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 Contact: Name: Senior VP and Head of R&D; Phone Number: 617-600-7378; Email: info@minervaneurosciences.com
• Study Contact Backup: Name: VP, Program Management; Phone Number: 617-600-7371; Email: info@minervaneurosciences.com

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
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

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): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

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