Galantamine and Memantine Combination for Cognitive Impairments in Schizophrenia

Study Overview
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Brief Summary
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Aim: To examine the efficacy of the combination of galantamine and memantine for the treatment of cognitive deficits in outpatients with schizophrenia. Hypothesis: A combination of galantamine and memantine will improve cognitive impairments in patients with schizophrenia. This is an open-label study to evaluate whether a six week course of galantamine ER and memantine XR is effective in improving the cognitive performance of patients with schizophrenia or schizoaffective disorder. The primary outcome measure will be the change in level of cognition as measured by the MATRICS Consensus Cognitive Battery (MCCB). The results of the MATRICS collaborative project recommended the need for standardized cognitive tests that better distinguish the different facets of cognitive dysfunction in schizophrenia. The MCCB will assess the following seven domains: attention/vigilance, reasoning and problem solving, processing speed, social cognition, verbal learning and memory, visual learning and memory, and working memory. The MCCB will be administered at baseline and at the end of the study. We will report total score and each domain score in the MCCB at baseline and six weeks.

Official Title
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A Proof-of Concept Trial of Galantamine and Memantine for Cognitive Impairments in Schizophrenia: Is the Combination Effective?

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: Galantamine ER
* Drug: Memantine XR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be male or female aged 18 to 55 years (inclusive). Have a DSM-5 diagnosis of schizophrenia or schizoaffective disorder confirmed by medical records. Duration of illness must be ≥ 1year. Be clinically stable for at least two months (i.e., has no more than a moderately severe severity rating on the following BPRS items: hallucination, unusual thought content and conceptual disorganization. Have not had a psychiatric hospitalization in the two months prior to screening. Be taking any 1st generation antipsychotic prescribed in the absence of a concomitant anticholinergic or 2nd generation antipsychotic and minimal extrapyramidal symptoms Have a Simpson-Angus Score (SAS) < 6 Be on current medication regimen for at least six weeks before screening at stable dose and frequency for at least 30 days before screening. Be in good general health and expected to complete the clinical study as designed. Subjects of childbearing potential must agree to use two forms of non-hormonal contraception (dual contraception) consistently during the screening and treatment periods of the trial, and for 30 days after the final dose of the study medications. Females of child-bearing potential must have a negative urine pregnancy test at baseline. This may also be done at subsequent visits if subject reports possibility of pregnancy. Have a negative urine drug screen at screening. This may be repeated at the discretion of the primary investigator. Have adequate hearing, vision, and language skills to perform the procedures specified in the protocol. Be capable of providing informed consent and have voluntarily provided informed consent. Exclusion Criteria: Have an active, clinically significant unstable medical condition with 30 days prior to screening. Have dementia. Are pregnant, breastfeeding, or planning to become pregnant Are taking or thinking about taking oral contraceptives or an injectable contraceptive. Are taking benztropine at a dose greater than 2 mg daily. Have a history of Pervasive Development Disorder. Have a history of significant head injury/trauma (defined by one of more of the following: loss of consciousness for more than one hour; recurring seizures resulting from the head injury; and/or clear cognitive sequelae of the injury requiring cognitive rehabilitation.) Have an allergy to anticholinesterase medications (galantamine, rivastigimine, donepezil) and memantine Have a DSM-5 diagnosis of alcohol and/or substance use disorder (other than caffeine and tobacco) within the last 6 months. Are taking a restricted medication: Amitriptyline, Doxepin, Imipramine, Flexeril, Clozapine, and/or cortisol (any oral, injectable, or topical steroid medication) Have a history of seizures excluding a childhood febrile seizure Have received ECT within the last three months prior to screening. Have participated in a clinical trial of any other psychotropic medication within last two months prior to screening. Have a severe or extremely severe severity rating on the BPRS items: hallucination or unusual thought content. Have more than a moderate severity rating on the BPRS item conceptual disorganization . Are currently taking 3 or more antipsychotic medications.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Galantamine ER, Memantine XR<br>Week 1, Galantamine ER 8 mg HS & Memantine XR 7 mg HS Week 2, Galantamine ER 16 mg HS & Memantine XR 14 mg HS Weeks 3-6, Galantamine ER 24 mg HS & Memantine XR 21 mg HS | Drug: Galantamine ER<br> <br> * Other names: Formerly known as Reminyl;Drug: Memantine XR<br> <br> * Other names: Namenda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Level of Cognition | The primary outcome measure will be the change in level of cognition as measured by the MATRICS Consensus Cognitive Battery (MCCB). In schizophrenia, usual composite scores are 20-39. In healthy controls, usual composite scores are normalized to 40-60. Higher values of composite scores mean better cognition. Test scores are normalized to healthy controls, therefore no min-max range is available. Final scores calculated by MATRICS Consensus Cognitive Battery software. Exact minimum/maximum are not known to provider. Overall composite scores are reported. | Baseline and 6-Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Free Tryptophan (TRP) | The secondary outcome measure will be change in metabolite values. Values were collected in triplicate. | Baseline and 6-Weeks | 
| Kynurenic Acid (KYNA) | The secondary outcome measure will be change in metabolite values. Values were collected in triplicate. MS* AUC is mass spectrometry times area under the curve. | Baseline and 6-Weeks | 
| Kynurenine (KYN) | The secondary outcome measure will be change in metabolite values. Values were collected in triplicate. | Baseline and 6-Weeks | 
| Picolinic Acid (PIC) | The secondary outcome measure will be change in metabolite values. Values were collected in triplicate. MS* AUC is mass spectrometry times area under the curve. | Baseline and 6-Weeks | 
| KYN/TRP | The secondary outcome measure will be change in metabolite values. Values were collected in triplicate. AUC ratio reported. | Baseline and 6-Weeks | 
| KYNA/KYN | The secondary outcome measure will be change in metabolite values. Values were collected in triplicate. AUC ratio reported. | Baseline and 6-Weeks | 
| PIC/KYN | The secondary outcome measure will be change in metabolite values. Values were collected in triplicate. AUC ratio reported. | Baseline and 6-Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Schizoaffective Disorder, Cognition, Cognitive Impairment, Galantamine, Memantine