Roflumilast and Donepezil to Reverse Scopolamine Induced Cognitive Deficits in Healthy Adults

A Randomized, Double-Blind, Placebo Controlled, 4-Period, Cross-Over Study to Evaluate the Effects of Single Oral Administrations of Roflumilast in Combination With Donepezil on Reversing Scopolamine (Hyoscine) Induced Deficits in Psychomotor and Cognitive Function in Healthy Adults

The purpose of this study is to determine whether scopolamine-induced cognitive impairment is attenuated by the administration of roflumilast in combination with donepezil.

The drug being tested in this study is called roflumilast. Roflumilast is being tested as a potential treatment for Alzheimer's disease. This study will look at roflumilast combined with a medication called donepezil, and their ability to reverse mimicked Alzheimer's disease symptoms that have been brought on by administration of a drug called scopolamine.

The study will enroll up to 28 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of four treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need). All participants will receive the following treatments at varying time points throughout the study:

• Roflumilast Dose A tablets
• Donepezil 10 mg capsules
• Placebo (dummy inactive pill) - this is a tablet or capsule that looks like the study drug but has no active ingredient
• Scopolamine 0.5 mg subcutaneous injection.

All participants will be asked to take 2 tablets and 1 capsule and will receive a scopolamine subcutaneous injection on the first day of 4 separate study periods. Participants will then be assessed for how the scopolamine affects their mental processes and whether the study drug improves this.

This single-center trial will be conducted in England. The overall time to participate in this study is up to 95 days. Participants will make 7 visits to the clinic, including 4 separate periods of 2 days confinement to the clinic, and a follow-up assessment 14 days after the last treatment period.

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. Is a healthy adult male.
4. Is aged 18 to 45 years, inclusive, at the time of informed consent.
5. Weighs at least 60 kg and has a body mass index (BMI) between 18 and 32 kg/m^2 inclusive at Screening.
6. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose.
7. Has clinical laboratory evaluations (including clinical chemistry, hematology and complete urinalysis) within the reference range for the testing laboratory, unless the results are deemed not to be clinically significant (CS) by the investigator at screening and Day -1 (Check-in) of Period 1.

Exclusion Criteria:

1. Has received any investigational compound within 3 months prior to the first dose of study medication.
2. Has received roflumilast, donepezil, or scopolamine in a previous clinical study or as a therapeutic agent.
3. Is an immediate family member, study site employee, or in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
4. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality which may impact the ability of the participant to participate or potentially confound the study results.
5. Contraindications to scopolamine: hypersensitivity to scopolamine and other belladonna alkaloids, and/or any component of the formulation, serious allergic reactions, wide and narrow angle glaucoma, gastrointestinal motility disorders (such as constipation, gastroesophageal reflux disease, irritable bowel syndrome), benign prostatic hyperplasia with urinary retention, asthma, chronic obstructive pulmonary disease (COPD), seizures, coronary artery disease, hypertension, and congestive heart failure.
6. Participants with existing psychiatric disease/condition including psychosis, affective disorder, anxiety disorder, borderline state and personality disorder according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, as assessed by the Mini International Neuropsychiatric Interview (MINI) or acute psychiatric episode within 6 months of Screening.
7. Has a known hypersensitivity to any component of the formulation of roflumilast, donepezil, scopolamine, or related compounds.
8. Has a positive urine drug result for drugs of abuse at Screening or Day -1 (Check-in) of each Period.
9. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the screening visit or is unwilling to agree to abstain from drug use or excessive alcohol use throughout the study.
10. Has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products.
11. Intends to donate sperm during the course of this study or for 12 weeks thereafter.
12. Any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking roflumilast, donepezil, scopolamine, or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.
13. Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, or erosive esophagitis, frequent [more than once per week] occurrence of heartburn.
14. Has had any surgical intervention within 6 months that may impact the bioavailability of the compound (eg, cholecystectomy, bariatric surgery).
15. Has a history of cancer within the past 5 years prior to the first dose of study medication. This criterion does not include those participants with basal cell or stage I squamous cell carcinoma of the skin who are eligible.
16. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV), human immunodeficiency virus (HIV) antibody/antigen at Screening.
17. Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in on Day -1 (Check-in of Period 1).
18. Cotinine test is positive at Screening or Check-in (Day -1 of each Period).
19. Has poor peripheral venous access.
20. Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 3 months prior to Day 1 of Period 1.
21. Has a Screening or Day -1 (Check-in) of Period 1 abnormal (clinically significant) electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator or qualified delegate.
22. Has abnormal Screening or Day -1 (Check-in) of Period 1 laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5 the upper limits of normal.
23. Has a current diagnosis or history of glaucoma or had a first-degree relative diagnosed with glaucoma.
24. Has a risk of suicide according to the investigator's clinical judgment (eg, per Columbia-Suicide Severity Rating Scale (C-SSRS) or has made a suicide attempt in the previous 6 months).
25. Has a history of depression associated with suicidal thinking and/or behavior.
26. 26. In the opinion of the investigator or sponsor, the participant is unsuitable for inclusion in the study.