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

Primary Purpose

Schizophrenia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Placebo

RO5545965

About this trial

This is an interventional treatment trial for Schizophrenia

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

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
Change in benzodiazepine or sleep medication regimen within 2 weeks prior to screening
Change in anti-EPS medication within two weeks prior to screening
Use of prohibited medications taken within 14 days or within 5 times the elimination half-life of the medication before the first study drug administration
Use of any strong or moderate inhibitor of cytochrome P 450 3A (CYP3A) or CYP2C8 and any inducer of CYP3A within 14 days or within 5 times the elimination half-life of the medication (whichever is longer) before the first study drug administration
Use of any other nutrients known to modulate CYP3A activity within 1 week before the first study drug administration

Sites / Locations

CNS Network
Parexel California Clinical Trials Medical Group
St Louis Clinical Trials

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Placebo Comparator

Experimental

Arm Label

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

Arm Description

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Apparent volume of distribution (Vz/F)

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

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

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

Apparent oral clearance (CL/F)

Secondary Outcome Measures

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

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)

Overall symptoms score of schizophrenia based on total PANSS

Symptom domains of schizophrenia based on PANSS factor subscales

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

Overall clinical status based on CGI-S scores

Overall clinical status based on CGI-Improvement (CGI-I) score

Overall global impression of negative symptoms based on CGI-S negative symptoms

Overall global impression of negative symptoms based on CGI-I negative symptoms

Area under the concentration-time curve (AUC)

Maximum observed plasma concentration (Cmax)

Number of participants with adverse events (AEs) and serious adverse events (SAEs)

Full Information

NCT ID

NCT02824055

First Posted

June 21, 2016

Last Updated

June 6, 2017

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT02824055

Brief Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2017

Overall Recruitment Status

Completed

Study Start Date

June 27, 2016 (Actual)

Primary Completion Date

April 24, 2017 (Actual)

Study Completion Date

April 24, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Schizophrenia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

33 (Actual)

8. Arms, Groups, and Interventions

Arm Title

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

Arm Type

Placebo Comparator

Arm Description

Arm Title

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

Arm Type

Placebo Comparator

Arm Description

Arm Title

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

Arm Type

Experimental

Arm Description

Arm Title

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

Arm Type

Experimental

Arm Description

Arm Title

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

Arm Type

Experimental

Arm Description

Arm Title

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

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

RO5545965

Intervention Description

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.

Primary Outcome Measure Information:

Title

Apparent volume of distribution (Vz/F)

Time Frame

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

Title

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

Time Frame

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

Title

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

Time Frame

Day 22 up to Day 92

Title

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

Time Frame

Day 22 up to Day 92

Title

Apparent oral clearance (CL/F)

Time Frame

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 Outcome Measure Information:

Title

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

Time Frame

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

Title

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)

Time Frame

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

Title

Overall symptoms score of schizophrenia based on total PANSS

Time Frame