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

NCT02051335 | Completed Phase 1 Results

• 3 other identifiers: ROF-ALZ_1022012-002089-11U1111-1151-7178
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Memory Impairment; Alzheimer's Disease

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour After Scopolamine Administration

  VRM measures the ability to encode and subsequently retrieve verbal information. This task begins with the first presentation phase in which 18 words are shown in turn on the screen. The participant is then asked to recall as many words as possible during the first immediate recall phase. The same 18 words are then shown in a second presentation phase which is followed by a second immediate recall phase. After a delay of approximately 20-30 minutes, a delayed recall stage is completed. The possible range of correct responses is 0 (worst) to 18 (best). Higher number of correct responses in the test indicates a better outcome. A negative change from baseline indicates a worsening of the score.

  Baseline and 1 hour after scopolamine administration on Day 1 of each treatment period. Baseline is defined as the assessment 1 hour before roflumilast/donepezil administration (3 hours before scopolamine administration).

• Change From Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour After Scopolamine Administration

  VRM measures the ability to encode and subsequently retrieve verbal information. This task begins with the first presentation phase in which 18 words are shown in turn on the screen. The participant is then asked to recall as many words as possible during the first immediate recall phase. The possible range of correct responses is 0 (worst) to 18 (best). Higher number of correct responses in the test indicates a better outcome. A negative change from baseline indicates a worsening of the score.

  Baseline and 1 hour after scopolamine administration on Day 1 of each treatment period.

Secondary Outcomes (9)

• Change From Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate and Delayed Recall at 2 and 4 Hours After Scopolamine Administration

  Baseline and 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.

• Change From Baseline in the Paired Associates Learning (PAL) Total Number of Errors Adjusted at All Time-points Assessed After Scopolamine Administration

  Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.

• Change From Baseline in the Rapid Visual Information Processing (RVP) A Prime Signal Detection at All Time-points Assessed After Scopolamine Administration

  Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.

• Change From Baseline in the Rapid Visual Information Processing (RVP) Median Latency at All Time-points Assessed After Scopolamine Administration

  Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.

• Change From Baseline in the Spatial Working Memory (SWM) Total Number of Between Errors at the 10-Box Stage and the 12-Box Stage at All Time-points Assessed After Scopolamine Administration

  Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.

Study Arms (4)

Sequence 1 (ABDC)

EXPERIMENTAL

Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 1, followed by roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 2, followed by roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 3, followed by roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 4. Each treatment period is separated by a 14-day washout period.

Drug: Roflumilast; Drug: Roflumilast placebo; Drug: Donepezil; Drug: Donepezil placebo; Drug: Scopolamine

Sequence 2 (BCAD)

EXPERIMENTAL

Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 1, followed by roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 2, followed by roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 3, followed by roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 4. Each treatment period is separated by a 14-day washout period.

Drug: Roflumilast; Drug: Roflumilast placebo; Drug: Donepezil; Drug: Donepezil placebo; Drug: Scopolamine

Sequence 3 (CDBA)

EXPERIMENTAL

Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 1, followed by roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 2, followed by roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 3, followed by roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 4. Each treatment period is separated by a 14-day washout period.

Drug: Roflumilast; Drug: Roflumilast placebo; Drug: Donepezil; Drug: Donepezil placebo; Drug: Scopolamine

Sequence 4 (DACB)

EXPERIMENTAL

Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 1, followed by roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 2, followed by roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 3, followed by roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1, Period 4. Each treatment period is separated by a 14-day washout period.

Drug: Roflumilast; Drug: Roflumilast placebo; Drug: Donepezil; Drug: Donepezil placebo; Drug: Scopolamine

Interventions

Roflumilast DRUG

Roflumilast tablets

Also known as: Daxas

Sequence 1 (ABDC); Sequence 2 (BCAD); Sequence 3 (CDBA); Sequence 4 (DACB)

Roflumilast placebo DRUG

Roflumilast placebo-matching tablets

Sequence 1 (ABDC); Sequence 2 (BCAD); Sequence 3 (CDBA); Sequence 4 (DACB)

Donepezil DRUG

Donepezil overencapsulated tablets

Also known as: Aricept

Sequence 1 (ABDC); Sequence 2 (BCAD); Sequence 3 (CDBA); Sequence 4 (DACB)

Donepezil placebo DRUG

Donepezil placebo-matching overencapsulated tablets

Sequence 1 (ABDC); Sequence 2 (BCAD); Sequence 3 (CDBA); Sequence 4 (DACB)

Scopolamine DRUG

Scopolamine subcutaneous injection

Also known as: Hyoscine hydrobromide

Sequence 1 (ABDC); Sequence 2 (BCAD); Sequence 3 (CDBA); Sequence 4 (DACB)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
• 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.
• Is a healthy adult male.
• Is aged 18 to 45 years, inclusive, at the time of informed consent.
• Weighs at least 60 kg and has a body mass index (BMI) between 18 and 32 kg/m\^2 inclusive at Screening.
• 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.
• 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.

You may not qualify if:

• Has received any investigational compound within 3 months prior to the first dose of study medication.
• Has received roflumilast, donepezil, or scopolamine in a previous clinical study or as a therapeutic agent.
• 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.
• 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.
• 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.
• 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.
• Has a known hypersensitivity to any component of the formulation of roflumilast, donepezil, scopolamine, or related compounds.
• Has a positive urine drug result for drugs of abuse at Screening or Day -1 (Check-in) of each Period.
• 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.
• Has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products.
• Intends to donate sperm during the course of this study or for 12 weeks thereafter.
• 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.
• 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.
• Has had any surgical intervention within 6 months that may impact the bioavailability of the compound (eg, cholecystectomy, bariatric surgery).
• 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.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Unknown Facility

London, United Kingdom

Location

MeSH Terms

Conditions

Memory Disorders; Alzheimer Disease

Interventions

Roflumilast; Donepezil; Scopolamine; Butylscopolammonium Bromide

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Dementia; Brain Diseases; Central Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Indans; Indenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Polycyclic Compounds; Scopolamine Derivatives; Tropanes; Azabicyclo Compounds; Aza Compounds; Belladonna Alkaloids; Solanaceous Alkaloids; Alkaloids; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring; Quaternary Ammonium Compounds; Amines

Results Point of Contact

• Title: AstraZeneca Clinical Study Information Center
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• AstraZeneca AstraZeneca

  AstraZeneca

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2014
• First Posted: January 31, 2014
• Study Start: January 1, 2014
• Primary Completion: May 1, 2014
• Study Completion: May 1, 2014
• Last Updated: February 1, 2017
• Results First Posted: August 17, 2015

Record last verified: 2016-09

Locations

GB (1)