A Pharmacodynamics, Safety, and Pharmacokinetics Study of THN201 Versus Donepezil in Healthy Male Volunteers

A Double Blind, Placebo-controlled, Randomized, 15-day Treatment, Pharmacodynamics, Safety, and Pharmacokinetics Study of THN201 Versus Donepezil Administered Orally to Healthy Male Volunteers Including a Scopolamine Challenge

This study explores the safety, pharmacodynamics and pharmacokinetics of THN201 a combination of donepezil and mefloquine to improve cognitive function in healthy male volunteers after impairment by a scopolamine challenge.

Study Overview

• Status: Completed
• Conditions: Cognitive Impairment; Alzheimer Disease
• Intervention / Treatment: Drug: THN 201; Drug: Donepezil; Drug: Placebo

Detailed Description

This is a double-blind, 3-arm, parallel group study of 15 days duration including a scopolamine challenge at D15. Healthy male subjects will receive daily doses of THN201 (donepezil 5 mg and mefloquine), donepezil 5 mg or placebo and one subcutaneous injection of scopolamine 0.5 mg on D15. Cognitive function, EEG and P300 will be assessed at baseline and before and after scopolamine challenge at D15. A final safety evaluation will be performed 2 weeks after the end of the treatment period. Pharmacokinetic assessments will be performed to obtain a time/concentration profile of donepezil and mefloquine.

• Study Type: Interventional
• Enrollment (Actual): 152
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Bordeaux, France
    • CHU Bordeaux
  • Clermont-Ferrand, France
    • CHU Clermont Ferrand
  • Grenoble, France
    • Chu Grenoble
  • Lille, France
    • CHU Lille
  • Marseille, France
    • CHU Marseille
  • Rennes, France
    • Biotrial
  • Toulouse, France
    • CHU Toulouse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• A body mass index (BMI), calculated as weight in kg/(height in m)², from 18 to 30 kg/m², inclusive
• Healthy as determined by the investigator after a comprehensive clinical assessment based on medical history, physical examination, clinical laboratory test results, vital sign measurements, blood pressure (BP), heart rate (HR) and digital 12-lead ECG readings (all results should be normal or, if out of range, they should be non-clinically significant as determined by the investigator)

Exclusion Criteria:

• Any significant cardiovascular (e.g. heart failure), pulmonary (including asthma), hepatic, renal, respiratory (e.g. asthma), gastrointestinal, endocrine (e.g. diabetes, dyslipidaemia), immunologic, dermatological, haematological, neurologic, psychiatric disease, history of any clinically important drug allergy, systemic or presence of infectious disease.
• Current suicide risk or history of suicide risk (C-SSRS baseline: "yes" answer to items 4 and/or 5).
• Brain imaging (MRI) at screening showing anatomical or vascular abnormality of any type.
• EEG examination at screening showing abnormal (epileptiform) activities.
• Symptomatic hypotension,
• Participants with, or with a history of cardiac arrhythmia or cardiac disease or a personal or family history of long QT syndrome or a family history of sudden death.
• Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician.
• Antimalarial medicine intake or returning from a malaria-endemic area within the 12 last months before the first IMP administration.
• Planning to visit a country requiring antimalarial chemoprophylaxis during the study period.
• History of adverse reaction after a previous mefloquine intake.
• Contraindication for the use of Aricept® or for one of its excipients.
• Contraindication for the use of piperidine derivative compounds or for other cholinesterase inhibitors.
• Contraindication for the use of Lariam® or for one of its excipients.
• Contraindication for the use of scopolamine S.C. injection.
• History or presence of drug or alcohol abuse (alcohol consumption > 21 units / week).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: THN201; THN201: Donepezil 5mg capsule and Mefloquine 10mg capsule once daily for 15 days	Drug: THN 201; THN 201: Donepezil 5 mg and Mefloquine 10 mg/d; Other Names: Mefloquine; Donepezil
ACTIVE_COMPARATOR: Donepezil; Donepezil 5mg capsule and Mefloquine placebo capsule once daily for 15 days	Drug: Donepezil; Donepezil 5 mg/d and Mefloquine placebo
PLACEBO_COMPARATOR: Placebo; Donepezil placebo capsule and Mefloquine placebo capsule once daily for 15 days	Drug: Placebo; Donepezil placebo and Mefloquine placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamics: Cognitive function measured with the Cognitive Drug Research (CDR) test battery	Main variable: Power of attention is the sum of the speed scores (msec) from three tests: Simple Reaction Time, Choice Reaction Time, and Digital Vigilance. Low values indicate better performance	15 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Adverse events	Number of subjects with spontaneously reported treatment related adverse events	29 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics Plasma concentration of donepezil and mefloquine	Time profile of plasma concentrations of donepezil and mefloquine	29 days
Pharmacodynamics measured by quantitative EEG (qEEG)	Spectral analysis of absolute and/or relative amplitude in delta, theta, alpha, beta and gamma bands;	15 days
Pharmacodynamics measured by event related EEG potentials (P300)	Auditory P300 parameters (amplitude, latency and AUC)	15 days

Collaborators and Investigators

• Sponsor: Theranexus
• Investigators: Principal Investigator: Régis Bordet, Prof., CHU Lille

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 27, 2018
• Primary Completion (ACTUAL): October 20, 2019
• Study Completion (ACTUAL): December 20, 2019

Study Registration Dates

• First Submitted: October 2, 2018
• First Submitted That Met QC Criteria: October 3, 2018
• First Posted (ACTUAL): October 9, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 22, 2020
• Last Update Submitted That Met QC Criteria: January 21, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Cholinergic Agents; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Nootropic Agents; Antimalarials; Cholinesterase Inhibitors; Donepezil; Mefloquine
• Other Study ID Numbers: THN201-101

Drug and device information, study documents

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