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

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ClinicalTrials.gov Identifier: NCT02291783
Recruitment Status : Completed
First Posted : November 14, 2014
Last Update Posted : June 20, 2017
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Alzheimer's Disease Drug: HTL0009936 Drug: HTL0009936 placebo Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of HTL0009936 in Healthy Subjects
Study Start Date : November 2013
Actual Primary Completion Date : July 2014
Actual Study Completion Date : July 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: HTL0009936
HTL0009936 single and multiple ascending oral doses.
Drug: HTL0009936
Single dose
Other Name: 9936, HTL0009936

Placebo Comparator: HTL0009936 Placebo
HTL0009936 matching placebo
Drug: HTL0009936 placebo
Placebo single dose
Other Name: Placebo




Primary Outcome Measures :
  1. Number of participants with Adverse Events, as a measure of safety and tolerability [ Time Frame: 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.

  2. Changes in Safety Lab parameters as a measure of safety and tolerability [ Time Frame: 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

  3. Changes in vital signs as a measure of safety and tolerability [ Time Frame: 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.

  4. Changes in 12-lead electrocardiograms as a measure of safety and tolerability [ Time Frame: 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 :
  1. Pharmacokinetic measures in plasma as measured by Peak plasma concentration (Cmax) [ Time Frame: 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.

  2. Pharmacokinetic measures in cerebro spinal fluid (CSF) in young males as measured by max observed CSF (Cmax CSF) [ Time Frame: Part 1 - 1h, 2h,3h post dose ]
    Maximum observed CSF concentration (Cmax CSF), area under the CSF concentration versus time

  3. Pharmacokinetic measures to assess the food effect as measured by ANOVA [ Time Frame: 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.

  4. Pharmacodynamic response as measured by pupillometry [ Time Frame: Multiple time points Day1 to 6h post dose Part 1 only. ]
    Changes in average pupil diameter as measured in 3 different conditions of lux.

  5. Pharmacokinetic measures in urine in young males and elderly male and female subjects as measured by amount of urine excreted at collection intervals [ Time Frame: 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

  6. Pharmacodynamic response as measured by Bond and Lader visual analogue scale [ Time Frame: 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

  7. Pharmacodynamic response as measured by changes in qEEG and Event Related Potentials (ERP) [ Time Frame: Screening, Day-1, Day 4, Day 9 multiple dosing regimen only ]
    qEEg and ERP (P50 sensory gating, Mismatch Negativity and P300)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02291783


Locations
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United Kingdom
Parexel Early Phase Clinical Unit
Harrow, Middlesex, United Kingdom, HA1 3UJ
Sponsors and Collaborators
Heptares Therapeutics Limited
Investigators
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Principal Investigator: Annelize Koch, MBChB Parexel
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Responsible Party: Heptares Therapeutics Limited
ClinicalTrials.gov Identifier: NCT02291783    
Other Study ID Numbers: 9936-101
2013-002307-34 ( EudraCT Number )
First Posted: November 14, 2014    Key Record Dates
Last Update Posted: June 20, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders