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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Negative Symptoms in Schizophrenia

Intervention / Treatment
-----------------
* Drug: Roluperidone 64 mg
* Drug: Olanzapine 10 MG


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Phase 1<br>Roluperidone 64 mg monotherapy administered as an oral dose daily for 7 days on Days 1-7. | Drug: Roluperidone 64 mg<br>* 64 mg/day oral<br>* Other names: MIN-101;|
| Experimental: Treatment Phase 2<br>Roluperidone 64 mg oral and olanzapine 10 mg oral administered at the same time daily for 10 days on Days 8-17. | Drug: Roluperidone 64 mg<br>* 64 mg/day oral<br>* Other names: MIN-101;Drug: Olanzapine 10 MG<br>* 10 mg/day oral<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Adverse event assessment throughout the study from the time of informed consent form signature to End of Study. | Up to Day 31 | 
| Abnormal Involuntary Movement Scale (AIMS) | AIMS is a rating scale to measure tardive dyskinesia. The AIMS test has a total of 12 items rating involuntary movements of various areas of the patient's body. These items are rated on a 5-point scale of severity from 0-4. The scale is rated from 0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe. Two of the 12 items refer to dental care. The remaining 10 items refer to body movements themselves. | Screening, Baseline, Days 7, 8, and 17, and Day 31 | 
| Barnes Akathisia Rating Scale (BARS) | BARS is a multiple-choice questionnaire that clinicians may use to provide an assessment of akathisia. The clinician or rater is instructed to observe the subject while standing and while sitting, at least 2 minutes each (total of at least 4 minutes in total). There are 4 areas where the subject is to be evaluated, 1 of these is objective, 2 are subjective, and the final is a global assessment. The BARS scale has 3 items that are rated from 0 (absence/no distress) to 3 (most severe). The BARS rating scale is scored by summing the scales for Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress Related to Restlessness yielding a total score ranging from 0 to 9. The Total score, which has a possible range from 0-9, is reported. Higher scores imply worse outcome. | Screening, Baseline, Days 7, 8, and 17, and Day 31 | 
| Columbia Suicide Severity Rating Scale (C-SSRS) | C-SSRS is a measure to identify and assess individuals at risk for suicide. Questions are phrased for an interview format but can be completed as a self-report measure if needed. It measures 4 constructs: severity of ideation, intensity of ideation, behavior, and lethality. It includes stem questions, which if endorsed, prompt additional follow-up questions to obtain more information. It is divided into: actual attempts, interrupted attempts, aborted attempts, & preparatory acts or behaviors. Interviewers establish presence or absence of these behaviors &, where applicable, number of attempts, both over the course of a lifetime and in period of interest (the last week or month). 5 aspects of suicidal ideation are queried: wish to be dead, nonspecific active suicidal thoughts, active ideation without intent to act, active ideation with some intent to act, & active ideation with specific plan or intent. Presence and frequency of these different thoughts are evaluated. | Screening, Baseline, Days 1, 7, 8, and 17, and Day 31 | 
| Pharmacokinetic evaluation of roluperidone - Maximum plasma concentration (Cmax) | Cmax of roluperidone and its metabolite following single dose and at steady state. | Days 1 through 19 | 
| Pharmacokinetic evaluation of roluperidone - Time to maximum plasma concentration (Tmax) | Tmax of roluperidone and its metabolite following single dose and at steady state. | Days 1 through 19 | 
| Pharmacokinetic evaluation of roluperidone - Area under the plasma concentration versus time curve (AUC) | AUC of roluperidone and its metabolite following single dose and at steady state. | Days 1 through 19 | 
| Pharmacokinetic evaluation of Co-administration - Maximum plasma concentration (Cmax) | Cmax of roluperidone and its metabolite when administered concomitantly with olanzapine. | Days 1 through 19 | 
| Pharmacokinetic evaluation of Co-administration - Time to maximum plasma concentration (Tmax) | Tmax of roluperidone and its metabolite when administered concomitantly with olanzapine. | Days 1 through 19 | 
| Pharmacokinetic evaluation of Co-administration - Area under the plasma concentration versus time curve (AUC) | AUC of roluperidone and its metabolite when administered concomitantly with olanzapine. | Days 1 through 19 | 
| Pharmacokinetic evaluation of Co-administration versus olanzapine monotherapy - Maximum plasma concentration (Cmax) | Cmax of olanzapine administered concomitantly with roluperidone compared to its pharmacokinetic profile based on monotherapy administration from published literature. | Days 1 through 19 | 
| Pharmacokinetic evaluation of Co-administration versus olanzapine monotherapy - Time to maximum plasma concentration (Tmax) | Tmax of olanzapine administered concomitantly with roluperidone compared to its pharmacokinetic profile based on monotherapy administration from published literature. | Days 1 through 19 | 
| Pharmacokinetic evaluation of Co-administration versus olanzapine monotherapy - Area under the plasma concentration versus time curve (AUC) | AUC of olanzapine administered concomitantly with roluperidone compared to its pharmacokinetic profile based on monotherapy administration from published literature. | Days 1 through 19 |