Effect of MMFS-202-302 on Cognitive Enhancement in Schizophrenia

• ClinicalTrials.gov Identifier: NCT02237235
• Recruitment Status: Completed
• First Posted: September 11, 2014
• Last Update Posted: September 5, 2017
• Sponsor: Northwestern University
• Collaborators: Neurocentria, Inc.; Brain & Behavior Research Foundation
• Information provided by (Responsible Party): Herbert Meltzer, Northwestern University

Tracking Information

• First Submitted Date: September 9, 2014
• First Posted Date: September 11, 2014
• Last Update Posted Date: September 5, 2017
• Study Start Date: August 2014
• Actual Primary Completion Date: August 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 31, 2017)

Matrics Consensus Cognitive Battery (MCCB) [ Time Frame: Baseline to Day 63 ]

Change from Baseline in MATRICS Consensus Cognitive Battery (MCCB) working memory domain.

Original Primary Outcome Measures (submitted: September 10, 2014)

Matrics Consensus Cognitive Battery (MCCB) [ Time Frame: One year ]

The primary outcome measure will be a time x group effect on one or more subscales of the MATRICS Cognitive Consensus Battery (MCCB). The MCCB consists of 9 cognitive tests covering seven domains. This will be augmented by additional neuropsychological measures of verbal fluency (FAS Phonemic Fluency), working memory (Brown-Peterson's Auditory Consonant Trigrams) and executive function (the Wisconsin Card Sorting Test).

Current Secondary Outcome Measures (submitted: August 31, 2017)

Overall clinical global impression of severity improvement measured by the Clinical Global Impressions Scale assessment of change (CGI-C) [ Time Frame: Day 63 ]

To support the primary endpoint of working memory, the CGI-C will demonstrate clinically relevant improvement of global function.

Original Secondary Outcome Measures (submitted: September 10, 2014)

Negative symptoms [ Time Frame: One year ]

To determine the effect of MgT on negative symptoms of schizophrenia, as measured by the Brief Negative Symptom Scale (BNSS), and imaging of brain reward networks (OMPFC, ACC, NAc, VTA).

Current Other Pre-specified Outcome Measures (submitted: August 31, 2017)

• Change from Baseline in cognition measured by the MATRICS Consensus Cognitive Battery (MCCB) total score [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in cognition measured by the MATRICS Consensus Cognitive Battery (MCCB) speed of processing domain subscale score [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in cognition measured by the MATRICS Consensus Cognitive Battery (MCCB) attention/vigilance domain subscale score [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in cognition measured by the MATRICS Consensus Cognitive Battery (MCCB) verbal learning domain subscale score [ Time Frame: Baseline to Days 42 and 63 ]
• Change from Baseline in cognition measured by the MATRICS Consensus Cognitive Battery (MCCB) visual learning domain subscale score [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in cognition measured by the MATRICS Consensus Cognitive Battery (MCCB) reasoning and problem solving domain subscale score [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in cognition measured by the MATRICS Consensus Cognitive Battery (MCCB) social cognition domain subscale score [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in cognition measured by the FAS Phonemic Fluency test [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in cognition measured by the Brown-Peterson's Auditory Consonant Trigrams test [ Time Frame: Baseline through Day 63 ]
• Change from Baseline in cognitive outcomes among subgroups of subjects with deficits in the respective cognitive domain [ Time Frame: Baseline to Day 63 ]
  Cognitive outcomes will be reanalyzed, restricted to the subgroup of subjects whose baseline score is at or below median for healthy age-matched norms (T-score of 50 or below) for the respective cognitive outcome of interest. Analogous analyses will be carried out using more conservative cutoffs of one half and one standard deviation below median (T-score of 45 and 40 or below).
• Change from Baseline in cognition measured by the Wisconsin Card Sorting Test [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in working memory composite score [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in Negative symptoms measured by the Brief Negative Symptom Scale (BNSS) [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in Negative symptoms measured by the Positive and Negative Syndrome Scale (PANSS) negative symptom subscale [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in Negative symptoms measured by the Calgary Depression Scale for Schizophrenia (CDSS) [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in Positive symptoms measured by the Positive and Negative Syndrome Scale (PANSS) positive symptom subscale [ Time Frame: Baseline to Days 42 and 63 ]
• Overall clinical global impression of severity improvement measured by the change from Baseline of Clinical Global Impressions Scale assessment of severity (CGI-S) [ Time Frame: Baseline to Day 63 ]
• Change from Baseline in brain structure and function [ Time Frame: Baseline to Day 63 ]
  Magnetic Resonance Imaging (MRI) measures of brain structure; resting state functional connectivity; and activation patterns during performance of a working memory paradigm, and of brain reward networks during affective/neutral image appraisal and reward/loss anticipation and outcome (regions of interest: OMPFC, ACC, NAc, VTA).
• Change from Baseline neural activity and connectivity during learning and memory recollection measured by EEG [ Time Frame: Baseline to Day 63 ]
• Change from Baseline of red blood cell magnesium levels in relation to efficacy outcome measures [ Time Frame: Baseline to Day 63 ]
  Red blood cell magnesium level will be evaluated as a putative surrogate biomarker of target engagement, as a predictor of efficacy.
• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Baseline through Day 63, or Early Termination ]
  To evaluate safety and tolerability of MMFS-202-302 in patients with schizophrenia or schizoaffective disorder maintained on a stable dose of an atypical antipsychotic, each grade of adverse event will be evaluated individually, as well as the total number of all grades of adverse events
• Responder analyses [ Time Frame: Baseline to Day 63 ]
  The number of subjects achieving a cutoff of improving at least one half of a standard deviation (T-score change > 5) on the working memory subscale of the MCCB will be compared between the MMFS-202-302 and Placebo groups. Analogous responder analyses will be carried out for other efficacy outcomes.

Original Other Pre-specified Outcome Measures (submitted: September 10, 2014)

Neuroimaging [ Time Frame: One year ]

4. To determine the effect of MgT as augmentation of atypical antipsychotic medication on both the behavioral performance and activation patterns in schizophrenia patients during a WM neuroimaging paradigm. Specifically, investigation in whether improvement from baseline task performance occurs for the MgT + APD group, and if this improvement is associated with increases in WM-related brain region activation (DLPFC & PPC).

Descriptive Information

• Brief Title: Effect of MMFS-202-302 on Cognitive Enhancement in Schizophrenia
• Official Title: Effect of MMFS-202-302 on Cognitive Enhancement in Schizophrenia
• Brief Summary: The goals of this study are to study MMFS-202-302 in a double blind, randomized, placebo-controlled 9-week study of its effect on ameliorating cognitive deficits in 60 patients with schizophrenia or schizoaffective disorder with stable levels of positive symptoms. Secondary end points will include changes in positive and negative symptoms. One dose of MMFS-202-302 will be studied and compared with placebo as adjunctive treatment to atypical antipsychotic drug treatment.

Detailed Description

One of the symptoms of schizophrenia is a problem with specific domains of cognition, even when the positive symptoms have been treated. The primary goal of this study is to determine the effectiveness of 9 weeks of supplementation with MMFS-202-302 as augmentation of atypical antipsychotic medication, to improve a critical specific domain of cognitive function, i.e., working memory, in patients with schizophrenia or schizoaffective disorder. To support this primary goal, global function will be assessed with the Clinical Global Impression assessment of change.

The investigators will also examine the effect of MMFS-202-302 on other domains of cognition (e.g. attention, executive function, declarative memory, etc.); negative symptoms of schizophrenia; positive symptoms of schizophrenia; MRI measures of brain structure, resting state functional connectivity, and function during evaluation of emotional/unemotional and rewarding/aversive images and anticipation and receipt of reward and punishment, and working memory; and EEG measurement of network interactivity during learning and memory recollection.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Schizophrenia
• Schizoaffective Disorder

Intervention

• Drug: MMFS-202-302

  Active ingredient: L-Threonic acid Magnesium salt.

  1 g (2 pills) by mouth once daily in the evening for 9 weeks

  Drug: MMFS-302 Active ingredient: L-Threonic Acid Magnesium Salt

  1 g (2 pills) by mouth once daily in the morning for 9 weeks

• Drug: Placebo
  Two tablets by mouth in the morning, and two tablets by mouth in the evening, daily for 9 weeks.

Study Arms

• Experimental: MMFS-202 -302

  MMFS-202: evening dose

  MMFS-302: morning dose

  Intervention: Drug: MMFS-202-302
• Placebo Comparator: Placebo
  Placebo
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 10, 2014): 60
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 2017
• Actual Primary Completion Date: August 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. All patients must be capable of giving written informed consent.
2. Male or female subjects of any race; between 18 to 60 years of age, inclusive.
3. No hospitalization other than for evaluation in the past four months
4. Resides in a stable living situation, according to the investigator's judgment.
5. Diagnosis of schizophrenia or schizoaffective disorder of at least one-year duration, as established by the SCID-I, and verified with medical records and/or confirmation of diagnosis by treating clinician. The illness is in a nonacute phase as determined by the subject's primary treating clinician
6. Current psychotropic drug treatment consists of monotherapy with an atypical antipsychotic drug.
7. No more than a mild level of EPS as determined by the Simpson Angus Scale (SAS) total score: ≤ 6
8. Not taking anticholinergic medication for EPS
9. No evidence of tardive dykinesia
10. Subjects healthy enough to complete a 9-week clinical trial
11. Women of childbearing potential must have a negative pregnancy test at screening and baseline, and agree to use adequate protection (i.e. double barrier method) for birth control.
12. Able to complete cognition assessments in English
13. General intellectual abilities falling broadly within the average estimated IQ > 80, as measured by the Wide Range Achievement Test - 4th Edition (WRAT-IV).

Exclusion Criteria:

1. Failure to perform screening or baseline examinations
2. Hospitalization within 8 weeks before screening, or change of antipsychotic medication or dose within 2 months prior to screening
3. Subjects who have participated in another clinical trial with an experimental medication within the past 2 months.
4. Patient has had cognitive battery similar to those used in this study within the last 12 months
5. Subjects with other DSM-V Axis I or Axis II primary diagnoses
6. Diagnosis of alcohol or substance abuse or dependence within the past 3 months,
7. Significant suicide risk as determined by the Columbia Suicide Severity Rating Scale (C-SSRS)
8. Subjects who plan to begin a new course of cognitive remediation therapy, or have been receiving cognitive remediation therapy for less than one year. .
9. History of myocardial infarction, unstable angina, uncontrolled hypotension or hypertension within 3 months before screening.
10. Clinically significant abnormality on screening ECG
11. Alanine transaminase (ALT) or aspartate transaminase (AST) > 2.5 times the upper limit of normal (ULN)
12. History of stroke, brain tumor, head trauma with loss of consciousness, or other clinically significant neurological condition within 12 months before screening
13. Subjects with other uncontrolled medical conditions, in the opinion of the investigator
14. Polypharmacy with two or more antipsychotic drugs or mood stabilizers
15. Use of benzodiazepines
16. Individuals with kidney dysfunction will not be enrolled, as dysfunctional kidneys may have difficulty clearing the magnesium from the body
17. Individuals who are currently taking magnesium supplements

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02237235
• Other Study ID Numbers: STU00098144
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Herbert Meltzer, Northwestern University
• Study Sponsor: Northwestern University

Collaborators

• Neurocentria, Inc.
• Brain & Behavior Research Foundation

Investigators

• Principal Investigator: Herbert Y Meltzer, MD; Northwestern University

• PRS Account: Northwestern University
• Verification Date: August 2017