Roflumilast Plus Antipsychotics Proof of Mechanism Study in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Intervention: Roflumilast; Placebo; Second generation antipsychotic
Intervention description: Roflumilast tablets; Roflumilast placebo-matching tablets; Second Generation Antipsychotic (SGA) medication for standard of care therapy will be sourced and managed locally by the site.
Intervention MeSH terms: Antipsychotic Agents
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: Drug therapy

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. In the opinion of the investigator, the participant is capable of understanding and
             complying with protocol requirements.

          2. Signs and dates a written, informed consent form and any required privacy
             authorization prior to the initiation of any study procedures.

          3. Meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual of
             Mental Disorders (DSM-V) by the Mini International Neuropsychiatric Interview (MINI).

          4. On a stable dose of second generation antipsychotics (SGA) for at least 2 months as
             documented by medical history and assessed by site staff.

          5. 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.

          6. Has cognitive impairment as per investigator judgment.

          7. Is aged 18 to 55 years, inclusive, at the time of informed consent.

          8. Weighs at least 60 kg and has a body mass index (BMI) between 18 and 32 kg/m^2
             inclusive at Screening.

          9. 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.

         10. 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.

         11. 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.

        Exclusion Criteria:

          1. Has received any investigational compound within 30 days prior to the first dose of
             study medication.

          2. Has received roflumilast in a previous clinical study or as a therapeutic agent.

          3. 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.

          4. 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.

          5. History of claustrophobia or inability to tolerate mock scanner environment during
             habituation/screening session.

          6. 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).

          7. Has a known hypersensitivity to any component of the formulation of roflumilast.

          8. Has a positive urine drug result for drugs of abuse at Screening or Day 1 for each
             treatment period.

          9. 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.

         10. The participant with a history in the last year or currently receiving treatment with
             clozapine.

         11. Has taken any excluded medication, supplements, or food products.

         12. 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.

         13. 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.

         14. 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).

         15. History of any surgical intervention known to impact absorption (eg, bariatric surgery
             or bowel resection).

         16. 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.

         17. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C
             antibody (HCV), human immunodeficiency virus (HIV) antibody/antigen at Screening.

         18. Has poor peripheral venous access.

         19. 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.

         20. 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.

         21. 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.

         22. Has abnormal Screening or Day 1 of Period 1 vital sign values that suggest a
             clinically significant underlying disease.

         23. 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).

         24. Has a current diagnosis of a significant psychiatric illness other than schizophrenia,
             per DSM-V and is in an acute phase/episode.

         25. In the opinion of the investigator or sponsor, the participant is unsuitable for
             inclusion in the study.