A Phase II, Cross-over Clinical Trial Evaluating the Efficacy and Safety of KVD900 in the On-demand Treatment of Angioedema Attacks in Adult Subjects With Hereditary Angioedema Type I or II

Study Overview
=================
Brief Summary
-----------------
This study is a randomized, double-blind, placebo-controlled, phase II, cross-over clinical trial evaluating the efficacy and safety of KVD900, in the treatment of hereditary angioedema attacks in adult subjects.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled, Phase II, Cross-over Clinical Trial Evaluating the Efficacy and Safety of KVD900, an Oral Plasma Kallikrein Inhibitor, in the On-demand Treatment of Angioedema Attacks in Adult Subjects With Hereditary Angioedema Type I or II

Conditions
-----------------
Hereditary Angioedema

Intervention / Treatment
-----------------
* Drug: KVD900
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female adult subjects 18 years of age and older. Confirmed diagnosis of HAE type I or II at anytime in the medical history At least 3 documented HAE attacks in the past 93 days, as supported by medical history. Access to and ability to use conventional attack treatment for attacks of HAE Adequate organ functions Females of childbearing potential must agree to use highly effective birth control from the Screening visit until the end of the trial follow-up procedures. Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months, do not require contraception during the study Males with female partners of childbearing potential must agree to be abstinent or else use a highly effective method of birth control as defined in inclusion 6 from the Screening visit until the end of the trial follow-up procedures Provide signed informed consent and are willing and capable of complying with study requirements and procedures Exclusion Criteria: Any concomitant diagnosis of another form of chronic angioedema, such as acquired C1 inhibitor (C1-INH) deficiency, HAE with normal C1-INH (also known as HAE type III), idiopathic angioedema, or angioedema associated with urticaria Current use of C1INH, androgens, or tranexamic acid for HAE prophylaxis Use of angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 93 days prior to initial study treatment. Use of androgens (e.g. stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) or antifibrinolytics within 30 days prior to initial study treatment. Use of lanadelumab within 10 weeks prior to initial study treatment. Use of strong CYP3A4/CYP2C9 inhibitors and inducers during participation in the trial Clinically significant abnormal ECG at Visit 1 and pre-dose at Visit 2. This includes, but is not limited to, a QT interval by Fredericia, QTcF > 470 msec (for women) or > 450 msec (for men), a PR > 220 msec or ventricular and/or atrial premature contractions that are more frequent than occasional and/or occur as couplets or higher in grouping Any clinically significant history of angina, myocardial infarction, syncope, clinically significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or any other cardiovascular abnormality Any other systemic dysfunction (e.g., gastrointestinal, renal, respiratory, cardiovascular) or significant disease or disorder which, in the opinion of the Investigator, would jeopardize the safety of the subject by taking part in the trial History of substance abuse or dependence that would interfere with the completion of the study, as determined by the Investigator Known lactose allergy or intolerance Known hypersensitivity to KVD900 or placebo or to any of the excipients Participation in an interventional investigational clinical study within 93 days or within 5 half-lives of the last dosing of investigational drug (whichever is longer) prior to initial study treatment Any pregnant or breast-feeding subject

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br>Subjects received a single dose of 600 mg KVD900. | Drug: KVD900<br>* KVD900 tablet 600 mg<br>|
| Experimental: Part 2 - Sequence 1: 600 mg KVD900, Then Placebo<br>Subjects received a single dose of 600 mg KVD900 to treat the first eligible HAE attack. Following resolution of this attack, subjects received a second single dose of placebo to treat the second eligible HAE attack. | Drug: KVD900<br>* KVD900 tablet 600 mg<br>Other: Placebo<br>* KVD900-matched Placebo Tablet<br>|
| Experimental: Part 2 - Sequence 2: Placebo, Then 600 mg KVD900<br>Subjects received a single dose of placebo to treat the first eligible HAE attack. Following resolution of this attack, subjects received a second single dose of 600 mg KVD900 to treat the second eligible HAE attack. | Drug: KVD900<br>* KVD900 tablet 600 mg<br>Other: Placebo<br>* KVD900-matched Placebo Tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Conventional Attack Treatment Use Within 12 Hours of Study Drug (Full Analysis Set) | The primary variable for statistical comparison between treatments in Part 2 of the study was time to use of conventional attack treatment (pdC1INH or rhC1INH intravenous [iv] or icatibant) within 12 hours of study drug. Censoring occurs where a subject did not use conventional attack treatment within 12h post-study drug dosing. When an endpoint result was non-calculable (NC) within 12 hours, if the event did occur, the event must have occurred >12 hours following study drug. | 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of HAE Attacks That Worsen in Severity by One Level or More on the PGI-S or Require Conventional Attack Treatment Within 12 Hours of Study Drug (Full Analysis Set) | The proportion of participant's HAE attacks to either worsen in attack severity on the PGI-S by one level or more or conventional attack treatment (pdC1INH or rhC1INH intravenous [iv] or icatibant) use are listed with censored observations flagged. Frequencies (n, %) of subjects experiencing a worsening on the PGI-S by one level or more or using conventional attack treatment and the number censored are presented. Y Row indicates participants who experienced a worsening in severity, and the N Row indicates participants who did not. | 12 hours | 
| Time to Either Worsening in HAE Attack Severity by One Level or More on the PGI-S or to Conventional Attack Treatment Use Within 12 Hours of Study Drug (Full Analysis Set) | HAE attack severity assessed using the Patient Global Impression of Severity scale (PGI-S). Censoring occurs where a subject did not worsen in severity or use conventional attack treatment (pdC1INH or rhC1INH intravenous [iv] or icatibant) within 12h post-study drug dosing. When an endpoint result was non-calculable (NC) within 12 hours, if the event did occur, the event must have occurred >12 hours following study drug. | 12 hours | 
| Time to Symptom Relief Defined as HAE Attack Rated as A Little Better or Higher on the PGI-C for Two Consecutive Time Points Within 12 Hours of Study Drug (Full Analysis Set) | Change in HAE attack severity assessed using the Patient Global Impression of Change 7-point transition question (PGI-C). Censoring occurs where an attack rating of a little better or higher for two consecutive time points does not occur or conventional attack treatment is used within 12h post-study drug dosing. When an endpoint result was non-calculable (NC) within 12 hours, if the event did occur, the event must have occurred >12 hours following study drug. | 12 hours | 
| Time to Symptom Relief Defined as 50% Reduction in Composite VAS Score for Three Consecutive Time Points Within 12 Hours of Study Drug (Full Analysis Set) | The HAE attack symptoms were assessed on a 100 mm visual analogue scale (VAS) ranging from 0 (none) to 100 (very severe). The Composite VAS score is defined as the mean score across all symptoms. Censoring occurs where a ≥50% reduction in Composite VAS Score for three consecutive time points does not occur or conventional attack treatment is used within 12h post-study drug dosing. When an endpoint result was non-calculable (NC) within 12 hours, if the event did occur the event must have occurred >12 hours following study drug. | 12 hours |