A Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Co-Administration of Roluperidone and Olanzapine in Adult Subjects With Moderate to Severe Negative Symptoms of Schizophrenia

A Phase 1b, In-Patient Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of the Co-Administration of Roluperidone and Olanzapine in Adult Subjects With Moderate to Severe Negative Symptoms of Schizophrenia

The goal of this clinical trial is to evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of the Co-Administration of Roluperidone and Olanzapine in Adult Subjects with Moderate to Severe Negative Symptoms of Schizophrenia.

The main question this clinical trial aims to answer are the pharmacodynamic and pharmacokinetic effects and safety of the concomitant therapy of Roluperidone with an established and widely used antipsychotic, such as olanzapine in order to provide further guidance to clinical practitioners that may prescribe off-label use of these drugs concomitantly in clinical practice.

Eligible Participants will undergo the following study phases in the clinic:

• Screening Phase: Between 2 and up to 28 days during which study eligibility will be established and subjects receiving psychotropics will be washed out. Subjects will remain inpatient at the clinical site at least through the end of Treatment Phase 2.
• Treatment Phase 1: After the Baseline Visit, Roluperidone 64 mg/day will be administered as a monotherapy for 7 days (Days 1-7).
• Treatment Phase 2: Concomitant administration of Olanzapine 10 mg/day and Roluperidone 64 mg/day for 10 days, starting on Day 8 (Days 8-17). Subjects may be discharged from the clinic at least 48 hours after the last administration of the study drugs and after the collection of the last plasma sample; however, the inpatient period may be extended at the discretion of the investigator.

End of Study (EOS): Will take place at least 14 days after the last dose of the study.

Inclusion Criteria:

• Provided informed consent
• Body mass index (BMI) < 35 kg/m2
• Meets the diagnostic criteria for schizophrenia as defined in the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5), as established by a full psychiatric interview in conjunction with the Mini International Neuropsychiatric Interview (MINI)
• Documented diagnosis of schizophrenia for at least 1 year before screening
• Stable in terms of both positive and negative symptoms of schizophrenia over the last 3 months
• Score of > 20 on the PANSS original negative symptoms subscale (Sum of N1+N2+N3+N4+N5+N6+N7) at Screening and Baseline (Day -1) AND < 4 points absolute difference between the 2 visits
• Discontinued psychotropic medications without risk to their clinical status or safety by Baseline
• Female subject, if not of childbearing potential, must be a woman who is post-menopausal or permanently sterilized
• Female subject, if of childbearing potential, must test negative for pregnancy and must be using a double barrier contraceptive method
• Must be normal metabolizer for P450 CYP 2D6, defined as a subject that has at least one functional allele (eg, *1, *2 or *35), as determined by study-specific genotyping test before the first drug dose is administered
• Has a caregiver or family member or health care personnel who can provide information towards assessment and support the subject in terms of compliance with the protocol

Exclusion Criteria:

• Current major depressive disorder, bipolar disorder, panic disorder, obsessive compulsive disorder, or intellectual disability (intellectual developmental disorder diagnosed by age 14)

• PANSS item score of > 4 on:

  • P4 Excitement/Hyperactivity
  • P6 Suspiciousness/persecution
  • P7 Hostility
  • G8 Uncooperativeness
  • G14 Poor impulse control

• CDSS total score > 6

• Score of ≥ 2 on any 2 of items 1, 2, or 3, or a score of ≥ 3 on item 4 of the Barnes Akathisia Rating Scale (BARS)

• Has had electroconvulsive therapy (ECT), vagal nerve stimulation (VNS), or repetitive trans-cranial magnetic stimulation (r-TMS) within the 6 months prior to the Screening visit or who are scheduled for ECT, VNS, or r-TMS at any time during the study

• Positive urine drug screen for drugs of abuse

• Currently taking proton pump inhibitors (PPI)

• Current systemic infection (eg, Hepatitis B, Hepatitis C, human immunodeficiency virus [HIV], tuberculosis)

• Requires or may require concomitant treatment with any other medication likely to increase QT interval

• Requires medication inhibiting CYP2D6

• Safety laboratory results show one or more of the following: potassium <3.4 mmol/L, or calcium <2.07 mmol/L, or magnesium <0.70 mmol/L