A Study to Evaluate The Effects of RO5545965 in Participants With Negative Symptoms of Schizophrenia Treated With Antipsychotics

NCT02824055 | Completed Phase 1

• 1 other identifier: BP29904
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 3

Brief Summary

This is a multicenter, randomized, double-blind, placebo-controlled, three period crossover study to evaluate the effects of RO5545965 on the functioning of key brain circuitry involved in negative symptoms using functional magnetic resonance imaging (fMRI) and reward-based learning in stable participants with mild to moderate negative symptoms of schizophrenia treated with antipsychotics. Participants will be randomized to one of six different sequences during which each participant will receive three 3-week treatment courses with RO5545965 5 milligrams (mg), RO5545965 15 mg and placebo. Each treatment period will be separated by a washout period of 14 days. Total duration of study will be approximately 17 weeks.

Conditions

Schizophrenia

Outcome Measures

Primary Outcomes (5)

• Apparent volume of distribution (Vz/F)

  Pre-dose on Days 8, 15, 22, 43, 50, 57, 78, 85 and 96; additional 2 hour post-dose on Days 15, 50, and 85

• Activity of the ventral striatum during reward expectation in a monetary incentive delay fMRI task as measured by blood oxygen level dependent (BOLD) activity

  Baseline (Day 1) up to end of study (up to 17 weeks)

• Performance in reward based learning tasks as measured by the working memory reinforcement learning task

  Day 22 up to Day 92

• Performance in reward based learning tasks as measured by the effort cost/benefit tradeoff task

  Day 22 up to Day 92

• Apparent oral clearance (CL/F)

  Pre-dose on Days 8, 15, 22, 43, 50, 57, 78, 85 and 96; additional 2 hour post-dose on Days 15, 50, and 85

Secondary Outcomes (12)

• Activity in the dorsolateral prefrontal cortex in the N-back working memory task as measured by BOLD activity

  Baseline (Day 1) up to end of study (up to 17 weeks)

• Cerebral blood flow in key brain areas (ventral striatum, orbitofrontal cortex) implicated in the etiology of negative symptoms as measured by arterial spin labeling (ASL)

  Baseline (Day 1) up to end of study (up to 17 weeks)

• Overall symptoms score of schizophrenia based on total PANSS

  Baseline (Day 1), Days 22, 57, and 92

• Symptom domains of schizophrenia based on PANSS factor subscales

  Baseline (Day 1), Days 22, 57, and 92

• Negative symptoms score of schizophrenia based on brief negative symptom scale (BNSS)

  Baseline (Day 1), Days 22, 57, and 92

Study Arms (6)

Placebo first; then RO5545965 15 mg; then RO5545965 5mg

PLACEBO COMPARATOR

Participants will receive placebo matched to RO5545965 capsules orally daily from Weeks 1 to 3 in first intervention period; then RO5545965 15 mg capsules (5 mg for 3 days, 10 mg for 3 days and 15 mg for 15 days) orally daily from Weeks 6 to 8 in second intervention period; followed by RO5545965 5 mg capsules orally daily from Weeks 11 to 13 in third intervention period. A washout period of minimum 14 days will be maintained between each period.

Drug: Placebo; Drug: RO5545965

Placebo first; then RO5545965 5 mg; then RO5545965 15 mg

PLACEBO COMPARATOR

Participants will receive placebo matched to RO5545965 capsules orally daily from Weeks 1 to 3 in first intervention period; then RO5545965 5 mg capsules orally daily from Weeks 6 to 8 in second intervention period; followed by RO5545965 15 mg capsules (5 mg for 3 days, 10 mg for 3 days and 15 mg for 15 days) orally daily from Weeks 11 to 13 in third intervention period. A washout period of minimum 14 days will be maintained between each period.

Drug: Placebo; Drug: RO5545965

RO5545965 15 mg first; then Placebo; then RO5545965 5 mg

EXPERIMENTAL

Participants will receive RO5545965 15 mg capsules (5 mg for 3 days, 10 mg for 3 days and 15 mg for 15 days) orally daily from Weeks 1 to 3 in first intervention period; then placebo matched to RO5545965 capsules orally daily from Weeks 6 to 8 in second intervention period; followed by RO5545965 5 mg capsules orally daily from Weeks 11 to 13 in third intervention period. A washout period of minimum 14 days will be maintained between each period.

Drug: Placebo; Drug: RO5545965

RO5545965 15 mg first; then RO5545965 5 mg; then Placebo

EXPERIMENTAL

Participants will receive RO5545965 15 mg capsules (5 mg for 3 days, 10 mg for 3 days and 15 mg for 15 days) orally daily from Weeks 1 to 3 in first intervention period; then RO5545965 5 mg capsules orally daily from Weeks 6 to 8 in second intervention period; followed by placebo matched to RO5545965 capsules orally daily from Weeks 11 to 13 in third intervention period. A washout period of minimum 14 days will be maintained between each period.

Drug: Placebo; Drug: RO5545965

RO5545965 5 mg first; then Placebo; then RO5545965 15 mg

EXPERIMENTAL

Participants will receive RO5545965 5 mg capsules orally daily from Weeks 1 to 3 in first intervention period; then placebo matched to RO5545965 capsules orally daily from Weeks 6 to 8 in second intervention period; followed by RO5545965 15 mg capsules (5 mg for 3 days, 10 mg for 3 days and 15 mg for 15 days) orally daily from Weeks 11 to 13 in third intervention period. A washout period of minimum 14 days will be maintained between each period.

Drug: Placebo; Drug: RO5545965

RO5545965 5 mg first; then RO5545965 15 mg; then Placebo

EXPERIMENTAL

Participants will receive RO5545965 5 mg capsules orally daily from Weeks 1 to 3 in first intervention period; then RO5545965 15 mg capsules (5 mg for 3 days, 10 mg for 3 days and 15 mg for 15 days) orally daily from Weeks 6 to 8 in second intervention period; followed by placebo matched to RO5545965 capsules orally daily from Weeks 11 to 13 in third intervention period. A washout period of minimum 14 days will be maintained between each period.

Drug: Placebo; Drug: RO5545965

Interventions

Placebo DRUG

Participants will receive placebo matched to RO5545965 capsules orally daily in any of the three intervention period.

Placebo first; then RO5545965 15 mg; then RO5545965 5mg; Placebo first; then RO5545965 5 mg; then RO5545965 15 mg; RO5545965 15 mg first; then Placebo; then RO5545965 5 mg; RO5545965 15 mg first; then RO5545965 5 mg; then Placebo; RO5545965 5 mg first; then Placebo; then RO5545965 15 mg; RO5545965 5 mg first; then RO5545965 15 mg; then Placebo

RO5545965 DRUG

Participants will receive RO5545965 5 mg capsules or RO5545965 15 mg capsules (5 mg for 3 days, 10 mg for 3 days and 15 mg for 15 days) orally daily in any of the three intervention period.

Placebo first; then RO5545965 15 mg; then RO5545965 5mg; Placebo first; then RO5545965 5 mg; then RO5545965 15 mg; RO5545965 15 mg first; then Placebo; then RO5545965 5 mg; RO5545965 15 mg first; then RO5545965 5 mg; then Placebo; RO5545965 5 mg first; then Placebo; then RO5545965 15 mg; RO5545965 5 mg first; then RO5545965 15 mg; then Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• A diagnostic and statistical manual of mental disorders-5 (DSM-5) diagnosis of schizophrenia as established by structured clinical interview for DSM-5-clinical trial (SCID-5-CT) at screening
• Participants with no hospitalization for worsening of schizophrenia within 3 months prior to screening
• Male and female participants with no childbearing capacity; females must be either surgically sterile or postmenopausal for at least 1 year
• Body mass index (BMI) greater than (\>) 18.5 kilograms per square meter (kg/m\^2) and less than (\<) 35 kg/m\^2
• Fluent in English, even if English is not the primary language
• Participants with clinical global impression-severity (CGI-S) score greater than or equal to (\>/=) 3 (mildly ill)
• Participants with a score of less than or equal to (\</=) 4 (moderate) on positive and negative syndrome scale (PANSS) items P7 (hostility), G8 (uncooperativeness) and G6 (depression)
• Participants with PANSS negative symptom factor score \>/=18
• Participants with calgary depression rating scale for schizophrenia (CDSS) score \</=8
• Participants on stable treatment, that is 6 weeks without change, with no more than two antipsychotics prior to screening

You may not qualify if:

• Moderate to severe substance use disorder within 6 months as defined by DSM-5
• Positive urine drug screen for amphetamines, methamphetamines, opiates, buprenorphine, methadone, cannabinoids, cocaine and barbiturates
• Participants at significant risk of suicide or harming him or herself or others according to the Investigator's judgment
• History of neuroleptic malignant syndrome
• A prior or current general medical condition that might be impairing cognition or other psychiatric functioning
• A movement disorder due to antipsychotic treatment not currently controlled with anti-extrapyramidal symptoms (anti-EPS) treatment or another movement disorder which might affect the ratings on the EPS scales
• Participants with a score \>2 (mild) in any of the four CGI-S items of the extrapyramidal symptom rating scale (ESRS-A)
• History of human immunodeficiency virus (HIV) infection, Hepatitis B, or Hepatitis C infection
• QTcF interval \>450 milliseconds (msec) (470 msec for females) or other significant abnormality on screening electrocardiogram (ECG) based on centralized reading
• Clinically significant abnormalities in laboratory safety test results
• Significant or unstable physical condition
• Receipt of an investigational drug within 90 days or 5 times the half-life of the investigational drug, whatever is longer, prior to screening
• Previously received RO5545965
• Electroconvulsive treatment (ECT) within 6 months prior to screening
• Current or 6 months prior to screening treatment with olanzapine or clozapine

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (3)

CNS Network

Garden Grove, California, 92845, United States

Location

Parexel California Clinical Trials Medical Group

Glendale, California, 91206, United States

Location

St Louis Clinical Trials

St Louis, Missouri, 63141, United States

Location

Related Publications (2)

• Omlor W, Cecere G, Huang GY, Spiller T, Misra AR, Rabe F, Kallen N, Kirschner M, Surbeck W, Burrer A, Garibaldi G, Holiga S, Dukart J, Umbricht D, Homan P. Exploratory analysis of the relationship between striatal connectivity and apathy during phosphodiesterase 10 inhibition in schizophrenia: findings from a randomized crossover trial. BMC Med. 2025 Mar 28;23(1):187. doi: 10.1186/s12916-025-04004-2.

  PMID: 40155941 DERIVED

• Umbricht D, Cheng WY, Lipsmeier F, Bamdadian A, Lindemann M. Deep Learning-Based Human Activity Recognition for Continuous Activity and Gesture Monitoring for Schizophrenia Patients With Negative Symptoms. Front Psychiatry. 2020 Sep 16;11:574375. doi: 10.3389/fpsyt.2020.574375. eCollection 2020.

  PMID: 33192706 DERIVED

MeSH Terms

Conditions

Schizophrenia

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 21, 2016
• First Posted: July 6, 2016
• Study Start: June 27, 2016
• Primary Completion: April 24, 2017
• Study Completion: April 24, 2017
• Last Updated: June 7, 2017

Record last verified: 2017-06

Locations

US (3)