Open-label, Single Center, Non-randomized, Fixed Sequence Phase 1 Drug-drug Interaction Study With LEO 32731 and Midazolam

This is a single center, non-randomized, open-label, fixed sequence study to investigate the effect of multiple oral dosing of LEO 32731 (up-titrated), on CYP3A activity in healthy male subjects using midazolam as a probe CYP3A substrate.

The study will be conducted in two seamless parts:

Part I - Maximal Tolerated Dose (MTD) Part II - Drug-Drug Interaction with midazolam

Study Overview

• Status: Completed
• Conditions: Drug Interaction Potentiation
• Intervention / Treatment: Drug: Midazolam; Drug: LEO 32731

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neu-Ulm, Germany, 89231
    • Nuvisan GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Subjects will, prior to any study related activities, have given their written informed consent to participate in the study and to abide by the study restrictions.
2. Subjects will be males between 18 and 55 years of age, inclusive.
3. Subjects will have a body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive.
4. Subjects must be in good health, as determined by medical history, physical examination, vital signs assessment, 12-lead ECG, and clinical laboratory evaluations.

5. Subjects (including those who have had a vasectomy) must agree to use condoms with spermicide during each sexual intercourse or must agree to be abstinent starting at first drug administration until 3 month after the final dosing.

   Also subjects must agree not to donate sperm in the same time period.

6. Subjects' female partner of childbearing potential must use an additional acceptable method of contraception. Eligible methods are: hormonal contraceptives (oral, injected, implanted, transdermal), intrauterine devices or systems (e.g. hormonal and non-hormonal IUD), barrier methods (condom and diaphragm, condom and cervical cap, etc.) in combination with a spermicide.

Exclusion Criteria:

1. Subjects who have received any prescribed systemic or topical medication within 14 days of the first dose administration unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety.
2. Subjects who have used any non-prescribed systemic or topical medication (including herbal remedies) within 7 days of the first dose administration (excluding occasional use of paracetamol or ibuprofen, e.g. in case of pain).
3. Subjects who have received any medications, including St John's Wort known to alter drug absorption or elimination processes (change the enzyme levels) within 30 days of the first dose administration of study drug.
4. Subjects who are still participating in a clinical study (e.g. attending follow-up visits) or who have participated in a clinical study involving administration of an investigational drug with new chemical entity within the past 60 days, or a marketed drug compound within the past 30 days prior to the first dosing.
5. Subjects who have donated any blood, plasma or platelets in 3 months prior to first dosing or who have made donations on more than 3 occasions within the 12 months preceding the first dose administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: All subjects; Part I - Maximum Tolerated Dose: All subjects will receive oral doses of LEO 32731 up-titrated from 10 mg bid on Days 1-3, 20 mg bid on Days 4-6 and 40 mg bid on Days 7-12. Part II - Drug-Drug Interaction: All subjects will receive oral doses of LEO 32731 in dose schedule decided upon data from Part I. Subjects will receive a single oral dose of 2.5 mg midazolam on Day -1 prior to the first dose of LEO 32731 and on Days 4, 7 and 17 of multiple dosing with LEO 32731.

Drug: Midazolam; Benzodiazepine; Drug: LEO 32731; LEO 32731 is being developed by LEO Pharma.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) parameters of midazolam AUC0-t	PK parameters AUC0-t will be analyzed on Day -1 and Day 17.	Day -1 and Day 17
Pharmacokinetic (PK) parameters of midazolam Cmax	PK parameter Cmax will be analyzed on Day -1 and Day 17.	Day -1 and Day 17

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC0-t midazolam	PK parameters of midazolam on Day 4 and Day 7 will only be calculated if relevant differences are seen in midazolam PK parameters between Day -1 and Day 17.	Day 4 and Day 7
AUC0-inf of midazolam	PK parameters of midazolam on Day 4 and Day 7 will only be calculated if relevant differences are seen in midazolam PK parameters between Day -1 and Day 17.	Day 4 and Day 7
Cmax of midazolam	PK parameters of midazolam on Day 4 and Day 7 will only be calculated if relevant differences are seen in midazolam PK parameters between Day -1 and Day 17.	Day 4 and Day 7
AUC0-inf of midazolam	Further PK parameters (AUC0-inf, tmax, t1/2, CL/F and Vz/F) of midazolam on Days -1 and 17 (if applicable these parameters will be calculated on Day 4 and Day 7, too).	Day -1 and Day 17
Tmax of midazolam	Further PK parameters (AUC0-inf, tmax, t1/2, CL/F and Vz/F) of midazolam on Days -1 and 17 (if applicable these parameters will be calculated on Day 4 and Day 7, too).	Day -1 and Day 17
t1/2 of midazolam	Further PK parameters (AUC0-inf, tmax, t1/2, CL/F and Vz/F) of midazolam on Days -1 and 17 (if applicable these parameters will be calculated on Day 4 and Day 7, too).	Day -1 and Day 17
CL/F of midazolam	Further PK parameters (AUC0-inf, tmax, t1/2, CL/F and Vz/F) of midazolam on Days -1 and 17 (if applicable these parameters will be calculated on Day 4 and Day 7, too).	Day -1 and Day 17
Vz/F of midazolam	Further PK parameters (AUC0-inf, tmax, t1/2, CL/F and Vz/F) of midazolam on Days -1 and 17 (if applicable these parameters will be calculated on Day 4 and Day 7, too).	Day -1 and Day 17

Collaborators and Investigators

• Sponsor: LEO Pharma

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2017
• Primary Completion (Actual): October 20, 2017
• Study Completion (Actual): October 20, 2017

Study Registration Dates

• First Submitted: April 12, 2017
• First Submitted That Met QC Criteria: April 19, 2017
• First Posted (Actual): April 24, 2017

Study Record Updates

• Last Update Posted (Actual): November 14, 2017
• Last Update Submitted That Met QC Criteria: November 9, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: LP0058-1324; 2016-003882-24 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No