A Phase 1 interventional study of Roflumilast and Placebo in Schizophrenia, sponsored by Takeda. Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 55 Years. Per ClinicalTrials.gov, last updated 2016-10-03.
Sponsored by Takeda · Phase 1, Interventional, and Treatment
The purpose of this study is to determine whether cognitive impairment associated with schizophrenia is attenuated by add-on roflumilast administration to second generation antipsychotics (SGA) in participants with stable schizophrenia.
The drug being tested in this study is called roflumilast. Roflumilast is being tested as an add-on treatment to second generation antipsychotics (SGA) to treat cognitive impairment in people with stable schizophrenia. This study will look at improvement in cognitive impairment associated with schizophrenia in people who take roflumilast as an add-on to SGA.
The study will enroll approximately 22 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of three treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need) All participants will receive the following treatments at different periods throughout the study:
All participants will be asked to take one tablet at the same time each day throughout the study.
This single-centre trial will be conducted in the United Kingdom. The overall time to participate in this study is up to 64 days. Participants will make 2 screening visits to the clinic and then must be brought to the clinic every day for dosing during each of 3 Treatment Periods. Each Treatment Period will be 8 days in duration. All participants will also make 1 final visit 14 days after last dose of study drug for a follow-up assessment.
3,471 studies on the registry are indexed under Schizophrenia; 471 are open to participants now.
This study's enrollment of 20 is below the median of 70 across 2,871 interventional studies indexed under Schizophrenia.
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Exclusion Criteria:
Roflumilast placebo-matching tablets, orally, once, daily, Days 1 through 8, Period 1, followed by a 14 day washout period, followed by roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8, Period 2, followed by a 14 day washout period, followed by roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8, Period 3. All participants will take a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Drug: Roflumilast · Drug: Placebo · Drug: Second generation antipsychotic
Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8, Period 1, followed by a 14 day washout period, followed by roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8, Period 2, followed by a 14 day washout period, followed by roflumilast placebo-matching tablets, orally, once, daily, Days 1 through 8, Period 3. All participants will take a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Drug: Roflumilast · Drug: Placebo · Drug: Second generation antipsychotic
Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8, Period 1, followed by a 14 day washout period, followed by roflumilast placebo-matching tablets, orally, once, daily, Days 1 through 8, Period 2, followed by a 14 day washout period, followed by roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8, Period 3. All participants will take a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Drug: Roflumilast · Drug: Placebo · Drug: Second generation antipsychotic
Roflumilast tablets
Also known as: DALIRESP®, DAXAS®
Roflumilast placebo-matching tablets
Second Generation Antipsychotic (SGA) medication for standard of care therapy will be sourced and managed locally by the site.
Change From Baseline in Spatial Span Test Score
The Spatial Span test assesses the participant's working memory. During this task, participants are presented with a board containing blue blocks randomly arranged. The rater first taps out a pattern of blocks, beginning with two blocks and increasing with participant proficiency, and the participant is tasked with tapping the same pattern. After discontinuation of this part of the subtest, the participant is then tasked with tapping out the reverse pattern after the rater's demonstration. These patterns also begin with two blocks and increase with participant proficiency. The total score for this subtest ranges from 0 (worst) to 32 (best). A positive change from Baseline indicates improvement. Analysis of Variance (ANOVA) with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in Hopkins Verbal Learning Test (HVLT) Score
The HVLT assesses the participant's verbal learning. The test consists of a list of 12 words from three taxonomic categories which are presented orally, and the participant is asked to recall as many as possible after each of three learning trials. The key outcome variable for this task is the total correct responses in the three learning trials. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Dorsolateral Prefrontal Cortex Activation During the Rewarded Delayed Response Working Memory
BOLD Functional magnetic resonance imaging (fMRI) changes in the blood-oxygen-level-dependent (BOLD) - signal, which changes in response to neural activity. Baseline fMRI measurements will be followed by rewarded delayed response Working Memory (WM) task measurements in which participants are required to remember the spatial location of a target stimulus (a dot) relative to a fixation cross. Participants are given feedback indicating success or failure. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in the Continuous Performance Test (CPT)
The CPT is a computerized test that assesses the participant's attention and vigilance. The participant was asked to attend to digits flashing on a computer screen and to click the mouse when the same string of digits flashed consecutively. The test consisted of 3 trials: the first contained 2-digit sequences, the second contained 3-digit sequences, and the third contained 4-digit sequences. Scoring was based the number of correct hits. The total score was an average of the 3 trials. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in Brief Assessment of Cognition in Schizophrenia: Symbol-Coding
The Brief Assessment of Cognition in Schizophrenia (BACS): Symbol-Coding assesses the participant's speed of processing. The test is a timed paper-and-pencil test in which the participant uses a key to write digits that correspond to nonsense symbols. The key outcome variable for this task is the total number of correct, valid symbols in 90 seconds. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period and treatment group as fixed effects and participant nested within treatment sequence as a random effect.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in Category Fluency Animal Naming Scores
The Category Fluency test assesses the participant's speed of processing. The test is administered orally, with the participant naming as many animals as he can in 1 minute. The key outcome variable for the test is the total number of correct, valid category words in 60 seconds. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Ventrolateral Prefrontal (VLPF) Cortex and Orbitofrontal (OFX) Cortex Activation During the Shift Trials
BOLD fMRI, a test that measures brain activity, was used during the Shifting Task at VLPF and OFX. Participants worked out which pair in a stimulus set consisting of a face and a building; transparent and overlapping, was the target. 1 pair appeared on the left of the screen, the other on the right. In each trial, participants indicated using a button box which side of the screen they thought the target was located on. Every second response, feedback was presented on the screen for 0.6 seconds, indicating whether or not the stimulus chosen was the target. If both of the last 2 choices were correct, the feedback was the word ''correct'' in green; otherwise, the feedback was the word ''incorrect'' in red. After 3 positive feedback events, a change of target occurred. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Ventral Striatum Activation During the Reward Trials
BOLD fMRI, a test that measures brain activity, was used during the Reward Task (Monetary Incentive Delay Test). Participants were instructed to respond as quickly as possible to a light-flash on the display screen. The flash was preceded by an arrow icon that informed participants about the consequences of their response to the flash stimulus. Four conditions were included in the paradigm, as follows: 1. Win condition (arrow up): win 2 pound sterling if the response was sufficiently fast. 2. Avoidance of loss condition (arrow down: lose 2 pound sterling if the response was too slow. 3. Verbal control (vertical double arrow): no gain or loss of money. 4. Passive control condition (horizontal double arrow): No response was required. Each of the above conditions was presented at least 10 times in a random order. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in P300 Amplitude at the Midline Parietal Electrode (Pz)
Brain electrical activity changes were quantified with electroencephalogram (EEG) battery tests. The P300 occurs after the presentation of a novel, behaviorally relevant target stimulus embedded among irrelevant stimuli. It reflects allocation of attention and activation of immediate memory. The amplitude of P300 indexes brain actions when the mental representation of the stimulus environment is updated, while its latency indexes stimulus classification speed unrelated to response selection processes. The participants are instructed to push a button when hearing the target stimulus, but not when hearing the standard. They are asked to press the button as fast as possible. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in Mismatch Negativity (MMN) Amplitude at the Midline Frontal Electrode (Fz)
EEG, a test that measures brain electrical activity was performed during the MMN. The MMN is an auditory event related potential that is elicited by any discriminable change in auditory stimulation irrespective of the participant or participant's attention. The response to stimuli is being recorded by EEG electrodes while participants read a book. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in Amplitude of the C1 Component of the Visual Evoked Potentials at the Midline Occipital Electrode (Oz)
EEG, a test that measures brain electrical activity was used. Participants had a baseline Visual Evoked Potentials (VEP) recording (2 minute checkerboard VEP) followed by a period of high frequency stimulation (2 minutes 9 Hz checkerboard stimulation). The VEP was repeated 2 minutes after the end of high frequency stimulation. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in High Beta/Low Gamma Power During Resting EEG
Participants are asked to open and close their eyes in 30 second alternating blocks to maintain an approximately constant level of arousal. The eyes closed EEG, a test that measures brain electrical activity, is dominated by alpha (8-14Hz) and the eyes open EEG dominated by beta (14-30Hz eyes open) with the two states analyzed separately to increase sensitivity to drug effects in these bands. Ratio is calculated as High Beta/Low Gamma Power. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in Frontal Theta Power (EEG) During N-Back Working Memory Task
EEG, a test that measures brain electrical activity, was performed during the n-back task. In the n-back task participants are required to monitor a series of letters and report when the current letter matches the letter n integers back, where n=1 (1-back) or n=2 (2-back), the latter requiring a greater working memory resources. The task requires continuous updating of information stores. In the 0-back condition (which does not require manipulation of material in working memory), participants respond to the appearance of a pre-specified letter. The task consists of alternating 30-second (s) blocks of 0-back with 1-back, and 2-back conditions, with letters displayed every 2 s for 1 s within each block. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score
PANSS assesses the positive symptoms, negative symptoms, and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Positive subscale consists of 7 items which assesses the positive symptoms with subscale score ranging from 7 to 49, where higher score indicates greater severity. Negative subscale consists of 7 items which assesses the negative symptoms with subscale score ranging from 7 to 49, where higher score indicates greater severity. General psychopathology subscale consists of 16 items which assesses the general symptoms of schizophrenia with subscale score ranging from 16 to 96, where higher score indicates greater severity. A negative change from Baseline indicates improvement. ANOVA with treatment sequence, study period and treatment group as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Percentage of Participants Who Experience at Least 1 Treatment-Emergent Adverse Event
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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time frame: From Day 1 until Day 63
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests
Percentage of participants with markedly abnormal safety laboratory tests (Hematology, Serum Chemistry and Urinalysis) collected throughout the study.
Time frame: From Day 1 until Day 63
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurement
Vital signs were oral body temperature, respiration rate, supine blood pressure (after 5 minutes resting), and pulse rate.
Time frame: From Day 1 until Day 63
Participants took part in the study at 1 investigative site in the United Kingdom from 13 March 2014 to 15 June 2015.
| Milestone | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg |
|---|---|---|---|
| Started | 6 | 7 | 7 |
| Completed | 6 | 7 | 5 |
| Not completed | 0 | 0 | 2 |
| Withdrew: Voluntary withdrawal | 0 | 0 | 2 |
| Milestone | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg |
|---|---|---|---|
| Started | 5 | 7 | 5 |
| Completed | 5 | 6 | 5 |
| Not completed | 0 | 1 | 0 |
| Withdrew: Voluntary withdrawal | 0 | 1 | 0 |
| Milestone | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg |
|---|---|---|---|
| Started | 5 | 5 | 5 |
| Completed | 5 | 5 | 5 |
| Not completed | 0 | 0 | 0 |
The Spatial Span test assesses the participant's working memory. During this task, participants are presented with a board containing blue blocks randomly arranged. The rater first taps out a pattern of blocks, beginning with two blocks and increasing with participant proficiency, and the participant is tasked with tapping the same pattern. After discontinuation of this part of the subtest, the participant is then tasked with tapping out the reverse pattern after the rater's demonstration. These patterns also begin with two blocks and increase with participant proficiency. The total score for this subtest ranges from 0 (worst) to 32 (best). A positive change from Baseline indicates improvement. Analysis of Variance (ANOVA) with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
| score on a scale | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in Spatial Span Test Score | -0.199 ± 0.5239 | 0.033 ± 0.5115 | -0.066 ± 0.5239 |
The HVLT assesses the participant's verbal learning. The test consists of a list of 12 words from three taxonomic categories which are presented orally, and the participant is asked to recall as many as possible after each of three learning trials. The key outcome variable for this task is the total correct responses in the three learning trials. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
| correct responses | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in Hopkins Verbal Learning Test (HVLT) Score | -1.699 ± 1.0813 | 0.239 ± 1.0617 | 0.677 ± 1.0829 |
BOLD Functional magnetic resonance imaging (fMRI) changes in the blood-oxygen-level-dependent (BOLD) - signal, which changes in response to neural activity. Baseline fMRI measurements will be followed by rewarded delayed response Working Memory (WM) task measurements in which participants are required to remember the spatial location of a target stimulus (a dot) relative to a fixation cross. Participants are given feedback indicating success or failure. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect.
| unitless parameter estimates | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Dorsolateral Prefrontal Cortex Activation During the Rewarded Delayed Response Working Memory | 0.500 ± 0.1737 | 0.576 ± 0.1737 | 0.329 ± 0.1737 |
The CPT is a computerized test that assesses the participant's attention and vigilance. The participant was asked to attend to digits flashing on a computer screen and to click the mouse when the same string of digits flashed consecutively. The test consisted of 3 trials: the first contained 2-digit sequences, the second contained 3-digit sequences, and the third contained 4-digit sequences. Scoring was based the number of correct hits. The total score was an average of the 3 trials. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
| correct hits | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in the Continuous Performance Test (CPT) | 0.077 ± 0.1030 | 0.071 ± 0.1012 | 0.228 ± 0.1031 |
The Brief Assessment of Cognition in Schizophrenia (BACS): Symbol-Coding assesses the participant's speed of processing. The test is a timed paper-and-pencil test in which the participant uses a key to write digits that correspond to nonsense symbols. The key outcome variable for this task is the total number of correct, valid symbols in 90 seconds. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period and treatment group as fixed effects and participant nested within treatment sequence as a random effect.
| correct symbols | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in Brief Assessment of Cognition in Schizophrenia: Symbol-Coding | 0.732 ± 1.8123 | 0.885 ± 1.7695 | 2.153 ± 1.8123 |
The Category Fluency test assesses the participant's speed of processing. The test is administered orally, with the participant naming as many animals as he can in 1 minute. The key outcome variable for the test is the total number of correct, valid category words in 60 seconds. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect.
| correct words | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in Category Fluency Animal Naming Scores | -0.711 ± 0.8187 | 1.039 ± 0.8000 | -1.468 ± 0.8188 |
BOLD fMRI, a test that measures brain activity, was used during the Shifting Task at VLPF and OFX. Participants worked out which pair in a stimulus set consisting of a face and a building; transparent and overlapping, was the target. 1 pair appeared on the left of the screen, the other on the right. In each trial, participants indicated using a button box which side of the screen they thought the target was located on. Every second response, feedback was presented on the screen for 0.6 seconds, indicating whether or not the stimulus chosen was the target. If both of the last 2 choices were correct, the feedback was the word ''correct'' in green; otherwise, the feedback was the word ''incorrect'' in red. After 3 positive feedback events, a change of target occurred. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
| unitless parameter estimates | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Ventrolateral Prefrontal Cortex (VLPF) | 0.911 ± 0.3433 | 0.657 ± 0.3433 | 0.755 ± 0.3433 |
| Orbitofrontal Cortex (OFX) | 0.650 ± 0.3123 | 0.473 ± 0.3123 | 0.340 ± 0.3123 |
BOLD fMRI, a test that measures brain activity, was used during the Reward Task (Monetary Incentive Delay Test). Participants were instructed to respond as quickly as possible to a light-flash on the display screen. The flash was preceded by an arrow icon that informed participants about the consequences of their response to the flash stimulus. Four conditions were included in the paradigm, as follows: 1. Win condition (arrow up): win 2 pound sterling if the response was sufficiently fast. 2. Avoidance of loss condition (arrow down: lose 2 pound sterling if the response was too slow. 3. Verbal control (vertical double arrow): no gain or loss of money. 4. Passive control condition (horizontal double arrow): No response was required. Each of the above conditions was presented at least 10 times in a random order. ANOVA with treatment sequence, study period, and treatment as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
| unitless parameter estimates | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Ventral Striatum Activation During the Reward Trials | 0.321 ± 1.0316 | 0.544 ± 1.0316 | -0.255 ± 1.0316 |
Brain electrical activity changes were quantified with electroencephalogram (EEG) battery tests. The P300 occurs after the presentation of a novel, behaviorally relevant target stimulus embedded among irrelevant stimuli. It reflects allocation of attention and activation of immediate memory. The amplitude of P300 indexes brain actions when the mental representation of the stimulus environment is updated, while its latency indexes stimulus classification speed unrelated to response selection processes. The participants are instructed to push a button when hearing the target stimulus, but not when hearing the standard. They are asked to press the button as fast as possible. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
| microvolts (μV) | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in P300 Amplitude at the Midline Parietal Electrode (Pz) | -0.641 ± 0.9377 | -0.963 ± 0.9523 | 0.555 ± 0.9659 |
EEG, a test that measures brain electrical activity was performed during the MMN. The MMN is an auditory event related potential that is elicited by any discriminable change in auditory stimulation irrespective of the participant or participant's attention. The response to stimuli is being recorded by EEG electrodes while participants read a book. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
| μV | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in Mismatch Negativity (MMN) Amplitude at the Midline Frontal Electrode (Fz) | -0.026 ± 0.2637 | 0.368 ± 0.2660 | -0.170 ± 0.2697 |
EEG, a test that measures brain electrical activity was used. Participants had a baseline Visual Evoked Potentials (VEP) recording (2 minute checkerboard VEP) followed by a period of high frequency stimulation (2 minutes 9 Hz checkerboard stimulation). The VEP was repeated 2 minutes after the end of high frequency stimulation. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
| μV | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in Amplitude of the C1 Component of the Visual Evoked Potentials at the Midline Occipital Electrode (Oz) | -0.499 ± 0.6358 | -0.405 ± 0.6358 | -0.160 ± 0.6512 |
Participants are asked to open and close their eyes in 30 second alternating blocks to maintain an approximately constant level of arousal. The eyes closed EEG, a test that measures brain electrical activity, is dominated by alpha (8-14Hz) and the eyes open EEG dominated by beta (14-30Hz eyes open) with the two states analyzed separately to increase sensitivity to drug effects in these bands. Ratio is calculated as High Beta/Low Gamma Power. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect.
| ratio | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in High Beta/Low Gamma Power During Resting EEG | -0.127 ± 0.0689 | -0.078 ± 0.0673 | -0.040 ± 0.0709 |
EEG, a test that measures brain electrical activity, was performed during the n-back task. In the n-back task participants are required to monitor a series of letters and report when the current letter matches the letter n integers back, where n=1 (1-back) or n=2 (2-back), the latter requiring a greater working memory resources. The task requires continuous updating of information stores. In the 0-back condition (which does not require manipulation of material in working memory), participants respond to the appearance of a pre-specified letter. The task consists of alternating 30-second (s) blocks of 0-back with 1-back, and 2-back conditions, with letters displayed every 2 s for 1 s within each block. A positive change from Baseline indicates improvement. ANOVA with treatment sequence, study period, and treatment as fixed effects and subject nested within treatment sequence as a random effect was used for analysis.
| μV | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Change From Baseline in Frontal Theta Power (EEG) During N-Back Working Memory Task | -0.068 ± 0.0482 | -0.073 ± 0.0490 | 0.002 ± 0.0497 |
PANSS assesses the positive symptoms, negative symptoms, and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Positive subscale consists of 7 items which assesses the positive symptoms with subscale score ranging from 7 to 49, where higher score indicates greater severity. Negative subscale consists of 7 items which assesses the negative symptoms with subscale score ranging from 7 to 49, where higher score indicates greater severity. General psychopathology subscale consists of 16 items which assesses the general symptoms of schizophrenia with subscale score ranging from 16 to 96, where higher score indicates greater severity. A negative change from Baseline indicates improvement. ANOVA with treatment sequence, study period and treatment group as fixed effects and participant nested within treatment sequence as a random effect was used for analysis.
| score on a scale | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Total Positive Score | -0.737 ± 0.9939 | -0.670 ± 0.9821 | -0.196 ± 1.0098 |
| Total Negative Score | 1.480 ± 1.0653 | 1.580 ± 1.0484 | 0.650 ± 1.0876 |
| Total General Psychopathology Score | 0.313 ± 1.5978 | -1.457 ± 1.5700 | -0.959 ± 1.6344 |
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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
| percentage of participants | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Percentage of Participants Who Experience at Least 1 Treatment-Emergent Adverse Event | 56.3 | 41.2 | 47.4 |
Percentage of participants with markedly abnormal safety laboratory tests (Hematology, Serum Chemistry and Urinalysis) collected throughout the study.
| percentage of participants | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg |
|---|---|---|---|
| Hematology | 0 | 0 | 20.0 |
| Serum Chemistry | 20.0 | 14.3 | 0 |
| Urinalysis | 0 | 0 | 0 |
Vital signs were oral body temperature, respiration rate, supine blood pressure (after 5 minutes resting), and pulse rate.
| percentage of participants | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurement | 0 | 0 | 0 |
Collected over Up to 63 Days. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | — | 1/16 (6.3%) | 8/16 (50%) |
| Roflumilast 100 μg | — | 0/17 (0%) | 7/17 (41.2%) |
| Roflumilast 250 μg | — | 0/19 (0%) | 9/19 (47.4%) |
| Event | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| Suicide attemptPsychiatric disorders | 1/16 | 0/17 | 0/19 |
| Event | Placebo | Roflumilast 100 μg | Roflumilast 250 μg |
|---|---|---|---|
| NasopharyngitisInfections and infestations | 1/16 | 2/17 | 1/19 |
| HeadacheNervous system disorders | 1/16 | 1/17 | 2/19 |
| PalpitationsCardiac disorders | 1/16 | 0/17 | 0/19 |
| ToothacheGastrointestinal disorders | 1/16 | 1/17 | 1/19 |
| Catheter site bruiseGeneral disorders | 1/16 | 0/17 | 0/19 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 1/16 | 0/17 | 0/19 |
| Suicidal ideationPsychiatric disorders | 1/16 | 0/17 | 0/19 |
| RashSkin and subcutaneous tissue disorders | 1/16 | 0/17 | 0/19 |
| Rash macularSkin and subcutaneous tissue disorders | 1/16 | 0/17 | 0/19 |
| Scar painSkin and subcutaneous tissue disorders | 1/16 | 0/17 | 0/19 |
All randomized participants.
| Age, Continuous(years) | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg | Total |
|---|---|---|---|---|
| Mean | 34.8 ± 10.13 | 36.9 ± 10.38 | 48.1 ± 10.93 | 40.2 ± 11.63 |
| Sex: Female, Male(Participants) | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg | Total |
|---|---|---|---|---|
| Female | 2 | 2 | 3 | 7 |
| Male | 4 | 5 | 4 | 13 |
| Race/Ethnicity, Customized(participants) | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg | Total |
|---|---|---|---|---|
| Asian | 0 | 1 | 1 | 2 |
| Black or African American | 5 | 5 | 4 | 14 |
| White | 1 | 1 | 2 | 4 |
| Region of Enrollment(participants) | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg | Total |
|---|---|---|---|---|
| United Kingdom | 6 | 7 | 7 | 20 |
| Height(cm) | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg | Total |
|---|---|---|---|---|
| Mean | 169.8 ± 8.68 | 175.0 ± 7.64 | 169.1 ± 10.96 | 171.4 ± 9.14 |
| Weight(kg) | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg | Total |
|---|---|---|---|---|
| Mean | 79.38 ± 4.804 | 85.09 ± 17.406 | 81.41 ± 15.470 | 82.09 ± 13.532 |
| Body Mass Index (BMI)(kg/m^2) | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg | Total |
|---|---|---|---|---|
| Mean | 27.75 ± 3.871 | 27.56 ± 3.823 | 28.20 ± 3.158 | 27.84 ± 3.433 |
| Tobacco Classification(participants) | Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Roflumilast 250 μg + Placebo + Roflumilast 100 μg | Total |
|---|---|---|---|---|
| Never used tobacco | 1 | 1 | 3 | 5 |
| Current tobacco user | 2 | 4 | 3 | 9 |
| Ex-tobacco user | 3 | 2 | 1 | 6 |
1 further baseline measures are reported on the registry.
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