The Use of AVL-3288 to Potentiate the Attention-Enhancing Effects of Low-Dose Nicotine
|ClinicalTrials.gov Identifier: NCT03281694|
Recruitment Status : Withdrawn (Drug supplier did not come through.)
First Posted : September 13, 2017
Last Update Posted : September 13, 2019
|Condition or disease||Intervention/treatment||Phase|
|Cognitive Change||Drug: Placebo Drug: Nicotine Drug: AVL-3288 Drug: Nicotine + AVL-3288||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||0 participants|
|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|
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.
placebo skin patch and placebo oral solution
nicotine skin patch (7 mg/24 hrs) and placebo oral solution
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)
- 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
- 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
- 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
- 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
- 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
- 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
- Vital signs: blood pressure [ Time Frame: hourly for 8 hours on each test day ]mm Hg
- Vital signs: heart rate [ Time Frame: hourly for 8 hours on each test day ]beats per minute
- ECG [ Time Frame: Before and 4 hours after ingestion of oral solution on each test day ]QTc interval