Clinical trial NCT05259917
Conditions: Hereditary Angioedema
Keywords: KONFIDENT Sebetralstat
Sponsor: KalVista Pharmaceuticals, Ltd.
Start date: 2022-02-22; Completion date: 2023-12-31
Enrollment: 136 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is a randomized, double-blind, placebo-controlled, phase III, three-way crossover clinical trial evaluating the efficacy and safety of KVD900, in the treatment of hereditary angioedema attacks in adolescent and adult Patients

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Placebo intervention 2: KVD900 600 mg intervention 3: KVD900 300 mg
Intervention descriptions: intervention 1: Placebo to KVD900 Tablet intervention 2: KVD900 Tablet 600 mg (2 x 300 mg) intervention 3: KVD900 Tablet 300 mg (1 x 300 mg)

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
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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 
KVD900-301/KVD900 
KONFIDENT Clinical Trial Protocol 
Version 4.1 (US Only), 04 May 2023 
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 
Version 4.1 (US Only), 04 May 2023 
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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Maurer M, Bork K, Martinez-Saguer I, et al. Management of patients with hereditary angioedema in 
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Venereol. 2019 Jan;33(1):163-169. doi: 10.1111/jdv.15232. 
Nordenfelt P, Nilsson M, Björkander J, Mallbris L, Lindfors A, Wahlgren CF. Hereditary Angioedema in 
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Nordenfelt P, Nilsson M, Lindfors A, Wahlgren CF, Björkander J. Health-related quality of life in relation 
to disease activity in adults with hereditary angioedema in Sweden. Allergy Asthma Proc. 2017 Nov 
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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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22;347(8):621-2. doi: 10.1056/NEJM200208223470820. 
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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. 
ORLADEYO™ 
(berotralstat) 
[package 
insert]. 
BioCryst 
Pharmaceuticals, 
Inc; 
2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214094s000lbl.pdf 
Rosen FS, Alper CA, Pensky J, Klemperer MR, Donaldson VH. Genetically determined heterogeneity of 
the C1 esterase inhibitor in patients with hereditary angioneurotic edema. J Clin Invest. 1971 
Oct;50(10):2143-9. doi: 10.1172/JCI106708. 
Rosen FS, Pensky J, Donaldson V, Charache P. Hereditary angioneurotic edema: two genetic variants. 
Science. 1965 May 14;148(3672):957-8. doi: 10.1126/science.148.3672.957. 
Sheffer AL, Campion M, Levy RJ, Li HH, Horn PT, Pullman WE. Ecallantide (DX-88) for acute hereditary 
angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies. J Allergy Clin Immunol. 2011 
Jul;128(1):153-159.e4. doi: 10.1016/j.jaci.2011.03.006. 
Taylor JMG, Murray S, Hsu C-H. Survival estimation and testing via multiple imputation. Stat Probability 
Letters 2002; 58: 221–232. 
US Department of Health and Human Services, Food and Drug Administration, Center for Biologics 
Evaluation and Research. Guidance for Industry. Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative Vaccine Clinical Trials., September 2007. 
World Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for 
Medical 
Research 
Involving 
Human 
Subjects. 
JAMA. 
2013;310(20):2191–2194. 
doi:10.1001/jama.2013.281053. 
Zanichelli A, Arcoleo F, Barca MP, et al. A nationwide survey of hereditary angioedema due to C1 inhibitor 
deficiency in Italy. Orphanet J Rare Dis. 2015 Feb 6;10:11. doi: 10.1186/s13023-015-0233-x. 
Zuraw B, Lumry WR, Johnston DT, et al. Oral once-daily berotralstat for the prevention of hereditary 
angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin 
Immunol. 2020 Oct 21:S0091-6749(20)31484-6. doi: 10.1016/j.jaci.2020.10.015. 
Page 67 of 67 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KalVista Pharmaceuticals Ltd 
KVD900-301 
(KONFIDENT) 
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 
1DEC2023 
Final Statistical Analysis Plan 
Version 2.0 
Prepared by: 
PPD 
929 North Front Street Wilmington 
NC 28401-3331 
Confidential 




 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KalVista Pharmaceuticals, Ltd 
Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
SAP AMENDMENT SUMMARY OF CHANGES 
The purpose of this amendment is to make changes to the KVD900-301 SAP Version 1.0 
signed off on 30 June 2023. The change from Version 1.0 to Version 2.0 of the SAP and 
rationale for key changes are as follows: 
• Revised the criteria for 'Qualifying HAE Attacks' to encompass all attacks treated 
with the investigational medicinal product (IMP). 
o Reasoning: This modification in the definition of qualifying HAE attacks 
ensures the inclusion of all attacks treated with the IMP in the efficacy 
analyses. Adhering to the intent-to-treat principle, this change eliminates 
potential bias arising from the exclusion of attacks due to poor assessment 
compliance. 
• Established guidelines for censoring attacks with underivable endpoints. 
o Reasoning: With the inclusion of all IMP-treated HAE attacks in the efficacy 
analyses, certain attacks lacking reliable assessment data resulted in endpoints 
that could not be determined. To address this issue, specific censoring rules 
were introduced. 
• Updated the Gehan score transformation test model for PGI-S based endpoints by 
adjusting for the baseline PGI-S category. 
o Reasoning: Upon review of study KVD900-201 results and a blinded review 
of IMP-treated attacks in this study, it is identified that baseline PGI-S score 
has a potentially meaningful impact on PGI-S based endpoints. Therefore, 
baseline PGI-S category (none or mild, moderate, and severe or very severe) 
was added to the Gehan score transformation test as a fixed effect to adjust for 
this potential confounding factor. 
• Redefined the endpoint 'time to the second IMP administration within 12 and 24 
hours’. 
o Reasoning: The initial definition considered any conventional medication use 
prior to the second IMP administration as an event equivalent to the second 
IMP use. However, since the second IMP use is a crucial aspect of the dosing 
regimen under study, it cannot be equated with conventional medication use 
or deemed a treatment failure. 
• Expanded the duration of the on-treatment period for adverse events in accordance 
with FDA recommendations. 
o Reasoning: Following the FDA's suggestion, the period for classifying 
adverse events as "on-treatment" was extended from two days to three days 
after the last administration of the study drug. This decision was substantiated 
by a thorough analysis of KVD900 concentration data obtained from 198 
healthy volunteers who were administered 600 mg film-coated tablets. The 
analysis revealed that existing concentrations ranged from 0.01 to 2.71% of 
Cmax at the 48-hour post-dose mark. This finding justified the conservative 
approach of extending the on-treatment period, ensuring a comprehensive 
evaluation of potential adverse events during this critical timeframe. 
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KalVista Pharmaceuticals, Ltd 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................8 
1. INTRODUCTION ..........................................................................................................10 
2. OBJECTIVES .................................................................................................................11 
2.1. 
PRIMARY OBJECTIVE AND ESTIMAND .................................................................. 11 
2.2. 
SECONDARY OBJECTIVE ...................................................................................... 11 
3. INVESTIGATIONAL PLAN ........................................................................................12 
3.1. 
OVERALL TRIAL DESIGN AND PLAN .................................................................... 12 
3.2. 
TRIAL ENDPOINTS................................................................................................ 12 
3.2.1. 
Primary Endpoint................................................................................................ 12 
3.2.2. 
Key Secondary Endpoints ................................................................................... 13 
3.2.3. 
Secondary Endpoints .......................................................................................... 13 
3.2.4. 
Exploratory Endpoints........................................................................................ 14 
3.3. 
TREATMENTS ....................................................................................................... 14 
3.4. 
DOSE ADJUSTMENT/MODIFICATIONS................................................................... 15 
4. GENERAL STATISTICAL CONSIDERATIONS .....................................................15 
4.1. 
MULTIPLICITY ADJUSTMENT ............................................................................... 17 
4.2. 
SAMPLE SIZE........................................................................................................ 18 
4.3. 
RANDOMIZATION, STRATIFICATION, AND BLINDING............................................ 19 
4.4. 
INTERCURRENT EVENT TYPES ............................................................................. 21 
4.5. 
ESTIMAND SPECIFICATIONS ................................................................................. 21 
4.6. 
ANALYSIS SETS.................................................................................................... 24 
4.6.1. 
Screened Set........................................................................................................ 25 
4.6.2. 
Randomized Set................................................................................................... 25 
4.6.3. 
Safety Set............................................................................................................. 25 
4.6.4. 
Full Analysis Set ................................................................................................. 25 
4.6.5. 
Per Protocol Set.................................................................................................. 25 
4.6.6. 
On-demand Full Analysis Set.............................................................................. 25 
4.6.7. 
Prophylaxis Full Analysis Set ............................................................................. 25 
5. STATISTICAL ANALYSIS ..........................................................................................26 
5.1. 
INCLUSION AND EXCLUSION CRITERIA ................................................................ 26 
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5.2. 
DISPOSITION ........................................................................................................ 26 
5.3. 
PROTOCOL DEVIATIONS....................................................................................... 27 
5.4. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................ 27 
5.4.1. 
Demographics..................................................................................................... 27 
5.5. 
MEDICAL HISTORY .............................................................................................. 27 
5.5.1. 
General Medical History .................................................................................... 27 
5.5.2. 
Disease-Specific History..................................................................................... 28 
5.6. 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................... 28 
5.6.1. 
Prior Medications ............................................................................................... 28 
5.6.2. 
Concomitant Medications ................................................................................... 28 
5.7. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ....................................... 28 
5.8. 
EFFICACY ANALYSIS............................................................................................ 29 
5.8.1. 
Efficacy Assessments........................................................................................... 29 
5.8.2. 
Primary Efficacy Endpoint ................................................................................. 30 
5.8.2.1. 
Primary Efficacy Analysis ........................................................................... 30 
5.8.2.2. 
Supplementary Analysis to the Primary Efficacy Endpoint......................... 31 
5.8.2.3. 
Sensitivity Analysis to the Primary Efficacy Endpoint................................ 32 
5.8.3. 
Key Secondary Efficacy Endpoints ..................................................................... 33 
5.8.3.1. 
Time to First Incidence of Decrease Within 12 hours ................................. 34 
5.8.3.2. 
Time to HAE Attack Resolution Within 24 hours ....................................... 35 
5.8.4. 
Secondary Efficacy Endpoints ............................................................................ 36 
5.8.4.1. 
PGI-C ........................................................................................................... 36 
5.8.4.2. 
PGI-S............................................................................................................ 37 
5.8.4.3. 
Conventional Attack Treatment ................................................................... 39 
5.8.4.4. 
Second IMP Administration......................................................................... 40 
5.8.4.5. 
Composite VAS............................................................................................ 41 
5.8.5. 
Exploratory Endpoints........................................................................................ 41 
5.8.5.1. 
Characteristics of the IMP-Treated HAE Attacks........................................ 41 
5.8.5.2. 
PGI-C ........................................................................................................... 42 
5.8.5.3. 
PGI-S............................................................................................................ 42 
5.8.5.4. 
Conventional Attack Treatment ................................................................... 43 
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Final Statistical Analysis Plan, Version 2.0 
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5.8.5.5. 
GA-NRS and VAS ....................................................................................... 44 
5.8.6. 
Subgroup and Subset Analyses ........................................................................... 45 
5.9. 
SAFETY ANALYSIS ............................................................................................... 47 
5.9.1. 
Adverse Events.................................................................................................... 47 
5.9.1.1. 
Relationship of Adverse Events to Trial Medication................................... 47 
5.9.1.2. 
Severity of Adverse Event............................................................................ 47 
5.9.1.3. 
Serious Adverse Events................................................................................ 47 
5.9.1.4. 
Treatment-Emergent Adverse Events .......................................................... 48 
5.9.1.5. 
Incomplete Dates.......................................................................................... 48 
5.9.1.6. 
Summaries of Adverse Events and Deaths .................................................. 49 
5.9.2. 
Clinical Laboratory Evaluations ........................................................................ 50 
5.9.2.1. 
Hematology .................................................................................................. 51 
5.9.2.2. 
Clinical Chemistry........................................................................................ 51 
5.9.2.3. 
Urinalysis ..................................................................................................... 51 
5.9.2.4. 
Liver Enzyme ............................................................................................... 51 
5.9.2.5. 
Electrolytes................................................................................................... 51 
5.9.2.6. 
Coagulation .................................................................................................. 51 
5.9.2.7. 
C1 Functional Level, C1 Antigen, and Complement C4 ............................. 51 
5.9.2.8. 
Pregnancy..................................................................................................... 51 
5.9.3. 
Vital Sign Measurements .................................................................................... 52 
5.9.4. 
Physical Examination ......................................................................................... 52 
5.9.5. 
Electrocardiogram.............................................................................................. 52 
6. INTERIM ANALYSIS ...................................................................................................53 
7. CHANGES IN THE PLANNED ANALYSIS ..............................................................53 
8. REFERENCES................................................................................................................54 
9. APPENDICES.................................................................................................................57 
9.1. 
KAPLAN-MEIER IMPUTATION UNDER INFORMATIVE CENSORING ASSUMPTION... 57 
9.2. 
DEFINITIONS AND PROGRAMMING CONVENTIONS ............................................... 59 
9.2.1. 
Algorithms Deriving Time-to-Event Endpoints .................................................. 59 
9.2.2. 
Handling of Conventional Medications with Missing Time in Time-to-Event 
Analyses .............................................................................................................. 60 
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9.2.3. 
Handling of Duplicate Records .......................................................................... 61 
9.2.4. 
Handling of Events Achieved after Endpoint Analysis Window ......................... 61 
9.2.5. 
Defining Prophylactic Treatment Status............................................................. 61 
9.3. 
SCHEDULE OF TRIAL PROCEDURES....................................................................... 63 
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Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
List of Abbreviations 
5LS 
5-point Likert Scale 
7TQ 
7-point Transition Question 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
C1-INH 
C1-esterase inhibitor 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GA-NRS 
General Anxiety Numeric Rating Scale 
GGT 
Gamma Glutamyl Transferase 
HAE 
Hereditary Angioedema 
HbA1c 
Glycosylated Hemoglobin 
HLGT 
High-Level Group Term 
HLT 
High-Level Term 
HR 
Heart Rate 
IcEv 
Intercurrent Event 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRS 
Imputing Risk Set 
kg 
Kilogram(s) 
LLT 
Lower-Level Term 
MCH 
Mean Corpuscular Hemoglobin 
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Final Statistical Analysis Plan, Version 2.0 
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Date Issued: 1DEC2023 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPV 
Mean Platelet Volume 
OD 
Once Daily 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
pH 
Potential Hydrogen 
PPS 
Per-Protocol Set 
PR 
Pulse Rate 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
QTcF 
Fridericia Correction of QTc 
RBC 
Red Blood Cell 
RDW 
Red Cell Distribution Width 
ROW 
Rest of World 
RR 
Respiration Rate 
RTSM 
Randomization and Trial Supply Management System 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
WHODD 
World Health Organization Drug Dictionary 
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KalVista Pharmaceuticals, Ltd 
Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) defines the statistical methods and data presentations 
to be used by PPD Biostatistics in the analysis and presentation of data for the KalVista 
Pharmaceuticals Limited trial KVD900-301, entitled “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”. 
Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disease 
caused by a deficiency in the C1-esterase inhibitor (C1-INH) protein and characterized by 
unpredictable tissue swelling due to an increase in vascular permeability. The prevalence 
of HAE ranges between 1 and 2 per 100,000 people worldwide with a point estimate of 1.5 
per 100,000 (Aygören-Pürsün et al. 2018). HAE types I and II account for approximately 
90% and 10% of HAE cases with C1-INH deficiency, respectively (Nordenfelt et al. 2016, 
Zanichelli et al. 2015). Both types of HAE are caused by a large variety of genetic 
mutations in the SERPING1 gene (Gosswein et al. 2008). These mutations result in 
production of reduced levels of functional C1-INH (HAE type I) or normal levels of 
dysfunctional C1-INH (HAE type II) (Donaldson and Evans 1963, Donaldson and Rosen 
1964, Rosen et al. 1965, Rosen et al. 1971). 
C1-INH inhibits key enzymes in the contact system (Kaplan and Joseph 2014), one of 
which is plasma kallikrein. Due to the deficiency in C1-INH associated with HAE, 
activated plasma kallikrein generates the vasoactive peptide hormone bradykinin, the 
mediator of vascular hyperpermeability that causes tissue swelling and pain (Fields et al. 
1983, Hulström and Svensjö 1979, Nussberger et al. 1998, Nussberger et al. 2002, 
Nussberger et al. 1999). 
HAE is a life-long condition with approximately 50% of patients experiencing their first 
attack before the age of 10 years (Bork et al. 2006, Nordenfelt et al. 2016) and more than 
75% experiencing their first attack before adulthood (Maurer et al. 2019). Attacks are 
episodic with considerable variations in frequency and severity (Bork et al. 2006, Javaud, 
Altar et al. 2019). Swelling has been shown to affect subcutaneous tissue (face, upper or 
lower extremities, genitals) in 82% of patients, abdominal organs (stomach, intestines) in 
78% of patients, and the upper airway (larynx, tongue) in 27% of patients (Nordenfelt et al. 
2016). Laryngeal attacks are infrequent (<5% of attacks) (Javaud, Altar et al. 2019) but are 
potentially life-threatening in patients who are unaware of their diagnosis (Bork et al. 
2012). Approximately 50% of all patients with HAE experience at least one laryngeal 
attack during their lifetime (Bork et al. 2003, Bork et al. 2006). 
Several precipitants can trigger HAE attacks; however, more than half of all HAE attacks 
are unpredictable and occur without an obvious trigger (Caballero et al. 2016). Common 
triggers of HAE attacks such as strenuous activity, mechanical trauma, or use of certain 
medications, may be somewhat predictable. However, other triggers such as infections, 
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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). 
This SAP covers all specified analysis for the final trial reports based on the following 
documents: 
• 
Final Protocol, Version 4.0, 26 April 2023 
• 
Final Protocol, Version 3.1, 11 October 2022 
• 
Final Protocol, Version 3.0, 26 May 2022 
• 
Final Protocol, Version 2.0, 10 February 2022 
• 
Final Protocol, Version 1.0, 18 October 2021 
• 
Electronic Case Report Form (eCRF) Version 1.0, 12 January 2022. 
2. 
OBJECTIVES 
2.1. 
Primary Objective and Estimand 
Primary Objective 
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 patient global impression 
of change (PGI-C) as at least “a little better” for 2 time 
points in a row within 12 hours of investigational 
medicinal product (IMP) administration in adolescent 
and adult patients with hereditary angioedema type I or 
II regardless of prohibited medications, as long as 
conventional on-demand treatment of HAE attacks has 
not been used and as if patient has not discontinued the 
trial. 
2.2. 
Secondary Objective 
The secondary objective of this trial is to investigate the safety and tolerability of 
KVD900. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Trial Design and Plan 
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 of the trial protocol). 
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 may 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. If utilized, 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 
3.2. 
Trial Endpoints 
3.2.1. Primary Endpoint 
The primary endpoint of this trial is: 
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• 
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 first IMP administration. 
3.2.2. 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. 
3.2.3. Secondary Endpoints 
The secondary endpoints of this trial are: 
• 
PGI-C: Number and percentage of attacks with beginning of symptom relief 
defined as at least “a little better” (2 time points in a row) within 2, 4, 6, 8, 10, 12, 
24, and 48 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. 
• 
Time to either (1) first incidence of PGI-C being rated ‘a little worse’ or lower for 
two time points in a row, or (2) use of conventional attack treatment, whichever 
comes first within 12 hours and 24 hours. 
• 
PGI-C: Time to at least “better” (2 time points in a row) within 24 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. 
• 
Time to either (1) first incidence of worsening in attack severity on the PGI-S by 
one level or more from baseline for two time points in a row, or (2) use of 
conventional attack treatment, whichever comes first within 12 hours and 24 hours. 
• 
PGI-S: Time to HAE attack resolution defined as “none” within 48 hours. 
• 
PGI-S: Number and percentage of attacks with first incidence of decrease in attack 
severity for two time points in a row within 4, 8, 12, 24, and 48 hours of the first 
IMP administration. 
• 
Time to first incidence of conventional attack treatment use within 12 hours and 
24 hours. 
• 
Number and percentage of attacks receiving conventional attack treatment within 
4, 8, 12, 24, and 48 hours of the first IMP administration. 
• 
Time to the second IMP administration within 12 hours and 24 hours. 
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• 
Number and percentage of attacks receiving second IMP administration within 
4, 8, 12, 24, and 48 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 IMP administration. 
3.2.4. Exploratory Endpoints 
The exploratory endpoints of this trial are: 
• 
Characteristics of the IMP-treated HAE attacks. 
• 
PGI-C score over time. 
• 
PGI-S: Number and percentage of attacks with attack resolution defined as “none” 
within 4, 8, 12, 24, and 48 hours of the first IMP administration. 
• 
PGI-S score over time. 
• 
GA-NRS: cumulative GA-NRS in AUC over 12 hours and 24 hours of the first 
IMP administration. 
• 
GA-NRS: number and percentage of attacks with first incidence of GA-NRS 
reduction of ≥2, ≥3, ≥4, or ≥5 points within 4, 8, 12, 24, and 48 hours of the first 
IMP administration. 
• 
GA-NRS score over time. 
• 
VAS score over time. 
3.3. 
Treatments 
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 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. 
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• 
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 (for further details, see section 16.3 of the trial protocol). 
3.4. 
Dose Adjustment/Modifications 
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. 
No IMP dose modifications are allowed in this trial. Tablets must be swallowed whole; 
tablets are not to be crushed or modified in any way. 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
The treatment will be presented by dose categories (300 mg KVD900, 600 mg KVD900, 
and Placebo).  Continuous data will be presented using descriptive statistics (i.e. n, mean, 
standard deviation (SD), median, first and third quartiles, minimum, and maximum). 
Categorical data will be presented using the patient count and percentage in each category. 
For the summary statistics of all numerical variables (unless otherwise specified), 
minimum and maximum will be displayed to the same level of precision. Mean, median, 
first and third quartiles will be displayed to one level of precision greater than the data 
collected. Standard deviation/standard error will be displayed to two levels of precision 
greater than the data collected. P-values will be rounded to four decimal places. If a 
p-value is less than 0.0001 it will be reported as “<0.0001.” If a p-value is greater than 
0.9999 it will be reported as “>0.9999.” Data will be displayed in all listings sorted by 
treatment sequence and patient number. 
Patients will be identified in the listings by a concatenated patient identification number. 
When count data are presented, the percentage will be suppressed when the count is zero in 
order to draw attention to the non-zero counts. A row denoted “Missing” will be included 
in count tabulations where specified on the shells to account for missing values. The 
denominator for all percentages will be the number of patients in that treatment within the 
analysis set of interest, unless otherwise specified. 
Unless otherwise specified, baseline will be defined as the last non-missing evaluation 
prior to or on the date that the first dose of treatment is taken. 
Study day is defined in relation to the date of the first dose of trial medication for the first 
HAE attack. Therefore, when an assessment date is before the first dose: 
Study day = assessment date - first dose date of trial medication 
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and when an assessment is on or after the first dose: 
Study day = assessment date - first dose date of trial medication+ 1 
Therefore, Study Day 1 is the day of first dose of IMP administration for the first HAE 
attack. 
For the purpose of inclusion in summary tables for prior and concomitant medications, 
incomplete start and stop dates will be imputed. 
Missing start dates (where UN and UNK indicate unknown or missing day and month 
respectively) will be handled as follows: 
• 
UN-MMM-YYYY: If the month and year are different from the month and year of 
the first dose of trial medication, assume 01-MMM-YYYY. If the month and year 
are the same as the first dose of trial medication month and year and the stop date 
(after any imputation) is on or after the first dose of trial medication, then assume 
the date of the first dose of trial medication. If the month and year are the same as 
the first dose of trial medication month and year and the stop date (after any 
imputation) is prior to the first dose of trial medication, then assume the stop date 
for the start date; 
• 
DD-UNK-YYYY/UN-UNK-YYYY: If the year is different from the year of first 
dose of trial medication, assume 01-JAN-YYYY of the collected year. If the year 
is the same as the first dose of trial medication year and the stop date (after any 
imputation) is on or after the first dose of trial medication, then assume the date of 
the first dose of trial medication. If the year is the same as the first dose of trial 
medication and the stop date (after any imputation) is prior to the first dose of trial 
medication, then assume the stop date for the start date. 
Missing stop dates (where UN and UNK indicate unknown or missing day and month 
respectively) will be handled as follows: 
• 
UN-MMM-YYYY: Assume the last day of the month; 
• 
DD-UNK-YYYY/UN-UNK-YYYY: Assume 31-DEC-YYYY. 
If a patient dies during the trial, the stop date will be imputed as the date of death if the 
imputed stop date is after date of death. 
A month is defined as 30.4 days . A year is defined as 365.25 days. 
Summary tables, figure and listings will be created using Version 9.4 (or later) of the 
SAS® software for Microsoft Windows (SAS Institute, Inc., Cary, North Carolina). 
There are 3 treatments in the trial: 
1. 300 mg KVD900 
2. 600 mg KVD900 
3. Placebo 
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4.1. 
Multiplicity Adjustment 
Two pairwise comparisons will be performed: 300 mg KVD900 versus placebo and 
600 mg KVD900 versus placebo. 
All statistical tests will be 2-sided with an overall alpha of 0.05. The primary efficacy 
endpoint analysis and key secondary endpoints will have Bonferroni multiplicity 
adjustment for multiple dose levels with a loop-back feature to allow two-way alpha 
passing (FDA, 2022). Therefore pairwise comparison tests will be 2-sided with an alpha of 
0.025 initially. If the primary and key secondary endpoints hypotheses within one of the 
pairwise comparison 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 higher alpha level of 0.05. In the outputs, the actual p-values and adjusted 
p-values will be presented. The analysis of the secondary or exploratory endpoints will not 
have multiplicity adjustment. 
Within each pairwise comparison, 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. Specifically, key secondary endpoint 1 will be tested only if the test on the 
primary endpoint is statistically significant. Key secondary endpoint 2 will be tested only if 
the test on the primary and key secondary endpoint 1 are statistically significant. The loop-
back feature allows for retesting of unrejected hypotheses at 0.05 alpha level if all 
hypotheses are rejected within the other pairwise comparison. Figure 2 shows the 
multiplicity adjustment diagram. 
Figure 2 Multiplicity Adjustment Diagram 
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4.2. 
Sample Size 
Approximately 114 patients will be randomized 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. 
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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 (to ensure approximately 84 attacks 
treated with placebo, KVD900 300mg and KVD900 600mg). 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. 
4.3. 
Randomization, Stratification, and Blinding 
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 1. 
Table 1. 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. 
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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. 
This trial will be performed in a double-blind, double dummy manner. 
The trial blind would 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 serious adverse events (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 Medical Monitor prior to breaking the blind. 
If an Investigator, site personnel performing assessments, or patient, is unblinded, it must 
be documented as a major protocol deviation. 
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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4.4. 
Intercurrent Event Types 
Table 2 Intercurrent Event Specifications 
Label 
Intercurrent Event Type 
Intercurrent event 1 (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 (for details see 
Section 12.3 of the trial protocol). 
IcEV3 (Conventional attack treatment) 
Use of conventional attack treatment that 
may interfere with outcome (for details see 
Section 12.1 of the trial protocol). 
4.5. 
Estimand Specifications 
Table 3 Estimand Specifications 
1. Primary Estimand 
Objective 
To demonstrate the clinical efficacy of KVD900 compared 
with placebo for the on-demand treatment of HAE attacks. 
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, as long as not conventional attack treatment 
use, and as if patient has 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 Conditions 
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. 
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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. Assume that an intercurrent event would not 
have occurred. Discontinued patients are censored at time 
of discontinuation (taken from last assessment done during 
the end of study visit). 
IcEV2 (Prohibited 
medications) 
Treatment policy. Assessments made after prohibited 
medication use(s) will be included in the analyses 
regardless of the medication use(s). 
IcEV3 (Conventional 
Attack treatment) 
Composite. Receiving conventional attack treatment prior 
to the beginning of symptom relief for an eligible attack 
will be considered as treatment failure; patients receiving 
conventional attack treatment will be censored at 12 hours 
for the impacted attack. 
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 attack treatment has not been used and as if 
patient has not discontinued the trial. 
2. Key Secondary 1 Estimand 
Objective 
To demonstrate the clinical efficacy of KVD900 compared 
with placebo for the on-demand treatment of HAE attacks. 
Estimand Label 
Key secondary 1 Estimand. 
Estimand Description 
Relative effect of each of the KVD900 dose groups versus 
placebo in shortening the time to first incidence of 
decrease from baseline for 2 time points in a row in PGI-S 
within 12 hours of the first IMP administration in 
adolescent and adult patients with hereditary angioedema 
type I or II regardless of prohibited medications, as long as 
conventional attack treatment has not been used and as if 
patient has not discontinued the trial. 
Target Population 
Adolescent and adult patients with hereditary angioedema 
type I or II. 
Endpoint 
The PGI-S: time to first incidence of decrease from 
baseline for two time points in a row within 12 hours of 
the first IMP administration. 
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Treatment Conditions 
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 first incidence of decreases 
from baseline for 2 time points in a row in PGI-S within 
12 hours of the first IMP administration. 
Intercurrent Event Strategy 
IcEV1 (discontinue due to 
Hypothetical. Assume that an intercurrent event would 
any reason) 
not have occurred. Discontinued patients are censored at 
time of discontinuation (taken from last assessment done 
during the end of study visit). 
IcEV2 (Prohibited 
medications) 
Treatment policy. Assessments made after prohibited 
medication use(s) will be included in the analyses 
regardless of the medication use(s). 
IcEV3 (Conventional 
Composite. Receiving conventional attack treatment prior 
Attack treatment) 
to the first incidence of PGI-S decreases for an eligible 
attack will be considered as treatment failure; patients 
receiving conventional attack treatment will be censored at 
12 hours for the impacted attack. 
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 attack treatment has not been used and as if 
patient has not discontinued the trial. 
3. Key Secondary 2 Estimand 
Objective 
To demonstrate the clinical efficacy of KVD900 compared 
with placebo for the on-demand treatment of HAE attacks. 
Estimand Label 
Key secondary 2 Estimand. 
Estimand Description 
Relative effect of each of the KVD900 dose groups versus 
placebo in shortening the time to HAE attack resolution 
defined as “none” on PGI-S within 24 hours of the first 
IMP administration in adolescent and adult patients with 
hereditary angioedema type I or II regardless of prohibited 
medications and without conventional attack treatment use 
and as if patient has not discontinued the trial. 
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Target Population 
Adolescent and adult patients with hereditary angioedema 
type I or II. 
Endpoint 
The PGI-S: Time to HAE attack resolution defined as 
“none” on PGI-S within 24 hours of the first IMP 
administration without conventional attack treatment use. 
Treatment Conditions 
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 HAE attack resolution 
defined as “none” on PGI-S within 24 hours of the first 
IMP administration without conventional attack treatment 
use. 
Intercurrent Event Strategy 
IcEV1 (discontinue due to 
any reason) 
Hypothetical. Assume that an intercurrent event would not 
have occurred. Discontinued patients are censored at time 
of discontinuation (taken from last assessment done during 
the end of study visit). 
IcEV2 (Prohibited 
medications) 
Treatment policy. Assessments made after prohibited 
medication use(s) will be included in the analyses 
regardless of the medication use(s). 
IcEV3 (Conventional 
Attack treatment) 
Composite. Receiving conventional attack treatment prior 
to the attack resolution for an eligible attack will be 
considered as treatment failure; patients receiving 
conventional attack treatment would be censored at 
24 hours for the impacted attack. 
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 attack treatment has not been used and patient 
did not discontinue the trial. 
4.6. 
Analysis Sets 
The following analysis population sets will be used in this trial: 
• 
Screened Set 
• 
Randomized Set 
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• 
Safety Set 
• 
Full Analysis Set 
• 
Per-Protocol Set 
• 
On-demand Full Analysis Set 
• 
Prophylaxis Full Analysis Set 
4.6.1. Screened Set 
The Screened Set includes all patients who have signed informed consent. 
4.6.2. Randomized Set 
The Randomized Set includes all patients who are randomized to a treatment sequence. 
4.6.3. Safety Set 
Safety Set (SAF) will include all patients who receive at least one dose of trial medication. 
If one or more patient(s) received the incorrect trial medication, data summarized using the 
SAF will be presented according to the actual treatment received. The SAF population will 
be the population for safety analyses. 
4.6.4. Full Analysis Set 
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 the incorrect trial medication, data summarized using the FAS will be presented 
according to the randomized treatment. The FAS population will be the population for 
efficacy analyses. Refer to Section 5.8 for the definition of qualifying HAE attack. 
4.6.5. Per Protocol Set 
Per-protocol Set (PPS) will includes 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. 
4.6.6. On-demand Full Analysis Set 
On-demand Full Analysis Set (on-demand FAS) will include FAS patients who enter the 
trial taking only conventional on-demand treatment. 
4.6.7. Prophylaxis Full Analysis Set 
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. 
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5. 
STATISTICAL ANALYSIS 
5.1. 
Inclusion and Exclusion Criteria 
The details of the inclusion and exclusion criteria can be found in Sections 9.1 and 9.2 of 
the trial protocol. Patient status of eligibility criteria met, inclusion criteria not met, and 
exclusion criteria met as well as corresponding details will be listed using the Screened 
Set. 
5.2. 
Disposition 
A by-patient listing of randomization information (including date of informed consent, 
date of randomization, treatment sequence, randomization number and kit numbers) for all 
randomized patients will be produced. 
The number and percentage of patients who are eligible for enrollment, and who failed 
screening and the reason for screen failure will be presented for the Screened Set. 
Additionally, the number and percentage of patients who have been randomized and who 
are in each analysis set including the SAF, FAS, PPS, on-demand FAS, and prophylaxis 
FAS will be presented by treatment sequence and overall for the Randomized Set. 
Patient disposition will be summarized including the number and percentage of patients 
who completed the study, completed each HAE attack period and who prematurely 
discontinued during the trial (and the primary reason) will be presented for each treatment 
sequence and overall, for SAF and FAS. Primary reasons for trial discontinuation may 
include any of the following listed reasons: 
• 
Adverse Event 
• 
Death 
• 
Protocol Violation 
• 
Lost to Follow-up 
• 
Physician Decision 
• 
Pregnancy 
• 
Screen Failure 
• 
Withdrawal by patient 
• 
Trial termination by Sponsor 
• 
Other 
Patient disposition, patient completing or terminating the trial, patient completing each 
attack period, and trial analysis sets will be listed by patient for all patients in the 
Randomized Set by treatment sequence and patient ID. 
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5.3. 
Protocol Deviations 
Protocol deviations will be identified and confirmed prior to database lock and 
summarized by the deviation categories shown in trial deviation rules document. Protocol 
deviations that are considered biasing primary endpoint outcome will be identified as 
major protocol deviations and will lead to patient exclusion from PPS. 
The major protocol deviations will be summarized by treatment sequence and overall for 
all patients in the Randomized Set. 
A by-patient listing of protocol deviations will also be presented by treatment sequence. A 
flag (Y/N) will be added to the listing to denote whether a patient has a major protocol 
deviation, and whether a patient is included or excluded from the PPS. 
5.4. 
Demographics and Baseline Characteristics 
5.4.1. Demographics 
A summary of demographics and baseline characteristics will be presented by treatment 
sequence and overall for the SAF. The demographic characteristics consist of age (years), 
sex, ethnicity, race, and fertility status. The baseline characteristics consist of height (m), 
weight (kg), and body mass index (BMI) (kg/m²). Body mass index is calculated as (body 
weight in kilograms)/(height in meters)2. 
Age (years), baseline height (m), baseline weight (kg), and baseline BMI (kg/m²) will be 
summarized using descriptive statistics. The number and percentage of patients by sex 
(Male, Female), ethnicity (Hispanic or Latino, Not Hispanic or Latino, and Not Reported) 
and race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Not Reported, and Other), will also be reported. 
Patient demographic and baseline characteristics will be presented in a listing by treatment 
sequence for all patients in the Randomized Set. 
5.5. 
Medical History 
5.5.1. General Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 26.0 or higher. The number and percentage of patients with any 
medical history will be summarized by treatment sequence and overall and for each body 
system. Body systems will be included as recorded on the eCRF. Percentages will be 
calculated based on number of patients in the FAS. 
Patient medical history data including specific details will be presented in a listing. 
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5.5.2. Disease-Specific History 
HAE attack history will be collected at the Screening Visit. The HAE attack history 
includes HAE type (type I or type II), date of diagnosis, start date of last attack prior to 
screening, relative type (primary and secondary relative), and current treatment regimen 
(prophylaxis and on-demand only). 
The number and percentage of patients with any HAE history will be summarized by 
treatment sequence and overall and for each HAE type, relative type, and treatment 
regimen. Percentages will be calculated based on number of patients in the FAS. Time 
since HAE diagnosis will be summarized using descriptive statistics for the FAS. 
Patient HAE history data including specific details described in this section will be 
presented in a listing. 
5.6. 
Prior and Concomitant Medications 
Information on prior and concomitant medications taken by patients are recorded in the 
eCRF. Prior and concomitant medication will be coded according to the latest World 
Health Organization drug dictionary (WHODD). Incomplete dates will be imputed 
following rules in Section 4. All medications will be listed. 
5.6.1. Prior Medications 
Prior medications (including conventional HAE medications) are defined as those 
medications taken within 4 weeks prior to the Screening Visit up to the first dose of IMP. 
Any medications and treatments taken prior to and not stopped prior to the first IMP will 
be counted in both prior and concomitant medication. The total number of prior 
medications and the number and percentages of patients with at least 1 prior medication 
will be summarized. The number and percentages of all prior medications will be 
summarized by drug class and preferred term. All summaries will be performed by 
treatment sequence and overall using the SAF. 
5.6.2. Concomitant Medications 
Concomitant medications are defined as those medications (including conventional HAE 
medications) ongoing at or started after the first dose of IMP. Concomitant medications 
will be summarized by drug class and preferred term for each treatment sequence and 
overall using the SAF. 
5.7. 
Extent of Exposure and Treatment Compliance 
Confirmation of dosing compliance will be performed during each televisit (via review of 
unused IMP). If the in-clinic visits cannot occur for the Final Visit/ET every effort will be 
made to perform the final accountability, and arrangements will be made to return any 
unused IMP. No IMP dose modifications are allowed in this trial. 
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The number of doses received and the number of tablets taken will be summarized using 
descriptive statistics. The number and percentage of patients receiving 0, 1, or 2 doses will 
also be presented. If a patient received a second dose of IMP, then the time between first 
dose of IMP administration and second dose of IMP administration will be calculated and 
summarized using descriptive statistics. Summaries will be provided by treatment and 
overall for the SAF. 
A by-patient listing of IMP administration and drug accountability will be provided by 
treatment sequence and on-treatment HAE attack (in chronological order). 
5.8. 
Efficacy Analysis 
All efficacy data will be summarized by randomized treatment. All efficacy analysis will 
be performed using the FAS and primary and key secondary endpoints analysis will be 
repeated using the PPS. Statistical tests will be 2-sided with an overall alpha of 0.05 unless 
otherwise specified. Treatment comparisons of interest will be pairwise comparisons of 
300 mg KVD900 versus placebo and 600 mg KVD900 versus placebo. 
Initially, statistical tests on both the primary and the key secondary endpoints will be at the 
same Bonferroni adjusted significance level alpha (0.025) 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) initially. Loop-back of unused alpha is allowed; see Section 4.1 for details. 
A qualifying HAE attack is defined as an IMP-treated HAE attack. All efficacy analyses 
will only include qualifying HAE attacks. Non-qualifying HAE attacks will be presented in 
a listing, with all available assessments for the attack presented. 
5.8.1. Efficacy Assessments 
Change in HAE attack severity will be assessed using the Patient Global Impression of 
Change (PGI-C) 7-point rating scale as much better, better, a little better, no change, a little 
worse, worse, much worse. 
HAE attack severity will be assessed on the Patient Global Impression of Severity (PGI-S) 
5-point rating scale 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. 
The type of HAE attack symptoms (abdominal pain, skin pain, skin swelling) will each be 
assessed on a 101-point visual analogue scale (VAS) anchored at 0 (none) to 100 (very 
severe). The composite VAS score will be derived as the average score across the three 
symptoms. 
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). 
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Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
5.8.2. Primary Efficacy Endpoint 
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, 
𝐻𝐻a: 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. 
5.8.2.1.Primary Efficacy Analysis 
PGI-C: Time to beginning of symptom relief is defined as an HAE attack being rated at 
least “a little better” (2 time points in a row) on the PGI-C within 12 hours of the first IMP 
administration and will be calculated as: 
Time to HAE attack being rated at least “a little better” (2 time points in a row) 
(hours) = Date/time of first rating of “a little better” or higher (i.e. better or much 
better) which is immediately followed by another rating of “a little better” or 
higher (without missing values in between) – Date/time of first IMP administration. 
Patients will be treated as right-censored at 12 hours 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) or 
receive conventional attack treatment prior to time to event within 12 hours of the first 
IMP administration. In the case of discontinuation that prevented event “a little better” or 
higher HAE attack rating occurrence, patients will be censored at the time of 
discontinuation (taken from last assessment done during the end of study visit). In the case 
of underivable time-to-event results due to lack of at least 2 consecutive post-baseline 
assessments, attacks will be censored at time 0. See Section 9.2.1 for detailed algorithms. 
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 IMP administration will be analyzed using Gehan 
score transformation test proposed by Feingold and Gillespie (1996). 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. That is, 
• 
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. 
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Final Statistical Analysis Plan, Version 2.0 
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Date Issued: 1DEC2023 
Gehan scores will be analyzed using a linear mixed model, including terms for sequence, 
period and treatment in the model as fixed effects and patient nested within sequence as a 
random effect. Least-squares means of treatment effects to show differences between 
treatments (600 mg versus placebo and 300 mg versus placebo) will be tested at alpha of 
0.025 level. Least-square means and standard errors will be presented by treatment. P-
values will be calculated for the comparison of each KVD900 dose versus placebo, along 
with the least-square mean treatment difference and corresponding 95% CI will be 
presented. Additionally, adjusted p-values for each pairwise comparison will also be 
presented with Bonferroni adjustment and loop-back feature. 
Kaplan-Meier estimates of the 25th percentile (Q1), the median and the 75th percentile (Q3) 
and corresponding 95% CI, of time to beginning of symptom relief will be presented by 
treatment. Kaplan-Meier survival curves will also be presented by treatment. Kaplan-Meier 
survival analysis will be performed using the SAS LIFETEST procedure. 
The time to beginning of symptom relief will be listed with censored observations flagged 
with ‘R’. The number and percentage of patients that meet beginning of symptom relief 
and the number censored will be presented by treatment. 
Moreover, PGI-S and PGI-C will be listed over time in listing. 
5.8.2.2.Supplementary Analysis to the Primary Efficacy Endpoint 
If not otherwise specified, the following supplementary analyses will be performed in the 
FAS and PPS. 
• 
The primary endpoint analysis will be repeated in the PPS. 
• 
For the primary endpoint analysis time to beginning of symptom relief within 
12 hours (by considering censoring rules also) will be categorized into intervals 
(0 to 1, >1 to 2, >2 to 4, >4 to 6, >6 to 8, >8 to 10, and >10 to 12 hours) and the 
number and percentage of attacks that fall into each category will be presented. If 
several categories have 0 counts, wider intervals (0 to 4, >4 to 8, >8 to 12 hours) 
will be considered. The number and percentage of patients in each category will be 
presented in a stacked bar graph by treatment. In addition, the time to event 
analysis will be conducted for time intervals within 1, 2, 4, 6, 8, 10, and 24 hours 
of the first IMP administration (similar to the analysis performed for the within 12 
hours of the first IMP administration interval). 
• 
For this supplementary analysis, outcomes of patients who took conventional 
attack treatment will be imputed with a hypothetical strategy, i.e. their time to 
beginning of symptom relief defined as at least “a little better” (2 times in a row) 
within 12 hours of IMP administration for PGI-C will be imputed as right-censored 
at the time of conventional attack treatment. The primary analysis will then be 
repeated. 
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Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
5.8.2.3.Sensitivity Analysis to the Primary Efficacy Endpoint 
Imputation Under Informative Censoring 
For this first sensitivity analysis, censored observations will be treated as missing data. 
Non parametric 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 
under various assumptions of the correlation between censoring and outcome. 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 1,000 times creating 1,000 imputed data sets. 
The primary analysis will be repeated on each of the 1,000 multiply imputed data sets and 
the results will be combined using Rubin’s method from PROC MIANALYZE (see 
implementation details presented in Appendix 9.1). 
Gehan’s Generalized Wilcoxon Test Sensitivity Analysis 
The Gehan’s generalized Wilcoxon test, proposed by Feingold and Gillespie (1996), 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 crossover trials with 
two sequences. 
For this sensitivity analysis, assuming no period effect, two separate 2x2 crossover design 
with a common placebo can be constructed. The first crossover trial would be for 300 mg 
KVD900 vs. Placebo and the second crossover trial would be for 600 mg KVD900 vs. 
Placebo. In this analysis, the sequence with KVD900-treated period prior to the placebo-
treated period will be pooled into a new active-placebo sequence; the sequence with 
KVD900-treated period after the placebo-treated period will be pooled into a new placebo-
active sequence. 
Randomized Treatment Sequence 
New Sequence Used in the Gehan’s Generalized 
Wilcoxon Test 
Treatment 
Sequence 
1st Eligible 
HAE Attack 
2nd Eligible 
HAE Attack 
3rd Eligible 
HAE Attack 
600 mg vs. placebo 
300 mg vs. placebo 
Active-
Placebo 
Sequence 
Placebo-
Active 
Sequence 
Active-
Placebo 
Sequence 
Placebo-
Active 
Sequence 
A 
Placebo 
600 mg 
300 mg 
Y 
Y 
B 
Placebo 
300 mg 
600 mg 
Y 
Y 
C 
300 mg 
600 mg 
Placebo 
Y 
Y 
D 
300 mg 
Placebo 
600 mg 
Y 
Y 
E 
600 mg 
300 mg 
Placebo 
Y 
Y 
F 
600 mg 
Placebo 
300 mg 
Y 
Y 
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Date Issued: 1DEC2023 
The following steps should be performed to implement this test based on the new 
sequences: 
1. For each patient, compute the difference between the Period 1 time to use (t1) and 
Period 2 time to use (t2), (i.e. t1 – t2), and order from smallest to largest difference. 
2. If there are any censored results involved in a calculation of the difference, the 
associated difference should also be flagged. However, any negative differences 
obtained as a result of subtracting a right-censored observation should now be 
flagged as ‘L’ (i.e. left-censored). 
3. For each of the derived differences, compute Ui = the number of observations 
definitely smaller than the ith minus the number definitely greater, for i = 1 to N 
(total sample size), where U1 is the smallest difference and UN is the largest 
difference. Note that the use of ‘definitely’ indicates that the censored observations 
should be taken into account accordingly (i.e. a negative difference of -50L cannot 
be considered definitely smaller than a negative difference of -30L due to the left-
censoring. Likewise, a positive difference of 50 cannot be considered definitely 
greater than a positive difference of 30R due to the right-censoring). In the instance 
of a right censored value of 12R in Period 1 and a non-censored value <12 in 
Period 2, the difference would be definitely greater than any negative difference but 
would not be definitely smaller than any value. In the instance of a non-censored 
value <12 in Period 1 and a right-censored value of 12R in Period 2, the difference 
would be definitely smaller than any positive difference but would not be definitely 
greater than any value. In the instance of a right censored value of 12R in both 
Period 1 and Period 2, the difference would not be definitely greater or definitely 
smaller than any value. 
4. Calculate W, which is the sum of the Ui’s for patients assigned to Sequence 1 only.  
5. Calculate the permutation variance of W, 
n1+n2 
2
∑ 
Ui
1 
var(W) = n1n2 × (n1 + n2)(n1 + n2 − 1) 
6. Derive the test statistic as W divided by its standard error (ඥ𝑽𝑽𝑽𝑽𝑽𝑽(𝑾𝑾) ), which is 
asymptotically normal N(0,1) under the null hypothesis, in order to obtain the p-
value for treatment effect (using SAS function PROBNORM). 
For each pairwise comparison, p-values from the Gehan’s generalized Wilcoxon test will 
be provided for exploratory purpose. 
5.8.3. Key Secondary Efficacy Endpoints 
The key secondary endpoints will be tested according to the fixed sequence closed testing 
procedure described in Section 4.1. 
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Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
5.8.3.1.Time to First Incidence of Decrease Within 12 hours 
PGI-S: Time to first incidence of decrease from baseline for two time points in a row within 
12 hours of the first IMP administration will be calculated as: 
Time to First Incidence of Decrease from Baseline for two time points in a row 
(hours) = Date/time of first incidence of decrease of symptom intensity from 
baseline for two time points in a row (with possible missing values in between) – 
Date/time of first IMP administration. 
For this endpoint we will use the hypothesis: 
𝐻𝐻0: 𝑡𝑡12𝑘𝑘− 𝑡𝑡12𝑝𝑝 =0, 
𝐻𝐻a: 𝑡𝑡12𝑘𝑘− 𝑡𝑡12𝑝𝑝 ≠0. 
Where 𝑡𝑡12𝑘𝑘 is the time to first incidence of decrease from baseline following KVD900 dose 
treatment and 𝑡𝑡12𝑝𝑝 is the time to first incidence of decrease from baseline following 
placebo treatment. 
Patients will be treated as right-censored at 12 hours if they do not have a decrease in 
PGI-S score from baseline for two time points in a row or receive conventional attack 
treatment prior to time to event within 12 hours of the first IMP administration. Patients 
who discontinue the study will be right-censored at the time of discontinuation (taken from 
last assessment done during the end of study visit). In the case of underivable time-to-event 
results due to lack of at least 2 post-baseline assessments, attacks will be censored at time 
0. See Section 9.2.1 for detailed algorithms. 
Gehan scores transformation of the time to first incidence of decrease from baseline for 
two time points in a row within 12 hours of the first IMP administration will be analyzed 
using a linear mixed model, including terms for sequence, period, baseline PGI-S category 
(none or mild, moderate, and severe or very severe), and treatment in the model as fixed 
effects and patient nested within sequence as a random effect. Least-squares means of 
treatment effects to show differences between treatments (600 mg versus placebo and 300 
mg versus placebo) will be tested at alpha of 0.025 -level. Least-square means and standard 
errors will be presented by treatment. P-values will be calculated for the comparison of 
each KVD900 dose group versus placebo, along with the least-square mean treatment 
difference and corresponding 95% CI will be presented. Additionally, adjusted p-values for 
each pairwise comparison will also be presented with Bonferroni adjustment allowing 
alpha loop-back. 
The number and percentage of patients that meet first incidence of decrease from baseline 
at two consecutive time points within 12 hours and the number censored will be presented 
by treatment. Kaplan-Meier estimates of the 25th percentile (Q1), the median, and the 75th 
percentile (Q3) and corresponding 95% CI of time to first incidence of decrease from 
baseline for two time points in a row within 12 hours will be presented by treatment.  
Kaplan-Meier survival curves will also be presented by treatment. 
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KalVista Pharmaceuticals, Ltd 
Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
The time to first incidence of decrease from baseline for two time points in a row within 
12 hours of first IMP administration will be listed with censored observations flagged with 
‘R’. 
5.8.3.2.Time to HAE Attack Resolution Within 24 hours 
PGI-S: Time to HAE attack resolution defined as “none” within 24 hours of the first IMP 
administration will be calculated as: 
Time to HAE attack resolution (hours) = Date/time of first rating of “None”– 
Date/time of first IMP administration. 
For this endpoint we will use the hypothesis: 
𝐻𝐻0: 𝑡𝑡24𝑘𝑘− 𝑡𝑡24𝑝𝑝 =0, 
𝐻𝐻a: 𝑡𝑡24𝑘𝑘− 𝑡𝑡24𝑝𝑝 ≠0. 
Where 𝑡𝑡24𝑘𝑘 is the time to HAE attack resolution defined as “none” within 24 hours of the 
first IMP administration following KVD900 dose treatment and 𝑡𝑡24𝑝𝑝 is the time to HAE 
attack resolution to “none” following placebo treatment. 
Patients will be treated as right-censored at 24 hours if they do not have a HAE attack 
resolution or received conventional attack treatment prior to time to event within 24 hours 
of IMP administration. Patients who discontinue the study will be right-censored at the 
time of discontinuation (taken from last assessment done during the end of study visit). In 
the case of underivable time-to-event results due to lack of at least 1 post-baseline 
assessment, attacks will be censored at time 0. See Section 9.2.1 for detailed algorithms. 
Gehan scores transformation of the time to HAE attack resolution defined as “none” within 
24 hours of the first IMP administration will be analyzed using a linear mixed model, 
including terms for sequence, period, baseline PGI-S category (none or mild, moderate, 
and severe or very severe), and treatment in the model as fixed effects and patient nested 
within sequence as a random effect. Least-squares means of treatment effects to show 
differences between treatments (600 mg versus placebo and 300 mg versus placebo) will 
be tested at alpha of 0.025 level. Least-square means and standard errors will be presented 
by treatment. P-values will be calculated for the comparison of each KVD900 dose group 
versus placebo, along with the least-square mean treatment difference and corresponding 
95% CI will be presented. Additionally, adjusted p-values for each pairwise comparison 
will also be presented with Bonferroni adjustment allowing alpha loop-back. 
The number and percentage of patients that meet HAE attack resolution within 24 hours 
and the number censored will be presented by treatment. Kaplan-Meier estimates of the 
25th percentile (Q1), the median, and the 75th percentile (Q3) and corresponding 95% CI of 
time to HAE attack resolution within 24 hours will be presented by treatment.  Kaplan-
Meier survival curves will also be presented by treatment. 
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KalVista Pharmaceuticals, Ltd 
Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
The time to HAE attack resolution within 24 hours of first IMP administration will be 
listed with censored observations flagged with ‘R’. 
5.8.4. Secondary Efficacy Endpoints 
5.8.4.1.PGI-C 
PGI-C: Number and percentage of attacks with beginning of symptom relief for 
2 time points in a row within 2, 4, 6, 8, 10, 12, 24, and 48 hours of the first IMP 
administration 
PGI-C: Number and percentage of attacks with beginning of symptom relief is defined as 
at least “a little better” (2 time points in a row without missing values in between) within 2, 
4, 6, 8, 10, 12, 24, and 48 hours of the first IMP administration and will be analyzed 
descriptively. 
Attacks that did not have at least 2 post-baseline assessments within the analyzed period 
will be excluded from this analysis. Patients who discontinued or received conventional 
attack treatment prior to time to event during a time period are considered as non-
responders for that period. The number and percentages of patients that meet HAE attacks 
with beginning of symptom relief will be presented by time point and treatment. Risk 
difference comparing each active KVD900 treatment to the placebo treatment, and 
corresponding exact 95% confidence interval (Santner, 1980) will be provided. 
PGI-C: Time to at least “better” for 2 time points in a row within 12 and 24 hours 
PGI-C: Time to at least “better” at 2 time points in a row will be calculated as: 
Time to at least better for two time points in a row (hours) = Date/time of first 
rating of “better” or higher immediately followed by another rating of “better” or 
higher (with possible missing values in between) – Date/time of first IMP 
administration. 
Patients will be treated as right-censored at 12 hours (or 24 hours for the corresponding 
endpoint) if they do not have an HAE attack rating of “better” or higher at two consecutive 
time points or receive conventional attack treatment prior to time to event within 12 hours 
(or 24 hours for the corresponding endpoint) of first IMP administration. Patients who 
discontinue the study will be right-censored at the time of discontinuation (taken from last 
assessment done during the end of study visit). In the case of underivable time-to-event 
results due to lack of at least 2 post-baseline assessments, attacks will be censored at time 
0. See Section 9.2.1 for detailed algorithms. 
Similar to the primary endpoint, Gehan scores transformation statistics and p-value will be 
provided for exploratory purposes. The number and percentage of patients who meet at 
least “better” at two consecutive time points within 12 hours (or 24 hours for the 
corresponding endpoint) and the number censored will be presented by treatment. 
Kaplan-Meier estimates of the 25th percentile (Q1), the median, and the 75th percentile 
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Date Issued: 1DEC2023 
(Q3) and corresponding 95% CI of time to at least “better” at two consecutive time points 
within 12 hours (or 24 hours for the corresponding endpoint) will be presented by 
treatment.  Kaplan-Meier survival curves will also be presented by treatment. 
The time to at least “better” at two time points in a row within 12 hours (or 24 hours for 
the corresponding endpoint) of first IMP administration will be listed with censored 
observations flagged with ‘R’. 
Time to either (1) first incidence of PGI-C being rated ‘a little worse’ or lower for 2 
time points in a row, or (2) use of conventional attack treatment, whichever comes 
first within 12 hours and 24 hours 
Time to HAE attack being rated “a little worse” or lower for 2 time points in a 
row (hours) = Date/time of first rating of “a little worse” or lower (i.e. worse or 
much worse) which is immediately followed by another rating of “a little worse” or 
lower (with possible missing values in between) – Date/time of first IMP 
administration. 
Time to conventional attack treatment use (h) = Date/time of first conventional 
attack treatment use –Date/time of study drug administration. 
Patients will be treated as right-censored at 12 hours (or 24 hours for the corresponding 
endpoint) if they do not achieve this endpoint within 12 hours (or 24 hours for the 
corresponding endpoint) of the first IMP administration. Patients who discontinue the 
study will be right-censored at the time of discontinuation (taken from last assessment 
done during the end of study visit). In the case of underivable time-to-event results due to 
lack of at least 2 post-baseline assessments, patients will be censored at time 0. See Section 
9.2.1 for detailed algorithms. 
Similar to the primary endpoint, Gehan scores transformation statistics and p-value will be 
provided for exploratory purposes. The number and percentage of patients who achieve the 
endpoint within 12 hours (or 24 hours for the corresponding endpoint) and the number 
censored will be presented by treatment. Kaplan-Meier estimates of the 25th percentile 
(Q1), the median, and the 75th percentile (Q3) and corresponding 95% CI of time-to-event 
will be presented by treatment. Kaplan-Meier survival curves will also be presented by 
treatment. 
The time to first Incidence of PGI-C being rated ‘a little worse’ or lower for two time 
points in a row, or use of conventional attack treatment within 12 hours (or 24 hours for 
the corresponding endpoint) will be listed with censored observations flagged with ‘R’. 
5.8.4.2.PGI-S 
PGI-S: Time to first incidence of decrease from baseline for 2 time points in a row 
within 24 hours 
PGI-S: Time to first incidence of decrease from baseline at 2 time points in a row within 
24 hours of the first IMP administration will be calculated as: 
37 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KalVista Pharmaceuticals, Ltd 
Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
Time to first incidence of symptom decrease from baseline for two time points 
in a row (hours) = Date/time of first incidence of decrease from baseline for two 
time points in a row (with possible missing values in between) – Date/time of first 
IMP administration. 
Patients will be treated as right-censored at 24 hours if they do not have a decrease in 
PGI-S score from baseline at two consecutive time points or receive conventional attack 
treatment prior to time to event within 24 hours of first IMP administration. Patients who 
discontinue the study will be right-censored at the time of discontinuation (taken from last 
assessment done during the end of study visit). In the case of underivable time-to-event 
results due to lack of at least 2 post-baseline assessments, attacks will be censored at time 
0. See Section 9.2.1 for detailed algorithms. 
Similar to the key secondary endpoint #1, Gehan scores transformation test statistics and p-
value will be provided for exploratory purposes. The number and percentage of patients 
who meet first incidence of decrease from baseline at two consecutive time points within 
24 hours the number censored will be presented treatment. Kaplan-Meier estimates of the 
25th percentile (Q1), the median, and the 75th percentile (Q3) and corresponding 95% CI of 
time to first incidence of decrease from baseline at two consecutive time points within 24 
hours will be presented by treatment.  Kaplan-Meier survival curves will also be presented 
by treatment. 
The time to first incidence of decrease from baseline at two consecutive time points within 
24 hours will be listed with censored observations flagged with ‘R’. 
PGI-S: Time to HAE attack resolution within 48 hours 
PGI-S: Time to HAE attack resolution defined as “none” within 48 hours of the first IMP 
administration will be calculated as: 
Time to HAE attack resolution (hours) = Date/time of first rating of “None”– 
Date/time of first IMP administration. 
Patients will be treated as right-censored at 48 hours if they do not have HAE attack 
resolution or received conventional attack treatment prior to time to event within 48 hours 
of IMP administration. Patients who discontinue the study will be right-censored at the 
time of discontinuation (taken from last assessment done during the end of study visit). In 
the case of underivable time-to-event results due to lack of at least 1 post-baseline 
assessment, attacks will be censored at time 0. See Section 9.2.1 for detailed algorithms. 
Similar to the key secondary endpoint #1, Gehan scores transformation test statistics and p-
value will be provided for exploratory purposes. The number and percentage of patients 
who meet attack resolution within 48 hours and the number censored will be presented by 
treatment. Kaplan-Meier estimates of the 25th percentile (Q1), the median, and the 75th 
percentile (Q3) and corresponding 95% CI of time to HAE attack resolution within 48 
hours will be presented by treatment.  Kaplan-Meier survival curves will also be presented 
by treatment. 
38 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
KalVista Pharmaceuticals, Ltd 
Final Statistical Analysis Plan, Version 2.0 
KVD900-301 
Date Issued: 1DEC2023 
The time to attack resolution within 48 hours will be listed with censored observations 
flagged with ‘R’. 
Time to either (1) first incidence of worsening in attack severity on the PGI-S by one 
level or more from baseline for 2 time points in a row, or (2) use of conventional 
attack treatment, whichever comes first within 12 hours and 24 hours 
Time to first incidence of worsening in attack severity by one level or more 
from baseline on the PGI-S for two time points in a row (hours) = Date/time of 
first incidence of increase from baseline on the PGI-S for two time points in a row 
(with possible missing values in between) – Date/time of first IMP administration. 
Time to conventional attack treatment use (h) = Date/time of first conventional 
attack treatment use –Date/time of study drug administration. 
Patients will be treated as right-censored at 12 hours (or 24 hours for the corresponding 
endpoint) if they do not achieve this endpoint within 12 hours (or 24 hours for the 
corresponding endpoint) of the first IMP administration. Patients who discontinue the 
study will be right-censored at the time of discontinuation (taken from last assessment 
done during the end of study visit). In the case of underivable time-to-event results due to 
lack of at least 2 post-baseline assessments, attacks will be censored at time 0. See Section 
9.2.1 for detailed algorithms. 
Similar to the key secondary endpoint #1, Gehan scores transformation test statistics and p-
value will be provided for exploratory purposes. The number and percentage of patients 
who receive the endpoint within 12 hours (or 24 hours for the corresponding endpoint) and 
the number censored will be presented by treatment. Kaplan-Meier estimates of the 25th 
percentile (Q1), the median, and the 75th percentile (Q3) and corresponding 95% CI of 
time-to-event will be presented by treatment.  Kaplan-Meier survival curves will also be 
presented by treatment. 
The time to either worsening in attack severity on the PGI-S by one level or more for two 
time points in a row or conventional attack treatment use within 12 hours (or 24 hours for 
the corresponding endpoint) will be listed with censored observations flagged with ‘R’. 
5.8.4.3.Conventional Attack Treatment 
Time to first incidence of conventional attack treatment use within 12 hours and 
24 hours 
Time to first incidence of conventional attack treatment use will be calculated as: 
Time to first incidence of conventional attack treatment use (hours) = 
Date/time of first incidence of conventional attack treatment use – Date/time of first 
IMP administration. 
Patients will be treated as right-censored at 12 hours (or 24 hours for the corresponding 
endpoint) if they do not have a conventional attack treatment use within 12 hours (or 
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24 hours for the corresponding endpoint) of the first IMP administration. Patients who 
discontinue the study will be right-censored at the time of discontinuation (taken from last 
assessment done during the end of study visit). 
Similar to the primary endpoint, Gehan scores transformation statistics and p-value will be 
provided for exploratory purposes. The number and percentage of patients who meet first 
incidence of conventional attack treatment use within 12 hours (or 24 hours for the 
corresponding endpoint) and the number censored will be presented by treatment. Kaplan-
Meier estimates of the 25th percentile (Q1), the median, and the 75th percentile (Q3) and 
corresponding 95% CI of time-to-event will be presented by treatment. Kaplan-Meier 
survival curves will also be presented by treatment. 
The time to first incidence of conventional attack treatment use within 12 hours (or 
24 hours for the corresponding endpoint) will be listed with censored observations flagged 
with ‘R’. 
5.8.4.4.Second IMP Administration 
Time to the second IMP administration within 12 hours and 24 hours 
Time to the second IMP administration (hours) = Date/time of the second IMP 
administration – Date/time of first IMP administration. 
Patients will be treated as right-censored at 12 hours (or 24 hours for the corresponding 
endpoint) if they do not achieve this endpoint within 12 hours (or 24 hours for the 
corresponding endpoint) of the first IMP administration. Patients who discontinue the 
study will be right-censored at the time of discontinuation (taken from last assessment 
done during the end of study visit). Attacks with conventional medication use prior to 
second IMP use will be censored at the time of conventional medication use. See Section 
9.2.1 for detailed algorithms. 
Similar to the primary endpoint, Gehan scores transformation statistics and p-value will be 
provided for exploratory purposes. The number and percentage of patients who achieve 
this endpoint within 12 hours (or 24 hours for the corresponding endpoint) and the number 
censored will be presented by treatment. Kaplan-Meier estimates of the 25th percentile 
(Q1), the median, and the 75th percentile (Q3) and corresponding 95% CI of time-to-event 
will be presented by treatment.  Kaplan-Meier survival curves will also be presented by 
treatment. 
The time to second IMP administration within 12 hours (or 24 hours for the corresponding 
endpoint) will be listed with censored observations flagged with ‘R’. 
Number and percentage of attacks with second IMP administration within 4, 8, 12, 
24, and 48 hours of the first IMP administration 
Number and percentage of attacks with second IMP administration within 4, 8, 12, 24, and 
48 hours of the first IMP administration will be analyzed descriptively. 
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Patients who discontinued or received conventional medication prior to time to event 
during a time period are considered as non-responders for that period. The number and 
percentages of patients that use second IMP administration or conventional treatment will 
be presented by time point and treatment. Risk difference comparing each active KVD900 
treatment to the placebo treatment, and corresponding exact 95% confidence interval 
(Santner, 1980) will be provided. 
5.8.4.5.Composite VAS 
Time to at least 50% decrease from baseline (3 time points in a row) within 12 and 
24 hours of the first IMP administration 
Composite VAS score is defined as the mean score across all 3 symptom scores. Time to at 
least a 50% decrease from baseline (3 time points in a row) will be calculated as: 
Time to at least 50% decrease (hours) = Date/time of first ≥50% decrease in 
composite VAS score for 3 consecutive time points (with possible missing values 
in between) – Date/time of first IMP administration. 
Patients will be treated as right-censored at 12 or 24 hours if a ≥50% reduction in 
composite VAS score for 3 consecutive time points does not occur or receive conventional 
attack treatment prior to time to event within 12 or 24 hours of IMP administration. 
Patients who discontinue the study will be right-censored at the time of discontinuation 
(taken from last assessment done during the end of study visit). In the case of underivable 
time-to-event results due to lack of at least 3 post-baseline assessments, attacks will be 
censored at time 0. See Section 9.2.1 for detailed algorithms. 
Similar to the primary endpoint, Gehan scores transformation statistics and p-value will be 
provided for exploratory purposes. The number and percentage of patients with a 50% 
reduction in composite VAS score for 3 consecutive time points and the number censored 
will be presented by treatment. Kaplan-Meier estimates of the 25th percentile (Q1), the 
median, and the 75th percentile (Q3) and corresponding 95% CI of time to a 50% reduction 
in composite VAS score for 3 consecutive time points will be presented by treatment. 
Kaplan-Meier survival curves will also be presented by treatment. 
The time to an at least 50% reduction in composite VAS score for 3 consecutive time 
points will be listed with censored observations flagged with ‘R’. 
5.8.5. Exploratory Endpoints 
5.8.5.1.Characteristics of the IMP-Treated HAE Attacks 
A summary of characteristics of the IMP-treated HAE attacks will be presented by 
treatment and overall for the FAS. The IMP-treated HAE attack characteristics consist of 
baseline PGI-S severity score, baseline VAS score, baseline primary attack location, 
baseline GA-NRS score, and time from attack onset to IMP administration. 
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The baseline PGI-S scores will be transformed into numeric values (recoded as 0 (none) to 
4 (very severe)) and descriptive statistics (n, mean, SD, minimum, Q1, median, Q3 and 
maximum) of baseline PGI-S values will be presented by treatment. Additionally, the 
number and percentage of attacks by baseline PGI-S category (None, Mild, Moderate, 
Severe, and Very Severe) will be presented by treatment and overall. 
Summary statistics on baseline GA-NRS scores will be presented by treatment. Baseline 
GA-NRS score will also be categorized into intervals (0 (not at all anxious), 1-3 (mildly 
anxious), 4-6 (moderately anxious) and 7-10 (extremely anxious)) and the number and 
percentage of patients that falling into each category will be presented by treatment and 
overall. 
Summary statistics on individual baseline VAS scores (abdominal pain, skin pain, and skin 
swelling) and composite baseline VAS scores will be presented by treatment and overall 
for the FAS. 
Summary statistics on the time from onset of attack to first IMP administration will be 
presented by treatment for the FAS. Additionally, the number and percentage of attacks by 
baseline time to IMP administration category (see Section 5.8.6 for categories ) will be 
reported by treatment and overall. 
Number and percentage of attacks by original baseline primary attack location 
(Head/Face/Neck, Torso, Arms/Hands, Genitals, Legs/Feet, Abdomen, and Larynx/Throat) 
and pooled baseline primary attack location (see Section 5.8.6 for categories) will be 
presented by treatment and overall. 
Baseline characteristics for the IMP-treated attacks will be presented in a listing by 
treatment for all patients in the FAS. 
5.8.5.2.PGI-C 
PGI-C Score Over Time 
The number and percentage of patients for each PGI-C score will be summarized by time 
point and treatment. Additionally, the PGI-C scores will be transformed into numeric 
values (recoded as -3 (much better) to 3 (much worse)) and descriptive statistics (n, mean, 
SD, minimum, Q1, median, Q3 and maximum) will be presented by time point and 
treatment. The mean values will also be presented graphically over time. In these 
summaries, assessments made after receiving conventional attack treatment will be 
excluded. 
5.8.5.3.PGI-S 
PGI-S: Number and percentage of attacks with first incidence of decrease in attack 
severity within 4, 8, 12, 24, and 48 hours of the first IMP administration 
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PGI-S: Number and percentage of attacks with first incidence of decrease in attack severity 
at 2 time points in a row (with possible missing values in between) within 4, 8, 12, 24, and 
48 hours of the first IMP administration will be analyzed descriptively. 
Attacks that did not have at least 2 post-baseline assessments within the analyzed period 
will be excluded from this analysis. Patients who discontinued or received conventional 
attack treatment prior to time to event during a time period are considered as non-
responders for that period. The number and percentages of patients that achieve decrease in 
attack severity will be presented by time point and treatment. Risk difference comparing 
each active KVD900 treatment to the placebo treatment, and corresponding exact 95% 
confidence interval (Santner, 1980) will be provided. 
PGI-S: Number and percentage of attacks with attack resolution within 4, 8, 12, 24, 
and 48 hours of the first IMP administration 
PGI-S: Number and percentage of attacks with attack resolution defined as ‘none’ within 
4, 8, 12, 24, and 48 hours of the first IMP administration will be analyzed descriptively. 
Attacks that did not have at least 1 post-baseline assessment within the analyzed period 
will be excluded from this analysis. Patients who discontinued or received conventional 
attack treatment prior to time to event during a time period are considered as non-
responders for that period. The number and percentages of patients that achieve attack 
resolution will be presented by time point and treatment. Risk difference comparing each 
active KVD900 treatment to the placebo treatment, and corresponding exact 95% 
confidence interval (Santner, 1980) will be provided. 
PGI-S Score Over Time 
The number and percentage of patients for each PGI-S score will be summarized by time 
point and treatment. Additionally, the PGI-S scores will be transformed into numeric 
values (recoded as 0 (none) to 4 (very severe)) and descriptive statistics (n, mean, SD, 
minimum, Q1, median, Q3 and maximum) of absolute and change from baseline values 
will be presented by time point and treatment. The mean absolute and change from 
baseline values will also be presented graphically over time. In these summaries, 
assessments made after receiving conventional attack treatment will be excluded. 
5.8.5.4.Conventional Attack Treatment 
Number and percentage of attacks receiving first conventional attack treatment 
within 4, 8, 12, 24, and 48 hours of the first IMP administration 
Number and percentage of attacks receiving conventional attack treatment within 4, 8, 12, 
24, and 48 hours of the first IMP administration will be analyzed descriptively. 
Patients who discontinued during a time period are considered as non-responders for that 
period. The number and percentages of patients that receive conventional attack treatment 
will be presented by time point and treatment. Risk difference comparing each active 
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KVD900 treatment to the placebo treatment, and corresponding exact 95% confidence 
interval (Santner, 1980) will be provided. 
5.8.5.5.GA-NRS and VAS 
GA-NRS: cumulative GA-NRS in AUC over 12 hours and 24 hours of the first IMP 
administration 
General Anxiety Numeric Rating Scale (GA-NRS): Cumulative GA-NRS expressed as 
area under the curve (AUC) over 12 hours and over 24 hours from the time of first IMP 
administration will be calculated separately. 
Baseline and time-adjusted AUC0-12 of the GA-NRS over time from 0 hour (pre-dose) up 
to 12 hours or up to the last time point prior to the time of conventional attack treatment 
use, whichever occurs first will be derived by linear trapezoidal rule. For a patient with k 
GA-NRS assessments at times 𝑡𝑡1 to 𝑡𝑡𝑘𝑘 , where 𝑡𝑡1 < 𝑡𝑡2 < ⋯ < 𝑡𝑡𝑘𝑘 , the AUC0-12 is computed 
as 
𝑘𝑘 
෍ 0.5 𝑥𝑥 (𝑔𝑔𝑖𝑖−1 + 𝑔𝑔𝑖𝑖)𝑥𝑥 (𝑡𝑡𝑖𝑖 − 𝑡𝑡𝑖𝑖−1)/(𝑡𝑡𝑘𝑘 − 𝑡𝑡1) 
𝑖𝑖=2 
where 𝑔𝑔𝑖𝑖 is the GA-NRS measured at timepoint ti and k is the length of time (12 hours or 
until the time of conventional attack treatment use whichever occurs first). 
Similarly, AUC0-24 will be calculated from 0 hours up to 24 hours or up to use of 
conventional attack treatment if this occurs prior to the 24 hour time point. 
In order to account for negative values, the net incremental AUC method will be employed 
(negative areas subtracted from positive areas). The AUCs will be evaluated with 
correction for baseline values by subtraction of the 0 hours from GA-NRS the post-dose 
scores prior to derivation. As the time interval for the calculation of the AUC is likely to 
vary between patients, the AUCs will also be time-adjusted by dividing the baseline-
adjusted AUC by the duration of time included in the AUC calculation (AUC/h). The 
actual time of assessment will be used in the calculation of the AUCs. The assessment time 
deviation will be calculated as actual date/time – theoretical date/time, where theoretical 
date/time is derived from the date/time of dose administration and nominal assessment 
time. 
Descriptive statistics (n, mean, SD, minimum, Q1, median, Q3 and maximum) will be 
presented for AUC0-12 and AUC0-24 by treatment. Statistical comparisons of the 
AUC0-12 and AUC0-24 between treatments will be performed using a mixed effects 
analysis of variance (ANOVA) with fixed effects of treatment, sequence, and period and 
patient nested within sequence as a random effect.  Least-squares means of treatment 
effects to show differences between treatments (600 mg versus placebo and 300 mg versus 
placebo) will be tested at 0.05 level. Least-square means and standard errors will be 
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presented by treatment. P-values will be calculated for the comparison of each KVD900 
dose group versus placebo, along with the least-square mean treatment difference and 
corresponding 95% CI will be presented. 
GA-NRS: Number and percentage of attacks with first incidence of GA-NRS 
reduction of ≥2, ≥3,  ≥4, or ≥5 points within 4, 8, 12, 24, and 48 hours of the first IMP 
administration 
Number and percentage of attacks with first incidence of GA-NRS reduction of ≥2, ≥3,  
≥4,  or ≥5 points within 4, 8, 12, 24, and 48 hours of the first IMP administration will be 
analyzed descriptively. 
Attacks that had a baseline GA-NRS score below a cutoff point will be excluded from the 
corresponding analysis. Attacks that did not have at least 1 post-baseline assessment within 
the analyzed period will be excluded from this analysis. Patients who discontinued or 
received conventional attack treatment prior to time to event during a time period are 
considered as non-responders for that period. The number and percentages of patients that 
achieve first instance of GA-NRS reduction of the corresponding cutoff point will be 
presented by time point and treatment. Risk difference comparing each active KVD900 
treatment to the placebo treatment, and corresponding exact 95% confidence interval 
(Santner, 1980) will be provided. The number and percentage of attacks with first 
incidence of GA-NRS reduction of ≥2, ≥3,  ≥4,  or ≥5 points within 4, 8, 12, 24, and 48 
hours of the first IMP administration will be presented graphically in a bar graph. 
GA-NRS Score Over Time 
The number and percentage of patients for each GA-NRS score will be summarized by 
time point and treatment. Additionally, descriptive statistics (n, mean, SD, minimum, Q1, 
median, Q3 and maximum) will be presented for GA-NRS scores by time point and 
treatment. The mean values will also be presented graphically over time. GA-NRS score 
will also be categorized into intervals (0 (not at all anxious), 1-3 (mildly anxious), 4-6 
(moderately anxious) and 7-10 (extremely anxious)) and the number and percentage of 
patients that falling into each category will be presented by time point and treatment. In 
these summaries, assessments made after receiving conventional attack treatment will be 
excluded. 
VAS Score Over Time 
Descriptive statistics (n, mean, SD, minimum, Q1, median, Q3 and maximum) will be 
presented for composite VAS scores by time point and treatment. The mean values will 
also be presented graphically over time. In these summaries, assessments made after 
receiving conventional attack treatment will be excluded. 
5.8.6. Subgroup and Subset Analyses 
Subgroup analyses of the primary and key secondary efficacy endpoints will be performed 
by sex (if provided), race, age group, prophylactic treatment status, region, type of HAE, 
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baseline primary attack location, attack severity at baseline based on PGI-S, number of 
doses received, and time from onset of attack to the first IMP administration. Frequencies 
and survival estimates will be presented for each subgroup. P-values will be added for 
exploratory purposes. The following categories will be used: 
• 
Sex:  Male, Female 
• 
Race: White, Black or African America, Asian, Other 
• 
Age group: Age <18 years, Age ≥18 years 
• 
Prophylactic treatment status: 
-
On Demand, on Prophylactic Treatment 
-
On Demand, on Kallikrein Prophylactic Treatment (including 
lanadelumab and berotralstat), on Other Prophylactic Treatment 
• 
Region: 
-
US, Ex-US 
-
North America (including US), Europe (including Austria, Bulgaria, 
France, Germany, Greece, Hungary, Italy, North Macedonia, Netherlands, 
Poland, Portugal, Romania, Slovakia, Spain, and United Kingdom), and 
Rest of the World (including Australia, Israel, and Japan) 
• 
Type of HAE: Type I, Type II 
• 
Baseline primary attack location: 
-
Laryngeal [an attack involving at least one laryngeal location, including 
the larynx/throat, regardless of other locations involved], Abdominal Only 
[an attack with Abdomen location only], Subcutaneous Only [an attack 
with Arms/Hands, Genitals, Legs/Feet, Head/Face/Neck, or Torso 
location(s) only], Abdominal and Subcutaneous [an attack with at least 
one abdominal location and at least one subcutaneous location] 
-
Neck and Above [an attack involving larynx/throat or Head/Face/Neck 
location(s), regardless of other locations involved], Abdominal [an attack 
involving Abdomen location and not involving larynx/throat or 
Head/Face/Neck locations, regardless of other locations involved], Other 
[an attack involving Arms/Hands, Genitals, Legs/Feet, or Torso 
location(s) only] 
• 
Attack severity at baseline based on PGI-S: None or Mild, Moderate, and Severe or 
Very Severe 
• 
Number of doses received: Single dose, Double doses or more 
• 
Time from onset of attack to the first IMP administration: 
-
< 30 minutes, ≥ 30 - < 60 minutes, ≥ 60 minutes 
-
≤ median, > median 
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The examination of primary and key secondary endpoints, utilizing both the on-demand 
FAS and the prophylaxis-FAS as outlined in the protocol, is the same as the subgroup 
analyses comparing the 'On-Demand' subgroup with the 'On Prophylactic Treatment' 
subgroup. 
5.9. 
Safety Analysis 
All safety data will be summarized by actual treatment received unless otherwise specified. 
Safety analysis will be performed using the SAF. Safety endpoints include adverse events 
(AEs), clinical laboratory assessments, vital signs, electrocardiogram (ECG), and physical 
examination findings. 
5.9.1. Adverse Events 
Clinical and laboratory adverse events (AEs) will be coded using the current version of the 
Medical Dictionary for Regulatory Activities (MedDRA Version 26.0 or higher). System 
organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term 
(PT), and lower-level term (LLT) will be provided in the AE dataset. HAE attacks will not 
be considered AEs unless they are considered SAEs. 
5.9.1.1.Relationship of Adverse Events to Trial Medication 
The investigator will provide an assessment of the relationship of the AE to the IMP on the 
case report form (CRF) to the question of “Related to Study Treatment.”. The possible 
relationships are “Related: A reasonable possibility exists that the IMP caused the AE”, 
and “Not Related: A reasonable possibility does not exist that the IMP cause the AE”. 
Events for which the investigator did not record relationship to IMP will be considered 
related to IMP for summary purposes. However, by-patient data listings will show the 
relationship as missing from that captured on the CRF. 
5.9.1.2.Severity of Adverse Event 
AEs are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. 
In the TEAE severity table, if a patient reported multiple occurrences of the same TEAE, 
only the most severe will be presented. 
The severity grade of events for which the investigator did not record severity will be 
categorized as “severe” for tabular summaries and as “missing” in data listings. 
5.9.1.3.Serious Adverse Events 
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definition of SAEs that were specified in the study protocol. The seriousness of an AE 
should be assessed by the Investigator independently from the severity of the AE. An SAE 
is defined as any untoward medical occurrence that at any dose results in death, is life-
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threatening, is a congenital anomaly/birth defect, requires in-patient hospitalization or 
prolongation, or results in significant disability/incapacity. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
5.9.1.4.Treatment-Emergent Adverse Events 
A treatment-emergent AE (TEAE) is defined as any AE that meets any of the following 
conditions, based on the actual AE dates (if partially missing, see Section 5.9.1.5): 
• 
begins on or after the first dose date of trial medication; 
• 
begins before the first dose date of trial medication and increases in severity on or 
after the first dose date of trial medication; 
• 
is completely missing a start date and the stop date; 
• 
is completely missing a start date and the stop date is on or after the first dose of 
trial medication. 
An AE will be assigned to the most recent treatment if it starts on or after the 
corresponding treatment first dose date. 
TEAEs can be further classified as on-treatment TEAEs. An on-treatment TEAE is defined 
as any TEAE occurring within 3 days post-dose. 
5.9.1.5.Incomplete Dates 
If there are incomplete dates recorded for an AE, the start day, month, year or stop day, 
month, year will be used to determine whether the AE is a TEAE and the treatment 
assignment. 
If the start date of the AE is incomplete and the AE stop date is not prior to the first dose 
date of study drug, then the month and year (or year alone if month is not recorded) of 
onset determine whether an AE is treatment emergent. The event is considered treatment 
emergent if the AE start date is the same as or after the month and year (or year) of the date 
of first dose of trial medication. 
Similarly, if the AE start date is missing and the stop date is incomplete then the month 
and year (or year alone if month is not recorded) of stop date will determine whether an 
AE is treatment emergent. The event is considered treatment emergent if the AE start date 
is missing and the stop date has the same as or after the month and year (or year) of the 
date of first dose of trial medication. 
If there are incomplete dates recorded for an AE and treatment emergent cannot be 
determined of the partial information, then the AE will be considered as TEAE. 
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If there are incomplete dates recorded for a TEAE and a treatment assignment cannot be 
determined based on the partial information, then the AE will be considered as a TEAE for 
all treatment that the patient receives. 
If there are incomplete dates recorded for an TEAE, with treatment assignment can be 
determined but on-treatment TEAE status cannot be determined based on the partial 
information, then the TEAE will be considered as an on-treatment TEAE for the 
corresponding treatment. 
If there are incomplete dates recorded for an TEAE, with treatment assignment or on-
treatment TEAE status cannot be determined based on the partial information, then the 
TEAE will be considered as an on-treatment TEAE for all treatment that the patient 
receives. 
5.9.1.6.Summaries of Adverse Events and Deaths 
The number and percentage of patients with any TEAE, any related TEAE, any grade 3 or 
higher TEAE, any related grade 3 or higher TEAE, any serious TEAE, and any related 
serious TEAE, as well as the total number of events for each category, will be summarized 
by treatment and KVD900 overall. The number of deaths due to an TEAE, hospitalization 
due to an TEAE and study discontinuation due to an TEAE will be summarized by 
treatment and KVD900 overall. The same presentation will be created for on-treatment 
TEAEs. 
The number and percentage of patients who experienced at least one TEAE, as well as the 
total number of TEAEs, will be summarized for each treatment and KVD900 overall by 
SOC and PT. This tabulation will be repeated for the TEAE categories as follow: 
• 
All TEAEs 
• 
All TEAEs by severity grade 
• 
All TEAEs related to study treatment 
• 
All TEAEs related to study treatment by severity grade 
• 
All treatment-emergent SAEs 
• 
All treatment-emergent SAEs related to study treatment 
• 
All on-treatment TEAEs 
• 
All on-treatment TEAEs by severity grade 
• 
All on-treatment TEAEs related to study treatment 
• 
All on-treatment TEAEs related to study treatment by severity grade 
• 
All on-treatment treatment-emergent SAEs 
• 
All on-treatment treatment-emergent SAEs related to study treatment 
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• 
All TEAEs leading to premature discontinuation of study drug 
• 
All TEAEs leading to study discontinuation 
• 
All TEAEs leading to death 
Multiple events will be counted only once per patient per treatment in each summary. AEs 
will be summarized and listed first in alphabetic order of SOC and then by PT in 
descending order of total frequency within each SOC. For summaries by grade, the most 
severe grade will be used for those AEs that occurred more than once in an individual 
patient per treatment during the study. 
In addition, data listings will be provided for the following: 
• 
All AEs 
• 
AEs related to study treatment 
• 
AEs with Severity Grade 3 or 4 
• 
SAEs 
• 
Deaths 
• 
AEs leading to premature discontinuation of study drug 
• 
AEs leading to premature discontinuation of study 
TEAEs and on-treatment TEAEs will be flagged within the listings. 
5.9.2. Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory. All summaries will be 
based on the conventional units. 
Descriptive statistics (n, mean, SD, minimum, Q1, median, Q3 and maximum) will be 
presented by visit and treatment sequence and overall for observed values and changes 
from baseline for clinical laboratory test results for patients in the SAF. Summaries will 
also be provided by last treatment received. 
Clinical laboratory results will be classified according to the reference ranges. The number 
of patients with a non-missing result, and the number and percentage of patients with a lab 
result below the lower limit of normal, within the normal range, and above the upper limit 
of normal, will be summarized by visit for each treatment sequence and overall. 
Summaries will also be provided by last treatment received. 
A by-patient listing for laboratory test results will be provided by treatment sequence and 
visit in chronological order for clinical laboratory tests separately. Values falling outside of 
the relevant reference range (High, Low) will be flagged in the data listings, as appropriate. 
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5.9.2.1.Hematology 
The following laboratory tests will be included: red blood cell (RBC), mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), mean platelet volume (MPV), red cell distribution width (RDW), 
nucleated RBC, white blood cell (WBC), neutrophils, eosinophils, basophils, lymphocytes, 
monocytes, platelets, granulocytes, hemoglobin, and hematocrit. Summary tables and 
listings will be presented as described in Section 5.9.2. 
5.9.2.2.Clinical Chemistry 
The following laboratory tests will be included: glycosylated hemoglobin (HBA1c), 
creatinine, glucose (random), triglycerides, blood urea nitrogen, total bilirubin, direct 
bilirubin, and total cholesterol. Summary tables and listings will be presented as described 
in Section 5.9.2. 
5.9.2.3.Urinalysis 
The following laboratory tests will be included: potential hydrogen (pH), protein, glucose, 
ketone, bilirubin, blood, nitrite, and albumin. Summary tables and listings will be 
presented as described in Section 5.9.2. 
5.9.2.4.Liver Enzyme 
The following laboratory tests will be included: alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase 
(GGT). Summary tables and listings will be presented as described in Section 5.9.2. 
5.9.2.5.Electrolytes 
The following laboratory tests will be included: sodium and potassium. Summary tables 
and listings will be presented as described in Section 5.9.2. 
5.9.2.6.Coagulation 
The following laboratory test will be included: international normalized ratio (INR). 
Summary tables and listings will be presented as described in Section 5.9.2. 
5.9.2.7.C1 Functional Level, C1 Antigen, and Complement C4 
The following laboratory test will be included: C1 esterase inhibitor (antigen), C1 esterase 
inhibitor (functional), and complement C4 results. Summary tables (except shift from 
baseline table) and listings will be presented as described in Section 5.9.2. 
5.9.2.8.Pregnancy 
Serum pregnancy tests will be performed on females of childbearing potential. A by-
patient listing for pregnancy test results will be provided by treatment sequence. 
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5.9.3. Vital Sign Measurements 
Vital sign measurements will include systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), pulse rate (bpm), and respiration rate (RR) (breaths/minute). 
Descriptive statistics (n, mean, SD, minimum, Q1, median, Q3 and maximum) will be 
presented by treatment sequence and overall for observed values and changes from 
baseline for vital signs measurements for patients in the SAF. Summaries will also be 
provided by last treatment received. 
A by-patient listing for all vital sign results will be presented by treatment sequence and 
visit. 
5.9.4. Physical Examination 
A physical examination will be performed by the investigator or his/her qualified designee 
according to the Schedule of Events (Appendix 9.3). 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; lymphatic; and other. 
Other visits noted in the Schedule of Events (Appendix 9.3) will include a symptom-
directed physical examination. 
For each physical examination assessment, the number and percentage of patients will be 
summarized for each body system and outcome (Normal, Abnormal [Not Clinically 
Significant, Clinically Significant], Not Done) and will be presented at each visit by 
treatment sequence and overall using the SAF. Summaries will also be provided by last 
treatment received. 
A by-patient listing for physical examination results will be presented by treatment 
sequence and visit. 
5.9.5. Electrocardiogram 
All patients will have a standard 12-lead ECG performed at the time points as scheduled 
(Appendix 9.3), that will be recorded in triplicate readings. ECG tests will include heart 
rate (HR; beats per minute), PR-interval (milliseconds [ms]), QRS-duration (ms), 
QT-interval (ms) and RR interval (milliseconds [ms]), and QTcF (Fridericia correction of 
QTc; ms). ECG results will be evaluated and interpretation results include Normal, 
Abnormal Not Clinically Significant, Abnormal Clinically Significant, and Not Done. 
Descriptive statistics (n, mean, SD, minimum, Q1, median, Q3 and maximum) will be 
presented by treatment sequence and overall for observed values and changes from 
baseline for ECG test results for patients in the SAF. Summaries will also be provided by 
last treatment received. 
Additionally, normal sinus rhythm (yes/no) and ECG interpretations (Normal, Abnormal 
Not Clinically Significant, Abnormal Clinically Significant, and Not Done) will be 
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presented with number and percentage of patients at each visit by treatment sequence and 
overall and separately by last treatment received. 
A by-patient listing for all ECG results and interpretation will be presented by treatment 
sequence and visit. 
6. 
INTERIM ANALYSIS 
There is no planned interim analysis for this trial. 
7. 
CHANGES IN THE PLANNED ANALYSIS 
Changes in the planned analysis are shown in Table 4. 
Table 4 Changes in the Planned Analysis 
Section 
Change in the Planned Analysis 
Rationale 
5.8.2.3 
The protocol Section 17.7.3 states to create 50 
imputed datasets for the multiple imputation 
sensitivity analysis. It is changed to 1,000 
dataset. 
A larger number of imputed 
dataset will improve the 
statistical properties of the 
estimators. 
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8. 
REFERENCES 
Aygören-Pürsün E, Bygum A, Beusterien K, et al. Estimation of EuroQol 5-Dimensions 
health status utility values in hereditary angioedema. Patient Prefer Adherence. 2016 Sep 
6;10:1699-707. doi: 10.2147/PPA.S100383. 
Aygören-Pürsün E, Bygum A, Grivcheva-Panovska V, et al. Oral Plasma Kallikrein 
Inhibitor for Prophylaxis in Hereditary Angioedema. N Engl J Med. 2018 Jul 
26;379(4):352-362. doi: 10.1056/NEJMoa1716995. 
Bork K, Hardt J, Schicketanz KH, Ressel N. Clinical studies of sudden upper airway 
obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. 
Arch Intern Med. 2003 May 26;163(10):1229-35. doi: 10.1001/archinte.163.10.1229. 
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning 
symptoms, affected organs, and course. Am J Med. 2006 Mar;119(3):267-74. doi: 
10.1016/j.amjmed.2005.09.064. 
Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema 
due to C1-INH deficiency. J Allergy Clin Immunol. 2012 Se p;130(3 ):692-7. do i: 
10.1016/j.jaci.2012.05.055. 
Caballero T, Aygören-Pürsün E, Bygum A, et al. The humanistic burden of hereditary 
angioedema: results from the Burden of Illness trial in Europe. Allergy Asthma Proc. 2014 
Jan-Fe b;35(1 ):47-53. do i: 10.2500/aap.2013.34.3685. 
Caballero T, Maurer M, Longhurst HJ, et al. Triggers and Prodromal Symptoms of 
Angioedema Attacks in Patients with Hereditary Angioedema. J Investig Allergol Clin 
Immunol. 2016;26(6):383-386. doi: 10.18176/jiaci.0102. 
Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema: 
Absence of serum inhibitor of ’' 1-esterase. Am J Med. 1963 Jul;35:37-44. doi: 
10.1016/0002-9343(63)90162-1. 
Donaldson VH, Rosen FS. Action of complement in hereditary angioneurotic edema: The 
role of ’'1-Esterase. J Clin Invest. 1964 Nov;43(11):2204-13. doi: 10.1172/JCI105094. 
Fields T, Ghebrehiwet B, Kaplan AP. Kinin formation in hereditary angioedema plasma: 
evidence against kinin derivation from C2 and in support of spontaneous formation of 
bradykinin. J Allergy Clin Immunol. 1983 Jul;72(1):54-60. doi: 10.1016/0091-
6749(83)90052-0. 
FDA. Guidance for Industry: Multiple Endpoints in Clinical Trials. 2022 Oct. 
Feingold M, Gillespie BW. Cross-over trials with censored data. Stat Med. 199 6; 1 5:953-
67. 
Gösswein T, Kocot A, Emmert G, et al. Mutational spectrum of the C1INH (SERPING1) 
gene in patients with hereditary angioedema. Cytogenet Genome Res. 2008;121(3-4):181-
8. doi: 10.1159/000138883. 
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Hulström D, Svensjö E. Intravital and electron microscopic trial of bradykinin-induced 
vascular permeability changes using FITC-dextran as a tracer. J Pathol. 1979 
No v;129(3 ):125-33. do i: 10.1002/path.1711290304. 
Javaud N, Altar A, Fain O, et al. Hereditary angioedema, emergency management of 
attacks by a call center. Eur J Intern Med. 2019 Sep;6 7:42-46. do i: 
10.1016/j.ejim.2019.05.007. 
Javaud N, Bouillet L, Rabetrano H, et al. Hereditary angioedema: Clinical presentation and 
socioeconomic cost of 200 French patients. J Allergy Clin Immunol Pract. 2019 
Jan;7(1):328-330. doi: 10.1016/j.jaip.2018.05.036. 
Kaplan AP, Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: 
dysregulation of an innate inflammatory pathway. Adv Immunol. 201 4;12 1:41-89. do i: 
10.1016/B978-0-12-800100-4.00002-7. 
Lumry WR, Craig T, Zuraw B, et al. Health-Related Quality of Life with Subcutaneous 
C1-Inhibitor for Prevention of Attacks of Hereditary Angioedema. J Allergy Clin Immunol 
Pract. 2018 Sep-Oct;6(5):1733-1741.e3. doi: 10.1016/j.jaip.2017.12.039. 
Maurer M, Bork K, Martinez-Saguer I, et al. Management of patients with hereditary 
angioedema in Germany: comparison with other countries in the Icatibant Outcome 
Survey. J Eur Acad Dermatol Venereol. 2019 Jan;33(1):163-169. doi: 10.1111/jdv.15232. 
Nordenfelt P, Nilsson M, Björkander J, Mallbris L, Lindfors A, Wahlgren CF. Hereditary 
Angioedema in Swedish Adults: Report From the National Cohort. Acta Derm Venereol. 
2016 May;96(4):540-5. doi: 10.2340/00015555-2274. 
Nordenfelt P, Nilsson M, Lindfors A, Wahlgren CF, Björkander J. Health-related quality 
of life in relation to disease activity in adults with hereditary angioedema in Sweden. 
Allergy Asthma Proc. 2017 Nov 30;38(6):447-455. doi: 10.2500/aap.2017.38.4087. 
Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma 
bradykinin in angio-oedema. Lancet. 1998 Jun 6;351(9117):1693-7. doi: 10.1016/S0140-
6736(97)09137-X. 
Nussberger J, Cugno M, Cicardi M, Agostoni A. Local bradykinin generation in hereditary 
angioedema. J Allergy Clin Immunol. 1999 Dec;104(6):1321-2. doi: 10.1016/s0091-
6749(99)70030-8. 
Nussberger J, Cugno M, Cicardi M. Bradykinin-mediated angioedema. N Engl J Med. 
2002 Aug 22;347(8):621-2. doi: 10.1056/NEJM200208223470820. 
O’Connor P. A nonparametric multiple imputation approach for survival data patient to 
informative censoring. Doctoral Dissertation. University of Arizona, 2020. Available at 
http://hdl.handle.net/10150/637722.Rosen FS, Pensky J, Donaldson V, Charache P. 
Hereditary angioneurotic edema: Two genetic variants. Science. 1965 May 
14;148(3672):957-8. doi: 10.1126/science.148.3672.957. 
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Rosen FS, Pensky J, Donaldson V, Charache P. Hereditary angioneurotic edema: two 
genetic variants. Science. 1965 May 14;148(3672):957-8. doi: 
10.1126/science.148.3672.957. 
Rosen FS, Alper CA, Pensky J, Klemperer MR, Donaldson VH. Genetically determined 
heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema. 
J Clin Invest. 1971 Oct;50(10):2143-9. doi: 10.1172/JCI106708. 
Santner, T. S. (1980). Small-sample confidence intervals for p1–− p2 and p1/p2 in 2 × 2 
contingency tables. J. Amer. Statist. Assoc., 75, 386–394. 
Taylor JMG, Murray S, Hsu C-H. Survival estimation and testing via multiple imputation. 
Stat Probability Letters 2002; 58: 221–232. 
Zanichelli A, Arcoleo F, Barca MP, et al. A nationwide survey of hereditary angioedema 
due to C1 inhibitor deficiency in Italy. Orphanet J Rare Dis. 2015 Feb 6;10:11. doi: 
10.1186/s13023-015-0233-x. 
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9. 
APPENDICES 
9.1. 
Kaplan-Meier Imputation under Informative Censoring 
Assumption 
For 𝑛𝑛 patients 𝑖𝑖 = 1, … . , 𝑛𝑛 we have data 𝑇𝑇𝑖𝑖 and 𝐷𝐷𝑖𝑖, where 𝑇𝑇𝑖𝑖 is the survival time if 𝐷𝐷𝑖𝑖 = 1 
and 𝑇𝑇𝑖𝑖 is the censoring time if 𝐷𝐷𝑖𝑖 = 0. Since there are 3 periods in the study, there will be 
3𝑛𝑛 observations for each patient. 
Each patient 𝑖𝑖 has data (𝑇𝑇𝑖𝑖 , 𝐷𝐷𝑖𝑖). 
Identify all censored times and order them in increasing order. Begin with the smallest and 
proceed to the largest starting from Step 2 below. 
Step 1: 
Specify Kendall’s 𝜏𝜏. Consider the following values for 𝜏𝜏 = ±0.5, ±0.3, ±0.1, 0. 
Step 2 (Define the Imputing Risk Set (IRS)): 
For each censored patient 𝑗𝑗 with censored time 𝑇𝑇𝑗𝑗 , 𝜏𝜏 is utilized to determine the size of the 
data set from which to impute failure times for the censored value. 
We will call it the Imputing Risk Set (IRS): this set will include only patients who were 
still at risk at time 𝑇𝑇𝑗𝑗 , that is, all patients  with longer survival (can be censored) times 
than 𝑇𝑇𝑗𝑗.  Let 𝑛𝑛𝑗𝑗 be the number of patients with longer survival or censored times than 
𝑇𝑇𝑗𝑗, 𝑗𝑗 = 1, … , 𝑚𝑚, where 𝑚𝑚 is the number of patients with censored times. 
The size of the IRS is defined as 
𝑛𝑛𝑗𝑗 ∗ (1 − |𝜏𝜏|𝑘𝑘 ) 
Where parameter k is used to control the potential bias. 
If |𝜏𝜏| < 1 𝑎𝑎𝑛𝑛𝑎𝑎 𝑘𝑘 < 1, the size of IRS will be decreased. 
If |𝜏𝜏| < 1 𝑎𝑎𝑛𝑛𝑎𝑎 𝑘𝑘 > 1, the size of IRS will be increased. 
Consider the following values for  𝑘𝑘 = 1.5, 1.25, 1, 0.75, 0.5. 
When 𝜏𝜏 = 0, this is the case of independent censoring and IRS size is 𝑛𝑛𝑗𝑗, all patients at risk 
at time 𝑗𝑗 are in the IRS. 
When 𝜏𝜏 > 0, the censored observation for patient 𝑗𝑗 at time 𝑇𝑇𝑗𝑗 is the anchor point for the 
neighborhood which extends to only values greater than 𝑇𝑇𝑗𝑗. This implies those patients 
who were at risk and had an observed time closer to 𝑇𝑇 are more likely to be included in the 
IRS. 
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This neighborhood would consist of the 
100 ∗ (1 − |𝜏𝜏|𝑘𝑘 )% of the 𝑛𝑛𝑗𝑗 patients still at risk at time 𝑇𝑇𝑗𝑗 that- are nearest to the censored 
patient j. 
For example, for 𝜏𝜏 = 0.5 and 𝑘𝑘 = 1, the IRS would contain 50% of all patients to the 
anchor point 𝑇𝑇𝑗𝑗 . 
When 𝜏𝜏 < 0, the anchor point would become patient 𝑚𝑚 at time 𝑇𝑇𝑚𝑚, 𝑚𝑚 being the patient 
with the longest survival time. This implies those patients who were at risk and had an 
observed time farther away from 𝑇𝑇𝑗𝑗 are more likely to be included in the IRS. 
For example, for 𝜏𝜏 = −0.5 and 𝑘𝑘 = 1, the IRS would contain 50% of all patients to the 
anchor point 𝑇𝑇𝑚𝑚. 
Step 3 (Impute a value from the IRS): 
Each value 𝑇𝑇𝑗𝑗, 𝑗𝑗 = 1, … , 𝑚𝑚 will be imputed from the corresponding IRS. 
Once the size of the IRS has been determined, Kaplan-Meier survival curve will be fit to 
only data from IRS. This will yield distinct survival estimates at every failure time, say, 
(𝑠𝑠(1), 𝑠𝑠(2), … , 𝑠𝑠(𝑖𝑖)) where 𝑖𝑖 is the number of failure times in the IRS. Then, take one 
minus each survival estimate and order from smallest to largest, 
𝑣𝑣 = (1 − 𝑠𝑠(1), 1 − 𝑠𝑠(2), … , 1 − 𝑠𝑠(𝑖𝑖)). 
Next, a random value 𝑢𝑢𝑗𝑗 is drawn from uniform distribution 𝑈𝑈(0,1) (𝑗𝑗 = 1, … , 𝑚𝑚 ). 
Specifically, if 𝑢𝑢 <= 1 − 𝑠𝑠(𝑖𝑖), then the survival time corresponding to the smallest value 
of 𝑣𝑣 that is larger than u is imputed and the indicator for this observation will be marked as 
censored. 
For example, if 1 − 𝑠𝑠(4) < 𝑢𝑢 < 1 − 𝑠𝑠(5), then the value being imputed for 𝑇𝑇𝑗𝑗 will be 
survival time associated with 𝑠𝑠(5), the fifth largest survival estimate. 
Ties don’t affect the imputed value since they have the same survival estimate. 
If 𝑢𝑢 > 1 − 𝑠𝑠(𝑖𝑖), then the survival time associated with the largest survival estimate 𝑠𝑠(1) 
is imputed and marked as “censored” observation ( not really censored but because the 
observation was used to impute, it will not be used in KM estimates at later times). 
The imputation procedure for censored 𝑇𝑇𝑗𝑗, 𝑗𝑗 = 1, … , 𝑚𝑚 ends when either all remaining 
survival times are “censored” observations or patient 𝑚𝑚 at time Tm is reached. When the 
procedure is terminated because only “censored” observations remain, and not all censored 
𝑇𝑇𝑗𝑗 are imputed, then these remaining censored observations will have their survival time 
imputed as largest survival in the dataset , 𝑇𝑇𝑚𝑚. If Tm is the largest censored time then no 
imputation occurs for that because there is no IRS for this 𝑇𝑇. 
Step 4: 
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Repeat steps 1-3 independently to create 1,000 imputed datasets for each of the 35 
combinations of 𝜏𝜏 and 𝑘𝑘 where each of the imputed datasets is the result of a bootstrap 
resampling process. 
Step 5: 
Compute the Gehan scores for all 35,000 datasets. 
Step 6: 
Analyze each dataset using the same mixed model as for primary analysis. 
Step 7: 
Combine the results from the 1,000 datasets with the same 𝜏𝜏 and 𝑘𝑘 using Rubin’s method 
from PROC MIANALYZE, and do it for each of the 35 combinations of 𝜏𝜏 and 𝑘𝑘. 
9.2. 
Definitions and Programming Conventions 
9.2.1. Algorithms Deriving Time-to-Event Endpoints 
Many time-to-event endpoints specified in this SAP encompass symptom assessments, 
usage of conventional medications, second IMP administration, or study discontinuation. 
This section outlines the algorithms that manage these situations collectively. 
For time-to event endpoints measuring symptom improvement (e.g., time to beginning of 
symptom relief, time to first incidence of decrease in PGI-S, etc.), the following algorithm 
will be followed to determine if an attack met the event or should be censored. Note: for 
the supplementary analysis right-censoring conventional medication use at the time of use, 
the censoring rule used in these algorithms will be changed accordingly. 
1. First, in the case of derivable time-to-event results, the attack will be treated as 
achieving the event if the symptom assessments are consistent with the event 
condition (unless the condition in 2) is met), or right-censored at the end of analysis 
window if it did not achieve the event. 
2. Second, if the attack was treated with conventional attack treatment within the 
analysis window and prior to the achievement of an event, then the attack will be 
treated as right-censored at the end of analysis window. 
3. Third, in the case of underivable time-to-event results, but a conventional 
medication was taken within the analysis window, the attack will be right-censored 
at the end of analysis window. 
4. Fourth, in the case of underivable time-to-event results, and no conventional 
medication was taken within the analysis window, the attack will be censored at 0 
hour. 
5. Fifth, In the case of discontinuation that prevented event occurrence within the 
analysis window, the attack will be censored at the time of discontinuation (taken 
from last assessment done during the end of study visit). 
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For time-to-event endpoints measuring symptom worsening (e.g., time to PGI-C ‘a little 
worse’ for two time points in a row, etc.), the following algorithm will be followed to 
determine if an attack met the event or should be censored: 
1. First, in the case of derivable time-to-event results, the attack will be treated as 
achieving the event if the symptom assessments are consistent with the event 
condition (unless the condition in 2) is met), or right-censored at 12 hours if it did 
not achieve the event. 
2. Second, if the attack was treated with conventional attack treatment within the 
analysis window and prior to the achievement of an event, then the attack will be 
treated as achieving the event at the time of conventional medication use. 
3. Third, in the case of underivable time-to-event results, but a conventional 
medication was taken within the analysis window, the attack will be treated as 
achieving the event at the time of conventional medication use. 
4. Fourth, in the case of underivable time-to-event results, and no conventional 
medication was taken within the analysis window, the attack will be censored at 0 
hour. 
5. Fifth, In the case of discontinuation that prevented event occurrence within the 
analysis window, the attack will be censored at the time of discontinuation (taken 
from last assessment done during the end of study visit). 
For the ‘time to the second IMP administration’ endpoint, the following algorithm will be 
followed to determine if an attack met the event or should be censored: 
1. First, the attack will be treated as achieving the event if the event condition is met 
(unless the condition in 2) is met), or right-censored at the end of analysis window 
if the event condition is not met. 
2. Second, if the attack was treated with conventional attack treatment within the 
analysis window and prior to the achievement of an event, then the attack will be 
treated as right-censored at the time of conventional medication use. 
3. Third, In the case of discontinuation that prevented event occurrence within the 
analysis window, the attack will be censored at the time of discontinuation (taken 
from last assessment done during the end of study visit). 
9.2.2. Handling of Conventional Medications with Missing Time in Time-to-
Event Analyses 
In time-to-event endpoint analyses, unless otherwise specified, time-to-event for an attack 
with conventional medication use during the analysis window will be right censored at the 
end of analysis window. In some cases, the time of conventional medication use was 
missing, while only the date of conventional medication use was available. These cases 
will be handled conservatively by assuming the conventional medication was used at the 
end of the analysis window, as reasonable. For example, for an endpoint with a 12-hour 
analysis window, if the conventional medication with missing time was taken on the same 
day of the first IMP dosing, or if the conventional medication with missing time was taken 
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on the next day of the first IMP dosing, but the first IMP dosing occurred after 12 pm, then 
the conventional medication will be considered as occurring at the time point of 12-hour 
post-dose. 
For the sensitivity analyses censoring conventional medication use at the time of use, 
conventional medications with missing time will be consistently right-censored at the end 
of analysis window, as reasonable. 
In cases where the occurrence of conventional medication use is the event of interest (e.g. 
time to first incidence of conventional medication use within 12 or 24 hours), instances 
where the exact timing of medication usage is missing are treated as if they happened at the 
end of the analysis window, as reasonable. 
9.2.3. Handling of Duplicate Records 
Duplicate assessments exist for a subset of nominal time points in some patients. These 
duplicate records were kept in the database to maintain study integrity. Statistical analysis 
will be made using the first record (as determined by the collection timestamp) if duplicate 
records exist for a nominal time point. All other duplicate records will be presented in 
listings. 
9.2.4. Handling of Events Achieved after Endpoint Analysis Window 
Actual assessment time will be used in calculating time-to-event results. When a qualifying 
attack achieves an endpoint at the last assessment time point, this data handling approach 
may result in a time-to-event that is achieved after the end of the endpoint analysis window 
(12, 24, or 48 hours depending on the endpoint). For example, an attack may achieve onset 
of symptom relief at 12.3 hours for an endpoint with a 12-hour assessment window. In 
order to correctly assess the survival results, time-to-event results in such cases will be set 
to the end of endpoint analysis window (12, 24, or 48 hours) in summary statistics and 
statistical modeling. Original time-to-event results will be presented in listings. 
9.2.5. Defining Prophylactic Treatment Status 
The On Demand or On Prophylactic Treatment subgroups will be defined based on data 
collected on HAE History CRF page. 
The On Demand, On Kallikrein Prophylactic Treatment, or On Other Prophylactic 
Treatment subgroups will be defined based on data collected on both HAE History CRF 
page and Concomitant Medication CRF page. See Table 5 for details. 
Table 5. Algorithms Deriving Prophylactic Treatment Status 
Subgroups 
Algorithms 
On Demand 
Patients with ‘On demand only’ selected for the ‘Treatment 
Regimen at Screening Visit’ question in the HAE History page. 
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On Kallikrein 
Prophylactic 
Treatment 
Patients with ‘’Prophylaxis’ selected for the ‘Treatment 
Regimen at Screening Visit’ question in the HAE History page 
and with lanadelumab or berotralstat medication reported on 
the Concomitant Medication page. 
On Other 
Prophylactic 
Treatment 
Patients with ‘’Prophylaxis’ selected for the ‘Treatment 
Regimen at Screening Visit’ question in the HAE History page 
and without lanadelumab or berotralstat medication reported 
on the Concomitant Medication page. 
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9.3. 
Schedule of trial Procedures 
Table 6. 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 
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Visit 
PGI-Cr 
VASr 
GA-NRSr 
Concomitant Medication Review 
Screening Randomizationa 
Treatment Period 
2nd 
3rd 
1st eligible 
HAE 
eligible 
eligible 
attackb 
HAE 
HAE 
attackb 
attackb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Visit/ETc 
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 early termination, the patient should return to the clinic as soon as possible within 1 week for the final visit. 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 a 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. 
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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 7. 
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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Table 7. Frequency of Patient Assessment 
Time Period following the 
First IMP Administration 
Frequency of Patient 
Assessment a 
Time Window for 
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 
the first dose of IMP 
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