A Phase 1 interventional study of Roflumilast and Roflumilast placebo in Memory Impairment and Alzheimer's Disease, sponsored by AstraZeneca. Completed at 1 site in United Kingdom. Open to male participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2017-02-01.
Sponsored by AstraZeneca · Phase 1, Interventional, and Treatment
The purpose of this study is to determine whether scopolamine-induced cognitive impairment is attenuated by the administration of roflumilast in combination with donepezil.
The drug being tested in this study is called roflumilast. Roflumilast is being tested as a potential treatment for Alzheimer's disease. This study will look at roflumilast combined with a medication called donepezil, and their ability to reverse mimicked Alzheimer's disease symptoms that have been brought on by administration of a drug called scopolamine.
The study will enroll up to 28 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of four treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need). All participants will receive the following treatments at varying time points throughout the study:
All participants will be asked to take 2 tablets and 1 capsule and will receive a scopolamine subcutaneous injection on the first day of 4 separate study periods. Participants will then be assessed for how the scopolamine affects their mental processes and whether the study drug improves this.
This single-center trial will be conducted in England. The overall time to participate in this study is up to 95 days. Participants will make 7 visits to the clinic, including 4 separate periods of 2 days confinement to the clinic, and a follow-up assessment 14 days after the last treatment period.
3,678 studies on the registry are indexed under Alzheimer Disease; 872 are open to participants now.
This study's enrollment of 27 is below the median of 70 across 2,808 interventional studies indexed under Alzheimer Disease.
Browse Alzheimer Disease studies →AstraZeneca is the lead sponsor of 3,429 studies on the registry; 270 are open to participants now.
Of its 357 completed or terminated interventional studies of FDA-regulated products, 173 (48%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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
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
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
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
Roflumilast tablets
Also known as: Daxas
Roflumilast placebo-matching tablets
Donepezil overencapsulated tablets
Also known as: Aricept
Donepezil placebo-matching overencapsulated tablets
Scopolamine subcutaneous injection
Also known as: Hyoscine hydrobromide
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.
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).
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.
Time frame: Baseline and 1 hour after scopolamine administration on Day 1 of each treatment period.
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
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.
Change From Baseline in the Paired Associates Learning (PAL) Total Number of Errors Adjusted at All Time-points Assessed After Scopolamine Administration
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.
Change From Baseline in the Rapid Visual Information Processing (RVP) A Prime Signal Detection at All Time-points Assessed After Scopolamine Administration
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.
Change From Baseline in the Rapid Visual Information Processing (RVP) Median Latency at All Time-points Assessed After Scopolamine Administration
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.
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
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.
Percentage of Participants Who Experience at Least 1 Treatment Emergent Adverse Event (TEAE)
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
Percentage of Participants With Markedly Abnormal Safety Laboratory Tests
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
Percentage of Participants With Markedly Abnormal Vital Sign Measurements at Least Once Post-dose
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
Percentage of Participants With Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post-Dose
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
Participants took part in the study at 1 investigative site in the United Kingdom from 16 January 2014 to 17 May 2014.
| Milestone | 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 |
| Milestone | Sequence 1 (ABDC) | Sequence 2 (BCAD) | Sequence 3 (CDBA) | Sequence 4 (DACB) |
|---|---|---|---|---|
| Started | 7 | 7 | 7 | 4 |
| Completed | 7 | 7 | 7 | 4 |
| Not completed | 0 | 0 | 0 | 0 |
| Milestone | 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 |
| Milestone | 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 |
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.
| correct responses | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| Change From Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Delayed Recall at 1 Hour After Scopolamine Administration | -6.7 ± 3.02 | -7.0 ± 3.33 | -7.4 ± 3.62 | -6.6 ± 2.68 |
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.
| correct responses | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| Change From Baseline in the Verbal Recall Memory (VRM) Total Number of Correct Responses for Immediate Recall at 1 Hour After Scopolamine Administration | -9.8 ± 4.77 | -7.7 ± 4.37 | -10.6 ± 5.09 | -7.7 ± 4.42 |
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.
| correct responses | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| 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 |
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.
| errors | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| 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 |
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.
| unitless | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| 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 |
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.
| msec | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| 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 |
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.
| errors | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| 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 |
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.
| percentage of participants | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| Percentage of Participants Who Experience at Least 1 Treatment Emergent Adverse Event (TEAE) | 30.4 | 65.2 | 24.0 | 51.9 |
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.
| percentage of participants | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| 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 |
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.
| percentage of participants | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| 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 |
The percentage of participants who meet markedly abnormal criteria specified by the protocol and statistical analysis plan=abnormal clinically significant.
| percentage of participants | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| Percentage of Participants With Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post-Dose | 0 | 0 | 0 | 0 |
Collected over 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 ).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| A: Placebo | — | 1/23 (4.3%) | 7/23 (30.4%) |
| B: Donepezil 10 mg | — | 0/23 (0%) | 9/23 (39.1%) |
| C: Roflumilast Dose A | — | 0/25 (0%) | 5/25 (20%) |
| D: Roflumilast Dose A + Donepezil 10 mg | — | 0/27 (0%) | 12/27 (44.4%) |
| Event | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| Viral infectionInfections and infestations | 1/23 | 0/23 | 0/25 | 0/27 |
| Event | A: Placebo | B: Donepezil 10 mg | C: Roflumilast Dose A | D: Roflumilast Dose A + Donepezil 10 mg |
|---|---|---|---|---|
| DizzinessNervous system disorders | 6/23 | 3/23 | 3/25 | 3/27 |
| NauseaGastrointestinal disorders | 0/23 | 3/23 | 0/25 | 5/27 |
| Dry mouthGastrointestinal disorders | 4/23 | 2/23 | 2/25 | 3/27 |
| Vision blurredEye disorders | 1/23 | 3/23 | 2/25 | 2/27 |
| Oropharyngeal painRespiratory, thoracic and mediastinal disorders | 0/23 | 2/23 | 0/25 | 0/27 |
| HeadacheNervous system disorders | 1/23 | 0/23 | 0/25 | 2/27 |
| Age, Continuous(years) | Sequence 1 (ABDC) | Sequence 2 (BCAD) | Sequence 3 (CDBA) | Sequence 4 (DACB) | Total |
|---|---|---|---|---|---|
| Mean | 31.9 ± 7.69 | 28.4 ± 6.73 | 34.1 ± 6.89 | 29.8 ± 5.12 | 31.1 ± 6.71 |
| Gender(Participants) | Sequence 1 (ABDC) | Sequence 2 (BCAD) | Sequence 3 (CDBA) | Sequence 4 (DACB) | Total |
|---|---|---|---|---|---|
| Female | 0 | 0 | 0 | 0 | 0 |
| Male | 7 | 7 | 7 | 6 | 27 |
| Race/Ethnicity, Customized(participants) | Sequence 1 (ABDC) | Sequence 2 (BCAD) | Sequence 3 (CDBA) | Sequence 4 (DACB) | Total |
|---|---|---|---|---|---|
| Asian | 3 | 2 | 0 | 1 | 6 |
| Black or African American | 0 | 1 | 3 | 2 | 6 |
| White | 4 | 4 | 4 | 3 | 15 |
| Region of Enrollment(participants) | Sequence 1 (ABDC) | Sequence 2 (BCAD) | Sequence 3 (CDBA) | Sequence 4 (DACB) | Total |
|---|---|---|---|---|---|
| United Kingdom | 7 | 7 | 7 | 6 | 27 |
| Height(cm) | Sequence 1 (ABDC) | Sequence 2 (BCAD) | Sequence 3 (CDBA) | Sequence 4 (DACB) | Total |
|---|---|---|---|---|---|
| Mean | 178.7 ± 6.65 | 177.3 ± 6.87 | 179.0 ± 5.23 | 174.5 ± 5.79 | 177.5 ± 6.08 |
| Weight(kg) | Sequence 1 (ABDC) | Sequence 2 (BCAD) | Sequence 3 (CDBA) | Sequence 4 (DACB) | Total |
|---|---|---|---|---|---|
| Mean | 82.16 ± 9.759 | 78.61 ± 7.189 | 81.53 ± 4.476 | 75.05 ± 7.036 | 79.50 ± 7.473 |
| Body Mass Index (BMI)(kg/m^2) | Sequence 1 (ABDC) | Sequence 2 (BCAD) | Sequence 3 (CDBA) | Sequence 4 (DACB) | Total |
|---|---|---|---|---|---|
| Mean | 25.76 ± 3.173 | 25.09 ± 2.683 | 25.49 ± 1.670 | 24.68 ± 2.568 | 25.27 ± 2.462 |
| Smoking Classification(participants) | Sequence 1 (ABDC) | Sequence 2 (BCAD) | Sequence 3 (CDBA) | Sequence 4 (DACB) | Total |
|---|---|---|---|---|---|
| Never Smoked | 7 | 7 | 6 | 6 | 26 |
| Current Smoker | 0 | 0 | 0 | 0 | 0 |
| Ex-smoker | 0 | 0 | 1 | 0 | 1 |
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