Roflumilast Plus Antipsychotics Proof of Mechanism Study in Schizophrenia

Inclusion Criteria

• 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.

Exclusion Criteria

• 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 dis