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
Overview
- Phase
- Phase 1
- Intervention
- Roluperidone 64 mg
- Conditions
- Negative Symptoms in Schizophrenia
- Sponsor
- Minerva Neurosciences
- Enrollment
- 17
- Locations
- 3
- Primary Endpoint
- Extrapyramidal Symptoms Assessed by Abnormal Involuntary Movement Scale (AIMS) - Change From Baseline in AIMS Component Movement
- Status
- Completed
- Last Updated
- last year
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.
Investigators
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
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
Arms & Interventions
Treatment Phase 1
Roluperidone 64 mg monotherapy administered as an oral dose daily for 7 days on Days 1-7.
Intervention: Roluperidone 64 mg
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.
Intervention: Roluperidone 64 mg
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.
Intervention: Olanzapine 10 MG
Outcomes
Primary Outcomes
Extrapyramidal Symptoms Assessed by Abnormal Involuntary Movement Scale (AIMS) - Change From Baseline in AIMS Component Movement
Time Frame: Overall - Change from Baseline to End of Study (Day 17)
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.
Barnes Akathisia Rating Scale (BARS)
Time Frame: Overall - Change from Baseline to End of Study (Day 17)
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.
Number of Subjects Who Experienced Suicidal Ideation or Behavior Events Per the Columbia Suicide Severity Rating Scale (C-SSRS)
Time Frame: Overall - End of Study (Day 17)
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).
Secondary Outcomes
- Pharmacokinetic Evaluation of Roluperidone - Maximum Plasma Concentration (Cmax)(Days 1 through 17)
- Pharmacokinetic Evaluation of Roluperidone - Time to Maximum Plasma Concentration (Tmax)(Days 1 through 17)
- Pharmacokinetic Evaluation of Roluperidone - Area Under the Plasma Concentration Versus Time Curve (AUC 0-24)(Days 1 through 17)
- Pharmacokinetic Evaluation of Roluperidone - Area Under the Plasma Concentration Versus Time Curve (AUC Inf)(Days 1 through 17)
- Plasma PK Parameter for Olanzapine Cmax(Treatment Phase 2 (Day 8 through Day 17))
- Plasma PK Parameter for Olanzapine Tmax(Treatment Phase 2 (Day 8 through Day 17))
- Plasma PK Parameter for Olanzapine AUC 0-24(Treatment Phase 2 (Day 8 through Day 17))
- Plasma PK Parameter for Olanzapine AUC Inf(Treatment Phase 2 (Day 8 through Day 17))
- Pharmacokinetic Evaluation of Co-administration Versus Roluperidone Monotherapy - Maximum Plasma Concentration (Cmax)(Days 1 through 17)
- Pharmacokinetic Evaluation of Co-administration - AUC 0-24(Days 1 through 17)