SchizophreniaPhase 1NCT02079844
Roflumilast Plus Antipsychotics Proof of Mechanism Study in Schizophrenia
A Phase 1 study testing Roflumilast and Second generation antipsychotic in people with Schizophrenia, run by Takeda at 1 site in United Kingdom.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Schizophrenia
- What is being tested?
- Roflumilast and Second generation antipsychotic
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Mar 2014to Jun 2015
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
- Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
- Meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) by the Mini International Neuropsychiatric Interview (MINI).
- On a stable dose of second generation antipsychotics (SGA) for at least 2 months as documented by medical history and assessed by site staff.
- Meets the following symptom criteria: (a) Positive and Negative Syndrome Scale (PANSS) Conceptual Disorganization item score ≤4 (b) PANSS Hallucinatory Behavior or Unusual Thought Content item scores ≤4 (c) PANSS Negative Subscale scores on all items ≤4.
- Has cognitive impairment as per investigator judgment.
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- Is aged 18 to 55 years, inclusive, at the time of informed consent.
- Weighs at least 60 kg and has a body mass index (BMI) between 18 and 32 kg/m^2 inclusive at Screening.
- A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose.
- A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use acceptable methods of contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose.
- Has clinical laboratory evaluations (including clinical chemistry, hematology and complete urinalysis) within the reference range for the testing laboratory, unless the results are deemed not to be clinically significant (NCS) by the investigator at screening and Day 1 of Period 1.
Who cannot join
- Has received any investigational compound within 30 days prior to the first dose of study medication.
- Has received roflumilast in a previous clinical study or as a therapeutic agent.
- Is an immediate family member, study site employee, or in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
- Has uncontrolled, clinically significant neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality which may impact the ability of the participant to participate or potentially confound the study results.
- History of claustrophobia or inability to tolerate mock scanner environment during habituation/screening session.
- Fulfillment of any of the magnetic resonance imaging (MRI) contraindications on the standard radiography screening questionnaire at the Centre for Neuroimaging Sciences, Institute of Psychiatry, King's College London (ie, history of surgery involving metal implants, metal body piercing, dentures, dental plates or bridges, any implanted device that is electrically, magnetically, and mechanically activated).
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- Has a known hypersensitivity to any component of the formulation of roflumilast.
- Has a positive urine drug result for drugs of abuse at Screening or Day 1 for each treatment period.
- Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 6 months prior to the screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.
- The participant with a history in the last year or currently receiving treatment with clozapine.
- Has taken any excluded medication, supplements, or food products.
- If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.
- Has evidence of current cardiovascular, hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking roflumilast or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.
- Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, or erosive esophagitis frequent occurrence [more than once per week] of heartburn).
- History of any surgical intervention known to impact absorption (eg, bariatric surgery or bowel resection).
- Has a history of cancer within the past 5 years prior to the first dose of study medication. This criterion does not include those participants with basal cell or stage I squamous cell carcinoma of the skin who are eligible.
- Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV), human immunodeficiency virus (HIV) antibody/antigen at Screening.
- Has poor peripheral venous access.
- Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 3 months prior to Day 1.
- Has a Screening or Day 1 of Period 1 abnormal (clinically significant) electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator.
- Has abnormal Screening or Day 1 of Period 1 laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5 the upper limits of normal.
- Has abnormal Screening or Day 1 of Period 1 vital sign values that suggest a clinically significant underlying disease.
- Has a risk of suicide according to the Investigator's clinical judgment (eg, per Columbia-Suicide Severity Rating Scale [C-SSRS] or has made a suicide attempt within 6 months prior to screening visit).
- Has a current diagnosis of a significant psychiatric illness other than schizophrenia, per DSM-V and is in an acute phase/episode.
- In the opinion of the investigator or sponsor, the participant is unsuitable for inclusion in the study.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized, Double-Blind, Placebo Controlled, 3-period, Proof of Mechanism, Cross-Over Study of Roflumilast Administered up to Steady State to Evaluate the Effects of Add-on Roflumilast to Second Generation Antipsychotics on Cognitive Impairment as Well as Brain Imaging (ie, fMRI) and Electrical Activity (ie, EEG) Changes Observed in Subjects With Stable Schizophrenia
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.
Read the detailed description
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:
- Roflumilast Dose A + SGA
- Roflumilast Dose B +SGA
- Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient + SGA.
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.
- Conditions
- Schizophrenia
- Being tested
- Roflumilast, Placebo, Second generation antipsychotic
- Keywords
- Drug therapy
- Medical subject headings
- Schizophrenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RoflumilastDrug
Also called DALIRESP®, DAXAS®
Roflumilast tablets
PlaceboDrug
Roflumilast placebo-matching tablets
Second generation antipsychoticDrug
Second Generation Antipsychotic (SGA) medication for standard of care therapy will be sourced and managed locally by the site.
| Study group | Role | What they receive |
|---|---|---|
| Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Experimental | 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. Receives: Drug: Roflumilast; Drug: Placebo; Drug: Second generation antipsychotic |
| Roflumilast 100 μg + Roflumilast 250 μg + Placebo | Experimental | 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. Receives: Drug: Roflumilast; Drug: Placebo; Drug: Second generation antipsychotic |
| Roflumilast 250 μg + Placebo + Roflumilast 100 μg | Experimental | 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. Receives: Drug: Roflumilast; Drug: Placebo; Drug: Second generation antipsychotic |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Secondary outcomes (14)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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:
- Win condition (arrow up): win 2 pound sterling if the response was sufficiently fast.
- Avoidance of loss condition (arrow down: lose 2 pound sterling if the response was too slow.
- Verbal control (vertical double arrow): no gain or loss of money.
- 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: From Day 1 until Day 63
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Mar 2014 (estimated)
- Study startMar 2014
- Primary completionJun 2015
- Study completionJun 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- More trials run by TakedaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Takeda
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director Clinical Science, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02079844
- Sponsor's protocol ID
- ROF-SCHZ_106
- Other IDs
- 2012-002091-13, U1111-1152-3899, 12/SC/0443
- Status last verified
- Aug 2016
- First submitted
- 4 Mar 2014
- Last updated
- 3 Oct 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Gilleen J, Farah Y, Davison C, Kerins S, Valdearenas L, Uz T, Lahu G, Tsai M, Ogrinc F, Reichenberg A, Williams SC, Mehta MA, Shergill SS. An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients. Psychopharmacology (Berl). 2021 May;238(5):1279-1289. doi: 10.1007/s00213-018-5134-y. Epub 2018 Dec 8.
PubMed 30536081
Study at a glance
From the registry record, last updated by the sponsor on 3 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double-Blind, Placebo Controlled, 3-period, Proof of Mechanism, Cross-Over Study of Roflumilast Administered up to Steady State to Evaluate the Effects of Add-on Roflumilast to Second Generation Antipsychotics on Cognitive Impairment as Well as Brain Imaging (ie, fMRI) and Electrical Activity (ie, EEG) Changes Observed in Subjects With Stable Schizophrenia
- ClinicalTrials.gov ID
- NCT02079844
- Acronym / sponsor ID
- ROF-SCHZ_106
- Conditions
- Schizophrenia
- Keywords
- Drug therapy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- TakedaIndustry (pharma, biotech, devices)
- Study start
- Mar 2014
- Primary completion
- Jun 2015 (actual)
- Study completion
- Jun 2015 (actual)
- First posted
- 6 Mar 2014 (estimated)
- Results
- Posted 3 Oct 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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:
- Roflumilast Dose A + SGA
- Roflumilast Dose B +SGA
- Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient + SGA.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Placebo + Roflumilast 100 μg + Roflumilast 250 μg | Experimental | Drug: Roflumilast, Drug: Placebo, Drug: Second generation antipsychoticRoflumilast 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 | Experimental | Drug: Roflumilast, Drug: Placebo, Drug: Second generation antipsychoticRoflumilast 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 | Experimental | Drug: Roflumilast, Drug: Placebo, Drug: Second generation antipsychoticRoflumilast 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. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (11 listed)
- In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
- Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
- Meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) by the Mini International Neuropsychiatric Interview (MINI).
- On a stable dose of second generation antipsychotics (SGA) for at least 2 months as documented by medical history and assessed by site staff.
- Meets the following symptom criteria: (a) Positive and Negative Syndrome Scale (PANSS) Conceptual Disorganization item score ≤4 (b) PANSS Hallucinatory Behavior or Unusual Thought Content item scores ≤4 (c) PANSS Negative Subscale scores on all items ≤4.
Key exclusion criteria (25 listed)
- Has received any investigational compound within 30 days prior to the first dose of study medication.
- Has received roflumilast in a previous clinical study or as a therapeutic agent.
- Is an immediate family member, study site employee, or in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
- Has uncontrolled, clinically significant neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality which may impact the ability of the participant to participate or potentially confound the study results.
- History of claustrophobia or inability to tolerate mock scanner environment during habituation/screening session.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RoflumilastAlso: DALIRESP®, DAXAS®Roflumilast tablets | Drug | Placebo + Roflumilast 100 μg + Roflumilast 250 μg, Roflumilast 100 μg + Roflumilast 250 μg + Placebo, Roflumilast 250 μg + Placebo + Roflumilast 100 μg |
| PlaceboRoflumilast placebo-matching tablets | Drug | Placebo + Roflumilast 100 μg + Roflumilast 250 μg, Roflumilast 100 μg + Roflumilast 250 μg + Placebo, Roflumilast 250 μg + Placebo + Roflumilast 100 μg |
| Second generation antipsychoticSecond Generation Antipsychotic (SGA) medication for standard of care therapy will be sourced and managed locally by the site. | Drug | Placebo + Roflumilast 100 μg + Roflumilast 250 μg, Roflumilast 100 μg + Roflumilast 250 μg + Placebo, Roflumilast 250 μg + Placebo + Roflumilast 100 μg |
Primary outcome
Change From Baseline in Spatial Span Test Score
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
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.
Change From Baseline in Hopkins Verbal Learning Test (HVLT) Score
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
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.
Dorsolateral Prefrontal Cortex Activation During the Rewarded Delayed Response Working Memory
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
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.
14 secondary outcomes
Change From Baseline in the Continuous Performance Test (CPT)
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
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Change From Baseline in Category Fluency Animal Naming Scores
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
Time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3
Ventral Striatum Activation During the Reward Trials
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)
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)
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)
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
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
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
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
Time frame: From Day 1 until Day 63
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests
Time frame: From Day 1 until Day 63
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurement
Time frame: From Day 1 until Day 63
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Oct 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 30536081Gilleen J, Farah Y, Davison C, Kerins S, Valdearenas L, Uz T, Lahu G, Tsai M, Ogrinc F, Reichenberg A, Williams SC, Mehta MA, Shergill SS. An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients. Psychopharmacology (Berl). 2021 May;238(5):1279-1289. doi: 10.1007/s00213-018-5134-y. Epub 2018 Dec 8.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director Clinical Science study director
Takeda
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Roflumilast and Second generation antipsychotic in people with Schizophrenia, run by Takeda at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Oct 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Oct 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline in Spatial Span Test Score (time frame: Baseline and Day 8 of Treatment Periods 1, 2 and 3). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02079844, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Oct 2016.