Placebo-Controlled Crossover Study to Evaluate Donepezil and MK-3134 for Reversal of Cognitive Impairment Associated With Scopolamine Administration (3134-005)(COMPLETED)

A Five-Period, Placebo-Controlled, Crossover Study to Evaluate the Effect of Donepezil and MK-3134 on Reversal of Cognitive Impairment Associated With a Single-Dose of Scopolamine.

The drug, scopolamine, can result in short-term impairments of cognitive function, attention, and memory that resemble those seen in aging and Alzheimer's disease. This study tested the capability of both individual and combined doses of MK-3134 and the current standard treatment: donepezil (Aricept), to reverse such impairments, following a single dose of scopolamine. Participants were evaluated after each of 5 different treatment periods (in a cross-over, double-dummy design): A: placebo to match both donepezil (oral [PO]) and MK-3134 (PO) followed by placebo scopolamine (subcutaneous [SQ]); B: placebo to match both donepezil (PO) and MK-3134 (PO), followed by scopolamine SQ; C: MK-3134 (PO) followed by scopolamine SQ; D: donepezil (PO) followed by scopolamine SQ; E: MK-3134 (PO) and donepezil (PO) followed by scopolamine SQ. The doses of MK3134, donepezil, and scopolamine were the same over all treatment arms in which the specified drug was administered. There were 8 total visits for each treatment period, including 5 Treatment Visits requiring 14-day intervals between visits for study-drug washout. Participants were assessed for cognitive function before and after each treatment period during the Treatment Visits.

Study Overview

• Status: Completed
• Conditions: Dementia
• Intervention / Treatment: Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Participants were eligible for inclusion in the study who were:

• Male between 18 and 40 years of age.
• Non-smokers, in good health (as defined in protocol), and were willing to follow study-related procedures.

Participants were not eligible for inclusion in the study if they:

• Had a history of illness that, in the opinion of the study investigator or as specified in protocol, might confound the results of the study or posed an potential, additional risk to the participant if they were to participate in the study.
• Were taking any medication (prescription, nonprescription, vitamin supplements or herbal, illicit or legitimate) except for acetaminophen.
• Had a history of any significant head injury/trauma.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A, B, D, E, C; Participants received treatment A, B, D, E, C for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)
Experimental: B, C, E, A, D; Participants received treatment B, C, E, A, D for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)
Experimental: C, D, A, B, E; Participants received treatment C, D, A, B, E for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)
Experimental: D, E, B, C, A; Participants received treatment D, E, B, C, A for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)
Experimental: E, A, C, D, B; Participants received treatment E, A, C, D, B for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)
Experimental: A, C, B, E, D; Participants received treatment A, C, B, E, D for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)
Experimental: B, D, C, A, E; Participants received treatment B, D, C, A, E for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)
Experimental: C, E, D, B, A; Participants received treatment C, E, D, B, A for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)
Experimental: D, A, E, C, B; Participants received treatment D, A, E, C, B for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)
Experimental: E, B, A, D, C; Participants received treatment E, B, A, D, C for Periods 1, 2, 3, 4, and 5, respectively.	Drug: A: Placebo to match Donepezil and MK-3134 + Placebo to match Scopolamine; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of placebo to match scopolamine SQ.; Drug: B: Placebo to match Donepezil and MK-3134 + Scopolamine 0.5 mg; Single doses of placebo to match both donepezil and MK-3134 PO, plus a single dose of scopolamine 0.5 mg SQ.; Drug: C: MK-3134 25 mg + Scopolamine 0.5 mg; A single dose of MK-3134 PO 25 mg, plus a single dose of scopolamine SQ 0.5 mg.; Drug: D: Donepezil 10 mg + Scopolamine 0.5 mg; A single dose of donepezil 10 mg PO, plus a single dose of scopolamine 0.5 mg SQ.; Other Names: Aricept (donepezil); Drug: E: Combo: Donepezil 10 mg + MK-3134 25 mg + Scopolamine 0.5 mg; A combination of single doses of all active drugs: donepezil 10 mg and MK-3134 25 mg PO, plus scopolamine, SQ.; Other Names: Aricept (donepezil)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CogState Early Phase Battery, Groton Maze Learning Test (GMLT) as measured by the number of errors on the GMLT over time (area under the GMLT-time curve) over hours 1-12.	Participants learned a hidden pathway through a maze (10 x 10 grid of tiles on a computer touch screen) using step-by-step guess, with trial and error feedback after each step. Once the pathway was learned, participants repeated the same pathway four more times. The number of pathway errors was used to indicate the level of cognitive function.	1, 2, 3, 4, 6, 8, and 12 hours relative to administration of SQ scopolamine or SQ placebo

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Cho W, Maruff P, Connell J, Gargano C, Calder N, Doran S, Fox-Bosetti S, Hassan A, Renger J, Herman G, Lines C, Verma A. Additive effects of a cholinesterase inhibitor and a histamine inverse agonist on scopolamine deficits in humans. Psychopharmacology (Berl). 2011 Dec;218(3):513-24. doi: 10.1007/s00213-011-2344-y. Epub 2011 Jun 7.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: August 12, 2010
• First Submitted That Met QC Criteria: August 12, 2010
• First Posted (Estimate): August 13, 2010

Study Record Updates

• Last Update Posted (Estimate): November 6, 2015
• Last Update Submitted That Met QC Criteria: November 5, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: dementia, cognitive impairment, neurodegeneration, Alzheimer's, acetylcholine, AchE
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Cognition Disorders; Dementia; Cognitive Dysfunction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Enzyme Inhibitors; Antiemetics; Gastrointestinal Agents; Adjuvants, Anesthesia; Nootropic Agents; Cholinesterase Inhibitors; Mydriatics; Donepezil; Scopolamine; Butylscopolammonium Bromide
• Other Study ID Numbers: 3134-005; 2007-001894-27 (EudraCT Number)