A Phase III, Crossover Trial Evaluating the Efficacy and Safety of KVD900 for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE)

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Hereditary Angioedema

Intervention / Treatment
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* Drug: Placebo
* Drug: KVD900 600 mg
* Drug: KVD900 300 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients 12 years of age and older. Confirmed diagnosis of HAE type I or II at any time in the medical history. Patient has access to and ability to use conventional on-demand treatment for HAE attacks. If a patient is receiving long-term prophylactic treatment with one of the protocol-allowed therapies, they must be 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. Patient's last dose of attenuated androgens other than danazol was at least 28 days prior to randomization. Patient: has had at least 2 documented HAE attacks within 3 months prior to screening or randomization; or 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 Patients must meet the contraception requirements. Patients must be able to swallow trial tablets whole. 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). Investigator believes that the patient is willing and able to adhere to all protocol requirements. Patient provides signed informed consent or assent (when applicable). A parent or legally authorized representative (LAR) must also provide signed informed consent when required. Exclusion Criteria: 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. 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. Use of angiotensin-converting enzyme (ACE) inhibitors after the Screening Visit or within 7 days prior to randomization. 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. Patients who require sustained use of strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers. Inadequate organ function, including but not limited to: Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) Aspartate aminotransferase (AST) >2x ULN Bilirubin direct >1.25x ULN International normalized ratio (INR) >1.2 Clinically significant hepatic impairment defined as a Child-Pugh B or C 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. History of substance abuse or dependence that would interfere with the completion of the trial, as determined by the Investigator. Known hypersensitivity to KVD900 or placebo or to any of the excipients. Prior participation in trial KVD900-201. Participation in any gene therapy treatment or trial for HAE. 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. Any pregnant or breastfeeding patient.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo to KVD900 Tablet<br>|
| Experimental: KVD900 600 mg<br> | Drug: KVD900 600 mg<br>* KVD900 Tablet 600 mg (2 x 300 mg)<br>|
| Experimental: KVD900 300 mg<br> | Drug: KVD900 300 mg<br>* KVD900 Tablet 300 mg (1 x 300 mg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to beginning of symptom relief Patient Global Impression of Change (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 investigational medicinal product (IMP) administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first incidence of decrease from baseline Patient Global Impression of Severity (PGI-S) (2 time points in a row) |  | within 12 hours of the first IMP administration. | 
| Time to HAE attack resolution (PGI-S) | Time to HAE attack resolution defined as none | within 24 hours of the first IMP administration. | 
| Proportion of attacks with beginning of symptom relief (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. | 
| Time to at least better (2 time points in a row) (PGI-C) |  | within 12 hours of the first IMP administration. | 
| Time to first incidence of decrease from baseline (2 time points in a row) (PGI-S) |  | within 24 hours of the first IMP administration. | 
| Time to at least a 50% decrease from baseline (3 time points in a row) Composite Visual Analogue Scale (VAS) |  | within 12 hours and within 24 hours of the first IMP administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KONFIDENT