A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of KRP-A218 in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
This first-in-human study has three parts. In Parts A and B, the safety, tolerability, and pharmacokinetics (PK) will be evaluated following administration of single and multiple doses of KRP-A218, including food-effect. In Part C, the drug-drug interaction (DDI) with itraconazole will be evaluated.

Official Title
-----------------
A First-in-Human, Phase I, Double-blind, Placebo-controlled, Single and Multiple Ascending Oral Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of KRP-A218 in Healthy Subjects, Including Food-Effect and Drug-drug Interaction With Itraconazole

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: KRP-A218
* Drug: Placebo
* Drug: itraconazole


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Male or female adults, between 20 and 55 years of age, inclusive. Body weight ≥50 kg, with body mass index (BMI) between 18.0 and 30.0 kg/m^2, inclusive. In good health, at Screening or Day -1 as assessed by the Investigator. Females will not be pregnant or lactating, and females of childbearing potential will agree to use contraception and to not donate eggs (ova, oocytes). Males will agree to use contraception and to not donate sperm. Able to comprehend and willing to sign an informed consent form (ICF) and to abide by the study restrictions. Key Exclusion Criteria: Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 90 days prior to dosing. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to dosing. Use or intend to use any prescription medications/products within 14 days or 5 half-lives (whichever is longer) prior to dosing, unless deemed acceptable by the Investigator. Use or intend to use slow release medications/products considered to still be active within 14 days prior to dosing, unless deemed acceptable by the Investigator. Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant derived preparations within 7 days prior to dosing, unless deemed acceptable by the Investigator. Use of tobacco or nicotine-containing products within 3 months prior to Day -1, or positive cotinine test at screening or Day -1. Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages within 7 days prior to Day -1. Consumption of caffeine- or xanthine-containing foods and beverages within 36 hours prior to Day -1. Participation in strenuous exercised within 7 days prior to Day -1. Receipt of blood products within 2 months prior to Day -1. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to screening, or platelets from 6 weeks prior to screening. Poor peripheral venous access. Have previously completed or withdrawn from this study or have previously received the investigational medicinal product (IMP). Subject is, in the opinion of the Investigator, unlikely to comply with the protocol or unsuitable to participate in this study for any reason. Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A single ascending dose (SAD) and Part B multiple ascending dose (MAD): KRP-A218<br>Administration Route: Oral | Drug: KRP-A218<br>* KRP-A218 tablet<br>|
| Placebo Comparator: Part A (SAD) and Part B (MAD): Placebo<br>Administration Route: Oral | Drug: Placebo<br>* Placebo tablet<br>|
| Experimental: Part C drug-drug interaction (DDI): KRP-A218 and itraconazole<br>Administration Route: Oral | Drug: KRP-A218<br>* KRP-A218 tablet<br>Drug: itraconazole<br>* 10 mg/mL oral solution<br>* Other names: Sporanox;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of participants with adverse events |  | Screening to follow-up (Approximately 6 weeks) | 
| Part B: Number of participants with adverse events |  | Screening to follow-up (Approximately 8 weeks) | 
| Part C: Area under concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) |  | Days 1 to 14 | 
| Part C: Area under curve from time 0 to the time of the last quantifiable concentration (AUC0-tlast) |  | Days 1 to 14 | 
| Part C: Maximum observed concentration (Cmax) |  | Days 1 to 14 | 
| Part C: Time of the maximum observed concentration (tmax) |  | Days 1 to 14 | 
| Part C: Apparent terminal elimination half-life (t1/2) |  | Days 1 to 14 | 
| Part C: Apparent total clearance (CL/F) |  | Days 1 to 14 | 
| Part C: Apparent volume of distribution during the terminal phase (Vz/F) |  | Days 1 to 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Area under concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) |  | Days 1 to 4 | 
| Part A: Area under curve from time 0 to the time of the last quantifiable concentration (AUC0-tlast) |  | Days 1 to 4 | 
| Part A: Maximum observed concentration (Cmax) |  | Days 1 to 4 | 
| Part A: Time of the maximum observed concentration (tmax) |  | Days 1 to 4 | 
| Part A: Apparent terminal elimination half-life (t1/2) |  | Days 1 to 4 | 
| Part A: Apparent total clearance (CL/F) |  | Days 1 to 4 | 
| Part A: Apparent volume of distribution during the terminal phase (Vz/F) |  | Days 1 to 4 | 
| Part B: Area under the concentration-time curve over a dosing interval (AUC0-τ) |  | Days 1 to 17 | 
| Part B: Area under concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) |  | Days 1 to 17 | 
| Part B: Area under curve from time 0 to the time of the last quantifiable concentration (AUC0-tlast) |  | Days 1 to 17 | 
| Part B: Maximum observed concentration (Cmax) |  | Days 1 to 17 | 
| Part B: Minimum observed concentration (Cmin) |  | Days 1 to 17 | 
| Part B: Time of the maximum observed concentration (tmax) |  | Days 1 to 17 | 
| Part B: Apparent terminal elimination half-life (t1/2) |  | Days 1 to 17 | 
| Part B: Apparent total clearance (CL/F) |  | Days 1 to 17 | 
| Part B: Apparent volume of distribution during the terminal phase (Vz/F) |  | Days 1 to 17 | 
| Part B: Observed accumulation ratio based on AUC0-τ (ARAUC0-τ) |  | Days 1 to 17 | 
| Part B: Observed accumulation ratio based on Cmax during the dosing interval (ARCmax) |  | Days 1 to 17 | 
| Part C: Number of participants with adverse events |  | Screening to follow-up (Approximately 7 weeks) |