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

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ClinicalTrials.gov Identifier: NCT02824055
Recruitment Status : Completed
First Posted : July 6, 2016
Last Update Posted : June 7, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: Placebo Drug: RO5545965 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Actual Study Start Date : June 27, 2016
Actual Primary Completion Date : April 24, 2017
Actual Study Completion Date : April 24, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Placebo Comparator: Placebo first; then RO5545965 15 mg; then RO5545965 5mg
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
Participants will receive placebo matched to RO5545965 capsules orally daily in any of the three intervention period.

Drug: 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.

Placebo Comparator: Placebo first; then RO5545965 5 mg; then RO5545965 15 mg
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
Participants will receive placebo matched to RO5545965 capsules orally daily in any of the three intervention period.

Drug: 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.

Experimental: RO5545965 15 mg first; then Placebo; then RO5545965 5 mg
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
Participants will receive placebo matched to RO5545965 capsules orally daily in any of the three intervention period.

Drug: 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.

Experimental: RO5545965 15 mg first; then RO5545965 5 mg; then Placebo
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
Participants will receive placebo matched to RO5545965 capsules orally daily in any of the three intervention period.

Drug: 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.

Experimental: RO5545965 5 mg first; then Placebo; then RO5545965 15 mg
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
Participants will receive placebo matched to RO5545965 capsules orally daily in any of the three intervention period.

Drug: 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.

Experimental: RO5545965 5 mg first; then RO5545965 15 mg; then Placebo
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
Participants will receive placebo matched to RO5545965 capsules orally daily in any of the three intervention period.

Drug: 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.




Primary Outcome Measures :
  1. 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 ]
  2. 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) ]
  3. Performance in reward based learning tasks as measured by the working memory reinforcement learning task [ Time Frame: Day 22 up to Day 92 ]
  4. Performance in reward based learning tasks as measured by the effort cost/benefit tradeoff task [ Time Frame: Day 22 up to Day 92 ]
  5. 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 Measures :
  1. 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) ]
  2. 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) ]
  3. Overall symptoms score of schizophrenia based on total PANSS [ Time Frame: Baseline (Day 1), Days 22, 57, and 92 ]
  4. Symptom domains of schizophrenia based on PANSS factor subscales [ Time Frame: Baseline (Day 1), Days 22, 57, and 92 ]
  5. Negative symptoms score of schizophrenia based on brief negative symptom scale (BNSS) [ Time Frame: Baseline (Day 1), Days 22, 57, and 92 ]
  6. Overall clinical status based on CGI-S scores [ Time Frame: Baseline (Day 1), Days 22, 57, and 92 ]
  7. Overall clinical status based on CGI-Improvement (CGI-I) score [ Time Frame: Baseline (Day 1), Days 22, 57, and 92 ]
  8. Overall global impression of negative symptoms based on CGI-S negative symptoms [ Time Frame: Baseline (Day 1), Days 22, 57, and 92 ]
  9. Overall global impression of negative symptoms based on CGI-I negative symptoms [ Time Frame: Baseline (Day 1), Days 22, 57, and 92 ]
  10. Area under the concentration-time curve (AUC) [ 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 ]
  11. Maximum observed plasma concentration (Cmax) [ 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 ]
  12. Number of participants with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Screening (Day -15 to Day -1) up to end of study (up to 17 weeks) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02824055


Locations
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United States, California
CNS Network
Garden Grove, California, United States, 92845
Parexel California Clinical Trials Medical Group
Glendale, California, United States, 91206
United States, Missouri
St Louis Clinical Trials
Saint Louis, Missouri, United States, 63141
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02824055    
Other Study ID Numbers: BP29904
First Posted: July 6, 2016    Key Record Dates
Last Update Posted: June 7, 2017
Last Verified: June 2017
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders