Roflumilast Plus Antipsychotics Proof of Mechanism Study in Schizophrenia

NCT02079844 | Completed Phase 1 Results

• 4 other identifiers: ROF-SCHZ_1062012-002091-13U1111-1152-389912/SC/0443
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Schizophrenia

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

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

Secondary Outcomes (14)

• Change From Baseline in the Continuous Performance Test (CPT)

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

• Change From Baseline in Brief Assessment of Cognition in Schizophrenia: Symbol-Coding

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

• Change From Baseline in Category Fluency Animal Naming Scores

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

• Ventrolateral Prefrontal (VLPF) Cortex and Orbitofrontal (OFX) Cortex Activation During the Shift Trials

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

• Ventral Striatum Activation During the Reward Trials

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

Study Arms (3)

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.

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.

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.

Drug: Roflumilast; Drug: Placebo; Drug: Second generation antipsychotic

Interventions

Roflumilast DRUG

Roflumilast tablets

Also known as: DALIRESP®, DAXAS®

Placebo + Roflumilast 100 μg + Roflumilast 250 μg; Roflumilast 100 μg + Roflumilast 250 μg + Placebo; Roflumilast 250 μg + Placebo + Roflumilast 100 μg

Placebo DRUG

Roflumilast placebo-matching tablets

Placebo + Roflumilast 100 μg + Roflumilast 250 μg; Roflumilast 100 μg + Roflumilast 250 μg + Placebo; Roflumilast 250 μg + Placebo + Roflumilast 100 μg

Second generation antipsychotic DRUG

Second Generation Antipsychotic (SGA) medication for standard of care therapy will be sourced and managed locally by the site.

Placebo + Roflumilast 100 μg + Roflumilast 250 μg; Roflumilast 100 μg + Roflumilast 250 μg + Placebo; Roflumilast 250 μg + Placebo + Roflumilast 100 μg

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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).
• 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).

Sponsors & Collaborators

• Takeda: lead

Study Sites (1)

Unknown Facility

Denmark Hill, London, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 30536081 DERIVED

MeSH Terms

Conditions

Schizophrenia

Interventions

Roflumilast

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Results Point of Contact

• Title: Medical Director, Clinical Science
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director Clinical Science

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2014
• First Posted: March 6, 2014
• Study Start: March 1, 2014
• Primary Completion: June 1, 2015
• Study Completion: June 1, 2015
• Last Updated: October 3, 2016
• Results First Posted: October 3, 2016

Record last verified: 2016-08

Locations

GB (1)