A Multi-center, Double-blind, Flexible-dose Efficacy Trial With Org 25935 Versus Placebo as add-on Therapy in Subjects With Predominant, Persistent Negative Symptoms of Schizophrenia Treated With a Stable Dose of a Second Generation Antipsychotic (GIANT)
Overview
- Phase
- Phase 2
- Intervention
- MK-8435 (Org 25935) 4-8 mg
- Conditions
- Schizophrenia
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 215
- Primary Endpoint
- Change From Baseline in Modified Scale for the Assessment of Negative Symptoms (SANS 1-22 Composite Score) at Week 12
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of this study is to determine whether MK-8435 (Org 25935) is more effective than placebo in improving negative symptoms in participants with schizophrenia who are concurrently treated with a stable dose of a second generation antipsychotic.
Detailed Description
The primary features of schizophrenia are characterized by positive (irrational thoughts and/or behavior) and negative symptoms. Negative symptoms are the gross absence of normal behavior and emotions, and usually include a general lack of engagement, social withdrawal, and loss of goal-directed behavior. Negative symptoms may strongly affect daytime activities and quality of life. The effects of currently available antipsychotics on negative symptoms are not satisfactory and leave much room for improvement. MK-8435 (Org 25935) is an investigational drug that may help to correct the above characteristics of schizophrenia by facilitating the messenger function of an amino acid in the brain, called glutamate. Preliminary data suggest that lowered glutamate levels in schizophrenia are associated with a failure to activate relevant areas in the forebrain and with prominent negative symptoms.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Is diagnosed with non-first episode schizophrenia meeting Diagnostic and Statistical Manual (Version IV) criteria
- •Is receiving stable treatment with one of the following SGA: aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone
- •Is in the non-acute phase of illness and clinically stable for 3 months prior to study start as demonstrated by: treatment with current SGA or at least 12 weeks prior to study start; no increase in the level of psychiatric care due to worsening symptoms for at least 12 weeks prior to study start; and no dose change of SGA or change in medication to treat the symptoms of schizophrenia for 4 weeks prior to study start
- •Has a score ≥4 on 3 or more of the following Positive and Negative Symptoms Scale (PANSS) negative subscale items at study start: blunted affect, emotional withdrawal, poor rapport, passive social withdrawal, lack of spontaneity, motor retardation, and active social avoidance
- •Has an overall PANSS negative subscale score \> 20
Exclusion Criteria
- •Has an overall PANSS positive subscale score ≥20
- •Has a score ≥5 on 2 or more of the following PANSS positive subscale items at study start: delusions, hallucinatory behavior, excitement, grandiosity, or suspiciousness/persecution
- •Has a score ≥9 on the modified InterSePT Scale for Suicidal Thinking
- •Has a score ≥9 on the Calgary Depression Scale for Schizophrenia
- •Has a score ≥3 on the clinical global impression of Parkinsonism of the abbreviated Extrapyramidal Symptom Rating Scale
- •Has untreated or uncompensated clinically significant renal, endocrine, hepatic, respiratory, cardiovascular, hematological, immunological or cerebrovascular disease, malignancy, or other chronic and/or degenerative process
- •Has a history of seizure disorder beyond childhood or is taking any anticonvulsants to prevent seizures
- •Has a diagnosis of mental retardation or organic brain syndrome
- •Has a clinically relevant visual disturbance, such as cataract, color blindness, macular degeneration, glaucoma, or retinal disease
- •Has a concurrent diagnosis of substance dependence other than nicotine or caffeine dependence in the past 6 months prior to study start
Arms & Interventions
MK-8435 (Org 25935) 8-16 mg per day
Participants will be maintained on a stable dose of Second Generation Antipsychotic (SGA) and receive 4-8 mg MK-8435 (Org 25935) BID, in the morning and the evening, as add-on treatment for up to 87 days. The dose of MK-8435 (Org 25935) can be titrated upward or downward within the specified dose range, as needed, up to Day 42 of the study. The dose must remain stable after Day 42 for the remainder of the study.
Intervention: MK-8435 (Org 25935) 4-8 mg
MK-8435 (Org 25935) 24-32 mg per day
Participants will be maintained on a stable dose of SGA and receive 12-16 mg MK-8435 (Org 25935) BID, in the morning and the evening, as add-on treatment for up to 87 days. The dose of MK-8435 (Org 25935) can be titrated upward or downward within the specified dose range, as needed, up to Day 42 of the study. The dose must remain stable after Day 42 for the remainder of the study.
Intervention: MK-8435 (Org 25935) 12-16 mg
Placebo
Participants will be maintained on a stable dose of SGA and receive matching placebo for MK-8435 (Org 25935) BID, in the morning and the evening, as add-on treatment for up to 87 days.
Intervention: Placebo
Outcomes
Primary Outcomes
Change From Baseline in Modified Scale for the Assessment of Negative Symptoms (SANS 1-22 Composite Score) at Week 12
Time Frame: Baseline and Week 12
SANS was a 25-item clinician-rated instrument for assessing the negative symptoms of schizophrenia. SANS 1-22 Composite Score consisted of the SANS 25 scale minus the last 3 questions (attention items). The remaining non-attention items (affective flattening, alogia, avolition-apathy, and anhedonia-asociality) comprised the SANS 1-22 Composite Score. For each item, symptom severity was rated on a 6-point scale, from 0=absent to 5=severe. The SANS 1-22 Composite Score had a total scoring range of 0 to 110. Higher scores indicated more impairment. The SANS 1-22 Composite Score was reported using data from the adjusted site rater. A negative change from baseline indicated an improvement in symptoms.
Secondary Outcomes
- Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) at Week 12(Baseline and Week 12)
- Change From Baseline in Sustained Attention Score at Week 12(Baseline and Week 12)
- Change From Baseline in Perception of Emotions Score at Week 12(Baseline and Week 12)
- Change From Baseline in Total Score of Positive and Negative Syndrome Scale (PANSS) for Schizophrenia at Week 12(Baseline and Week 12)
- Change From Baseline in Verbal Memory Score at Week 12(Baseline and Week 12)
- Change From Baseline in Non-Verbal Reasoning Score at Week 12(Baseline and Week 12)
- Change From Baseline in Visual Memory Score at Week 12(Baseline and Week 12)
- Change From Baseline in Speed of Complex Information Processing Score at Week 12(Baseline and Week 12)
- Change From Baseline in Working Memory Score at Week 12(Baseline and Week 12)
- Change From Baseline in Executive Functioning Score at Week 12(Baseline and Week 12)
- Change From Baseline in Composite Memory Score at Week 12(Baseline and Week 12)
- Change From Baseline in Extrapyramidal Symptoms Rating Scale Score at Week 12(Baseline and Week 12)