A study to evaluate if different doses of KVD900 are safe and effective in treating attacks in patients with hereditary angioedema

ISRCTN	ISRCTN14762022
DOI	https://doi.org/10.1186/ISRCTN14762022
EudraCT/CTIS number	2021-001226-21
IRAS number	1004998
ClinicalTrials.gov number	NCT05259917
Secondary identifying numbers	KVD900-301, IRAS 1004998, CPMS 51516

Submission date: 22/03/2022
Registration date: 16/09/2022
Last edited: 10/06/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Haematological Disorders

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Hereditary angioedema is a disorder characterized by recurrent episodes of severe swelling (angioedema). The most common areas of the body to develop swelling are the limbs, face, intestinal tract, and airway.
This study is being done to understand how well KVD900 300 mg or KVD900 600 mg works against placebo to bring relief from an attack of hereditary angioedema (HAE).

Who can participate?
Approximately 114 patients with HAE Type I or II will be enrolled into the trial. Patients will be enrolled from several different countries.

What does the study involve?
In this study every patient will treat one attack with 300 mg KVD900, one attack with 600 mg of KVD900 and one attack with placebo. The order the patients use the treatments will be assigned by chance. During each treated attack the patients will answer several questions regarding their symptoms during the course of the treatment.
Participants will be asked to attend the site approximately for 2 visits and have 4 tele visits. It is anticipated that it will take approximately 25 weeks for each patient to complete the screening assessments and treat 3 eligible attacks. In addition to the questions regarding the HAE attack symptoms and effectiveness of the treatments, patients will undergo routine safety assessments, such as laboratory assessments and physicals.

What are the possible benefits and risks of participating?
Benefits:
Taking part in this study may or may not help to treat HAE. Participants' health could improve, stay the same, or get worse. However, the data we get during this study may help doctors learn more about the study drug and the disease and this may help future patients with HAE.
Risks:
KalVista is still building its knowledge about the safety of KVD900. The study drug has so far only been used in small groups of healthy people and patients with HAE, therefore some side effects are not yet known. The most common side effect experienced to date has been a headache.

Where is the study run from?
Barts Health NHS Trust
Leeds Teaching Hospitals NHS Trust
Frimley Health NHS Trust
University Hospitals Birmingham NHS Foundation Trust
Cardiff and Vale University Health Board

When is the study starting and how long is it expected to run for?
January 2022 to December 2023

Who is funding the study?
KalVista Pharmaceuticals Ltd (UK)

Who is the main contact?
Dr Sorena Kiani-Alikhan, skiani@nhs.net

Study website

Contact information

Mr Michael Smith
Scientific

KalVista Pharmaceuticals Ltd
Porton Science Park
Bybrook Road
Porton Down
Salisbury
SP4 0BF
United Kingdom

Phone	+18018597818
Email	mds@kalvista.com

Dr Sorena Kiani-Alikhan
Principal Investigator

Royal Free London NHS Foundation Trust
Royal Free Hospital
Pond Street
London
NW3 2QG
United Kingdom

Phone	+44 20 7794 0500 Ext: 34906
Email	skiani@nhs.net

Study information

Study design	Interventional double-blind randomized cross-over placebo-controlled trial
Primary study design	Interventional
Secondary study design	Randomised cross over trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a participant information sheet
Scientific 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
Study acronym	KONFIDENT
Study objectives	To demonstrate the clinical efficacy of KVD900 compared with placebo for the on-demand treatment of HAE attacks. To investigate the safety and tolerability of KVD900.
Ethics approval(s)	Approved 16/05/2022, West of Scotland REC1 (West of Scotland Research Ethics Service, Ward 11, Dykebar Hospital, Grahamston Road, Paisley, PA2 7DE, UK; +44 (0)141 3140213; WoSREC1@ggc.scot.nhs.uk),), ref: 22/WS/0042
Health condition(s) or problem(s) studied	Hereditary angioedema (HAE) type I or type II.
Intervention	Patients will be assigned to receive 3 treatments in randomized, double-dummy 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.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase III
Drug / device / biological / vaccine name(s)	KVD900, sebetralstat
Primary outcome measure	PGI C: Time to beginning of symptom relief defined as at least “a little better” (2 timepoints in a row) within 12 hours of the first IMP administration.
Secondary outcome measures	Current secondary outcome measures as of 26/10/2023: 1. PGI-S: Time to first incidence of decrease from baseline (2 time points in a row) within 12 hours of the first IMP administration. 2. PGI-S: Time to HAE attack resolution defined as “none” within 24 hours of the first IMP administration 3. 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 4. PGI:C Time to at least "better" (2 time points in a row) within 12 hours of the first IMP administration. 5. PGI:S: Time to first incidence of decrease from baseline (2 time points in a row) within 24 hours of the first IMP administration. 6. 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 _____ Previous secondary outcome measures: 1. PGI-S: Time to first incidence of decrease from baseline within 12 hours of the first IMP administration 2. PGI-S: Time to HAE attack resolution defined as “none” within 24 hours of the first IMP administration 3. 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 4. PGI-C: Time to at least "better" within 12 hours of the first IMP administration 5. PGI-S: Time to first incidence of decrease from baseline within 24 hours of the first IMP administration 6. 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
Overall study start date	20/01/2022
Completion date	31/12/2023

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	12 Years
Sex	Both
Target number of participants	114
Total final enrolment	136
Key inclusion criteria	Current inclusion criteria as of 26/10/2023: 1. Male or female patients 12 years of age and older with a weight of >30 kg 2. Confirmed diagnosis of HAE type I or II at any time in the medical history. 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 be on a stable dose and regimen for at least 3 months prior to the Screening Visit and be willing to remain on a stable dose and regimen for the duration of the trial. 5. Patient’s last dose of attenuated androgens was at least 28 days prior to randomization. 6. Patient: 6.1. Has had a least two documented HAE attacks within 3 months prior to screening or randomisation; or 6.2. Is a completer of the KVD824-201 trial within 3 months prior to randomization and meets all other entry criteria to enroll in KVD900-301.7. Patients must meet the contraception requirements. 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 (LAR) must also provide signed informed consent when required. _____ Previous inclusion criteria as of 04/11/2022: 1. Male or female patients 12 years of age and older with a weight of >30kg 2. Confirmed diagnosis of HAE type I or II at any time in the medical history. 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 be on a stable dose and regimen for at least 3 months prior to the Screening Visit and be willing to remain on a stable dose and regimen for the duration of the trial. 5. Patient’s last dose of attenuated androgens was at least 28 days prior to randomization. 6. Patient: 6.1. Has had at least two documented HAE attacks within 3 months prior to randomization; or 6.2. Is a completer of the KVD824-201 trial within 3 months prior to randomization and meets all other entry criteria to enroll in KVD900-301.7. Patients must meet the contraception requirements. 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 (LAR) must also provide signed informed consent when required. _____ Previous inclusion criteria: 1. Male or female patients 12 years of age and older with a weight of >30kg 2. Confirmed diagnosis of HAE type I or II at any time in the medical history. 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 these medicines indicated for HAE: intravenous (iv) or sc plasma-derived C1-INH, and/or lanadelumab, they must be on a stable dose and regimen for at least 3 months prior to the Screening Visit and be willing to remain on a stable dose and regimen for the duration of the trial. 5. Patient’s last dose of attenuated androgens was at least 28 days prior to randomization. 6. Patient has had at least 2 documented HAE attacks within 3 months prior to randomization. 7. Patients must meet the contraception requirements. 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 (LAR) must also provide signed informed consent when required.
Key exclusion criteria	Current exclusion criteria as of 04/11/2022: 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. 6. Inadequate organ function, including but not limited to: 6.1. Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) 6.2. Aspartate aminotransferase (AST) >2x ULN 6.3. Bilirubin direct >1.25x ULN 6.4. International normalized ratio (INR) >1.2 6.5. 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 the investigational drug prior to screening. 13. Any pregnant or breastfeeding patient. _____ Previous 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. Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors and inducers during participation in the trial, starting within 5 half-lives of the Screening Visit. 6. Inadequate organ function, including but not limited to: 6.1. Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) 6.2. Aspartate aminotransferase (AST) >2x ULN 6.3. Bilirubin direct >1.25x ULN 6.4. International normalized ratio (INR) >1.2 6.5. 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, including an investigational COVID-19 vaccine trial, within 4 weeks of the last dosing of the investigational drug prior to screening. 13. Any pregnant or breastfeeding patient.
Date of first enrolment	23/02/2022
Date of final enrolment	11/08/2023

Locations

Countries of recruitment

Australia
Bulgaria
Canada
France
Germany
Greece
Hungary
Israel
Italy
Japan
Netherlands
New Zealand
North Macedonia
Poland
Portugal
Romania
Slovakia
Spain
United Kingdom
United States of America

Study participating centres

Barts Health NHS Trust

The Royal London Hospital
Whitechapel Road
London
E1 1FR
United Kingdom

Frimley Health NHS Trust

Frimley Park Hospital
Portsmouth Road
Camberley
GU16 7UJ
United Kingdom

Leeds Teaching Hospital NHS Trust

St James's University Hospital
Beckett Street
Leeds
LS7 9AP
United Kingdom

University Hospitals Birmingham NHS Foundation Trust

Birmingham Heartlands Hospital
Bordesley Green East
Birmingham
B15 2GW
United Kingdom

Cardiff and Vale University Health Board

Cardiff and Vale UHB Headquarters
University Hospital of Wales (UHW)
Heath Park
Cardiff
Cardiff
CF14 4XW
United Kingdom

Sponsor information

KalVista Pharmaceuticals Ltd
Industry

Porton Science Park
Bybrook Road
Porton Down
Salisbury
SP4 0BF
United Kingdom

Phone	+44 1980 753 002
Email	clinicalstudies@kalvista.com

Funders

Funder type

Industry

KalVista Pharmaceuticals Ltd

No information available

Results and Publications

Intention to publish date	30/06/2024
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
Publication and dissemination plan	Peer reviewed scientific journals Internal report Conference presentation Publication on website Submission to regulatory authorities The sponsor is committed to responsible sharing of clinical data with the goal of advancing medical science and improving patient care. A description of this study will be available at http://www.ClinicalTrials.gov. This website will not include information that can identify participants. At the most, the website will include a summary of the results. This can be searched for and accessed at any time. A brief report of this study will be available at https://clinicaltrialsregister.eu .In addition, the study will be available on the United Kingdom clinical trial registry. These websites will not include data that can identify participants. They will include a scientific report of the results of the study. These websites can be searched for at any time by searching 2021-001226-21 or the protocol number KVD900-301. After this study is over, a brief report of the overall results will be prepared for the general public. The study results may also be shared with scientific journals and the scientific community. Whenever the results of the study are shared or published, participants identity will remain private.
IPD sharing plan	Current IPD sharing statement as of 03/03/2023: The datasets generated during the KVD900 (sebetralstat) trials are not expected to be made available due to the stage of development (i.e., pre-marketing authorization) and to ensure the protection of individual patient data. Due to the rarity of the disease, it may be possible to link anonymized patient data back to individual patients. Therefore, only aggregate data will be shared through regular publicly available methods (e.g., ClinicalTrials.gov, euclinicaltrials.eu, scientific publications). Previous IPD sharing statement: Independent researchers will be permitted to use anonymised data collected from participants during this study to conduct additional scientific research, which may be unrelated to the study medication. The data provided to external researchers will not include identifiable information. All data generated or analysed during this study will be included in the subsequent results publication

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No
Results article		31/05/2024	10/06/2024	Yes	No

Editorial Notes

10/06/2024: Publication reference added.
02/04/2024: The following changes were made to the study record:
1. Total final enrolment added.
2. The overall study end date was changed from 01/11/2023 to 31/12/2023.
3. The intention to publish date was changed from 01/05/2024 to 30/06/2024.
26/10/2023: The following changes were made to the trial record:
1. The contact details were changed.
2. The secondary outcome measures were changed.
3. The inclusion criteria were changed.
4. The recruitment end date was changed from 30/05/2023 to 11/08/2023.
5. The countries of recruitment Slovakia, North Macedonia were added.
6. The study participating centre Cardiff and Vale University Health Board was added.
03/03/2023: IPD sharing statement updated.
04/11/2022: The following changes were made to the trial record:
1. Trial website added.
2. The inclusion and exclusion criteria were updated.
3. Portugal and Japan were added to the countries of recruitment.
03/10/2022: Internal review.
20/05/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 20/05/2022.
22/03/2022: Trial's existence confirmed by NHS HRA.