Phase 2 Trial of a Nicotinic Agonist in Schizophrenia

Phase 2

Completed

• Conditions: Schizophrenia
• Interventions: Drug: Placebo; Drug: 3-(2,4 dimethoxybenzylidene anabaseine) 150 mg; Drug: 3-(2,4 dimethoxybenzylidene anabaseine) 75 mg

• Registration Number: NCT00100165
• Lead Sponsor: University of Colorado, Denver

Brief Summary

The study hypothesis is that 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A), an orally administered nicotinic cholinergic agonist, will improve attention and other neuropsychological dysfunctions in schizophrenia, leading to improved psychosocial outcome.

Detailed Description

The objective of the trial is to determine if dosing 3-(2,4 dimethoxybenzylidene anabaseine) twice daily for 4 weeks will improve cognition and be safe. Secondary goals are to determine if these neurocognitive effects also have effects on neurobiological paradigms previously shown to be responsive to nicotinic receptor stimulation: suppression of P50 auditory evoked response, saccadic intrusions during smooth pursuit eye movements, and hemodynamic activity in the hippocampus during smooth pursuit eye movements as measured by functional magnetic resonance imaging. The purpose of these neurobiological measures is to assess whether the response to 3-(2,4 dimethoxybenzylidene anabaseine) is consistent with activation of nicotinic receptors. In addition, the investigators will assess clinical response using a battery of clinical assessment scales and assessments of daily living functions. The purpose of these assessments is to address the FDA requirement of a clinical effect beyond change in laboratory neuropsychological performance. This study and the subsequent two studies will also include assessments of the safety of 3-(2,4 dimethoxybenzylidene anabaseine) and related compounds.

The purpose of the trial is to lay the groundwork for Phase III investigation. If this trial finds that 3-(2,4 dimethoxybenzylidene anabaseine) has effects at a safe dose, without tachyphylaxis, then the investigators intend to proceed to a Phase III trial, where the clinical importance of this effect can be measured.

The trial will be a double blind trial with placebo control. The order of doses and placebo will be randomized.

The Phase 1 study was completed in January, 2005, with 12 non-smoking schizophrenics subjects. The subjects were concurrently treated with neuroleptics throughout the study. They received 3 treatments, each for 1 day, in a double-blind crossover design. The treatments were 3-(2,4 dimethoxybenzylidene anabaseine) (150 mg + 75 mg 2 hours later), 3-(2,4 dimethoxybenzylidene anabaseine)(75 mg + 37.5 mg 2 hours later), and placebo. A significant effect on neurocognition, as measured by the Repeatable Battery for Assessment of Neuropsychological Status, and on sensory gating, as measured by P50 auditory evoked potentials was observed. Subjects reported no significant symptoms. One subject's white blood cell count decreased from just above normal limits on placebo to just below normal levels on 3-(2,4 dimethoxybenzylidene anabaseine)(150 + 75 mg 2 hours later). He did not receive further exposure to drug and his white blood cell count returned to normal at the next testing, 2 days later.

Study Timeline

• Study First Submitted: 2004-12-23
• Study First Submitted QC: 2004-12-23
• Study First Posted: 2004-12-24
• Study Start: 2005-01
• Primary Completion: 2007-07
• Study Completion: 2007-07
• Results First Submitted: 2016-08-24
• Status Verified: 2020-01
• Results First Submitted QC: 2020-01-27
• Last Update Submitted: 2020-01-27
• Results First Posted: 2020-01-29
• Last Update Posted: 2020-01-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 29

Inclusion Criteria

• Schizophrenia
• Currently treated with neuroleptic drugs

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Exclusion Criteria

• Treatment with clozapine;
• Head injury or neurological condition;
• Cardiovascular disease;
• Substance abuse or dependence, including nicotine

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
placebo	Placebo	Patient receives placebo twice per day in a blinded capsule.
3-(2,4 dimethoxybenzylidene anabaseine) 150 mg	3-(2,4 dimethoxybenzylidene anabaseine) 150 mg	Patient receives 3-(2,4 dimethoxybenzylidene anabaseine) 150 mg twice per day in a blinded capsule.
3-(2,4 dimethoxybenzylidene anabaseine)75 mg	3-(2,4 dimethoxybenzylidene anabaseine) 75 mg	Patient receives 3-(2,4 dimethoxybenzylidene anabaseine) 75 mg twice per day in a blinded capsule.

Primary Outcome Measures

Name	Time	Method
Neurocognitive Performance	1 month	The measurement of neurocognitive performance on 6 domains, speed of processing, attention/vigilance, working memory, verbal learning, visual learning and reasoning/problem solving. Each domain is compared to a normative sample of schizophrenia subjects and the performance is determined and compared by a T-Test to the subjects baseline performance to determine the effect of drug or placebo. The scale is the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia Neurocognitive Consensus Combined Battery, range 0-100. A higher score indicates better performance.

Secondary Outcome Measures

Name	Time	Method
Scale for the Assessment of Negative Symptoms (SANS)	1 month	The Scale for the Assessment of Negative Symptoms measures the measure negative symptoms in schizophrenia by measuring the domains of anhedonia, alogia, avolition and anhedonia in schizophrenia on a scale from 1 to 20 that sums the global scores of all 4 domains, each of which are rated on a scale of 1-5. Higher scores indicate greater severity of negative symptoms

Trial Locations

Locations (1)

VA Eastern Colorado Health Care System, Denver, CO; 🇺🇸 Denver, Colorado, United States