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

Study Overview
=================
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.

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

Conditions
-----------------
Alzheimer's Disease

Intervention / Treatment
-----------------
* Drug: HTL0009936
* Drug: HTL0009936 placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HTL0009936<br>HTL0009936 single and multiple ascending oral doses. | Drug: HTL0009936<br>* Single dose<br>* Other names: 9936, HTL0009936;|
| Placebo Comparator: HTL0009936 Placebo<br>HTL0009936 matching placebo | Drug: HTL0009936 placebo<br>* Placebo single dose<br>* 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 |