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

A Multiple Part, Phase 1 Crossover Study in Healthy Subjects to Evaluate the Pharmacokinetic (PK) Profile of KVD824 Following Single and Multiple Doses of Novel KVD824 Modified Release (MR) Formulations Compared to a Reference KVD824 Immediate Release (IR) Formulation

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.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Drug: KVD824 Prototype 1 modified-release tablet; Drug: KVD824 Prototype 2 modified-release tablet; Drug: KVD824 Prototype 3 modified-release tablet; Drug: Placebo to KVD824 Prototype 1; Drug: KVD824 Immediate-Release Capsule

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 Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom
    • KalVista Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 - Period 1 - Prototype 1 600 mg (single dose fasted); 600 mg (2 x 300 mg) KVD824 prototype 1 modified-release tablet dosed orally in fasted state as a single dose	Drug: KVD824 Prototype 1 modified-release tablet; 300 mg modified-release tablet
Experimental: Part 1 - Period 3 - Prototype 2 600 mg (single dose fasted); 600 mg (2 x 300 mg) KVD824 prototype 2 modified-release tablet dosed orally in fasted state as a single dose	Drug: KVD824 Prototype 2 modified-release tablet; 300 mg modified-release tablet
Experimental: Part 1 - Period 4 - Prototype 1 900 mg (single dose fasted); 900 mg (3 x 300 mg) KVD824 prototype 1 modified-release tablet dosed orally in fasted state as a single dose	Drug: KVD824 Prototype 1 modified-release tablet; 300 mg modified-release tablet
Experimental: Part 1 - Period 5 - Prototype 1 600 mg and Prototype 3 300 mg (single dose fasted); 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	Drug: KVD824 Prototype 1 modified-release tablet; 300 mg modified-release tablet; Drug: KVD824 Prototype 3 modified-release tablet; 300 mg modified-release tablet
Experimental: Part 1 - Period 6 - Prototype 1 900 mg (single dose fed); 900 mg (3 x 300 mg) KVD824 prototype 1 modified-release tablet dosed orally in fed state as a single dose	Drug: KVD824 Prototype 1 modified-release tablet; 300 mg modified-release tablet
Experimental: Part 3 - KVD824 Prototype 1 600 mg (multiple dose fed); 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.	Drug: KVD824 Prototype 1 modified-release tablet; 300 mg modified-release tablet
Placebo Comparator: Part 3 - Placebo to KVD824 Prototype 1 600 mg (multiple dose fed); 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.	Drug: Placebo to KVD824 Prototype 1; Placebo to 300 mg KVD824 Prototype 1 modified-release tablet
Experimental: Part 3 - KVD824 Prototype 1 900 mg (multiple dose fed); 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.	Drug: KVD824 Prototype 1 modified-release tablet; 300 mg modified-release tablet
Placebo Comparator: Part 3 - Placebo to KVD824 Prototype 1 900 mg (multiple dose fed); 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.	Drug: Placebo to KVD824 Prototype 1; Placebo to 300 mg KVD824 Prototype 1 modified-release tablet
Experimental: Part 3 - KVD824 Prototype 1 900 mg (multiple dose fasted); 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.	Drug: KVD824 Prototype 1 modified-release tablet; 300 mg modified-release tablet
Placebo Comparator: Part 3 - Placebo to KVD824 Prototype 1 900 mg (multiple dose fasted); 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.	Drug: Placebo to KVD824 Prototype 1; Placebo to 300 mg KVD824 Prototype 1 modified-release tablet
Active Comparator: Part 1 - Period 2 - KVD824 IR Capsule 600 mg (single dose fasted); 600 mg (2 x 300 mg) KVD824 immediate release Capsule dosed orally in fasted state as a single dose	Drug: KVD824 Immediate-Release Capsule; 300 mg immediate-release capsule

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: KalVista Pharmaceuticals, Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2020
• Primary Completion (Actual): December 1, 2020
• Study Completion (Actual): December 1, 2020

Study Registration Dates

• First Submitted: October 26, 2021
• First Submitted That Met QC Criteria: November 3, 2021
• First Posted (Actual): November 12, 2021

Study Record Updates

• Last Update Posted (Actual): November 12, 2021
• Last Update Submitted That Met QC Criteria: November 3, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary
• Other Study ID Numbers: KVD824-102

Drug and device information, study documents

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