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

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 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

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Drug: Placebo; Drug: KVD900 600 mg; Drug: KVD900 300 mg

• Study Type: Interventional
• Enrollment (Actual): 136
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Campbelltown, New South Wales, Australia, 2560
      • KalVista Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1431
    • KalVista Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M3B 3S6
      • KalVista Investigative Site
• France
  • Grenoble Cedex 9, France, 38043
    • KalVista Investigative Site
  • Lille, France, 59000
    • KalVista Investigative Site
  • Lille, France, 59037
    • KalVista Investigative Site
  • Paris, France, 75571
    • KalVista Investigative Site
• Germany
  • Berlin, Germany, 12203
    • KalVista Investigative Site
  • Mainz, Germany, 55131
    • KalVista Investigative Site
  • Mörfelden-Walldorf, Germany, 64546
    • KalVista Investigative Site
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • KalVista Investigative Site
• Greece
  • Athens, Greece, 11521
    • KalVista Investigative Site
  • Athens, Greece, 11527
    • KalVista Investigative Site
• Hungary
  • Budapest, Hungary, 1088
    • KalVista Investigative Site
• Israel
  • Haifa, Israel, 31048
    • KalVista Investigative Site
  • Petach Tikvah, Israel, 49202
    • KalVista Investigative Site
  • Ramat Gan, Israel, 52621
    • KalVista Investigative Site
  • Tel Aviv, Israel, 64239
    • KalVista Investigative Site
• Italy
  • Padova, Italy, 35128
    • KalVista Investigative Site
  • San Donato Milanese, Italy, 20097
    • KalVista Investigative Site
• Japan
  • Chiba-shi, Japan, 260-8677
    • KalVista Investgative Site
  • Gunma, Japan, 371-8511
    • KalVista Investigative Site
  • Hiroshima City, Japan, 730-8518
    • KalVista Investigative Site
  • Saitama, Japan, 340-0041
    • KalVista Investigative Site
  • Yokohama, Japan, 236-0004
    • KalVista Investigative Site
  • Osaka
    • Takatsuki-shi, Osaka, Japan, 569-8686
      • KalVista Investgative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • KalVista Investigative Site
• New Zealand
  • Auckland, New Zealand, 1023
    • KalVista Investigative Site
• North Macedonia
  • Skopje, North Macedonia, 1000
    • KalVista Investigative Site
• Poland
  • Białystok, Poland, 15-276
    • KalVista Investigative Site
  • Kraków, Poland, 31-503
    • KalVista Investigative Site
  • Łódź, Poland, 92-213
    • KalVista Investigative Site
• Portugal
  • Porto, Portugal, 4200-319
    • KalVista Investigative Site
• Puerto Rico
  • San Juan, Puerto Rico, 00918
    • KalVista Investigative Site
• Romania
  • Mureş
    • Sângeorgiu De Mureş, Mureş, Romania, 547530
      • KalVista Investigative Site
• Slovakia
  • Martin, Slovakia, 03659
    • KalVista Investigative Site
• Spain
  • Barcelona, Spain, 08035
    • KalVista Investigative Site
  • Barcelona, Spain, 08907
    • KalVista Investigative Site
  • Madrid, Spain, 28046
    • KalVista Investigative Site
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • KalVista Investigative Site
  • Cardiff, United Kingdom, CF14 4XW
    • KalVista Investigative Site
  • Frimley, United Kingdom, GU16 7UJ
    • KalVista Investigative Site
  • Leeds, United Kingdom, LS9 7TF
    • KalVista Investigative Site
  • London, United Kingdom, E1 1FR
    • KalVista Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • KalVista Investigative Site
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • KalVista Investigative Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • KalVista Investigative Site
  • California
    • San Diego, California, United States, 92122
      • KalVista Investigative Site
    • San Diego, California, United States, 92123
      • KalVista Investigative Site
    • Santa Monica, California, United States, 90404
      • KalVista Investigative Site
  • Colorado
    • Centennial, Colorado, United States, 80112
      • KalVista Investigative Site
    • Colorado Springs, Colorado, United States, 80907
      • KalVista Investigative Site
  • Florida
    • Tampa, Florida, United States, 33613
      • KalVista Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • KalVista Investigative Site
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • KalVista Investigative Site
  • Kentucky
    • Louisville, Kentucky, United States, 40215
      • KalVista Investigative Site
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • KalVista Investigative Site
  • Minnesota
    • Plymouth, Minnesota, United States, 55446
      • KalVista Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 61414
      • KalVista Investigative Site
  • New York
    • New York, New York, United States, 10029
      • KalVista Investigative Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28277
      • KalVista Investigative Site
  • Ohio
    • Toledo, Ohio, United States, 43617
      • KalVista Investigative Site
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • KalVista Investigative Site
  • Texas
    • Dallas, Texas, United States, 75231
      • KalVista Investigative Site
  • Utah
    • Layton, Utah, United States, 84041
      • KalVista Investigative Site
  • Washington
    • Spokane, Washington, United States, 99202
      • KalVista Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. has had at least 2 documented HAE attacks within 3 months prior to screening or randomization; or
  2. 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:

  1. Alanine aminotransferase (ALT) >2x upper limit of normal (ULN)
  2. Aspartate aminotransferase (AST) >2x ULN
  3. Bilirubin direct >1.25x ULN
  4. International normalized ratio (INR) >1.2
  5. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo to KVD900 Tablet
Experimental: KVD900 600 mg	Drug: KVD900 600 mg; KVD900 Tablet 600 mg (2 x 300 mg)
Experimental: KVD900 300 mg	Drug: KVD900 300 mg; KVD900 Tablet 300 mg (1 x 300 mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Beginning of Symptom Relief Patient Global Impression of Change (PGI-C)	The analysis of time to the beginning of symptom relief defined as at least "a little better" (2 time points in a row) on the PGI-C within 12 hours of the first IMP administration using the Gehan score transformation test for Full Analysis Set (FAS). Attacks were treated as right-censored at 12 hours if they did not achieve beginning of symptom relief defined by PGI-C as at least "a little better" (2 time points in a row) or received conventional attack treatment prior to time-to-event within 12 hours of the first IMP administration. When an endpoint result was non-evaluable (NE) within 12 hours, if the event did occur, the event must have occurred >12 hours following study drug.	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)	First incidence of decrease in attack severity at two time points in a row (with possible missing values in between) within 12 hours of the first IMP administration. Attacks were treated as right-censored at 12 hours if they did not have a decrease in PGI-S score from baseline for 2 time points in a row or received conventional attack treatment prior to time-to-event within 12 hours of the first IMP administration. When an endpoint result was non-evaluable (NE) within 12 hours, if the event did occur, the event must have occurred >12 hours following study drug.	Within 12 hours of the first IMP administration.
Time to Complete HAE Attack Resolution (PGI-S)	Time to complete HAE attack resolution defined as "none". Attacks were treated as right-censored at 24 hours if they did reach complete HAE attack resolution or received conventional attack treatment prior to time-to-event within 24 hours of IMP administration. When an endpoint result was non-evaluable (NE) within 24 hours, if the event did occur, the event must have occurred >24 hours following study drug.	Within 24 hours of the first IMP administration.

Collaborators and Investigators

• Sponsor: KalVista Pharmaceuticals, Ltd.
• Investigators: Study Director: Study Director, KalVista Pharmaceuticals, Ltd.

Publications and helpful links

General Publications

• Riedl MA, Farkas H, Aygoren-Pursun E, Psarros F, Soteres DF, Staevska M, Cancian M, Hagin D, Honda D, Melamed I, Savic S, Stobiecki M, Busse PJ, Dias de Castro E, Agmon-Levin N, Gower R, Kessel A, Kurowski M, Lleonart R, Grivcheva Panovska V, Wedner HJ, Audhya PK, Hao J, Iverson M, Smith MD, Yea CM, Lumry WR, Zanichelli A, Bernstein JA, Maurer M, Cohn DM; KONFIDENT Investigators. Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks. N Engl J Med. 2024 Jul 4;391(1):32-43. doi: 10.1056/NEJMoa2314192. Epub 2024 May 31.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2022
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: February 4, 2022
• First Submitted That Met QC Criteria: February 28, 2022
• First Posted (Actual): March 2, 2022

Study Record Updates

• Last Update Posted (Actual): May 2, 2025
• Last Update Submitted That Met QC Criteria: April 25, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: KONFIDENT; Sebetralstat
• Additional Relevant MeSH Terms: Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immunologic Deficiency Syndromes; Skin Diseases; Urticaria; Skin Diseases, Vascular; Angioedema; Angioedemas, Hereditary
• Other Study ID Numbers: KVD900-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will not be shared until all global regulatory filings are complete

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No