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.

Study Overview

• Status: Completed
• Conditions: Negative Symptoms in Schizophrenia
• Intervention / Treatment: Drug: Roluperidone 64 mg; Drug: Olanzapine 10 MG

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Garden Grove, California, United States, 92845
      • Collaborative Neuroscience Research, LLC
  • Maryland
    • Gaithersburg, Maryland, United States, 20877
      • CBH Health, LLC
  • New Jersey
    • Marlton, New Jersey, United States, 08053
      • Hassman Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Phase 1; Roluperidone 64 mg monotherapy administered as an oral dose daily for 7 days on Days 1-7.	Drug: Roluperidone 64 mg; 64 mg/day oral; Other Names: MIN-101
Experimental: Treatment Phase 2; 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; 64 mg/day oral; Other Names: MIN-101; Drug: Olanzapine 10 MG; 10 mg/day oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extrapyramidal Symptoms Assessed by Abnormal Involuntary Movement Scale (AIMS) - Change From Baseline in AIMS Component Movement	AIMS is a rating scale to measure tardive dyskinesia (TD). For the scoring, the AIMS scale has 14 items. The first 10 items (under categories of Facial and Oral Movements, Extremity Movements, Trunk Movements, and Global Judgements) are rated from 0 (none) to 4 (severe); the remaining 4 items (Dental Status) are rated "yes" and "no" and not counted. The analysis is limited to items 1 to 10, with each rated from 0 to 4. The total score is the sum of all 10 items and with values ranging from 0 to 40. Overall change from baseline to End of Study (Day 17) in AIMS was reported for the Safety Set. Higher scores imply worse outcome.	Overall - Change from Baseline to End of Study (Day 17)
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.	Overall - Change from Baseline to End of Study (Day 17)
Number of Subjects Who Experienced Suicidal Ideation or Behavior Events Per the 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. For the composite endpoint of suicidal ideation or behavior (1-10), the number and percent of subjects in the Overall Safety Set who experience any one of the ten suicidal ideation or behavior events at End of Study (Day 17).	Overall - End of Study (Day 17)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Evaluation of Roluperidone - Maximum Plasma Concentration (Cmax)	Cmax of roluperidone and its metabolite following single dose and at steady state, and when administered concomitantly with olanzapine.	Days 1 through 17
Pharmacokinetic Evaluation of Roluperidone - Time to Maximum Plasma Concentration (Tmax)	Tmax of roluperidone and its metabolite following single dose and at steady state, and when administered concomitantly with olanzapine.	Days 1 through 17
Pharmacokinetic Evaluation of Roluperidone - Area Under the Plasma Concentration Versus Time Curve (AUC 0-24)	AUC of roluperidone and its metabolite following single dose and at steady state, and when administered concomitantly with olanzapine.	Days 1 through 17
Pharmacokinetic Evaluation of Roluperidone - Area Under the Plasma Concentration Versus Time Curve (AUC Inf)	AUC of roluperidone and its metabolite following single dose and at steady state, and when administered concomitantly with olanzapine.	Days 1 through 17
Plasma PK Parameter for Olanzapine Cmax	Cmax of olanzapine administered concomitantly with roluperidone	Treatment Phase 2 (Day 8 through Day 17)
Plasma PK Parameter for Olanzapine Tmax	Tmax of olanzapine administered concomitantly with roluperidone	Treatment Phase 2 (Day 8 through Day 17)
Plasma PK Parameter for Olanzapine AUC 0-24	AUC 0-24 olanzapine administered concomitantly with roluperidone	Treatment Phase 2 (Day 8 through Day 17)
Plasma PK Parameter for Olanzapine AUC Inf	AUC inf olanzapine administered concomitantly with roluperidone	Treatment Phase 2 (Day 8 through Day 17)
Pharmacokinetic Evaluation of Co-administration Versus Roluperidone Monotherapy - Maximum Plasma Concentration (Cmax)	Comparison of roluperidone on Day 17 with olanzapine to roluperidone alone on Day 7 for Cmax. The geometric mean and geometric coefficient of variation are reported for the analytes roluperidone and its metabolite.	Days 1 through 17
Pharmacokinetic Evaluation of Co-administration - AUC 0-24	Comparison of roluperidone on Day 17 with olanzapine to roluperidone alone on Day 7 for AUC 0-24. The geometric mean and geometric coefficient of variation are reported for the analytes roluperidone and its metabolite.	Days 1 through 17

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive and Negative Symptoms Scale (PANSS)	PANSS was designed to be used in patients with schizophrenia to measure the overall severity of schizophrenia symptoms. The scale has been validated, is reliable and is acceptable to regulatory health authorities as a primary scale to determine efficacy of intervention in schizophrenia. The patient is rated from 1 (absent) to 7 (extreme) on 30 different symptoms based on the interview as well as reports of family members or primary care hospital workers. Higher scores indicate more severe symptoms.	Screening, Baseline, Days 7 and 17, and Day 31
Calgary Depression Scale for Schizophrenia (CDSS)	CDSS was specifically developed to assess the level of depression in schizophrenia. It has been extensively evaluated in both relapsed and remitted patients and appears sensitive to change. The scale is designed for use by an experienced rater and is not intended for self-assessment. The patient is rated on 9 different symptoms and ratings of the items are defined according to operational criteria from 0 to 3. A higher score predicts the presence of a major depressive episode.	Screening, Baseline, Days 7 and 17, and Day 31
Clinical Global Impression - Severity Rating (CGI-S)	CGI-S is a clinician-rated scale that is designed to rate the severity of the patient's illness at the time of assessment, including knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function relative to the clinician's past experience with patients who have the same diagnosis and improvement with treatment. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating, according to: normal (not at all ill) = 1; borderline mentally ill = 2; mildly ill = 3; moderately ill = 4; markedly ill = 5; severely ill = 6; or extremely ill = 7.	Screening, Baseline, Days 7 and 17, and Day 31

Collaborators and Investigators

• Sponsor: Minerva Neurosciences

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2023
• Primary Completion (Actual): January 12, 2024
• Study Completion (Actual): January 12, 2024

Study Registration Dates

• First Submitted: October 13, 2023
• First Submitted That Met QC Criteria: October 24, 2023
• First Posted (Actual): October 30, 2023

Study Record Updates

• Last Update Posted (Actual): March 26, 2025
• Last Update Submitted That Met QC Criteria: March 6, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Central Nervous System Depressants; Neurotransmitter Agents; Membrane Transport Modulators; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Antipsychotic Agents; Olanzapine
• Other Study ID Numbers: MIN-101C18

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No