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

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)

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: MK-8435 (Org 25935) 4-8 mg; Drug: MK-8435 (Org 25935) 12-16 mg; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 215
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: MK-8435 (Org 25935) 4-8 mg; Administered orally 2 times a day (BID) for a final concentration of 8-16 mg/day
Experimental: 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.	Drug: MK-8435 (Org 25935) 12-16 mg; Administered orally BID for a final concentration of 24-32 mg/day
Placebo Comparator: 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.	Drug: Placebo; Matching placebo for MK-8435 (Org 25935) administered orally BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Modified Scale for the Assessment of Negative Symptoms (SANS 1-22 Composite Score) at 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.	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Score of Positive and Negative Syndrome Scale (PANSS) for Schizophrenia at Week 12	PANSS was a 30-item clinician-rated instrument used for assessing the positive, negative, and general psychopathology symptoms of schizophrenia. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme, with a total scoring range of 30 to 210. Higher scores indicated more impairment. A negative change from baseline indicated an improvement in symptoms.	Baseline and Week 12
Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) at Week 12	CDSS was a 9-item clinician-rated instrument used to evaluate depression in participants who have schizophrenia. For each item, symptom severity was rated on a 4-point scale, from 0=absent to 3=severe, with a total scoring range of 0 to 27. Higher scores indicated more impairment. A negative change from baseline indicated an improvement in symptoms.	Baseline and Week 12
Change From Baseline in Perception of Emotions Score at Week 12	Perception of emotion was measured by computer using the CNS-Vital Signs Neurocognitive Test Battery. The participant identified different emotional states (happy, sad, angry, and calm [neutral]) presented in pictures of faces by choosing the appropriate word for the emotion. The raw score was the sum of correct responses minus errors. The standard scores were normalized from raw scores and presented an age-matched score relative to a normative comparison database. Higher scores were better.	Baseline and Week 12
Change From Baseline in Non-Verbal Reasoning Score at Week 12	Non-verbal reasoning was measured by computer using the CNS-Vital Signs Neurocognitive Test Battery. The participant solved 15 visual analogies composed of geometric 2x2, 3x3, or 4x4 puzzles by choosing the most appropriate geometric figure that solved the matrix. The raw score was the sum of correct responses minus errors. The standard scores were normalized from raw scores and presented an age-matched score relative to a normative comparison database. Higher scores were better.	Baseline and Week 12
Change From Baseline in Verbal Memory Score at Week 12	Verbal memory was measured by computer using the CNS-Vital Signs Neurocognitive Test Battery. The participant remembered 15 words within a field of 15 distractors immediately and after a twenty minute delay. The raw score was the sum of correct responses. The standard scores were normalized from raw scores and presented an age-matched score relative to a normative comparison database. Higher scores were better.	Baseline and Week 12
Change From Baseline in Visual Memory Score at Week 12	Visual memory was measured by computer using the CNS-Vital Signs Neurocognitive Test Battery. The participant remembered 15 geometric figures within a field of 15 distractors immediately and after a twenty minute delay. The raw score was the sum of correct responses. The standard scores were normalized from raw scores and presented an age-matched score relative to a normative comparison database. Higher scores were better.	Baseline and Week 12
Change From Baseline in Speed of Complex Information Processing Score at Week 12	Speed of complex information processing was measured by computer using the CNS-Vital Signs Neurocognitive Test Battery-Symbol-digit Coding Test. The participant linked numbers to digits. The test consisted of serial presentations of screens, each containing a bank of 8 symbols above and 8 empty boxes below. The participant typed the number that corresponded to the symbol highlighted. The raw score was the processing time in milliseconds. The standard scores were normalized from raw scores and presented an age-matched score relative to a normative comparison database. Higher scores were better.	Baseline and Week 12
Change From Baseline in Working Memory Score at Week 12	Working memory was measured by computer using the CNS-Vital Signs Neurocognitive Test Battery-4-Part Continuous Performance Test. The participant was presented with targets and remembered target presentation sequencing in order to respond to the directions. Only Part 4 of the 4 Part Continuous Performance Test contributed towards the working memory score. The raw score was the sum of correct responses minus errors. The standard scores were normalized from raw scores and presented an age-matched score relative to a normative comparison database. Higher scores were better.	Baseline and Week 12
Change From Baseline in Sustained Attention Score at Week 12	Sustained attention was measured by computer using the CNS-Vital Signs Neurocognitive Test Battery-4-Part Continuous Performance Test. The participant was asked to identify a target shape/color when presented with a battery of different geometric shapes/colors. Only Parts 2 to 4 of the 4 Part Continuous Performance Test contributed towards the sustained attention score. The raw score was the sum of correct responses minus errors. The standard scores were normalized from raw scores and presented an age-matched score relative to a normative comparison database. Higher scores were better.	Baseline and Week 12
Change From Baseline in Executive Functioning Score at Week 12	Executive functioning was measured by computer using the CNS-Vital Signs Neurocognitive Test Battery-Shifting Attention Test. The participant matched geometric shapes either by shape or color. The raw score was the sum of correct responses minus errors. The standard scores were normalized from raw scores and presented an age-matched score relative to a normative comparison database. Higher scores were better.	Baseline and Week 12
Change From Baseline in Composite Memory Score at Week 12	Composite memory was a composite of verbal memory and visual memory and was measured by computer using the CNS-Vital Signs Neurocognitive Test Battery. The raw score was the sum of correct responses. The standard scores were normalized from raw scores and presented an age-matched score relative to a normative comparison database. Higher scores were better.	Baseline and Week 12
Change From Baseline in Extrapyramidal Symptoms Rating Scale Score at Week 12	The abbreviated Extrapyramidal Symptoms Rating Scale (ESRS-A) was a sum of the severity rating of a 24-item instrument assessing four types of movement disorders: parkinsonism, dystonia, dyskinesia, and akathisia. Each item was rated on a 7-point scale, from 0=absent to 6=severe. Higher scores indicated more impairment. A negative change from baseline indicated an improvement.	Baseline and Week 12

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2007
• Primary Completion (Actual): October 24, 2008
• Study Completion (Actual): October 24, 2008

Study Registration Dates

• First Submitted: July 28, 2008
• First Submitted That Met QC Criteria: July 29, 2008
• First Posted (Estimate): July 30, 2008

Study Record Updates

• Last Update Posted (Actual): October 16, 2018
• Last Update Submitted That Met QC Criteria: September 17, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Negative symptoms; Add-on treatment; Glycine Uptake inhibitor; Second Generation Antipsychotic
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia
• Other Study ID Numbers: P05695 (Other Identifier: Schering-Plough Protocol Number); MK-8435-001 (Other Identifier: Merck Registration Number); 172003 (Other Identifier: Organon Protocol Number); 2006-003080-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf