraCT Number: 
2021-000136-59 
 
Date of Protocol: 
31 March 2022, Version 5.0 
05 May 2021, Version 4.0 
29 March 2021, Version 3.0 
16 February 2021, Version 2.0 
27 January 2021, Version 1.0 
 
Compliance 
 
This trial will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International 
Conference on Harmonization), ethical principles that have 
their origin in the Declaration of Helsinki and all applicable 
national and local regulations. 
 
 
The information in this document is confidential and is proprietary to KalVista Pharmaceuticals Ltd. It 
is understood that information in this document shall not be disclosed to any third party, in any form, 
without prior written consent of an authorized officer of KalVista Pharmaceuticals Ltd. 

 
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1. SIGNATURE PAGE 
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial to Evaluate the Efficacy and 
Safety of Three Dose Levels of KVD824, an Oral Plasma Kallikrein Inhibitor, for Long-Term 
Prophylactic Treatment of Hereditary Angioedema Type I or II 
 
 
This trial protocol was subjected to critical review. The information it contains is consistent with current 
knowledge of the risks and benefits of the investigational medicinal product, as well as with the moral, 
ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki 
(World Medical Association 2013), and the guidelines on Good Clinical Practice (GCP). 
 
 
 
 
 
 
_____________________________________ 
Paul Audhya, MD, MBA 
Chief Medical Officer 
KalVista Pharmaceuticals, Ltd. 
 
 
 
 
 
 
_____________________________________ 
Matthew Iverson, MPH 
Vice President, Clinical 
KalVista Pharmaceuticals, Ltd. 
 
 

 
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2. DECLARATION OF THE INVESTIGATOR 
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial to Evaluate the Efficacy and 
Safety of Three Dose Levels of KVD824, an Oral Plasma Kallikrein Inhibitor, for Long-Term 
Prophylactic Treatment of Hereditary Angioedema Type I or II 
 
All documentation for this trial that is supplied to me and that has not been previously published will 
be kept in the strictest confidence. This documentation includes this trial protocol, Investigator's 
Brochure (IB), electronic case report form (eCRF), and other scientific data. 
 
The trial will not be commenced without the prior written approval of a properly constituted Ethics 
Committee (EC)/Institutional Review Board (IRB). No substantial changes will be made to the trial 
protocol without the prior written approval of the Sponsor and the EC/IRB, except where necessary 
to eliminate an immediate hazard to the subjects. 
 
I have read and understood and agree to abide by all the conditions and instructions contained in this 
protocol and will conduct the trial in compliance with regulatory requirements and Good Clinical 
Practice (GCP). 
 
 
 
 
 
_____________________________________ 
_____________________ 
Investigator Signature 
 
 
 
Date 
 
_____________________________________ 
Name (block letters) 
 

 
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CHANGES FROM PROTOCOL VERSION 4.0 TO VERSION 5.0 AND RATIONALE FOR THESE 
CHANGES 
Changes introduced into Version 5.0 of the protocol are as follows:  
 
Clarified that serious adverse events will be collected beginning at the time of informed 
consent through the Week 12/Early Termination Visit. 
 
Extended the timing in which subjects may be retested if Screening functional C1-esterase 
inhibitor and C4 levels are below the normal range from occurring during the Screening Period 
to occurring prior to randomization, and clarified that diagnostic testing results may be 
obtained from documented historical testing. 
 
Changed the timing of allowable last dose of attenuated androgens prior to study entry from 
prior to randomization to prior to first dose of investigational medicinal product (IMP). 
 
Added a safety draw for clinical chemistry and liver enzymes at Week 4. 
 
Added liver-related adverse event that meets Hy’s Law in more than 1 subject as a trial 
stopping criterion. 
 
Removed IMP temperature storage ranges from the protocol and clarified that IMP is to be 
stored at room temperature as labeled. 
 
Added procedural details for Investigators if unblinding a subject is needed. 
 
Minor typographical corrections and editorial changes are not described above. 
 

 
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TABLE OF CONTENTS 
1. 
SIGNATURE PAGE .................................................................................................................. 2 
2. 
DECLARATION OF THE INVESTIGATOR ............................................................................... 3 
3. 
SYNOPSIS ............................................................................................................................... 8 
4. 
KEY CONTACT LIST .............................................................................................................. 19 
5. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................... 20 
6. 
INTRODUCTION .................................................................................................................... 23 
6.1 
Background .................................................................................................................. 23 
6.2 
Trial Rationale .............................................................................................................. 23 
6.3 
Benefit/Risk .................................................................................................................. 24 
6.3.1 
Impact of COVID-19 on Benefit-Risk Assessment ................................................. 24 
6.3.2 
COVID-19 Vaccination .......................................................................................... 24 
7. 
OBJECTIVES AND ENDPOINTS ........................................................................................... 25 
7.1 
Objectives .................................................................................................................... 25 
7.1.1 
Primary .................................................................................................................. 25 
7.1.2 
Secondary ............................................................................................................. 25 
7.2 
Endpoints ..................................................................................................................... 25 
7.2.1 
Primary endpoint ................................................................................................... 25 
7.2.2 
Secondary endpoints ............................................................................................. 25 
7.2.3 
Exploratory endpoints ............................................................................................ 25 
7.3 
Estimands .................................................................................................................... 26 
8. 
TRIAL DESIGN ....................................................................................................................... 27 
8.1 
Overall Design .............................................................................................................. 27 
8.2 
Scientific Rationale for Trial Design .............................................................................. 27 
8.3 
Justification for Dose .................................................................................................... 28 
8.4 
End of Trial Definition ................................................................................................... 28 
9. 
TRIAL POPULATION .............................................................................................................. 29 
9.1 
Inclusion Criteria ........................................................................................................... 29 
9.2 
Exclusion Criteria ......................................................................................................... 30 
10. INVESTIGATIONAL MEDICINAL PRODUCT ......................................................................... 32 
10.1 
Investigational Medicinal Product Administration .......................................................... 32 
10.2 
Packaging and Labeling ............................................................................................... 32 
10.3 
Storage and Drug Accountability .................................................................................. 32 
10.4 
Trial Medication Compliance ........................................................................................ 33 
11. MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .................................. 34 
11.1 
Subject Numbers Identification ..................................................................................... 34 
11.2 
Randomization Scheme ............................................................................................... 34 
11.3 
Blinding ........................................................................................................................ 34 
12. PERMITTED THERAPIES AND PROHIBITED THERAPIES .................................................. 36 

 
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12.1 
Permitted Therapies ..................................................................................................... 36 
12.2 
Prohibited Therapies .................................................................................................... 36 
13. SUBJECT DISCONTINUATION .............................................................................................. 37 
14. TRIAL STOPPING CRITERIA ................................................................................................. 38 
15. ASSESSMENTS ..................................................................................................................... 39 
15.1 
Subject Demographics and Medical History ................................................................. 39 
15.2 
Efficacy Assessments................................................................................................... 39 
15.2.1 
Investigator-Confirmed HAE Attack ....................................................................... 39 
15.2.2 
Angioedema Control Test (AECT) ......................................................................... 40 
15.2.3 
Angioedema Quality of Life Questionnaire (AE-QoL) ............................................. 40 
15.2.4 
Treatment Satisfaction Questionnaire for Medication (TSQM) ............................... 40 
15.3 
Safety Assessments ..................................................................................................... 41 
15.3.1 
Physical Examinations .......................................................................................... 41 
15.3.2 
Vital Signs ............................................................................................................. 41 
15.3.3 
12-Lead Electrocardiogram (ECG) ........................................................................ 41 
15.3.4 
Clinical Safety Laboratory Assessments ................................................................ 42 
16. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................................... 43 
16.1 
Adverse Events ............................................................................................................ 43 
16.2 
Serious Adverse Events ............................................................................................... 43 
16.3 
Time Period and Frequency for Collection .................................................................... 43 
16.4 
Method of Detection ..................................................................................................... 43 
16.5 
Severity ........................................................................................................................ 44 
16.6 
Relationship ................................................................................................................. 44 
16.7 
Reporting ...................................................................................................................... 44 
16.7.1 
Reporting AEs to EC/IRB and Regulatory Authorities ............................................ 44 
16.7.2 
Reporting Serious Adverse Events ........................................................................ 44 
16.7.3 
Reporting Suspected Unexpected Serious Adverse Reactions.............................. 45 
16.8 
Pregnancy .................................................................................................................... 45 
16.9 
Treatment of Overdose ................................................................................................. 46 
17. TRIAL PROCEDURES ............................................................................................................ 47 
17.1 
Screening Period .......................................................................................................... 47 
17.1.1 
Screening Visit (In-Clinic or Home Health Visit) ..................................................... 47 
17.1.2 
Run-In Period ........................................................................................................ 48 
17.2 
Randomization Visit (In-Clinic or Home Health Visit) .................................................... 49 
17.3 
Treatment Period .......................................................................................................... 49 
17.4 
Week 2 and 6 (In-clinic or Home Health Visit) .............................................................. 50 
17.5 
Week 4 (Brief In-clinic/Site lab Visit or Home Health Visit) ............................................ 50 
17.6 
Week 12/Early Termination (In-Clinic or Home Health Visits) ....................................... 50 
18. STATISTICAL CONSIDERATIONS ........................................................................................ 52 

 
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18.1 
Sample Size Determination .......................................................................................... 52 
18.2 
Estimands and Intercurrent Events ............................................................................... 52 
18.3 
Populations for Analyses .............................................................................................. 53 
18.4 
General Considerations ................................................................................................ 54 
18.4.1 
Bonferroni Multiplicity Adjustment .......................................................................... 54 
18.5 
Analysis of Disposition .................................................................................................. 54 
18.6 
Demographics and Baseline Characteristics ................................................................ 55 
18.7 
Statistical Analysis of Efficacy Endpoints ...................................................................... 55 
18.7.1 
Primary Endpoint(s) ............................................................................................... 55 
18.7.2 
Multiple Imputation Analysis .................................................................................. 57 
18.7.3 
Secondary Endpoint(s) .......................................................................................... 58 
18.7.4 
Exploratory Endpoint(s) ......................................................................................... 58 
18.8 
Safety Analyses ............................................................................................................ 58 
18.9 
Interim Analyses ........................................................................................................... 59 
19. TRIAL ADMINISTRATION ...................................................................................................... 60 
19.1 
Direct Access to Source Data/Documents .................................................................... 60 
19.2 
Quality Control and Quality Assurance ......................................................................... 60 
19.3 
Ethics ........................................................................................................................... 60 
19.3.1 
Regulatory and Ethical Considerations .................................................................. 60 
19.3.2 
Informed Consent/Assent ...................................................................................... 60 
19.3.3 
Subject Confidentiality ........................................................................................... 60 
19.4 
Data Handling and Record Keeping ............................................................................. 60 
19.4.1 
Source Documents ................................................................................................ 60 
19.4.2 
Trial Monitoring ..................................................................................................... 61 
19.4.3 
Database Management ......................................................................................... 61 
19.4.4 
Retention of Trial Records ..................................................................................... 61 
19.5 
Financing and Insurance .............................................................................................. 61 
19.5.1 
Financial Disclosure .............................................................................................. 61 
19.5.2 
Trial Insurance ...................................................................................................... 61 
19.6 
Publication Policy ......................................................................................................... 61 
19.7 
Trial Master File ............................................................................................................ 62 
19.8 
Premature Trial Closure ............................................................................................... 62 
20. REFERENCES ....................................................................................................................... 63 
  
 
 

 
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3. SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial to Evaluate the 
Efficacy and Safety of Three Dose Levels of KVD824, an Oral Plasma Kallikrein 
Inhibitor, for Long-Term Prophylactic Treatment of Hereditary Angioedema Type I or II 
Trial No 
KVD824-201 
Protocol Name 
KOMPLETE 
Phase 
2 
Trial Centers 
HAE treatment centers worldwide 
Objectives 
Primary Objective 
• 
To demonstrate the clinical efficacy of prophylactic treatment with KVD824 
compared with placebo in preventing hereditary angioedema (HAE) attacks. 
Secondary Objectives 
• 
To further characterize the clinical efficacy of KVD824. 
• 
To investigate the safety and tolerability of KVD824. 
Trial Design 
KOMPLETE is a multicenter, randomized, double-blind, placebo-controlled, parallel 
group, phase 2 clinical trial to investigate the efficacy and safety of prophylactic 
treatment with three dose levels of KVD824 in subjects with HAE Type I or II. Subjects 
will be recruited through HAE treatment centers worldwide.  
This trial will be conducted on an outpatient basis and will comprise in-clinic visits or 
home health visits when in-clinic visits cannot be conducted (e.g. in the event of a 
pandemic or other reason that prevents the subject from attending the in-clinic visits). 
Screening Period 
Screening Visit 
The Screening Period includes the Screening Visit and Run-in Period. All subjects will 
sign an Informed Consent Form prior to any trial-related procedures being performed. 
Consent may be collected through a remote e-consenting solution if allowed through 
country and site regulations. Subjects will be 18 years of age or older at the time of 
screening and will have a diagnosis of HAE Type I or II.  
During the visit a physical exam, 12-lead electrocardiogram (ECG), laboratory tests, 
and other assessments as outlined in the Schedule of Events (Table 1) will also be 
performed. 
Site personnel will train subjects on the requirements for reporting attacks and the 
information subjects will be expected to provide in the electronic diary (eDiary) provided 
by the study sponsor. The subject will confirm understanding of what is required for 
reporting attacks.  
 

 
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Run-in Period 
Screened subjects will enter a Run-in Period of up to 8 weeks in duration. 
The start of the Run-in Period is determined by the type of HAE therapy being used by 
the subject at the time of Screening, as follows: 
• 
Use of On-demand Therapy Only for Treatment of HAE Attacks: Subjects 
using only on-demand therapy will enter the Run-in Period upon completion of 
Screening Visit eDiary assessments.  
• 
Use of Prophylaxis Therapy for Treatment of HAE Attacks: Subjects using any 
prophylaxis therapy will enter the Run-in Period following the first Investigator-
confirmed HAE attack after discontinuation of all prophylactic therapy. This attack 
does not count towards the total attacks required to meet the run-in eligibility 
criteria. Subjects must enter the Run-in Period within 8 weeks of completion of 
Screening Visit eDiary assessments. 
During the Run-in Period, all subjects must meet one of the following eligibility criteria: 
• 
Two Investigator-confirmed attacks in the first 4-week period. 
• 
Three Investigator-confirmed attacks in ≤8 weeks. 
Once the above Run-In Period criterion is met subjects may proceed to the 
Randomization Visit. Subjects who do not meet the run-in criterion will be ineligible to 
randomize and will not be allowed to re-screen. 
Randomization Visit 
Subjects will complete a Randomization Visit within approximately 10 days of 
completing the Run-in Period. Subjects will be randomized 1:1:1:1 to receive one of 
the following treatments to be taken twice daily: 
• 
300 mg (1 x 300 mg tablet) KVD824 
• 
600 mg (2 x 300 mg tablets) KVD824 
• 
900 mg (3 x 300 mg tablets) KVD824  
• 
Matching placebo  
It will be ensured that a balanced number of subjects assigned to placebo receive either 
1, 2, or 3 tablets. Arrangements will be made to dispense to the subject blinded 
investigational medicinal product (IMP) for twice daily oral self-administration for 
12 weeks. The IMP will be shipped directly to subjects via a courier service or will be 
dispensed at the study clinic as required by local regulations or per the site’s local 
practice. 
Randomization will be stratified by the number of Investigator-confirmed HAE attacks 
during the Run-In Period (i.e. ≤3 attacks/4 weeks or >3 attacks/4 weeks).  
A symptom-directed physical exam, 12-lead ECG, laboratory tests and other 
assessments as outlined in the Schedule of Events (Table 1) will also be performed 
during the visit. 
Treatment Period 
The Treatment Period is 12 weeks in duration and starts with the first dose of IMP. 
Subjects will be instructed to take their first dose with their next morning meal after 
receipt of the IMP. During the Treatment Period, subjects will self-administer IMP twice 
daily (either 300, 600, or 900 mg KVD824 or matching placebo) approximately 12 hours 

 
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apart with their morning and evening meals in accordance with their randomized 
assignment. Both the Investigator and subject will be blinded to the assigned treatment, 
but not to the number of tablets assigned (1, 2 or 3).  
Use of the following treatments is not permitted during the trial: 
• 
Long or short-term prophylaxis for HAE including: 
o 
C1-esterase inhibitor (C1-INH) for prophylaxis (e.g. Haegarda, Cinryze, 
Berinert, Ruconest) 
o 
Lanadelumab  
o 
Attenuated 
androgens 
(e.g. 
stanozolol, 
danazol, 
oxandrolone, 
methyltestosterone, testosterone) 
o 
Anti-fibrinolytics (e.g. tranexamic acid) 
o 
Berotralstat 
o 
Other investigational therapies for HAE prophylaxis (e.g. garadacimab, 
PKK-LRx, PHVS416) 
• 
Angiotensin-converting enzyme (ACE) inhibitors 
• 
Estrogen-containing medications with systemic absorption including: 
o 
oral contraceptives including ethinylestradiol or hormonal replacement therapy 
• 
Strong CYP3A4 inhibitors and inducers 
• 
Narrow therapeutic index drugs metabolized by CYP3A4 or CYP2C9, or 
transported by OAT1, OCT2, and OATP1B1, as determined by the Investigator, 
are also prohibited throughout the trial. 
Treatment of HAE attacks during the trial, including the Run-in Period, should be 
managed per the Investigator’s conventional care of their subjects, including use of on-
demand therapies that the Investigator deems as medically appropriate. Use of C1-INH 
will be permitted as an on-demand therapy but not as a long or short-term prophylaxis. 
Administration of the investigational product and trial procedures will continue without 
alteration to the protocol-specified schedule even if the subject requires an on-demand 
treatment for an HAE attack during the trial. 
During the trial, subjects will be instructed to record details of each HAE attack into an 
eDiary. Should a subject become incapacitated during an attack and unable to record 
details, this information can be recorded once the incapacitation has resolved. The 
subject will record the start and stop date/time of each attack, location(s), symptom(s) 
including prodromal, impact on activity, use of conventional treatment of each attack, 
and severity. 
As soon as possible following the completion of each attack and within no more than 
5 working days, contact will be made between the site staff and the subject to confirm, 
clarify, and correct any recorded eDiary data. Site staff who collect the HAE attack 
information from the subject must be designated and qualified to perform this task. 
Additionally, the designated site staff will ask questions about each attack to assist the 
Investigator (or qualified designee) with their confirmation of each attack.  
 
 

 
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The Investigator (or qualified designee) will assess whether the reported attack was 
caused by HAE. To be classified as an Investigator-confirmed 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 distension, 
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 determine 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 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). 
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. The 
collection, reporting, and assessment of attacks in this trial will be done in accordance 
with KalVista’s HAE Attack Document (K-HAD). Site personnel will be trained on the 
K-HAD prior to screening subjects at their site. The Investigator (or qualified designee) 
will rate the severity of each attack. 
During the Treatment Period, subjects will complete an in-clinic or home health visit at 
Week 2, Week 4, Week 6, and Week 12/Early Termination (ET). A 12-lead ECG, 
laboratory tests, and other assessments as outlined in the Schedule of Events (Table 
1) will be performed during the in-clinic or home health visit. Visits should occur within 
3 days of Week 2, 4, and 6. The Week 12/ET Visit should occur within 7 days after the 
final dose of IMP. 
Subjects will also complete quality of life assessments at the Screening Visit, 4 and 8 
weeks after the start of dosing, and at the final dose as described in the Schedule of 
Events (Table 1). The Treatment Satisfaction Questionnaire for Medication (TSQM) will 
be completed with the final dose. 
Investigational 
Medicinal 
Products 
KVD824 (300 mg) modified-release tablet. 
Placebo to KVD824 tablet. 
No IMP dose modifications are allowed in this trial. 
Tablets must be swallowed whole; tablets are not to be crushed or modified in any way. 
Tablets should be taken approximately 12 hours apart with the morning and evening 
meal. 
Number of 
Subjects 
Approximately 48 subjects will be randomized into the trial. 
Population 
The trial population will include male and female subjects 18 years of age and older 
with a confirmed diagnosis of HAE Type I or II. 
 

 
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Inclusion Criteria  
1) Male or female subjects 18 years of age and older. 
2) Confirmed diagnosis of HAE type I or II at any time in the medical history: 
a) Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria) AND EITHER 
b) Diagnostic testing results obtained prior to randomization that confirm HAE 
Type I or II: 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. Testing may be obtained from central 
or local laboratories or obtained from documented historical testing results. 
Subjects may be retested at any time prior to randomization if results are 
incongruent with clinical history or believed by the Investigator to be 
confounded by recent prophylactic or therapeutic C1-INH use, OR 
c) Documented genetic results that confirm known mutations for HAE Type I or 
II. 
3) Subject has access to and ability to use conventional treatment for HAE attacks. 
4) Subject is willing to cease any current medications being taken for HAE prophylaxis 
and Investigator determines that doing so would not place the subject at any undue 
safety risk. 
5) Subject’s last dose of attenuated androgens was at least 28 days prior to first dose 
of IMP. 
6) During the Run-in Period subject meets one of the following criteria: 
a) Two Investigator-confirmed attacks in the first 4-week period. 
b) Three Investigator-confirmed attacks in ≤8 weeks. 
7) Subjects who are fertile and heterosexually active must adhere to contraception 
requirements throughout the trial as follows: 
a) Female subjects must agree to use at least one highly effective contraception 
method from the Screening Visit until the end of the trial. Highly effective 
methods of contraception include: 
i) 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
oral/injectable/implantable 
(hormonal 
contraception 
that 
contains estrogen including ethinylestradiol is excluded per Exclusion 4). 
ii) Intrauterine device (IUD). 
iii) Intrauterine hormone–releasing system (IUS). 
iv) Bilateral tubal occlusion. 
v) Vasectomized partner (provided that the partner is the sole sexual partner 
of the female subject of childbearing potential and that the vasectomized 
partner has received medical assessment of surgical success). 
b) Male subjects with a female partner of childbearing potential must agree to use 
condoms for the entire Treatment Period AND for 90 days following the final 
dose of IMP. Female partners are encouraged to use contraception as outlined 
in Inclusion 7a) from the Screening Visit until the end of the trial. Hormonal 
contraception that contains estrogen including ethinylestradiol is acceptable 
for the female partner. 
8) Subjects who are not fertile or not sexually active, as defined below, do not require 
contraception. 
a) Subjects who refrain from heterosexual intercourse during the trial if the 
reliability of the heterosexual abstinence has been evaluated in relation to the 
duration of the clinical trial and is the preferred and usual lifestyle of the subject. 
b) Male subjects who are surgically sterile (e.g. vasectomized with medical 
assessment of surgical success). 
c) Female subjects who are surgically sterile (e.g. status post hysterectomy, 

 
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bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at 
least 12 months. 
9) Subjects must be able to swallow trial tablets whole. 
10) Subjects assessed by the Investigator must be able to appropriately receive and 
store IMP, and be able to read, understand, and complete the eDiary. 
11) Investigator believes that the subject is willing and able to adhere to all protocol 
requirements. 
12) Subject provides signed informed consent and is willing and capable of complying 
with trial requirements and procedures. 
Exclusion Criteria 
1) Any concomitant diagnosis of another form of chronic angioedema, such as 
acquired C1 inhibitor deficiency, HAE with normal C1-INH (previously known as 
HAE Type III), idiopathic angioedema, or angioedema associated with urticaria. 
2) A clinically significant history of poor response to C1-INH therapy or plasma 
kallikrein inhibitor therapy for the management of HAE, in the opinion of the 
Investigator.  
3) Use of ACE inhibitors after the Screening Visit or within 7 days prior to 
randomization. 
4) Any estrogen containing medications with systemic absorption (such as oral 
contraceptives including ethinylestradiol or hormonal replacement therapy) after 
the Screening Visit or within 7 days prior to randomization. 
5) Use of narrow therapeutic index drugs metabolized by CYP3A4 or CYP2C9 or 
transported by OAT1, OCT2, and OATP1B1, starting at screening, as determined 
by the Investigator. 
6) Use of strong CYP3A4 inhibitors and inducers during participation in the trial, 
starting at the Screening Visit. 
Note: These medications include but are not limited to the following:  
Inhibitors: 
boceprevir, 
clarithromycin, 
cobicistat, 
dasabuvir, 
denoprevir, 
elvitegravir, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, 
nelfinavir ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, tipranavir, troleandomycin, and voriconazole. 
Inducers: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, 
rifampin, St. John’s Wort. 
7) Inadequate organ function, including but not limited to; 
a) Alanine aminotransferase (ALT) > 2x ULN. 
b) Aspartate aminotransferase (AST) > 2x ULN. 
c) Bilirubin direct > 1.25x ULN. 
d) International normalized ratio (INR) > 1.2. 
e) Clinically significant hepatic impairment defined as a Child-Pugh B or C. 
f) 
Estimated glomerular filtration rate (eGFR) <60 mL/min. 
8) Any clinically significant comorbidity or systemic dysfunction that in the opinion of 
the Investigator would jeopardize the safety of the subject by participating in the 
trial. 
9) History of substance abuse or dependence that would interfere with the completion 
of the trial, as determined by the Investigator. 
10) Known hypersensitivity to KVD824 or placebo or to any of the excipients. 
11) Any prior use of any gene therapy treatment for HAE. 
12) Participation in any interventional investigational clinical trial, including an 
investigational COVID-19 vaccine trial, within 4 weeks of the last dosing of 
investigational drug prior to screening. 
13) Any pregnant or breastfeeding subject. 

 
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Assessments 
Efficacy Variables 
• 
Number (count) of Investigator-confirmed HAE attacks  
• 
Confirmation of attack by Investigator 
• 
Assessment of severity by the investigator (or qualified designee) 
• 
HAE attack descriptions using an eDiary, including:  
o 
Start and stop date/time of each attack 
o 
Location(s) of each attack 
o 
Symptom(s) including prodromal 
o 
Impact on activity 
o 
Use of conventional treatment of each attack 
o 
Subject assessment of severity 
• 
Quality of Life 
o 
Angioedema Control Test (AECT) 
o 
Angioedema Quality of Life Questionnaire (AE-QoL) 
o 
TSQM 
Safety Variables 
• 
Adverse Events, including serious adverse events 
• 
Laboratory test results 
• 
12-lead ECG 
• 
Vital signs 
• 
Physical examination findings 
Criteria for 
Evaluation of 
Efficacy 
Primary Endpoint 
• 
Rate of Investigator-confirmed HAE attacks during the Treatment Period. 
Secondary Endpoints 
• 
Proportion of subjects without Investigator-confirmed HAE attacks during the 
Treatment Period. 
• 
Rate of Investigator-confirmed HAE attacks that require conventional 
treatment during the Treatment Period. 
• 
AE-QoL total score and domain scores during the Treatment Period. 
• 
AECT score and domain scores during the Treatment Period. 
• 
Proportion of subjects with an AECT score ≥12 at the end of the Treatment 
Period. 
Exploratory Endpoints 
• 
Rate of Investigator-confirmed HAE attacks during the Treatment Period, by 
severity. 
• 
Rate of conventional treatment used during the Treatment Period. 
• 
TSQM total scores at the end of the Treatment Period. 
General 
Statistical 
Methods and 
Types of 
Analyses 
The statistical analysis plan (SAP) and associated templates for tables, listing and 
figures will be developed in a separate document that will provide a technical and 
detailed elaboration of the principal features stated in the protocol and will be 
developed and finalized prior to trial unblinding.  
Summary tables, figure and listings will be created using Version 9.4 (or later) of the 
SAS® software for Microsoft Windows (SAS Institute, Inc., Cary, North Carolina). 
Qualitative data will be analyzed by number of observed values, and number and 
percentage of subjects per category. 

 
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Quantitative data will be analyzed by number of observed values, mean and standard 
deviation (SD), median, first and third quartiles, minimum, and maximum. 
All statistical tests will be 2-sided with an alpha of 0.05. The primary efficacy endpoint 
analysis will have Bonferroni multiplicity adjustment for multiple dose levels, therefore 
pairwise comparison tests will be 2-sided with an alpha of 0.0167. The analysis of the 
secondary or exploratory endpoints will not have multiplicity adjustments. 
The primary endpoint will be analyzed by negative binomial regression with 
randomization stratification factor of baseline attack rate per 4 weeks during the Run-
In Period as a fixed covariate and treatment as a fixed factor and the logarithm of time 
each subject was observed “while on treatment” used as an offset variable in the 
model. This model will be used to estimate rate of HAE attacks while on treatment and 
rate ratio of HAE attacks (each of the KVD824 dose groups versus placebo) with 95% 
confidence interval and 2-sided p-value. 
 

 
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Table 1: 
Schedule of Events  
 
Screening Perioda 
Randomization Visit 
Treatment Periodb 
Visit 
Screening Visit 
Run-In Period 
(up to 8 weeks 
prior to 
Randomization) 
Week 2 
Week 4 
Week 6 
Week 12/ET 
In-clinic or Home Health Visitc 
X 
 
X 
X 
 
X 
X 
Informed Consentd 
X 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
X 
 
 
 
 
HAE Diagnostic Lab Teste 
X 
 
 
 
 
 
 
Medical Historyf 
X 
 
 
 
 
 
 
Demographicsg 
X 
 
 
 
 
 
 
Physical Examinationh 
X 
 
X 
 
 
 
X 
Vital Signsi 
X 
 
X 
X 
 
X 
X 
12-lead ECGj 
X 
 
X 
X 
 
X 
X 
Safety Laboratoryk 
X 
 
X 
X 
X 
X 
X 
Pregnancy Testl 
X 
 
X 
X 
 
X 
X 
Subject eDiary Training  
X 
 
 
 
 
 
 
Randomize to Treatment (prior to or during Randomization Visit) 
 
 
X 
 
 
 
 
Subject eDiary Re-training (if necessary) 
 
 
X 
X 
 
X 
 
IMP Dispensing/ Accountability/Returnm 
 
 
X 
X 
 
X 
X 
IMP Dosing 
 
 
 
BID dosing for up to 12 weeks 
HAE Attack Site Follow-upn 
 
 

 
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Table 1: 
Schedule of Events  
 
Screening Perioda 
Randomization Visit 
Treatment Periodb 
Visit 
Screening Visit 
Run-In Period 
(up to 8 weeks 
prior to 
Randomization) 
Week 2 
Week 4 
Week 6 
Week 12/ET 
AE-QOL and AECT Questionnaireso 
X 
 
 
 
TSQM 
 
 
 
 
 
 
X 
Prior and Concomitant Medication Review 
 
Adverse Event Reviewp 
 
Abbreviations: AE-QOL=Angioedema Quality of Life Questionnaire; AECT=Angioedema Control Test; C1-INH=C1-esterase inhibitor; EC = Ethics Committee; ECG=electrocardiogram; 
eDiary=electronic diary; ET=Early Termination; HAE=hereditary angioedema; IMP=investigational medicinal product; IRB = Institutional Review Board; TSQM=Treatment Satisfaction 
Questionnaire for Medication. 
a Procedures for the Screening Visit may take place on different days; however, all procedures should be completed within 4 weeks of starting the visit. For prophylactic subjects, the 
Run-in Period must start within 8 weeks from completion of Screening Visit eDiary assessments. 
b The start of the Treatment Period begins with the first dose of IMP with the morning meal after the IMP is received; visits for Week 2, Week 4 (lab draw), and Week 6 should occur 
within ±3 days. Week 12/ET should occur within 7 days after the last dose of IMP.  
c If a subject cannot attend a trial in-clinic visit (scheduled or unscheduled), a visit at the subject’s home is permitted to occur, if permitted by the relevant regulatory authority, site’s 
EC/IRB, local regulations, and the subject via informed consent. The home visit will be performed by an appropriately delegated home healthcare service provider. Information 
captured during a home health visit will mirror that captured during an in-clinic visit. The home health visits will only occur in the event of a pandemic or other reason that prevents 
the subject from attending the in-clinic visits. 
d Consent may be collected through a e-consenting solution if allowed through country and site regulations. 
e Diagnostic testing must be available for subjects without genetic confirmation of HAE Type I or II. 
f Medical history includes any relevant previous and concurrent diseases, HAE disease history; therapies and supplements taken within the past 4 weeks; and previous participation 
in interventional clinical studies in the past 4 weeks. 
g Demographics: year of birth; height (meters [m]; without shoes); weight (kilograms [kg]); race and ethnicity (if allowed); and sex.  
h Complete physical examination at screening only, all others will be symptom directed. In the case of a home health visit, the home healthcare nurse will conduct an abbreviated 
physical examination, and the Investigator will conduct the symptom-directed physical examination via televisit. 
i Vital signs include pulse rate, respiratory rate, and systolic and diastolic blood pressure after subject has been resting for at least 5 minutes. 
j ECG to be recorded after subject has rested supine for at least 5 minutes.  

 
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k Laboratory assessments performed by a central laboratory; repeat laboratory assessments may be performed. At the Week 4 visit, a safety lab sample will be drawn to assess 
clinical chemistry and liver enzymes. This sample can be obtained at a brief in-clinic or site lab visit or can be obtained by a Home Health service provider. 
l Serum pregnancy test will be performed on females of childbearing potential.  
m During the Randomization visit, arrangements will be made to dispense the assigned IMP. The IMP will be shipped directly to the subject via a courier service or dispensed at the 
study clinic as required by local requirements or per the site’s local practice, as described in the pharmacy manual. IMP accountability will be performed at the Week 2, 6, and 12/ET 
visits. Drug accountability will be reviewed at each in-clinic or home health visit (via review of unused IMP), and re-training will occur, if necessary. All unused IMP will be returned 
at the in-clinic Week 12/ET Visit. If the Week 12/ET Visit is performed by Home Health, arrangements will be made to return any unused IMP via courier. 
n As soon as possible following the completion of each attack and within no more than 5 working days, contact will be made between the site staff and the subject to confirm, clarify, 
and correct any recorded eDiary data. Site staff who collect the HAE attack information from the subject must be designated and qualified to perform this task. Additionally, the 
designated site staff will ask questions about each attack to assist the Investigator (or qualified designee) with their confirmation of each attack. The Investigator (or qualified 
designee) will rate the severity of each attack. 
o AE-QOL and AECT Questionnaires will be collected in the eDiary at the Screening Visit, 4 and 8 weeks post initial dose, and with the last dose of IMP. 
p Adverse events recorded from the first dose of KVD824 or placebo up to and including the Week 12/ET Visit. Serious AEs recorded from the time of signing the informed consent 
up to and including the Week 12/ET Visit.  

 
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4. KEY CONTACT LIST 
Sponsor 
KalVista Pharmaceuticals, Ltd.  
Porton Science Park 
Bybrook Road  
Porton Down  
Salisbury, SP4 0BF  
United Kingdom 
Matthew Iverson, MPH 
Vice President, Clinical 
Phone: +1 (801) 201-2852 
Email: matthew.iverson@kalvista.com 
Sponsor Medical Expert 
Paul Audhya, MD, MBA 
Chief Medical Officer 
Phone: +1 (919) 986-0360 
Email: paul.audhya @kalvista.com 
Contract Research Organization 
PPD Development, L.P. 
929 North Front Street, 
Wilmington, NC 28401   
USA 
Central Laboratory 
PPD Laboratories US 
2 Tesseneer Drive 
Highland Heights, KY 41067 
USA 
Medical Monitor 
Branislav Gvozdenovic, MD, PhD 
PPD Serbia, Belgrade 
Phone: 
North America: 1-888-483-7729  
EMEA, APAC: + 44 1223 374 240 
 
Pharmacovigilance for SAE 
Reporting 
 
Arriello Ireland Limited 
SAE Reporting Email: kalvista.safety@arriello.com 
SAE Reporting Fax #:  
North America: +1 888 215 1304;  
EMEA, APAC: +420 296 181 216 
All other contact details are located in trial-specific documentation. 

 
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5. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
AECT 
Angioedema Control Test 
AE-QoL 
Angioedema Quality of Life 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BID 
twice daily dosing 
BMI 
body mass index 
C1-INH 
C1-esterase inhibitor 
CRO  
Contract Research Organization 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
F 
fraction of non-missing data 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
HAE 
hereditary angioedema 
HbA1c 
glycosylated hemoglobin 
HDPE 
High Density Polyethylene 

 
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HCG 
Human chorionic gonadotropin 
HR 
heart rate 
IB 
Investigator’s Brochure 
IcEV 
intercurrent event 
ICH 
International Council on Harmonization 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
International normalized ratio  
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone–releasing system 
K-HAD 
KalVista’s HAE Attack Document 
kg 
kilogram(s) 
LOE 
lack of efficacy 
m 
meter(s) 
MAR 
missing at random 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minute 
mL 
milliliter(s) 
ms 
millisecond(s) 
MNAR 
missing not at random 
NAcomplete 
complete number of HAE attacks 
NAimputed 
missing number of HAE attacks 
NAobserved 
observed number of HAE attacks 
QoL 
quality-of-life 
pH 
potential hydrogen 
PR 
pulse rate 

 
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QTcF 
Fridericia correction of QTc 
RBC 
red blood cell 
RR 
respiratory rate 
RTSM 
Randomization and Trial Supply Management System 
s 
second(s) 
SAE 
serious adverse event 
SAF 
safety set 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
TDD 
total daily dose 
TEAE 
treatment-emergent adverse event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
upper limit of normal 

 
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6. INTRODUCTION 
6.1 
Background 
Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disease caused by a 
deficiency in the C1-esterase inhibitor (C1-INH) protein and characterized by unpredictable tissue 
swelling due to an increase in vascular permeability. The prevalence of HAE ranges between 1 and 2 per 
100,000 people worldwide with a point estimate of 1.5 per 100,000 (Aygören-Pürsün et al. 2018). HAE 
Types I and II account for approximately 90% and 10% of HAE cases with C1-INH deficiency, respectively 
(Nordenfelt et al. 2016, Zanichelli et al. 2015). Both types of HAE are caused by a large variety of genetic 
mutations in the SERPING1 gene (Gosswein et al. 2008). These mutations result in production of reduced 
levels of functional C1-INH (HAE Type I) or normal levels of dysfunctional C1-INH (HAE Type II) 
(Donaldson and Evans 1963, Donaldson and Rosen 1964, Rosen et al. 1965, Rosen et al. 1971). 
 
C1-INH inhibits key enzymes in the contact system (Kaplan and Joseph 2014), one of which is plasma 
kallikrein. Due to the deficiency in C1-INH associated with HAE, activated plasma kallikrein generates 
the vasoactive peptide hormone bradykinin, the mediator of vascular hyperpermeability that causes 
tissue swelling and pain (Fields et al. 1983, Hulström and Svensjö 1979, Nussberger et al. 1998, 
Nussberger et al. 2002, Nussberger et al. 1999). 
 
HAE is a life-long condition with approximately 50% of patients experiencing their first attack before the 
age of 10 years (Bork et al. 2006, Nordenfelt et al. 2016) and more than 75% experiencing their first 
attack before adulthood (Maurer et al. 2019). Attacks are episodic with considerable variations in 
frequency and severity (Bork et al. 2006, Javaud, Altar et al. 2019). Swelling has been shown to affect 
subcutaneous tissue (face, upper or lower extremities, genitals) in 82% of patients, abdominal organs 
(stomach, intestines) in 78% of patients, and the upper airway (larynx, tongue) in 27% of patients 
(Nordenfelt et al. 2016). Laryngeal attacks are infrequent (<5% of attacks) (Javaud, Altar et al. 2019) but 
are potentially life-threatening in patients who are unaware of their diagnosis (Bork et al. 2012). 
Approximately 50% of all patients with HAE experience at least one laryngeal attack during their lifetime 
(Bork et al. 2003, Bork et al. 2006). 
 
Several precipitants can trigger HAE attacks; however, more than half of all HAE attacks are 
unpredictable and occur without an obvious trigger (Caballero et al. 2016). Common triggers of HAE 
attacks such as strenuous activity, mechanical trauma, or use of certain medications, may be somewhat 
predictable. However, other triggers such as infections, fatigue, or emotional stress are difficult to predict 
(Caballero et al. 2016). Although patients with HAE have been shown to have high health-related quality 
of life scores (Javaud, Bouillet et al. 2019, Lumry et al. 2018), physical and emotional impairment persists 
in their daily lives and may extend beyond the duration of the attacks (Aygören-Pürsün et al. 2016, 
Caballero et al. 2014, Nordenfelt et al. 2017). 
6.2 
Trial Rationale 
Recurrent swelling in patients with HAE is predominantly a consequence of excessive generation of 
bradykinin due to dysregulated plasma kallikrein activity (Fields et al. 1983, Nussberger et al. 1998, 
2002). Therefore, inhibition of plasma kallikrein activation has emerged as a target for the treatment of 
HAE. For example, treatment with ecallantide, a specific inhibitor of plasma kallikrein given 
subcutaneously, led to significantly better treatment outcome scores compared with placebo (Cicardi et 
al. 2010, Sheffer et al. 2011). The oral small-molecule inhibitor of plasma kallikrein berotralstat 

 
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(Aygören-Pürsün, Bygum et al. 2018, Zuraw et al. 2020) and the plasma kallikrein monoclonal antibody 
lanadelumab (Banerji et al. 2017, Banerji et al. 2018) have been shown to lower the rate of attacks in 
HAE patients compared with placebo, highlighting the role that plasma kallikrein plays in this disease.  
 
KVD824 is a potent and selective small-molecule inhibitor of plasma kallikrein, a major effector in HAE 
attacks. Orally administered KVD824 achieves sustained and dose-dependent blockade of plasma 
kallikrein activity. Inhibition of kallikrein is maintained under fed and fasted conditions. KVD824 further 
protects high molecular weight kininogen from cleavage, thereby blocking the generation of bradykinin. 
Refer to the Investigator’s Brochure (IB) for further detail on KVD824.  
6.3 
Benefit/Risk 
KVD824 was evaluated in two Phase 1 studies in adult healthy volunteers. Pharmacodynamic 
evaluations of KVD824 have demonstrated that KVD824 inhibits plasma kallikrein activity ex-vivo at 
levels exceeding equivalent concentrations for berotralstat, a currently approved, once daily, oral plasma 
kallikrein inhibitor indicated for the prevention of HAE attacks. KVD824 achieved adequate plasma 
concentrations with sustained plasma kallikrein suppression over a 12- to 14-hour time interval. These 
data support further investigation of KVD824 as an orally administered treatment with adequate plasma 
kallikrein suppression to potentially prevent or reduce the occurrence of HAE attacks. 
 
Preclinical investigations, including in-vitro and in-vivo safety pharmacology studies and animal studies 
in mice, rats, and non-human primates support KVD824 administration in humans. The doses of 
modified-release KVD824 to be given in this trial were well tolerated in a previous clinical trial comprising 
16 subjects who received single doses of KVD824 up to 900 mg and 21 subjects who received at least 
600 mg twice a day for 14 days (Study KVD824-102). All adverse events observed in these studies were 
of mild and of short duration. No Grade 3 (severe) or serious adverse events (SAE) were reported. 
 
Subjects participating in this study will have access to conventional on-demand therapy to treat HAE 
attacks. Subjects will be instructed to contact the dedicated trial physician or qualified designee in case 
of any safety concerns. In the case of hypersensitivity, subjects are expected to contact the dedicated 
trial physician or qualified designee or contact the nearest emergency service. The site staff will contact 
the subject after HAE attacks to complete trial assessments. 
6.3.1 Impact of COVID-19 on Benefit-Risk Assessment 
Significant suppression of plasma kallikrein levels exists as a genetic condition (prekallikrein deficiency) 
(Girolami et al. 2010) and through therapeutic intervention with, for example, lanadelumab, a monoclonal 
antibody against plasma kallikrein (Banerji et al. 2018). Neither the familial condition nor administration 
with lanadelumab in subjects with HAE is known to increase susceptibility to viral infections or lead to 
increased infections in general. Also, epidemiological studies among subjects with HAE have not shown 
increased risks of infections (Zanichelli et al. 2015). At present plasma kallikrein inhibition with KVD824 
is unlikely to confer susceptibility or aggravation of symptoms to infection with severe acute respiratory 
syndrome coronavirus-2 (SARS-CoV-2). 
6.3.2 COVID-19 Vaccination 
There are no known risks or expected interaction with KVD824 and COVID-19 vaccines. Subjects may 
receive an approved COVID-19 vaccine, i.e., a vaccine that has received Emergency Use 
Authorization/Conditional Marketing Authorization (or approved/licensed) before, during, or after being in 
this trial. When feasible, the full vaccination series should be completed prior to enrollment.  

 
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7. OBJECTIVES AND ENDPOINTS 
7.1 
Objectives 
7.1.1 Primary 
The primary objective of this trial is to demonstrate the clinical efficacy of prophylactic treatment with 
KVD824 compared with placebo in preventing hereditary angioedema (HAE) attacks. 
7.1.2 Secondary 
Secondary objectives of this trial are: 
• 
To further characterize the clinical efficacy of KVD824. 
• 
To investigate the safety and tolerability of KVD824. 
7.2 
Endpoints 
7.2.1 Primary endpoint 
The primary endpoint of this trial is the rate of Investigator-confirmed HAE attacks during the Treatment 
Period. 
7.2.2 Secondary endpoints 
Secondary endpoints of this trial are: 
• 
Proportion of subjects without Investigator-confirmed HAE attacks during the Treatment Period. 
• 
Rate of Investigator-confirmed HAE attacks that require conventional treatment during the 
Treatment Period. 
• 
Angioedema Quality of Life Questionnaire (AE-QoL) total score and domain scores during the 
Treatment Period. 
• 
Angioedema Control Test (AECT) score and domain scores during the Treatment Period. 
• 
Proportion of subjects with an AECT score ≥12 at the end of the Treatment Period. 
7.2.3 Exploratory endpoints 
Exploratory endpoints of this trial are: 
• 
Rate of Investigator-confirmed HAE attacks during the Treatment Period, by severity. 
• 
Rate of conventional treatment used during the Treatment Period. 
• 
Treatment Satisfaction Questionnaire for Medication (TSQM) total scores at the end of the 
Treatment Period. 
 
 

 
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7.3 
Estimands 
Table 2: 
Primary Objective and Estimand 
Objective Description 
Estimand Description (Including Endpoint) 
To demonstrate the clinical efficacy of 
prophylactic treatment with KVD824 compared 
with placebo in preventing hereditary 
angioedema (HAE) attacks. 
 
Rate of Investigator-confirmed HAE attacks during the 
Treatment Period. 
Rate ratio of Investigator-confirmed HAE attacks while on 
treatment (each of the KVD824 dose groups versus 
placebo) in subjects with a confirmed diagnosis of HAE 
Type I or II who have at least 1.5 attacks per 4 weeks while 
off prophylactic treatment. Number of attacks will be 
measured ‘while on treatment’ over up to 12 weeks or until 
their treatment stops or changes (expressed as number of 
attacks on treatment). Subjects may receive on-demand 
conventional care for HAE attacks but receipt of additional 
treatments as a prophylactic would constitute a change and 
the end of the period considered ‘while on treatment.’ 
 

 
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8. TRIAL DESIGN 
8.1 
Overall Design 
KOMPLETE is a multicenter, randomized, double-blind, placebo-controlled, phase 2 clinical trial to 
investigate the efficacy and safety of prophylactic treatment with three dose levels of KVD824 in subjects 
with HAE Type I or II. Subjects will be recruited through HAE treatment centers worldwide. This trial will 
be conducted on an outpatient basis and will comprise in-clinic visits. If in-clinic visits cannot be conducted 
(e.g. in the event of a pandemic or other reason that prevents the subject from attending the in-clinic 
visits), Home Health visits will be used to perform these visits if permitted by the relevant regulatory 
authority, site’s Ethics Committee (EC)/Institutional Review Board (IRB), local regulations, and the 
subject via informed consent. The home visit will be performed by an appropriately delegated home 
healthcare service provider. Information captured during a home health visit will mirror that captured in 
an in-clinic visit. A trial diagram is presented in Figure 1. 
 
Figure 1: Trial Diagram 
8.2 
Scientific Rationale for Trial Design 
This phase 2 trial is the first clinical investigation of the potential efficacy of KVD824 in the prophylactic 
treatment of attacks of HAE. The randomized, placebo-controlled parallel group trial design is a standard 
approach for differentiation between the efficacy and safety profiles of an active and placebo treatments 
when administered to subjects with HAE Type I or II. 
 

 
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The trial population is representative of the likely target population for the product. The sample size of 
approximately 48 randomized subjects is required to conclusively evaluate a clinically relevant treatment 
effect. A trial duration of 12 weeks is adequate to assess the primary and secondary objectives of the 
trial and other HAE prophylaxis trials. 
 
The twice daily oral dose levels selected for the current clinical trial of KVD824 (300, 600, and 900 mg) 
are supported by animal toxicology data and were shown in phase 1 trials (of maximum 14-day duration) 
to be well tolerated and to result in potentially beneficial ex-vivo pharmacodynamic effects. 
 
The endpoints for this trial are commonly measured in HAE and are clinically relevant. The safety 
measures are routinely used for the evaluation of safety and tolerability of an investigational product. 
8.3 
Justification for Dose 
A twice daily dose of KVD824 (300, 600, and 900 mg) is supported by the ex-vivo pharmacodynamic 
bioactivity, pharmacokinetic, safety, and efficacy of KVD824 from previous clinical trials and nonclinical 
studies that found KVD824 to be well tolerated and to result in potentially beneficial pharmacodynamic 
effects. 
8.4 
End of Trial Definition 
The end of this trial is defined as the last subject’s last visit. 

 
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9. TRIAL POPULATION 
HAE treatment centers worldwide will randomize approximately 48 subjects into the trial. 
9.1 
Inclusion Criteria 
1) 
Male or female subjects 18 years of age and older. 
2) 
Confirmed diagnosis of HAE Type I or II at any time in the medical history: 
a) Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic 
swelling episodes without accompanying urticaria) AND EITHER 
b) Diagnostic testing results obtained prior to randomization that confirm HAE Type I or II: 
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. 
Testing may be obtained from central or local laboratories or obtained from documented 
historical testing results. Subjects may be retested at any time prior to randomization if results 
are incongruent with clinical history or believed by the Investigator to be confounded by recent 
prophylactic or therapeutic C1-INH use, OR 
c) 
Documented genetic results that confirm known mutations for HAE Type I or II. 
3) 
Subject has access to and ability to use conventional treatment for HAE attacks. 
4) 
Subject is willing to cease any current medications being taken for HAE prophylaxis and 
Investigator determines that doing so would not place the subject at any undue safety risk. 
5) 
Subject’s last dose of attenuated androgens was at least 28 days prior to first dose of IMP. 
6) 
During the Run-in Period subject meets one of the following criteria: 
a) Two Investigator-confirmed attacks in the first 4-week period. 
b) Three Investigator-confirmed attacks in ≤8 weeks.  
7) 
Subjects who are fertile and heterosexually active must adhere to contraception requirements 
throughout the trial as follows: 
a) Female subjects must agree to use at least one highly effective contraception method from 
the Screening Visit until the end of the trial. Highly effective methods of contraception include: 
i) 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral/injectable/implantable (hormonal contraception that contains estrogen including 
ethinylestradiol is excluded per Exclusion 4). 
ii) 
Intrauterine device (IUD). 
iii) 
Intrauterine hormone–releasing system (IUS). 
iv) 
Bilateral tubal occlusion. 
v) 
Vasectomized partner (provided that the partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of surgical success). 
b) Male subjects with a female partner of childbearing potential must agree to use condoms for 
the entire Treatment Period AND for 90 days following the final dose of investigational 
medicinal product (IMP). Female partners are encouraged to use contraception as outlined 
in Inclusion 7a) from the Screening Visit until the end of the trial. Hormonal contraception that 
contains estrogen including ethinylestradiol is acceptable for the female partner. 

 
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8) 
Subjects who are not fertile or not sexually active, as defined below, do not require contraception. 
a) Subjects who refrain from heterosexual intercourse during the trial if the reliability of the 
heterosexual abstinence has been evaluated in relation to the duration of the clinical trial and 
is the preferred and usual lifestyle of the subject. 
b) Male subjects who are surgically sterile (e.g. vasectomized with medical assessment of 
surgical success). 
c) 
Female subjects who are surgically sterile (e.g. status post hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months. 
9) 
Subjects must be able to swallow trial tablets whole. 
10) 
Subjects assessed by the Investigator must be able to appropriately receive and store IMP, and 
be able to read, understand, and complete the eDiary.  
11) 
Investigator believes that the subject is willing and able to adhere to all protocol requirements. 
12) 
Subject provides signed informed consent and is willing and capable of complying with trial 
requirements and procedures. 
9.2 
Exclusion Criteria 
1) 
Any concomitant diagnosis of another form of chronic angioedema, such as acquired C1 inhibitor 
deficiency, HAE with normal C1-INH (previously known as HAE Type III), idiopathic angioedema, 
or angioedema associated with urticaria. 
2) 
A clinically significant history of poor response to C1-INH therapy or plasma kallikrein inhibitor 
therapy, for the management of HAE, in the opinion of the Investigator.  
3) 
Use of angiotensin-converting enzyme (ACE) inhibitors after the Screening Visit or within 7 days 
prior to randomization. 
4) 
Any estrogen containing medications with systemic absorption (such as oral contraceptives 
including ethinylestradiol or hormonal replacement therapy) after the Screening Visit or within 7 
days prior to randomization. 
5) 
Use of narrow therapeutic index drugs metabolized by CYP3A4 or CYP2C9 or transported by 
OAT1, OCT2, and OATP1B1 starting at screening, as determined by the Investigator. 
6) 
Use of strong CYP3A4 inhibitors and inducers during participation in the trial, starting at the 
Screening Visit. 
Note: These medications include but are not limited to the following:  
Inhibitors: boceprevir, clarithromycin, cobicistat, dasabuvir, denoprevir, elvitegravir, idelalisib, 
indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir ombitasvir, paritaprevir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, and 
voriconazole. 
Inducers: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s 
Wort. 
7) 
Inadequate organ function including but not limited to: 

 
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a) Alanine aminotransferase (ALT) > 2x ULN 
b) Aspartate aminotransferase (AST) > 2x ULN 
c) 
Bilirubin direct > 1.25x ULN 
d) International normalized ratio (INR) > 1.2 
e) Clinically significant hepatic impairment defined as a Child-Pugh B or C 
f) 
eGFR <60 mL/min 
8) 
Any clinically significant comorbidity or systemic dysfunction that, in the opinion of the Investigator, 
would jeopardize the safety of the subject by participating in the trial. 
9) 
History of substance abuse or dependence that would interfere with the completion of the trial, as 
determined by the Investigator. 
10) 
Known hypersensitivity to KVD824 or placebo or to any of the excipients. 
11) 
Any prior use of any gene therapy treatment for HAE. 
12) 
Participation in any interventional investigational clinical trial, including an investigational COVID-
19 vaccine trial, within 4 weeks of the last dosing of investigational drug prior to screening. 
13) 
Any pregnant or breastfeeding subject. 

 
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10. INVESTIGATIONAL MEDICINAL PRODUCT 
For clinical trial use, KVD824 has been formulated as 300 mg modified-release tablets.  
 
The active ingredient in the tablets is KVD824. It is present as the hydrochloride salt. All doses refer to 
freebase equivalent. 
 
Further information about KVD824 300 mg modified-release tablets and matching placebo can be found 
in the IB. 
10.1 
Investigational Medicinal Product Administration 
Subjects will be randomized in 1:1:1:1 fashion to receive one of the following treatments to be taken twice 
daily: 
• 
300 mg (1 x 300 mg tablet) KVD824 (total daily dose [TDD] of 600 mg)  
• 
600 mg (2 x 300 mg tablets) KVD824 (TDD of 1,200 mg) 
• 
900 mg (3 x 300 mg tablets) KVD824 (TDD of 1,800 mg), or  
• 
Matching placebo  
 
The placebo group will receive either 1, 2, or 3 placebo tablets. Randomization will be stratified by the 
number of Investigator-confirmed HAE attacks during the Run-in Period (i.e. ≤3 attacks/4 weeks or >3 
attacks/4 weeks).  
 
During the Randomization Visit, arrangements will be made to dispense to the subject blinded IMP for 
12 weeks of IMP administration. The IMP will be shipped directly to the subject via a courier service or 
will be dispensed at the study clinic as required by local regulations or per the site’s local practice, as 
described in the Pharmacy Manual. 
 
Subjects will be instructed to take their first dose with their next morning meal after receipt of the IMP. 
Subjects will be instructed to take IMP twice daily, approximately 12 hours apart with their morning and 
evening meals. 
 
No IMP dose modifications are allowed in this trial. 
10.2 
Packaging and Labeling 
The investigational products (i.e. KVD824 or placebo) will be packaged and labeled according to current 
International Conference on Harmonisation (ICH) Good Manufacturing Practice and Good Clinical 
Practice (GCP) guidelines and national legal requirements. The IMP will be packaged in appropriately 
labeled High Density Polyethylene (HDPE) containers. 
 
Subjects will be provided with instructions concerning the storage of the IMP at home. 
10.3 
Storage and Drug Accountability 
Prior to receipt by the subject, IMP will be stored at room temperature as labeled.  
 

 
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IMP will only be dispensed to the identified subjects of this trial following the procedures described in 
Pharmacy Manual. All supplies of the investigational products must be accounted for at the end of the 
trial. Qualified site personnel will inventory unused IMP at Week 2, Week 6, and Week 12/Early 
Termination (ET) visits.  
 
IMP that has been dispensed to a subject and returned unused must not be re-dispensed for a different 
subject. Unused IMP must not be used for any purpose other than the present trial.  
 
After completion of the trial and following Sponsor approval, all unused IMP will either be returned to the 
Sponsor or designee or sent for destruction. 
10.4 
Trial Medication Compliance 
Subjects will be provided with instructions on IMP administration and the relevant documentation thereof. 
In addition, subjects will bring their unused IMP to every in-clinic trial visit. Drug accountability will be 
reviewed at in-clinic or home health visit (via review of unused IMP), and re-training will occur, if 
necessary. If in-clinic visits cannot occur the accountability will occur during the home health visit. If a 
home health visit occurs for Week 12/ET, arrangements will be made to return any unused IMP. 

 
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11. MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
11.1 
Subject Numbers Identification 
Each subject will receive a unique subject identification number.  
11.2 
Randomization Scheme 
Subjects will complete a Randomization Visit during which they will be randomized on a 1:1:1:1 basis to 
receive 300, 600, or 900 mg KVD824 or matching placebo. It will be ensured that a balanced number of 
subjects assigned placebo receive either 1, 2, or 3 tablets. 
 
Subjects must not be randomized unless all eligibility criteria have been met. 
11.3 
Blinding 
Subjects, Investigators, and site personnel will not be blinded to the number of tablets a subject is 
assigned (1, 2, or 3 tablets) but will be blinded to the treatment administered until the trial is complete 
and the database is locked. A double-dummy design could not be incorporated, as stability with mixed 
blister packaging was not available for this proof-of-concept trial and using multiple bottles for each dose 
to allow a double-dummy design would add significant risk of increasing the potential for dosing errors. 
The potential for dosing errors is more significant than potential bias introduced by the knowledge of the 
dose level (i.e. number of tablets). Lastly, other trials in HAE have utilized a trial design with the dose 
level unblinded and the treatment (i.e. active vs. placebo) blinded. 
 
The trial blind should not be broken except in a medical emergency (where knowledge of the IMP received 
would affect the treatment of the emergency) or regulatory requirement (e.g. for SAEs or death). The 
subject’s safety takes priority over any other considerations in determining if a treatment assignment 
should be unblinded. The decision to break the trial blind will be made solely by the Investigator; efforts 
should be made to contact the Sponsor and Medical Monitor prior to breaking the blind.  
 
Before breaking the blind of an individual subject’s treatment, the Investigator should determine that the 
unblinded information is necessary, i.e. that it will alter the subject’s immediate management. In many 
cases, particularly when the emergency is clearly not related to the IMP, the problem may be properly 
managed by assuming that the subject is receiving active product. 
 
The Investigator will be able to unblind a subject at any time by logging into the Rave Randomization and 
Trial Supply Management (RTSM) system, selecting the correct subject number, and selecting the 
unblind option. Following the unblinding of the IMP for a subject, the Investigator should inform the 
Sponsor and Medical Monitor. In addition to this, the date, time, and reason for unblinding must be 
recorded in the Rave RTSM system. 
 
If an Investigator, site personnel performing assessments, or subject, is unblinded, it must be 
documented as a major protocol deviation. 
 
Suspected unexpected serious adverse reactions (SUSARs), which are subject to expedited reporting, 
should be unblinded before submission to the Regulatory Authorities. 
 

 
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The overall randomization code will be broken only for reporting purposes. This will occur once all final 
clinical data have been entered into the database and all data queries have been resolved and the 
assignment of subject to the analysis sets has been completed. 

 
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12. PERMITTED THERAPIES AND PROHIBITED THERAPIES 
12.1 
Permitted Therapies 
Treatment of HAE attacks during the trial, including the Run-in Period, are to be managed per the 
Investigator’s conventional care of their subjects, including use of on-demand therapies that the 
Investigator deems as medically appropriate. Use of C1-INH will be permitted as an on-demand therapy 
but not as a long or short-term prophylaxis. Administration of the investigational product and trial 
procedures will continue without alteration to the protocol-specified schedule even if the subject requires 
an on-demand treatment for an HAE attack during the trial. 
12.2 
Prohibited Therapies 
Subjects must cease any current medications being taken for HAE prophylaxis throughout the trial. 
Medications and therapies that preclude a subject from enrolling in the trial are listed in Section 9.2. 
 
The following therapy is NOT permitted throughout the trial (i.e. from Screening Visit until after the final 
trial visit [Week 12/ET Visit]): 
• 
Long or short-term prophylaxis for HAE including: 
o 
C1-INH for prophylaxis (e.g. Haegarda, Cinryze, Berinert, Ruconest) 
o 
Lanadelumab 
o 
Attenuated androgens (e.g. stanozolol, danazol, oxandrolone, methyltestosterone, 
testosterone) 
 
In addition, the subject’s last dose of attenuated androgens must be at least 28 days prior 
to first dose of IMP. 
o 
Anti-fibrinolytics (e.g. tranexamic acid) 
o 
Berotralstat 
o 
Other investigational therapies for HAE prophylaxis (e.g. garadacimab, PKK-LRx, PHVS416) 
• 
ACE inhibitors 
• 
Estrogen-containing medications with systemic absorption including: 
o 
Oral contraceptives including ethinylestradiol or hormonal replacement therapy 
• 
Strong CYP3A4 inhibitors and inducers (see Section 9.2 for list of medications) 
• 
Narrow therapeutic index drugs metabolized by CYP3A4 or CYP2C9 or transported by OAT1, 
OCT2, and OATP1B1, as determined by the Investigator, are also prohibited throughout the trial. 
Details of all medications, therapies and supplements administered within 4 weeks prior to the Screening 
Visit until the end of the trial will be recorded in the electronic case report form (eCRF). Prior medications 
are defined as those medications taken within 4 weeks prior to the Screening Visit up to the first dose of 
IMP; concomitant medications are defined as those medications ongoing at or started after the first dose 
of IMP. 

 
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13. SUBJECT DISCONTINUATION 
Subjects may withdraw their consent from the trial at any time at their own request for any reason without 
prejudice to their medical care. If a subject withdraws consent for disclosure of future information, the 
Sponsor may retain and continue to use any data collected before such withdrawal of consent. 
 
The subject also may be discontinued at any time by the Investigator for any of the following reasons: 
• 
AEs 
• 
At the discretion of the Investigator 
• 
Administrative reasons (e.g. lack of subject compliance to trial visits/procedures, lost to follow-up). 
 
The Investigator will discontinue a subject from the trial for the reasons listed below if the event is 
determined to be related to IMP; clinically significant laboratory findings must be confirmed: 
• 
ALT or AST > 3 times ULN and with either direct bilirubin > 2 times ULN or INR increased from 
baseline and is > 1.5 times ULN, or 
• 
Any SAE or a clinically significant Grade 4 adverse event (note: a clinically significant Grade 4 
laboratory abnormality is considered a Grade 4 adverse event). 
 
If a subject is discontinued from the trial, every attempt will be made to complete and document the ET 
visit as soon as possible. If the subject is discontinued from the trial after receiving IMP, every effort will 
be made to ensure that the relevant safety assessments are completed. The subject may also be asked 
by the Investigator to complete other trial assessments. Subjects who prematurely discontinue from the 
trial will continue to have access to medical care and will be treated as per routine medical practice. 
 
The reason for and date of discontinuation will be recorded (e.g., withdrawal of consent, lost to follow-up, 
discontinuation due to an AE). If the reason for discontinuation is the occurrence of an AE, the subject 
will be followed up until the AE has resolved or is considered chronic or stable or the AE has been clearly 
shown to be unrelated to the IMP. 
 
Discontinued subjects will not be replaced; subject/randomization numbers will not be reused. 
If a subject does not complete a scheduled visit, every effort should be made to contact the subject to 
reschedule the visit. All efforts should be documented in the subject’s medical source record. A subject 
will be considered lost to follow-up if subject cannot be reached after 4 weeks from the scheduled visit. 

 
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14. 
TRIAL STOPPING CRITERIA 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or events that 
suggest a possible hazard to subjects if the trial continues, the trial may be terminated after appropriate 
consultation between the relevant parties.  
 
The trial will be terminated if the following occur and are determined to be related to IMP by the treating 
Investigator: 
 
Death in any subject. 
 
The occurrence in any subject of a life-threatening SAE not related to HAE.  
 
Liver-related AE that meets Hy’s Law in more than 1 subject (FDA Guidance for Industry, 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 2009; Zimmerman, 1968):  
1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation of >3× the 
upper limit of normal (ULN) 
2. Total bilirubin (TBL) elevation of >2× ULN 
3. Absence of initial findings of cholestasis (i.e., absence of elevation of alkaline phosphatase 
[ALP] to >2× ULN) 
4. No other reason can be found to explain the combination of increased ALT and TBL, such 
as viral hepatitis A through E; other preexisting or acute liver disease; or another drug 
capable of causing the observed injury. 
 
Similar Grade 3 or higher AE, excluding liver-related AE, in more than 1 subject (note: clinically 
significant Grade 3 laboratory abnormalities are considered Grade 3 AEs, clinically significant 
laboratory findings must be confirmed).  

 
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15. ASSESSMENTS 
The following assessments will be performed and recorded in the eCRF. The Schedule of Events by Visit 
is displayed in Table 1. 
15.1 
Subject Demographics and Medical History 
Demographic and baseline data will include year of birth, height (meters [m]; without shoes), weight (kg), 
race and ethnicity (if allowed), and sex. 
 
Medical history will capture any relevant previous and concurrent diseases, HAE disease history; 
therapies and supplements taken within the past 4 weeks; and participation in interventional clinical 
studies in the past 4 weeks. 
15.2 
Efficacy Assessments 
15.2.1  Investigator-Confirmed HAE Attack  
When an attack of HAE occurs, the subject will provide a description of the HAE attack in the Subject 
eDiary. Should a subject become incapacitated during an attack and unable to record details, this 
information can be recorded once the incapacitation has resolved. This description will include: 
• 
Start and stop date/time of each attack 
• 
Location(s) of each attack 
• 
Symptom(s) including prodromal 
• 
Impact on activity  
• 
Use of conventional treatment of each attack 
• 
Subject assessment of attack severity 
 
As soon as possible following the completion of each attack and within no more than 5 working days, 
contact will be made between the site staff and the subject to confirm, clarify, and correct any recorded 
eDiary data. Site staff who collect the HAE attack information from the subject must be designated and 
qualified to perform this task. Additionally, the designated site staff will ask questions about each attack 
to assist the Investigator (or qualified designee) with their confirmation of each attack. The investigator 
(or qualified designee) will rate the severity of each attack according to the following scale: 
• 
Mild 
• 
Moderate 
• 
Severe 
 
The Investigator (or qualified designee) will assess whether the reported attack was caused by HAE. To 
be classified as an Investigator-confirmed 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, 
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• 
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 clinically determine 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 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). 
 
The collection, reporting, and assessment of attacks in this trial will be done in accordance with KalVista’s 
HAE Attack Document (K-HAD). Site personnel will be trained on the K-HAD prior to screening subjects 
at their site. 
15.2.2 Angioedema Control Test (AECT)  
The AECT is a validated, self-administered, retrospective 4-item patient-reported outcome measure for 
patients with recurrent angioedema used to quantify disease control and to aid treatment decisions 
(Weller et al. 2020). The questionnaire addresses the frequency of angioedema, angioedema-related 
quality-of-life (QoL) impairment, unpredictability of angioedema attacks, and angioedema control by the 
current treatment approach. Each of the 4 AECT items is scored from 0 to 4 points with higher scores 
indicating a higher level of angioedema control. The AECT score is calculated by summing up all 4 item 
scores, with a minimum and maximum possible score of 0 and 16 points. AECT will be collected per the 
Schedule of Events (Table 1). 
1. 
In the last 4 weeks, how often have you had angioedema? 
2. 
In the last 4 weeks, how much as your quality of life been affected by angioedema? 
3. 
In the last 4 weeks, how much has the unpredictability of your angioedema bothered you? 
4. 
In the last 4 weeks, how well has your angioedema been controlled by your therapy? 
15.2.3 Angioedema Quality of Life Questionnaire (AE-QoL) 
The AE-QoL is a symptom-specific health-related QoL instrument for patients with recurrent angioedema. 
It consists of 17 items that can be grouped together to a total score or to 4 different domain scores 
(“Functioning,” “Fatigue/Mood,” “Fears/Shame,” and “Food”) that collectively evaluate the extent of 
angioedema-dependent QoL impairment during the previous 4 weeks. Each AE-QoL question has 
5 answer options (scored 1-5), with lower and higher scores indicting less and more adverse impact, 
respectively. The total score is calculated, which is then transformed into a linear scale that ranges from 
0 to 100, with a score of 100 indicating the worst possible impairment. A minimal clinically important 
difference of 6 points has been described (Weller et al. 2012, Weller et al. 2016). AE-QoL will be collected 
per the Schedule of Events (Table 1). 
15.2.4 Treatment Satisfaction Questionnaire for Medication (TSQM) 
The TSQM is a psychometrically sound and valid measure of the major dimensions of patients' 
satisfaction with medication (Atkinson et al. 2004). The questionnaire comprises 14 questions that are 
scaled on a 7-point bipolar scale ranging from “Extremely Satisfied” to “Extremely Dissatisfied.” TSQM 
will be collected per the Schedule of Events (Table 1). 
• 
How satisfied or dissatisfied are you with the ability of the medication to prevent or treat your 
condition? 

 
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• 
How satisfied or dissatisfied are you with the way the medication relieves your symptoms? 
• 
How satisfied or dissatisfied are you with the amount of time it takes the medication to start 
working? 
• 
As a result of taking this medication, do you currently experience any side effects at all? 
• 
How bothersome are the side effects of the medication you take to treat your condition? 
• 
To what extent do the side effects interfere with your physical health and ability to function 
(i.e. strength, energy levels, etc.)? 
• 
To what extent do the side effects interfere with your mental function (i.e. ability to think clearly, 
stay awake, etc.)? 
• 
To what degree have medication side effects affected your overall satisfaction with the 
medication? 
• 
How easy or difficult is it to use the medication in its current form? 
• 
How easy or difficult is it to plan when you will use the medication each time?  
• 
How convenient or inconvenient is it to take the medication as instructed? 
• 
Overall, how confident are you that taking this medication is a good thing for you? 
• 
How certain are you that the good things about your medication outweigh the bad things? 
• 
Taking all things into account, how satisfied or dissatisfied are you with this medication? 
15.3 
Safety Assessments 
15.3.1 Physical Examinations 
A physical examination will be performed by the Investigator or his/her qualified designee according to 
the Schedule of Events (Table 1). A complete physical examination will be performed at Screening only 
and will include the following body systems: general appearance; ears, nose, and throat; head and neck; 
ophthalmological; respiratory; cardiovascular; abdomen; neurological; extremities; dermatological; and 
lymphatic. Other visits noted in the Schedule of Events (Table 1) will include a symptom-directed physical 
examination. 
 
In the case of a home health visit, the home healthcare nurse will conduct an abbreviated physical 
examination, and the Investigator will conduct the symptom-directed physical examination via televisit. 
15.3.2 Vital Signs 
Vital signs will be assessed after the subject has been at rest for at least 5 minutes in accordance with 
the Schedule of Events (Table 1). Vital signs will include blood pressure (SBP and DBP; mmHg), pulse 
rate (PR; beats per minute), and respiration rate ([RR] breaths per minute). 
15.3.3 12-Lead Electrocardiogram (ECG) 
A 12-lead ECG will be recorded after the subject has rested supine for at least 5 minutes in accordance 
with the Schedule of Events (Table 1). Heart rate (HR; beats per minute), PR-interval (milliseconds [ms]), 
QRS-duration (ms), QT-interval (ms) and RR-interval (milliseconds [ms]) will be recorded; QTcF 
(Fridericia correction of QTc; ms) calculated as per standard practice. 

 
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15.3.4 Clinical Safety Laboratory Assessments 
Blood samples (approximately 60 mL) will be taken using standard venipuncture techniques. The central 
laboratory will provide a Laboratory Manual with detailed procedures. Safety labs will be collected per 
the Schedule of Events (Table 3). 
Table 3: 
Laboratory Assessments 
Hematology: 
RBC 
MCV 
MCH 
MCHC 
MPV 
RDW 
Nucleated RBC 
WBC 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Platelets 
Granulocytes 
Hemoglobin 
Hematocrit 
Urinalysis: 
pH 
Protein 
Glucose 
Ketone 
Bilirubin 
Blood 
Nitrite 
Albumin 
 
Reflex to microscopic panel, 
as required 
Clinical chemistry: 
HbA1c  
Creatinine 
Glucose (Random) 
Triglycerides 
eGFR 
Urea, Blood Nitrogen 
Bilirubin, Direct 
Cholesterol, Total 
Liver enzymes: 
ALP 
AST 
ALT 
GGT 
Electrolytes: 
Sodium 
Potassium 
Coagulation: 
INR 
C1 Functional Level: 
C1 Esterase Inhibitor 
Activity 
 
 
C1 Antigen: 
 C1 Esterase Inhibitor 
Protein 
 
 
Complement C4: 
Complement C4 
 
 
Pregnancy test (serum): 
In female subjects of childbearing potential. HCG Qualitative 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HbA1c=glycosylated 
hemoglobin; GGT=gamma glutamyl transferase; eGFR=estimated glomerular filtration rate HCG=human chorionic gonadotropin; 
INR=International Normalized Ratio; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean 
corpuscular volume; MPV=mean platelet volume; pH=potential hydrogen; RBC=red blood cell; RDW=red cell distribution width; WBC=white 
blood cell differential, immature granulocytes. 
 
The Investigator must review screening laboratory results for subject eligibility prior to randomizing the 
subject. Laboratory tests may be repeated at the Investigator’s discretion and any associated safety issue 
should be followed up as per the Investigator’s clinical judgement until resolution/stabilization. Clinically 
significant laboratory abnormalities, as determined by the treating Investigator, will be recorded as 
adverse events after the start of KVD824 dosing. 

 
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16. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
16.1 
Adverse Events 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
 
When possible, signs and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event. If an AE increases in severity it will be recorded as a new AE. Documentation 
regarding the AE should be made as to the nature, date of onset, end date, severity, relationship to the 
IMP, action(s) taken, seriousness, and outcome of any sign or symptom observed by the physician or 
reported by the subject upon questioning. 
 
HAE attacks will not be considered AEs unless they are considered SAEs. 
16.2 
Serious Adverse Events 
Any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event (medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious, such as important medical events that 
might not be immediately life-threatening or result in death or hospitalization but might jeopardize 
the subject or might require intervention to prevent one of the other). 
16.3 
Time Period and Frequency for Collection 
The period of observation for AEs extends from the time of the subject’s first dose of IMP until the 
Week 12/ET Visit. The period of observation for SAEs extends from the time of signing the informed 
consent until the Week 12/ET Visit. Ongoing AEs/SAEs at the Week 12/ET Visit will be followed up until 
the event has resolved or is considered chronic or stable or the event has been clearly shown to be 
unrelated to the IMP. Any relevant diseases occurring between the Screening Visit and the first dose of 
IMP are to be captured as medical history unless it is determined to be an SAE.  
16.4 
Method of Detection 
All AEs spontaneously reported by the subject and/or in response to an open question from trial personnel 
or revealed by observation, physical examination, or other diagnostic procedures will be recorded. 

 
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16.5 
Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as determined 
by the Investigator or reported to him/her by the subject. The assessment of severity is made irrespective 
of relationship to IMP or seriousness of the event and should be evaluated according to the Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(US Department of Health and Human Services 2007) where possible: 
• 
Mild (Grade 1) 
• 
Moderate (Grade 2) 
• 
Severe (Grade 3) 
• 
Potentially Life-Threatening (Grade 4) 
16.6 
Relationship 
The relationship of each AE to the IMP should be determined by the Investigator using these 
explanations: 
• 
Related: A reasonable possibility exists that the IMP caused the AE. 
• 
Not related: A reasonable possibility does not exist that the IMP caused the AE. 
 
“Reasonable possibility” means there is evidence to suggest a causal relationship between the IMP and 
the AE.  
 
Types of evidence that would suggest a causal relationship between the IMP and the AE include: A single 
occurrence of an event that is uncommon and known to be strongly associated with IMP exposure (e.g. 
hepatic injury, Stevens-Johnson Syndrome); one or more occurrences of an event that is not commonly 
associated with IMP exposure, but is otherwise uncommon in the population exposed to the IMP (e.g. 
tendon rupture); an aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that commonly 
occur in the trial population independent of drug therapy) that indicates those events occur more 
frequently in the IMP group than in a concurrent or historical control group. 
16.7 
Reporting 
16.7.1 Reporting AEs to EC/IRB and Regulatory Authorities  
The Investigator is responsible for informing the local EC/IRB of any applicable safety reports in 
compliance with local regulations. Copies of all correspondence and documentation relating to reporting 
of any safety reports to the local EC/IRB should be maintained in the Investigator Site Files. 
 
The Sponsor, or its designee, will inform Investigators, central ECs/IRBs and Regulatory Authorities of 
applicable safety reports, as required. 
16.7.2 Reporting Serious Adverse Events 
All SAEs, regardless of relationship to the IMP, must be immediately reported within 24 hours of 
awareness by any site staff. If it is not possible to complete all sections of the SAE form within 24 hours 
of becoming aware of the SAE, transmission of the form must not be delayed, and the outstanding 
information should be sent on a follow-up SAE form. All information relevant to the SAE must be recorded. 

 
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The Investigator is obligated to pursue and obtain information requested by the Sponsor in addition to 
that information reported on the SAE form. All subjects experiencing a SAE must be followed up and the 
outcome reported. 
 
SAE forms are to be submitted to kalvista.safety@arriello.com or sent by fax to +1 888 215 1304 (North 
America) or +420 296 181 216 (EMEA, APAC). 
 
The Investigator should obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the subject; provide 
the Sponsor with a complete case history, which includes a statement as to whether the event was or 
was not suspected to be related to the use of the IMP. 
16.7.3 Reporting Suspected Unexpected Serious Adverse Reactions 
A SUSAR is an AE that meets all the following criteria: 
• 
Serious: as defined in Section 16.2 of this protocol. 
• 
Unexpected: AE is not consistent with the Reference Safety Information (found in the 
Investigator’s Brochure).  
• 
Suspected: relationship to IMP is suspected to be related as defined in Section 16.6 of this 
protocol. 
 
All SUSARs should be reported to the relevant Regulatory Authority, EC/IRB, and investigators as per 
the regulatory requirement and timelines. 
16.8 
Pregnancy 
Preliminary dose range finding embryofetal development toxicity studies indicate that KVD824 was 
generally well tolerated (noting that excessive body weight loss is evident at high dose levels).  
 
A female subject who becomes pregnant while participating in the trial must notify the Investigator 
immediately. The subject must discontinue treatment with the investigational product but may continue 
other trial procedures at the discretion of the Investigator. The procedure for discontinuation of a subject 
will be followed, as described in Section 13. 
 
Pregnancy alone is not an AE unless there is a suspicion that the IMP may have interfered with the 
effectiveness of a contraceptive medication. 
 
All pregnancies must be reported by the Investigator to the Sponsor or designee within 5 days after 
becoming aware of the pregnancy. Pregnancies will be reported using the pregnancy reporting form and 
submitted to kalvista.safety@arriello.com. The Investigator should make every effort possible to follow-
up and document the course and the outcome of all pregnancies and live births up to 1 year of age even 
if the subject was discontinued from the trial or if the trial has finished. 
 
If a female partner of a male trial subject who has been exposed to the IMP becomes pregnant and 
consents to having the pregnancy followed, the pregnancy and outcome of pregnancy should be 
monitored according to the same guidelines as for female subjects who become pregnant during the trial. 

 
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16.9 
Treatment of Overdose 
No specific antidote to KVD824 is known and treatment of overdose should be supportive. 

 
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17. TRIAL PROCEDURES 
KOMPLETE will be conducted on an outpatient basis and will comprise in-clinic visits.  If in-clinic visits 
cannot be conducted (e.g. in the event of a pandemic or other reason that prevents the subject from 
attending the in-clinic visits), Home Health visits will be used to perform these visits if permitted by the 
relevant regulatory authority, site’s Ethics Committee (EC)/Institutional Review Board (IRB), local 
regulations, and the subject via informed consent. The home visit will be performed by an appropriately 
delegated home healthcare service provider. Information captured during a home health visit will mirror 
that captured in an in-clinic visit.  
 
If a home health visit cannot be conducted (e.g. due to country restrictions or quarantine), then a televisit 
should be performed followed by a visit to occur as soon as is reasonably possible. The televisit could 
entail the use of an interactive audio and video telecommunications system that permits real-time 
communication between the site and subject at home, or it could entail a telephone call.  
 
The IMP will be shipped directly to the subject via a courier service or will be dispensed at the study clinic 
as required by local regulations or per the site’s local practice, as described in the Pharmacy Manual. 
 
Informed consent must be obtained for all subjects participating in the trial prior to performing any trial-
related activities. 
 
Trial procedures are summarized by trial visit in the Schedule of Events (Table 1). 
17.1 
Screening Period 
17.1.1 Screening Visit (In-Clinic or Home Health Visit) 
The Screening Period includes an outpatient Screening Visit followed by a Run-in Period. Procedures for 
the Screening Visit may take place on different days; however, all procedures should be completed within 
4 weeks of starting the visit. All subjects will sign an Informed Consent Form (ICF) prior to any trial-related 
procedures being performed. Consent may be collected through a remote e-consenting solution if allowed 
through country and site regulations. Following full discussion of the trial and the signing of the ICF, a 
subject number will be assigned (Section 11.1). 
 
The following activities will be performed during the Screening Visit: 
• 
Eligibility assessment evaluating all results of the screening assessment results against the 
inclusion and exclusion criteria (Section 9). 
• 
HAE diagnostic lab test (or confirmation against documented historical testing results) for subjects 
without genetic confirmation of HAE Type I or II. 
• 
Full medical history (Section 15.1), including any relevant previous and concurrent diseases, HAE 
disease history; therapies and supplements taken within the past 4 weeks; and previous 
participation in interventional clinical studies in the past 4 weeks. 
• 
Demographic information including year of birth; race and ethnicity (if allowed); and sex 
(Section 15.1). 
• 
Height (m; without shoes) and weight (kg) (Section 15.1). Body mass index will be calculated. 
• 
Complete physical examination (Section 15.3.1). 

 
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• 
Vital signs (SBP and DBP, PR, and RR). BP and PR recorded after subject has been resting for 
at least 5 minutes (Section 15.3.2). 
• 
12-lead ECG after subject has been supine for at least 5 minutes (Section 15.3.3). 
• 
AE-QOL Questionnaire (Section 15.2.3). 
• 
AECT Questionnaire (Section 15.2.2). 
• 
Serum pregnancy test (female subjects of childbearing potential). 
• 
Blood and urine samples for clinical laboratory tests (Section 15.3.4). 
• 
Subject eDiary training on the requirements for reporting attacks, and information subjects will be 
expected to provide in the eDiary. The subject will confirm understanding of what is required for 
reporting attacks.  
17.1.2 Run-In Period 
Screened subjects will enter a Run-in Period of up to 8 weeks in duration. The start of the Run-in Period 
is determined by the type of HAE therapy being used by the subject at the time of Screening, as follows: 
• 
Use of On-demand Therapy Only for Treatment of HAE Attacks: Subjects using only 
on-demand therapy will enter the Run-in Period upon completion of Screening Visit eDiary 
assessments.  
• 
Use of Prophylaxis Therapy for Treatment of HAE Attacks: Subjects using any prophylaxis 
therapy will enter the Run-in Period following the first Investigator-confirmed HAE attack after 
discontinuation of all prophylactic therapy. This attack does not count towards the total attacks 
required to meet the run-in eligibility criteria. Subjects must enter the Run-in Period within 8 weeks 
of completion of Screening Visit the eDiary assessments. 
 
Treatment of HAE attacks during the trial, including the Run-in Period, are to be managed per the 
Investigator’s conventional care of their subjects, including use of on-demand therapies that the 
Investigator deems as medically appropriate. 
 
As soon as possible following the completion of each attack and within no more than 5 working days, 
contact will be made between the site staff and the subject to confirm, clarify, and correct any recorded 
eDiary data. Site staff who collect the HAE attack information from the subject must be designated and 
qualified to perform this task. Additionally, the designated site staff will ask questions about each attack 
to assist the Investigator (or qualified designee) with their confirmation of each attack. The investigator 
(or qualified designee) will rate the severity of each attack. 
 
During the Run-in Period all subjects must meet one of the following eligibility criteria: 
• 
Two Investigator-confirmed attacks in the first 4-week period. 
• 
Three Investigator-confirmed attacks in ≤8 weeks. 
 
Once the above Run-in Period criterion is met subjects may proceed to the Randomization Visit. 
 
Subjects who do not meet the Run-in Period criterion will be ineligible to randomize and will not be allowed 
to re-screen. 

 
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17.2 
Randomization Visit (In-Clinic or Home Health Visit) 
The Randomization Visit will be an in-person, outpatient visit, and will occur within approximately 10 days 
of completing the Run-in Period. 
 
Subjects will be randomized in 1:1:1:1 fashion to receive one of the following treatments: 
• 
300 mg (1 x 300 mg tablet) KVD824 
• 
600 mg (2 x 300 mg tablets) KVD824 
• 
900 mg (3 x 300 mg tablets) KVD824 
• 
Matching placebo  
 
It will be ensured that a balanced number of subjects assigned placebo receive either 1, 2, or 3 tablets. 
 
Arrangements will be made to dispense to the subject blinded IMP for twice daily oral self-administration 
for 12 weeks. The IMP will be shipped directly to the subject via a courier service or will be dispensed at 
the study clinic as required by local regulations or per the site’s local practice, as described in the 
Pharmacy Manual. 
 
The following activities will be performed during the Randomization Visit: 
• 
Eligibility assessment evaluating all results of the screening assessment results against the 
inclusion and exclusion criteria (Section 9). 
• 
Symptom-directed physical examination (Section 15.3.1). 
• 
Vital signs (SBP and DBP, PR, and RR). BP and PR recorded after subject has been resting for 
at least 5 minutes (Section 15.3.2). 
• 
12-lead ECG after subject has been supine for at least 5 minutes (Section 15.3.3). 
• 
Blood and urine samples for clinical laboratory tests (Section 15.3.4). 
• 
Serum pregnancy test (female subjects of childbearing potential). 
• 
Subject eDiary re-training, if necessary. 
• 
Concomitant medication review. 
• 
Randomize subject 1:1:1:1 to receive 300, 600, or 900 mg KVD824 or matching placebo. 
o Randomization may occur prior to the Randomization Visit if the site will be dispensing IMP 
during the in-clinic Randomization Visit; however, Run-in eligibility must be confirmed prior to 
randomizing the subject. 
• 
Make arrangements to dispense the assigned IMP to subjects. 
17.3 
Treatment Period 
The Treatment Period is 12 weeks in duration and starts with the first dose of IMP. Subjects will be 
instructed to take their first dose with their next morning meal after receipt of the IMP. During the 
Treatment Period, subjects will self-administer IMP twice daily approximately 12 hours apart with their 
morning and evening meals in accordance with their randomized assignment. Both the Investigator and 
subject will be blinded to the assigned treatment, but not to the number of tablets assigned (1, 2, or 3 
tablets).  
 

 
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Treatment of HAE attacks is to be managed per the Investigator’s conventional care of their subjects, 
including use of on-demand therapies that the Investigator deems as medically appropriate. Use of 
C1-INH will be permitted as an on-demand therapy but not as a long or short-term prophylaxis. 
Administration of the investigational product and trial procedures will continue without alteration to the 
protocol-specified schedule even if the subject requires an on-demand treatment for an HAE attack during 
the trial. 
 
When an attack of HAE occurs, the subject will provide a description of the HAE attack in the Subject 
eDiary and will be assessed by trial staff as outlined in Section 15.2.1. 
 
Visits should occur within 3 days of Week 2, 4, and 6. The Week 12/ET Visit should occur within 7 days 
after the final dose of IMP. 
 
Subjects will complete the AE-QOL Questionnaire (Section 15.2.3) and the AECT Questionnaire 
(Section 15.2.2) at Screening Visit, 4 and 8 weeks after the start of dosing, and the final dose. TSQM will 
be completed after the final dose (Section 15.2.4). 
17.4 
Week 2 and 6 (In-clinic or Home Health Visit) 
During the Week 2 and Week 6 visit, the following activities will be performed: 
• 
Vital signs (SBP and DBP, PR, and RR). BP and PR recorded after subject has been resting for 
at least 5 minutes (Section 15.3.2). 
• 
12-lead ECG after subject has been supine for at least 5 minutes (Section 15.3.3). 
• 
Blood and urine samples for clinical laboratory tests (Section 15.3.4). 
• 
Serum pregnancy test (female subjects of childbearing potential). 
• 
Subject eDiary reviewed with re-training, if necessary. 
• 
IMP accountability. 
• 
Concomitant medication review. 
• 
AEs recorded (Section 16). 
17.5 
Week 4 (Brief In-clinic/Site lab Visit or Home Health Visit) 
During the Week 4 visit, a single safety lab sample will be drawn to assess liver enzymes and clinical 
chemistry (Section 15.3.4). This sample can be obtained at a brief in-clinic or site lab visit or can be 
obtained by a Home Health service provider. 
17.6 
Week 12/Early Termination (In-Clinic or Home Health Visits) 
At the Week 12/ET Visit the subject will return to the clinic for the final visit at which the following 
procedures will be conducted: 
• 
Symptom-directed physical examination (Section 15.3.1). 
• 
Vital signs (SBP and DBP, PR, and RR). BP and PR recorded after subject has been resting for 
at least 5 minutes (Section 15.3.2). 
• 
12-lead ECG after subject has been supine for at least 5 minutes (Section 15.3.3). 
• 
Blood and urine samples for clinical laboratory tests (Section 15.3.4). 

 
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• 
Serum pregnancy test (female subjects of childbearing potential). 
• 
Return IMP (or arrange for return if in-clinic visit is not possible). 
• 
AE-QOL Questionnaire collected with the last dose of IMP (Section 15.2.3). 
• 
AECT Questionnaire collected with the last dose of IMP (Section 15.2.1). 
• 
TSQM Questionnaire collected with the last dose of IMP (Section 15.2.4). 
• 
Concomitant medication review. 
• 
AEs recorded (Section 16). 

 
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18. STATISTICAL CONSIDERATIONS 
18.1 
Sample Size Determination 
A total sample size of approximately 48 subjects (~12 randomized per dose-level) will provide at least 
90% power to detect a 70% reduction in the monthly rate of attacks, between each active dose and 
placebo, using a two-sided 5% test, adjusted with Bonferroni correction. This assumes an average of at 
least 2 attacks/4 weeks on placebo and a Poisson distribution with approximately 90% subjects 
completing the 12 weeks. This sample size will also provide more than 80% power to detect a smaller 
effect of 50% reduction in attack rate. In addition, this sample size also ensures nearly 90% power to 
detect a 70% reduction should the attack rate in the placebo group be lower than expected at 1 attack/4 
weeks. It is assumed that the rate of HAE attacks follows a Poisson distribution, therefore, the test for 
the ratio of two Poisson rates was used for the sample size calculation, however, negative binomial 
regression is used as a primary analysis to correct for potential overdispersion in the model. Sample size 
calculations were performed using PASS v20.0.3. 
18.2 
Estimands and Intercurrent Events  
Intercurrent event types (IcEVs) are displayed in Table 4 and estimand(s) with rationale for strategies to 
address IcEVs are summarized in Table 5.  
Table 4: 
Intercurrent Event Types 
Label 
Intercurrent Event Type 
IcEV1 (Death) 
Death from any cause. 
IcEV2 (Discontinue TEAE) 
Discontinuation of IMP due to TEAE or tolerability issue.  
IcEV3 (Discontinue LOE) 
Discontinuation of IMP due to LOE where HAE symptoms are at an 
unacceptable level. 
IcEV4 (Prohibited 
medications) 
Use of prohibited medications that may interfere with outcome (Section 12.2). 
IcEV5 (Treatment change) 
Switch of treatments, or sustained use of other prophylactic medications either 
instead or as additional treatment (i.e. taken for the purpose of prophylaxis 
rather than treating HAE attacks).  
IcEV6 (Discontinue logistical) 
Discontinuation of IMP due to reasons unrelated to treatment such as logistical 
issues (e.g. during pandemic, personal reasons such as moving area or 
burden of clinic visits). 
Abbreviations: HAE=hereditary angioedema; IcEV=Intercurrent event types; IMP=investigational medicinal product; LOE=lack of efficacy; 
TEAE=treatment emergent adverse event.  
 

 
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Table 5: 
Estimand(s) with Rationale for Strategies to Address Intercurrent Events  
Estimand Label 
Primary Estimand  
Estimand Description 
Rate ratio of Investigator-confirmed HAE attacks while on treatment (each of 
the KVD824 dose groups versus placebo)) in subjects with a confirmed 
diagnosis of HAE Type I or II who have at least 1.5 attacks per 4 weeks 
while off prophylactic treatment. Number of attacks will be measured ‘while 
on treatment’ over up to 12 weeks or until their treatment stops or changes 
(expressed as number of attacks on treatment). Subjects receive on-demand 
conventional care for HAE attacks but receipt of additional treatments as a 
prophylactic would constitute a change and the end of the period considered 
‘while on treatment.’  
Target Population 
Subjects with a confirmed diagnosis of HAE Type I or II who have at least 
1.5 attacks per 4 weeks while off prophylactic treatment and would meet 
other trial inclusion criteria. 
Endpoint 
Rate of Investigator-confirmed HAE attacks during the Treatment Period. 
Treatment Condition(s) 
Twice daily oral self-administration: prophylactic KVD824 doses versus 
Reference: placebo, on top of conventional care including on-demand 
treatment for an HAE attack. 
Population-Level Summary 
Rate ratio of HAE attacks while on treatment (each of the KVD824 dose 
groups versus placebo).  
Intercurrent Event Strategy  
 
 IcV1 (Death) 
While on treatment. 
 IcEV2 (Discontinue TEAE) 
While on treatment. 
 IcEV3 (Discontinue LOE) 
While on treatment. 
 IcEV4 (Prohibited medications) 
While on treatment. 
 IcEV5 (Treatment change) 
While on treatment. 
 IcEV6 (Discontinue logistical) 
While on treatment. 
Rationale for Strategies 
The primary focus of this phase 2 trial is to evaluate the attack rate over a 
period while on assigned treatment prior to the occurrence of intercurrent 
events without use of prohibited medications or additional prophylactic 
treatments. In the case of an unacceptable level of attacks or tolerability 
issues resulting in changes to treatment, the measurement period ends.  
Abbreviations: HAE= hereditary angioedema; IcEV=Intercurrent event types; IMP=investigational medicinal product; LOE=lack of efficacy; 
TEAE=treatment emergent adverse event. 
18.3 
Populations for Analyses 
• 
Screened Set includes all subjects who have signed informed consent. 
• 
Enrolled Set includes all subjects who have signed informed consent and begun the Run-In 
Period. 
• 
Randomized Set includes all subjects who are randomized. 
• 
Safety Set (SAF) will include all subjects who are randomized and receive at least one dose of 
IMP. 

 
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• 
Full Analysis Set (FAS) will include all subjects who are randomized, receive at least 1 dose of 
IMP, and have post baseline HAE diary data recorded. Subjects will be analyzed according to 
randomized treatment. The FAS population will be the population for efficacy analyses. 
• 
Per-protocol Set (PPS) includes all subjects from FAS who complete 12 weeks and who do not 
have pre-defined major protocol deviations that may affect primary efficacy endpoint.  
18.4 
General Considerations 
The statistical analysis plan (SAP) and associated templates for tables, listing and figures will be 
developed in a separate document that will provide a technical and detailed elaboration of the principal 
features stated in the protocol and will be developed and finalized prior to trial unblinding. Any deviations 
from the planned analyses will be described and justified in the final Clinical Study Report (CSR). 
 
Summary tables, figure and listings will be created using Version 9.4 (or later) of the SAS® software for 
Microsoft Windows (SAS Institute, Inc., Cary, North Carolina). 
 
The following descriptive statistics will be provided depending on the nature of considered data: 
• 
Qualitative data: number of observed values, number and percentage of subjects per category. 
• 
Quantitative data: number of observed values, mean and standard deviation (SD), median, first 
and third quartiles, minimum, and maximum. 
 
All statistical tests will be 2-sided with an alpha of 0.05. The primary efficacy endpoint analysis will have 
Bonferroni multiplicity adjustment for multiple dose levels, therefore pairwise comparison tests will be 
2-sided with an alpha of 0.0167. The analysis of the secondary or exploratory endpoints will not have 
multiplicity adjustments. 
 
There are 4 treatment groups in the trial:  
1. 
subjects received 300 mg (1 x 300 mg tablet) KVD824 
2. 
subjects received 600 mg (2 x 300 mg tablet) KVD824 
3. 
subjects received 900 mg (3 x 300 mg tablet) KVD824 
4. 
subjects received placebo (all subjects who received matching placebo of 1, 2 or 3 tablets) 
18.4.1 Bonferroni Multiplicity Adjustment 
Bonferroni adjusted significance level is obtained by dividing the original significance level 0.05 by the 
number of comparisons on the attack rate between each KVD824 dose level and placebo (i.e. the 
adjusted significance level is 0.0167 [0.05 divided by 3]). 
18.5 
Analysis of Disposition 
Subject disposition will be presented for all subjects. The number and percentage of subjects who have 
been randomized and included in SAF, FAS, and PPS will be presented by treatment group and overall. 
 
The number and percentage of subjects who prematurely discontinued during the trial will be presented 
for each treatment group and overall, for SAF and FAS. Primary reasons for premature discontinuation 
from the trial will be summarized by treatment group and overall, for SAF and FAS. Subject disposition, 

 
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subjects completing and terminating the trial, and trial analysis sets will be listed by subject for all subjects 
in the Enrolled Set. 
18.6 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics including age, sex, race, ethnicity, height at screening, 
weight at screening, and body mass index (BMI) at screening will be summarized by treatment group 
using descriptive statistics for the SAF and FAS. Baseline attack rates (calculated as the number of 
attacks occurred during the Run-in Period adjusted by time), medical history, HAE history, prior and 
concomitant medication will be summarized by treatment group for the SAF and FAS. 
18.7 
Statistical Analysis of Efficacy Endpoints 
18.7.1 Primary Endpoint(s) 
Primary analysis hypothesis: The null hypothesis is that the rate ratio of investigator-confirmed HAE 
attacks while on treatment (each of the KVD824 dose groups versus placebo) is 1 (no difference between 
active dose and placebo treatment groups) versus the alternative hypothesis that the rate ratio of 
investigator-confirmed HAE attacks while on treatment (each of the KVD824 dose groups versus 
placebo) is not 1. 
 
Table 6 gives a summary of analysis methods, strategy for handling missing data, and sensitivity analysis 
for the primary endpoint. 
 

 
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Table 6: 
Summary of Statistical Methods and Sensitivity Analyses for Primary Endpoint 
Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity/Supplementary 
Analysis 
Analysis 
Set 
Imputation/Data/
Censoring Rules 
Primary Analysis 
Model/Method 
Primary 
Estimand   
Rate ratio of investigator-
confirmed HAE attacks 
while on treatment (each of 
the KVD824 dose groups 
versus placebo) in subjects 
with a confirmed diagnosis 
of HAE Type I or II who 
have at least 1.5 attacks 
per 4 weeks while off 
prophylactic treatment. 
Number of attacks will be 
measured ‘while on 
treatment’ over up to 
12 weeks or until their 
treatment stops or 
changes. Subjects may 
receive on-demand 
conventional care for HAE 
attacks but receipt of 
additional treatments as a 
prophylactic would 
constitute a change and 
the end of the period 
considered ‘while on 
treatment.’  
FAS 
Data after 
occurrence of 
intercurrent 
events will not be 
utilized. 
Negative binomial 
regression with 
randomization stratification 
factor of baseline attack 
rate per 4 weeks during 
run-in period as a fixed 
covariate and treatment as 
a fixed factor and the 
logarithm of time each 
subject was observed 
‘while on treatment’ will be 
used as an offset variable 
in the model. This model 
will be used to estimate 
rate of HAE attacks while 
on treatment and rate ratio 
of HAE attacks (each of the 
KVD824 dose groups 
versus placebo) with 95% 
confidence interval and 2-
sided p-value. 
Sensitivity: For subjects who 
discontinue prematurely from 
Treatment Period or with the data 
censored after an intercurrent 
event, the remaining part of the 
Treatment Period will be imputed 
1,000 times using the bootstrap 
method (Section 18.7.2). 
The same analysis method, 
negative binomial regression model 
will be performed on 1,000 imputed 
bootstrap samples. The results 
from the individual models will be 
combined using Rubin’s formulae 
from PROC MIANALYZE. 
Supplementary: repeat primary 
analysis on PPS. 
 
Abbreviations: FAS=Full Analysis Set; HAE=hereditary angioedema; PPS=Per Protocol Set. 

 
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18.7.2 Multiple Imputation Analysis 
Analysis based on imputing missing values by drop out reason is the sensitivity analysis to the primary 
efficacy analysis. The primary imputation method within this sensitivity analysis is described below. 
 
A subject is considered to have missing values in case he/she discontinues treatment prematurely and 
does not finish the Treatment Period or has an IcEV making the data collected after the IcEV considered 
irrelevant. 
 
Fraction of non-missing data (F) during the Treatment Period is defined as the number of participation 
days divided by 84 (12 x 7 – scheduled length of the 12 weeks Treatment Period). 
 
The observed number of HAE attacks (NAobserved) is the number of HAE attacks recorded in the eDiary 
and observed during the Treatment Period when the subject was on treatment and prior to an intercurrent 
event. 
 
The missing number of HAE attacks (NAimputed) which will be imputed as the number of HAE attacks 
over 12 weeks then adjusted (1 – F) to take into account the fraction of time observed, i.e. to derive the 
number of HAE attacks which would have occurred between drop out and Week 12. 
 
The complete number of HAE attacks (NAcomplete) which will be used for the sensitivity analysis will be 
calculated as 
NAcomplete = (1 – F) x NAimputed +  NAobserved. (Equation 1) 
and rounded up to the nearest integer. 
 
If a subject discontinues prematurely from the Treatment Period, the remaining part of this period will be 
imputed using the bootstrap method: 
1) 
Draw a bootstrap sample with replacement from all FAS subjects of the same treatment group 
with no missing values (the subjects completed 12 weeks Treatment Period) using PROC 
SURVEYSELECT. 
2) 
Use the following rules to calculate the number of missing HAE attacks (NAimputed) for the missing 
data for each bootstrap sample: 
a) Missing data are considered as missing at random (MAR) if the dropout reasons / intercurrent 
events are not related to the IMP (e.g. site closure, personal reasons). For subjects with MAR 
data, the value of missing number of HAE attacks (NAimputed) will be the median of NAobserved 
of all subjects who have complete data within the same treatment group.  
b) Data which are missing due to dropout/intercurrent event for the following reasons are 
considered missing not at random (MNAR): discontinued due to IMP-related AEs, death, or 
lack of efficacy. For subjects with MNAR data, the median (𝑥𝑥෤) of the worst 25% observed data 
of the bootstrap sample from subjects who have complete data within the same treatment 
group will be determined. The value of the NAimputed equals the maximum NAobserved among all 
these subjects if NAobserved > 𝑥𝑥෤, and 𝑥𝑥෤ otherwise. 
c)  Data which are missing because of protocol violations, other, withdrawal by subjects or 
physician decision will be reviewed, and a decision of classifying them into the categories as 
described in a) or b) will be made and documented prior to unblinding.  

 
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3) 
After NAimputed is calculated, the complete number of HAE attacks will be calculated using 
Equation 1 as NAcomplete = NAimputed + NAobserved. The complete bootstrap sample with imputed 
values (NAcomplete) will be analyzed by fitting the primary analysis model. 
4) 
Repeat above 3 steps for 1,000 times.  
5) 
The model summaries will be combined from the 1,000 imputed bootstrap samples using Rubin’s 
rule from PROC MIANALYZE. 
18.7.3 Secondary Endpoint(s) 
No formal hypotheses will be tested for secondary endpoints. All statistical tests for the secondary efficacy 
endpoints will be considered of exploratory nature, pairwise comparisons will be performed between each 
KVD824 dose level and placebo, but no adjustment will be made for multiplicity. 
 
Proportion of subjects without Investigator-confirmed HAE attacks during the Treatment Period will be 
analyzed using logistic regression with treatment as fixed effect and randomization stratification factor as 
a fixed covariate in the model. Rate of Investigator-confirmed HAE attacks that require conventional 
treatment during the Treatment Period will be analyzed using negative binomial regression similar to the 
primary analysis. AE-QoL total score and domain scores during the Treatment Period and AECT score 
and domain scores during the Treatment Period will be analyzed using analysis of variance (ANOVA) or 
analysis of covariance (ANCOVA). Baseline value for the secondary endpoints will be defined as the 
most recent non-missing measurement collected prior to the first dose of IMP. 
 
Proportion of subjects with an AECT score ≥12 at the end of the Treatment Period will be analyzed using 
logistic regression with treatment as fixed effect and randomization stratification factor as a fixed 
covariate in the model. 
 
Additional statistical models may be considered, and details will be provided in the SAP. 
18.7.4 Exploratory Endpoint(s) 
No formal hypotheses will be tested for exploratory endpoints. All statistical tests for the exploratory 
efficacy endpoints will be considered of exploratory nature, pairwise comparisons will be performed 
between each KVD824 dose level and placebo, but no adjustment will be made for multiplicity. 
 
Rate of Investigator-confirmed HAE attacks during the Treatment Period by severity will be analyzed 
using negative binomial regression similar to the primary analysis including additional fixed covariate for 
severity. Rate of conventional treatment used during the Treatment Period will be analyzed using 
negative binomial regression similar to the primary analysis. TSQM total scores at the end of the 
Treatment Period will be analyzed using ANOVA or ANCOVA. Additional statistical models may be 
considered, and details will be provided in the SAP. 
18.8 
Safety Analyses 
Safety analyses will be performed by treatment group using the SAF. Safety endpoints include AE, clinical 
laboratory assessments, vital signs, ECG, and physical examination findings as described in the 
Sections 15.3 and 16.1.  
 
The AEs and SAEs recorded during the trial will be summarized by system organ class (SOC), preferred 
term, and treatment group, and will include the total number of events with number and percentage of 

 
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subjects with AEs. Adverse events and medical history will be coded using the most current version of 
Medical Dictionary for Regulatory Activities (MedDRA). 
 
Summaries of the number and percentage of subjects (and number of events) for AEs, severe AEs, 
SAEs, AEs with an outcome of death, AEs leading to discontinuation of the trial treatment will be provided. 
 
For physical examination, ECG, and laboratory variables (measured by the central laboratory), the 
number and percentage of subjects with normal or abnormal results will be presented at each scheduled 
visits by treatment group. Descriptive statistics for continuous variables will be provided at scheduled 
visits together with a summary of changes from baseline for each parameter by treatment group. Shift 
tables by treatment group will be provided when appropriate. 
18.9 
Interim Analyses 
Not applicable. 

 
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19. TRIAL ADMINISTRATION 
19.1 
Direct Access to Source Data/Documents 
The Investigator will allow Sponsor representatives, authorized regulatory authority inspectors, and the 
EC/IRB to have direct access to all documents pertaining to the trial. 
 
These groups may audit and review source data and will follow local regulations regarding data 
protection. The Investigator will provide support for these audits. 
19.2 
Quality Control and Quality Assurance 
The Sponsor and Contract Research Organization (CRO) will utilize a system of quality assurance. Within 
this system, Standard Operating Procedures (SOPs) from the Sponsor and CRO will be followed to 
ensure the clinical trial is conducted in compliance with regulatory requirements and GCP. Quality control 
will be applied to each stage of data handling. 
19.3 
Ethics 
19.3.1 Regulatory and Ethical Considerations 
The procedures set out in this clinical trial protocol are designed to ensure that the Sponsor and the 
Investigator abide by the principles of the ICH guidelines on GCP, applicable local regulatory 
requirements, and the Declaration of Helsinki (World Medical Association 2013). The clinical trial will also 
follow national and local legal requirements. 
 
The trial protocol and relevant documents will be approved by EC/IRB and Regulatory Authorities. The 
Investigator will provide periodic reports, as required, to the EC/IRB and Regulatory Authorities. 
19.3.2 Informed Consent/Assent 
Informed consent/assent will be obtained from the subject according to the regulatory and legal 
requirements of the participating country. This may be captured electronically or via paper. The 
Investigator will not undertake any investigation specifically required for the clinical trial until valid 
consent/assent has been obtained. 
19.3.3 Subject Confidentiality 
The anonymity of participating subjects must be maintained. Subjects will be specified on trial documents 
by their subject ID, not by name. Documents that identify the subject (e.g. informed consent document) 
must be maintained in confidence by the Investigator per GCP and local regulations. 
 
The Investigator agrees not to use or disclose protected health information other than as permitted or 
required by subject authorization or as required by law. 
19.4 
Data Handling and Record Keeping 
19.4.1 Source Documents 
All source documents from which eCRF entries are derived should be placed in the subject’s trial records. 
Source documents usually may include laboratory assessments, trial specific examinations, and any 
other documents that support the data collected in the eCRF. The Investigator will ensure the accuracy, 

 
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completeness, and timeliness of the data. The review of medical records will be performed in a manner 
to ensure that subject confidentiality is maintained. 
19.4.2 Trial Monitoring 
The Sponsor or Sponsor’s designee will verify the qualifications of each Investigator, site facilities, and 
inform the Investigator of responsibilities and the procedures for ensuring adequate and correct 
documentation. 
 
The Investigator will maintain adequate and accurate records of data pertinent to the clinical trial for each 
trial subject. Frequent communication between the trial site and the Sponsor (or designee) is essential to 
ensure that the trial is monitored adequately.  
 
All aspects of the trial will be carefully monitored with respect to GCP, Sponsor and CRO SOPs, and the 
trial specific Monitoring Plan to ensure compliance with applicable government regulations. The 
Monitor(s) will have access to all records necessary to ensure integrity of the data and will periodically 
review the progress of the trial with the Investigator.  
19.4.3 Database Management 
All data generated by the site personnel will be captured electronically at each trial site using eCRFs. A 
complete audit trail will be maintained of all data changes. 
 
The specific procedures to be used for data entry and query resolution using the eCRF will be provided 
to trial sites. Applicable site personnel will receive training on the eCRF. Edit checks and manual review 
will be used to identify any errors or inconsistencies in the data. 
19.4.4 Retention of Trial Records 
Essential documents, including all trial records, should be retained according to ICH guidelines. These 
documents should be retained for a longer period if required by the applicable local regulations. 
 
If the responsible Investigator retires, relocates or for any other reason withdraws from the responsibility 
of keeping the trial 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. 
19.5 
Financing and Insurance 
19.5.1 Financial Disclosure 
All Investigators and required trial personnel will complete a financial disclosure statement. 
19.5.2 Trial Insurance 
Clinical trial insurance will be maintained per local regulations. 
19.6 
Publication Policy 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted with the 
Sponsor in advance. The rights and obligations of Investigators and the Sponsor concerning any formal 
presentation or publication of data collected as a direct or indirect result of this trial will be addressed 
specifically in the Clinical Trial Agreement for the trial. 

 
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19.7 
Trial Master File 
A Trial Master File (TMF) will be maintained by the Sponsor (or designee). Documents and other 
materials that pertain to the conduct of the trial, quality of the data, and compliance with GCP will be 
collected in the TMF. 
19.8 
Premature Trial Closure 
The Sponsor reserves the right to prematurely terminate or halt the trial either at a particular site or at all 
trial sites at any time after appropriate discussion with the Sponsor and Investigator(s). If the trial is halted 
or terminated for safety reasons, then all Investigators and the relevant Regulatory Agencies will be 
notified per local regulations. The Investigator at each trial site will advise their EC/IRB. 
 

 
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20. REFERENCES 
Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, Rowland CR. Validation of a general 
measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), 
using a national panel study of chronic disease. Health Qual Life Outcomes. 2004 Feb 26;2:12. doi: 
10.1186/1477-7525-2-12.  
Aygören-Pürsün E, Bygum A, Beusterien K, et al. Estimation of EuroQol 5-Dimensions health status utility 
values in hereditary angioedema. Patient Prefer Adherence. 2016 Sep 6;10:1699-707. doi: 
10.2147/PPA.S100383.  
Aygören-Pürsün E, Bygum A, Grivcheva-Panovska V, et al. Oral Plasma Kallikrein Inhibitor for 
Prophylaxis in Hereditary Angioedema. N Engl J Med. 2018 Jul 26;379(4):352-362. doi: 
10.1056/NEJMoa1716995.  
Aygören-Pürsün E, Magerl M, Maetzel A, Maurer M. Epidemiology of Bradykinin-mediated angioedema: 
a systematic investigation of epidemiological studies. Orphanet J Rare Dis. 2018 May 4;13(1):73. doi: 
10.1186/s13023-018-0815-5. 
Banerji A, Busse P, Shennak M, et al. Inhibiting Plasma Kallikrein for Hereditary Angioedema 
Prophylaxis. N Engl J Med. 2017 Feb 23;376(8):717-728. doi: 10.1056/NEJMoa1605767.  
Banerji A, Riedl MA, Bernstein JA, et al. Effect of Lanadelumab Compared with Placebo on Prevention 
of Hereditary Angioedema Attacks: A Randomized Clinical Trial. JAMA. 2018 Nov 27;320(20):2108-2121. 
doi: 10.1001/jama.2018.16773. Erratum in: JAMA. 2019 Apr 23;321(16):1636.  
Bork K, Hardt J, Schicketanz KH, Ressel N. Clinical studies of sudden upper airway obstruction in patients 
with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Intern Med. 2003 May 
26;163(10):1229-35. doi: 10.1001/archinte.163.10.1229. 
Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH 
deficiency. J Allergy Clin Immunol. 2012 Sep;130(3):692-7. doi: 10.1016/j.jaci.2012.05.055. 
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, 
affected organs, and course. Am J Med. 2006 Mar;119(3):267-74. doi: 10.1016/j.amjmed.2005.09.064. 
Caballero T, Aygören-Pürsün E, Bygum A, et al. The humanistic burden of hereditary angioedema: 
results from the Burden of Illness Study in Europe. Allergy Asthma Proc. 2014 Jan-Feb;35(1):47-53. doi: 
10.2500/aap.2013.34.3685. 
Caballero T, Maurer M, Longhurst HJ, et al. Triggers and Prodromal Symptoms of Angioedema Attacks 
in Patients with Hereditary Angioedema. J Investig Allergol Clin Immunol. 2016;26(6):383-386. doi: 
10.18176/jiaci.0102.  
Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary 
angioedema. N Engl J Med. 2010 Aug 5;363(6):523-31. doi: 10.1056/NEJMoa0905079. 
Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema: Absence of 
serum inhibitor of C' 1-esterase. Am J Med. 1963 Jul;35:37-44. doi: 10.1016/0002-9343(63)90162-1. 
Donaldson VH, Rosen FS. Action of complement in hereditary angioneurotic edema: The role of C'1-
Esterase. J Clin Invest. 1964 Nov;43(11):2204-13. doi: 10.1172/JCI105094.  

 
CONFIDENTIAL 
KVD824-201/KVD824 
KOMPLETE Clinical Trial Protocol 
31 March 2022, Version 5.0 
 
Page 64 of 66 
Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: premarketing clinical 
evaluation. US Dept of Health and Human Services, Center for Drug Evaluation and Research, Center 
for Biologics Evaluation and Research, 07/2009. 
Fields T, Ghebrehiwet B, Kaplan AP. Kinin formation in hereditary angioedema plasma: evidence against 
kinin derivation from C2 and in support of "spontaneous" formation of bradykinin. J Allergy Clin Immunol. 
1983 Jul;72(1):54-60. doi: 10.1016/0091-6749(83)90052-0.  
Germenis AE, Speletas M. Genetics of Hereditary Angioedema Revisited. Clin Rev Allergy Immunol. 
2016 Oct;51(2):170-82. doi: 10.1007/s12016-016-8543-x.  
Girolami A, Scarparo P, Candeo N, Lombardi AM. Congenital prekallikrein deficiency. Expert Rev 
Hematol. 2010 Dec;3(6):685-95. doi: 10.1586/ehm.10.69.  
Gösswein T, Kocot A, Emmert G, et al. Mutational spectrum of the C1INH (SERPING1) gene in patients 
with hereditary angioedema. Cytogenet Genome Res. 2008;121(3-4):181-8. doi: 10.1159/000138883.  
Hulström D, Svensjö E. Intravital and electron microscopic study of bradykinin-induced vascular 
permeability changes using FITC-dextran as a tracer. J Pathol. 1979 Nov;129(3):125-33. doi: 
10.1002/path.1711290304.  
Javaud N, Altar A, Fain O, et al. Hereditary angioedema, emergency management of attacks by a call 
center. Eur J Intern Med. 2019 Sep;67:42-46. doi: 10.1016/j.ejim.2019.05.007.  
Javaud N, Bouillet L, Rabetrano H, et al. Hereditary angioedema: Clinical presentation and 
socioeconomic cost of 200 French patients. J Allergy Clin Immunol Pract. 2019 Jan;7(1):328-330. doi: 
10.1016/j.jaip.2018.05.036. 
Kaplan AP, Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an 
innate inflammatory pathway. Adv Immunol. 2014;121:41-89. doi: 10.1016/B978-0-12-800100-
4.00002-7. 
Lumry WR, Craig T, Zuraw B, et al. Health-Related Quality of Life with Subcutaneous C1-Inhibitor for 
Prevention of Attacks of Hereditary Angioedema. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1733-
1741.e3. doi: 10.1016/j.jaip.2017.12.039. 
Maurer M, Bork K, Martinez-Saguer I, et al. Management of patients with hereditary angioedema in 
Germany: comparison with other countries in the Icatibant Outcome Survey. J Eur Acad Dermatol 
Venereol. 2019 Jan;33(1):163-169. doi: 10.1111/jdv.15232. 
Nordenfelt P, Nilsson M, Björkander J, Mallbris L, Lindfors A, Wahlgren CF. Hereditary Angioedema in 
Swedish Adults: Report From the National Cohort. Acta Derm Venereol. 2016 May;96(4):540-5. doi: 
10.2340/00015555-2274.  
Nordenfelt P, Nilsson M, Lindfors A, Wahlgren CF, Björkander J. Health-related quality of life in relation 
to disease activity in adults with hereditary angioedema in Sweden. Allergy Asthma Proc. 2017 Nov 
30;38(6):447-455. doi: 10.2500/aap.2017.38.4087.  
Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-
oedema. Lancet. 1998 Jun 6;351(9117):1693-7. doi: 10.1016/S0140-6736(97)09137-X.  

 
CONFIDENTIAL 
KVD824-201/KVD824 
KOMPLETE Clinical Trial Protocol 
31 March 2022, Version 5.0 
 
Page 65 of 66 
Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-
oedema. Lancet. 1998 Jun 6;351(9117):1693-7. doi: 10.1016/S0140-6736(97)09137-X. 
Nussberger J, Cugno M, Cicardi M, Agostoni A. Local bradykinin generation in hereditary angioedema. 
J Allergy Clin Immunol. 1999 Dec;104(6):1321-2. doi: 10.1016/s0091-6749(99)70030-8.  
Nussberger J, Cugno M, Cicardi M. Bradykinin-mediated angioedema. N Engl J Med. 2002 Aug 
22;347(8):621-2. doi: 10.1056/NEJM200208223470820.  
Rosen FS, Alper CA, Pensky J, Klemperer MR, Donaldson VH. Genetically determined heterogeneity of 
the C1 esterase inhibitor in patients with hereditary angioneurotic edema. J Clin Invest. 1971 
Oct;50(10):2143-9. doi: 10.1172/JCI106708.  
Rosen FS, Pensky J, Donaldson V, Charache P. Hereditary angioneurotic edema: Two genetic variants. 
Science. 1965 May 14;148(3672):957-8. doi: 10.1126/science.148.3672.957.  
Rosen FS, Pensky J, Donaldson V, Charache P. Hereditary angioneurotic edema: two genetic variants. 
Science. 1965 May 14;148(3672):957-8. doi: 10.1126/science.148.3672.957.  
Sheffer AL, Campion M, Levy RJ, Li HH, Horn PT, Pullman WE. Ecallantide (DX-88) for acute hereditary 
angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies. J Allergy Clin Immunol. 2011 
Jul;128(1):153-159.e4. doi: 10.1016/j.jaci.2011.03.006.  
US Department of Health and Human Services, Food and Drug Administration, Center for Biologics 
Evaluation and Research. Guidance for Industry. Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials., September 2007. 
Weller K, Donoso T, Magerl M, et al. Development of the Angioedema Control Test-A patient-reported 
outcome measure that assesses disease control in patients with recurrent angioedema. Allergy. 2020 
May;75(5):1165-1177. doi: 10.1111/all.14144. 
Weller K, Donoso T, Magerl M, et al. Validation of the Angioedema Control Test (AECT)-A Patient-
Reported Outcome Instrument for Assessing Angioedema Control. J Allergy Clin Immunol Pract. 2020 
Jun;8(6):2050-2057.e4. doi: 10.1016/j.jaip.2020.02.038. 
Weller K, Donoso T, Magerl M, et al. Validation of the Angioedema Control Test (AECT)-A Patient-
Reported Outcome Instrument for Assessing Angioedema Control. J Allergy Clin Immunol Pract. 2020 
Jun;8(6):2050-2057.e4. doi: 10.1016/j.jaip.2020.02.038. 
Weller K, Groffik A, Magerl M, et al. Development and construct validation of the angioedema quality of 
life questionnaire. Allergy. 2012 Oct;67(10):1289-98. doi: 10.1111/all.12007.  
Weller K, Magerl M, Peveling-Oberhag A, Martus P, Staubach P, Maurer M. The Angioedema Quality of 
Life Questionnaire (AE-QoL) - assessment of sensitivity to change and minimal clinically important 
difference. Allergy. 2016 Aug;71(8):1203-9. doi: 10.1111/all.12900. 
World Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for 
Medical 
Research 
Involving 
Human 
Subjects. 
JAMA. 
2013;310(20):2191–2194. 
doi:10.1001/jama.2013.281053. 
Zanichelli A, Arcoleo F, Barca MP, et al. A nationwide survey of hereditary angioedema due to C1 inhibitor 
deficiency in Italy. Orphanet J Rare Dis. 2015 Feb 6;10:11. doi: 10.1186/s13023-015-0233-x. 

 
CONFIDENTIAL 
KVD824-201/KVD824 
KOMPLETE Clinical Trial Protocol 
31 March 2022, Version 5.0 
 
Page 66 of 66 
Zimmerman HJ. The spectrum of hepatotoxicity. Perspect Biol Med. 1968 Autumn;12(1):135-61. 
Zuraw B, Lumry WR, Johnston DT, et al. Oral once-daily berotralstat for the prevention of hereditary 
angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin 
Immunol. 2020 Oct 21:S0091-6749(20)31484-6. doi: 10.1016/j.jaci.2020.10.015.