Trial Outcomes & Findings for Roflumilast Plus Antipsychotics Proof of Mechanism Study in Schizophrenia (NCT NCT02079844)

NCT ID: NCT02079844

Last Updated: 2016-10-03

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 20 participants
• Primary outcome timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3
• Results posted on: 2016-10-03

Participant Flow

Participants took part in the study at 1 investigative site in the United Kingdom from 13 March 2014 to 15 June 2015.

Participants with a diagnosis of schizophrenia were enrolled equally in 1 of 3 treatment sequences which determined the order the following 3 treatments were received: placebo, once a day roflumilast 100 μg, roflumilast 250 μg.

Participant milestones

Measure	Placebo + Roflumilast 100 μg + Roflumilast 250 μg 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.	Roflumilast 100 μg + Roflumilast 250 μg + Placebo 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.	Roflumilast 250 μg + Placebo + Roflumilast 100 μg 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.
Treatment Period 1 STARTED	6	7	7
Treatment Period 1 COMPLETED	6	7	5
Treatment Period 1 NOT COMPLETED	0	0	2
Treatment Period 2 STARTED	5	7	5
Treatment Period 2 COMPLETED	5	6	5
Treatment Period 2 NOT COMPLETED	0	1	0
Treatment Period 3 STARTED	5	5	5
Treatment Period 3 COMPLETED	5	5	5
Treatment Period 3 NOT COMPLETED	0	0	0

Reasons for withdrawal

Measure	Placebo + Roflumilast 100 μg + Roflumilast 250 μg 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.	Roflumilast 100 μg + Roflumilast 250 μg + Placebo 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.	Roflumilast 250 μg + Placebo + Roflumilast 100 μg 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.
Treatment Period 1 Voluntary Withdrawal	0	0	2
Treatment Period 2 Voluntary Withdrawal	0	1	0

Baseline Characteristics

Roflumilast Plus Antipsychotics Proof of Mechanism Study in Schizophrenia

Baseline characteristics by cohort

Measure	Placebo + Roflumilast 100 μg + Roflumilast 250 μg n=6 Participants 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.	Roflumilast 100 μg + Roflumilast 250 μg + Placebo n=7 Participants 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.	Roflumilast 250 μg + Placebo + Roflumilast 100 μg n=7 Participants 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.	Total n=20 Participants Total of all reporting groups
Age, Continuous	34.8 years STANDARD_DEVIATION 10.13 • n=5 Participants	36.9 years STANDARD_DEVIATION 10.38 • n=7 Participants	48.1 years STANDARD_DEVIATION 10.93 • n=5 Participants	40.2 years STANDARD_DEVIATION 11.63 • n=4 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	13 Participants n=4 Participants
Race/Ethnicity, Customized Asian	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants
Race/Ethnicity, Customized Black or African American	5 participants n=5 Participants	5 participants n=7 Participants	4 participants n=5 Participants	14 participants n=4 Participants
Race/Ethnicity, Customized White	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants	4 participants n=4 Participants
Region of Enrollment United Kingdom	6 participants n=5 Participants	7 participants n=7 Participants	7 participants n=5 Participants	20 participants n=4 Participants
Height	169.8 cm STANDARD_DEVIATION 8.68 • n=5 Participants	175.0 cm STANDARD_DEVIATION 7.64 • n=7 Participants	169.1 cm STANDARD_DEVIATION 10.96 • n=5 Participants	171.4 cm STANDARD_DEVIATION 9.14 • n=4 Participants
Weight	79.38 kg STANDARD_DEVIATION 4.804 • n=5 Participants	85.09 kg STANDARD_DEVIATION 17.406 • n=7 Participants	81.41 kg STANDARD_DEVIATION 15.470 • n=5 Participants	82.09 kg STANDARD_DEVIATION 13.532 • n=4 Participants
Body Mass Index (BMI)	27.75 kg/m^2 STANDARD_DEVIATION 3.871 • n=5 Participants	27.56 kg/m^2 STANDARD_DEVIATION 3.823 • n=7 Participants	28.20 kg/m^2 STANDARD_DEVIATION 3.158 • n=5 Participants	27.84 kg/m^2 STANDARD_DEVIATION 3.433 • n=4 Participants
Tobacco Classification Never used tobacco	1 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants	5 participants n=4 Participants
Tobacco Classification Current tobacco user	2 participants n=5 Participants	4 participants n=7 Participants	3 participants n=5 Participants	9 participants n=4 Participants
Tobacco Classification Ex-tobacco user	3 participants n=5 Participants	2 participants n=7 Participants	1 participants n=5 Participants	6 participants n=4 Participants
Caffeine Classification Consumes caffeine	4 participants n=5 Participants	5 participants n=7 Participants	5 participants n=5 Participants	14 participants n=4 Participants
Caffeine Classification Does not consume caffeine	2 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants	6 participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available at both Baseline and Day 8 for analysis.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=16 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in Spatial Span Test Score	-0.199 score on a scale Standard Error 0.5239	0.033 score on a scale Standard Error 0.5115	-0.066 score on a scale Standard Error 0.5239

PRIMARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available at both Baseline and Day 8 for analysis.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=16 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in Hopkins Verbal Learning Test (HVLT) Score	-1.699 correct responses Standard Error 1.0813	0.239 correct responses Standard Error 1.0617	0.677 correct responses Standard Error 1.0829

PRIMARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis.

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.

Outcome measures

Measure	Placebo n=10 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=10 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=10 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Dorsolateral Prefrontal Cortex Activation During the Rewarded Delayed Response Working Memory	0.500 unitless parameter estimates Standard Error 0.1737	0.576 unitless parameter estimates Standard Error 0.1737	0.329 unitless parameter estimates Standard Error 0.1737

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=16 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in the Continuous Performance Test (CPT)	0.077 correct hits Standard Error 0.1030	0.071 correct hits Standard Error 0.1012	0.228 correct hits Standard Error 0.1031

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=16 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in Brief Assessment of Cognition in Schizophrenia: Symbol-Coding	0.732 correct symbols Standard Error 1.8123	0.885 correct symbols Standard Error 1.7695	2.153 correct symbols Standard Error 1.8123

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=16 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in Category Fluency Animal Naming Scores	-0.711 correct words Standard Error 0.8187	1.039 correct words Standard Error 0.8000	-1.468 correct words Standard Error 0.8188

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis.

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.

Outcome measures

Measure	Placebo n=10 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=10 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=10 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Ventrolateral Prefrontal (VLPF) Cortex and Orbitofrontal (OFX) Cortex Activation During the Shift Trials Ventrolateral Prefrontal Cortex (VLPF)	0.911 unitless parameter estimates Standard Error 0.3433	0.657 unitless parameter estimates Standard Error 0.3433	0.755 unitless parameter estimates Standard Error 0.3433
Ventrolateral Prefrontal (VLPF) Cortex and Orbitofrontal (OFX) Cortex Activation During the Shift Trials Orbitofrontal Cortex (OFX)	0.650 unitless parameter estimates Standard Error 0.3123	0.473 unitless parameter estimates Standard Error 0.3123	0.340 unitless parameter estimates Standard Error 0.3123

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis.

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.

Outcome measures

Measure	Placebo n=8 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=8 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=8 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Ventral Striatum Activation During the Reward Trials	0.321 unitless parameter estimates Standard Error 1.0316	0.544 unitless parameter estimates Standard Error 1.0316	-0.255 unitless parameter estimates Standard Error 1.0316

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis at Baseline and Day 8.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=16 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=15 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in P300 Amplitude at the Midline Parietal Electrode (Pz)	-0.641 microvolts (μV) Standard Error 0.9377	-0.963 microvolts (μV) Standard Error 0.9523	0.555 microvolts (μV) Standard Error 0.9659

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis at Baseline and Day 8.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=16 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=15 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in Mismatch Negativity (MMN) Amplitude at the Midline Frontal Electrode (Fz)	-0.026 μV Standard Error 0.2637	0.368 μV Standard Error 0.2660	-0.170 μV Standard Error 0.2697

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=16 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=15 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in Amplitude of the C1 Component of the Visual Evoked Potentials at the Midline Occipital Electrode (Oz)	-0.499 μV Standard Error 0.6358	-0.405 μV Standard Error 0.6358	-0.160 μV Standard Error 0.6512

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis at Baseline and Day 8.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=15 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in High Beta/Low Gamma Power During Resting EEG	-0.127 ratio Standard Error 0.0689	-0.078 ratio Standard Error 0.0673	-0.040 ratio Standard Error 0.0709

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis at Baseline and Day 8.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=16 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=15 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in Frontal Theta Power (EEG) During N-Back Working Memory Task	-0.068 μV Standard Error 0.0482	-0.073 μV Standard Error 0.0490	0.002 μV Standard Error 0.0497

SECONDARY outcome

Timeframe: Baseline and Day 8 of Treatment Periods 1, 2 and 3

Population: Participants from the Pharmacodynamic Analysis Set, all randomized participants who received at least 1 dose of study drug and had at least 1 pharmacodynamic result post-dose, with data available for analysis at Baseline and Day 8.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=15 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score Total Positive Score	-0.737 score on a scale Standard Error 0.9939	-0.670 score on a scale Standard Error 0.9821	-0.196 score on a scale Standard Error 1.0098
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score Total Negative Score	1.480 score on a scale Standard Error 1.0653	1.580 score on a scale Standard Error 1.0484	0.650 score on a scale Standard Error 1.0876
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score Total General Psychopathology Score	0.313 score on a scale Standard Error 1.5978	-1.457 score on a scale Standard Error 1.5700	-0.959 score on a scale Standard Error 1.6344

SECONDARY outcome

Timeframe: From Day 1 until Day 63

Population: Safety population included all randomized participants who received at least 1 dose of study drug.

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.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=19 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Percentage of Participants Who Experience at Least 1 Treatment-Emergent Adverse Event	56.3 percentage of participants	41.2 percentage of participants	47.4 percentage of participants

SECONDARY outcome

Timeframe: From Day 1 until Day 63

Population: Safety population, including all randomized participants who received at least 1 dose of study drug and completed the laboratory tests during treatment.

Percentage of participants with markedly abnormal safety laboratory tests (Hematology, Serum Chemistry and Urinalysis) collected throughout the study.

Outcome measures

Measure	Placebo n=5 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=7 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=5 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests Serum Chemistry	20.0 percentage of participants	14.3 percentage of participants	0 percentage of participants
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests Hematology	0 percentage of participants	0 percentage of participants	20.0 percentage of participants
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests Urinalysis	0 percentage of participants	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: From Day 1 until Day 63

Population: Safety population, including all randomized participants who received at least 1 dose of study drug and completed the vital sign tests on Day 8 of each treatment period.

Vital signs were oral body temperature, respiration rate, supine blood pressure (after 5 minutes resting), and pulse rate.

Outcome measures

Measure	Placebo n=16 Participants Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 Participants Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=16 Participants Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurement	0 percentage of participants	0 percentage of participants	0 percentage of participants

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Roflumilast 100 μg

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Roflumilast 250 μg

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=16 participants at risk Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 participants at risk Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=19 participants at risk Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Psychiatric disorders Suicide attempt	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Other adverse events

Measure	Placebo n=16 participants at risk Roflumilast placebo-matching tablets orally, once, daily on Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 100 μg n=17 participants at risk Roflumilast 100 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.	Roflumilast 250 μg n=19 participants at risk Roflumilast 250 μg tablets, orally, once, daily, Days 1 through 8. All participants took a stable dose of second generation antipsychotics throughout the duration of the treatment period.
Cardiac disorders Palpitations	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Toothache	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diarrhoea	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Gingival swelling	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Nausea	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Vomiting	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Catheter site bruise	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Influenza like illness	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Nasopharyngitis	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	11.8% 2/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Beta haemolytic streptococcal infection	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Tinea pedis	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Arthralgia	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Headache	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	10.5% 2/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Anxiety	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Depressed mood	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Insomnia	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Middle insomnia	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.9% 1/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Suicidal ideation	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Eczema	0.00% 0/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Rash	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Rash macular	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Scar pain	6.2% 1/16 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/17 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 63 Days At each visit the investigator had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Additional Information

Medical Director, Clinical Science

Takeda

Phone: +1-877-825-3327

Email: trialdisclosures@takeda.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER