Phase I, Healthy Subject, Safety, Tolerability and Pharmacokinetic Study of an M1 Agonist to Treat Cognitive Impairment

A Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of HTL0009936 in Healthy Subjects

The purpose of this study is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics in young and elderly healthy volunteers of HTL9936, a selective M1 receptor agonist intended for the treatment of cognitive disorders.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: HTL0009936; Drug: HTL0009936 placebo

Detailed Description

The purpose of this study is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics in young and elderly healthy volunteers of HTL9936, a selective M1 receptor agonist intended for the treatment of cognitive disorders. This study is a single ascending dose study.

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Middlesex
    • Harrow, Middlesex, United Kingdom, HA1 3UJ
      • PAREXEL Early Phase Clinical Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Body mass index of ≥19 and ≤ 30kg/m²
• Healthy subject free from any clinically significant illness or disease
• Female subjects must be ≥65 years

Exclusion Criteria:

• Subject who is predicted to be a CYP2D6 poor or ultra rapid metabolizer
• History of hypersensitivity to study drug
• History of epilepsy or seizures
• Subject with previous history of suicidal behavior
• Subjects with significant hearing impairment
• Subjects with an abnormal EEG

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HTL0009936; HTL0009936 single and multiple ascending oral doses.	Drug: HTL0009936; Single dose; Other Names: 9936, HTL0009936
Placebo Comparator: HTL0009936 Placebo; HTL0009936 matching placebo	Drug: HTL0009936 placebo; Placebo single dose; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with Adverse Events, as a measure of safety and tolerability	AE reports include a description of the AE, date and time of onset and resolution, intensity, and relationship to IMP.	From signing of informed consent up to 30 days after the final visit
Changes in Safety Lab parameters as a measure of safety and tolerability	Hematology, clinical chemistry, urinalysis	Screening, Day-1, at select dosing days, and at 5 to 7 days post dose for single doseand 15 to 17 days post first dose in multiple dosing.
Changes in vital signs as a measure of safety and tolerability	Pulse rate,body temperature,blood pressure, and orthostatic changes.	Screening, Day-1, at select dosing days and at 5 to 7 days post dose for single dose, and 15 to 17 days post first dose in multiple dosing.
Changes in 12-lead electrocardiograms as a measure of safety and tolerability	Change in ECG parameters	Screening, pre-dose, at select dosing days and at 5 to 7 days post dose for single dose,and 15 to 17 days post first dose in multiple dosing.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic measures in plasma as measured by Peak plasma concentration (Cmax)	Peak plasma concentration (Cmax), time at occurrence of Cmax (tmax), Area under the plasma concentration versus time curve (AUC) 0-t, 0- infinity, percent of AUC 0-infinity, Cmax normalized by dose, AUC 0-t normalized for dose.	Pre-dose, multiple time points to 24h, at select dosing days, and 5 to 7 days post dosefor single dose,and 15 to 17 days post first dose in multiple dosing.
Pharmacokinetic measures in cerebro spinal fluid (CSF) in young males as measured by max observed CSF (Cmax CSF)	Maximum observed CSF concentration (Cmax CSF), area under the CSF concentration versus time	Part 1 - 1h, 2h,3h post dose
Pharmacokinetic measures to assess the food effect as measured by ANOVA	Food effect analysis will be based on analysis of variance (ANOVA) for treatment differences.	Pre-dose, multiple time points to 24h, and at 12h, 24h and 5 to 7 days post dose.
Pharmacodynamic response as measured by pupillometry	Changes in average pupil diameter as measured in 3 different conditions of lux.	Multiple time points Day1 to 6h post dose Part 1 only.
Pharmacokinetic measures in urine in young males and elderly male and female subjects as measured by amount of urine excreted at collection intervals	Amount excreted in urine at each collection interval (Ae1-t2) all parts. Cumulative amount excreted to 12h and 24h (Ae0-t) depending on Part. Cumulative urine excreted of unchanged drug to 24h (Fe%) and to 12h depending on Part. Volume of urine collected during each collection interval (Vur), and renal clearance (CLr) all parts	Pre-dose,multiple 4h collection intervals to 24h post dose on select dosing days to Day 10 for multiple dosing.
Pharmacodynamic response as measured by Bond and Lader visual analogue scale	Changes in 3 factor scores (Alertness, Contentedness and Calmness) which will be derived from the individual VAS scores	Day 1 at multiple timepoints to 24h post dose.
Pharmacodynamic response as measured by changes in qEEG and Event Related Potentials (ERP)	qEEg and ERP (P50 sensory gating, Mismatch Negativity and P300)	Screening, Day-1, Day 4, Day 9 multiple dosing regimen only

Collaborators and Investigators

• Sponsor: Heptares Therapeutics Limited
• Investigators: Principal Investigator: Annelize Koch, MBChB, Parexel

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: October 7, 2014
• First Submitted That Met QC Criteria: November 11, 2014
• First Posted (Estimate): November 14, 2014

Study Record Updates

• Last Update Posted (Actual): June 20, 2017
• Last Update Submitted That Met QC Criteria: June 19, 2017
• Last Verified: June 1, 2017

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
• Other Study ID Numbers: 9936-101; 2013-002307-34 (EudraCT Number)

Plan for Individual participant data (IPD)

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