Roflumilast and Donepezil to Reverse Scopolamine Induced Cognitive Deficits in Healthy Adults
Condition: Memory Impairment; Alzheimer's Disease
MeSH terms: Alzheimer Disease
Intervention: Roflumilast; Roflumilast placebo; Donepezil; Donepezil placebo; Scopolamine
Intervention description: Roflumilast tablets; Roflumilast placebo-matching tablets; Donepezil overencapsulated tablets; Donepezil placebo-matching overencapsulated tablets; Scopolamine subcutaneous injection
Intervention MeSH terms: Scopolamine; Donepezil; Butylscopolammonium Bromide
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 27.0
Sex: Male
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Drug therapy

Summary:

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

Eligibility criteria:

        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.