Adjuvant Treatment With a Glycine Uptake Inhibitor in Participants With Negative Symptoms of Schizophrenia (P05695) (MK-8435-001) (GIANT)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 2

Conditions: Schizophrenia

Treatments: Drug: Placebo; Drug: MK-8435 (Org 25935) 4-8 mg; Drug: MK-8435 (Org 25935) 12-16 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT00725075

172003 (Other Identifier)

2006-003080-31 (EudraCT Number)

MK-8435-001 (Other Identifier)

P05695 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 215 patients

Sex: All

Ages: 18 to 55 years old

Volunteers: No Healthy Volunteers

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
• Has a positive result on the urine alcohol/drug screen for alcohol or illicit drugs
• Is pregnant or breastfeeding
• Is being treated with high doses of benzodiazepines (>4 mg per day lorazepam or equivalent)
• Has an imminent risk of self-harm or harm to others
• Has been treated with clozapine in the past 6 months prior to study start
• Has been treated with lithium, valproate, lamotrigine, pregabalin, gabapentin, or carbamazepine in the past 12 weeks prior to study start
• Has started treatment or has had a dose change of an (additional) antipsychotic, antidepressant,hypnotic or anxiolytic in the past 4 weeks prior to study start
• Has had no demonstrated benefit of antipsychotic treatment within the previous five years

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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215 participants in 3 patient groups, including a placebo group

MK-8435 (Org 25935) 8-16 mg per day

Experimental group

Description:

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.

Treatment:

Drug: MK-8435 (Org 25935) 4-8 mg

MK-8435 (Org 25935) 24-32 mg per day

Experimental group

Description:

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.

Treatment:

Drug: MK-8435 (Org 25935) 12-16 mg

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo