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

Phase 1

Completed

• Conditions: Alzheimer's Disease
• Interventions: Drug: HTL0009936; Drug: HTL0009936 placebo

• Registration Number: NCT02291783
• Lead Sponsor: Heptares Therapeutics Limited

Brief Summary

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.

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 Timeline

• Study Start: 2013-11
• Primary Completion: 2014-07
• Study Completion: 2014-07
• Study First Submitted: 2014-10-07
• Study First Submitted QC: 2014-11-11
• Study First Posted: 2014-11-14
• Status Verified: 2017-06
• Last Update Submitted: 2017-06-19
• Last Update Posted: 2017-06-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 108

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HTL0009936	HTL0009936	HTL0009936 single and multiple ascending oral doses.
HTL0009936 Placebo	HTL0009936 placebo	HTL0009936 matching placebo

Primary Outcome Measures

Name	Time	Method
Number of participants with Adverse Events, as a measure of safety and tolerability	From signing of informed consent up to 30 days after the final visit	AE reports include a description of the AE, date and time of onset and resolution, intensity, and relationship to IMP.
Changes in vital signs as a measure of safety and tolerability	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.	Pulse rate,body temperature,blood pressure, and orthostatic changes.
Changes in Safety Lab parameters as a measure of safety and tolerability	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.	Hematology, clinical chemistry, urinalysis
Changes in 12-lead electrocardiograms as a measure of safety and tolerability	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.	Change in ECG parameters

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic measures in cerebro spinal fluid (CSF) in young males as measured by max observed CSF (Cmax CSF)	Part 1 - 1h, 2h,3h post dose	Maximum observed CSF concentration (Cmax CSF), area under the CSF concentration versus time
Pharmacokinetic measures to assess the food effect as measured by ANOVA	Pre-dose, multiple time points to 24h, and at 12h, 24h and 5 to 7 days post dose.	Food effect analysis will be based on analysis of variance (ANOVA) for treatment differences.
Pharmacodynamic response as measured by pupillometry	Multiple time points Day1 to 6h post dose Part 1 only.	Changes in average pupil diameter as measured in 3 different conditions of lux.
Pharmacokinetic measures in urine in young males and elderly male and female subjects as measured by amount of urine excreted at collection intervals	Pre-dose,multiple 4h collection intervals to 24h post dose on select dosing days to Day 10 for multiple dosing.	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
Pharmacodynamic response as measured by Bond and Lader visual analogue scale	Day 1 at multiple timepoints to 24h post dose.	Changes in 3 factor scores (Alertness, Contentedness and Calmness) which will be derived from the individual VAS scores
Pharmacodynamic response as measured by changes in qEEG and Event Related Potentials (ERP)	Screening, Day-1, Day 4, Day 9 multiple dosing regimen only	qEEg and ERP (P50 sensory gating, Mismatch Negativity and P300)
Pharmacokinetic measures in plasma as measured by Peak plasma concentration (Cmax)	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.	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.

Trial Locations

Locations (1)

Parexel Early Phase Clinical Unit; 🇬🇧 Harrow, Middlesex, United Kingdom