Clinical trial NCT00725075: Adjuvant Treatment With a Glycine Uptake Inhibitor in Participants With Negative Symptoms of Schizophrenia (P05695) (MK-8435-001)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Schizophrenia
Keywords: Negative symptoms
Glycine Uptake inhibitor
Add-on treatment
Second Generation Antipsychotic
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2008-07-30
Enrollment: 215
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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
* 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

Primary outcomes:
measure: Change From Baseline in Modified Scale for the Assessment of Negative Symptoms (SANS 1-22 Composite Score) at Week 12
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Change From Baseline in Total Score of Positive and Negative Syndrome Scale (PANSS) for Schizophrenia at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Perception of Emotions Score at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Non-Verbal Reasoning Score at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Verbal Memory Score at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Visual Memory Score at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Speed of Complex Information Processing Score at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Working Memory Score at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Sustained Attention Score at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Executive Functioning Score at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Composite Memory Score at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Extrapyramidal Symptoms Rating Scale Score at Week 12
timeFrame: Baseline and Week 12
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Schoemaker JH, Jansen WT, Schipper J, Szegedi A. The selective glycine uptake inhibitor org 25935 as an adjunctive treatment to atypical antipsychotics in predominant persistent negative symptoms of schizophrenia: results from the GIANT trial. J Clin Psychopharmacol. 2014 Apr;34(2):190-8. doi: 10.1097/JCP.0000000000000073.