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

NCT05118958 | Completed Phase 1 DMC

• 1 other identifier: KVD824-102
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

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.

Conditions

Hereditary Angioedema

Outcome Measures

Primary Outcomes (30)

• 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 Outcomes (5)

• Safety - Adverse Events

  Change from pre-dose to last visit (up to 14 days)

• Safety - Serious Adverse Events

  Change from pre-dose to last visit (up to 14 days)

• Safety - Laboratory Assessments

  Throughout the trial to last visit (up to 14 days)

• Safety - Vital Signs

  Throughout the trial to last visit (up to 14 days)

• Safety - ECG

  Throughout the trial to last visit (up to 14 days)

Study Arms (12)

Part 1 - Period 1 - Prototype 1 600 mg (single dose fasted)

EXPERIMENTAL

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

Part 1 - Period 3 - Prototype 2 600 mg (single dose fasted)

EXPERIMENTAL

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

Part 1 - Period 4 - Prototype 1 900 mg (single dose fasted)

EXPERIMENTAL

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

Part 1 - Period 5 - Prototype 1 600 mg and Prototype 3 300 mg (single dose fasted)

EXPERIMENTAL

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; Drug: KVD824 Prototype 3 modified-release tablet

Part 1 - Period 6 - Prototype 1 900 mg (single dose fed)

EXPERIMENTAL

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

Part 3 - KVD824 Prototype 1 600 mg (multiple dose fed)

EXPERIMENTAL

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

Part 3 - Placebo to KVD824 Prototype 1 600 mg (multiple dose fed)

PLACEBO COMPARATOR

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

Part 3 - KVD824 Prototype 1 900 mg (multiple dose fed)

EXPERIMENTAL

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

Part 3 - Placebo to KVD824 Prototype 1 900 mg (multiple dose fed)

PLACEBO COMPARATOR

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

Part 3 - KVD824 Prototype 1 900 mg (multiple dose fasted)

EXPERIMENTAL

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

Part 3 - Placebo to KVD824 Prototype 1 900 mg (multiple dose fasted)

PLACEBO COMPARATOR

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

Part 1 - Period 2 - KVD824 IR Capsule 600 mg (single dose fasted)

ACTIVE COMPARATOR

600 mg (2 x 300 mg) KVD824 immediate release Capsule dosed orally in fasted state as a single dose

Drug: KVD824 Immediate-Release Capsule

Interventions

KVD824 Prototype 1 modified-release tablet DRUG

300 mg modified-release tablet

Part 1 - Period 1 - Prototype 1 600 mg (single dose fasted); Part 1 - Period 4 - Prototype 1 900 mg (single dose fasted); Part 1 - Period 5 - Prototype 1 600 mg and Prototype 3 300 mg (single dose fasted); Part 1 - Period 6 - Prototype 1 900 mg (single dose fed); Part 3 - KVD824 Prototype 1 600 mg (multiple dose fed); Part 3 - KVD824 Prototype 1 900 mg (multiple dose fasted); Part 3 - KVD824 Prototype 1 900 mg (multiple dose fed)

KVD824 Prototype 2 modified-release tablet DRUG

300 mg modified-release tablet

Part 1 - Period 3 - Prototype 2 600 mg (single dose fasted)

KVD824 Immediate-Release Capsule DRUG

300 mg immediate-release capsule

Part 1 - Period 2 - KVD824 IR Capsule 600 mg (single dose fasted)

Placebo to KVD824 Prototype 1 DRUG

Placebo to 300 mg KVD824 Prototype 1 modified-release tablet

Part 3 - Placebo to KVD824 Prototype 1 600 mg (multiple dose fed); Part 3 - Placebo to KVD824 Prototype 1 900 mg (multiple dose fasted); Part 3 - Placebo to KVD824 Prototype 1 900 mg (multiple dose fed)

KVD824 Prototype 3 modified-release tablet DRUG

300 mg modified-release tablet

Part 1 - Period 5 - Prototype 1 600 mg and Prototype 3 300 mg (single dose fasted)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1.
• Subjects who are study site employees, sponsor employees, or immediate family members of site or sponsor employees.
• 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.
• History of any drug or alcohol abuse in the past 2 years.
• 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).
• A confirmed positive alcohol breath test at screening or admission.
• 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.
• Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
• 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).
• Subjects with pregnant or lactating partners.
• Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening.
• Clinically significant abnormal clinical chemistry, haematology, coagulation or urinalysis as judged by the investigator. Subjects with Gilbert's Syndrome are allowed.
• Confirmed positive drugs of abuse test result.
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results.
• Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance of \<70 mL/min using the Cockcroft-Gault equation.

Sponsors & Collaborators

• KalVista Pharmaceuticals, Ltd.: lead

Study Sites (1)

KalVista Investigative Site

Nottingham, United Kingdom

Location

MeSH Terms

Conditions

Angioedemas, Hereditary

Condition Hierarchy (Ancestors)

Angioedema; Vascular Diseases; Cardiovascular Diseases; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Urticaria; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Immunologic Deficiency Syndromes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Initial open-label crossover (Part 1) followed by double-blind, randomised, placebo-controlled part (Part 3).
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2021
• First Posted: November 12, 2021
• Study Start: May 19, 2020
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2020
• Last Updated: November 12, 2021

Record last verified: 2021-11

Locations

GB (1)