A Randomized, Double-blind, Placebo-controlled, Phase II, Cross-over Clinical Trial Evaluating the Efficacy and Safety of KVD900, an Oral Plasma Kallikrein Inhibitor, in the On-demand Treatment of Angioedema Attacks in Adult Subjects With Hereditary Angioedema Type I or II
Phase: PHASE2
Conditions: Hereditary Angioedema
Sponsor: KalVista Pharmaceuticals, Ltd.

KalVista Pharmaceuticals, Ltd. 
Clinical Study Protocol 
KVD900-201 
CONFIDENTIAL 
PROTOCOL TITLE 
A randomized, double-blind, placebo-controlled, phase II, cross-over clinical trial evaluating the 
efficacy and safety of KVD900, an oral plasma kallikrein inhibitor, in the on-demand treatment of 
angioedema attacks in adult subjects with hereditary angioedema type I or II 
Sponsor: 
KalVista Pharmaceuticals, Ltd. 
Porton Science Park 
Bybrook Road 
Porton Down 
Salisbury, SP4 0BF 
United Kingdom 
Clinical Research Organization: 
Orion Clinical Services Ltd (Orion) 
7 Bath Road, Slough 
Berkshire SL1 3UA 
United Kingdom 
Sponsor Protocol No.: 
KVD900-201 
IND No.: 
143807 
EudraCT number: 
2018-004489-32 
Study Drug Name: 
KVD900 100 mg Film Coated Tablet 
Development Phase: 
2 
Date of Protocol: 
24 November 2020, Final V5.3 (US only) 
Date of Previous Protocol: 
24 March 2020, Final V4.3 (US only) 
The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), with the Declaration of Helsinki and with other applicable regulatory 
requirements. 
This document contains confidential information of KalVista Pharmaceuticals, Ltd. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 
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SIGNATURE PAGE 
Clinical Study Protocol 
CONFIDENTIAL 
Title: A randomized, double-blind, placebo-controlled, phase II, cross-over clinical trial 
evaluating the efficacy and safety of KVD900, an oral plasma kallikrein inhibitor, in the 
on-demand treatment of angioedema attacks in adult subjects with hereditary angioedema type 
I or II 
This study protocol was subjected to critical review. The information it contains is consistent with 
current knowledge of the risks and benefits of the investigation al medicinal product, as well as 
with the moral, ethical, and scientific principles governing clinical research as set out in the 
· 
of Helsinki (2013), and the guidelines on Good Clinical Practice (GCP). 
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Clinical Study Protocol 
KVD900-201 
CONFIDENTIAL 
Declaration of the Investigator 
Title: A randomized, double-blind, placebo-controlled, phase II, cross-over clinical trial 
evaluating the efficacy and safety of KVD900, an oral plasma kallikrein inhibitor, in the 
on-demand treatment of angioedema attacks in adult subjects with hereditary angioedema type 
I or II 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure (IB), electronic case report form (eCRF), and other scientific 
data. 
The study will not be commenced without the prior written approval of a properly constituted 
Independent Ethics Committee (IEC)/ Institutional Review Board (IRB). No substantial changes 
will be made to the study protocol without the prior written approval of the Sponsor and the IEC/ 
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. 
Responsible Investigator of the local study centre 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
Phone number 
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Clinical Study Protocol 
KVD900-201 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Title 
A randomized, double-blind, placebo-controlled, phase II, cross-over 
clinical trial evaluating the efficacy and safety of KVD900, an oral plasma 
kallikrein inhibitor, in the on-demand treatment of angioedema attacks in 
adult subjects with hereditary angioedema type I or II. 
Sponsor Study 
No. 
KVD900-201 
Phase 
2 
Sponsor 
KalVista Pharmaceuticals Ltd 
Study Centre(s) 
Multiple clinical sites in Europe and US 
Objectives 
Primary Objective: 
• 
To investigate the efficacy of KVD900 compared to placebo in 
halting the progression of a peripheral or abdominal attack of 
hereditary angioedema (HAE). 
Secondary Objectives: 
• 
To investigate the safety and tolerability of KVD900. 
• 
To investigate the pharmacokinetic (PK) profile of KVD900 when 
taken during the intercritical period between HAE attacks. 
• 
To investigate the pharmacodynamic (PD) profile of KVD900 in 
reducing the concentration of residual cleaved high molecular 
weight kininogen (HK) during the intercritical period between 
HAE attacks. 
• 
To investigate the PD profile of KVD900 in reducing activated 
plasma enzyme activity during the intercritical period between 
HAE attacks. 
Note: Subjects enrolled at US study sites will not contribute data for PK 
and PD analysis. 
Setup 
This is a phase 2, two-part, two-sequence, two-period (2x2) cross-over 
clinical trial: Subjects with HAE type I or II will be recruited through HAE 
treatment centres in Europe and US. 
In Part 1, subjects will receive a single oral dose of 600 mg KVD900 to 
investigate the safety of KVD900 during the intercritical period between 
HAE attacks. 
Eligible adult subjects ≥18 years old will undergo a screening assessment 
for study inclusion, receive study drug, followed by a 4h, in-clinic, safety 
assessment. 
In Part 2, the subjects will be randomized 1:1 to 2 treatment sequences. 
This part of the study will be conducted away from the clinic or hospital. 
In Sequence 1 (study arm 1) subjects will receive a single dose of 600 mg 
KVD900 to treat the first eligible HAE attack. Following resolution of this 
attack, subjects will receive a second single dose of placebo to treat the 
second eligible HAE attack. 
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In Sequence 2 (study arm 2) subjects will receive a single dose of placebo 
to treat the first eligible HAE attack. Following resolution of this attack, 
subjects will receive a second single dose of 600 mg KVD900 to treat the 
second eligible HAE attack. 
A minimum of 48-hour washout period required between each dose of 
study drug. 
Laryngeal or facial attacks are not eligible for treatment. HAE attacks must 
be treated within the first hour of onset and before reaching severe on the 
global attack severity scale. Subjects must also be able to identify the start 
of a HAE attack. Upon onset of the eligible HAE attack, subjects will notify 
the dedicated study physician or qualified designee with a description of 
the HAE attack. The dedicated study physician or qualified designee will 
confirm eligibility of the HAE attack and agree to study drug being 
administered. HAE attacks require documentation, on the Subject Diary, of 
attack location, attack symptoms, time of onset, attack severity, and time 
of last substantial meal prior to dosing. Subjects will take study drug, as 
instructed, and will complete timed assessments of their HAE attack 
symptoms for a 48h period as documented below in Table 1 (S). The 
dedicated study physician or qualified designee will contact the subject 
within 24h of the eligible HAE attack to confirm the subject’s safety and 
wellbeing. Subjects will be instructed to contact the dedicated study 
physician or qualified designee in case of any safety concerns. In the case 
of hypersensitivity, subjects are to contact the dedicated study physician 
or qualified designee or contact the nearest emergency service. The 
dedicated study physician or qualified designee will be available 24h/day 
and 7 days/week to receive subject calls. 
Table 1 (S): 
Frequency of Subject Assessment 
Time Period following 
Frequency of Subject 
Allowed Time Window 
Study Drug 
Assessment* 
for Assessment 
Administration 
0h – 4h 
Every 30 min 
None 
4h – 12h 
Every 1h 
+/- 15 min 
12h – 24h 
Every 3h 
+/- 30 min 
36h 
Once 
+/- 60 min 
48h 
Once 
+/- 60 min 
*In the event that conventional attack treatment is used, the subject should 
perform assessments every 30 min for 4 h following first administration of 
conventional attack treatment. After this, the subject should revert back to original 
frequency of assessments based on time of study drug administration. 
Subjects will return to the clinic following the first HAE attack, prior to the 
second HAE attack, to undergo safety checks including adverse 
event (AE) reporting, vital sign recording, and Subject Diary review. 
Once two HAE attacks have been treated in Part 2, the subject will return 
to the clinic to undergo final safety checks including AE reporting, vital sign 
recording and blood sampling for laboratory safety measurements. 
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Conventional attack treatment is permitted after 4h, or earlier as 
warranted, following study drug intake, provided HAE attack symptoms are 
judged severe enough by the subject to require treatment as per the 
subject’s usual treatment regimen, or are deemed ineligible for study drug 
treatment, or are associated with laryngeal or facial symptoms. Prior to 
use of conventional attack treatment, subjects will notify the dedicated 
study physician or qualified designee who will confirm conventional 
treatment is appropriate per protocol and subject report of symptom 
severity. Subjects are permitted to treat their HAE attacks with their 
conventional attack treatment (pdC1INH or rhC1INH intravenous [iv] or 
icatibant). 
Investigational 
Medicinal 
Product 
KVD900 100 mg Film-Coated Tablet. 
Placebo to KVD900 100 mg Film-Coated Tablet. 
No study drug dose modifications are allowed in this study. 
Number of 
Subjects 
Approximately 60 subjects will be enrolled into the study to ensure 
approximately 50 subjects complete the study. 
Population 
The study population will include male and female subjects 18 years of 
age or older with HAE type I or II. 
Inclusion Criteria: 
1. Male or female adult subjects 18 years of age and older. 
2. Confirmed diagnosis of HAE type I or II at anytime in the medical 
history: 
a. Documented clinical history consistent with HAE 
(subcutaneous or mucosal, nonpruritic swelling episodes 
without accompanying urticaria) AND 
b. C1-esterase inhibitor (C1-INH) antigen or functional level < 
40% of the normal level. Subjects with antigen or functional 
C1-INH level 40-50% of the normal level may be enrolled if 
they also have a C4 level below the normal range and a 
family history consistent with HAE type I or II. 
3. At least 3 documented HAE attacks in the past 93 days, as 
supported by medical history. 
4. Access to and ability to use conventional attack treatment for 
attacks of HAE. 
5. Adequate organ functions as defined below: 
a. Hemoglobin within normal range; 
b. International normalized ratio (INR)< 1.2; 
c. Activated partial thromboplastin time (aPTT) ≤ upper limit of 
normal (ULN); 
d. Creatinine < 1x ULN; 
e. Creatinine clearance (CrCl) ≥ 60 mL/min; 
f. 
Alanine aminotransferase (ALT) ≤ 2x ULN; 
g. Aspartate aminotransferase (AST) ≤ 2x ULN; 
h. Total bilirubin ≤ 1.5x ULN; 
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i. 
Leucocytes ≤ 1.5x ULN; 
j. 
Thrombocytes ≤ 1.5x ULN. 
6. Female of childbearing potential must agree to use highly effective 
birth control from the Screening visit until the end of the trial follow-
up procedures. 
Highly effective methods of birth control include: 
a. Progestogen-only hormonal contraception associated with 
inhibition of ovulation: oral / injectable / implantable. 
(Hormonal contraception that contains estrogen is excluded 
per exclusion criterion 3). 
b. Intrauterine device (IUD). 
c. Intrauterine hormone–releasing system (IUS). 
d. Bilateral tubal occlusion. 
e. Vasectomised partner (provided that the partner is the sole 
sexual partner of the female subject of childbearing 
potential and that the vasectomised partner has received 
medical assessment of the surgical success). 
f. 
Sexual abstinence (this method is not acceptable in 
Switzerland). 
Note: Sexual abstinence will only be considered a highly effective 
method if it is defined as refraining from heterosexual intercourse. 
The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and 
usual lifestyle of the subject. 
7. Females of non-childbearing potential, defined as surgically sterile 
(status post hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation) or post-menopausal for at least 12 months, do not require 
contraception during the study. 
8. Males with female partners of childbearing potential must agree to 
be abstinent or else use a highly effective method of birth control 
as defined in inclusion criterion 6 from the Screening visit until the 
end of the trial follow-up procedures. 
9. Provide signed informed consent and are willing and capable of 
complying with study requirements and procedures. 
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Exclusion Criteria: 
1. Any concomitant diagnosis of another form of chronic angioedema, 
such as acquired C1 inhibitor deficiency, HAE with normal C1-INH 
(also known as HAE type III), idiopathic angioedema, or 
angioedema associated with urticaria. 
2. Current use of C1INH, androgens, lanadelumab or tranexamic acid 
for HAE prophylaxis. 
3. Use of angiotensin-converting enzyme (ACE) inhibitors or any 
estrogen-containing medications with systemic absorption (such as 
oral contraceptives or hormonal replacement therapy) within 
93 days prior to initial study treatment. 
4. Use of androgens (e.g. stanozolol, danazol, oxandrolone, 
methyltestosterones, testosterone) or antifibrinolytics within 30 
days prior to initial study treatment. 
5. Use of lanadelumab within 10 weeks prior to initial study treatment. 
6. Use of strong CYP3A4/CYP2C9 inhibitors and inducers during 
participation in the trial. 
Note: These medications include but are not limited to the following: 
cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, 
voriconazole, ritonavir, boceprevir, telaprevir, troleandomycin, 
clarithromycin, carbamazepine, enzalutamide, mitotane, phenytoin, 
phenobarbital, fluconazole, isoniazid, metronidazole, paroxetine, 
sulfamethoxazole, rifampicin, St. John’s Wort, diltiazem, idelalisib, 
nefazodone and nelfinavir. 
7. Clinically significant abnormal electrocardiogram (ECG) at Visit 1 
and pre-dose at Visit 2. This includes, but is not limited to, a 
QTcF > 470 msec (for women) or > 450 msec (for men), a 
PR > 220 msec or ventricular and/or atrial premature contractions 
that are more frequent than occasional and/or occur as couplets or 
higher in grouping. 
8. Any clinically significant history of angina, myocardial infarction, 
syncope, clinically significant cardiac arrhythmias, left ventricular 
hypertrophy, cardiomyopathy, or any other cardiovascular 
abnormality. 
9. Any other systemic dysfunction (e.g., gastrointestinal, renal, 
respiratory, cardiovascular) or significant disease or disorder 
which, in the opinion of the Investigator, would jeopardize the 
safety of the subject by taking part in the trial. 
10. History of substance abuse or dependence that would interefere 
with the completion of the study, as determined by the Investigator. 
11. Known lactose allergy or intolerance. 
12. Known hypersensitivity to KVD900 or placebo or to any of the 
excipients. 
13. Participation in an interventional investigational clinical study within 
93 days or within 5 half-lives of the last dosing of investigational 
drug (whichever is longer) prior to initial study treatment. 
14. Any pregnant or breast-feeding subject. 
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Assessments 
Criteria for 
Evaluation of 
Efficacy 
Part 1: Vital signs (systolic blood pressure [SBP], diastolic blood pressure 
[DBP], pulse rate [PR], respiratory rate [RR] and body temperature) will be 
measured at pre-dose (0h), 1h, and 4h post-dose. Samples for post-
treatment safety laboratory assessments will be taken at 4h post-dose. 
Part 2: Following study drug intake, subject assessments of overall 
HAE attack severity and change in HAE attack severity will take place for 
a 48h period as documented in Table 1 (S). 
Efficacy Variables: 
Time to use of conventional attack treatment will be assessed. The subject 
diary will capture the efficacy endpoints including time to use of 
conventional attack treatment and HAE attack severity. 
Overall HAE attack severity will be assessed on the Patient Global 
Impression of Severity (PGI-S) 5-point Likert scale (5LS) scored as none, 
mild, moderate, severe and very severe. 
Change in HAE attack severity will be assessed using the Patient Global 
Impression of Change (PGI-C) 7-point transition question (7TQ), scored as 
Much better / Better / A little better / No change / A little worse / Worse / 
Much worse. 
The type of HAE attack symptoms (abdominal pain, skin pain and skin 
swelling) will each be assessed on a 100 mm visual analogue scale (VAS) 
anchored at 0 (none) and 100 (very severe). 
Safety Variables: 
• 
AEs, including serious adverse events (SAEs). 
• 
Laboratory test results (clinical chemistry, hematology, coagulation, 
and urinalysis). 
• 
Vital signs (SBP, DBP, PR, RR, body temperature). 
• 
Physical examination findings. 
• 
ECG results. 
• 
Pregnancy test (female subjects of child-bearing potential). 
Primary Efficacy Endpoints: 
• 
Time to use of conventional attack treatment within 12h of study drug. 
Secondary Efficacy Endpoints: 
• 
PGI-S (5LS) 
o Worsening (including use of conventional attack treatment) 
• 
Proportion of HAE attacks that (1) worsen by one level or more 
from baseline or (2) use conventional attack treatment within 
12h of study drug 
• 
Time to (1) worsening by one level or more from baseline, or 
(2) use of conventional attack treatment, whichever comes first 
within 12h of study drug 
• 
PGI-C (7TQ) 
o Improvement 
• 
Time to symptom relief (A little better or higher, 2 time points in 
a row) within 12h of study drug 
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• 
Visual Analogue Scale (VAS) 
o Improvement 
• 
Time to symptom relief (50% reduction from baseline in 
composite VAS, 3 time points in a row) within 12h of study 
drug. 
Exploratory Endpoints: 
• 
Use of Conventional Treatment 
o Proportion of HAE attacks that require conventional attack 
treatment within 12h and 24h of study drug 
o Time to use of conventional attack treatment within 24h of study 
drug 
• 
PGI-S (5LS) 
o Area Under the Curve (AUC) 
• 
Cumulative PGI-S (5LS) expressed as AUC within 12h and 24h 
of study drug 
o Worsening (including use of conventional attack treatment) 
• 
Proportion of HAE attacks that (1) worsen by one level or more 
from baseline or (2) use of conventional attack treatment within 
24h of study drug 
• 
Time to (1) worsening by one level or more from baseline or (2) 
use of conventional attack treatment, whichever comes first, 
within 24h of study drug 
o Worsening Only 
• 
Time to worsening by one level or more from baseline within 
12h and 24h of study drug 
o Improvement 
• 
Proportion of HAE attacks that improve by one level or more 
from baseline within 12h and 24h of study drug 
• 
Time to improvement by one level or more from baseline within 
12h and 24h of study drug 
• 
Proportion of subjects with HAE attack resolution (rating of 
none) within 12h and 24h of study drug 
• 
Time to HAE attack resolution (rating of none) within 12h and 
24h of study drug 
o Stable or Improvement 
• 
Proportion of HAE attacks that are stable or improved from 
baseline within 12h and 24h of study drug 
• 
PGI-C (7TQ) 
o AUC 
• 
Cumulative PGI-C (7TQ) expressed as AUC within 12h and 
24h of study drug 
o Worsening (including use of conventional attack treatment) 
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• 
Proportion of HAE attacks that are (1) rated A little worse or 
higher, 2 time points in a row or (2) use of conventional attack 
treatment within 12h and 24h of study drug 
• 
Time to HAE attack being (1) rated A little worse or higher, 2 
time points in a row, or (2) use of conventional attack 
treatment, whichever comes first, within 12h and 24h of study 
drug 
o Worsening Only 
• 
Time to HAE attack being rated A little worse or higher, 2 time 
points in a row, within 12h and 24h of study drug 
o Improvement 
• 
Proportion of HAE attacks that are rated A little better or higher, 
2 time points in a row, within 12h and 24h of study drug 
• 
Time to HAE attack being rated A little better or higher, 2 time 
points in a row, within 24h of study drug 
• 
Proportion of HAE attacks that are rated Better or higher within 
12h and 24h of study drug 
• 
Time to HAE attack being rated Better or higher within 12h and 
24h of study drug 
o Stable or Improvement 
• 
Proportion of HAE attacks that are stable or improved within 
12h and 24h of study drug 
• 
Visual Analogue Scale (VAS) 
o AUC 
• 
Cumulative composite VAS expressed as AUC within 12h and 
24h of study drug  
o Improvement 
• 
Proportion of HAE attacks with symptom relief (50% reduction 
from baseline in composite VAS, 3 time points in a row) within 
12h and 24h of study drug 
• 
Time to symptom relief (50% reduction in composite VAS, 3 
time points in a row) within 24h of study drug 
General 
Statistical 
Methods and 
Types of
Analyses 
Analysis Sets: 
• 
Safety set (SAF): Subjects who have taken at least one dose of study 
drug (including the study drug dose in Part 1). 
• 
Full analysis set (for efficacy) (FAS): All randomized subjects who 
received both doses of study drug in Part 2. 
• 
Per protocol set (for efficacy) (PPS): Randomized subjects in Part 2 
who received KVD900 both doses of study drug in Part 2 and have 
no major protocol deviations. 
• 
PK / PD analysis set: All subjects for whom PK / PD samples were 
taken in Part 1. (Note: Subjects enrolled at US study sites will not 
contribute data for PK and PD analysis.) 
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Final, Version 5.3 
Sample Size: 
A sample size of approximately 50 subjects (25 per sequence) is proposed 
to provide 90% power for testing at the 5% alpha level (2-sided) for the 
primary endpoint of time to use of conventional attack treatment within 12h 
of stud dru . 
1 
1 
• 
imately 60 
subjects will be enrolled to ensure that approximately 50 subjects 
complete the study. 
An oversampling by 20% (10 subjects) is proposed to account for subjects 
that may not complete both treatment periods due to infrequent or 
ineligible HAE attacks or for subjects who discontinue the trial early, for 
whatever reason. Thus, study enrolment will be considered sufficient to 
address the primary efficacy hypothesis after approximately 50 subjects 
have completed both treatment periods. Since further exposure is not 
required and could be considered unnecessary, ongoing subjects who 
have not completed both periods will be asked to return to the study site 
and complete Visit 4 (Early Discontinuation visit). Data from all subjects, 
complete and incomplete, will be analyzed in the safety set. 
General Considerations: 
Individual subject data will be presented in subject data listings. 
Appropriate descriptive statistics will be calculated for continuous and 
categorical data and summarized in tabular format. 
Safety Analyses: 
AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary (v21.0 or higher) and classified by 
preferred term and system organ class (SOC). Listings of treatment-
emergent adverse events (TEAEs), serious TEAEs, and TEAEs causing 
premature discontinuation will be provided by treatment group, and further 
classified by TEAE severity and relationship to study drug. 
Efficacy Analyses: 
Primary Endpoint 
The primary endpoint, time to use of conventional attack treatment within 
12h of stud dru 
onal 
attack treatment is not used within 12h of study drug administration. 
Secondary Endpoints 
For comparisons of proportions 
will be used to 
compare the treatment arms. 
Secondary and exploratory endpoints, using time to event as the unit of 
analysis, will be analyzed using a similar approach to that used for the 
primary endpoint. 
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Note: Subjects enrolled at US study sites will not contribute data for PK 
and PD analysis. 
PK Analysis: 
Non-compartmental PK parameters will include, but are not limited to, 
maximum concentration in plasma (Cmax), time to reach Cmax in plasma 
(tmax), area under the curve from time 0 to last measurable concentration 
(AUC0-t), apparent clearance (CL/F), apparent volume of distribution 
(Vd/F) and estimated terminal elimination half-life (t½). 
The PK parameters of KVD900 will be determined from the individual 
concentration versus time data using Phoenix WinNonlin. In case of a 
deviation from the theoretical time, the actual time of blood sample will be 
used in the calculation of the derived PK parameters. Individual 
concentrations and derived PK parameters of KVD900 in plasma will be 
listed and summarized for each treatment. Individual and geometric mean 
concentration-time data will be plotted on linear and semi-logarithmic 
scales. 
PD Analysis: 
KVD900’s effect on plasma kallikrein (PKa) activity will be analyzed using 
two exploratory measures of PKa enzyme activity in plasma: 
• 
An assay to determine inhibition of exogenously activated plasma 
kallikrein enzyme activity from plasma samples obtained before and 
after receiving KVD900. 
• 
An assay to measure the level of protection of cleavage of high 
molecular weight kininogen (HK) substrate (contained in whole 
plasma) from plasma kallikrein enzyme activity. 
The PD will be summarized for each treatment. Individual and mean data 
will be provided as a report addendum located in the appendix of the final 
Clinical Study Report. 
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LIST OF STUDY PERSONNEL 
Sponsor 
Contract Research 
Organization and Medical 
Monitoring 
Final, Version 5.3 
KalVista Pharmaceuticals, Ltd. 
Porton Science Park 
Bybrook Road 
Porton Down 
Salisbury, SP4 0BF 
United Kingdom 
Orion Clinical Services Ltd (Orion) 
7 Bath Road, Slough 
Berkshire SL 1 3UA 
United Kingdom 
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TABLE OF CONTENTS 
CHANGES FROM LOCAL PROTOCOL VERSION 4.3 TO VERSION 5.3 AND 
RATIONALE FOR THESE CHANGES ................................................................. 4 
PROTOCOL SYNOPSIS .................................................................................................. 8 
LIST OF STUDY PERSONNEL ...................................................................................... 18 
TABLE OF CONTENTS ................................................................................................. 19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................... 22 
1 
INTRODUCTION AND BACKGROUND ............................................................. 25 
 
Rationale for the Study ................................................................................ 25 
 
Benefit Risk Assessment ............................................................................. 25 
2 
STUDY OBJECTIVES ........................................................................................ 27 
 
Primary Objective ......................................................................................... 27 
 
Secondary Objective(s) ................................................................................ 27 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ............................................. 28 
 
Overview ........................................................................................................ 28 
 
Criteria for Evaluation of the Study ............................................................ 31 
3.2.1 
Efficacy Endpoints ............................................................................. 31 
3.2.2 
Safety Endpoints ............................................................................... 33 
 
Justification of the Study Design ................................................................ 33 
4 
STUDY POPULATION ....................................................................................... 34 
 
Inclusion Criteria .......................................................................................... 34 
 
Exclusion Criteria ......................................................................................... 35 
 
Subject Withdrawal ...................................................................................... 36 
4.3.1 
Withdrawal from Study ...................................................................... 36 
4.3.2 
Withdrawal from Treatment ............................................................... 37 
4.3.3 
Lost to Follow-up ............................................................................... 37 
4.3.4 
Withdrawal Procedures ..................................................................... 37 
 
Planned Sample Size and Number of Study Centres ................................ 38 
 
Subject Identification and Randomization ................................................. 38 
4.5.1 
Subject Identification ......................................................................... 38 
4.5.2 
Randomization Scheme .................................................................... 38 
4.5.3 
Allocation / Randomization of Subjects to Treatment ........................ 38 
5 
STUDY DRUG .................................................................................................... 39 
 
Identity ........................................................................................................... 39 
 
Administration .............................................................................................. 39 
 
Packaging, Labelling and Storage .............................................................. 39 
 
Blinding and Breaking the Blind ................................................................. 40 
 
Drug Accountability ..................................................................................... 40 
 
Compliance ................................................................................................... 41 
 
Concomitant Medications / Therapy ........................................................... 41 
 
Conventional Attack Treatment .................................................................. 42 
6 
VARIABLES AND METHODS OF ASSESSMENT ............................................ 43 
 
Efficacy Variables ......................................................................................... 43 
1.1 
1.2 
2.1 
2.2 
3.1 
3.2 
3.3 
4.1 
4.2 
4.3 
4.4 
4.5 
5.1 
5.2 
5.3 
5.4 
5.5 
5.6 
5.7 
5.8 
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Safety Variables ............................................................................................ 43 
6.2.1 
Adverse Events ................................................................................. 43 
6.2.2 
Laboratory Variables ......................................................................... 47 
 
Methods of Assessment .............................................................................. 49 
6.3.1 
Subject Demography ......................................................................... 49 
6.3.2 
Medical History .................................................................................. 49 
6.3.3 
Previous and Concomitant Medications ............................................ 49 
6.3.4 
Vital Signs .......................................................................................... 50 
6.3.5 
Physical Examinations ....................................................................... 50 
6.3.6 
Electrocardiogram ............................................................................. 50 
6.3.7 
Safety Laboratory Assessments ........................................................ 50 
6.3.8 
Efficacy Assessments ........................................................................ 50 
6.3.9 
Pharmacokinetic Blood Sampling ...................................................... 51 
6.3.10 
Pharmacodynamic Assessments ...................................................... 51 
7 
STUDY CONDUCT ............................................................................................. 52 
 
Schedule of Procedures .............................................................................. 52 
 
Procedures by Visit ...................................................................................... 54 
7.2.1 
Screening Phase ............................................................................... 54 
7.2.2 
Treatment Phase ............................................................................... 54 
7.2.3 
End of Study / Early Discontinuation ................................................. 57 
7.2.4 
Early Discontinuation / Withdrawal .................................................... 57 
8 
STATISTICAL METHODS .................................................................................. 58 
 
Study Subjects .............................................................................................. 58 
8.1.1 
Disposition of Subjects ...................................................................... 58 
8.1.2 
Protocol Deviations ............................................................................ 58 
8.1.3 
Analysis Sets ..................................................................................... 58 
 
General Considerations ............................................................................... 59 
 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications ................................................................................................... 59 
 
Treatment Compliance ................................................................................. 60 
 
Efficacy Analyses ......................................................................................... 60 
8.5.1 
Primary Efficacy Analysis .................................................................. 60 
8.5.2 
Secondary and Exploratory Efficacy Analyses .................................. 60 
 
Safety Analyses ............................................................................................ 62 
8.6.1 
Adverse Events ................................................................................. 62 
8.6.2 
Laboratory Assessments ................................................................... 63 
8.6.3 
Vital Signs .......................................................................................... 63 
8.6.4 
Physical Examination ........................................................................ 64 
8.6.5 
Electrocardiograms ............................................................................ 64 
 
Pharmacokinetic / Pharmacodynamic Analysis ........................................ 64 
8.7.1 
Pharmacokinetic Analysis .................................................................. 64 
8.7.2 
Pharmacodynamic Analysis .............................................................. 64 
 
Interim Analyses ........................................................................................... 64 
 
Determination of Sample Size ..................................................................... 65 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ................................... 66 
 
Data Quality Assurance ............................................................................... 66 
9.1.1 
Database Management and Quality Control ..................................... 66 
 
Case Report Forms and Source Documentation ....................................... 66 
6.2 
6.3 
7.1 
7.2 
8.1 
8.2 
8.3 
8.4 
8.5 
8.6 
8.7 
8.8 
8.9 
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9.2.1 
Data Collection .................................................................................. 67 
 
Access to Source Data ................................................................................. 67 
 
Data Processing ........................................................................................... 67 
 
Archiving Study Records ............................................................................. 68 
 
Good Clinical Practice ................................................................................. 68 
 
Informed Consent ......................................................................................... 68 
 
Protocol Approval and Amendment ........................................................... 69 
 
Duration of the Study ................................................................................... 69 
 
Premature Termination of the Study .......................................................... 69 
 
Confidentiality ............................................................................................... 69 
 
Other Ethical and Regulatory Issues .......................................................... 70 
 
Publication Policy ......................................................................................... 70 
 
Insurance ....................................................................................................... 70 
10 
DEFINITION OF END OF TRIAL ........................................................................ 71 
11 
REFERENCE LIST ............................................................................................. 72 
 
Tables in Text 
Table 1: Laboratory Assessments ................................................................................ 48 
Table 2:  Frequency of Subject Assessment ................................................................. 50 
Table 3:  Schedule of Procedures ................................................................................. 52 
 
Figures in Text 
Figure 1: Study Flow Chart ............................................................................................ 30 
 
9.3 
9.4 
9.5 
9.6 
9.7 
9.8 
9.9 
9.10 
9.11 
9.12 
9.13 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
5LS 
5-point Likert scale 
7TQ 
7-point transition question 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC0-t 
area under the curve from time 0 to last sample 
BMI 
body mass index 
C1-INH 
C1-esterase inhibitor 
CL/F 
apparent clearance 
Cmax 
maximum concentration in plasma 
CRA 
Clinical Research Associate 
CrCl 
creatinine clearance 
DBP 
diastolic blood pressure 
DRL 
Drug Reference List 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data collection 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
H 
hour(s) 
HAE 
hereditary angioedema 
HgA1c 
glycosylated hemoglobin 
HK 
high molecular weight kininogen 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonization 
ID 
Identification 

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IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone–releasing system 
Iv 
Intravenous 
Kg 
kilogram(s) 
M 
meter(s) 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minute(s) 
mL 
Milliliter(s) 
NOAEL 
No-observed Adverse Effect Level 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PD 
Pharmacodynamic 
pH 
potential hydrogen 
PK 
Pharmacokinetic 
PKa 
plasma kallikrein 
PPS 
per protocol set 
PR 
pulse rate 
PT 
prothrombin time 
PV 
Pharmacovigilance 
QP 
Qualified Person 
RR 
respiratory rate 
SAE 
serious adverse event 
SAF 
safety set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 

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SUSAR 
suspected unexpected serious adverse reaction 
t½ 
estimated terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach Cmax in plasma 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
Vd/F 
apparent volume of distribution 
WHO 
World Health Organization 
 
 

KalVista Pharmaceuticals, Ltd. 
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1 
INTRODUCTION AND BACKGROUND 
Clinical Study Protocol 
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Hereditary angioedema (HAE) is a rare genetic disease characterized by repeated episodes of 
non-pitting edema that can affect any cutaneous or mucosa! surface. Swelling of the face, 
larynx, tongue, extremities, stomach, bowels, and genitals is common and can be associated 
with significant morbidity and mortality. The most common form of HAE is autosomal dominant 
and results from a loss-of-function mutation in the gene that codes for C1 inhibitor protein. 
Under normal circumstances, a functional level of C1 inhibitor in plasma prevents over-
activation of the complement system and over-production of the vasoactive mediator, 
bradykinin. Deficiency of C1 inhibitor allows for excessive release of bradykinin and complement 
anaphylatoxins, which results in increased endothelial permeability and edema (Kaplan and 
Joseph, 2017). 
1.1 
Rationale for the Study 
Bradykinin is formed by the action of a protease enzyme, plasma kallikrein (PKa), on a 
precursor molecule, kininogen, leading to the release of active bradykinin into the circulation. In 
the absence of C1 inhibitor (as is the case in HAE), excessive bradykinin activity triggers the 
HAE attacks. It is therefore logical to target PKa as a treatment strategy in HAE. 
It is therefore a plausible hypothesis that treatment with a single dose of KVD900 600 mg may 
halt the progression of HAE attacks. 
Refer to the Investigator's Brochure (1B) for further detail on KVD900. 
1.2 
Benefit Risk Assessment 
In contrast to other available on-demand treatments for HAE attacks, KVD900 is 
orally-administered, is rapidly absorbed from the tablet formulation and has been shown in 
healthy volunteers to have a time profile for kallikrein inhibition 
which 
is appropriate for the treatment of this condition. A single dose o 
mg may e reasonably 
expected to bring relief to or halt the progression of an attack of HAE. The double-blind, 
placebo-controlled crossover design of Part 2 of the study has been chosen as an appropriate 
initial test of that hypothesis. 
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The two-part design of the current study has been chosen in order to confirm under open-label, 
clinic-supervised conditions (Part 1) that administration of a single 600 mg dose of KVD900 is 
tolerated by individual subjects before that dose is administered away from the clinic or hospital 
in Part 2 of the study. Further safety features of Part 2 include the exclusion of laryngeal or 
facial attacks and the availability of conventional attack treatment from 4h after study treatment, 
or earlier, as warranted. 
Overall, study KVD900-201 is considered to have a positive benefit-risk balance given that: 
I 
I 
Inhibition of plasma kallikrein is not a novel mechanism for the treatment of HAE. There are 
currently approved plasma kallikrein inhibitors that do not have known target-related AEs. 
-
The initial dose of KVD900 600 mg will be taken in the clinic under the supervision of the 
Investigator. 
-
The dose of KVD900 to be taken in Part 2 (away from the clinic or hospital) will only be 
taken once a study physician or qualified designee has confirmed the HAE attack to be 
eligible and, importantly, that it is not a laryngeal or facial attack. In this case, subjects will 
treat immediately with their conventional attack treatment (pdC1 INH or rhC1 INH 
intravenous [iv] or icatibant). The dedicated study physician or qualified designee will also 
contact the subject within 24h of the eligible HAE attack to confirm the subject's safety and 
wellbeing. Subjects will be instructed to contact the dedicated study physician or qualified 
designee in case of any safety concerns. In the case of hypersensitivity, subjects are to 
contact the dedicated study physician or qualified designee or contact the nearest 
emergency service. The dedicated study physician or qualified designee will be available 
24h/day and 7 days/week to receive subject calls. 
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2 
STUDY OBJECTIVES 
 
Primary Objective 
• 
To investigate the efficacy of KVD900 compared to placebo in halting the progression of 
a peripheral or abdominal attack of HAE. 
 
Secondary Objective(s) 
• 
To investigate the safety and tolerability of KVD900. 
• 
To investigate the pharmacokinetic (PK) profile of KVD900 when taken during the 
intercritical period between HAE attacks. 
• 
To investigate the pharmacodynamic (PD) profile of KVD900 in reducing the 
concentration of residual cleaved high molecular weight kininogen (HK) during the 
intercritical period between HAE attacks. 
• 
To investigate the PD profile of KVD900 in reducing activated plasma enzyme activity 
during the intercritical period between HAE attacks. 
Note: Subjects enrolled at US study sites will not contribute data for PK and PD analysis. 
2.1 
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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
 
Overview 
This is a phase 2, randomized, two-part, two-sequence, two-period (2x2) cross-over clinical trial 
to evaluate the efficacy, safety, and tolerability of KVD900 compared to placebo in halting the 
progression of a peripheral or abdominal attack in adult subjects with HAE type I or II. 
Approximately 60 subjects will be enrolled into the study to ensure approximately 50 subjects 
complete the study. 
The study will be in two parts with the same cohort of subjects completing both parts (Figure 1). 
In Part 1, subjects will receive a single oral dose of 600 mg KVD900 to investigate the safety of 
KVD900 during the intercritical period between HAE attacks. Eligible adult subjects ≥18 years 
old will undergo a screening assessment for study inclusion, receive study drug, followed by a 
4h, in-clinic, safety assessment. 
In Part 2, the subjects will be randomized 1:1 to 2 treatment sequences. This part of the study 
will occur away from the clinic or hospital. 
In Sequence 1 (study arm 1) subjects will receive a single dose of 600 mg KVD900 to treat the 
first eligible HAE attack. Following resolution of this attack, subjects will receive a second single 
dose of placebo to treat the second eligible HAE attack. 
In Sequence 2 (study arm 2) subjects will receive a single dose of placebo to treat the first 
eligible HAE attack. Following resolution of this attack, subjects will receive a second single 
dose of 600 mg KVD900 to treat the second eligible HAE attack. 
The final clinic visit will take place once both eligible HAE attacks have been treated. 
The maximum duration of the study for each randomized subject is likely to be approximately 
19 weeks. 
The study schedule of events will be as follows: 
Screening Phase (Visit 1): The screening period will be up to 28 days. All subjects will sign an 
Informed Consent Form (ICF) prior to any study related procedures being performed. 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. 
Part 1 (Visit 2): On the day of first study drug administration the subject’s eligibility will be 
reconfirmed and baseline assessments will be performed. Eligible subjects will receive a single 
oral dose of KVD900 600 mg. Vital signs (systolic blood pressure [SBP], diastolic blood 
pressure [DBP], pulse rate [PR], respiratory rate [RR] and body temperature) will be measured 
at pre-dose (0h), 1h, and 4h post-dose. Samples for post-treatment safety laboratory 
assessments will be taken at 4h post-dose. 
Part 2: This will be conducted away from the clinic or hospital. Laryngeal or facial attacks are 
not eligible for treatment. Eligible HAE attacks must be treated within the first hour of onset and 
before reaching severe on the global attack severity scale. Subjects must also be able to 
identify the start of an HAE attack. Upon onset of the HAE attack, subjects will notify the 
dedicated study physician or qualified designee with a description of the HAE attack symptoms. 
The dedicated study physician or qualified designee will confirm eligibility of the HAE attack and 
agree to study drug being administered. HAE attacks require documentation, on the Subject 
Diary, of attack location, attack symptoms, time of onset, attack severity, and time of last 
substantial meal prior to dosing prior to dosing. Subjects will take study drug, as instructed, and 
will complete timed assessments of their HAE attack symptoms for a 48h period following study 
3.1 

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drug intake as documented in Table 2. The dedicated study physician or qualified designee will 
contact the subject within 24h of the eligible HAE attack to confirm the subject's safety and 
wellbeing. Subjects will be instructed to contact the dedicated study physician or qualified 
designee in case of any safety concerns. In the case of hypersensitivity, subjects are to contact 
the dedicated study physician or qualified designee or contact the nearest emergency service. 
The dedicated study physician or qualified designee will be available 24h/day and 7 days/week 
to receive subject calls. 
Subjects will return to the clinic (Visit 3) following the first eligible HAE attack, prior to the 
second eligible HAE attack, to undergo safety checks including AE reporting, vital sign 
recording, and Subject Diary review. 
End of study visit (Visit 4): Once two eligible HAE attacks have been treated in Part 2, the 
subject will return to the clinic to undergo final safety checks including AE reporting, vital sign 
recording and blood sampling for laboratory safety measurements. 
Early Discontinuation: If any subject discontinues the trial early, (i.e. before having treated two 
eligible HAE attacks within Part 2) every effort should be made to complete Visit 4 (Early 
Discontinuation visit) as soon as possible and, whenever possible, prior to starting any new 
medication or treatment. All attempts will be made to avoid early discontinuation 
Study Termination: A sample size of approximately 50 subjects completing both treatment 
periods (25 per sequence) is proposed to provide 90% power for testing at the 5% alpha level 
(2-sided) for the rima 
end oint of time to use of conventional attack treatment within 12h of 
stud dru . 
e assump I0n o minima corre a I0n s ou 
sample size. 
An oversampling by 20% (10 subjects) is proposed to account for subjects that may not 
complete both treatment periods due to infrequent or ineligible HAE attacks or for subjects who 
discontinue the trial early, for whatever reason. Thus, study enrolment will be considered 
sufficient to address the primary efficacy hypothesis after approximately 50 subjects have 
completed both treatment periods. Since further exposure is not required and could be 
considered unnecessary, ongoing subjects who have not completed both periods will be asked 
to return to the study site and complete Visit 4 (Early Discontinuation visit). Data from all 
subjects, complete and incomplete, will be analyzed in the safety set. 
Conventional Attack Treatment: Conventional attack treatment is permitted after 4h, or earlier 
as warranted, following study drug intake, provided HAE attack symptoms are judged severe 
enough by the subject to require treatment as per the subject's usual treatment regimen, or are 
associated with laryngeal or facial symptoms. Prior to use of conventional attack treatment, 
subjects will notify the dedicated study physician or qualified designee who will confirm 
conventional attack treatment is appropriate per protocol and subject report of symptom 
severity. Subjects are permitted to treat their HAE attacks with their conventional attack 
treatment (pdC1 INH or rhC1 INH iv or icatibant). 
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Figure 1: 
Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 1 
KVD900 600 mg 
N = 60 
1:1 Randomization 
Part 2, Sequence 1 
N = 30 
KVD900 600 mg (1st attack) 
Placebo (2nd attack) 
End of study visit once ~50 subjects 
have had two attacks treated in Part 2 
Part 2, Sequence 2 
N = 30 
Placebo (1st attack) 
KVD900 600 mg (2nd attack) 
Screening (28 days) 
Eligible subjects with  
N = 60 
1 
T 
1 
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Criteria for Evaluation of the Study 
3.2.1 Efficacy Endpoints 
 Primary Efficacy Endpoints 
• 
Time to use of conventional attack treatment within 12h of study drug. 
 Secondary Efficacy Endpoints 
• 
Patient Global Impression of Severity (PGI-S) 5-point Likert scale (5LS): 
o 
Worsening (including use of conventional attack treatment): 
 
Proportion of HAE attacks that (1) worsen by one level or more from 
baseline or (2) use conventional attack treatment within 12h of study 
drug. 
 
Time to (1) worsening by one level or more from baseline, or (2) use of 
conventional attack treatment, whichever comes first within 12h of study 
drug. 
• 
Patient Global Impression of Change (PGI-C) 7-point transition question (7TQ): 
o Improvement: 
 
Time to symptom relief (A little better or higher, 2 time points in a row) 
within 12h of study drug. 
• 
Visual Analogue Scale (VAS): 
o Improvement: 
 
Time to symptom relief (50% reduction from baseline in composite VAS, 3 
time points in a row) within 12h of study drug. 
 Exploratory Endpoints 
• 
Use of Conventional Treatment: 
o Proportion of HAE attacks that require conventional attack treatment within 12h 
and 24h of study drug. 
o Time to use of conventional attack treatment within 24h of study drug. 
• 
PGI-S (5LS): 
o Area Under the Curve (AUC): 
 
Cumulative PGI-S (5LS) expressed as AUC within 12h and 24h of study 
drug. 
o Worsening (including use of conventional attack treatment): 
 
Proportion of HAE attacks that (1) worsen by one level or more from 
baseline or (2) use of conventional attack treatment within 24h of study 
drug. 
 
Time to (1) worsening by one level or more from baseline or (2) use of 
conventional attack treatment, whichever comes first, within 24h of study 
drug. 
3.2 
3.2.1 .1 
3.2.1 .2 
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o Worsening Only: 
 
Time to worsening by one level or more from baseline within 12h and 24h 
of study drug. 
o Improvement: 
 
Proportion of HAE attacks that improve by one level or more from 
baseline within 12h and 24h of study drug. 
 
Time to improvement by one level or more from baseline within 12h and 
24h of study drug. 
 
Proportion of subjects with HAE attack resolution (rating of none) within 
12h and 24h of study drug. 
 
Time to HAE attack resolution (rating of none) within 12h and 24h of 
study drug. 
o Stable or Improvement: 
 
Proportion of HAE attacks that are stable or improved from baseline 
within 12h and 24h of study drug. 
• 
PGI-C (7TQ): 
o AUC: 
 
Cumulative PGI-C (7TQ) expressed as AUC within 12h and 24h of study 
drug. 
o Worsening (including use of conventional attack treatment): 
 
Proportion of HAE attacks that are (1) rated A little worse or higher, 2 time 
points in a row or (2) use of conventional attack treatment within 12h and 
24h of study drug. 
 
Time to HAE attack being (1) rated A little worse or higher, 2 time points 
in a row, or (2) use of conventional attack treatment, whichever comes 
first, within 12h and 24h of study drug. 
o Worsening Only: 
 
Time to HAE attack being rated A little worse or higher, 2 time points in a 
row, within 12h and 24h of study drug. 
o Improvement: 
 
Proportion of HAE attacks that are rated A little better or higher, 2 time 
points in a row, within 12h and 24h of study drug. 
 
Time to HAE attack being rated A little better or higher, 2 time points in a 
row, within 24h of study drug. 
 
Proportion of HAE attacks that are rated Better or higher within 12h and 
24h of study drug. 
 
Time to HAE attack being rated Better or higher within 12h and 24h of 
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o Stable or Improvement: 
 
Proportion of HAE attacks that are stable or improved within 12h and 24h 
of study drug. 
• 
Visual Analogue Scale (VAS): 
o AUC: 
 
Cumulative composite VAS expressed as AUC within 12h and 24h of 
study drug. 
o Improvement: 
 
Proportion of HAE attacks with symptom relief (50% reduction from 
baseline in composite VAS, 3 time points in a row) within 12h and 24h of 
study drug. 
 
Time to symptom relief (50% reduction in composite VAS, 3 time points in 
a row) within 24h of study drug. 
3.2.2 Safety Endpoints 
• 
AEs, including SAEs. 
• 
Physical exam findings. 
• 
Electrocardiogram (ECG) results. 
• 
Laboratory test results (clinical chemistry, hematology, coagulation, and urinalysis). 
• 
Vital signs (SBP, DBP, PR, RR and body temperature). 
 
Justification of the Study Design 
This phase 2 study is the first clinical investigation of the potential efficacy of KVD900 in the on-
demand treatment of attacks of HAE. The two-part design has been chosen to allow preliminary 
assessment of the safety and tolerability of the drug in this population between HAE attacks and 
in a controlled clinic environment before moving on to compare efficacy against placebo in 
peripheral or abdominal attacks away from the clinic or hospital. Laryngeal and facial attacks 
are excluded for safety reasons at this early stage of development. 
The study population is representative of the likely target population for the product. The 
analysis sample size of approximately 50 subjects is required to conclusively evaluate a 
clinically relevant treatment effect. Approximately 60 subjects will be enrolled into the study to 
ensure a total of approximately 50 subjects complete the study. 
The single oral 600 mg dose of KVD900 is supported by animal toxicology data and was shown 
in the first-in-man study to be well tolerated and to result in potentially beneficial PD effects. 
The endpoints are commonly-measured in HAE and are clinically relevant. 
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4 
STUDY POPULATION 
The study population will include male and female subjects 18 years of age or older with 
HAE type I or II. 
Subjects must fulfill all of the following criteria both at Visit 1 (Screening) and on Visit 2 to be 
eligible for inclusion in the study. 
 
Inclusion Criteria 
Subject must fulfill all of the following inclusion criteria at Visit 1 (Screening) and on Visit 2 to be 
eligible for inclusion in the study: 
1. Male or female adult subjects 18 years of age and older. 
2. Confirmed diagnosis of HAE type I or II at anytime in the medical history: 
a) Documented clinical history consistent with HAE (subcutaneous or mucosal, 
nonpruritic swelling episodes without accompanying urticaria) AND 
b) C1-esterase inhibitor (C1-INH) antigen or functional level < 40% of the normal 
level. Subjects with antigen or functional C1-INH level 40-50% of the normal level 
may be enrolled if they also have a C4 level below the normal range and a family 
history consistent with HAE type I or II. 
3. At least 3 documented HAE attacks in the past 93 days, as supported by medical 
history. 
4. Access to and ability to use conventional attack treatment for attacks of HAE. 
5. Adequate organ functions as defined below: 
a) Hemoglobin within normal range; 
b) International normalized ratio (INR)< 1.2; 
c) Activated partial thromboplastin time (aPTT) ≤ upper limit of normal (ULN); 
d) Creatinine < 1x ULN; 
e) Creatinine clearance (CrCl) ≥ 60 mL/min; 
f) Alanine aminotransferase (ALT) ≤ 2x ULN; 
g) Aspartate aminotransferase (AST) ≤ 2x ULN; 
h) Total bilirubin ≤ 1.5x ULN; 
i) 
Leucocytes ≤ 1.5x ULN; 
j) 
Thrombocytes ≤ 1.5x ULN. 
6. Females of childbearing potential must agree to use highly effective birth control from the 
Screening visit until the end of the trial follow-up procedures. 
Highly effective methods of birth control include: 
− 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral / injectable / implantable. (Hormonal contraception that contains estrogen is 
excluded per exclusion criterion 3). 
− 
Intrauterine device (IUD). 
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− 
Intrauterine hormone–releasing system (IUS). 
− 
Bilateral tubal occlusion. 
− 
Vasectomised partner (provided that the partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomised partner has 
received medical assessment of the surgical success). 
− 
Sexual abstinence (this method is not acceptable in Switzerland). 
Note: Sexual abstinence will only be considered a highly effective method if it is defined 
as refraining from heterosexual intercourse. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. 
7. Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months, do not require contraception during the study. 
8. Males with female partners of childbearing potential must agree to be abstinent or else 
use a highly effective method of birth control as defined in inclusion 6 from the Screening 
visit until the end of the trial follow-up procedures. 
9. Provide signed informed consent and are willing and capable of complying with study 
requirements and procedures. 
 
Exclusion Criteria 
Subjects will be excluded from the study if one or more of the following statements are 
applicable at Screening (Visit 1) and on Visit 2: 
1. Any concomitant diagnosis of another form of chronic angioedema, such as acquired 
C1 inhibitor deficiency, HAE with normal C1-INH (also known as HAE type III), idiopathic 
angioedema, or angioedema associated with urticaria. 
2. Current use of C1INH, androgens, lanadelumab, or tranexamic acid for HAE 
prophylaxis. 
3. Use of angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systemic absorption (such as oral contraceptives or hormonal 
replacement therapy) within 93 days prior to initial study treatment. 
4. Use of androgens (e.g. stanozolol, danazol, oxandrolone, methyltestosterones, 
testosterone) or antifibrinolytics within 30 days prior to initial study treatment. 
5. Use of lanadelumab within 10 weeks prior to initial study treatment.  
6. Use of strong CYP3A4/CYP2C9 inhibitors and inducers during participation in the trial. 
Note: These medications include but are not limited to the following: cobicistat, conivaptan, 
itraconazole, ketoconazole, posaconazole, voriconazole, ritonavir, boceprevir, telaprevir, 
troleandomycin, clarithromycin, carbamazepine, enzalutamide, mitotane, phenytoin, 
phenobarbital, fluconazole, isoniazid, metronidazole, paroxetine, sulfamethoxazole, rifampicin, St. 
John’s Wort, diltiazem, idelalisib, nefazodone and nelfinavir. 
7. Clinically significant abnormal ECG at Visit 1 and pre-dose at Visit 2. This includes, but 
is not limited to, a QTcF > 470 msec (for women) or > 450 msec (for men), a 
PR > 220 msec or ventricular and/or atrial premature contractions that are more frequent 
than occasional and/or occur as couplets or higher in grouping. 
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8. Any clinically significant history of angina, myocardial infarction, syncope, clinically 
significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any 
other cardiovascular abnormality. 
9. Any other systemic dysfunction (e.g., gastrointestinal, renal, respiratory, cardiovascular) 
or significant disease or disorder which, in the opinion of the Investigator, would 
jeopardize the safety of the subject by taking part in the trial. 
10. History of substance abuse or dependence that would interefere with the completion of 
the study, as determined by the Investigator. 
11. Known lactose allergy or intolerance. 
12. Known hypersensitivity to KVD900 or placebo or to any of the excipients. 
13. Participation in an interventional investigational clinical study within 93 days or within 
5 half-lives of the last dosing of investigational drug (whichever is longer) prior to initial 
study treatment. 
14. Any pregnant or breast-feeding subject. 
4.3 
Subject Withdrawal 
4.3.1 
Withdrawal from Study 
Subjects are free to withdraw from participation in the study at any time, for any reason (or 
without providing reasons) and without prejudice to further treatment or they may be 
discontinued by the Investigator, if deemed in their best medical interests. 
Subjects will also be withdrawn if the entire study is terminated prematurely as described in 
Section 9.10. 
The Sponsor has the right to terminate the study at any time and for any reason. In the event, 
the Investigators will be informed of the reason for study termination by written notification. 
A sample size of approximately 50 subjects completing both treatment periods (25 per 
sequence) is proposed to provide 90% power for testing at the 5% alpha level (2-sided) for the 
. 
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size. 
An oversampling by 20% (10 subjects) is proposed to account for subjects that may not 
complete both treatment periods due to infrequent or ineligible HAE attacks or for subjects who 
discontinue the trial early, for whatever reason. Thus, study enrolment will be considered 
sufficient to address the primary efficacy hypothesis after approximately 50 subjects have 
completed both treatment periods. Since further exposure is not required and could be 
considered unnecessary, ongoing subjects who have not completed both periods will be asked 
to return to the study site and complete Visit 4 (Early Discontinuation visit). Data from all 
subjects, complete and incomplete, will be analyzed in the safety set. 
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4.3.2 Withdrawal from Treatment 
Subjects have the right to stop study treatment at any time, without prejudice to their medical 
care. 
The Investigator may also discontinue a subject from further study drug dosing or withdraw a 
subject from the study at any time for the following reasons: 
• 
ALT or AST > 8x ULN. 
• 
ALT or AST > 5x ULN for more than 2 weeks. 
• 
ALT or AST > 3x ULN and (total bilirubin > 2x ULN or INR > 1.5). 
• 
ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
• 
Creatinine level increase of > 0.3 mg/dL or creatinine 2.0x baseline value. 
• 
Positive pregnancy test. 
• 
AEs, SAEs. 
• 
At the discretion of the Investigator. 
• 
Administrative reasons (e.g., lack of subject compliance to study visits / procedures, 
lost to follow-up). 
4.3.3 Lost to Follow-up 
If a subject does not return for a scheduled visit, every effort should be made at least once 
every month to contact the subject to reschedule the visit. All efforts should be documented in 
the subject’s medical source record. A subject is considered lost to follow–up if subject cannot 
be reached after 93 days from the scheduled visit. However, if the subject re–initiates contact 
beyond 93 days, the available data may still be collected on the electronic case report 
form (eCRF), provided that subject consent has not been withdrawn. 
4.3.4 Withdrawal Procedures 
Subjects who withdraw or are withdrawn from the study will complete Visit 4 as soon as possible 
(Section 7.2.4). The reason for discontinuation / withdrawal will be documented in the eCRF and 
the Medical Monitor must be informed immediately. If the reason for withdrawal is the 
occurrence of an AE, the subject will be followed up until the AE has resolved or is considered 
chronic and stable or the AE has been clearly shown to be unrelated to the study drug. 
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Planned Sample Size and Number of Study Centres 
Multiple clinical sites in Europe and US will enroll approximately 60 subjects into the study. Only 
study sites with experience in the conduct of HAE clinical studies will be selected. See 
Section 8.9 for a discussion of sample size. 
 
Subject Identification and Randomization 
4.5.1 Subject Identification 
Each subject will receive a unique screening identification (ID) number. Subjects who are 
screen failures and are not randomized will retain their screening ID number. 
4.5.2 Randomization Scheme 
Subjects will be randomized on a 1:1 basis to the two sequences for Part 2 (KVD900 600 mg 
followed by placebo or placebo followed by KVD900 600 mg).  
4.5.3 Allocation / Randomization of Subjects to Treatment 
Subjects must not be randomized unless all eligibility criteria have been met. 
Subjects who satisfy all the entry criteria will be assigned to a treatment sequence according to 
the randomization scheme. Each randomized subject will receive a unique randomization 
number. Subjects will be randomized in a 1:1 ratio to Sequence 1 (KVD900 followed by 
placebo) or Sequence 2 (placebo followed by KVD900).  
The actual treatment sequence for each subject will be determined by the randomization 
scheme. The randomization scheme will be produced by a computer software program that 
incorporates a standard procedure for generating randomization numbers.  
The randomization scheme will inform the Investigator of the kit ID number to be allocated to the 
subject. 
The first dose of study drug will be the open label single 600 mg oral dose comprised of 6 x 
KVD900 100 mg Film Coated Tablets administered in the clinic during Part 1, after completion 
of all pre–dose assessments. 
Randomized subjects who are discontinued (Section 4.3) from further study drug administration 
or are terminated from the study for any reason, regardless of whether study drug was taken or 
not, will not have their screening / randomization code be reused. 
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Further information about KVD900 100 mg Film-Coated Tablet can be found in the 18. 
5.2 
Administration 
A single open-label dose of KVD900 600 mg (6 x 100 mg tablets) will be administered under the 
supervision of the clinic staff in Part 1. 
In Part 2 each subject, having contacted the dedicated study physician or qualified designee 
with a description of the HAE attack symptoms and obtained the dedicated study physician or 
qualified designee's confirmation of HAE attack eligibility and agreement to use study drug, will 
self-administer a single dose of KVD900 600 mg (6 x 100 mg tablets) or matching placebo 
tablets in response to the first qualifying attack of HAE. 
Subjects will return to the clinic following the first eligible HAE attack and will be dispensed the 
opposite study drug to take home for treatment of the second eligible HAE attack. 
Note: A minimum of 48-hour washout period required between each dose of study drug. Refer 
also to Section 5.8 for the required washout period prior to dosing with the study drug in the 
event a subject receives treatment with C1 INH or icatibant (all doses) during the study. 
Subjects will be provided with instructions on study drug administration and the relevant 
documentation thereof in the Subject Diary. 
No study drug dose modifications are allowed in this study. 
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Packaging, Labelling and Storage 
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Blinding and Breaking the Blind 
Part 2 of the study will be performed in a double–blind manner. 
The study blind should not be broken except in a medical emergency (where knowledge of the 
study drug received would affect the treatment of the emergency) or regulatory requirement1 
(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 study 
blind will be made solely by the Investigator. 
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 study 
drug, the problem may be properly managed by assuming that the subject is receiving active 
product. 
Following the unblinding of the study drug 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 subject’s eCRF system, and any associated AE report.  
If an Investigator, site personnel performing assessments, or subject, is unblinded, the subject 
must be listed as major protocol deviation. 
Suspected unexpected serious adverse reactions (SUSARs), which are subject to expedited 
reporting, should be unblinded before submission to the Regulatory Authorities. 
The overall randomization code will be broken only for reporting purposes. This will occur once 
all final clinical data have been entered onto the database and all data queries have been 
resolved, and the assignment of subject to the analysis sets has been completed. 
 
Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability records 
throughout the study. 
The Investigator or designee is responsible for verifying accurate delivery of the study drug and 
acknowledging receipt thereof by completing and processing the relevant accompanying 
documentation as required. A copy will be retained for the Investigator Site File. 
The Investigator or designee will maintain accountability records that must document all study 
drug received from the Sponsor, dispensed (as per the protocol / amendment[s]) to the subjects, 
returned by the subjects, and returned to the Sponsor or sent for destruction (following Sponsor 
approval). In addition to this, the accountability records will document any additional relevant 
information received by the Investigator or Pharmacist. 
Records should include dates, quantities, batch numbers, expiration dates, and any unique 
code numbers assigned to the study drug and / or subjects. 
The Investigator or designee will dispense the study drug only to the identified subjects of this 
study following the procedures described in this study protocol and documented in the subject 
dispensing log. 
 
1 The study team (Sponsor and Orion) and Investigator are not unblinded for the purposes of regulatory 
reporting. 
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Study drug inventory / dispensing will be documented in the source documentation and the 
eCRF for each subject. The Investigator is responsible for all study drug. Written documentation 
is mandatory. 
Subjects will be instructed to return all unused study drug and packaging to the clinic at their 
subsequent visits (Visits 3 and 4). 
All drug accountability forms will be routinely reviewed by the Orion Clinical Research 
Associate (CRA). 
The site staff should aim to follow up on the reasons for any missing study drug or other 
discrepancies noted after performing the relevant study drug accountability. 
Study drug that has been dispensed to a subject and returned unused must not be re-dispensed 
for a different subject. Unused study drug must not be used for any purpose other than the 
present study.  
After completion of the study and following Sponsor approval, all unused study drug will either 
be returned to the Sponsor or sent for destruction within 8 weeks of the last dose. 
 
Compliance 
In Part 1, study drug administration and dispensing procedures shall be conducted by qualified 
staff at the clinical site; study drug administration must be recorded in the source data and 
eCRF. 
In Part 2, subjects will be provided with instructions on study drug administration and the 
relevant documentation thereof in the Subject Diary. Subjects will also be instructed to return all 
used and unused study drug and packaging to the clinic at their subsequent visits (Visits 3 and 
4). 
 
Concomitant Medications / Therapy 
The concomitant use of the following medications will not be allowed in the study: 
• 
Conventional attack treatment during 4h following study drug intake in Part 2 unless 
clinically necessary. (Conventional attack treatment is permitted after 4 h or earlier as 
warranted, as described in Section 5.8.) 
• 
Use of ACE inhibitors or any estrogen-containing medications with systemic absorption 
(such as oral contraceptives or hormonal replacement therapy) within 93 days prior to 
initial study treatment. 
• 
Use of androgens (e.g. stanozolol, danazol, oxandrolone, methyltestosterone, 
testosterone) or antifibrinolytics within 30 days prior to initial study treatment. 
• 
Use of lanadelumab within 10 weeks prior to initial study treatment. 
• 
Use of strong CYP3A4/CYP2C9 inhibitors and inducers during participation in the trial.  
o These medications include but are not limited to the following: cobicistat, 
conivaptan, itraconazole, ketoconazole, posaconazole, voriconazole, ritonavir, 
boceprevir, telaprevir, troleandomycin, clarithromycin, carbamazepine, 
enzalutamide, mitotane, phenytoin, phenobarbital, fluconazole, isoniazid, 
metronidazole, paroxetine, sulfamethoxazole, rifampicin, St. John’s Wort, 
diltiazem, idelalisib, nefazodone and nelfinavir. 
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• 
Any medication that in the opinion of the Investigator may influence the interpretation of 
the safety and / or efficacy parameters in this study. 
Caution must be used regarding the use of the following medications during participation in the 
trial: 
• 
Moderate CYP3A4/CYP2C9 inhibitors and inducers. 
• 
CYP2C8, CYP2B6 and CYP2C19 inhibitors and inducers. 
Details of all medications, therapies and supplements administered within 93 days prior to the 
Visit 1 (Screening visit) until the end of the study will be recorded in the eCRF. Prior medications 
are defined as those medications that stop prior to administration of first treatment at Visit 2; 
concomitant medications are defined as those medications started after first administration of 
study drug at Visit 2 until the end of study. 
 
Conventional Attack Treatment 
Conventional attack treatment is permitted after 4h, or earlier as warranted, following study drug 
intake, provided HAE attack symptoms are judged severe enough by the subject to require 
treatment as per the subject’s usual treatment regimen, or are deemed ineligible for study drug 
treatment, or are associated with laryngeal or facial symptoms. Subjects are permitted to treat 
their HAE attacks with their conventional attack treatment (pdC1INH or rhC1INH iv or icatibant). 
Subjects will attempt to contact their study physician or qualified designee prior to use of 
conventional attack treatment. The dedicated study physician or qualified designee should 
confirm that conventional attack treatment is appropriate per the protocol and HAE attack 
severity. Should the subject be unable to reach their study physician or qualified designee prior 
to taking conventional attack treatment, subjects may take their conventional attack treatment 
as needed. Time to use of conventional attack treatment will be entered in the subject diary.  
Note: In the event a subject receives treatment with C1INH or icatibant (all doses) during the 
study, the following washout periods are required prior to the subsequent dosing with the study 
drug: 
• 
7-day washout period required for C1INH. 
• 
3-day washout period required for icatibant. 
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6 
VARIABLES AND METHODS OF ASSESSMENT 
 
Efficacy Variables 
Efficacy variables of interest in this study are: 
• 
Time to use of conventional attack treatment captured in the subject diary. 
o What time did you take your conventional HAE attack medication? 
• 
Overall HAE attack severity assessed on the PGI-S (5LS) scored as none, mild, 
moderate, severe and very severe. 
o Please indicate the overall severity of your HAE attack right now. 
• 
Change in HAE attack severity assessed using the PGI-C (7TQ), scored as Much better 
/ Better / A little better / No change / A little worse / Worse / Much worse. 
o How would you describe your overall HAE attack symptoms right now, compared 
to how you were when you took the study drug? 
• 
The type of HAE attack symptoms (abdominal pain, skin pain and skin swelling) each 
assessed on a 100 mm visual analogue scale (VAS) anchored at 0 (none) and 100 (very 
severe). 
o How much abdominal pain / skin pain / skin swelling are you experiencing right 
now? 
 
Safety Variables 
Safety variables of interest in this study are: 
• 
AEs, including SAEs. 
• 
Laboratory test results (clinical chemistry, hematology, coagulation, and urinalysis) 
• 
Vital signs (SBP, DBP, PR, RR and body temperature). 
• 
Physical examination findings. 
• 
ECG results. 
6.2.1 Adverse Events 
It is of the utmost importance that all staff involved in the study are familiar with the content of 
this section. It is the Investigator’s responsibility to ensure compliance with reporting of AEs 
from his/her site. 
An AE is defined as any untoward medical occurrence associated with the use of an IMP in 
humans, whether or not considered IMP-related. An AE can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IMP, without any judgment about causality. An AE can arise from any use of the IMP 
(e.g. off-label use, use in combination with another drug or medical device) and from any route 
of administration, formulation, or dose, including an overdose. 
All AEs spontaneously reported by the subject and / or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded in the source document and on the appropriate pages of the eCRF. 
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Any clinically relevant deterioration in a clinical finding is considered an AE and must be 
recorded. 
Laboratory abnormalities or other abnormal assessments (e.g., physical examination, vital 
signs, etc.) that require clinical intervention or further investigation (beyond ordering a repeat 
[confirmatory] test) should be reported as AEs (unless they are associated with an already 
reported clinical event). 
 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 study drug or seriousness of the event and 
should be evaluated according to the following scale: 
• 
Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere with the 
subject’s daily activities. 
• 
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with 
the subject’s daily activities. 
• 
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities. 
 Relationship to Study Drug 
The relationship of each AE to the study drug should be determined by the Investigator using 
these explanations: 
• 
Suspected: A reasonable possibility exists that the study drug caused the AE. 
• 
Not Suspected: A reasonable possibility does not exist that the study drug caused the AE. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
study drug caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study drug and the AE.  
Types of evidence that would suggest a causal relationship between the study drug and the AE 
include: A single occurrence of an event that is uncommon and known to be strongly associated 
with study drug exposure (e.g. hepatic injury, Stevens-Johnson Syndrome); one or more 
occurrences of an event that is not commonly associated with study drug exposure, but is 
otherwise uncommon in the population exposed to the study drug (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 study population independent of drug therapy) that indicates those events occur more 
frequently in the study drug-sequence group than in a concurrent or historical control group. 
 Expectedness 
The expectedness of an AE should be determined based upon existing safety information about 
the study drug using these explanations: 
• 
Unexpected: An AE that is not listed in the IB or is not listed at the specificity or severity that 
has been observed. 
• 
Expected: An AE that is listed in the IB at the specificity and severity that has been 
observed. 
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AEs that are mentioned in the IB as occurring with a class of products or as anticipated from the 
pharmacological / mechanical (or other) properties of the product, but are not specifically 
mentioned as occurring with the particular product under investigation are to be considered 
unexpected. 
The Investigator should initially classify the expectedness of an AE, but the final classification is 
subject to the Sponsor’s determination. 
 Serious Adverse Events 
An AE is considered serious if, in the view of either the Investigator or Sponsor, it results in any 
of the following outcomes: 
• 
Death. 
• 
A life-threatening AE. 
Note: An AE is considered “life-threatening” if, in the view of either the Investigator or Sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization. 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if less than 24h). For 
chronic or long-term inpatients, inpatient admission includes transfer within the hospital to an acute / 
intensive care inpatient unit. Inpatient hospitalization does not include: Emergency room visits; 
outpatient / same-day / ambulatory procedures; observation / short stay units; rehabilitation facilities; 
hospice facilities; nursing homes; or clinical research / phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension of an inpatient 
hospitalization beyond the stay anticipated or required for the reason for the initial admission as 
determined by the Investigator or treating physician. 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• 
A congenital anomaly / birth defect. 
• 
Important medical events. 
Note: Important medical events may not result in death, are life-threatening, or require hospitalization 
and may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
 Reporting Adverse Events 
All AEs which occur from the time of signing of the ICF up to and including Visit 4 / Early 
Discontinuation, must be recorded in the eCRF. 
When possible, signs and symptoms indicating a common underlying pathology should be 
noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to the study drug, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning. 
If an AE increases in severity it will be recorded as a new AE. 
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6.2.1.6 Reporting Suspected Unexpected Adverse Reactions 
A SUSAR is an AE that meets all the following criteria: 
• 
Serious 
• 
Unexpected 
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• 
Reasonable possibility of a causal relationship between the AE and the study drug. 
SUSARs are to be reported to Orion Pharmacovigilance (PV) within 24h of awareness. All 
SUSARs should be reported to the relevant Regulatory Authority, Independent Ethics 
Committee (IEC), Institutional Review Board (IRB) and investigators as per the regulatory 
requirement and timelines. 
6.2.1.7 Reporting Serious Adverse Events 
All SAEs, regardless of relationship to the study drug, must be immediately reported on the SAE 
form within 24h of awareness by any site staff. If it is not possible to complete all sections of the 
SAE form within 24h 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 on the appropriate eCRF. The Investigator is obligated to 
pursue and obtain information requested by Orion PV and I or the Sponsor in addition to that 
information reported on the SAE form and eCRF. All subjects experiencing a SAE must be 
followed up and the outcome reported. 
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 Orion PV and 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 study drug. 
Contact information for Orion PV SAEs : 
6.2.1.8 Reporting Adverse Events to Independent Ethics Committees / Regulatory Authorities 
The Investigator is responsible for informing the local IEC/ central IRB of the applicable safety 
reports in compliance with local regulations. Copies of all correspondence and documentation 
relating to reporting of any safety reports to the local IEC/ central IRB should be maintained in 
the Investigator Site Files. 
The Sponsor, or its designee, Orion Clinical Services, will inform Investigators, central IECs and 
regulatory authorities of applicable safety reports, as required. 
6.2.1.9 Adverse Event Follow-up 
All AEs irrespective of the suspected causality, will be monitored until the AE has resolved or 
until the end of the study, unless the subject is lost to follow-up or withdraws consent or the 
subject died prior to the end of the study. All SAEs, irrespective of the suspected causality, will 
be monitored until the SAE has resolved or until the subject is lost to follow-up or the subject 
has died. 
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 Pregnancy 
The Sponsor has a responsibility to monitor the outcome of pregnancies where there has been 
maternal exposure to the study drug. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. 
Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions (see below). Hospitalization for normal delivery of a healthy newborn 
should not be considered a SAE. 
All pregnancies must be reported by the Investigator to Orion PV on the pregnancy notification 
form immediately after becoming aware of the pregnancy. The Investigator must follow-up and 
document the course and the outcome of all pregnancies even if the subject was discontinued 
from the study or if the study has finished. 
All outcomes of pregnancy must be reported by the Investigator to Orion PV on the pregnancy 
outcome form immediately after becoming aware of the normal delivery or elective abortion. 
Any SAE that occurs during pregnancy (including SAEs occurring after last administration of 
study drug) must be recorded on the SAE report form (e.g., maternal serious complications, 
spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
anomaly, or birth defect) and reported within 24h in accordance with the procedure for reporting 
SAEs. 
If a female partner of a male study subject who has been exposed to the study drug becomes 
pregnant, the pregnancy and outcome of pregnancy should be monitored according to the same 
guidelines as for female subjects who become pregnant during the study. 
6.2.2 Laboratory Variables 
Laboratory assessments as detailed in Table 1 will be performed by a laboratory. Before starting 
the study, the lab will supply a list of the normal ranges and units of measurement. 
Blood samples (approximately 50 mL) will be taken using standard venipuncture techniques. A 
lab manual will be provided by the laboratory; this will contain very detailed instructions for 
collection, storage, and shipment of samples (e.g., what kind of tubes, what kind of sample 
preparation, mailing addresses, etc.). 
The laboratory variables as detailed in Table 1 will be determined in accordance with the 
Schedule of Procedures (Table 3). 
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Table 1: 
Laboratory Assessments 
Hematology: 
erythrocytes 
MCV 
MCH 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Platelets 
Leukocytes 
Hemoglobin 
Hematocrit 
Urinalysis: 
pH 
Protein 
Glucose 
Ketone 
Bilirubin 
Blood 
Nitrite 
Microalbuminemia 
Proteinuria 
Clinical chemistry: 
HgA1c 
Creatinine 
Glucose 
Triglycerides 
Urea 
Uric acid 
Bilirubin 
Cholesterol 
Liver enzymes: 
Alkaline phosphatase 
AST 
ALT 
GGT 
Electrolytes: 
Sodium 
Potassium 
Coagulation: 
PT, aPTT 
Pregnancy test: 
In female subjects of childbearing potential. 
Serum pregnancy test at all visits; urine pregnancy test at Visit 2 as 
well to confirm pregnancy status prior to dosing. 
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; GGT = gamma glutamyl transferase; HgA1c = Glycosylated hemoglobin; MCH = mean corpuscular 
hemoglobin; MCV = mean corpuscular volume; pH = potential hydrogen; PT = prothrombin time. 
 
The Investigator must review screening laboratory results for subject eligibility prior to enrolling. 
Laboratory tests can 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. 
Laboratory data will be electronically transferred to the clinical database at specified time points 
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Methods of Assessment 
The following assessments will be conducted and recorded in the eCRF. The Schedule of 
Procedures and Procedures by Visit can be found in Sections 7.1 and 7.2, respectively. 
6.3.1 Subject Demography 
Subject demography will be performed at Visit 1 (Screening visit) and consists of: 
• 
Date of birth 
• 
Height (meters [m]; without shoes) 
• 
Weight (kilograms [kg]; without shoes or overcoat)  
• 
Race and ethnicity 
• 
Gender 
6.3.2 Medical History 
For the documentation of the medical history, any relevant previous and concurrent diseases 
will be documented. 
The medical history will be obtained by interviewing the subject or by inspecting relevant 
medical records.  
For coding of medical history, see Section 9.4. 
 HAE Disease History 
HAE disease history will be recorded at Visit 1 (Screening visit). For disease history the 
following will be documented: 
• 
Date of first symptoms of HAE 
• 
Date of first diagnosis of HAE 
• 
HAE attack profile in the past 93 days 
o Location of the attacks 
o Number of the attacks 
o Maximum severity of the attacks 
• 
Family history of HAE 
• 
Most recent C1-INH antigen or functional level as per medical history 
• 
Most recent C4 level as per medical history 
6.3.3 Previous and Concomitant Medications 
Previous and concomitant medication will be documented as described in Section 5.7. 
6.3 
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6.3.4 Vital Signs 
Vital signs will be assessed at rest (5 minutes in a supine position) in accordance with the 
Schedule of Procedures (Table 3). Vital signs should be conducted prior to study drug 
administration and 1h and 4h post-study drug administration during Part 1. 
Vital signs include: 
• 
Blood pressure (SBP and DBP; mmHg) 
• 
PR (beats per minute) 
• 
Respiration rate (breaths per minute) 
• 
Body temperature (°C) 
6.3.5 Physical Examinations 
Complete physical examinations will be performed in accordance with the Schedule of 
Procedures (Table 3). 
6.3.6 Electrocardiogram 
A 12-lead ECG recorded over at least 10 seconds after the subject has rested supine on a bed 
for at least 5 min. HR, PR, QRS, QT and RR will be recorded; QTcF calculated as per standard 
practice. 
6.3.7 Safety Laboratory Assessments 
Laboratory assessments will be conducted in accordance with Section 6.2.2. The laboratory will 
provide a lab manual with detailed procedures. Safety labs will be collected per the Schedule of 
Procedures (Table 3). 
6.3.8 Efficacy Assessments 
Efficacy assessments will be performed in accordance with the Schedule of 
Procedures (Table 3). 
There are no efficacy assessments in Part 1. 
In Part 2, following study drug intake, subject assessments of overall HAE attack severity and 
change in HAE attack severity will be undertaken as follows (Table 2): 
Table 2:  
Frequency of Subject Assessment 
Time Period following Study 
Drug Administration 
Frequency of Subject 
Assessment* 
Allowed Time Window for 
Assessment 
0h – 4h 
Every 30 min 
None 
4h – 12h 
Every 1h 
+/- 15 min 
12h – 24h 
Every 3h 
+/- 30 min 
36h 
Once 
+/- 60 min 
48h 
Once 
+/- 60 min 
*In the event that conventional attack treatment is used (Section 5.8), the subject should perform 
assessments every 30 min for 4h following first administration of conventional attack treatment. After this, 
the subject should revert back to original frequency of assessments based on time of study drug 
administration. 
 

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6.3.9 Pharmacokinetic Blood Sampling 
Not applicable for US study sites. 
6.3.10 Pharmacodynamic Assessments 
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STUDY CONDUCT 
7.1 
Schedule of Procedures 
A list of procedures to be conducted, by visit, is described in Table 3. 
Table 3: 
Schedule of Procedures 
Screening 
Part 1 
Part 2 
Clinic Visit (V) 
Visit 1 
Visit 2* 
1st eligible11 
Visit 3* 
HAE attack 
Informed Consent 
X 
Eligibility Assessment 
X 
X 
Medical Historya 
X 
Demographicsb 
X 
Physical Examinationc 
X 
(X)C 
X 
Vital Signsd 
X 
x a 
X 
Electrocardiogramm 
X 
xm 
X 
Safety Laboratorye 
X 
xe 
X 
Pregnancy Test1 
X 
X! 
X 
serum 
serum & urine 
serum 
Concomitant Medications 
X 
X 
X 
Adverse Eventsg 
X 
X 
X 
Randomize subject 
X 
Subject Diary completion 
training, dispensing and 
X 
X 
return 
C1 INH / icatibant washout 
X 
X 
checki 
Dosek 
X 
X 
Study drug dispensing and 
X 
X 
return 
Overall attack severity 
X 
(PGI-S SLS)h 
Change in attack severity 
X 
(PGI-C 7TQ)h 
Abdominal pain (VAS)h 
X 
Skin pain (VAS)h 
X 
Skin swelling (VAS)h 
X 
24h telephone follow-up1 
X 
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End of 
Study/ED* 
2nd eligible11 
Visit 4* 
HAE attack 
X 
X 
X 
X 
X 
serum 
X 
X 
Xi 
X 
X 
Xi 
X 
X 
X 
X 
X 
X 
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Abbreviations: AE = adverse event; BMI = body mass index; ECG = electrocardiogram; ED = early discontinuation; 
HAE = hereditary angioedema; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of 
Severity; 5LS=5-point Likert scale; 7TQ=7-point transition question; VAS=visual analogue scale; 
*Visit 2 to occur within 28 days of Visit 1 (Screening visit). 
*Visit 3 to occur as soon as is practicable (within 7 days) following the 1st home-treated HAE attack. 
*Visit 4 to occur as soon as is practicable (within 7 days) following the 2nd home-treated HAE attack. Upon subject 
withdrawal, Visit 4 to be completed as soon as possible and, whenever possible, prior to starting any new medication 
or treatment. 
# When a HAE attack occurs, the subject will telephone the dedicated study physician or qualified designee with a 
description of the HAE attack documented in the Subject Diary. The dedicated study physician or qualified designee 
will confirm if the HAE attack is eligible for treatment with the study drug (Section 7.2.2.2). If the HAE attack is not 
eligible for treatment with the study drug, the subject will commence conventional attack treatment. 
a Medical history includes any relevant previous and concurrent diseases, HAE disease history (date of first 
symptoms of HAE; date of first diagnosis of HAE; HAE attack profile in the past 93 days [location of the attacks; 
number of the attacks; maximum severity of the attacks]; family history of HAE; most recent C1-INH antigen or 
functional level as per medical history; most recent C4 level as per medical history) and therapies and supplements 
taken within the past 93 days, previous participation in interventional clinical studies in the past 93 days. 
b Demographics: Date of birth; height (meters [m]; without shoes); weight (kilograms [kg]; without shoes or overcoat); 
race and ethnicity; gender. Calculation of BMI will be automated in the database. 
c Complete physical examination. Physical examination at Visit 2 if clinically indicated. 
d Vital signs include pulse rate (PR), respiratory rate (RR), systolic and diastolic blood pressure (SBP, DBP), and 
body temperature (°C). Visit 2: Vital signs taken pre-dose (0h), 1h, and 4h post-dose. 
e Laboratory assessments performed by a laboratory as described in Table 1. Visit 2 labs collected at 4h post-dose. 
f Female subjects of childbearing potential.  
− 
Visit 1: Serum pregnancy test; 
− 
Visit 2: Serum and urine pregnancy test; collected prior to study drug dosing; 
− 
Visit 3: Serum pregnancy test; 
− 
Visit 4: Serum pregnancy test. 
g AEs recorded from the time of signing of the informed consent form (ICF) up to and including to Visit 4 / ED. 
h The subject complete timed assessments of his / her HAE attack symptoms for a 48h period following drug intake 
as documented in Table 2. 
i Study drug and Subject Diary return only. 
j Note: In the event a subject receives treatment with C1INH or icatibant (all doses) during the study, the following 
washout periods are required prior to the subsequent dosing with study drug: 
• 
7-day washout period required for C1INH. 
• 
3-day washout period required for icatibant. 
k Note: A minimum of 48-hour washout period required between each dose of study drug. 
l The dedicated study physician or qualified designee will contact the subject within 24h of the eligible HAE attack to 
confirm the subject’s safety and wellbeing. 
m A 12-lead ECG recorded over at least 10 seconds after the subject has rested supine on a bed for at least 5 min. 
HR, PR, QRS, QT and RR will be recorded; QTcF calculated as per standard practice. 
− 
Visit 2: ECG performed within 30 min pre-dose and approximately 1h post-dose. 
 
 
 

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Procedures by Visit 
Prior to any study activities, subjects will be asked to read and sign an ICF that has been 
approved by an IEC/ IRB and the Sponsor and which complies with regulatory requirements. 
All times should be recorded using the 24-hour clock (e.g., 23:20, not 11:20 pm). 
7.2.1 Screening Phase 
 Visit 1 
Subjects will undergo screening during Visit 1. Following full discussion of the study and the 
signing of the ICF, a screening subject ID number will be assigned (Section 4.5). 
The following screening and baseline assessments will be performed: 
• 
Eligibility assessment evaluating all results of the screening assessment results against 
the inclusion and exclusion criteria (Section 4). 
• 
Full medical history (Section 6.3.2), including HAE history (Section 6.3.2.1), concomitant 
illnesses / diseases and medications (Section 6.3.3), therapies and supplements taken 
within the past 93 days, previous participation in interventional clinical studies in the past 
93 days. 
• 
Demographic information including race, ethnicity and date of birth (Section 6.3.1). 
• 
Height (m; without shoes) and weight (kg; without shoes or overcoat) (Section 6.3.1). 
Calculation of body mass index (BMI) will be calculated automatically in the database. 
• 
Complete physical examination (Section 6.3.5). 
• 
Vital signs (SBP and DBP, PR, RR, and body temperature). BP and PR recorded after 
subject has been supine for 5 minutes (Section 6.3.4). 
• 
12-lead ECG (Section 6.3.6). 
• 
Blood and urine samples (Section 6.3.7). 
• 
Serum pregnancy test (female subjects of childbearing potential). 
• 
AEs recorded from time of ICF signature (Section 6.2.1). 
• 
Review the study procedures and study visit schedule with the subject. 
7.2.2 Treatment Phase 
 Part 1: Visit 2 
Subjects should attend the clinic for Visit 2 within 28 days following Visit 1 (Screening visit).  
The following assessments will be performed: 
• 
Reconfirm eligibility (Section 4). 
• 
Physical examination (if clinically indicated) (Section 6.3.5). 
• 
Vital signs (SBP and DBP, PR, RR, and body temperature): Pre-dose (0h), 1h, and 4h 
post-dose (Section 6.3.4). 
• 
12-lead ECG (within 30 min pre-dose and approximately 1h post-dose) (Section 6.3.6). 
• 
Blood and urine samples collected 4h post-dose (Section 6.3.7). 
7.2 
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• 
Serum and urine pregnancy test (female subjects of childbearing potential); collected 
prior to study drug dosing. 
• 
Change to the concomitant medication (Section 6.3.3). 
• 
Review and collection of AEs (Section 6.2.1). 
• 
Randomize subject. 
• 
Dispense Subject Diary and provide Subject Diary completion training. 
• 
Check washout periods for treatment with C1INH or icatibant (all doses) have been 
respected prior to dosing with the study drug: 
o 7-day washout period required for C1INH. 
o 3-day washout period required for icatibant. 
• 
Administer the study drug (KVD900 600 mg [equivalent to 6 x 100 mg tablets]) 
(Section 5.2). 
• 
Dispense study drug to be taken at first HAE attack. 
Following a check on the subject’s well-being and safety, and a recap of the procedures to be 
followed in relation to HAE attacks at home, the subject may be discharged from the clinic once 
the 4h post-dose procedures have been completed. 
 Part 2: First HAE attack 
When an attack of HAE occurs, the subject will telephone the dedicated study physician or 
qualified designee with a description of the HAE attack documented in the Subject Diary. This 
description will include: 
• 
Attack location. 
• 
Attack symptoms (e.g. swelling, pain, vomiting). 
• 
Time of onset. 
• 
Attack severity. 
• 
Time of last substantial meal. 
The dedicated study physician or qualified designee will assess the HAE attack against the 
following criteria for a qualifying attack: 
• 
Attack location below the neck (laryngeal or facial attacks are not eligible). 
• 
Attack onset < 1h. 
• 
Attack severity less than severe on the PGI-S (5LS). 
The dedicated study physician or qualified designee will check that the following washout 
periods for treatment with C1INH or icatibant (all doses) have been respected prior to dosing 
with the study drug: 
o 7-day washout period required for C1INH. 
o 3-day washout period required for icatibant. 
If all these criteria are met, the dedicated study physician or qualified designee will instruct the 
subject to take the assigned study drug for the first eligible HAE attack. This will consist of 
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6 tablets, each containing either 100 mg KVD900 (total dose 600 mg) or matching placebo 
tablets. If the HAE attack is not eligible for treatment with the study drug, the subject will 
commence conventional attack treatment. 
The subject will then complete timed assessments of his / her HAE attack symptoms for a 48h 
period following drug intake as documented in Table 2. 
Overall HAE attack severity will be assessed on the PGI-S (5LS) scored as none, mild, 
moderate, severe and very severe. 
Change in HAE attack severity will be assessed using the PGI-C (7TQ), scored as Much better / 
Better / A little better / No change / A little worse / Worse / Much worse. 
The type of HAE attack symptoms (abdominal pain, skin pain and skin swelling) will each be 
assessed on a 100 mm VAS anchored at 0 (none) and 100 (very severe). 
Conventional attack treatment is permitted after 4h, or earlier as warranted, following study drug 
intake, provided HAE attack symptoms are judged severe enough by the subject to require 
treatment as per the subject’s usual treatment regimen, or are deemed ineligible for study drug 
treatment, or are associated with laryngeal or facial symptoms. Prior to use of conventional 
attack treatment, subjects will notify the dedicated study physician or qualified designee who will 
confirm conventional treatment is appropriate per protocol and subject report of symptom 
severity. Subjects are permitted to treat their HAE attacks with their conventional attack 
treatment (pdC1INH or rhC1INH iv or icatibant). 
The dedicated study physician or qualified designee will contact the subject within 24h of the 
eligible HAE attack to confirm the subject’s safety and wellbeing. Subjects will be instructed to 
contact the dedicated study physician or qualified designee in case of any safety concerns. In 
the case of hypersensitivity, subjects are to contact the dedicated study physician or qualified 
designee or contact the nearest emergency service. The dedicated study physician or qualified 
designee will be available 24h/day and 7 days/week to receive subject calls. 
The dedicated study physician or qualified designee will document all contact with the subject in 
the subjects’ source documentation (i.e., medical records). 
 Part 2: Visit 3 
As soon as is practicable (within 7 days), following the first home-treated HAE attack of Part 2, 
the subject will return to the clinic at which the following procedures will be conducted: 
• 
Collect the Subject Diary containing the subject’s assessments relating to the first 
HAE attack treated in Part 2. 
• 
Accountability of any unused study drug/study drug packaging returned by the 
subject. 
• 
Vital signs (SBP and DBP, PR, RR, and body temperature; Section 6.3.4). 
• 
12-lead ECG (Section 6.3.6). 
• 
Complete physical examination (Section 6.3.5). 
• 
Blood and urine samples (Section 6.3.7). 
• 
Serum pregnancy test (female subjects of childbearing potential). 
• 
Changes to concomitant medication (Section 6.3.3). 
• 
Review and collection of AEs (Section 6.2.1). 
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• 
Dispense Subject Diary for second HAE attack of Part 2 and provide Subject Diary 
completion training. 
• 
Dispense assigned study drug to be taken at second HAE attack. 
 Part 2: Second HAE attack 
The procedures to be followed by the subject in relation to the second HAE attack during Part 2 
will be identical to those described in Section 7.2.2.2 above except that, when so instructed by 
the dedicated study physician or qualified designee, the subject will take the assigned study 
drug for the second HAE attack. 
Note: A minimum of 48-hour washout period required between each dose of study drug. 
7.2.3 End of Study / Early Discontinuation 
 Visit 4 
As soon as is practicable (within 7 days) following the second home-treated HAE attack of 
Part 2, the subject will return to the clinic within 7 days for Visit 4 at which the following 
procedures will be conducted: 
• 
Collect the Subject Diary containing the subject’s assessments relating to the first and 
second treated HAE attacks in Part 2. 
• 
Accountability of any unused study drug / study drug packaging returned by the subject. 
• 
Vital signs (SBP and DBP, PR, RR, and body temperature; Section 6.3.4). 
• 
12-lead ECG (Section 6.3.6). 
• 
Complete physical examination (Section 6.3.5). 
• 
Blood and urine samples (Section 6.3.7). 
• 
Serum pregnancy test (female subjects of childbearing potential). 
• 
Change to the concomitant medication (Section 6.3.3). 
• 
Change in AE status (Section 6.2.1). 
Following completion of study procedures and dosing, subjects will resume their standard 
treatment and medical care for HAE. 
7.2.4 Early Discontinuation / Withdrawal 
If any subject discontinues the trial early (Section 4.3), every effort should be made to complete 
Visit 4 (Section 7.2.3) as soon as possible and, whenever possible, prior to starting any new 
medication or treatment. All attempts will be made to avoid early discontinuation. 
Once approximately 50 subjects have successfully completed Parts 1 and 2 of the study, the 
remaining enrolled subjects will be asked to return to the clinic for Visit 4 and return all unused 
study drug (Section 7.2.3). 
7.2.2.4 
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8 
STATISTICAL METHODS 
The statistical considerations in this section summarize the plan for data analysis of this study. 
Before unblinding, a separate statistical analysis plan (SAP) will be finalized, providing detailed 
methods for the analyses outlined below. The SAP will supersede the protocol in the case of 
any inconsistencies between the two documents. Any deviations from the planned analyses 
described in the SAP will be described and justified in the final Clinical Study Report. 
Subjects will be randomized in a 1:1 ratio to 1 of the 2 sequence groups for Part 2: KVD900 
600 mg followed by placebo or placebo followed by KVD900 600 mg. 
 
Study Subjects 
8.1.1 Disposition of Subjects 
The number and percentage of subjects screened, entering and completing each study part will 
be presented, stratified by treatment. Reasons for withdrawal pre- and post-randomization will 
also be summarized. 
8.1.2 Protocol Deviations 
Deviations from the protocol including violations of inclusion / exclusion criteria will be assessed 
as “minor” or “major” in cooperation with the Sponsor. Major deviations from the protocol that 
have the potential to impact the efficacy results will lead to the exclusion of a subject from the 
Per Protocol Set (PPS). Deviations will be defined prior to unblinding. 
8.1.3 Analysis Sets 
Analysis sets are defined as follows: 
• 
Safety set (SAF): Subjects who have taken at least one dose of study drug (including the 
study drug dose in Part 1). 
• 
Full analysis set (for efficacy) (FAS): All randomized subjects who received both doses 
of study drug in Part 2. 
• 
Per protocol set (for efficacy) (PPS): Randomized subjects in Part 2 who received both 
doses of study drug in Part 2 and have no major protocol deviations. 
• 
PK / PD analysis set: All subjects for whom PK / PD samples were taken in Part 1. 
(Note: Subjects enrolled at US study sites will not contribute data for PK and PD 
analysis.) 
The primary efficacy analysis will be based on the FAS. A secondary analysis will also be 
performed based upon the PPS unless the FAS and PPS are the same. All safety analyses will 
be based upon the SAF. 
Demographic and baseline characteristics will be evaluated for the SAF, FAS and for the PPS. If 
one or more subject(s) received incorrect trial drug, these data will also be presented for the 
SAF. 
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General Considerations 
All statistical tests will be two-sided and will be performed at the 5% level of significance, unless 
otherwise stated. Continuous data will be summarized by treatment group using descriptive 
statistics (number, arithmetic mean, median, standard deviation [SD], minimum, and maximum). 
Categorical data will be summarized by treatment group using frequency tables (frequencies 
and percentages). 
All analyses will be carried out using SAS Version 9.4 or higher or using other validated 
software. 
Analysis and data conventions: 
Definition of baseline 
The baseline assessment will be the latest, valid pre-dose assessment available for each dose 
in Part 1 and Part 2. 
Unscheduled assessments 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing AEs) will be included in listings, but not 
summaries. If more than one laboratory value is available for a given visit, the first valid 
observation will be used in summaries and all observations will be presented in listings. It is 
noted that invalid laboratory data may not be used (from hemolyzed samples, mishandled 
samples, quantity not sufficient, or other conditions that would render values invalid).  
Missing data conventions 
Statistical handling of missing assessments, e.g. measurements not collected during sleep at 
night, will be outlined in the SAP. 
Multiplicity Considerations 
No multiplicity adjustments are planned in this Phase 2 study. 
Other considerations 
Treatment by centre interactions will not be conducted. Any outliers that are detected during the 
blinded review of the data will be investigated. If necessary, queries will be issued to the 
Investigator, to either correct or confirm the outlier. 
 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications 
Demographic data, medical history, concomitant diseases, and concomitant medications will be 
summarized via descriptive statistics, as appropriate, (overall and by sequence group). 
Medical history, concomitant medications and AEs will be coded to Medical Dictionary for 
Regulatory Activities (MedDRA Version 21.0 or higher) and World Health Organization (WHO) 
Drug dictionaries, as appropriate, for the purpose of summarization. 
8.2 
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Treatment Compliance 
Study drug in Part 1 of the study will be administered under the direct supervision of the site 
staff and hence compliance is not expected to be problematic. 
Compliance in Part 2 of the study will be assessed by review of returned study drug and subject 
diaries. Non-compliance is not expected to be significant, given the single treatment and short 
length of the assessment period. 
Refer also to Section 5.6. 
 
Efficacy Analyses 
All efficacy variables will be displayed in subject listings. 
8.5.1 Primary Efficacy Analysis 
 Hypothesis to be Tested 
The null hypothesis is that the time to use of conventional attack treatment following KVD900 
treatment and the time to conventional attack treatment following placebo treatment are 
identical: 
H0: tk - tp = 0, 
where tk is the time to use of conventional attack treatment following KVD900 treatment 
in Part 2 and tp is the time to conventional attack treatment following placebo treatment. 
The alternative hypothesis is that the time to use of conventional attack treatment following 
KVD900 treatment is different from the time to conventional attack treatment following placebo 
treatment: 
Ha: tk - tp ≠ 0. 
 Statistical Methods 
The primary endpoint, time to use of conventional attack treatment within 12h of study drug, will 
be analyzed using a 
 
to reflect the repeat measures on each subject. Subjects will be treated as censored if 
conventional attack treatment is not used within 12h of study drug.  
8.5.2 
Secondary and Exploratory Efficacy Analyses 
The secondary efficacy endpoints, which will be analyzed for Part 2 of the study, are: 
• 
PGI-S (5LS): 
o Worsening (including use of conventional attack treatment): 
• 
Proportion of HAE attacks that (1) worsen by one level or more from baseline or 
(2) use conventional attack treatment within 12h of study drug. 
• 
Time to (1) worsening by one level or more from baseline, or (2) use of 
conventional attack treatment, whichever comes first within 12h of study drug. 
8.4 
8.5 
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• 
PGI-C (7TQ): 
o Improvement: 
• 
Time to symptom relief (A little better or higher, 2 time points in a row) within 12h 
of study drug. 
• 
Visual Analogue Scale (VAS): 
o Improvement: 
• 
Time to symptom relief (50% reduction from baseline in composite VAS, 3 time 
points in a row) within 12h of study drug. 
The exploratory endpoints are: 
• 
Use of Conventional Treatment: 
o Proportion of HAE attacks that require conventional attack treatment within 12h and 24h 
of study drug. 
o Time to use of conventional attack treatment within 24h of study drug. 
• 
PGI-S (5LS): 
o AUC: 
• 
Cumulative PGI-S (5LS) expressed as AUC within 12h and 24h of study drug. 
o Worsening (including use of conventional attack treatment): 
• 
Proportion of HAE attacks that (1) worsen by one level or more from baseline or 
(2) use of conventional attack treatment within 24h of study drug. 
• 
Time to (1) worsening by one level or more from baseline or (2) use of 
conventional attack treatment, whichever comes first, within 24h of study drug. 
o Worsening Only: 
• 
Time to worsening by one level or more from baseline within 12h and 24h of 
study drug. 
o Improvement: 
• 
Proportion of HAE attacks that improve by one level or more from baseline within 
12h and 24h of study drug. 
• 
Time to improvement by one level or more from baseline within 12h and 24h of 
study drug. 
• 
Proportion of subjects with HAE attack resolution (rating of none) within 12h and 
24h of study drug. 
• 
Time to HAE attack resolution (rating of none) within 12h and 24h of study drug. 
o Stable or Improvement: 
• 
Proportion of HAE attacks that are stable or improved from baseline within 12h 
and 24h of study drug. 
• 
PGI-C (7TQ): 
o AUC: 
• 
Cumulative PGI-C (7TQ) expressed as AUC within 12h and 24h of study drug. 
o Worsening (including use of conventional attack treatment): 

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• 
Proportion of HAE attacks that are (1) rated A little worse or higher, 2 time points 
in a row or (2) use of conventional attack treatment within 12h and 24h of study 
drug. 
• 
Time to HAE attack being (1) rated A little worse or higher, 2 time points in a row, 
or (2) use of conventional attack treatment, whichever comes first, within 12h and 
24h of study drug. 
o Worsening Only: 
• 
Time to HAE attack being rated A little worse or higher, 2 time points in a row, 
within 12h and 24h of study drug. 
o Improvement: 
• 
Proportion of HAE attacks that are rated A little better or higher, 2 time points in a 
row, within 12h and 24h of study drug. 
• 
Time to HAE attack being rated A little better or higher, 2 time points in a row, 
within 24h of study drug. 
• 
Proportion of HAE attacks that are rated Better or higher within 12h and 24h of 
study drug. 
• 
Time to HAE attack being rated Better or higher within 12h and 24h of study 
drug. 
o Stable or Improvement: 
• 
Proportion of HAE attacks that are stable or improved within 12h and 24h of 
study drug. 
• 
Visual Analogue Scale (VAS): 
o AUC: 
• 
Cumulative composite VAS expressed as AUC within 12h and 24h of study drug. 
o Improvement: 
• 
Proportion of HAE attacks with symptom relief (50% reduction from baseline in 
composite VAS, 3 time points in a row) within 12h and 24h of study drug. 
• 
Time to symptom relief (50% reduction in composite VAS, 3 time points in a row) 
within 24h of study drug. 
For comparisons of proportions, 
will be used to compare the treatment 
arms. Secondary and exploratory endpoints, using time to event as the unit of analysis, will be 
analyzed in the same way as the primary endpoint, 
 
. 
 
Safety Analyses 
Safety endpoints include AEs / SAEs, physical exam findings, ECG results, laboratory test 
results (clinical chemistry, hematology, coagulation, and urinalysis), and vital signs (SBP, DBP, 
PR, RR and body temperature). 
8.6.1 Adverse Events 
AEs will be coded using the MedDRA dictionary (v21.0 or higher). Frequencies and percentages 
of subjects with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs 
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causing premature discontinuation will be provided by treatment group. An AE is treatment 
emergent if it 1) occurs after the first dose of study drug in Part 1 or Part 2 or 2) if it is present 
prior to receipt of randomized study treatment but worsens in severity or increases in frequency 
after the first dose of study drug.  
Frequency counts will be given of subjects with TEAEs by system organ class (SOC) and 
preferred term; by SOC, preferred term and maximal severity; by SOC, preferred term and 
strongest relationship; by SOC and preferred term for SAEs; and by SOC, preferred term, and 
day of onset. AEs will be classified by SOC and preferred term in the MedDRA coding 
dictionary. AEs will be tabulated both as the total events (regardless of relationship to treatment) 
and as drug-related events (by treatment period: (1) active, combined for treatment taken in Part 
1 and Part 2, and (2) placebo (taken in Part 2). The number of subjects with one or more events 
versus no events will be calculated for each treatment. 
Subject listings of all AEs will be provided as well as listings of deaths, SAEs, and AEs leading 
to discontinuation. 
The following summaries will be provided: 
• 
Relationship between AE SOC and verbatim text. 
• 
On-treatment AEs: Number and percentage of subjects reporting each AE, each AE 
leading to withdrawal, each SAE, each drug-related SAE, each fatal AE, and most 
frequent by treatment. 
• 
Post-treatment AEs: Number and percentage of subjects reporting each AE. 
• 
Listing of all AEs. 
• 
Summary of Most Frequent AEs. 
8.6.2 Laboratory Assessments 
Laboratory assay results include clinical chemistry, hematology, coagulation, and urinalysis. 
Continuous parameters will be summarized using descriptive statistics for each treatment group 
and for all subjects at each visit. Changes from baseline will also be summarized for each 
treatment group and for all subjects where appropriate. Each categorical parameter will be 
summarized using frequency counts and percentages for each treatment group and for all 
subjects. A shift table of the changes from baseline will also be presented. 
The high / low criteria will be determined based on the reference ranges provided by the 
laboratory. Summaries of assessments outside the normal range and the changes from 
baseline relative to the normal range will also be produced. A subject listing of laboratory 
assessments will also be produced and will include changes from baseline at each visit. Data 
from subjects who have values outside the normal range will be specified in this listing. 
8.6.3 Vital Signs 
Vital sign measurements, including PR, RR, blood pressure (SBP, DBP), and body temperature 
will be summarized for baseline (pre-treatment, Visit 2). 
PR, RR, blood pressure (SBP, DBP) and body temperature will be summarized by time point 
throughout Part 1 using continuous descriptive statistics for all subjects. Change from baseline 
during Part 1will also be summarized for all subjects. 
SBP and DBP, PR, respiration rate, and body temperature will be summarized by treatment 
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A subject listing will also be produced and will include changes from baseline by time point 
throughout Part 1. 
8.6.4 Physical Examination 
A subject listing of the Visit 1 (Screening), Visit 3, and Visit 4 physical examination findings will 
be produced. 
8.6.5 
Electrocardiograms 
Twelve-lead ECG data (observed and change from baseline) will be listed for each subject and 
time point. Observed values as well as change from baseline at each time point will be 
summarized descriptively in tabular format. An ECG shift table will be presented. Clinically 
significant worsening from baseline or new clinically significant ECG abnormalities that were 
considered AEs by the Investigator will be presented in the AE analyses. 
8.7 
Pharmacokinetic / Pharmacodynamic Analysis 
Note that PK/PD blood samples will not be collected from subjects enrolled at US study sites. 
8.7.1 
Pharmacokinetic Analysis 
Non-compartmental PK parameters will include, but are not limited to, maximum concentration 
in plasma (Cmax), time to reach Cmax in plasma (tmax), area under the curve from time O to last 
measurable concentration (AUCo-1), apparent clearance (CUF), apparent volume of distribution 
(Vd/F) and estimated terminal elimination half-life (t½). A complete list of PK parameters 
planned to be calculated will be described in the SAP. 
The PK parameters of KVD900 will be determined from the individual concentration versus time 
data using Phoenix WinNonlin. In case of a deviation from the theoretical time, the actual time of 
blood sample will be used in the calculation of the derived PK parameters. Individual 
concentrations and derived PK parameters of KVD900 in plasma will be listed and summarized 
for each treatment. Individual and geometric mean concentration-time data will be plotted on 
linear and semi-logarithmic scales. 
8. 7 .2 
Pharmacodynamic Analysis 
KVD900's effect on PKa activity will be analyzed using two exploratory measures of PKa 
enzyme activity in plasma: 
I 
I 
The PD will be summarized for each treatment. Individual and mean data will be provided as a 
report addendum located in the appendix of the final Clinical Study Report. 
8.8 
Interim Analyses 
No interim analyses are planned. 
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Determination of Sample Size 
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Approximately 60 subjects will be enrolled to ensure that approximately 50 subjects complete 
the study. A sample size of approximately 50 subjects completing both treatment periods (25 
per sequence) is proposed to provide 90% power for testing at the 5% alpha level (2-sided) for 
th 
. 
d 
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t 
f 
f 
I tt 
k t 
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t ·th· 12h f t d d 
I 
I 
I 
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pie 
size. 
An oversampling by 20% (10 subjects) is proposed to account for subjects that may not 
complete both treatment periods due to infrequent or ineligible HAE attacks or for subjects who 
discontinue the trial early, for whatever reason. Thus, study enrolment will be considered 
sufficient to address the primary efficacy hypothesis after approximately 50 subjects have 
completed both treatment periods. Since further exposure is not required and could be 
considered unnecessary, ongoing subjects who have not completed both periods will be asked 
to return to the study site and complete Visit 4 (Early Discontinuation visit). Data from all 
subjects, complete and incomplete, will be analyzed in the safety set. 
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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
 
Data Quality Assurance 
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of each 
Investigator, inspect the site facilities, and inform the Investigator of responsibilities and the 
procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. All 
information recorded on the eCRF system for this study must be consistent with the subjects’ 
source documentation (i.e., medical records). 
9.1.1 Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study centre 
using eCRFs. Data from external sources (such as laboratory data) will be imported into the 
database. Once the eCRF clinical data have been submitted to the central server at the 
independent data centre, corrections to the data fields will be captured in an audit trail. The 
reason for change, the name of the person who performed the change, together with the time 
and date will be logged to provide an audit trail.  
If additional corrections are needed, the responsible Orion CRA or data manager will raise a 
query in the electronic data collection (EDC) application. The appropriate staff at the study site 
will answer queries sent to the Investigator. The name of the staff member responding to the 
query and time and date stamp will be captured to provide an audit trail. Once all source data 
verification is complete and all queries are closed, the eCRF page will be frozen. 
The specific procedures to be used for data entry and query resolution using the EDC system / 
eCRF will be provided to study sites in a training manual. In addition, site personnel will receive 
training on the EDC system / eCRF. 
 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the eCRF. All source documents from 
which eCRF entries are derived should be placed in the subject’s medical records. 
Measurements for which source documents are usually available include laboratory 
assessments, and study specific examinations.  
Data that will be entered directly into the eCRF system (i.e., for which there is no prior written or 
electronic record of data) are considered to be source data. 
The original eCRF entries for each subject may be checked against source documents at the 
study site by the Orion CRA. 
After review by the Orion CRA, completed eCRF entries will be uploaded and forwarded to 
Orion. Instances of missing or uninterpretable data will be discussed with the Investigator for 
resolution.  
The specific procedures to be used for data entry and query resolution using the eCRF will be 
provided to study sites in a training manual. In addition, site personnel will receive training on 
the EDC system / eCRF. 
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9.2.1 Data Collection  
The Investigators (and appropriately authorized staff) will be given access to an on-line 
web-based EDC system which is 21 CFR Part 11 compliant. This system is specifically 
designed for the collection of the clinical data in electronic format. Access and right to the 
EDC system will be carefully controlled and configured according to each individual’s role 
throughout the study. In general, only the Investigator and authorized staff will be able to enter 
data and make corrections in the eCRFs. 
The eCRF should be completed for each subject included in the study and should reflect the 
latest observations on the subjects participating in the study. Therefore, the eCRFs are to be 
completed as soon as possible during or immediately after the subject’s visit or assessment. 
The Investigator must verify that all data entries in the eCRF are accurate and correct. If some 
assessments cannot be done, or if certain information is unavailable, not applicable or unknown, 
the Investigator should indicate this in the eCRF.  
Computerized data–check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and the site 
will be informed about new issues to be resolved on-line. All discrepancies will be solved on–
line directly by the Investigator or by authorized staff. Off–line edit checks will be done to 
examine relationships over time and across panels to facilitate quality data. 
After completion, the Investigator will be required to electronically sign off the clinical data. 
Data about all study product dispensed to the subject and any dosage changes will be tracked 
on the eCRF.  
 
Access to Source Data 
During the study, the Orion CRA will make site visits to review protocol compliance, compare 
eCRF entries and individual subject’s source medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements. The 
review of medical records will be performed in a manner to ensure that subject confidentiality is 
maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, Regulatory 
Authorities of certain countries, IECs, IRBs and / or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and / or on–site audit inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator assures 
Orion and the Sponsor of the necessary support at all times. 
 
Data Processing 
All data will be entered by site personnel into the EDC system / eCRF (as detailed in 
Section 9.2.1). 
The data-review and data-handling document, to be developed during the initiation phase of the 
study, will include specifications for consistency and plausibility checks on data and will also 
include data-handling rules for obvious data errors. Query / correction sheets for unresolved 
queries will be sent to the study CRAs for resolution with the Investigator. The database will be 
updated on the basis of signed corrections. 
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Previous and concomitant medications will be coded using the WHO Drug Reference 
List (DRL), which employs the Anatomical Therapeutic Chemical (ATC) classification system. 
Medical history / current medical conditions and AEs will be coded using the 
MedDRA terminology. 
Previous and concomitant diseases as well as AEs will be coded with MedDRA. 
The versions of the coding dictionaries will be provided in the Clinical Study Report. 
 
Archiving Study Records 
According to International Council on Harmonization (ICH) guidelines, essential documents 
should be retained for a minimum of 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the IMP. However, these documents should be retained for a longer period if 
required by the applicable legal requirements. 
 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the Good Clinical Practice (GCP)2 guidelines of the ICH, 
and of the Declaration of Helsinki (2013)3. The study also will be carried out in keeping with 
local legal requirements. 
 
Informed Consent 
Before each subject is admitted to the study, informed consent will be obtained from the subject 
according to the regulatory and legal requirements of the participating country. As part of this 
procedure, the Investigator or designee must explain orally and in writing the nature, duration, 
and purpose of the trial, and the action of the study drug in such a manner that the subject is 
aware of the potential risks, inconveniences, or adverse effects that may occur. The subject will 
be informed that he / she is free to withdraw from the trial at any time. The subject will be given 
sufficient time to ask questions, understand and to take a decision on his participation. The 
consent form must be dated and signed by both the subject and the person obtaining the 
consent in two copies. One of the copies will be given to the subject and the other will be 
retained by the Investigator as part of the study records. The Investigator will not undertake any 
investigation specifically required only for the clinical study until valid consent has been 
obtained. The terms of the consent and when it was obtained must also be documented in the 
eCRF. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to 
the protocol. If the consent form is revised, it must be reviewed and approved by the appropriate 
IEC, IRB and signed by all subjects subsequently enrolled in the study as well as those currently 
enrolled in the study. 
 
2 International Council for Harmonization (ICH) E6 – Good Clinical Practice (GCP) (R2). 
3 World Health Association Declaration of Helsinki. Recommendations guiding physicians in biomedical research 
involving human subjects. (as adopted by the 64th World Medical Assembly General Assembly, Fortaleza, Brazil, 
October 2013) 
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Protocol Approval and Amendment 
Before the start of the study, the study protocol and / or other relevant documents will be 
approved by the IEC/ IRB/ Regulatory Authorities. The Sponsor must ensure that all ethical and 
legal requirements have been met before the first subject is enrolled in the study. 
Substantial protocol amendments must be submitted to the Regulatory Authority(ies) for 
approval prior to implementation and to the IECs/IRBs for approval as per local regulations. 
Administrative changes which are not deemed substantial may be made without the need for 
IEC / /IRB/ Regulatory Authority approval. All amendments will be distributed to all protocol 
recipients, with appropriate instructions. 
 
Duration of the Study 
For an individual subject, the maximum duration of the study is likely to be approximately 
19 weeks (including up 28 days for screening, 1 day for Part 1, expect up to 93 days duration for 
subject to experience 2 qualified HAE attacks, and approximately 2 weeks between 2nd HAE 
attack and Visit 4). 
 
Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or events 
that suggest a possible hazard to subjects if the study continues, the study may be terminated 
after appropriate consultation between the relevant parties. The study may also be terminated 
early at the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• 
The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled 
in the study. 
• 
Failure to enroll subjects at an acceptable rate. 
• 
A decision on the part of the Sponsor to suspend or discontinue development of the 
drug. 
The termination of the study after approximately 50 completed subjects is not considered 
premature termination of the study. 
 
Confidentiality 
Personal data of the subject shall be processed in a manner that ensures it has appropriate 
security. This includes protection against unauthorized or unlawful processing and against 
accidental loss, destruction or damage and by using appropriate technical or organizational 
measures. One such measure is by the Investigator ensuring that the subjects’ personally 
identifiable information is replaced through the use of pseudonymization. 
On the eCRFs or other documents submitted to the Sponsor and / or delegate, subjects will 
NOT be identified by their names but by the assigned subject number and their initials to ensure 
confidentiality of the subject’ information and that data minimization principles are maintained. 
If subject names are included in error on copies of documents submitted to Sponsor and / or 
delegate, the names (except for initials) will be erased or securely destroyed and the assigned 
subject number added to the document. 
9.8 
9.9 
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The Investigator should keep a separate log (Patient Master List) of patient’s codes (assigned 
patient number), names, addresses, telephone numbers and hospital numbers. The bodily 
material that is sent to the sponsor and / or delegates (including laboratories) assisting with the 
study research, will only contain the patient’s code. Documents not intended for submission to 
Sponsor and / or delegate (e.g. signed consent forms) should be maintained by the Investigator 
in strict confidence and not disclosed to any parties outside of this approved agreement. eCRFs 
should be protected by use of strong encryption. 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his / her research team must not disclose such information without prior written 
approval from the Sponsor. 
 
Other Ethical and Regulatory Issues  
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to all parties – Regulatory 
Authorities, Investigators, and IECs/ IRBs. 
A significant safety issue is one that has a significant impact on the course of the clinical study 
or program (including the potential for suspension of the development program or amendments 
to protocols) or warrants immediate update of informed consent. 
 
Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the study for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals. If necessary, Regulatory Authorities will be notified of the 
Investigator's name, address, qualifications, and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the Sponsor in advance. Details are provided in a separate document. 
 
Insurance 
In accordance with legal requirements, the Sponsor will take out insurance covering potential 
damage for all subjects who participate in the clinical trial prior to commencement of the trial. 
The name of the insurance company as well as the date of the initial insurance certificate will be 
provided to the IEC and will be mentioned in the subject information sheet. 
All participating subjects or their legal representatives will be informed about the existence of 
the insurance policy and will have the right to review its terms and conditions. 
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10 DEFINITION OF END OF TRIAL 
The end of trial is defined as last subject last visit.  

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