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

Study identifier:ROF-ALZ_102

ClinicalTrials.gov identifier:NCT02051335

EudraCT identifier:2012-002089-11

CTIS identifier:N/A

Study Complete

Official Title

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

Medical condition

Memory impairment

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Roflumilast, Roflumilast placebo, Donepezil, Donepezil placebo, Scopolamine

Sex

Male

Actual Enrollment

Study type

Interventional

Age

18 Years - 45 Years

Date

Study Start Date: 01 Jan 2014

Primary Completion Date: 01 May 2014

Study Completion Date: 01 May 2014

Study design

Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Sept 2016 by AstraZeneca

Collaborators

Inclusion and exclusion 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.

Location

London, United Kingdom

Arms	Assigned Interventions
Experimental: Sequence 1 (ABDC) 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 Roflumilast tablets Other Name: Daxas Drug: Roflumilast placebo Roflumilast placebo-matching tablets Drug: Donepezil Donepezil overencapsulated tablets Other Name: Aricept Drug: Donepezil placebo Donepezil placebo-matching overencapsulated tablets Drug: Scopolamine Scopolamine subcutaneous injection Other Name: Hyoscine hydrobromide
Experimental: Sequence 2 (BCAD) 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 Roflumilast tablets Other Name: Daxas Drug: Roflumilast placebo Roflumilast placebo-matching tablets Drug: Donepezil Donepezil overencapsulated tablets Other Name: Aricept Drug: Donepezil placebo Donepezil placebo-matching overencapsulated tablets Drug: Scopolamine Scopolamine subcutaneous injection Other Name: Hyoscine hydrobromide
Experimental: Sequence 3 (CDBA) 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 Roflumilast tablets Other Name: Daxas Drug: Roflumilast placebo Roflumilast placebo-matching tablets Drug: Donepezil Donepezil overencapsulated tablets Other Name: Aricept Drug: Donepezil placebo Donepezil placebo-matching overencapsulated tablets Drug: Scopolamine Scopolamine subcutaneous injection Other Name: Hyoscine hydrobromide
Experimental: Sequence 4 (DACB) 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 Roflumilast tablets Other Name: Daxas Drug: Roflumilast placebo Roflumilast placebo-matching tablets Drug: Donepezil Donepezil overencapsulated tablets Other Name: Aricept Drug: Donepezil placebo Donepezil placebo-matching overencapsulated tablets Drug: Scopolamine Scopolamine subcutaneous injection Other Name: Hyoscine hydrobromide

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants took part in the study at 1 investigative site in the United Kingdom from 16 January 2014 to 17 May 2014.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with a diagnosis of Alzeimer’s disease were enrolled equally in a 4 period, 4 treatment crossover study. Treatment A: Placebo, Treatment B: Donepezil, Treatment C: Roflumilast and Treatment D: Roflumilast + Donepezil. All participants received scopolamine on Day 1 of each treatment period.

Reporting Groups

	Description
Sequence 1 (ABDC)	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.
Sequence 2 (BCAD)	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.
Sequence 3 (CDBA)	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.
Sequence 4 (DACB)	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.

Participant Flow for 4 periods

Period 1: Period 1

	Sequence 1 (ABDC)	Sequence 2 (BCAD)	Sequence 3 (CDBA)	Sequence 4 (DACB)
STARTED	7	7	7	6
COMPLETED	7	7	7	6
NOT COMPLETED	0	0	0	0

Period 2: Period 2

	Sequence 1 (ABDC)	Sequence 2 (BCAD)	Sequence 3 (CDBA)	Sequence 4 (DACB)
STARTED	7	7	7	4^[1]
COMPLETED	7	7	7	4
NOT COMPLETED	0	0	0	0

[1]	2 Participants received treatment in Period 1 but discontinued prior to Period 2.

Period 3: Period 3

	Sequence 1 (ABDC)	Sequence 2 (BCAD)	Sequence 3 (CDBA)	Sequence 4 (DACB)
STARTED	7	7	5^[1]	4
COMPLETED	7	7	5	4
NOT COMPLETED	0	0	0	0

[1]	2 Participants received treatment in Period 2 but discontinued prior to Period 3.

Period 4: Period 4

	Sequence 1 (ABDC)	Sequence 2 (BCAD)	Sequence 3 (CDBA)	Sequence 4 (DACB)
STARTED	7	7	5	4
COMPLETED	7	7	5	4
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Sequence 1 (ABDC)	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.
Sequence 2 (BCAD)	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.
Sequence 3 (CDBA)	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.
Sequence 4 (DACB)	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.

Baseline Measures

	Sequence 1 (ABDC)	Sequence 2 (BCAD)	Sequence 3 (CDBA)	Sequence 4 (DACB)	Total
Number of Participants [units: Participants]	7	7	7	6	27
Age Continuous [units: years] Mean ± Standard Deviation	31.9 ± 7.69	28.4 ± 6.73	34.1 ± 6.89	29.8 ± 5.12	31.1 ± 6.71
Gender, Male/Female [units: participants]
Female	0	0	0	0	0
Male	7	7	7	6	27
Race/Ethnicity, Customized [units: participants]
Asian	3	2	0	1	6
Black or African American	0	1	3	2	6
White	4	4	4	3	15
Region of Enrollment [units: participants] United Kingdom	7	7	7	6	27
Height [units: cm] Mean ± Standard Deviation	178.7 ± 6.65	177.3 ± 6.87	179.0 ± 5.23	174.5 ± 5.79	177.5 ± 6.08
Weight [units: kg] Mean ± Standard Deviation	82.16 ± 9.759	78.61 ± 7.189	81.53 ± 4.476	75.05 ± 7.036	79.50 ± 7.473
Body Mass Index (BMI) [units: kg/m^2] Mean ± Standard Deviation	25.76 ± 3.173	25.09 ± 2.683	25.49 ± 1.670	24.68 ± 2.568	25.27 ± 2.462
Smoking Classification [units: participants]
Never Smoked	7	7	6	6	26
Current Smoker	0	0	0	0	0
Ex-smoker	0	0	1	0	1

Outcome Measures

1. Primary Outcome Measure: Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour after Scopolamine Administration [ Time Frame: 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). ]

Measure Type	Primary
Measure Name	Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour after Scopolamine Administration
Measure Description	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.
Time Frame	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).
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants from the Full Analysis Set with data available for analysis at the given time-point.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour after Scopolamine Administration [units: correct responses] Mean (Standard Deviation)	-6.7 (3.02)	-7.0 (3.33)	-7.4 (3.62)	-6.6 (2.68)

Statistical Analysis 1 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour after Scopolamine Administration

Groups^[1]	A: Placebo, B: Donepezil 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.573
Other^[5]	-0.31
Standard Error of the mean	± 0.556
95% Confidence Interval	( -1.4 to 0.8 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
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[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour after Scopolamine Administration

Groups^[1]	A: Placebo, C: Roflumilast Dose A
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.210
Other^[5]	-0.70
Standard Error of the mean	± 0.550
95% Confidence Interval	( -1.8 to 0.4 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour after Scopolamine Administration

Groups^[1]	A: Placebo, D: Roflumilast Dose A + Donepezil 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.821
Other^[5]	0.12
Standard Error of the mean	± 0.547
95% Confidence Interval	( -1.0 to 1.2 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour after Scopolamine Administration

Groups^[1]	B: Donepezil 10 mg, D: Roflumilast Dose A + Donepezil 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.426
Other^[5]	0.44
Standard Error of the mean	± 0.549
95% Confidence Interval	( -0.7 to 1.5 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour after Scopolamine Administration

Groups^[1]	C: Roflumilast Dose A, D: Roflumilast Dose A + Donepezil 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.126
Other^[5]	0.82
Standard Error of the mean	± 0.530
95% Confidence Interval	( -0.2 to 1.9 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour after Scopolamine Administration [ Time Frame: Baseline and 1 hour after scopolamine administration on Day 1 of each treatment period. ]

Measure Type	Primary
Measure Name	Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour after Scopolamine Administration
Measure Description	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.
Time Frame	Baseline and 1 hour after scopolamine administration on Day 1 of each treatment period.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants from the Full Analysis Set with data available for analysis at the given time-point.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour after Scopolamine Administration [units: correct responses] Mean (Standard Deviation)	-9.8 (4.77)	-7.7 (4.37)	-10.6 (5.09)	-7.7 (4.42)

Statistical Analysis 1 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour after Scopolamine Administration

Groups^[1]	A: Placebo, B: Donepezil 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.057
Other^[5]	1.93
Standard Error of the mean	± 0.992
95% Confidence Interval	( -0.1 to 3.9 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour after Scopolamine Administration

Groups^[1]	A: Placebo, C: Roflumilast Dose A
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.394
Other^[5]	-0.84
Standard Error of the mean	± 0.981
95% Confidence Interval	( -2.8 to 1.1 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour after Scopolamine Administration

Groups^[1]	A: Placebo, D: Roflumilast Dose A + Donepezil 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.042
Other^[5]	2.01
Standard Error of the mean	± 0.972
95% Confidence Interval	( 0.1 to 4.0 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour after Scopolamine Administration

Groups^[1]	B: Donepezil 10 mg, D: Roflumilast Dose A + Donepezil 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.928
Other^[5]	0.09
Standard Error of the mean	± 0.974
95% Confidence Interval	( -1.9 to 2.0 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Change from Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour after Scopolamine Administration

Groups^[1]	C: Roflumilast Dose A, D: Roflumilast Dose A + Donepezil 10 mg
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANOVA
P-Value^[4]	0.004
Other^[5]	2.86
Standard Error of the mean	± 0.943
95% Confidence Interval	( 1.0 to 4.7 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-values were obtained using an ANOVA model with sequence, period, and treatment as fixed effects and participant nested within sequence as a random effect.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: 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 [ Time Frame: Baseline and 2 and 4 hours after scopolamine administration on Day 1 of each treatment period. ]

Measure Type	Secondary
Measure Name	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
Measure Description	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.
Time Frame	Baseline and 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants from the Full Analysis Set with data available for analysis at the given time-point.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
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 [units: correct responses] Mean (Standard Deviation)
Immediate Recall: 2 hours post Scopolamine	-10.1 (5.02)	-7.3 (4.06)	-9.9 (5.20)	-6.5 (4.38)
Immediate Recall: 4 hours post Scopolamine	-8.3 (5.64)	-7.6 (4.59)	-7.9 (4.50)	-6.1 (4.23)
Delayed Recall: 2 hours post Scopolamine	-6.3 (2.08)	-5.6 (2.87)	-6.8 (3.67)	-5.9 (3.06)
Delayed Recall: 4 hours post Scopolamine	-5.5 (2.64)	-5.6 (3.34)	-5.9 (2.98)	-5.3 (2.50)

No statistical analysis provided for 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

4. Secondary Outcome Measure: Change from Baseline in the Paired Associates Learning (PAL) Total Number of Errors Adjusted at all Time-points Assessed after Scopolamine Administration [ Time Frame: Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period. ]

Measure Type	Secondary
Measure Name	Change from Baseline in the Paired Associates Learning (PAL) Total Number of Errors Adjusted at all Time-points Assessed after Scopolamine Administration
Measure Description	PAL assesses visuospatial associative learning and memory. Boxes are displayed on the screen and open in a randomised order to reveal a number of patterns. The patterns are then displayed in the middle of the screen, one at a time, and the participant must touch the box where the pattern was originally located. If the participant makes an error, the patterns are re-presented to remind the participant of their locations. If the participant has not responded correctly within six attempts, ie, one presentation and five re-presentations, the task is terminated. As the task progresses the difficulty level increases with the number of patterns to be remembered. For participants who fail to complete all levels, an adjusted total is calculated that takes into account errors predicted in the stages that were not attempted. The possible range for total errors is 0 (best) to 91 (worst). Fewer number of errors in the test indicates a better outcome.
Time Frame	Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants from the Full Analysis Set with data available for analysis at the given time-point.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
Change from Baseline in the Paired Associates Learning (PAL) Total Number of Errors Adjusted at all Time-points Assessed after Scopolamine Administration [units: errors] Mean (Standard Deviation)
1 hour post Scopolamine	8.0 (12.73)	11.5 (15.98)	1.6 (10.70)	7.5 (14.38)
2 hours post Scopolamine	3.0 (10.11)	3.0 (7.23)	-0.7 (11.96)	2.9 (9.12)
4 hours post Scopolamine	2.3 (9.09)	7.7 (16.00)	0.2 (8.34)	3.1 (9.31)

No statistical analysis provided for Change from Baseline in the Paired Associates Learning (PAL) Total Number of Errors Adjusted at all Time-points Assessed after Scopolamine Administration

5. Secondary Outcome Measure: Change from Baseline in the Rapid Visual Information Processing (RVP) A Prime Signal Detection at all Time-points Assessed after Scopolamine Administration [ Time Frame: Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period. ]

Measure Type	Secondary
Measure Name	Change from Baseline in the Rapid Visual Information Processing (RVP) A Prime Signal Detection at all Time-points Assessed after Scopolamine Administration
Measure Description	RVP is a task of continuous performance and visual sustained attention. The task consists of a 2-minute practice stage and a 7-minute assessed stage. There is a white box in the centre of the screen in which single digits from 2 to 9 appear one at a time in a pseudo-random order at a rate of 100 digits per minute. Participants must detect target sequences of digits (2-4-6, 3-5-7, and 4-6-8) and touch a button when they see the last digit of a target sequence. Nine target sequences appear every 100 numbers. A prime (A′) is a signal detection measure that reflects target sensitivity regardless of the participant’s tendency, or bias, to respond. Detection sensitivity for RVP A’ prime: 0 to 1. Lower numbers in the test indicates worsening in the performance.
Time Frame	Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants from the Full Analysis Set with data available for analysis at the given time-point.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
Change from Baseline in the Rapid Visual Information Processing (RVP) A Prime Signal Detection at all Time-points Assessed after Scopolamine Administration [units: unitless] Mean (Standard Deviation)
1 hour post Scopolamine	-0.0184 (0.03206)	-0.0107 (0.03661)	-0.0290 (0.03090)	-0.0157 (0.03742)
2 hours post Scopolamine	-0.0297 (0.03799)	-0.0151 (0.03249)	-0.0315 (0.03810)	-0.0282 (0.04667)
4 hours post Scopolamine	-0.0201 (0.03972)	-0.0106 (0.02948)	-0.0227 (0.03534)	-0.0114 (0.03530)

No statistical analysis provided for Change from Baseline in the Rapid Visual Information Processing (RVP) A Prime Signal Detection at all Time-points Assessed after Scopolamine Administration

6. Secondary Outcome Measure: Change from Baseline in the Rapid Visual Information Processing (RVP) Median Latency at all Time-points Assessed after Scopolamine Administration [ Time Frame: Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period. ]

Measure Type	Secondary
Measure Name	Change from Baseline in the Rapid Visual Information Processing (RVP) Median Latency at all Time-points Assessed after Scopolamine Administration
Measure Description	RVP is a task of continuous performance and visual sustained attention. The task consists of a 2-minute practice stage and a 7-minute assessed stage. There is a white box in the centre of the screen in which single digits from 2 to 9 appear one at a time in a pseudo-random order at a rate of 100 digits per minute. Participants must detect target sequences of digits (2-4-6, 3-5-7, and 4-6-8) and touch a button when they see the last digit of a target sequence. Nine target sequences appear every 100 numbers. Assessment will be based on a median latency. The possible range for RVP median latency is 100 (worst) to 1900 (best). Higher number in the test indicates a better outcome. “Median latency” is a measure captured by computerized test measure and given as “one” time value (between 100 and 1900). The “mean” of these values is presented.
Time Frame	Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants from the Full Analysis Set with data available for analysis at the given time-point.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
Change from Baseline in the Rapid Visual Information Processing (RVP) Median Latency at all Time-points Assessed after Scopolamine Administration [units: msec] Mean (Standard Deviation)
1 hour post Scopolamine	10.63 (39.631)	-7.35 (36.659)	5.62 (36.538)	2.59 (42.550)
2 hours post Scopolamine	10.83 (45.635)	-4.89 (42.713)	10.62 (40.063)	0.13 (55.005)
4 hours post Scopolamine	13.13 (42.087)	-5.39 (33.696)	3.90 (39.485)	-8.98 (41.002)

No statistical analysis provided for Change from Baseline in the Rapid Visual Information Processing (RVP) Median Latency at all Time-points Assessed after Scopolamine Administration

7. Secondary Outcome Measure: 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 [ Time Frame: Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period. ]

Measure Type	Secondary
Measure Name	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
Measure Description	SWM assesses the ability to retain spatial information and manipulate it in working memory. In this task, colored boxes are shown on the screen, and participants must search for blue tokens by touching the colored boxes to open them. When the blue token has been found the participant has to place the token in the black column (‘home’) on the right-hand side of the screen by touching this area. The participant must not return to a box where a token has previously been found. The task becomes more difficult as the number of boxes increases (one trial at each of 6-box and 8-box stages; three trials at each of 10-box and 12-box stages). Between Errors is the total number of times the participant revisits a box in which a token has previously been found in the same problem. The possible range of errors is 0 (best) to 1040 (worst). Lower number of errors in the test indicates a better outcome.
Time Frame	Baseline and at 1, 2 and 4 hours after scopolamine administration on Day 1 of each treatment period.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants from the Full Analysis Set with data available for analysis at the given time-point.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
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 [units: errors] Mean (Standard Deviation)
1 hour post Scopolamine	23.8 (36.96)	25.7 (27.77)	31.7 (22.66)	16.5 (22.87)
2 hours post Scopolamine	28.4 (22.57)	13.4 (27.47)	29.6 (23.88)	18.2 (22.18)
4 hours post Scopolamine	31.1 (29.88)	19.7 (25.46)	32.8 (26.62)	7.7 (21.09)

No statistical analysis provided for 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

8. Secondary Outcome Measure: Percentage of Participants who Experience at Least 1 Treatment Emergent Adverse Event (TEAE) [ Time Frame: Day 1 up to Day 95 ]

Measure Type	Secondary
Measure Name	Percentage of Participants who Experience at Least 1 Treatment Emergent Adverse Event (TEAE)
Measure Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as any adverse event, regardless of relationship to study drug that occurs or worsens after the first dose of study drug and no more than 14 days after the last dose of study drug.
Time Frame	Day 1 up to Day 95
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Analysis Set included all enrolled participants who received at least one dose of study drug.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
Percentage of Participants who Experience at Least 1 Treatment Emergent Adverse Event (TEAE) [units: percentage of participants]	30.4	65.2	24.0	51.9

No statistical analysis provided for Percentage of Participants who Experience at Least 1 Treatment Emergent Adverse Event (TEAE)

9. Secondary Outcome Measure: Percentage of Participants with Markedly Abnormal Safety Laboratory Tests [ Time Frame: Day 1 up to Day 95 ]

Measure Type	Secondary
Measure Name	Percentage of Participants with Markedly Abnormal Safety Laboratory Tests
Measure Description	The percentage of participants with any markedly abnormal standard safety laboratory values, including hematology, serum chemistries, and urinalysis. LLN=lower limit of normal. ULN=upper limit of normal.
Time Frame	Day 1 up to Day 95
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Analysis Set included all enrolled participants who received at least one dose of study drug.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
Percentage of Participants with Markedly Abnormal Safety Laboratory Tests [units: percentage of participants]
Hematocrit <0.8 x LLN (n=22,23,25,27)	0	0	0	0
Hematocrit >1.2 x ULN (n=22,23,25,27)	0	0	0	0
Hemoglobin <0.8 x LLN (n=22,23,25,27)	0	0	0	0
Hemoglobin >1.2 x ULN (n=22,23,25,27)	0	0	0	0
Platelet Count <75 x 10^3/μL (n=22,23,25,27)	0	0	0	0
Platelet Count >600 x 10^3/μL (n=22,23,25,27)	0	0	0	0
Red Blood Cells <0.8 x LLN (n=22,23,25,27)	0	0	0	0
Red Blood Cells >1.2 x ULN (n=22,23,25,27)	0	0	0	0
White Blood Cells <0.5 x LLN (n=22,23,25,27)	0	0	0	0
White Blood Cells >1.5 x ULN (n=22,23,25,27)	0	0	0	0
Alanine Aminotransferase >3 x ULN	0	0	0	0
Albumin <2.5 g/dL	0	0	0	0
Alkaline Phosphatase >3 x ULN	0	0	0	0
Aspartate Aminotransferase >3xULN	0	0	0	0
Blood Urea Nitrogen >10.7 mmol/L	0	0	0	0
Calcium <1.75 mmol/L	0	0	0	0
Calcium >2.88 mmol/L	0	0	0	0
Creatine Kinase >5 x ULN	0	0	0	0
Creatinine >2.0 mg/dL	0	0	0	0
Gamma Glutamyl Transpeptidase >3xULN	0	0	0	0
Potassium <3.0 mmol/L	0	0	0	0
Potassium >6.0 mmol/L	0	0	0	0
Sodium <130 mmol/L	0	0	0	0
Sodium >150 mmol/L	0	0	0	0
Total Bilirubin >2.0 mg/dL	0	0	0	0
Total Protein <0.8 x LLN	0	0	0	0
Total Protein >1.2 x ULN	0	0	0	0

No statistical analysis provided for Percentage of Participants with Markedly Abnormal Safety Laboratory Tests

10. Secondary Outcome Measure: Percentage of Participants with Markedly Abnormal Vital Sign Measurements at Least Once Post-dose [ Time Frame: Day 1 up to Day 95 ]

Measure Type	Secondary
Measure Name	Percentage of Participants with Markedly Abnormal Vital Sign Measurements at Least Once Post-dose
Measure Description	The percentage of participants who meet markedly abnormal criteria for vital signs, including oral body temperature, respiration rate, pulse, and resting blood pressure and after standing.
Time Frame	Day 1 up to Day 95
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Analysis Set included all enrolled participants who received at least one dose of study drug.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
Percentage of Participants with Markedly Abnormal Vital Sign Measurements at Least Once Post-dose [units: percentage of participants]
Pulse <50 bpm	26.1	21.7	28.0	33.3
Pulse >120 bpm	0	0	0	0
Systolic Blood Pressure <85 mmHg	0	0	0	0
Systolic Blood Pressure >180 mmHg	0	0	0	0
Diastolic Blood Pressure <50 mmHg	0	8.7	0	11.1
Diastolic Blood Pressure >110 mmHg	0	0	0	0

No statistical analysis provided for Percentage of Participants with Markedly Abnormal Vital Sign Measurements at Least Once Post-dose

11. Secondary Outcome Measure: Percentage of Participants with Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post-Dose [ Time Frame: Day 1 up to Day 95 ]

Measure Type	Secondary
Measure Name	Percentage of Participants with Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post-Dose
Measure Description	The percentage of participants who meet markedly abnormal criteria specified by the protocol and statistical analysis plan=abnormal clinically significant.
Time Frame	Day 1 up to Day 95
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Analysis Set included all enrolled participants who received at least one dose of study drug.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Measured Values

	A: Placebo	B: Donepezil 10 mg	C: Roflumilast Dose A	D: Roflumilast Dose A + Donepezil 10 mg
Number of Participants Analyzed [units:participants]	23	23	25	27
Percentage of Participants with Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post-Dose [units: percentage of participants]	0	0	0	0

No statistical analysis provided for Percentage of Participants with Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post-Dose

Serious Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days after the last dose of study drug (Up to ).
Additional Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Serious Adverse Events

A: Placebo

B: Donepezil 10 mg

C: Roflumilast Dose A

D: Roflumilast Dose A + Donepezil 10 mg

Total, serious adverse events

# participants affected / at risk

1/23 (4.35%)

0/23 (0.00%)

0/25 (0.00%)

0/27 (0.00%)

Infections and infestations

Viral infection¹,^†

# participants affected / at risk

1/23 (4.35%)

0/23 (0.00%)

0/25 (0.00%)

0/27 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (17.0)

Other Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days after the last dose of study drug (Up to ).
Additional Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
A: Placebo	Roflumilast placebo-matching tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
B: Donepezil 10 mg	Roflumilast placebo-matching tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
C: Roflumilast Dose A	Roflumilast Dose A tablets, orally, donepezil placebo-matching overencapsulated tablets, orally, and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.
D: Roflumilast Dose A + Donepezil 10 mg	Roflumilast Dose A tablets, orally, donepezil 10 mg, overencapsulated tablets, orally and scopolamine 0.5 mg subcutaneous injection, once, Day 1 in any of the 4 treatment periods.

Other Adverse Events

A: Placebo

B: Donepezil 10 mg

C: Roflumilast Dose A

D: Roflumilast Dose A + Donepezil 10 mg

Total, other (not including serious) adverse events

# participants affected / at risk

7/23 (30.43%)

9/23 (39.13%)

5/25 (20.00%)

12/27 (44.44%)

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

6/23 (26.09%)

3/23 (13.04%)

3/25 (12.00%)

3/27 (11.11%)

Gastrointestinal disorders

Dry mouth¹,^†

# participants affected / at risk

4/23 (17.39%)

2/23 (8.70%)

2/25 (8.00%)

3/27 (11.11%)

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

0/23 (0.00%)

3/23 (13.04%)

0/25 (0.00%)

5/27 (18.52%)

Eye disorders

Vision blurred¹,^†

# participants affected / at risk

1/23 (4.35%)

3/23 (13.04%)

2/25 (8.00%)

2/27 (7.41%)

Nervous system disorders

Headache¹,^†

# participants affected / at risk

1/23 (4.35%)

0/23 (0.00%)

0/25 (0.00%)

2/27 (7.41%)

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹,^†

# participants affected / at risk

0/23 (0.00%)

2/23 (8.70%)

0/25 (0.00%)

0/27 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (17.0)

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda’s sole discretion.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	AstraZeneca Clinical Study Information Center
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

AstraZeneca AstraZeneca

AstraZeneca

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Trial Results Summaries