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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo; Drug: KRP-A218; Drug: itraconazole

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom, LS2 9LH
    • Labcorp Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A single ascending dose (SAD) and Part B multiple ascending dose (MAD): KRP-A218; Administration Route: Oral	Drug: KRP-A218; KRP-A218 tablet
Placebo Comparator: Part A (SAD) and Part B (MAD): Placebo; Administration Route: Oral	Drug: Placebo; Placebo tablet
Experimental: Part C drug-drug interaction (DDI): KRP-A218 and itraconazole; Administration Route: Oral	Drug: KRP-A218; KRP-A218 tablet; Drug: itraconazole; 10 mg/mL oral solution; 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	A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded.	Screening to follow-up (Approximately 6 weeks)
Part B: Number of Participants With Adverse Events	A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded.	Screening to follow-up (Approximately 8 weeks)
Part C: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity)	The area under concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity) following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole	Days 1 to 11
Part C: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)	The area under concentration-time curve from time 0 extrapolated to last quantifiable concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole	Days 1 to 11
Part C: Maximum Observed Concentration (Cmax)	The maximum observed concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole	Days 1 to 11
Part C: Time of the Maximum Observed Concentration (Tmax)	The time of the maximum observed concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole	Days 1 to 11
Part C: Apparent Terminal Elimination Half-life (t1/2)	The apparent terminal elimination half-life following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole	Days 1 to 11
Part C: Apparent Total Clearance (CL/F)	The apparent total clearance following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole	Days 1 to 11
Part C: Apparent Volume of Distribution During the Terminal Phase (Vz/F)	The apparent volume of distribution during the terminal phase following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole	Days 1 to 11

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity)	Area under concentration-time curve from time 0 extrapolated to infinity following single oral dose of KRP-A218	Day 1
Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)	Area under curve from time 0 to the time of the last quantifiable concentration following single oral dose of KRP-A218	Day 1
Part A: Maximum Observed Concentration (Cmax)	Maximum observed concentration following single oral dose of KRP-A218	Day 1
Part A: Time of the Maximum Observed Concentration (Tmax)	Time of the maximum observed concentration following single oral dose of KRP-A218	Day 1
Part A: Apparent Terminal Elimination Half-life (t1/2)	Apparent terminal elimination half-life following single oral dose of KRP-A218	Day 1
Part A: Apparent Total Clearance (CL/F)	Apparent total clearance following single oral dose of KRP-A218	Day 1
Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F)	Apparent volume of distribution during the terminal phase following single oral dose of KRP-A218	Day 1
Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ)	Assessment of the area under the concentration-time curve over a dosing interval (AUC0-τ)	Days 1 and 14
Part B: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity)	Assessment of the area under concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity)	Day 1
Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)	Assessment of the area under curve from time 0 to the time of the last quantifiable concentration (AUC0-tlast)	Days 1 and 14
Part B: Maximum Observed Concentration (Cmax)	Assessment of the maximum observed concentration (Cmax)	Days 1 and 14
Part B: Minimum Observed Concentration (Cmin)	Assessment of the minimum observed concentration (Cmin)	Day 14
Part B: Time of the Maximum Observed Concentration (Tmax)	Assessment of the time of the maximum observed concentration (Tmax)	Days 1 and 14
Part B: Apparent Terminal Elimination Half-life (t1/2)	Assessment of the apparent terminal elimination half-life (t1/2)	Days 1 and 14
Part B: Apparent Total Clearance (CL/F)	Assessment of the apparent total clearance (CL/F)	Days 1 and 14
Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F)	Assessment of the apparent volume of distribution during the terminal phase (Vz/F)	Days 1 and 14
Part B: Observed Accumulation Ratio Based on Area Under the Concentration-Time Curve Over a Dosing Interval (ARAUC0-T)	Observed accumulation ratio based on area under the concentration-time curve over a dosing interval (ARAUC0-T) in Part B	Day 14
Part B: Observed Accumulation Ratio Based on Maximum Observed Concentration During the Dosing Interval (ARCmax)	Observed accumulation ratio based on maximum observed concentration during the dosing interval (ARCmax) in Part B	Day 14
Part C: Number of Participants With Adverse Events	A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded.	Screening to follow-up (Approximately 7 weeks)

Collaborators and Investigators

• Sponsor: Kyorin Pharmaceutical Co.,Ltd
• Investigators: Study Chair: Yoji Mimaki, Kyorin Pharmaceutical Co.,Ltd

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2021
• Primary Completion (Actual): April 21, 2022
• Study Completion (Actual): April 21, 2022

Study Registration Dates

• First Submitted: May 27, 2021
• First Submitted That Met QC Criteria: May 27, 2021
• First Posted (Actual): June 1, 2021

Study Record Updates

• Last Update Posted (Estimated): January 8, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole
• Other Study ID Numbers: KRPA218-T101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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