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The Use of AVL-3288 to Potentiate the Attention-Enhancing Effects of Low-Dose Nicotine

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03281694
Recruitment Status : Withdrawn (Drug supplier did not come through.)
First Posted : September 13, 2017
Last Update Posted : September 13, 2019
Sponsor:
Information provided by (Responsible Party):
Robert Buchanan, University of Maryland, Baltimore

Brief Summary:
Single-center, randomized, double-blind, placebo-controlled, proof-of-principle study to evaluate potential cognitive benefits of a single oral dose of AVL-3288 (3 mg) in the presence and absence of transdermal nicotine (7 mg/24 hrs) in healthy non-smokers, while monitoring the safety and tolerability of AVL-3288.

Condition or disease Intervention/treatment Phase
Cognitive Change Drug: Placebo Drug: Nicotine Drug: AVL-3288 Drug: Nicotine + AVL-3288 Phase 1

Detailed Description:

Nicotinic acetylcholine receptor (nAChR) agonists such as nicotine have been shown to enhance cognitive performance, especially functions in the attention domain. Efforts have been made to develop similar compounds as therapeutic agents for disorders such as schizophrenia or Alzheimer's disease. Over the last two decades, drug development has invested into novel nAChR agonists. Effects have generally been in the expected direction, but tended to be of small magnitude. A potential way of increasing the effect size ceiling is by co-administering a nAChR positive allosteric modulator (PAM). PAMs generally do not activate the nAChR on their own but bind to a second, modulatory site and facilitate agonist-induced responses. The present study is aimed at testing the effects of AVL-3288, a PAM selective for the α7 nAChR subtype that is thought to be of particular relevance for cognition in schizophrenia, on cognitive task performance, and on nicotine-induced improvements in cognitive task performance, in healthy adult non-smokers.

The aim of the present study is to provide the proof-of-principle that the attention-enhancing effects of the prototypical nAChR agonist nicotine can be potentiated by an α7 nAChR PAM (AVL-3288). Potentiation of nAChR agonist effects by PAMs have been shown in preclinical behavioral assays. The availability of AVL-3288 as a safe pure nAChR PAM for human research allows testing the hypothesis that nicotine and AVL-3288 will have additive or synergistic effects, such that the attention-enhancing effects of nicotine and AVL-3288 combined will be greater than the effects of either drug alone.

AVL-3288 has shown preclinical efficacy in rat paradigms of attention and memory, including models of cognitive dysfunction1-3. A human study in healthy adults reported no adverse effects associated with AVL-3288, tested at doses of 3, 10, and 30 mg. Some of the participants tested with 3 mg were smokers, some on nicotine replacement.

The present study will adopt a repeated measures design, in which a single group of 24 healthy non-smokers will complete 4 test sessions, in each of which they perform the same three cognitive paradigms. In each session, a skin patch will be administered 5 hrs prior to testing, and a solution (3 mL) will be administered by mouth 1 hr prior to testing. The skin patch is either a 7 mg/24 hrs nicotine patch or a placebo patch. The solution either contains AVL-3288 (3 mg) or is inactive diluent only. Over the 4 test sessions, each participant will be tested with Placebo + Placebo, Nicotine + Placebo, Placebo + AVL-3288, and Nicotine + AVL-3288, in a 2x2 factorial design. The sequence of test conditions will be only known to the statistician and pharmacist and counterbalanced across subjects.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description: The study will be double-blind. Only the statistician performing randomization and the dispensing pharmacist will know the sequence of test conditions.
Primary Purpose: Basic Science
Official Title: The Use of AVL-3288 to Potentiate the Attention-Enhancing Effects of Low-Dose Nicotine
Estimated Study Start Date : May 2018
Estimated Primary Completion Date : February 2019
Estimated Study Completion Date : February 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Nicotine - AVL-3288 Interaction Study
Over four different test days, all participants will be tested with Placebo, Nicotine, AVL-3288, and Nicotine + AVL-3288, in a counterbalanced sequence.
Drug: Placebo
placebo skin patch and placebo oral solution

Drug: Nicotine
nicotine skin patch (7 mg/24 hrs) and placebo oral solution

Drug: AVL-3288
placebo skin patch and AVL-3288 oral solution (3 mg)

Drug: Nicotine + AVL-3288
nicotine skin patch (7 mg/24 hrs) and AVL-3288 oral solution (3 mg)




Primary Outcome Measures :
  1. Spatial Attentional Resource Allocation Task reaction time [ Time Frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day ]
    average reaction time of trials with a signal detection response

  2. Spatial Attentional Resource Allocation Task omission errors [ Time Frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day ]
    percentage of trials on which no response was registered

  3. Rapid Visual Information Processing Task signal detection [ Time Frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day ]
    signal detection index based on hit rate and false alarm rate

  4. Rapid Visual Information Processing Task reaction time [ Time Frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day ]
    average reaction time on trials with a correct response

  5. Change Detection Task accuracy [ Time Frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day ]
    % of correct responses

  6. Change Detection reaction time [ Time Frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day ]
    average reaction time across trials


Secondary Outcome Measures :
  1. Vital signs: blood pressure [ Time Frame: hourly for 8 hours on each test day ]
    mm Hg

  2. Vital signs: heart rate [ Time Frame: hourly for 8 hours on each test day ]
    beats per minute

  3. ECG [ Time Frame: Before and 4 hours after ingestion of oral solution on each test day ]
    QTc interval



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Aged 21-50 years.
  • Male or female willing to use qualified methods of contraception for the study duration and up to 2 months after its end. Qualified methods are: intrauterine device, condoms, oral contraceptives, surgical sterilization of the subject or the partner at least one year in advance, or postmenopausal status of the female defined as at least two years without menstruation.
  • No exposure to any nicotine-containing product in the last year.
  • Smoked no more that 40 cigarettes, cigars or cigarillos in lifetime.
  • Normal or corrected to normal vision (at least 20/80).
  • Body weight 110-220 lbs.

Exclusion Criteria:

  • Pregnant or breast-feeding.
  • DSM Axis I mood, anxiety or psychotic disorder.
  • Drug or alcohol abuse or dependence currently or in the last 2 years.
  • Cardiovascular or cerebrovascular disease, such as history of myocardial infarction and ischemia, heart failure, angina, stroke, severe arrhythmias, or EKG abnormalities (see below).
  • Uncontrolled hypertension (resting systolic BP >150 or diastolic >95 mm Hg).
  • Hypotension (resting systolic BP below 90 or diastolic below 60).
  • Significant kidney or liver impairment.
  • Moderate to severe asthma.
  • Type I diabetes.
  • Gastrointestinal illness.
  • Use of any prescription or over-the-counter medication except birth control or non-steroidal antiinflammatory drugs on an as-needed basis.
  • History of or current neurological illnesses, such as stroke, seizure disorders, neurodegenerative diseases, or organic brain syndrome.
  • Learning disability, mental retardation, or any other condition that impedes cognition.
  • Any surgeries requiring full anesthesia scheduled within 2 weeks of any of the study test sessions.
  • Inability to perform the Rapid Visual Information Processing Task.
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Responsible Party: Robert Buchanan, Professor, Director Maryland Psychiatric Research Center, University of Maryland, Baltimore
ClinicalTrials.gov Identifier: NCT03281694    
Other Study ID Numbers: HP-0009999
First Posted: September 13, 2017    Key Record Dates
Last Update Posted: September 13, 2019
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Study data will be made available, in de-identified form, to Anvyl LLC (Irvine, CA).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Robert Buchanan, University of Maryland, Baltimore:
nicotine
positive allosteric modulator
attention
cognition
Additional relevant MeSH terms:
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Nicotine
Ganglionic Stimulants
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Nicotinic Agonists
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action