Clinical trial NCT00100165: Phase 2 Trial of a Nicotinic Agonist in Schizophrenia
Official title: Phase 2 Trial of the Nicotinic Agonist 3-(2,4 Dimethoxybenzylidene Anabaseine) in Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Schizophrenia
Keywords: Schizophrenia
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: VA Office of Research and Development
First posted: 2004-12-24
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* Schizophrenia
* Currently treated with neuroleptic drugs

Exclusion Criteria:

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

Primary outcomes:
measure: Neurocognitive Performance
timeFrame: 1 month
Secondary outcomes:
measure: Scale for the Assessment of Negative Symptoms (SANS)
timeFrame: 1 month
Other outcomes:
Locations:
city: Denver
country: United States
facility: VA Eastern Colorado Health Care System, Denver, CO
state: Colorado
Study officials:
affiliation: VA Eastern Colorado Health Care System, Denver, CO
name: Robert Freedman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tregellas JR, Tanabe J, Rojas DC, Shatti S, Olincy A, Johnson L, Martin LF, Soti F, Kem WR, Leonard S, Freedman R. Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia. Biol Psychiatry. 2011 Jan 1;69(1):7-11. doi: 10.1016/j.biopsych.2010.07.004. Epub 2010 Aug 21.
citation: Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1040-7. doi: 10.1176/appi.ajp.2008.07071135. Epub 2008 Apr 1.