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

Hereditary Angioedema Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05118958
• Other study ID #: KVD824-102
• Status: Completed
• Phase: Phase 1
• Start date: May 19, 2020
• Est. completion date: December 1, 2020

Study information

• Verified date: November 2021
• Source: KalVista Pharmaceuticals, Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: December 1, 2020
• Est. primary completion date: December 1, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Angioedema
• Hereditary Angioedema

Intervention

Drug:
• KVD824 Prototype 1 modified-release tablet
300 mg modified-release tablet
• KVD824 Prototype 2 modified-release tablet
300 mg modified-release tablet
• KVD824 Immediate-Release Capsule
300 mg immediate-release capsule
• Placebo to KVD824 Prototype 1
Placebo to 300 mg KVD824 Prototype 1 modified-release tablet
• KVD824 Prototype 3 modified-release tablet
300 mg modified-release tablet

Locations

Country	Name	City	State
United Kingdom	KalVista Investigative Site	Nottingham

Sponsors (1)

Lead Sponsor	Collaborator
KalVista Pharmaceuticals, Ltd.

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetics - Tlag	Time prior to the first measurable concentration after single and multiple doses of KVD824	Days 1, 10 and 14
Primary	Pharmacokinetics - Tmax	Time of maximum observed concentration after single and multiple doses of KVD824 with and without food	Days 1, 10 and 14
Primary	Pharmacokinetics - Cmax	Maximum observed concentration after single and multiple doses of KVD824 with and without food	Days 1, 10 and 14
Primary	Pharmacokinetics - Cmax/Dose	Maximum observed concentration divided by dose	Days 1, 10 and 14
Primary	Pharmacokinetics - C12	Plasma concentration observed at time 12 h after single and multiple doses	Days 1, 10 and 14
Primary	Pharmacokinetics - C24	Plasma concentration observed at time 24 h after single and multiple doses	Days 1, 10 and 14
Primary	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
Primary	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
Primary	Pharmacokinetics - Cavg	Average concentration (AUC(0-tau)/tau)	Days 2-14
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Pharmacokinetics - AUC(0-tau)	Area under the curve for the defined interval between doses (tau)	Days 1, 10 and 14
Primary	Pharmacokinetics - AUC(0-inf)	Area under the curve from time 0 extrapolated to infinity	Days 1, 10 and 14
Primary	Pharmacokinetics - AUC(0-inf)/D	Area under the curve from time 0 extrapolated to infinity divided by dose	Days 1, 10 and 14
Primary	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
Primary	Pharmacokinetics - T1/2	Terminal elimination half-life after single and multiple doses of KVD824 with and without food	Days 1, 10 and 14
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Pharmacokinetics - Frel Cmax	Relative bioavailability based on Cmax	Days 1, 10 and 14
Primary	Pharmacokinetics - Frel AUC(0-12)	Relative bioavailability based on AUC(0-12)	Days 1, 10 and 14
Primary	Pharmacokinetics - Frel AUC(0-inf)	Relative bioavailability based on AUC(0-inf)	Days 1, 10 and 14
Primary	Pharmacokinetics - AR Cmax	Accumulation ratio based on Cmax repeated dose/Cmax single dose	Days 1, 10 and 14
Primary	Pharmacokinetics - Fluctuation	Peak to trough fluctuation (Cmax-Cmin)/Cavg × 100	Days 1, 10 and 14
Secondary	Safety - Adverse Events	Number of Subjects with Adverse Events	Change from pre-dose to last visit (up to 14 days)
Secondary	Safety - Serious Adverse Events	Number of Subjects with Serious Adverse Events	Change from pre-dose to last visit (up to 14 days)
Secondary	Safety - Laboratory Assessments	Number of participants with clinically significant changes in laboratory assessments	Throughout the trial to last visit (up to 14 days)
Secondary	Safety - Vital Signs	Number of participants with clinically significant changes in vital signs	Throughout the trial to last visit (up to 14 days)
Secondary	Safety - ECG	Number of participants with clinically significant changes in electrocardiogram (ECG) measurements	Throughout the trial to last visit (up to 14 days)