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

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.

Study Overview

• Status: Withdrawn
• Conditions: Cognitive Change
• Intervention / Treatment: Drug: Placebo; Drug: Nicotine; Drug: AVL-3288; Drug: Nicotine + AVL-3288

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.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spatial Attentional Resource Allocation Task reaction time	average reaction time of trials with a signal detection response	5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
Spatial Attentional Resource Allocation Task omission errors	percentage of trials on which no response was registered	5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
Rapid Visual Information Processing Task signal detection	signal detection index based on hit rate and false alarm rate	5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
Rapid Visual Information Processing Task reaction time	average reaction time on trials with a correct response	5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
Change Detection Task accuracy	% of correct responses	5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
Change Detection reaction time	average reaction time across trials	5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vital signs: blood pressure	mm Hg	hourly for 8 hours on each test day
Vital signs: heart rate	beats per minute	hourly for 8 hours on each test day
ECG	QTc interval	Before and 4 hours after ingestion of oral solution on each test day

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2018
• Primary Completion (Anticipated): February 1, 2019
• Study Completion (Anticipated): February 1, 2019

Study Registration Dates

• First Submitted: September 6, 2017
• First Submitted That Met QC Criteria: September 8, 2017
• First Posted (Actual): September 13, 2017

Study Record Updates

• Last Update Posted (Actual): September 13, 2019
• Last Update Submitted That Met QC Criteria: September 11, 2019
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: cognition; nicotine; attention; positive allosteric modulator
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Nicotine
• Other Study ID Numbers: HP-0009999

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study data will be made available, in de-identified form, to Anvyl LLC (Irvine, CA).

Drug and device information, study documents

• 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