Phase 2 Trial of a Nicotinic Agonist in Schizophrenia (DMXB-A)

University of Colorado Denver (CU Denver)

Status and phase: Completed; Phase 2

Conditions: Schizophrenia

Treatments: Drug: 3-(2,4 dimethoxybenzylidene anabaseine) 75 mg; Drug: Placebo; Drug: 3-(2,4 dimethoxybenzylidene anabaseine) 150 mg

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT00100165

VISN 19 MIRECC (Other Grant/Funding Number)

08-0837

Details and patient eligibility

About

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.

Full 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.

Enrollment: 29 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

---

29 participants in 3 patient groups, including a placebo group

3-(2,4 dimethoxybenzylidene anabaseine) 150 mg

Experimental group

Description:

Patient receives 3-(2,4 dimethoxybenzylidene anabaseine) 150 mg twice per day in a blinded capsule.

Treatment:

Drug: 3-(2,4 dimethoxybenzylidene anabaseine) 150 mg

3-(2,4 dimethoxybenzylidene anabaseine)75 mg

Experimental group

Description:

Patient receives 3-(2,4 dimethoxybenzylidene anabaseine) 75 mg twice per day in a blinded capsule.

Treatment:

Drug: 3-(2,4 dimethoxybenzylidene anabaseine) 75 mg

placebo

Placebo Comparator group

Description:

Patient receives placebo twice per day in a blinded capsule.

Treatment:

Drug: Placebo