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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hereditary Angioedema

Intervention / Treatment
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* Drug: KVD824 Prototype 1 modified-release tablet
* Drug: KVD824 Prototype 2 modified-release tablet
* Drug: KVD824 Immediate-Release Capsule
* Drug: Placebo to KVD824 Prototype 1
* Drug: KVD824 Prototype 3 modified-release tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator. Subjects with a history of cholecystectomy or gall stones. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active. Donation or loss of greater than 400 mL of blood within the previous 3 months. 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. Failure to satisfy the investigator of fitness to participate for any other reason.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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) |