Roflumilast Plus Antipsychotics Proof of Mechanism Study in Schizophrenia

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.

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.

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.