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

Schizophrenia Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02824055
• Other study ID #: BP29904
• Status: Completed
• Phase: Phase 1
• First received: June 21, 2016
• Last updated: June 6, 2017
• Start date: June 27, 2016
• Est. completion date: April 24, 2017

Study information

• Verified date: June 2017
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: April 24, 2017
• Est. primary completion date: April 24, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Schizophrenia

Intervention

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

Locations

Country	Name	City	State
United States	CNS Network	Garden Grove	California
United States	Parexel California Clinical Trials Medical Group	Glendale	California
United States	St Louis Clinical Trials	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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)
Primary	Performance in reward based learning tasks as measured by the working memory reinforcement learning task		Day 22 up to Day 92
Primary	Performance in reward based learning tasks as measured by the effort cost/benefit tradeoff task		Day 22 up to Day 92
Primary	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	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)
Secondary	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)
Secondary	Overall symptoms score of schizophrenia based on total PANSS		Baseline (Day 1), Days 22, 57, and 92
Secondary	Symptom domains of schizophrenia based on PANSS factor subscales		Baseline (Day 1), Days 22, 57, and 92
Secondary	Negative symptoms score of schizophrenia based on brief negative symptom scale (BNSS)		Baseline (Day 1), Days 22, 57, and 92
Secondary	Overall clinical status based on CGI-S scores		Baseline (Day 1), Days 22, 57, and 92
Secondary	Overall clinical status based on CGI-Improvement (CGI-I) score		Baseline (Day 1), Days 22, 57, and 92
Secondary	Overall global impression of negative symptoms based on CGI-S negative symptoms		Baseline (Day 1), Days 22, 57, and 92
Secondary	Overall global impression of negative symptoms based on CGI-I negative symptoms		Baseline (Day 1), Days 22, 57, and 92
Secondary	Area under the concentration-time curve (AUC)		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	Maximum observed plasma concentration (Cmax)		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	Number of participants with adverse events (AEs) and serious adverse events (SAEs)		Screening (Day -15 to Day -1) up to end of study (up to 17 weeks)