Phase 1 Crossover Study in Healthy Subjects to Evaluate the PK Profile of KVD824 Following Single and Multiple Doses of Modified Release (MR) Formulations

Phase 1

Completed

• Conditions: Hereditary Angioedema
• Interventions: Drug: KVD824 Prototype 1 modified-release tablet; Drug: KVD824 Prototype 2 modified-release tablet; Drug: Placebo to KVD824 Prototype 1; Drug: KVD824 Immediate-Release Capsule; Drug: KVD824 Prototype 3 modified-release tablet

• Registration Number: NCT05118958
• Lead Sponsor: KalVista Pharmaceuticals, Ltd.

Brief Summary

This is a 3 part, phase 1 crossover study in healthy subjects to evaluate the pharmacokinetic profile of KVD824 following single and multiple doses of novel KVD824 modified-release formulations compared with a reference KVD824 immediate release formulation.

Detailed Description

Part 1 of the study was a single-centre, open-label, non-randomised, 6-period crossover study designed to investigate the PK and safety of KVD824 MR prototype formulations (with or without an additional KVD824 IR capsule) compared to a reference KVD824 IR capsule formulation in healthy male and female subjects. Part 2 was an optional part designed to investigate the PK and safety of a selected KVD824 MR prototype tablet formulation (with or without an additional KVD824 IR capsule) in healthy male and female subjects in both the fed and fasted state. Note: this Part was not conducted as sufficient information on food effect was collected in the other Parts of the study.

Part 3 was a single-centre, randomised, double-blind, placebo-controlled, multiple dose group study to investigate the PK and safety of a selected KVD824 MR prototype tablet formulation (with or without an additional KVD824 IR capsule) in healthy male and female subjects. Part 3 started following completion of Part 1.

Study Timeline

• Study Start: 2020-05-19
• Primary Completion: 2020-12-01
• Study Completion: 2020-12-01
• Study First Submitted: 2021-10-26
• Status Verified: 2021-11
• Study First Submitted QC: 2021-11-03
• Last Update Submitted: 2021-11-03
• Study First Posted: 2021-11-12
• Last Update Posted: 2021-11-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 37

Inclusion Criteria

1. Healthy males or non-pregnant, non-lactating healthy females.
2. Aged 18 to 55 years, inclusive at the time of signing informed consent.
3. Body mass index (BMI) of 18.0 to 32.0 kg/m2 as measured at screening.
4. Must be willing and able to communicate and participate in the whole study.
5. Must provide written informed consent.
6. Must agree to adhere to the contraception requirements.

Read More

Exclusion Criteria

1. Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1.
2. Subjects who are study site employees, sponsor employees, or immediate family members of site or sponsor employees.
3. Subjects who have previously been administered IMP in this study. Subjects who have taken part in one part of this study are not permitted to take part in any other study part.
4. History of any drug or alcohol abuse in the past 2 years.
5. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type).
6. A confirmed positive alcohol breath test at screening or admission.
7. Current smokers and those who have smoked within the last 12 months. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission.
8. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
9. Females of childbearing potential who are pregnant or lactating (all female subjects must have a negative serum pregnancy test at screening and urine pregnancy test on admission).
10. Subjects with pregnant or lactating partners.
11. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening.
12. Clinically significant abnormal clinical chemistry, haematology, coagulation or urinalysis as judged by the investigator. Subjects with Gilbert's Syndrome are allowed.
13. Confirmed positive drugs of abuse test result.
14. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results.
15. Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance of <70 mL/min using the Cockcroft-Gault equation.
16. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
17. Subjects with a history of cholecystectomy or gall stones.
18. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
19. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active.
20. Donation or loss of greater than 400 mL of blood within the previous 3 months.
21. Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies (other than up to 4 g of paracetamol per day, HRT or hormonal contraception) in the 14 days before IMP administration.
22. Failure to satisfy the investigator of fitness to participate for any other reason.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Part 3 - KVD824 Prototype 1 600 mg (multiple dose fed)	KVD824 Prototype 1 modified-release tablet	600 mg (2 x 300 mg) KVD824 prototype 1 modified-release tablet dosed orally twice daily in fed state for 13 days with a single dose on day 14.
Part 1 - Period 3 - Prototype 2 600 mg (single dose fasted)	KVD824 Prototype 2 modified-release tablet	600 mg (2 x 300 mg) KVD824 prototype 2 modified-release tablet dosed orally in fasted state as a single dose
Part 1 - Period 4 - Prototype 1 900 mg (single dose fasted)	KVD824 Prototype 1 modified-release tablet	900 mg (3 x 300 mg) KVD824 prototype 1 modified-release tablet dosed orally in fasted state as a single dose
Part 1 - Period 6 - Prototype 1 900 mg (single dose fed)	KVD824 Prototype 1 modified-release tablet	900 mg (3 x 300 mg) KVD824 prototype 1 modified-release tablet dosed orally in fed state as a single dose
Part 3 - KVD824 Prototype 1 900 mg (multiple dose fed)	KVD824 Prototype 1 modified-release tablet	900 mg (3 x 300 mg) KVD824 prototype 1 modified-release tablet dosed orally twice daily in fed state for 13 days with a single dose on day 14.
Part 1 - Period 1 - Prototype 1 600 mg (single dose fasted)	KVD824 Prototype 1 modified-release tablet	600 mg (2 x 300 mg) KVD824 prototype 1 modified-release tablet dosed orally in fasted state as a single dose
Part 1 - Period 5 - Prototype 1 600 mg and Prototype 3 300 mg (single dose fasted)	KVD824 Prototype 3 modified-release tablet	600 mg (2 x 300 mg) KVD824 prototype 1 modified-release tablet plus 300 mg (1 x 300 mg) Prototype 3 dosed orally in fasted state as a single dose
Part 3 - Placebo to KVD824 Prototype 1 900 mg (multiple dose fasted)	Placebo to KVD824 Prototype 1	Placebo to 900 mg KVD824 prototype 1 modified-release tablet dosed orally twice daily in fasted state for 13 days with a single dose on day 14.
Part 1 - Period 2 - KVD824 IR Capsule 600 mg (single dose fasted)	KVD824 Immediate-Release Capsule	600 mg (2 x 300 mg) KVD824 immediate release Capsule dosed orally in fasted state as a single dose
Part 1 - Period 5 - Prototype 1 600 mg and Prototype 3 300 mg (single dose fasted)	KVD824 Prototype 1 modified-release tablet	600 mg (2 x 300 mg) KVD824 prototype 1 modified-release tablet plus 300 mg (1 x 300 mg) Prototype 3 dosed orally in fasted state as a single dose
Part 3 - KVD824 Prototype 1 900 mg (multiple dose fasted)	KVD824 Prototype 1 modified-release tablet	900 mg (3 x 300 mg) KVD824 prototype 1 modified-release tablet dosed orally twice daily in fasted state for 13 days with a single dose on day 14.
Part 3 - Placebo to KVD824 Prototype 1 600 mg (multiple dose fed)	Placebo to KVD824 Prototype 1	Placebo to 600 mg KVD824 prototype 1 modified-release tablet dosed orally twice daily in fed state for 13 days with a single dose on day 14.
Part 3 - Placebo to KVD824 Prototype 1 900 mg (multiple dose fed)	Placebo to KVD824 Prototype 1	Placebo to 900 mg KVD824 prototype 1 modified-release tablet dosed orally twice daily in fed state for 13 days with a single dose on day 14.

Primary Outcome Measures

Name	Time	Method
Pharmacokinetics - Cmax	Days 1, 10 and 14	Maximum observed concentration after single and multiple doses of KVD824 with and without food
Pharmacokinetics - Ctrough	Days 2-14	Concentration prior to the morning dose on Days 2-14 and prior to the evening dose on Days 2-13
Pharmacokinetics - T1/2	Days 1, 10 and 14	Terminal elimination half-life after single and multiple doses of KVD824 with and without food
Pharmacokinetics - Lambda-z	Days 1, 10 and 14	First order rate constant associated with the terminal (log-linear) portion of the curve after single and multiple doses
Pharmacokinetics - Frel AUC(0-12)	Days 1, 10 and 14	Relative bioavailability based on AUC(0-12)
Pharmacokinetics - Tlag	Days 1, 10 and 14	Time prior to the first measurable concentration after single and multiple doses of KVD824
Pharmacokinetics - AUC(0-tau)	Days 1, 10 and 14	Area under the curve for the defined interval between doses (tau)
Pharmacokinetics - AUC(0-inf)/D	Days 1, 10 and 14	Area under the curve from time 0 extrapolated to infinity divided by dose
Pharmacokinetics - AUCextrap	Days 1, 10 and 14	Area under the curve from time of the last measurable concentration to infinity as a percentage of the area under the curve extrapolated to infinity
Pharmacokinetics - CL/F	Days 1, 10 and 14	Total body clearance calculated after a single extravascular administration where F (fraction of dose bioavailable) is unknown
Pharmacokinetics - Vz/Flau	Days 1, 10 and 14	Apparent volume of distribution based on the terminal phase calculated using AUC(0-tau) after extravascular administration where F (fraction of dose bioavailable) is unknown
Pharmacokinetics - AUC(0-24)/Dose	Days 1, 10 and 14	Area under the curve from time 0 to 24 hours post-dose divided by dose
Pharmacokinetics - AUC(0-last)	Days 1, 10 and 14	Area under the curve from time 0 to the time of last measurable concentration after single and multiple doses
Pharmacokinetics - AUC(0-inf)	Days 1, 10 and 14	Area under the curve from time 0 extrapolated to infinity
Pharmacokinetics - AR Cmax	Days 1, 10 and 14	Accumulation ratio based on Cmax repeated dose/Cmax single dose
Pharmacokinetics - Tmax	Days 1, 10 and 14	Time of maximum observed concentration after single and multiple doses of KVD824 with and without food
Pharmacokinetics - Cmax/Dose	Days 1, 10 and 14	Maximum observed concentration divided by dose
Pharmacokinetics - C12	Days 1, 10 and 14	Plasma concentration observed at time 12 h after single and multiple doses
Pharmacokinetics - Cmin	Days 2-14	Minimum observed concentration during the dosing interval (between dose time and dose time plus tau) after single and multiple doses of KVD824 with and without food
Pharmacokinetics - AUC(0-12)/Dose	Days 1, 10 and 14	Area under the curve from time 0 to 12 hours post-dose divided by dose
Pharmacokinetics - AUC(0-24)	Days 1, 10 and 14	Area under the curve from time 0 to 24 hours post-dose after single and multiple doses
Pharmacokinetics - Frel Cmax	Days 1, 10 and 14	Relative bioavailability based on Cmax
Pharmacokinetics - C24	Days 1, 10 and 14	Plasma concentration observed at time 24 h after single and multiple doses
Pharmacokinetics - Cavg	Days 2-14	Average concentration (AUC(0-tau)/tau)
Pharmacokinetics - AUC(0-12)	Days 1, 10 and 14	Area under the curve from time 0 to 12 hours post-dose after single and multiple doses
Pharmacokinetics - AUC(0-last)/Dose	Days 1, 10 and 14	Area under the curve from time 0 to the time of last measurable concentration divided by dose
Pharmacokinetics - CL/Ftau	Days 1, 10 and 14	Total body clearance calculated using AUC(0-tau) after repeated extravascular administration, where F (fraction of dose bioavailable) is unknown
Pharmacokinetics - Vz/F	Days 1, 10 and 14	Apparent volume of distribution based on the terminal phase calculated using AUC(0-inf) after a single extravascular administration where F (fraction of dose bioavailable) is unknown
Pharmacokinetics - Fluctuation	Days 1, 10 and 14	Peak to trough fluctuation (Cmax-Cmin)/Cavg × 100
Pharmacokinetics - Frel AUC(0-inf)	Days 1, 10 and 14	Relative bioavailability based on AUC(0-inf)

Secondary Outcome Measures

Name	Time	Method
Safety - Vital Signs	Throughout the trial to last visit (up to 14 days)	Number of participants with clinically significant changes in vital signs
Safety - Laboratory Assessments	Throughout the trial to last visit (up to 14 days)	Number of participants with clinically significant changes in laboratory assessments
Safety - Serious Adverse Events	Change from pre-dose to last visit (up to 14 days)	Number of Subjects with Serious Adverse Events
Safety - Adverse Events	Change from pre-dose to last visit (up to 14 days)	Number of Subjects with Adverse Events
Safety - ECG	Throughout the trial to last visit (up to 14 days)	Number of participants with clinically significant changes in electrocardiogram (ECG) measurements

Trial Locations

Locations (1)

KalVista Investigative Site; 🇬🇧 Nottingham, United Kingdom