A Randomized, Double-Blind, Placebo-Controlled, Phase 3, Three-way Crossover Trial to Evaluate the Efficacy and Safety of Two Dose Levels of KVD900, an Oral Plasma Kallikrein Inhibitor, for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema Type I or II
Phase: PHASE3
Conditions: Hereditary Angioedema
Sponsor: KalVista Pharmaceuticals, Ltd.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
PROTOCOL TITLE 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3, Three-way Crossover Trial to Evaluate 
the Efficacy and Safety of Two Dose Levels of KVD900, an Oral Plasma Kallikrein Inhibitor, for 
On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients with Hereditary 
Angioedema Type I or II 
Protocol Number: 
KVD900-301 
Protocol Name: 
KONFIDENT 
Compound: 
KVD900 (300 mg Film-Coated Tablet) 
Trial Phase: 
3 
Sponsor: 
KalVista Pharmaceuticals Ltd 
Porton Science Park 
Bybrook Road 
Porton Down 
Salisbury, SP4 0BF 
United Kingdom 
IND Number: 
143807 
EudraCT Number: 
2021-001226-21 
Date of Protocol: 
04 May 2023 (US Only), Version 4.1 
11 October 2022 (US Only), Version 3.1 
26 May 2022, Version 3.0 
10 February 2022, Version 2.0 
18 October 2021, Version 1.0 
Compliance 
This trial will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International 
Council for Harmonisation), ethical principles that have their 
origin in the Declaration of Helsinki and all applicable national 
and local regulations. 
The information in this document is confidential and is proprietary to KalVista Pharmaceuticals Ltd. It 
is understood that information in this document shall not be disclosed to any third party, in any form, 
without prior written consent of an authorized officer of KalVista Pharmaceuticals Ltd. 
Page 1 of 67 

 
CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
 
Page 2 of 67 
1. 
SIGNATURE PAGE 
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3, Three-way Crossover Trial to 
Evaluate the Efficacy and Safety of Two Dose Levels of KVD900, an Oral Plasma Kallikrein Inhibitor, 
for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients with Hereditary 
Angioedema Type I or II  
 
This trial protocol was subjected to critical review. The information it contains is consistent with current 
knowledge of the risks and benefits of the investigational medicinal product, as well as with the moral, 
ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki 
(World Medical Association 2013) and the guidelines on Good Clinical Practice (GCP). 
Chief Medical Officer 
KalVista Pharmaceuticals Ltd 
Vice President, Clinical 
KalVista Pharmaceuticals Ltd 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________ 
_____________________ 
_____________________________________ 
CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
2. 
DECLARATION OF THE INVESTIGATOR 
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3, Three-way Crossover Trial to 
Evaluate the Efficacy and Safety of Two Dose Levels of KVD900, an Oral Plasma Kallikrein Inhibitor, 
for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients with Hereditary 
Angioedema Type I or II 
All documentation for this trial that is supplied to me and that has not been previously published will 
be kept in the strictest confidence. This documentation includes this trial protocol, Investigator's 
Brochure (IB), electronic case report form (eCRF), and other scientific data. 
The trial will not be commenced without the prior written approval of a properly constituted Ethics 
Committee (EC)/Institutional Review Board (IRB). No substantial changes will be made to the trial 
protocol without the prior written approval of the Sponsor and the EC/IRB, except where necessary 
to eliminate an immediate hazard to the patients. 
I have read and understood and agree to abide by all the conditions and instructions contained in this 
protocol and will conduct the trial in compliance with regulatory requirements and Good Clinical 
Practice (GCP). 
Investigator Signature 
Date 
Name (block letters) 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
The purpose of this amendment is to make statistical analysis changes to the protocol as requested 
by the US Food and Drug Administration (FDA) and to clarify statistical analyses to be performed for 
this trial. The changes from Version 3.1 to Version 4.1 of the protocol are as follows: 
• 
Corrected inclusion criterion 6a) to specify that patients who have had at least 
2 documented attacks prior to screening meet this inclusion criterion (in addition to patients 
who have had at least 2 documented attacks prior to randomization). 
o 
Rationale: The purpose of this change was to correct the inclusion criterion to meet 
the Sponsor’s original intent, which was to ensure that patients are attacking 
frequently enough to have 3 HAE attacks during the trial period. The 2 documented 
attacks can occur prior to screening or prior to randomization; however, the protocol 
inadvertently did not include ‘screening’ in the criterion. 
• 
Modified the censoring strategy for conventional on-demand treatment from a hypothetical 
strategy to a composite strategy. 
o 
Rationale: Per FDA recommendation, receiving conventional on-demand attack 
treatment should be considered as a treatment failure. Using a composite strategy, 
time-to-event results for attacks with conventional on-demand attack treatment use 
will be censored at the end of analysis window, which represents the worst-case 
scenario. 
• 
Changed the Full Analysis Set definition from requiring IMP treatment for at least 2 periods 
to just 1 period. 
o 
Rationale: The analysis method used for the primary analyses doesn’t require 
observations from at least 2 periods. Therefore, this update to the FAS allows more 
on-treatment attacks to be included in the primary efficacy analyses. 
• 
Added alpha loop-back feature in the multiplicity adjustment strategy. 
o 
Rationale: The Bonferroni multiplicity adjustment method is conservative; allowing 
alpha loop-back will improve the power of the hypothesis testing and maintain the 
overall Type I error rate of 0.05. 
• 
Updated key secondary endpoint #1 to assess sustained improvement by requiring at least 
2 time points in a row with the same (or better) measurement. 
o 
Rationale: This change was made per FDA recommendation. Requiring sustained 
improvement will reduce the impact of spontaneous or unsustained improvement. 
• 
Added additional subgroup analyses. 
o 
Rationale: Added subgroup analyses to investigate consistency in treatment effects 
in additional subgroups. 
• 
Clarified that additional endpoints may be added to the Statistical Analysis Plan. 
Minor typographical corrections and editorial changes are not described above. 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE.....................................................................................................................2 
2. 
DECLARATION OF THE INVESTIGATOR .................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ...................................................................4 
3. 
SYNOPSIS ..................................................................................................................................9 
4. 
KEY CONTACT LIST.................................................................................................................19 
5. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................20 
6. 
INTRODUCTION .......................................................................................................................23 
6.1 
Background.....................................................................................................................23 
6.2 
Trial Rationale.................................................................................................................23 
6.3 
Benefit/Risk.....................................................................................................................24 
6.3.1 
Impact of COVID-19 on Benefit-Risk Assessment...................................................26 
6.3.2 
COVID-19 Vaccination.............................................................................................26 
7. 
OBJECTIVES AND ENDPOINTS..............................................................................................27 
7.1 
Objectives .......................................................................................................................27 
7.1.1 
Primary ....................................................................................................................27 
7.1.2 
Secondary................................................................................................................27 
7.2 
Endpoints ........................................................................................................................27 
7.2.1 
Primary Endpoint .....................................................................................................27 
7.2.2 
Key Secondary Endpoints .......................................................................................27 
7.2.3 
Secondary Endpoints...............................................................................................27 
7.2.4 
Exploratory Endpoints..............................................................................................27 
7.3 
Estimands .......................................................................................................................28 
8. 
TRIAL DESIGN..........................................................................................................................29 
8.1 
Overall Design ................................................................................................................29 
8.2 
Scientific Rationale for Trial Design ................................................................................29 
8.3 
Justification for Dose.......................................................................................................30 
8.4 
End of Trial Definition......................................................................................................30 
9. 
TRIAL POPULATION ................................................................................................................31 
9.1 
Inclusion Criteria .............................................................................................................31 
9.2 
Exclusion Criteria ............................................................................................................32 
10. INVESTIGATIONAL MEDICINAL PRODUCT ...........................................................................34 
10.1 
Investigational Medicinal Product Administration............................................................34 
10.2 
Packaging and Labeling..................................................................................................34 
10.3 
Storage and Drug Accountability ....................................................................................35 
10.4 
Trial Medication Compliance...........................................................................................35 
11. MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING....................................36 
11.1 
Patient Numbers Identification ........................................................................................36 
11.2 
Randomization Scheme..................................................................................................36 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
11.3 
Blinding ...........................................................................................................................36 
12. PERMITTED THERAPIES AND PROHIBITED THERAPIES....................................................38 
12.1 
Conventional On-Demand Treatment .............................................................................38 
12.2 
Long- and Short-term Prophylactic Treatment................................................................38 
12.3 
Prohibited Therapies.......................................................................................................38 
13. PATIENT DISCONTINUTION....................................................................................................40 
14. ASSESSMENTS........................................................................................................................41 
14.1 
Patient Demographics and Medical History ....................................................................41 
14.2 
Efficacy Assessments .....................................................................................................41 
14.3 
Safety Assessments .......................................................................................................42 
14.3.1 
Physical Examinations.............................................................................................42 
14.3.2 
Vital Signs................................................................................................................42 
14.3.3 
12-Lead Electrocardiogram .....................................................................................42 
14.3.4 
Clinical Safety Laboratory Assessments .................................................................42 
15. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.......................................................44 
15.1 
Adverse Events...............................................................................................................44 
15.2 
Serious Adverse Events..................................................................................................44 
15.3 
Time Period and Frequency for Collection......................................................................44 
15.4 
Method of Detection........................................................................................................44 
15.5 
Severity ...........................................................................................................................45 
15.6 
Relationship ....................................................................................................................45 
15.7 
Reporting ........................................................................................................................45 
15.7.1 
Reporting AEs to EC/IRB and Regulatory Authorities .............................................45 
15.7.2 
Reporting Serious Adverse Events or Urgent Safety Measures..............................45 
15.7.3 
Reporting Suspected Unexpected Serious Adverse Reactions...............................46 
15.8 
Pregnancy.......................................................................................................................46 
15.9 
Treatment of Overdose ...................................................................................................47 
16. TRIAL PROCEDURES ..............................................................................................................48 
16.1 
Screening Period ............................................................................................................48 
16.1.1 
Screening Visit (In-Clinic or Home Health Visit).......................................................48 
16.2 
Randomization Visit (Televisit or In-Clinic) .....................................................................49 
16.3 
Treatment Period ............................................................................................................49 
16.3.1 
First, Second, and Third Eligible HAE Attack (Televisit)..........................................51 
16.3.2 
Final Visit/Early Termination (In-Clinic or Home Health Visits)................................52 
17. STATISTICAL CONSIDERATIONS...........................................................................................53 
17.1 
Sample Size Determination ............................................................................................53 
17.2 
Estimands and Intercurrent Events.................................................................................54 
17.3 
Populations for Analyses ................................................................................................55 
17.4 
General Considerations ..................................................................................................55 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
17.4.1 
Multiplicity Adjustment .............................................................................................55 
17.5 
Analysis of Disposition ....................................................................................................56 
17.6 
Demographics and Baseline Characteristics ..................................................................56 
17.7 
Statistical Analysis of Efficacy Endpoints........................................................................57 
17.7.1 
Primary Endpoint .....................................................................................................57 
17.7.2 
Gehan Score Transformation Test ..........................................................................59 
17.7.3 
Imputation under Informative Censoring..................................................................59 
17.7.4 
Gehan’s Generalized Wilcoxon Test .......................................................................59 
17.7.5 
Key Secondary Endpoints .......................................................................................59 
17.7.6 
Subgroup and Subset Analyses ..............................................................................60 
17.7.7 
Other Endpoints.......................................................................................................60 
17.7.8 
Exploratory Endpoint(s) ...........................................................................................60 
17.8 
Safety Analyses ..............................................................................................................61 
17.9 
Interim Analyses .............................................................................................................61 
18. TRIAL ADMINISTRATION.........................................................................................................62 
18.1 
Direct Access to Source Data/Documents......................................................................62 
18.2 
Quality Control and Quality Assurance ...........................................................................62 
18.3 
Ethics ..............................................................................................................................62 
18.3.1 
Regulatory and Ethical Considerations....................................................................62 
18.3.2 
Informed Consent/Assent ........................................................................................62 
18.3.3 
Patient Confidentiality ..............................................................................................62 
18.4 
Data Handling and Record Keeping ...............................................................................63 
18.4.1 
Source Documents ..................................................................................................63 
18.4.2 
Trial Monitoring ........................................................................................................63 
18.4.3 
Database Management ...........................................................................................63 
18.4.4 
Retention of Trial Records .......................................................................................63 
18.5 
Financing and Insurance.................................................................................................63 
18.5.1 
Financial Disclosure.................................................................................................63 
18.5.2 
Trial Insurance .........................................................................................................64 
18.6 
Publication Policy............................................................................................................64 
18.7 
Trial Master File ..............................................................................................................64 
18.8 
Premature Trial Closure..................................................................................................64 
18.9 
Selection of Coordinating Investigator ............................................................................64 
19. REFERENCES ..........................................................................................................................65 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
LIST OF TABLES AND FIGURES 
Table 1: 
Schedule of Events .........................................................................................................17 
Table 2: 
Primary Objective and Estimand.....................................................................................28 
Table 3: 
Sample Randomization Schedule...................................................................................36 
Table 4: 
Frequency of Patient Assessment ..................................................................................42 
Table 5: 
Laboratory Assessments ................................................................................................43 
Table 6: 
Intercurrent Event Types.................................................................................................54 
Table 7: 
Estimands with Rationale for Strategies to Address Intercurrent Events........................54 
Table 8: 
Summary of Statistical Methods and Sensitivity Analyses for Primary Endpoint............58 
Figure 1: Trial Diagram ..................................................................................................................29 
Figure 2: Schematic of Repeat Dosing ..........................................................................................51 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
3. 
SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3, Three-way Crossover 
Trial to Evaluate the Efficacy and Safety of Two Dose Levels of KVD900, an Oral 
Plasma Kallikrein Inhibitor, for On-Demand Treatment of Angioedema Attacks in 
Adolescent and Adult Patients with Hereditary Angioedema Type I or II 
Trial No 
KVD900-301 
Protocol Name 
KONFIDENT 
Phase 
3 
Trial Centers 
Hereditary angioedema (HAE) treatment centers worldwide 
Objectives 
Primary Objective 
• 
To demonstrate the clinical efficacy of KVD900 compared with placebo for the 
on-demand treatment of HAE attacks. 
Secondary Objective 
• 
To investigate the safety and tolerability of KVD900. 
Trial Design &
KONFIDENT is a double-blind, randomized, placebo-controlled, multicenter clinical 
Procedures 
trial in patients 12 years or older with HAE type I or II. Patients will be randomized to 
6 treatment sequences in a 3-way crossover design. Eligible attacks will initially be 
treated with a single dose of placebo, 300 mg, or 600 mg KVD900 per attack. If needed 
(as determined by the patient), a second dose of IMP may be administered for each 
attack. 
The estimated duration of this trial for each randomized patient will be approximately 
25 weeks from Screening through the Final Visit and includes the treatment of 3 eligible 
attacks during the Treatment Period. 
The trial will be conducted at HAE treatment centers worldwide on an outpatient basis 
and will comprise in-clinic and televisits. A televisit can be conducted via a telephone 
call or via an interactive audio/video system. 
Screening Visit 
Eligible patients ≥12 years old will undergo a screening assessment for trial inclusion. 
All patients will provide informed consent or assent prior to any trial- related procedures 
being performed. Informed consent and assent may be collected through e-consent if 
allowed through country and site regulations. 
During the visit, a physical exam, 12-lead electrocardiogram (ECG), laboratory tests 
(including diagnostic testing for HAE), and other assessments as outlined in the 
Schedule of Events (Table 1) will be performed. 
Site personnel will train patients on the information they will be expected to provide in 
the electronic diary (eDiary) and the use of investigational medicinal product (IMP). 
Randomization Visit 
Within 4 weeks of the Screening Visit, patients will participate in a Randomization Visit. 
Patients will be assigned to receive 3 treatments in randomized, double-dummy 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
blinded, crossover fashion based on their assignment to 1 of 6 treatment sequences. 
Randomization will occur in a 1:1:1:1:1:1 ratio using a permuted-block randomization 
method to ensure a balanced assignment to each treatment sequence. Each patient 
will receive the following treatments: 
• 
300 mg KVD900 (1 x 300 mg tablet plus 1 matching placebo tablet) 
• 
600 mg KVD900 (2 x 300 mg tablets) 
• 
2 matching placebo tablets 
Patients will treat each eligible attack with up to 2 doses of IMP, administered at least 
3 hours apart. The second dose, if taken, will be the same assigned treatment as the 
first dose. 
In this trial, the IMP will be shipped directly to the patients via a courier service or will 
be dispensed at the trial clinic as required by local regulations or per the site’s local 
practice, as described in the Pharmacy Manual. 
Treatment of Eligible HAE Attacks 
Patients will treat 3 separate, eligible HAE attacks with their assigned IMP treatment 
for that attack. For an HAE attack to be considered eligible for treatment with IMP, the 
attack must meet the following criteria: 
• 
The attack is not a severe laryngeal attack. 
• 
Patient must be able to identify the start time of the attack. 
• 
At least 48 hours have elapsed since patient has used conventional on--demand 
treatment or IMP to treat an HAE attack. 
• 
Patient must be able to complete at least the first 4 hours of eDiary assessments 
following the first administration of IMP. 
• 
Post-attack televisit has been completed for the previous eligible attack (applicable 
to eligible attacks 2 and 3 only). 
Eligible attacks should initially be treated with a single administration of IMP. Patients 
will be encouraged to treat as soon as possible after recognition of the start of the 
attack. 
If needed (as determined by the patient), a second dose of IMP may be administered 
for each attack, as follows: 
Non-laryngeal attacks 
For each eligible HAE attack, a second dose of IMP may be taken: 
• 
after 3 hours if HAE attack symptoms are considered severe enough by the patient 
to require a second dose of IMP. 
After the second dose of IMP, conventional on-demand treatment may be taken: 
• 
after 1 hour if HAE attack symptoms are considered severe enough by the patient 
to require treatment with conventional treatment. 
If symptoms progress to airway involvement, patients may treat with conventional 
on-demand treatment at any time. 
Laryngeal attacks 
After the first dose of IMP, conventional on-demand treatment may be taken at any 
time: 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
• 
if HAE attack symptoms worsen or if HAE attack symptoms are considered severe 
enough by the patient to require immediate treatment. 
Attacks that do not meet eligibility may be treated with conventional on-demand 
treatment per the patient’s usual treatment regimen. 
Conventional on-demand treatments may include plasma derived C1-inhibitor 
(pdC1-INH) intravenous (iv), recombinant human C1-esterase inhibitor (rC1-INH) iv, 
icatibant subcutaneous (sc), or ecallantide sc. 
Patients with safety or tolerability concerns will contact the Investigator or designee as 
soon as possible or the nearest emergency service as appropriate. 
Study Call Center 
After the first dose of IMP and prior to the second dose or conventional on-demand 
treatment, patients will be required to call a designated Study Call Center to be 
reminded of the repeat dosing criteria and the eDiary assessment requirements. 
Patients are to contact the Call Center: 
1) After the first dose of IMP 
2) Prior to a second dose of IMP 
3) Prior to a dose of conventional on-demand treatment. 
The Call Center staff will also instruct patients experiencing laryngeal attacks to call 
their study doctor. 
Patient eDiary 
For each HAE attack treated with IMP, patients will record information in an eDiary, 
including attack location, attack symptoms, date/time of onset, attack severity, time of 
second IMP dose, if applicable, and use of conventional on-demand treatment, if 
applicable. Patients will complete timed assessments of their HAE attack through 
48 hours as documented in Table S1. Patients should complete all timed diary 
assessments except during sleep; however, patients must complete at least the first 
4 hours of diary assessments following the first administration of IMP. 
Table S1: 
Frequency of Patient Assessment 
Time Period following the 
Frequency of Patient 
Time Window for 
First IMP Administration 
Assessment a 
Assessment 
0 to 4 hours 
Every 0.5 hour 
± 0.25 hour 
5 to 12 hours 
Every 1 hour 
± 0.5 hour 
14 to 24 hours 
Every 2 hours 
± 1 hour 
25 to 48 hours 
Every 12 hours 
± 3 hours 
a If a second dose of IMP or additional doses of conventional on-demand treatment are needed, patients will 
complete diary assessments prior to taking each additional dose. After re-dosing, the planned post-dose 
diary assessments will then continue through 48 hours after first dose of IMP. 
Post-Attack Televisit 
A televisit (between the site staff and the patient) will be completed following each 
administration of IMP to ensure the safety and wellbeing of the patient, to confirm IMP 
accountability, to review the patient diary (and retrain, if necessary), and to undergo an 
AE and concomitant medication review. The televisit will occur by the next working day 
after the completion of the patient diary (visit window: +1 week). 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
Final Visit/Early Termination 
Once 3 HAE attacks have been treated, or upon early termination, the patient should 
return to the clinic for the final visit as soon as possible within 1 week of completing all 
patient diary assessments to undergo final safety checks including AE reporting, vital 
sign recording, and blood sampling for laboratory safety measurements. Whenever 
possible, this visit should be completed prior to starting any new medication or 
treatment. 
Investigational
KVD900 (300 mg) film-coated tablet. 
Medicinal 
Products 
Placebo for KVD900 tablet. 
No IMP dose modifications are allowed in this trial. 
Tablets must be swallowed whole and are not to be crushed or modified in any way. 
Eligible attacks should initially be treated with a single administration of IMP as soon 
as possible after recognition of the start of the attack. If needed (as determined by the 
patient), a second dose of IMP may be administered for each attack. 
Number of 
Patients 
Approximately 114 patients will be randomized into the trial to ensure approximately 
84 patients (including approximately 12 adolescents) complete the trial. 
Population 
The trial population will include male and female patients 12 years of age and older 
with a confirmed diagnosis of HAE type I or II. 
The trial population will comprise 2 subsets: (1) patients who enter the trial taking only 
conventional on-demand treatment; and (2) patients who enter the trial on a stable 
dose and regimen of long-term prophylactic treatment. 
Inclusion Criteria 
1) Male or female patients 12 years of age and older. 
2) Confirmed diagnosis of HAE type I or II at any time in the medical history: 
a) Documented clinical history consistent with HAE (sc or mucosal, nonpruritic 
swelling episodes without accompanying urticaria) AND EITHER 
i) 
Diagnostic testing results obtained prior to randomization that confirm HAE 
type I or II: C1-INH functional level <40% of the normal level. Patients with 
functional C1-INH level 40-50% of the normal level may be enrolled if they 
also have a C4 level below the normal range. Testing may be obtained 
from central or local laboratories or obtained from documented historical 
testing results. Patients may be retested at any time prior to randomization 
if results are incongruent with clinical history or believed by the Investigator 
to be confounded by recent prophylactic or therapeutic C1-INH use, OR 
ii) Documented genetic results that confirm known mutations for HAE type I 
or II. 
3) Patient has access to and ability to use conventional on-demand treatment for HAE 
attacks. 
4) If a patient is receiving long-term prophylactic treatment with one of the 
protocol-allowed therapies, they must have been on a stable dose and regimen for 
at least 3 months prior to the Screening Visit (except for danazol, which requires a 
stable dose and regimen for 6 months prior to the Screening Visit). Patient must 
be willing to remain on a stable dose and regimen for the duration of the trial. 
5) Patient’s last dose of attenuated androgens other than danazol was at least 
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CONFIDENTIAL 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
28 days prior to randomization. 
6) Patient: 
a) has had at least 2 documented HAE attacks within 3 months prior to screening 
or randomization; or 
b) is a completer of the KVD824-201 trial within 3 months prior to randomization 
and meets all other entry criteria to enroll in KVD900-301. 
7) Patients must meet one of the following contraception requirements as follows: 
a) Female patients who are fertile and heterosexually active must agree to use 
contraception from the Screening Visit until the Final or Early Termination (ET) 
Visit. Acceptable methods of contraception include one or more of the 
following: 
i) 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
oral/injectable/implantable 
(hormonal 
contraception 
that 
contains estrogen including ethinylestradiol is excluded per Exclusion 
Criterion 4). 
ii) Intrauterine device. 
iii) Intrauterine hormone–releasing system. 
iv) Bilateral tubal occlusion. 
v) Vasectomized partner (provided that the partner is the sole heterosexual 
partner of the female patient of childbearing potential and that the 
vasectomized partner has received medical assessment of surgical 
success). 
vi) Male or female condom. 
vii) Cap, diaphragm, or sponge with spermicide. 
b) Patients who are not fertile or not heterosexually active, as defined below, do 
not require contraception. If the patient’s status changes during the course of 
the trial, they will be required to meet the requirements specified in Inclusion 
Criterion 7a). 
i) 
Female patients who refrain from heterosexual intercourse during the trial 
if the reliability of the heterosexual abstinence has been evaluated in 
relation to the duration of the clinical trial and is the preferred and usual 
lifestyle of the patient. 
ii) Female patients who are surgically sterile (e.g. status post hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months. 
iii) Female patients who are premenarche and remain premenarcheal until 
the end of the trial. 
c) Male patients (including female partners) do not require contraception. 
8) Patients must be able to swallow trial tablets whole. 
9) Patients, as assessed by the Investigator, must be able to appropriately receive 
and store IMP, and be able to read, understand, and complete the eDiary. 
10) Investigator believes that the patient is willing and able to adhere to all protocol 
requirements. 
11) Patient provides signed informed consent or assent (when applicable). A parent or 
legally authorized representative must also provide signed informed consent when 
required. 
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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 (previously known as 
HAE type III), idiopathic angioedema, or angioedema associated with urticaria. 
2) A clinically significant history of poor response to bradykinin receptor 2 (BR2) 
blocker, C1-INH therapy, or plasma kallikrein inhibitor therapy for the management 
of HAE, in the opinion of the Investigator. 
3) Use of angiotensin-converting enzyme (ACE) inhibitors after the Screening Visit or 
within 7 days prior to randomization. 
4) Any estrogen-containing medications with systemic absorption (such as oral 
contraceptives including ethinylestradiol or hormonal replacement therapy) within 
7 days prior to the Screening Visit. 
5) Patients who require sustained use of strong cytochrome P450 3A4 (CYP3A4) 
inhibitors or inducers . 
Note: These medications include but are not limited to the following: 
Inhibitors: 
boceprevir, 
clarithromycin, 
cobicistat, 
dasabuvir, 
denoprevir, 
elvitegravir, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, 
nelfinavir ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, tipranavir, troleandomycin, and voriconazole. 
Inducers: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, 
rifampin, St. John’s Wort. 
6) Inadequate organ function, including but not limited to: 
a) Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) 
b) Aspartate aminotransferase (AST) >2x ULN 
c) Bilirubin direct >1.25x ULN 
d) International normalized ratio (INR) >1.2 
e) Clinically significant hepatic impairment defined as a Child-Pugh B or C. 
7) Any clinically significant comorbidity or systemic dysfunction, which in the opinion 
of the Investigator, would jeopardize the safety of the patient by participating in the 
trial. 
8) History of substance abuse or dependence that would interfere with the completion 
of the trial, as determined by the Investigator. 
9) Known hypersensitivity to KVD900 or placebo or to any of the excipients. 
10) Prior participation in trial KVD900-201. 
11) Participation in any gene therapy treatment or trial for HAE. 
12) Participation in any interventional investigational clinical trial (with the exception of 
KVD824-201), including an investigational COVID-19 vaccine trial, within 4 weeks 
of the last dosing of investigational drug prior to Screening. 
13) Any pregnant or breastfeeding patient. 
Assessments 
Efficacy Variables 
• 
Patient global impression of change (PGI-C) scored on a 7-point rating scale as 
much better, better, a little better, no change, a little worse, worse, much worse. 
• 
Patient global impression of severity (PGI-S) scored on a 5-point rating scale as 
none, mild, moderate, severe, and very severe. 
• 
Visual analog scale (VAS) anchored at 0 (none) and 100 (very severe) for 
abdominal pain, skin pain, and skin swelling. 
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• 
Modified General Anxiety – Numeric Rating Scale (GA-NRS) scored on an 
11-point scale anchored at 0 (not at all anxious) and 10 (extremely anxious). 
• 
Use of conventional on-demand treatment. 
Safety Variables 
• 
Adverse events, including serious adverse events. 
• 
Laboratory test results. 
• 
12-lead ECG. 
• 
Vital signs. 
• 
Physical examination findings. 
Criteria for 
Primary Endpoint 
Evaluation of 
Efficacy 
• 
PGI-C: Time to beginning of symptom relief defined as at least “a little better” 
(2 time points in a row) within 12 hours of the first IMP administration. 
Key Secondary Endpoints 
• 
PGI-S: Time to first incidence of decrease from baseline (2 time points in a row) 
within 12 hours of the first IMP administration. 
• 
PGI-S: Time to HAE attack resolution defined as “none” within 24 hours of the first 
IMP administration. 
Secondary Endpoints 
• 
PGI-C: Proportion of attacks with beginning of symptom relief defined as at least 
“a little better” (2 time points in a row) within 4 hours and within 12 hours of the 
first IMP administration. 
• 
PGI-C: Time to at least “better” (2 time points in a row) within 12 hours of the first 
IMP administration. 
• 
PGI-S: Time to first incidence of decrease from baseline (2 time points in a row) 
within 24 hours of the first IMP administration. 
• 
Composite VAS: Time to at least a 50% decrease from baseline (3 time points in 
a row) within 12 hours and within 24 hours of the first IMP administration. 
Exploratory Endpoints 
• 
GA-NRS: Cumulative GA-NRS expressed as area under the curve over 12 and 
24 hours of the first IMP administration. 
General 
Continuous data will be summarized by treatment group using descriptive statistics 
Statistical 
(number, arithmetic mean, median, standard deviation, minimum, and maximum). 
Methods and 
Categorical data will be summarized by treatment group using frequency tables 
Types of
(frequencies and percentages). 
Analyses 
All analyses will be carried out using SAS Version 9.4 or higher or using other validated 
software. 
There are 3 treatment groups in the trial: 
1. 
300 mg KVD900 
2. 
600 mg KVD900 
3. 
Placebo for KVD900 
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Two pairwise comparisons will be performed: 300 mg KVD900 versus placebo and 
600 mg KVD900 versus placebo. 
Confirmatory efficacy analysis will be performed on the Full Analysis Set: 
A fixed sequence closed testing procedure will be followed. In a fixed sequence closed 
testing procedure the formal inferential testing can proceed to the next step only when 
statistical significance is declared in the current step. If the testing sequence is stopped, 
the remaining endpoints in the testing sequence will be considered exploratory. The 
fixed testing procedure will be employed first on the primary and then on the key 
secondary endpoints 1 and 2, separately for each dose comparison to placebo. 
Statistical tests on both the primary and the key secondary endpoints will be at the 
same significance level alpha (0.025) with a loop-back feature to allow two-way alpha 
passing. Significance level 0.025 is Bonferroni adjusted significance level obtained by 
dividing the original significance level 0.05 by the number of comparisons within 
endpoint family between each KVD900 dose level and placebo, i.e. the adjusted 
significance level is 0.025 (0.05 divided by 2). If the primary and key secondary 
endpoints hypotheses within one of the pairwise comparisons are not all rejected at 
0.025 alpha level, but the hypotheses for the other pairwise comparison are all rejected, 
then the unused alpha from the rejected hypotheses can be directed to loop-back to 
the unrejected hypotheses, which is then re-tested at the alpha level of 0.05. 
The analysis of the secondary or exploratory endpoints will not have multiplicity 
adjustments. 
Primary analysis hypothesis 
The null hypothesis is that there is no difference in survival distribution of the time to 
beginning of symptom relief defined by the PGI-C as at least “a little better” for 2 time 
points in a row within 12 hours of the first IMP administration (no difference between 
each dose of KVD900 group versus placebo group) versus the alternative hypothesis 
that the survival distributions are different (each of the KVD900 dose groups versus 
placebo). 
𝐻𝐻0: 𝑡𝑡𝑘𝑘 − 𝑡𝑡𝑝𝑝 = 0, 
where tk is the time to “a little better” or higher rating of HAE attack following KVD900 
dose treatment and tp is the time to “a little better” or higher rating of HAE attack 
following placebo. 
𝐻𝐻𝑎𝑎: 𝑡𝑡𝑘𝑘 − 𝑡𝑡𝑝𝑝 ≠ 0. 
The primary endpoint will be analyzed using Gehan Score Transformation test 
proposed by Feingold and Gillespie (1996) for crossover trials with censored data. 
The number of patients with the primary endpoint event will be summarized by 
frequencies and survival estimates, the summaries will be presented by treatment. 
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Table 1: 
Schedule of Events 
Visit 
Screening Randomizationa 
Treatment Period 
Final 
Visit/ETc
1st eligible
HAE attackb 
2nd eligible
HAE attackb 
3rd eligible
HAE attackb 
In-clinicd 
X 
X 
X 
TeleVisite 
X 
X 
X 
Informed Consent/Assentf 
X 
Eligibility Assessment 
X 
X 
HAE Diagnostic Lab Testg 
X 
Medical Historyh 
X 
12-lead ECGi 
X 
X 
Demographicsj 
X 
Physical Examinationk 
X 
X 
Vital Signsl 
X 
X 
Safety Laboratorym 
X 
X 
Pregnancy Testn 
X 
X 
Randomize patient in RTSM 
X 
Patient diary training 
X 
X 
Patient diary retraining 
X 
X 
X 
Conventional on-demand treatment washouto 
Dosep 
X 
X 
X 
IMP dispensing/return/accountabilityq 
X 
X 
PGI-Sr 
X 
X 
X 
PGI-Cr 
X 
X 
X 
VASr 
X 
X 
X 
GA-NRSr 
X 
X 
X 
Concomitant Medication Review 
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Visit 
Screening Randomizationa 
Treatment Period 
Final 
Visit/ETc
1st eligible
HAE attackb 
2nd eligible
HAE attackb 
3rd eligible
HAE attackb 
Adverse Event Reviews 
Abbreviations: C1-INH=C1-esterase inhibitor; ECG=electrocardiogram; eDiary=electronic diary; ET=Early Termination; GA-NRS= General Anxiety – Numeric Rating Scale; 
HAE=hereditary angioedema; IMP=investigational medicinal product; PGI-C=patient global impression of change; PGI-S=patient global impression of severity; RTSM=Randomization 
Trial Supply Management System; VAS=visual analog scale. 
a 
Randomization to occur within 4 weeks of the Screening Visit. The Randomization Visit may be a televisit or an in-clinic visit. 
b 
For each of the 3 eligible HAE attacks, a televisit will occur by the next working day after the completion of the patient diary (visit window: +1 week). A televisit must occur before 
treating the next eligible attack. 
c 
Once 3 HAE attacks have been treated with IMP, or upon patient ET, the patient should return to the clinic for the final visit as soon as possible within 1 week of completing all 
patient diary assessments. Whenever possible this visit should be completed prior to starting any new medication or treatment. 
d 
If an in-clinic visit cannot be conducted (e.g. in the event of a pandemic or other reason that prevents the patient from attending in-clinic visits), home health visits will be used to 
perform these visits. Information captured during a home health visit will mirror that captured during an in-clinic visit. 
e 
A televisit can be conducted via a telephone call or via an interactive audio/video system. 
f 
Consent and assent may be collected through e-consent if allowed through country and site regulations. 
g 
Diagnostic testing must be available for patients without genetic confirmation of HAE type I or II. 
h 
Medical history includes any relevant previous and concurrent diseases, HAE disease history including the attack history and corresponding treatment for the past 3 months; 
therapies and supplements taken within the past 4 weeks; and previous participation in interventional clinical trials in the past 4 weeks. 
i 
ECG to be recorded after patient has rested supine for at least 5 minutes. 
j 
Demographics: Year of birth; height (meters [m]; without shoes); weight (kilograms [kg]); race and ethnicity (if allowed); and sex. 
k 
Complete physical examination at Screening only, all others will be symptom directed. In the case of a home health visit, the home healthcare nurse will conduct an abbreviated 
physical examination, and the Investigator will conduct the symptom-directed physical examination via televisit. 
l 
Vital signs include pulse rate, respiratory rate, and systolic and diastolic blood pressure after patient has been resting at least 5 minutes. 
m 
Laboratory assessments, including C1-INH functional level, performed by a central laboratory; repeat laboratory assessments may be performed. 
n 
Serum pregnancy test will be performed on females of childbearing potential at Screening and at the Final/ET visit. 
o 
If a patient takes conventional on-demand treatment during the trial, a 48-hour washout period is required prior to the subsequent dosing with IMP. 
p 
Eligible attacks should be treated with IMP as soon as possible after recognition of the start of the attack. A minimum 48-hour washout period is required between each eligible 
attack and last dose of IMP or conventional on-demand treatment. After the first dose of IMP and prior to the second dose or conventional on-demand treatment, patients will be 
required to call a designated Study Call Center to be reminded of the repeat dosing criteria. The Call Center staff will remind patients of the rules for re-dosing and the eDiary 
assessment requirements. 
q 
Arrangements will be made to dispense the assigned IMP. The IMP will be shipped to the patient via a courier service or will be dispensed at the trial clinic as required by local 
regulations or per the site’s local practice, as described in the Pharmacy Manual. Confirmation of dosing compliance will be performed at each of the HAE attack televisits. All 
unused IMP and packaging will be returned at the in-clinic Final Visit/ET Visit. If the Final Visit/ET Visit is performed by Home Health, arrangements will be made to return any 
unused IMP and packaging via courier. 
r 
Patients will complete timed assessments of HAE attack symptoms through 48 hours following first dose of IMP. Patient assessments will be performed as outlined in Table S1. 
s 
Adverse events recorded from the first dose of KVD900 or placebo up to and including to Final Visit/ET. Serious AEs recorded from the time of signing the informed consent up to 
and including the Final Visit/ET. 
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5. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BR2 
bradykinin receptor 2 
C1-INH 
C1-esterase inhibitor 
CRO 
Contract Research Organization 
CYP3A4 
cytochrome P450 3A4 
DBP 
diastolic blood pressure 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ET 
early termination 
FAS 
Full Analysis Set 
GA-NRS 
General Anxiety – Numeric Rating Scale 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
HAE 
hereditary angioedema 
HbA1c 
glycosylated hemoglobin 
HCG 
human chorionic gonadotropin 
HED 
human equivalent dose 
HK 
high molecular weight kininogen 
HR 
heart rate 
IB 
Investigator’s Brochure 
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IcEv 
intercurrent event 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
iv 
intravenous 
kg 
kilogram(s) 
MCH 
mean corpuscular hemoglobin 
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MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPV 
mean platelet volume 
mL 
milliliter(s) 
ms 
millisecond(s) 
NOAEL 
no-observed adverse effect level 
pdC1-INH 
plasma derived C1-inhibitor concentrate 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
pH 
potential hydrogen 
PK 
pharmacokinetic 
PPS 
Per-protocol Set 
PR 
pulse rate 
QTcF 
Fridericia correction of QTc 
RBC 
red blood cell 
RDW 
red cell distribution width 
rhC1-INH 
recombinant human C1-esterase inhibitor 
RR 
respiration rate 
RTSM 
Randomization and Trial Supply Management System 
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s 
second(s) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
sc 
subcutaneous 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
USM 
Urgent Safety Measure 
VAS 
visual analogue scale 
WBC 
white blood cell 
WHO 
World Health Organization 
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6. 
INTRODUCTION 
6.1 
Background 
Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disease caused by a 
deficiency in the C1-esterase inhibitor (C1-INH) protein and characterized by unpredictable tissue 
swelling due to an increase in vascular permeability. The prevalence of HAE ranges between 1 and 2 per 
100,000 people worldwide with a point estimate of 1.5 per 100,000 (Aygören-Pürsün et al. 2018). HAE 
types I and II account for approximately 90% and 10% of HAE cases with C1-INH deficiency, respectively 
(Nordenfelt et al. 2016, Zanichelli et al. 2015). Both types of HAE are caused by a large variety of genetic 
mutations in the SERPING1 gene (Gösswein et al. 2008). These mutations result in production of reduced 
levels of functional C1-INH (HAE type I) or normal levels of dysfunctional C1-INH (HAE type II) 
(Donaldson and Evans 1963, Donaldson and Rosen 1964, Rosen et al. 1965, Rosen et al. 1971). 
C1-INH inhibits key enzymes in the contact system (Kaplan and Joseph 2014), one of which is plasma 
kallikrein. Due to the deficiency in C1-INH associated with HAE, activated plasma kallikrein generates 
the vasoactive peptide hormone bradykinin, the mediator of vascular hyperpermeability that causes 
tissue swelling and pain (Fields et al. 1983, Hulström and Svensjö 1979, Nussberger et al. 1998, 
Nussberger et al. 2002, Nussberger et al. 1999). 
HAE is a life-long condition with approximately 50% of patients experiencing their first attack before the 
age of 10 years (Bork et al. 2006, Nordenfelt et al. 2016) and more than 75% experiencing their first 
attack before adulthood (Maurer et al. 2019). Attacks are episodic with considerable variations in 
frequency and severity (Bork et al. 2006, Javaud, Altar et al. 2019). Swelling has been shown to affect 
subcutaneous (sc) tissue (face, upper or lower extremities, genitals) in 82% of patients, abdominal organs 
(stomach, intestines) in 78% of patients, and the upper airway (larynx, tongue) in 27% of patients 
(Nordenfelt et al. 2016). Laryngeal attacks are infrequent (<5% of attacks) (Javaud, Altar et al. 2019) but 
are potentially life-threatening in patients who are unaware of their diagnosis (Bork et al. 2012). 
Approximately 50% of all patients with HAE experience at least one laryngeal attack during their lifetime 
(Bork et al. 2003, Bork et al. 2006). 
Several precipitants can trigger HAE attacks; however, more than half of all HAE attacks are 
unpredictable and occur without an obvious trigger (Caballero et al. 2016). Common triggers of HAE 
attacks such as strenuous activity, mechanical trauma, or use of certain medications, may be somewhat 
predictable. However, other triggers such as infections, fatigue, or emotional stress are difficult to predict 
(Caballero et al. 2016). Although patients with HAE have been shown to have high health-related quality 
of life scores (Javaud, Bouillet et al. 2019, Lumry et al. 2018), physical and emotional impairment persists 
in their daily lives and may extend beyond the duration of the attacks (Aygören-Pürsün et al. 2016, 
Caballero et al. 2014, Nordenfelt et al. 2017). 
6.2 
Trial Rationale 
Recurrent swelling in patients with HAE is predominantly a consequence of excessive generation of 
bradykinin due to dysregulated plasma kallikrein activity (Fields et al. 1983, Nussberger et al. 1998, 
2002). Therefore, inhibition of plasma kallikrein activation has emerged as a target for the treatment of 
HAE. For example, treatment with ecallantide, a specific inhibitor of plasma kallikrein given 
subcutaneously, led to significantly better treatment outcome scores compared with placebo (Cicardi et 
al. 2010, Sheffer et al. 2011). The oral small-molecule inhibitor of plasma kallikrein berotralstat 
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(Aygören-Pürsün, Bygum et al. 2018, Zuraw et al. 2020) and the plasma kallikrein monoclonal antibody 
lanadelumab (Banerji et al. 2017, Banerji et al. 2018) have been shown to lower the rate of attacks in 
HAE patients compared with placebo, highlighting the role that plasma kallikrein plays in this disease. 
KVD900 has been shown in a range of nonclinical experiments to be a selective inhibitor of plasma 
kallikrein. This activity was confirmed in a completed trial (KVD900-101) of KVD900 in healthy volunteers 
at dose levels up to 600 mg. Within 1 hour of dosing mean protection of high molecular weight kininogen 
(HK) cleavage was >85%. Protection was maintained at >75% for 6 hours and >45% for 10 hours at a 
dose of 600 mg. Forty percent (40%) HK protection is achieved by C1-INH levels typically present in 
control plasma samples. It is therefore a plausible hypothesis that treatment with a single dose of KVD900 
600 mg may halt the progression of HAE attacks. This hypothesis was tested in a Phase 2 trial 
(KVD900-201) for the on-demand treatment of HAE attacks. The trial was a cross-over in which 
53 patients with either type I or II HAE completed. Results showed a significant difference between 
600 mg KVD900 and placebo for the primary endpoint of time to conventional treatment use and 
secondary endpoints of attack improvement using Patient Global Impression of Change (PGI-C), Patient 
Global Impression of Severity (PGI-S), and a composite visual analogue scale (VAS) measuring 
symptoms of the attack. 
Refer to the Investigator’s Brochure (IB) for further detail on KVD900. 
6.3 
Benefit/Risk 
Good Laboratory Practice repeat dose toxicology studies (rats and monkeys), genetic toxicology, safety 
pharmacology, and reproductive toxicology studies (rats and rabbits) have been completed. The 
non-clinical program is supportive of the included population and of the dosing regimen outlined in the 
trial. 
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 a Phase 1 trial in healthy volunteers 
(KVD900-101) to have a time profile for plasma kallikrein inhibition (30 minutes to 10 hours post-dose) 
which is appropriate for the treatment of this condition. A single dose of 600 mg was found to bring relief 
from an attack of HAE in a single Phase 2 efficacy trial (KVD900-201). Key endpoints included the time 
to beginning of symptom relief using the PGI-C, the time to improvement using the PGI-S, the time to 
symptom relief in the composite VAS, and the time to conventional attack treatment usage. All key 
efficacy endpoints were met with p<0.0064. KVD900 reduced the time to patient-reported outcome on 
the PGI-C (1.6 hours vs. 9 hours, KVD900 vs. Placebo), PGI-S (9.0 hours vs. >24 hours, KVD900 vs. 
placebo), and the composite VAS (6 hours vs. 19 hours, KVD900 vs. placebo). Additionally, time to use 
of conventional attack treatment within 12 hours was significantly longer for KVD900 versus placebo 
(p-value=0.0010). 
In the completed Phase 1 healthy volunteer trials and a Phase 2 trial in patients with type I or II HAE, 
single and multiple doses (up to three 600 mg doses within 24 hours) of KVD900 were well tolerated with 
no serious adverse events (SAEs) or deaths. A total of 104 healthy volunteers, across 3 clinical trials 
(KVD900-101, KVD900-102, KVD900-103) were administered KVD900 and 28 were administered 
placebo, and of those volunteers, 32.7% and 35.7%, experienced at least 1 adverse event (AE), 
respectively. The most common AE was headache, which occurred in 7.7% and 7.1% of healthy 
volunteers administered KVD900 and placebo, respectively. 
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In the blinded portion of the Phase 2 trial (KVD900-201) completed in patients with type I or II HAE, at 
least 1 AE while on treatment was deemed by the Investigator to be related to the investigational 
medicinal product (IMP) and was reported for 3 of 58 patients (5.2%) administered KVD900 (AEs of 
abdominal pain, back pain, and headache) and 2 of 55 patients (3.6%) administered placebo (AEs of 
anal incontinence and headache). 
A completed multiple dose trial of 600 mg KVD900 in healthy normal volunteers (KVD900-102) assessed 
the pharmacokinetic (PK) and changes to cardiac parameters of 600 mg KVD900 given every 2 hours 
for 3 total administrations (i.e. 1,800 mg KVD900 within 4 hours). Safety evaluation did not identify any 
clinically significant changes in vital signs, safety electrocardiogram (ECG), physical exam finding, or 
laboratory results approximately 24 hours post-dose as well as 5 to 7 days post dose. There were no 
clinically meaningful AEs with the most common AE being headache. Furthermore, an analysis of the 
impact of KVD900 on heart rate (HR) and QTc showed no clinically meaningful changes to HR or QTc 
(defined as >10 ms increase) following supratherapeutic concentrations of KVD900. 
The current trial (KVD900-301) will evaluate two dose levels of KVD900 (with the option for patients to 
take a second dose of IMP to treat each attack) for the on-demand treatment of HAE attacks under 
randomized, double-blind, placebo-controlled conditions. Ex vivo testing suggests that a dose of 300 mg 
may also bring relief to an attack of HAE. The randomized, double-blind, placebo-controlled, three-way 
crossover design of this trial has been chosen as an appropriate test of that hypothesis. 
Adolescents (12 to 17 years old) will be included in this trial. A population PK model has been built which 
predicted KVD900 exposure in a simulation population containing 600 subjects (400 females and 
200 males) 12 to 17.9 years of age with body weight ranging from 31.0 to 93.3 kg. The population PK 
model predicted overall KVD900 exposure in an adolescent population (12 to 17 years old) to be similar 
to that in healthy adults for a single 600 mg dose of KVD900 under fasted conditions. 
While laryngeal attacks may be treated in KVD900-301, only mild and moderate attacks will be allowed, 
and patients will be instructed to treat immediately with conventional on-demand treatment if laryngeal 
attack symptoms worsen. 
For a subset of the trial population, the trial permits the use of HAE prophylaxis therapies as detailed in 
Section 12.1. Given the difference in clearance mechanisms between KVD900 and allowed HAE 
prophylaxis treatment (lanadelumab; C1-INH) it is not anticipated that KVD900 would cause drug-drug 
interactions with these medications. The potential for these medications to affect the PK of small 
molecules such as KVD900 is generally limited to proinflammatory cytokines or that cause increases in 
proinflammatory cytokine levels (FDA Guidance for Industry, Drug-Drug Interaction Assessment for 
Therapeutic Proteins, 2020). The prophylaxis treatments allowed do not fall into these categories, and 
therefore it is not anticipated that the PK profiles of KVD900 or the allowed HAE prophylactic treatments 
would be impacted (European Medicines Agency, Takhzyro ([lanadelumab] Assessment Report, 2018). 
As androgens and anti-fibrinolytics are not strong inducers or inhibitors of CYP3A4, it is not anticipated 
that they would affect the PK profile of KVD900. Likewise, given the relatively weak CYP450 in vitro 
inhibition and induction elicited by KVD900, and the various clearance mechanisms of androgens and 
anti-fibrinolytics, it is not expected that KVD900 would notably affect the PK of these agents. Based on 
available data on berotralstat and KVD900, it is assumed that co-administration with KVD900 would have 
little to no impact on the PK of berotralstat. Data have shown an increase of 45% and 124% in Cmax and 
AUC, respectively, of midazolam (a prototypical cytochrome P450 3A4 [CYP3A4] substrate) with co-
administration of berotralstat (BioCryst Pharmaceuticals, Inc, 2020). KVD900 is not expected to be a 
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more sensitive CYP3A4 substrate than midazolam; therefore, a similar increase in Cmax and AUC can be 
assumed. An increase in exposure to this magnitude would not be a clinically significant increase for 
KVD900. 
Overall, trial KVD900-301 is considered to have a positive benefit-risk balance given that: 
• 
Inhibition of plasma kallikrein is an established mechanism for the treatment of HAE. There are 
currently approved plasma kallikrein inhibitors that do not have known target-related AEs. 
• 
Non-clinical studies support the dosing regimen and also the inclusion of women of child-bearing 
potential. 
• 
Pharmacological data indicate that doses of 300 or 600 mg may be effective to bring relief to an 
attack of HAE. The high dose level of KVD900 to be given in this trial, 600 mg, was well tolerated 
in previous clinical trials in 104 healthy volunteers and 68 patients with type I or II HAE. 
• 
Administration of up to 3 doses of 600 mg KVD900 administered 2, 4, or 8 hours apart was well 
tolerated in KVD900-102 and supports the planned dosing regimen in this trial of up to 2 doses 
for HAE attack treatment. 
• 
600 mg KVD900 was shown to be efficacious and significantly different from placebo in time to 
conventional treatment use and symptom improvement in the PGI-C, PGI-S, and composite VAS 
in patients with type I or II HAE in the Phase 2 clinical trial (KVD900-201). 
6.3.1 Impact of COVID-19 on Benefit-Risk Assessment 
Significant suppression of plasma kallikrein activity exists as a genetic condition (prekallikrein deficiency) 
(Girolami et al. 2010) and through therapeutic intervention with, for example, lanadelumab, a monoclonal 
antibody against plasma kallikrein (Banerji et al. 2018). Neither the familial condition nor administration 
of lanadelumab in patients with HAE is known to increase susceptibility to viral infections or lead to 
increased infections in general. Also, epidemiological studies among patients with HAE have not shown 
increased risks of infections (Zanichelli et al. 2015). At present, plasma kallikrein inhibition with KVD900 
is unlikely to confer susceptibility or aggravation of symptoms to infection with severe acute respiratory 
syndrome coronavirus-2 (SARS-CoV-2). 
6.3.2 COVID-19 Vaccination 
There are no known risks or expected interaction with KVD900 and COVID-19 vaccines. Patients may 
receive an approved COVID-19 vaccine, i.e. a vaccine that has received Emergency Use 
Authorization/Conditional Marketing Authorization (or approved/licensed) before, during, or after being in 
this trial. When feasible, the full vaccination series should be completed prior to enrollment. If a patient 
participated in an investigational COVID-19 vaccine trial, 4 weeks after the last dosing should elapse 
prior to Screening. 
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7. 
OBJECTIVES AND ENDPOINTS 
7.1 
Objectives 
7.1.1 Primary 
The primary objective of this trial is to demonstrate the clinical efficacy of KVD900 compared with placebo 
for the on-demand treatment of HAE attacks. 
7.1.2 Secondary 
The secondary objective of this trial is to investigate the safety and tolerability of KVD900. 
7.2 
Endpoints 
7.2.1 Primary Endpoint 
The primary endpoint of this trial is: 
• 
PGI-C: Time to beginning of symptom relief defined as at least “a little better” (2 time points in a 
row) within 12 hours of the first IMP administration. 
7.2.2 Key Secondary Endpoints 
Key secondary endpoints of this trial are: 
• 
PGI-S: Time to first incidence of decrease from baseline (2 time points in a row) within 12 hours 
of the first IMP administration. 
• 
PGI-S: Time to HAE attack resolution defined as “none” within 24 hours of the first IMP 
administration. 
7.2.3 Secondary Endpoints 
The secondary endpoint of this trial are: 
• 
PGI-C: Proportion of attacks with beginning of symptom relief defined as at least “a little better” 
(2 time points in a row) within 4 hours and within 12 hours of the first IMP administration. 
• 
PGI-C: Time to at least “better” (2 time points in a row) within 12 hours of the first IMP 
administration. 
• 
PGI-S: Time to first incidence of decrease from baseline (2 time points in a row) within 24 hours 
of the first IMP administration. 
• 
Composite VAS: Time to at least a 50% decrease from baseline (3 time points in a row) within 
12 hours and within 24 hours of the first IMP administration. 
7.2.4 Exploratory Endpoints 
• 
General Anxiety Numeric Rating Scale (GA-NRS): Cumulative GA-NRS expressed as area under 
the curve (AUC) over 12 and 24 hours of the first IMP administration. 
Additional endpoints may be defined in the SAP. 
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7.3 
Estimands 
Table 2: 
Primary Objective and Estimand 
Objective Description 
Estimand Description (Including Endpoint) 
To demonstrate the clinical efficacy of 
KVD900 compared with placebo for the 
on-demand treatment of HAE attacks. 
Relative effect of each of the KVD900 dose groups versus placebo 
in shortening the time to beginning of symptom relief defined by the 
PGI-C as at least “a little better” for 2 time points in a row within 
12 hours of the first IMP administration in adolescent and adult 
patients with hereditary angioedema type I or II regardless of 
prohibited medications and as long as conventional on-demand 
treatment of HAE attacks had not been used and as if patients had 
not discontinued the trial. 
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8. 
TRIAL DESIGN 
8.1 
Overall Design 
KONFIDENT is a double-blind, randomized, placebo-controlled, multicenter clinical trial in patients 
12 years or older with HAE type I or II. Patients will be randomized to 6 treatment sequences in a 3-way 
crossover design. Eligible attacks will initially be treated with a single dose of placebo, 300 mg, or 600 mg 
KVD900 per attack with a minimum 48-hour washout period between each eligible attack and last dose 
of IMP or conventional on-demand treatment. If needed (as determined by the patient), a second dose 
of IMP may be administered for each attack (for further detail, see Section 10.1). 
The estimated duration of this trial for each randomized patient will be approximately 25 weeks from 
Screening through the Final Visit and includes the treatment of 3 eligible attacks during the Treatment 
Period. 
This trial will be conducted at HAE treatment centers on an outpatient basis and will comprise in-clinic 
and televisits. A televisit can be conducted via a telephone call or via an interactive audio/video system. 
If an in-clinic visit cannot be conducted (e.g. in the event of a pandemic or other reason that prevents the 
patient from attending the in-clinic visit) home health visits will be used to perform these visits if permitted 
by the relevant regulatory authority, site’s Ethics Committee (EC)/ Institutional Review Board (IRB), local 
regulations, and the patient via informed consent. The home visit will be performed by an appropriately 
delegated home healthcare service provider. Information captured during a home health visit will mirror 
that captured in an in-clinic visit. A trial diagram is presented in Figure 1. 
Figure 1: 
Trial Diagram 
8.2 
Scientific Rationale for Trial Design 
This Phase 3 trial will investigate the efficacy of two dose levels of KVD900 in the on-demand treatment 
of attacks of HAE. The randomized, placebo-controlled, 3-way crossover trial design is a standard 
approach for differentiation between the efficacy and safety profiles of multiple dose levels of IMP and 
placebo treatments when administered to patients with HAE type I or II. 
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The trial population is representative of the likely target population for the product. The sample size of 
approximately 114 randomized patients to ensure approximately 84 completed patients (including 
approximately 12 adolescents) is required to conclusively evaluate a clinically relevant treatment effect. 
Treatment of three separate eligible HAE attacks with IMP and placebo is adequate to assess the primary 
and secondary objectives of the trial. 
The high dose level of KVD900 to be given in this trial, 600 mg, was well tolerated in previous Phase 1 
and Phase 2 clinical trials. Refer to the IB for further detail on completed KVD900 clinical trials. 
A lower single dose of 300 mg may be reasonably expected to bring relief to or halt the progression of 
an attack of HAE. 
The endpoints for this trial are commonly measured in HAE and are clinically relevant. The safety 
measures are routinely used for the evaluation of safety and tolerability of an investigational product. 
8.3 
Justification for Dose 
Up to 2 doses of KVD900 (300 and 600 mg) per eligible HAE attack administered at least 3 hours apart 
is supported by the ex-vivo pharmacodynamic bioactivity, PK, safety, and efficacy of KVD900 from 
previous clinical trials and nonclinical studies that found KVD900 to be well tolerated and to result in 
pharmacodynamic effects with the potential to deliver clinical efficacy (see the KVD900 IB for further 
details). 
8.4 
End of Trial Definition 
The end of this trial is defined as the last patient’s last visit. 
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9. 
TRIAL POPULATION 
HAE treatment centers worldwide will randomize approximately 114 patients into the trial to ensure 
approximately 84 patients (including approximately 12 adolescents) complete the trial. 
The trial population will include a subset of patients who enter the trial taking only conventional 
on-demand treatment, and a subset of patients who enter the trial on a stable dose and regimen of 
long-term prophylactic treatment. 
9.1 
Inclusion Criteria 
1) 
Male or female patients 12 years of age and older. 
2) 
Confirmed diagnosis of HAE type I or II at any time in the medical history: 
a) 
Documented clinical history consistent with HAE (sc or
episodes without accompanying urticaria) AND EITHER 
 mucosal, nonpruritic swelling 
i) 
Diagnostic testing results obtained prior to randomization that confirm HAE type I or II: 
C1-INH functional level <40% of the normal level. Patients with functional C1-INH level 
40-50% of the normal level may be enrolled if they also have a C4 level below the 
normal range. Testing may be obtained from central or local laboratories or obtained 
from documented historical testing results. Patients may be retested at any time prior 
to randomization if results are incongruent with clinical history or believed by the 
Investigator to be confounded by recent prophylactic or therapeutic C1-INH use, OR 
ii) 
Documented genetic results that confirm known mutations for HAE type I or II. 
3) 
Patient has access to and ability to use conventional on-demand treatment for HAE attacks. 
4) 
If a patient is receiving long-term prophylactic treatment with one of the protocol-allowed 
therapies, they must have been on a stable dose and regimen for at least 3 months prior to the 
Screening Visit (except for danazol, which requires a stable dose and regimen for 6 months prior 
to the Screening Visit). Patient must be willing to remain on a stable dose and regimen for the 
duration of the trial. 
5) 
Patient’s last dose of attenuated androgens other than danazol was at least 28 days prior to 
randomization. 
6) 
Patient: 
a) has had at least 2 documented HAE attacks within 3 months prior to screening or randomization; 
or 
b) is a completer of the KVD824-201 trial within 3 months prior to randomization and meets all other 
entry criteria to enroll in KVD900-301. 
7) 
Patients must meet one of the following contraception requirements as follows: 
a) 
Female patients who are fertile and heterosexually active must agree to use contraception 
from the Screening Visit until the Final or Early Termination (ET) Visit. Acceptable methods 
of contraception include one or more of the following: 
i) 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral/injectable/implantable (hormonal contraception that contains estrogen including 
ethinylestradiol is excluded per Exclusion Criterion 4). 
ii) 
Intrauterine device. 
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iii) Intrauterine hormone–releasing system. 
iv) Bilateral tubal occlusion. 
v) 
Vasectomized partner (provided that the partner is the sole heterosexual partner of the 
female patient of childbearing potential and that the vasectomized partner has received 
medical assessment of surgical success). 
vi) Male or female condom. 
vii) Cap, diaphragm, or sponge with spermicide. 
b) 
Patients who are not fertile or not heterosexually active, as defined below, do not require 
contraception. If the patient’s status changes during the course of the trial, they will be 
required to meet the requirements specified in Inclusion Criterion 7a). 
i) 
Female patients who refrain from heterosexual intercourse during the trial if the reliability 
of the heterosexual abstinence has been evaluated in relation to the duration of the 
clinical trial and is the preferred and usual lifestyle of the patient. 
ii) 
Female patients who are surgically sterile (e.g. status post hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months. 
iii) Female patients who are premenarche and remain premenarcheal until the end of the 
trial. 
c) Male patients (including female partners) do not require contraception. 
8) 
Patients must be able to swallow trial tablets whole. 
9) 
Patients, as assessed by the Investigator, must be able to appropriately receive and store IMP, 
and be able to read, understand, and complete the electronic diary (eDiary). 
10) 
Investigator believes that the patient is willing and able to adhere to all protocol requirements. 
11) 
Patient provides signed informed consent or assent (when applicable). A parent or legally 
authorized representative must also provide signed informed consent when required. 
9.2 
Exclusion Criteria 
1) 
Any concomitant diagnosis of another form of chronic angioedema, such as acquired C1-inhibitor 
deficiency, HAE with normal C1-INH (previously known as HAE type III), idiopathic angioedema, 
or angioedema associated with urticaria. 
2) 
A clinically significant history of poor response to bradykinin receptor 2 (BR2) blocker, C1-INH 
therapy, or plasma kallikrein inhibitor therapy for the management of HAE, in the opinion of the 
Investigator. 
3) 
Use of angiotensin-converting enzyme (ACE) inhibitors after the Screening Visit or within 7 days 
prior to randomization. 
4) 
Any estrogen-containing medications with systemic absorption (such as oral contraceptives 
including ethinylestradiol or hormonal replacement therapy) within 7 days prior to the Screening 
Visit. 
5) 
Patients who require sustained use of strong cytochrome P450 3A4 (CYP3A4) inhibitors or 
inducers. 
Note: These medications include but are not limited to the following: 
Inhibitors: boceprevir, clarithromycin, cobicistat, dasabuvir, denoprevir, elvitegravir, idelalisib, 
indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir ombitasvir, paritaprevir, 
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posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, and 
voriconazole. 
Inducers: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s 
Wort. 
6) 
Inadequate organ function, including but not limited to: 
a) 
Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) 
b) 
Aspartate aminotransferase (AST) >2x ULN 
c) 
Bilirubin direct >1.25x ULN 
d) 
International normalized ratio (INR) >1.2 
e) 
Clinically significant hepatic impairment defined as a Child-Pugh B or C. 
7) 
Any clinically significant comorbidity or systemic dysfunction, which in the opinion of the 
Investigator, would jeopardize the safety of the patient by participating in the trial. 
8) 
History of substance abuse or dependence that would interfere with the completion of the trial, as 
determined by the Investigator. 
9) 
Known hypersensitivity to KVD900 or placebo or to any of the excipients. 
10) 
Prior participation in trial KVD900-201. 
11) 
Participation in any gene therapy treatment or trial for HAE. 
12) 
Participation in any interventional investigational clinical trial (with the exception of KVD824-201), 
including an investigational COVID-19 vaccine trial, within 4 weeks of the last dosing of 
investigational drug prior to Screening. 
13) 
Any pregnant or breastfeeding patient. 
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10. 
INVESTIGATIONAL MEDICINAL PRODUCT 
For clinical trial use, KVD900 has been formulated as 300 mg film-coated tablets. 
The active ingredient in the tablets is KVD900. 
Further information about KVD900 300 mg film-coated tablets and matching placebo can be found in the 
IB. 
10.1 
Investigational Medicinal Product Administration 
Patients will be assigned to receive the following three treatments in randomized, double-dummy blinded, 
crossover fashion to treat three separate eligible HAE attacks: 
• 
300 mg KVD900 (1 x 300 mg tablet plus 1 matching placebo tablet) 
• 
600 mg KVD900 (2 x 300 mg tablets) 
• 
Placebo for KVD900 (2 matching placebo tablets) 
For an HAE attack to be considered eligible for treatment with IMP, the attack must meet the criteria 
specified in Section 16.3. Attacks that do not meet eligibility may be treated with conventional on-demand 
treatment per the patient’s usual treatment regimen. 
Patients will treat each eligible attack with up to 2 doses of IMP, administered at least 3 hours apart. The 
second dose, if taken, will be the same assigned treatment as the first dose. 
Patients will initially self-administer a single dose of KVD900 300 mg (1 x 300 mg tablet plus 1 placebo 
tablet), 600 mg (2 x 300 mg tablets), or 2 matching placebo tablets in response to each eligible attack of 
HAE. If needed (as determined by the patient), a second dose of IMP may be administered for each 
attack (for details, see Section 16.3). 
The post-attack televisit should be scheduled as soon as possible following IMP intake and completion 
of eDiary assessments. Patients with safety or tolerability concerns will contact the Investigator or 
designee as soon as possible or the nearest emergency service as appropriate. 
The IMP will be shipped directly to the patient via a courier service or can be dispensed on site as required 
by local regulations or per the site’s local practice, as described in the Pharmacy Manual. Patients will be 
provided with instructions on IMP administration. 
No IMP dose modifications are allowed in this trial. 
10.2 
Packaging and Labeling 
The investigational products (i.e. KVD900 or placebo) will be packaged and labeled according to current 
International Council for Harmonisation (ICH) Good Manufacturing Practice and Good Clinical Practice 
(GCP) guidelines and national legal requirements. The IMP will be packaged in appropriately labeled 
polyvinyl chloride/polyethylene/polyvinylidene chloride blisters sealed with an aluminum foil lid. The 
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blisters will be set into cardboard drawers contained in a cardboard cassette. The drawers will be 
numbered from 1 to 3, intended to be used in numerical order, one drawer per attack. 
Patients will be provided with instructions concerning the dosing and storage of the IMP at home. 
10.3 
Storage and Drug Accountability 
Prior to receipt by the patient, IMP will be stored at room temperature as labeled. 
IMP will only be dispensed to the identified patients of this trial following the procedures described in 
Pharmacy Manual. All supplies of the investigational products must be accounted for at the end of the 
trial. Qualified site personnel will inventory IMP at each televisit and at the Final/ET Visit. 
IMP that has been dispensed to a patient and returned unused must not be re-dispensed for a different 
patient. Unused IMP must not be used for any purpose other than the present trial. 
After completion of the trial and following Sponsor approval, all unused IMP will either be returned to the 
Sponsor or designee for destruction. IMP may also be destroyed on site after Sponsor approval. 
10.4 
Trial Medication Compliance 
Patients will be provided with instructions on IMP administration. In addition, confirmation of dosing 
compliance will be performed during each televisit (via review of unused IMP), and re-training will occur, 
if necessary. If the in-clinic visits cannot occur for the Final Visit/ET the accountability will occur during 
the home health visit, and arrangements will be made to return any unused IMP. 
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11. 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
11.1 
Patient Numbers Identification 
Each patient will receive a unique patient identification number. 
11.2 
Randomization Scheme 
Within 4 weeks of the Screening Visit, patients will participate in a Randomization Visit. Patients will be 
assigned to receive 3 treatments in randomized crossover fashion based on their assignment to 1 of 6 
treatment sequences. Randomization will be stratified by whether the patient enters the trial taking only 
conventional on-demand treatment vs. on a stable dose and regimen of long-term prophylactic treatment. 
Randomization will occur using a Randomization and Trial Supply Management System (RTSM) in a 
1:1:1:1:1:1 ratio using a permuted-block randomization method to ensure a balanced assignment to each 
treatment sequence. A sample randomization schedule is presented in Table 3. 
Table 3: 
Sample Randomization Schedule 
Treatment Sequence 
1st Eligible HAE Attack 
2nd Eligible HAE Attack 
3rd Eligible HAE Attack 
A 
Placebo 
600 mg 
300 mg 
B 
Placebo 
300 mg 
600 mg 
C 
300 mg 
600 mg 
Placebo 
D 
300 mg 
Placebo 
600 mg 
E 
600 mg 
300 mg 
Placebo 
F 
600 mg 
Placebo 
300 mg 
Patients must not be randomized unless all eligibility criteria have been met. 
11.3 
Blinding 
This trial will be performed in a double-blind, double-dummy manner. 
The trial blind should not be broken except in a medical emergency (where knowledge of the IMP received 
would affect the treatment of the emergency) or regulatory requirement (e.g. for SAEs or death). The 
patient’s safety takes priority over any other considerations in determining if a treatment assignment 
should be unblinded. The decision to break the trial blind will be made solely by the Investigator. Efforts 
should be made to contact the Sponsor and the Medical Monitor prior to breaking the blind. 
Before breaking the blind of an individual patient’s treatment, the Investigator should determine that the 
unblinded information is necessary, i.e. that it will alter the patient’s immediate management. In many 
cases, particularly when the emergency is clearly not related to the IMP, the problem may be properly 
managed by assuming that the patient is receiving active product. Refer to the Medidata Rave RTSM 
and RAVE Electronic Data Capture Overview Training Material for the process to break blind. 
Following the unblinding of the IMP for a patient, the Investigator should inform the Sponsor and Medical 
Monitor. In addition to this, the date, time, and reason for unblinding must be recorded. 
If an Investigator, site personnel performing assessments, or patient, is unblinded, it must be documented 
as a major protocol deviation. 
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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 into the database and all data queries have been resolved and the 
assignment of patient to the analysis sets has been completed. 
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12. 
PERMITTED THERAPIES AND PROHIBITED THERAPIES 
12.1 
Conventional On-Demand Treatment 
Conventional on-demand treatment is permitted as outlined in Section 16.3. Attacks that are not treated 
with IMP may be treated with conventional on-demand treatment per the patient’s usual treatment 
regimen. 
Conventional on-demand treatments include plasma derived C1-inhibitor (pdC1-INH) iv, recombinant 
human C1-esterase inhibitor (rC1-INH) iv, icatibant sc, or ecallantide sc. 
12.2 
Long- and Short-term Prophylactic Treatment 
Patients who enter the trial using long-term prophylactic treatment must be on a stable dose and regimen 
for at least 3 months prior to the Screening Visit and remain stable during participation in the trial. Patients 
who do not enter the trial on a stable dose and regimen for at least 3 months prior to the Screening Visit 
will not be permitted to use long-term prophylactic treatment. They may use C1-INH as an on-demand or 
short-term prophylactic treatment but not as a long-term prophylactic treatment during the trial. 
The following long-term prophylactic therapies for HAE are allowed during the trial: 
• 
iv or sc plasma-derived C1-INH 
• 
Lanadelumab 
• 
Berotralstat 
• 
Danazol (requires a stable dose and regimen for at least 6 months prior to the Screening Visit) 
Note: In the event a patient takes conventional on-demand treatment or short-term prophylaxis during 
the trial, a 48-hour washout period is required prior to the subsequent dosing with IMP. 
12.3 
Prohibited Therapies 
Medications and therapies that preclude a patient from enrolling in the trial are listed in Section 9.2. 
The following therapies are not permitted for any patients during the trial: 
• 
Attenuated androgens other than danazol (e.g. stanozolol, oxandrolone, methyltestosterone, 
testosterone) 
• 
Anti-fibrinolytics (e.g. tranexamic acid) 
• 
Other investigational therapies for HAE prophylaxis (e.g. garadacimab, PKK-LRx, PHVS416) 
• 
ACE inhibitors 
• 
Estrogen-containing medications with systemic absorption including: 
o 
Oral contraceptives including ethinylestradiol or hormonal replacement therapy 
• 
Sustained use of strong CYP3A4 inhibitors and inducers (see Section 9.2 [Exclusion Criterion 5)] 
for list of trial medications) 
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o If use of a CYP3A4 inhibitor or inducer is required for treatment of a medical condition 
during the trial, IMP use should be discontinued and may not be re-started until 5 half-lives 
have elapsed since stopping the CYP3A4 inhibitor or inducer. Conventional on-demand 
treatment may be used while the patient is using the CYP3A4 inhibitor or inducer. 
Details of all medications, therapies, and supplements administered within 4 weeks prior to the Screening 
Visit until the end of the trial will be recorded in the electronic case report form (eCRF). Prior medications 
are defined as those medications taken within 4 weeks prior to the Screening Visit up to the first dose of 
IMP; concomitant medications are defined as those medications ongoing at or started after the first dose 
of IMP. 
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13. 
PATIENT DISCONTINUTION 
Patients may withdraw their consent from the trial at any time at their own request for any reason without 
prejudice to their medical care. If a patient withdraws consent for disclosure of future information, the 
Sponsor may retain and continue to use any data collected before such withdrawal of consent. 
The patient also may be discontinued at any time by the Investigator for any of the following reasons: 
• 
AEs. 
• 
At the discretion of the Investigator. 
• 
Administrative reasons (e.g. lack of patient compliance to trial visits/procedures, lost to follow-up). 
If a patient is discontinued from the trial, every attempt will be made to complete and document the ET 
visit as soon as possible. If the patient is discontinued from the trial after receiving IMP, every effort will 
be made to ensure that the relevant safety assessments are completed. The patient may also be asked 
by the Investigator to complete other trial assessments. Patients who prematurely discontinue from the 
trial will continue to have access to medical care and will be treated as per routine medical practice. 
The reason for and date of discontinuation will be recorded (e.g. withdrawal of consent, lost to follow-up, 
discontinuation due to an AE). If the reason for discontinuation is the occurrence of an AE, the patient 
will be followed up until the AE has resolved or is considered chronic or stable or the AE has been clearly 
shown to be unrelated to the IMP. 
Discontinued patients will not be replaced; patient/randomization numbers will not be reused. If a patient 
does not complete a scheduled visit, every effort should be made to contact the patient to reschedule the 
visit. All efforts should be documented in the patient’s medical source record. A patient will be considered 
lost to follow-up if patient cannot be reached after 4 weeks from the scheduled visit. 
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14. 
ASSESSMENTS 
The following assessments will be performed and recorded in the eCRF. The Schedule of Events by Visit 
is displayed in Table 1. 
14.1 
Patient Demographics and Medical History 
Demographic and baseline data will include year of birth, height (meters [m]; without shoes), weight (kg), 
race and ethnicity (if allowed), and sex. 
Medical history will capture any relevant previous and concurrent diseases, HAE disease history including 
the attack history and corresponding treatment for the past 3 months; therapies and supplements taken 
within the past 4 weeks; and participation in interventional clinical or COVID-19 trials in the past 4 weeks. 
14.2 
Efficacy Assessments 
Efficacy variables of interest in this trial are: 
• 
Change in overall HAE attack symptoms assessed using the PGI-C, scored on a 7-point rating 
scale 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 trial medication? 
• 
Time of conventional on-demand treatment use captured in the patient diary. 
o 
What time did you take your conventional HAE attack medication? 
• 
Overall HAE attack severity assessed on the PGI-S scored on a 5-point rating scale as none, 
mild, moderate, severe, very severe. 
o 
What is your overall HAE attack severity right now? 
• 
The type of HAE attack symptoms (abdominal pain, skin pain and skin swelling) each assessed 
on a 101-point VAS anchored at 0 (none) and 100 (very severe). 
o 
How much abdominal pain/skin pain/skin swelling are you experiencing right now? 
• 
Current anxiety level assessed on the Modified GA-NRS using an 11-point scale anchored at 0 
(not at all anxious) and 10 (extremely anxious). 
o 
How anxious do you feel right now? 
For each HAE attack treated with IMP, patients will record information in an eDiary, including attack 
location, attack symptoms, date/time of onset, attack severity, time of second IMP dose, if applicable, 
and use of conventional on-demand treatment, if applicable. Patients will complete timed assessments 
of their HAE attack through 48 hours as documented in Table 4. Patients should complete all timed diary 
assessments except during sleep; however, patients must complete at least the first 4 hours of diary 
assessments following the first administration of IMP. 
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Table 4: 
Frequency of Patient Assessment 
Time Period following the First 
IMP Administration 
Frequency of Patient 
Assessment a 
Allowed Time Window for 
Assessment 
0 to 4 hours 
Every 0.5 hours 
± 0.25 hour 
5 to 12 hours 
Every 1 hour 
± 0.5 hour 
14 to 24 hours 
Every 2 hours 
± 1 hour 
25 to 48 hours 
Every 12 hours 
± 3 hours 
IMP=investigational medicinal product 
a If a second dose of IMP or additional doses of conventional on-demand treatment are needed, patients will complete diary 
assessments prior to taking each additional dose. The planned post-dose diary assessments will then continue according to the 
table after re-dosing. Patients will also be required to call a designated Study Call Center (for details and timing, see 
Section 16.3.1). 
14.3 
Safety Assessments 
14.3.1 Physical Examinations 
A physical examination will be performed by the Investigator or his/her qualified designee according to 
the Schedule of Events (Table 1). A complete physical examination will be performed at Screening only 
and will include the following body systems: general appearance; ears, nose, and throat; head and neck; 
ophthalmological; respiratory; cardiovascular; abdomen; neurological; extremities; dermatological; and 
lymphatic. Other visits noted in the Schedule of Events (Table 1) will include a symptom-directed physical 
examination. 
In the case of a home health visit, the home healthcare nurse will conduct an abbreviated physical 
examination, and the Investigator will conduct the symptom-directed physical examination via televisit. 
14.3.2 Vital Signs 
Vital signs will be assessed after the patient has been at rest for at least 5 minutes in accordance with 
the Schedule of Events (Table 1). Vital signs will include blood pressure (systolic blood pressure [SBP] 
and diastolic blood pressure [DBP]; mmHg), pulse rate (PR; beats per minute), and respiration rate ([RR] 
breaths per minute). 
14.3.3 12-Lead Electrocardiogram 
A 12-lead ECG will be recorded after the patient has rested supine for at least 5 minutes in accordance 
with the Schedule of Events (Table 1). Heart rate (beats per minute), PR-interval (milliseconds [ms]), 
QRS-duration (ms), QT-interval (ms) and RR-interval (seconds [ms]) will be recorded; QTcF (Fridericia 
correction of QTc; ms) calculated as per standard practice. 
14.3.4 Clinical Safety Laboratory Assessments 
Blood samples (approximately 40 mL) will be taken using standard venipuncture techniques. The central 
laboratory will provide a Laboratory Manual with detailed procedures. Safety labs (Table 5) will be 
collected per the Schedule of Events (Table 1). 
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Table 5: 
Laboratory Assessments 
Hematology: 
RBC 
MCV 
MCH 
MCHC 
MPV 
RDW 
Nucleated RBC 
WBC 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Platelets 
Granulocytes 
Hemoglobin 
Hematocrit 
Urinalysis: 
pH 
Protein 
Glucose 
Ketone 
Bilirubin 
Blood 
Nitrite 
Albumin 
Reflex to microscopic panel, 
as required 
Clinical chemistry: 
HbA1c 
Creatinine 
Glucose (Random) 
Triglycerides 
Urea, Blood Nitrogen 
Bilirubin, Total 
Bilirubin, Direct 
Cholesterol, Total 
Liver enzymes: 
ALP 
AST 
ALT 
GGT 
Electrolytes: 
Sodium 
Potassium 
Coagulation 
INR 
C1 Functional Level: 
C1-Esterase Inhibitor 
Activity 
C1 Antigen: 
C1-Esterase Inhibitor 
Protein 
Complement C4: 
Complement C4 
Pregnancy test (serum): 
In female patients of childbearing potential. HCG Qualitative and Quantitative 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HbA1c=glycosylated 
hemoglobin; GGT=gamma glutamyl transferase; HCG=human chorionic gonadotropin; INR=international normalized ratio; MCH=mean 
corpuscular hemoglobin; MCV=mean corpuscular volume; MCHC=mean corpuscular hemoglobin concentration; MPV=mean platelet volume; 
pH=potential hydrogen; RBC=red blood cell; RDW=red cell distribution width; WBC=white blood cell differential, immature granulocytes. 
The Investigator must review screening laboratory results for patient eligibility prior to randomizing the 
patient. Laboratory tests may be repeated at the Investigator’s discretion and any associated safety issue 
should be followed up as per the Investigator’s clinical judgement until resolution/stabilization. Repeat 
laboratory assessments may be performed. 
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15. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
15.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. AEs will be 
recorded from the first dose of IMP up to and including the Final Visit/ET. Any non-serious AEs occurring 
prior to the first dose of IMP should be recorded as medical history. 
When possible, signs and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event. If an AE increases in severity it will be recorded as a new AE. Documentation 
regarding the AE should be made as to the nature, date of onset, end date, severity, relationship to the 
IMP, action(s) taken, seriousness, and outcome of any sign or symptom observed by the physician or 
reported by the patient upon questioning. 
HAE attacks will not be considered AEs unless they are considered SAEs. 
15.2 
Serious Adverse Events 
Any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event (medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious, such as important medical events that 
might not be immediately life-threatening or result in death or hospitalization but might jeopardize 
the patient or might require intervention to prevent one of the other). 
SAEs will be recorded from the time of signing the informed consent up to and including the Final Visit/ET. 
15.3 
Time Period and Frequency for Collection 
The period of observation for AEs extends from the time of the patient’s first dose of IMP until the Final/ET 
Visit. Ongoing AEs at the Final/ET Visit will be followed up until the AE has resolved or is considered 
chronic or stable or the AE has been clearly shown to be unrelated to the IMP. The period of observation 
for SAEs extends from the time of signing the informed consent until the Final/ET Visit. 
15.4 
Method of Detection 
All AEs spontaneously reported by the patient and/or in response to an open question from trial personnel 
or revealed by observation, physical examination, or other diagnostic procedures will be recorded. 
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15.5 
Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as determined 
by the Investigator or reported to him/her by the patient. The assessment of severity is made irrespective 
of relationship to IMP or seriousness of the event and should be evaluated according to the Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(US Department of Health and Human Services, 2007) where possible: 
• 
Mild (Grade 1) 
• 
Moderate (Grade 2) 
• 
Severe (Grade 3) 
• 
Potentially Life-Threatening (Grade 4) 
15.6 
Relationship 
The relationship of each AE to the IMP should be determined by the Investigator using these 
explanations: 
• 
Related: A reasonable possibility exists that the IMP caused the AE. 
• 
Not related: A reasonable possibility does not exist that the IMP caused the AE. 
“Reasonable possibility” means there is evidence to suggest a causal relationship between the IMP and 
the AE. 
Types of evidence that would suggest a causal relationship between the IMP and the AE include: A single 
occurrence of an event that is uncommon and known to be strongly associated with IMP exposure (e.g. 
hepatic injury, Stevens-Johnson Syndrome); one or more occurrences of an event that is not commonly 
associated with IMP exposure, but is otherwise uncommon in the population exposed to the IMP (e.g. 
tendon rupture); an aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that commonly 
occur in the trial population independent of drug therapy) that indicates those events occur more 
frequently in the IMP group than in a concurrent or historical control group. 
15.7 
Reporting 
15.7.1 Reporting AEs to EC/IRB and Regulatory Authorities 
The Investigator is responsible for informing the local EC/IRB of any applicable safety reports in 
compliance with local regulations. Copies of all correspondence and documentation relating to reporting 
of any safety reports to the local EC/IRB should be maintained in the Investigator Site Files. 
The Sponsor, or its designee, will inform Investigators, central ECs/IRBs and Regulatory Authorities of 
applicable safety reports, as required. 
15.7.2 Reporting Serious Adverse Events or Urgent Safety Measures 
Urgent Safety Measures (USMs) are procedures that may be undertaken by the Sponsor or the 
Investigator to protect a research patient from an immediate hazard to their health or safety.  USMs can 
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Pregnancy alone is not an AE unless there is a suspicion that the IMP may have interfered with the 
effectiveness of a contraceptive medication. 
All pregnancies must be reported by the Investigator to the Sponsor or designee within 5 days after 
becoming aware of the pregnancy. Pregnancies will be reported using the pregnancy reporting form and 
submitted to 
. The Investigator should make every effort possible to follow-up 
and document the course and the outcome of all pregnancies and live births up to 1 year of age even if 
the patient was discontinued from the trial or if the trial has finished. 
If a female partner of a male trial patient who has been exposed to the IMP becomes pregnant and 
consents to having the pregnancy followed, the pregnancy and outcome of pregnancy should be 
monitored according to the same guidelines as for female patients who become pregnant during the trial. 
15.9 
Treatment of Overdose 
No specific antidote to KVD900 is known and treatment of overdose should be supportive. 
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KONFIDENT Clinical Trial Protocol 
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16. 
TRIAL PROCEDURES 
This trial will be conducted on an outpatient basis and will comprise in-clinic and televisits. A televisit can 
be conducted via a telephone call or via an interactive audio/video system. If an in-clinic visit cannot be 
conducted (e.g. in the event of a pandemic or other reason that prevents the patient from attending in-
clinic visits), home health visits will be used to perform these visits, if permitted by the relevant regulatory 
authority, site’s EC/IRB, local regulations, and the patient via informed consent. The home visit will be 
performed by an appropriately delegated home healthcare service provider. Information captured during 
a home health visit will mirror that captured in an in-clinic visit. The IMP will be shipped to the patient via 
a courier service as described in the Pharmacy Manual. If local regulations or the site’s local practices 
do not allow the IMP to be delivered to the patient via courier service, then the patient will need to return 
to the clinic for the Randomization Visit where IMP will be dispensed. 
Informed consent must be obtained for all patients participating in the trial prior to performing any 
trial-related activities. 
Trial procedures are summarized by trial visit in the Schedule of Events (Table 1). 
16.1 
Screening Period 
16.1.1 Screening Visit (In-Clinic or Home Health Visit) 
Patients will undergo an in-clinic or home health visit for the Screening Visit. All patients will sign an 
Informed Consent Form (ICF) and provide assent (if applicable) prior to any trial-related procedures being 
performed. Consent/assent may be collected through e-consent, if allowed through country and site 
regulations. Following full discussion of the trial and the signing of the informed consent/assent, a patient 
number will be assigned (Section 11.1). 
The following activities will be performed during the Screening Visit: 
• 
Eligibility assessment evaluating all results of the screening assessment results against the 
inclusion and exclusion criteria (Section 9). 
• 
HAE diagnostic lab test (or confirmation against documented historical testing results) for patients 
without genetic confirmation of HAE type I or II. 
• 
Full medical history (Section 14.1), including any relevant previous and concurrent diseases, HAE 
disease history including the attack history and corresponding treatment for the past 3 months; 
therapies and supplements taken within the past 4 weeks; and previous participation in 
interventional clinical trials in the past 4 weeks. 
• 
Demographic information including year of birth; race and ethnicity (if allowed); and sex 
(Section 14.1). 
• 
Height (m; without shoes) and weight (kg) (Section 14.1). 
• 
Complete physical examination (Section 14.3.1). 
• 
Vital signs (SBP and DBP, PR, and RR). BP and PR recorded after patient has been resting for 
at least 5 minutes (Section 14.3.2). 
• 
12-lead ECG after patient has been supine for at least 5 minutes (Section 14.3.3). 
• 
Serum pregnancy test (female patients of childbearing potential). 
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• 
Blood and urine samples for clinical laboratory tests (Section 14.3.4). 
• 
Patient eDiary training on the information they will be expected to provide in the eDiary and the 
use of IMP. 
16.2 
Randomization Visit (Televisit or In-Clinic) 
The Randomization Visit may be a televisit or an in-clinic visit and will occur within 4 weeks of completing 
the Screening Visit. A televisit can be conducted via a telephone call or via an interactive audio/video 
system. 
The following activities will be performed during the Randomization Visit: 
• 
Eligibility assessment evaluating all results of the screening assessment results against the 
inclusion and exclusion criteria (Section 9). 
• 
Patient eDiary training. 
• 
Prior medication review. 
• 
Randomize patient in RTSM. 
• 
Dispense or ship the assigned, blinded IMP to patients. 
The IMP will be shipped directly to the patient via a courier service or will be dispensed at the trial clinic 
as required by local regulations or per the site’s local practice, as described in the Pharmacy Manual. 
16.3 
Treatment Period 
The Treatment Period will begin when the first HAE eligible attack occurs. Patients will treat 3 separate, 
eligible HAE attacks with their assigned IMP treatment for that attack. For an HAE attack to be considered 
eligible for treatment with IMP, the attack must meet the following criteria: 
• 
The attack is not a severe laryngeal attack. 
• 
Patient must be able to identify the start time of the attack. 
• 
At least 48 hours have elapsed since patient has used conventional on-demand treatment or IMP 
to treat an HAE attack. 
• 
Patient must be able to complete at least the first 4 hours of diary assessments following the first 
administration of IMP. 
• 
Post-attack televisit has been completed for the previous eligible attack (applicable to eligible 
attacks 2 and 3 only). 
Patients will treat each attack with up to 2 of doses IMP, administered at least 3 hours apart. Eligible 
attacks should initially be treated with a single administration of IMP. Patients will be encouraged to treat 
as soon as possible after recognition of the start of the attack. 
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If needed (as determined by the patient), a second dose of IMP may be administered for each 
non-laryngeal or laryngeal attack, as follows (see Figure 2 for schematic): 
Non-laryngeal attacks 
For each eligible HAE attack, a second dose of IMP may be taken: 
• 
after 3 hours if HAE attack symptoms are considered severe enough by the patient to require a 
second dose of IMP. 
After the second dose of IMP, conventional on-demand treatment may be taken: 
• 
after 1 hour if HAE attack symptoms are considered severe enough by the patient to require 
treatment with conventional treatment. 
If symptoms progress to airway involvement, patients may treat with conventional on-demand treatment 
at any time. 
Laryngeal attacks 
After the first dose of IMP, conventional on-demand treatment may be taken at any time: 
• 
if HAE attack symptoms worsen or if HAE attack symptoms are considered severe enough by the 
patient to require immediate treatment. 
Patients with safety or tolerability concerns will contact the Investigator or designee as soon as possible 
or the nearest emergency service as appropriate. 
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Figure 2: 
Schematic of Repeat Dosing 
16.3.1 First, Second, and Third Eligible HAE Attack (Televisit) 
At the time of the first, second, and third HAE attack, the following activities will be performed: 
Patient Activities 
• 
Patients will contact the Call Center after the first dose of IMP, prior to a second dose of IMP, and 
prior to a dose of conventional on-demand treatment. 
• 
Call Center staff will remind patients of the rules for re-dosing and the eDiary assessment 
requirements and will instruct patients experiencing laryngeal attacks to call their study doctor. 
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• 
Patients will complete timed assessments of HAE attack symptoms, including PGI-C, PGI-S, VAS 
and GA-NRS through 48-hour period following first dose of IMP. 
Site Staff Activities 
For each of the 3 eligible HAE attacks, a televisit will occur by the next working day after the completion 
of the patient diary (visit window: +1 week), during which the clinical site staff will perform the following: 
• 
Patient eDiary reviewed with re-training, if necessary. 
• 
Concomitant medication review. 
• 
AEs recorded (Section 15). 
16.3.2 Final Visit/Early Termination (In-Clinic or Home Health Visits) 
Once 3 separate HAE attacks have been treated with IMP, or upon patient ET, the patient should return 
to the clinic for the final visit as soon as possible within 1 week of completing all patient diary 
assessments. Whenever possible this visit should be completed prior to starting any new medication or 
treatment. At the Final Visit (or ET) the patient will return to the clinic and the following procedures will 
be conducted: 
• 
Symptom-directed physical examination (Section 14.3.1). In the case of a home health visit, the 
home healthcare nurse will conduct an abbreviated physical examination, and the Investigator 
will conduct the symptom-directed physical examination via televisit. 
• 
Vital signs (SBP and DBP, PR, and RR). BP and PR recorded after patient has been resting for 
at least 5 minutes (Section 14.3.2). 
• 
12-lead ECG after patient has been supine for at least 5 minutes (Section 14.3.3). 
• 
Blood and urine samples for clinical laboratory tests (Section 14.3.4). 
• 
Serum pregnancy test (female patients of childbearing potential). 
• 
Return unused IMP and IMP packaging (or arrange for return if in-clinic visit is not possible). 
• 
Concomitant medication review. 
• 
AEs recorded (Section 15). 
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KONFIDENT Clinical Trial Protocol 
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17. 
STATISTICAL CONSIDERATIONS 
17.1 
Sample Size Determination 
Approximately 114 patients will be randomized into the trial to ensure approximately 84 patients 
(including approximately 12 adolescents) complete the trial. The trial population will comprise 2 subsets: 
(1) patients who enter the trial taking only conventional on-demand treatment; and (2) patients who enter 
the trial on a stable dose and regimen of long-term prophylactic treatment. 
1. 
Based on the population and results from the Phase 2 trial (KVD900-201), a sample size of 
66 patients completing the trial would provide 90% power for testing each pairwise comparison 
(KVD900 versus placebo) at the 2.5% alpha level (2-sided) for the primary endpoint of time to 
beginning of symptom relief of the HAE attack as defined by PGI-C as at least “a little better” for 
2 time points in a row within 12 hours of the first IMP administration. This sample size was derived 
using the assumption that median time to symptom relief of the HAE attack is 1.6 hours in active 
dose arm and 9 hours in placebo arm from trial KVD900-201. It was assumed that patients begin 
the trial together and will be followed for the same period of time, 49% of patients in control group 
and 17% of patients in KVD900 dose group are assumed to be lost-to-follow-up (right-censored). 
There is no commercially available software for sample size calculation based on the 
Feingold and Gillespie (1996) method. Taking a conservative approach and using 
simulation-based procedure for power calculations for a parallel group design, the two-sided two-
group survival comparison Gehan-Wilcoxon test has approximately 90% power to detect a 
median time ratio of 5.6 (9/1.6) with a target 2-sided significance level of 2.5% when there are 66 
patients in each treatment group. 
2. 
The treatment effect observed in the Phase 2 trial (KVD900-201) is assumed to be representative 
of the entire KVD900-301 population. However, additional trial populations will be enrolled 
(e.g. adolescent patients and patients that enter the trial on a stable dose and regimen of 
long-term prophylactic treatment) where the treatment effect has not been previously 
characterized. Therefore, a total of 84 patients completing the trial is proposed. This conservative 
approach increases the likelihood of maintaining at least 90% power in the event that the true 
treatment effect in the KVD900-301 population is different to that observed in the KVD900-201 
trial. 
Assuming there is approximately 30% dropout or non-completion rate, consistent with the Phase 2 trial, 
the oversampling by 30 patients (84 + 30 = 114) is proposed to account for patients that may not complete 
all treatment periods due to infrequent or ineligible HAE attacks or for patients who discontinue the trial 
early, for whatever reason. 
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17.2 
Estimands and Intercurrent Events 
Table 6: 
Intercurrent Event Types 
Label 
Intercurrent Event Type 
IcEv1 (Discontinue trial due to 
any reason) 
Discontinuation of trial due to any reason 
IcEv2 (Prohibited medications) 
Use of prohibited medications that may interfere with outcome 
(Section 12.3) 
IcEv3 (Conventional on-demand 
treatment) 
Use of conventional on-demand treatment that may interfere with outcome 
(Section 12.1) 
Abbreviations: IcEv=intercurrent event 
Table 7: 
Estimands with Rationale for Strategies to Address Intercurrent Events 
Estimand Label 
Primary Estimand. 
Estimand Description 
Relative effect of each of the KVD900 dose groups versus placebo in 
shortening the time to beginning of symptom relief defined by the PGI-C as 
at least “a little better” for 2 time points in a row within 12 hours of the first 
IMP administration in adolescent and adult patients with hereditary 
angioedema type I or II regardless of prohibited medications and as long 
as conventional on-demand treatment for HAE attacks had not been used 
and as if patients had not discontinued the trial. 
Target Population 
Adolescent and adult patients with hereditary angioedema type I or II . 
Endpoint 
The PGI-C: Time to beginning of symptom relief defined as at least “a little 
better” (2 time points in a row) within 12 hours of the first IMP 
administration. 
Treatment Condition(s) 
Initially, a single dose of KVD900 300 mg, 600 mg, or matching placebo 
tablets in response to each eligible attack of HAE. If needed (as determined 
by the patient), a second dose of IMP may be administered for each attack. 
Attacks that do not meet eligibility may be treated with conventional on-
demand treatment per the patient’s usual treatment regimen. 
Population-Level Summary 
Difference in median time to beginning of symptom relief defined by the 
PGI-C as at least “a little better” for 2 time points in a row within 12 hours of 
the first IMP administration. 
Intercurrent Event Strategy 
IcEv1 (Discontinue due to any 
reason) 
Hypothetical. 
IcEv2 (Prohibited medications) 
Treatment policy. 
IcEv3 (Conventional on-
demand treatment) 
Composite. 
Rationale for Strategies 
The primary focus of this Phase 3 trial is to demonstrate the clinical efficacy 
of KVD900 compared with placebo for the on-demand treatment of HAE 
attacks regardless of the prohibited medication taken as long as 
conventional on-demand treatment has not been used and as if patient did 
not discontinue the trial. 
Abbreviations: HAE=hereditary angioedema; IcEv=intercurrent event; IMP=investigational medicinal product; PGI-C=Patient Global Impression 
of Change 
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17.3 
Populations for Analyses 
• 
Safety Set will include all patients who receive at least one dose of trial medication. 
• 
Full Analysis Set (FAS) will include all randomized patients who receive trial medication from at 
least one period for respective qualifying HAE attack. If one or more patient(s) received incorrect 
trial medication, data summarized using the FAS will be presented according to the randomized 
treatment. The FAS population will be the population for confirmatory efficacy analyses. 
• 
Per-protocol Set (PPS) will include all randomized patients who receive trial medication from at 
least one period for respective qualifying HAE attack, and who do not have major protocol 
deviations that may affect primary efficacy endpoint. 
Subgroup analysis sets 
• 
On-demand Full Analysis Set (on-demand FAS) will include FAS patients who enter the trial taking 
only conventional on-demand treatment.  
• 
Prophylaxis Full Analysis Set (prophylaxis-FAS) will include FAS patients who enter the trial on a 
stable dose and regimen of long-term prophylactic treatment. 
17.4 
General Considerations 
Continuous data will be summarized by treatment group using descriptive statistics (number, arithmetic 
mean, median, standard deviation, 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. 
The primary efficacy endpoint confirmatory analysis will have Bonferroni multiplicity adjustment for 
multiple dose levels, therefore pairwise comparison tests will be 2-sided with an alpha of 0.025. The 
analysis of the secondary or exploratory endpoints will not have multiplicity adjustments. 
There are 3 treatment groups in the trial: 
1. 
300 mg KVD900 
2. 
600 mg KVD900 
3. 
Placebo 
Two pairwise comparisons will be performed: 300 mg KVD900 versus placebo and 600 mg KVD900 
versus placebo. 
17.4.1 Multiplicity Adjustment 
Fixed sequence closed testing procedure will be followed. In a fixed sequence closed testing procedure 
the formal inferential testing can proceed to the next step only when statistical significance is declared in 
the current step. If the testing sequence is stopped, the remaining endpoints in the testing sequence will 
be considered exploratory. The fixed testing procedure will be employed first on the primary and then on 
the key secondary endpoints 1 and 2, separately for each dose comparison to placebo. 
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Primary Endpoint 
• 
PGI-C: Time to beginning of symptom relief defined as at least “a little better” (2 time points in a 
row) within 12 hours of the first IMP administration. 
Key Secondary Endpoints 
• 
PGI-S: Time to first incidence of decrease from baseline (2 time points in a row) within 12 hours 
of the first IMP administration. 
• 
PGI-S: Time to HAE attack resolution defined as “none” within 24 hours of the first IMP 
administration. 
Statistical tests on both the primary and the key secondary endpoints will be at the same significance 
level alpha (0.025) with a loop-back feature to allow two-way alpha passing. Key secondary endpoint 1 
will be tested only if the test on the primary endpoint is statistically significant. Testing within a dose level 
will be stopped if the test on the primary endpoint could not reject null hypothesis for that KVD900 dose 
level at significance level of 0.025. 
Key secondary endpoint 2 will be tested only if the test on the key secondary endpoint 1 is statistically 
significant. Testing within a dose level will be stopped if the test on the key secondary endpoint 1 could 
not reject null hypothesis for that KVD900 dose level at significance level of 0.025. 
Significance level 0.025 is Bonferroni adjusted significance level obtained by dividing the original 
significance level 0.05 by the number of comparisons within endpoint family between each KVD900 dose 
level and placebo, i.e. the adjusted significance level is 0.025 (0.05 divided by 2). If the primary and key 
secondary endpoints hypotheses within one of the pairwise comparisons are not all rejected at 0.025 
alpha level, but the hypotheses for the other pairwise comparison are all rejected, then the unused alpha 
from the rejected hypotheses can be directed to loop-back to the unrejected hypotheses, which is then 
re-tested at the alpha level of 0.05. 
17.5 
Analysis of Disposition 
The number and percentage of patients screened, entering, and completing each trial part will be 
presented by treatment. Reasons for withdrawal will be summarized. 
17.6 
Demographics and Baseline Characteristics 
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. 
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17.7 
Statistical Analysis of Efficacy Endpoints 
17.7.1 Primary Endpoint 
Primary Analysis Hypothesis 
The null hypothesis is that there is no difference in survival distribution of the time to beginning of 
symptom relief defined by the PGI-C as at least “a little better” for 2 time points in a row within 12 hours 
of the first IMP administration (no difference between each dose of KVD900 group versus placebo group) 
versus the alternative hypothesis that the survival distributions are different (each of the KVD900 dose 
groups versus placebo). 
𝐻𝐻0: 𝑡𝑡𝑘𝑘 − 𝑡𝑡𝑝𝑝 = 0, 
where 𝑡𝑡𝑘𝑘 is the time to “a little better” or higher rating of HAE attack following KVD900 dose treatment 
and 𝑡𝑡𝑝𝑝 is the time to “a little better” or higher rating of HAE attack following placebo. 
𝐻𝐻𝑎𝑎: 𝑡𝑡𝑘𝑘 − 𝑡𝑡𝑝𝑝 ≠ 0. 
The number of patients with the primary endpoint event will be summarized by frequencies and survival 
estimates, the summaries will be presented by treatment. 
Table 8 gives a summary of analysis methods, strategy for handling missing data, and sensitivity analysis 
for the primary endpoint. 
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Table 8: 
Summary of Statistical Methods and Sensitivity Analyses for Primary Endpoint 
Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity/ Supplementary
Analysis 
Analysis 
Set 
Imputation/Data/
Censoring Rules 
Primary Analysis Model/
Method 
Primary 
Estimand 
Relative effect of each of 
the KVD900 dose groups 
versus placebo in 
shortening the time to 
beginning of symptom 
relief defined by the 
PGI-C as at least “a little 
better” for 2 time points in 
a row within 12 hours of 
the first IMP 
administration in 
adolescent and adult 
patients with hereditary 
angioedema type I or II 
regardless of prohibited 
medications and as if 
conventional on-demand 
treatment for HAE attacks 
had not been used and 
patients had not 
discontinued the trial. 
FAS 
Patients will be treated 
as right-censored if they 
do not achieve 
beginning of symptom 
relief defined by PGI-C 
as at least “a little better” 
(2 time points in a row) 
within 12 hours of the 
first IMP administration 
(plasma KVD900 levels 
are expected to be low 
by 12 hours). In the case 
intercurrent events 
prevented event “a little 
better” or higher HAE 
attack rating occurrence, 
patients will be 
censored. 
Time to beginning of 
symptom relief defined by 
the PGI-C as at least “a little 
better” for 2 time points in a 
row within 12 hours of the 
first IMP administration will 
be analyzed using Gehan 
score transformation test 
proposed by Feingold and 
Gillespie (1996) 
(Section 17.7.2) 
Sensitivity Analysis 1: Perform 
imputation under informative 
censoring (Section 17.7.3) and 
repeat primary analysis. 
Sensitivity Analysis 2: 
Generalized Wilcoxon test 
proposed by Feingold and 
Gillespie (1996) adapted for 3x3 
design (Section 17.7.4). 
Supplementary Analysis 1: 
repeat primary analysis on PPS. 
Supplementary Analysis 2: 
Time to beginning of symptom 
relief will be categorized into 
intervals and the number and 
percentage of attacks that fall into 
each category will be presented. 
Supplementary Analysis 3: 
Perform imputation for patients 
who took rescue medication after 
having worsened using a 
hypothetical strategy, i.e. their 
time to beginning of symptom 
relief will be imputed as right-
censored at time of rescue 
medication. Repeat primary 
analysis. 
Abbreviations: FAS=Full Analysis Set; HAE=hereditary angioedema; IMP=investigational medicinal product; PGI-C=Patient Global Impression of Change; PPS=Per-protocol set 
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17.7.2 Gehan Score Transformation Test 
The Gehan Score Transformation test was proposed by Feingold and Gillespie (1996). For this test, 
applicable to any cross-over design, they propose to transform each observation to a score and then 
apply the procedures for complete data to the scores: “Scores for censored data are analogous to ranks 
for complete data, and this score transformation approach is analogous to the rank transformation 
analysis often used for complete data”. To perform the test, each observation will be transformed to 
Gehan score. Gehan score for the ith observation is the number of observations in the entire data set 
clearly smaller than the ith minus the number clearly larger. For uncensored observations, the Gehan 
score is the number of uncensored observations strictly smaller, minus the number of uncensored 
observations strictly greater, minus the number of right-censored observations equal or greater. For 
right-censored observations, the Gehan score is the number of uncensored observations smaller or 
equal. 
Gehan scores will be analyzed using a linear mixed model, including terms for sequence, period and 
treatment in the model as fixed effects and sequence within patient as a random effect. Least-squares 
means of treatment effects to show differences between treatments (placebo versus 600 mg versus 
300 mg) will be tested at 0.025 level. 
17.7.3 Imputation under Informative Censoring 
For this first sensitivity analysis, censored observations will be treated as missing data. Nonparametric 
multiple imputation under informative censoring assumption will be applied to impute censored data. 
Informative censoring assumes correlation between failure and censoring time (Taylor et al. 2002, 
O’Connor 2020). Censored or missing outcome values will be imputed from a distribution derived from 
remaining at risk patients. The first steps of the imputation method will be to identify this distribution, 
followed by the random selection of the imputed value until new multiple imputed data set is created. The 
procedure will be independently repeated 50 times creating 50 multiply imputed data sets. The primary 
analysis will be repeated on each of the 50 multiply imputed data sets and the results will be combined 
using Rubin’s method. Details on the test implementation will be provided in the Statistical Analysis Plan 
(SAP). 
17.7.4 Gehan’s Generalized Wilcoxon Test 
The Gehan’s generalized Wilcoxon test was also proposed by Feingold and Gillespie (1996). The test is 
a non-parametric test for comparing time-to-event data and is an extension of the Wilcoxon rank sum test 
in the presence of censoring. The test was designed for trials with two sequences. 
This supplementary analysis will explore adapting this test for 3x3 crossover design, by pooling 
pre-specified sequences and implementing this test as if comparing two treatment groups, the pairwise 
difference between periods (corresponding to the relevant KVD900 dose versus placebo) in time to at 
least “a little better” (2 time points in a row) within 12 hours of the first IMP administration using PGI-C 
will be calculated, separately by sequence. Details on the test implementation will be provided in the 
SAP. 
17.7.5 Key Secondary Endpoints 
• 
PGI-S: Time to first incidence of decrease from baseline (2 time points in a row) within 12 hours 
of the first IMP administration. 
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• 
PGI-S: Time to HAE attack resolution defined as “none” within 24 hours of the first IMP 
administration. 
HAE attack severity will be assessed on the PGI-S 5-point Likert scale scored as none, mild, moderate, 
severe, and very severe. A decrease in severity is defined as any change to any less severe level post 
baseline, than the score reported at baseline. 
Key secondary endpoints will be analyzed with the same approach as primary endpoint analysis method 
(Gehan Score Transformation test, Section 17.7.2). For both key secondary endpoints (Section 7.2.2) 
the same as for primary endpoint hypotheses (Section 17.7.1) will be tested. 
Key secondary endpoints will be tested according to the fixed sequence closed testing procedure 
(Section 17.4.1). 
Key secondary endpoints will be summarized by frequencies and survival estimates; the summaries will 
be presented by treatment. 
17.7.6 Subgroup and Subset Analyses 
Subgroup analyses of the primary and key secondary efficacy endpoint will be performed by primary 
attack location at HAE attack onset, gender, age, prophylactic treatment status, type of HAE, Baseline 
severity, region, time from onset of attack to the first IMP administration, and number of doses received. 
Frequencies and survival estimates will be presented for each subgroup. Subgroups by time of attacks 
may also be investigated. 
Analysis of the primary and key secondary efficacy endpoints will be performed on the on-demand FAS 
and the prophylaxis-FAS. 
17.7.7 Other Endpoints 
Secondary endpoints listed in Section 7.2.3 are time-to-event endpoints. The time-to-event endpoints will 
be summarized by frequencies of the events and Kaplan-Meier estimates or survival estimates as 
appropriate. The summaries will be presented by treatment. 
Additional endpoints may be defined in the SAP. The details of the statistical analysis will be provided in 
the SAP. 
17.7.8 Exploratory Endpoint(s) 
Baseline- and time-adjusted AUCs of the GA-NRS over time from 0 hour (pre-dose) up to 12 hours and 
up to 24 hours or up to the last time point prior to the time of conventional on-demand treatment use, 
whichever occurs first will be derived by linear trapezoidal rule. Details on AUC calculation will be 
provided in the SAP. AUCs will be summarized descriptively. A statistical comparison of the AUCs 
between treatments will be performed using a mixed effects analysis of variance with fixed effects of 
treatment, sequence, and period and patient nested within sequence as a random effect. 
Additional endpoints may be defined in the SAP. 
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17.8 
Safety Analyses 
Safety analyses will be performed by treatment group using the safety set. Safety endpoints include AE, 
clinical laboratory assessments, vital signs, ECG findings as described in Sections 14.3 and 15.1. 
Adverse events and SAEs recorded during the trial will be summarized by system organ class, preferred 
term, and treatment. Adverse events and medical history will be coded using the most current version of 
MedDRA. 
Frequencies and percentages of patients with treatment-emergent adverse events (TEAEs), serious 
TEAEs, and TEAEs causing premature discontinuation will be provided by treatment group. 
Patient listings of all AEs will be provided as well as listings of deaths, SAEs, and AEs leading to 
discontinuation. 
For physical examination, ECG, vital signs, and laboratory variables (measured by the central laboratory), 
the number and percentage of patients with normal or abnormal results will be presented at each 
scheduled visit by sequence. Descriptive statistics for continuous variables will be provided at scheduled 
visits together with a summary of changes from baseline for each parameter by sequence. 
17.9 
Interim Analyses 
Not applicable. 
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18. 
TRIAL ADMINISTRATION 
18.1 
Direct Access to Source Data/Documents 
The Investigator will allow Sponsor representatives, authorized regulatory authority inspectors, and the 
EC/IRB to have direct access to all documents pertaining to the trial. 
These groups may audit and review source data and will follow local regulations regarding data 
protection. The Investigator will provide support for these audits. 
18.2 
Quality Control and Quality Assurance 
The Sponsor and Contract Research Organization (CRO) will utilize a system of quality assurance. Within 
this system, Standard Operating Procedures (SOPs) from the Sponsor and CRO will be followed to 
ensure the clinical trial is conducted in compliance with regulatory requirements and GCP. Quality control 
will be applied to each stage of data handling. 
18.3 
Ethics 
18.3.1 Regulatory and Ethical Considerations 
The procedures set out in this clinical trial protocol are designed to ensure that the Sponsor and the 
Investigator abide by the principles of the ICH guidelines on GCP, applicable local regulatory 
requirements, and the Declaration of Helsinki (World Medical Association, 2013). The clinical trial will 
also follow national and local legal requirements. 
The trial protocol and relevant documents will be approved by EC/IRB and Regulatory Authorities. The 
Investigator will provide periodic reports, as required, to the EC/IRB and Regulatory Authorities. 
18.3.2 Informed Consent/Assent 
Informed consent/assent will be obtained from the patient according to the regulatory and legal 
requirements of the participating country. This may be captured electronically or via paper. The 
Investigator will not undertake any investigation specifically required for the clinical trial until valid 
consent/assent has been obtained. 
18.3.3 Patient Confidentiality 
The anonymity of participating patients must be maintained. Patients will be specified on trial documents 
by their patient ID, not by name. Documents that identify the patient (e.g. informed consent document) 
must be maintained in confidence by the Investigator per GCP and local regulations. 
The Investigator agrees not to use or disclose protected health information other than as permitted or 
required by patient authorization or as required by law. 
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18.4 
Data Handling and Record Keeping 
18.4.1 Source Documents 
All source documents from which eCRF entries are derived should be placed in the patient’s trial records. 
Source documents may include laboratory assessments, trial specific examinations, and any other 
documents that support the data collected in the eCRF. The Investigator will ensure the accuracy, 
completeness, and timeliness of the data. The review of medical records will be performed in a manner 
to ensure that patient confidentiality is maintained. 
18.4.2 Trial Monitoring 
The Sponsor or Sponsor’s designee will verify the qualifications of each Investigator, site facilities, and 
inform the Investigator of responsibilities and the procedures for ensuring adequate and correct 
documentation. 
The Investigator will maintain adequate and accurate records of data pertinent to the clinical trial for each 
trial patient. Frequent communication between the trial site and the Sponsor (or designee) is essential to 
ensure that the trial is monitored adequately. 
All aspects of the trial will be carefully monitored with respect to GCP, Sponsor and CRO SOPs, and the 
trial specific Monitoring Plan to ensure compliance with applicable government regulations. The 
Monitor(s) will have access to all records necessary to ensure integrity of the data and will periodically 
review the progress of the trial with the Investigator. 
18.4.3 Database Management 
All data generated by the site personnel will be captured electronically at each trial site using eCRFs. A 
complete audit trail will be maintained of all data changes. 
The specific procedures to be used for data entry and query resolution using the eCRF will be provided 
to trial sites. Applicable site personnel will receive training on the eCRF. Edit checks and manual review 
will be used to identify any errors or inconsistencies in the data. 
18.4.4 Retention of Trial Records 
Essential documents, including all trial records, should be retained according to ICH guidelines. These 
documents should be retained for a longer period if required by the applicable local regulations. 
If the responsible Investigator retires, relocates or for any other reason withdraws from the responsibility 
of keeping the trial records, custody must be transferred to a person who will accept the responsibility. 
The Sponsor representative must be notified in writing of the name and address of the new custodian, 
prior to the transfer. 
18.5 
Financing and Insurance 
18.5.1 Financial Disclosure 
All Investigators and required trial personnel will complete a financial disclosure statement. 
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18.5.2 Trial Insurance 
Clinical trial insurance will be maintained per local regulations. 
18.6 
Publication Policy 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted with the 
Sponsor in advance. The rights and obligations of Investigators and the Sponsor concerning any formal 
presentation or publication of data collected as a direct or indirect result of this trial will be addressed 
specifically in the Clinical Trial Agreement for the trial. 
18.7 
Trial Master File 
A Trial Master File (TMF) will be maintained by the Sponsor (or designee). Documents and other 
materials that pertain to the conduct of the trial, quality of the data, and compliance with GCP will be 
collected in the TMF. 
18.8 
Premature Trial Closure 
The Sponsor reserves the right to prematurely terminate or halt the trial either at a particular site or at all 
trial sites at any time after appropriate discussion with the Sponsor and Investigator(s). If the trial is halted 
or terminated for safety reasons, then all Investigators and the relevant Regulatory Agencies will be 
notified per local regulations. The Investigator at each trial site will advise their EC/IRB. 
18.9 
Selection of Coordinating Investigator 
A coordinating (principal) investigator will be appointed as a signatory on the clinical study report in 
accordance with EMEA guidance and Sponsor requirements. 
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19. 
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Nordenfelt P, Nilsson M, Björkander J, Mallbris L, Lindfors A, Wahlgren CF. Hereditary Angioedema in 
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to disease activity in adults with hereditary angioedema in Sweden. Allergy Asthma Proc. 2017 Nov 
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Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-
oedema. Lancet. 1998 Jun 6;351(9117):1693-7. doi: 10.1016/S0140-6736(97)09137-X. 
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Nussberger J, Cugno M, Cicardi M, Agostoni A. Local bradykinin generation in hereditary angioedema. 
J Allergy Clin Immunol. 1999 Dec;104(6):1321-2. doi: 10.1016/s0091-6749(99)70030-8. 
O’Connor P. A nonparametric multiple imputation approach for survival data subject to informative 
censoring. 
Doctoral 
Dissertation. 
University 
of 
Arizona, 
2020. 
Available 
at 
http://hdl.handle.net/10150/637722. 
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