Nicotinic Cholinergic Modulation as a Novel Treatment Strategy for Aggression Associated With Autism

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02552147
• Collaborator: Autism Speaks (Other)
• Enrollment: 8
• Location: 1
• Arms: 2
• Duration (Months): 26.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Some individuals with autism spectrum disorders (ASD) also demonstrate irritability or aggression, which can interfere with functioning. The purpose of this pilot study is to test whether transdermal nicotine is effective for irritability and/or aggression in adults with ASD using a double-blind, placebo-controlled clinical trial. Subjects will participate in three visits. At the first visit, subjects are screened for eligibility and enrolled. Baseline measures include rating scales and a frustrative computerized task. They will then wear seven days of transdermal nicotine or placebo. Visit two is on day seven and the study measures are repeated, vital signs and side effects monitored. Subjects will return for a third and final visit on day 21 to repeat the study measures performed during visit two.

Condition or Disease	Intervention/Treatment	Phase
Autism Spectrum Disorder; Aggression; Irritability	Drug: Transdermal nicotine; Other: Transdermal placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Nicotinic Cholinergic Modulation as a Novel Treatment Strategy for Aggression Associated With Autism
• Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Nov 17, 2017
• Actual Study Completion Date: Nov 17, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Transdermal nicotine first, placebo last Subject will receive transdermal nicotine 7 mg daily for 7 days, placebo patch for 7 days, then placebo patch for a final 7 days.	Drug: Transdermal nicotine; Other: Transdermal placebo
Experimental: Transdermal placebo first, nicotine last Subject will receive transdermal placebo daily for 7 days, placebo patch for another 7 days, then transdermal nicotine 7 mg daily for a final 7 days.	Drug: Transdermal nicotine; Other: Transdermal placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Aberrant Behavior Checklist Irritability Subscale (ABC-I) [Baseline and 7 days.]

   Aberrant Behavior Checklist (ABC) measures symptom subscales for individuals with neurodevelopmental disorders. The ABC-irritability subscale measures irritability and related symptoms and the subscale score range is 0 (least symptomatic) to 45 (most symptomatic). The ABC is completed by parents/caregivers.

Secondary Outcome Measures

1. Change in Social Responsiveness Scale-Adults (SRS-A) [Baseline and 7 days.]

   The Social Responsiveness Scale (SRS) - 2 quantifies impairments in social behaviors seen in autism spectrum disorder and related conditions and their severity. The version used in this study is completed by parents/caregivers. The raw score range is 0 (unaffected) to > 134 (extremely affected). The ABC is completed by parents/caregivers.

2. Change in Qualitative Description of Irritability and Aggression Symptoms [Baseline and 7 days]

   Brief qualitative reports of the patient's subjective experience will be recorded by asking "In what ways did you find the patch helpful or harmful during the past week, if at all?".

3. Change in Frustration and Irritability Ratings During Frustration-induction Go-NoGo Task [Baseline and one week]

   Subjects will perform a computerized frustration-induction task and complete a rating scale of irritability and frustration levels.

4. Change in State/Trait Anxiety Inventory (STAI) Score [Baseline and day 7]

   The State-Trait Anxiety Inventory (STAI) is a measure of trait and state anxiety. It ranges from a score of 20 (least affected) to 80 (most affected).

5. Nightly Sleep Quality [Day 7]

   Caregivers rated nightly sleep quality from 0 (worst) to 10 (best). Average rating for each treatment week is compared.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Age: 18-60

• Gender: All

• Language: Communicative in English

• Participants with a prior diagnosis of DSM-5 ASD at some point in their lifetime OR a DSM-4 diagnosis of Autism OR a DSM-4 diagnosis of Asperger's syndrome OR a DSM-4 diagnosis of Pervasive Developmental Disorder Not Otherwise Specified.

• Symptoms of irritability, agitation or aggression as reported by parent and/or participant

• Aberrant behavior checklist - Irritability Subscale (ABC-I) score of 16 or higher

• No changes in psychotropic medications within the past 14 days.

• Either lives with a primary caregiver or closely engaged with a primary caregiver who interacts with the patient daily

• BMI > 17.5 and < 45

Exclusion criteria:

• Age < 18 or > 60

• BMI < 17.5 or > 45

• Currently using tobacco or any nicotine products (transdermal, gum, e-cigarettes)

• Changes in psychotropic medication management within the past 14 days

• Previous allergy to transdermal patches

• Patients with heart rate > 100 or < 50 or known history of cardiac rhythm abnormalities

• Systolic blood pressure > 150 or < 95; diastolic blood pressure > 90 or < 50

• No symptoms of irritability, agitation, or aggression as reported by parent and/or participant

• ABC-I score of less than 16

• No primary caregiver, or primary caregiver unable to assist with rating scales

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University	New Haven	Connecticut	United States	06511

Sponsors and Collaborators

• Yale University
• Autism Speaks

Investigators

• Principal Investigator: Alan S Lewis, MD, PhD, Lecturer in psychiatry

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 29, 2017
• Informed Consent Form - Nov 29, 2017

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT02552147
• Other Study ID Numbers: 1502015384
• First Posted: Sep 16, 2015
• Last Update Posted: May 6, 2022
• Last Verified: May 1, 2022

• Keywords provided by Yale University: Autism spectrum disorder; Aggression; Irritability; Nicotine; Nicotinic acetylcholine receptor; Nicotinic agonist; Adult autism
• Additional relevant MeSH terms: Autistic Disorder; Autism Spectrum Disorder; Aggression; Nicotine

Study Results

Participant Flow

Arm/Group Title	Transdermal Placebo First, Nicotine Last	Transdermal Nicotine First, Placebo Last
Arm/Group Description	Subject will receive transdermal placebo daily for 7 days, placebo patch for another 7 days, then transdermal nicotine 7 mg daily for a final 7 days. Transdermal nicotine Transdermal placebo	Subject will receive transdermal nicotine 7 mg daily for 7 days, placebo patch for 7 days, then placebo patch for a final 7 days. Transdermal nicotine Transdermal placebo
Period Title: First Intervention (7 Days)
STARTED	4	4
COMPLETED	3	4
NOT COMPLETED	1	0
Period Title: First Intervention (7 Days)
STARTED	3	4
COMPLETED	3	4
NOT COMPLETED	0	0
Period Title: First Intervention (7 Days)
STARTED	3	4
COMPLETED	1	4
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	Participants randomized to receive either transdermal nicotine or placebo
Overall Participants	7
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24 (3)
Sex: Female, Male (Count of Participants)
Female	1 14.3%
Male	6 85.7%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
United States	7 100%
Aberrant Behavior Checklist-Irritability (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	25 (8)
Aberrant Behavior Checklist-Lethargy/Social withdrawal (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	20 (13)
Aberrant Behavior Checklist-Stereotypic behavior (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	9 (7)
Aberrant Behavior Checklist-Hyperactivity (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	26 (11)
Aberrant Behavior Checklist-Inappropriate speech (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6 (4)
Social Responsiveness Scale-2 (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	177 (25)
Number on antipsychotic medication (Count of Participants)
Count of Participants [Participants]	5 71.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Aberrant Behavior Checklist Irritability Subscale (ABC-I)
Description	Aberrant Behavior Checklist (ABC) measures symptom subscales for individuals with neurodevelopmental disorders. The ABC-irritability subscale measures irritability and related symptoms and the subscale score range is 0 (least symptomatic) to 45 (most symptomatic). The ABC is completed by parents/caregivers.
Time Frame	Baseline and 7 days.

Outcome Measure Data

Analysis Population Description

All participants who completing all study visits and for which ratings scales were completed in accordance with study protocol.

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	-12 (3)	-7 (8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.44
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-tailed

2. Secondary Outcome

Title	Change in Social Responsiveness Scale-Adults (SRS-A)
Description	The Social Responsiveness Scale (SRS) - 2 quantifies impairments in social behaviors seen in autism spectrum disorder and related conditions and their severity. The version used in this study is completed by parents/caregivers. The raw score range is 0 (unaffected) to > 134 (extremely affected). The ABC is completed by parents/caregivers.
Time Frame	Baseline and 7 days.

Outcome Measure Data

Analysis Population Description

All participants completing all study visits and for which ratings scales were completed in accordance with study protocol.

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	-1 (25)	-15 (23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.38
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-tailed

3. Secondary Outcome

Title	Change in Qualitative Description of Irritability and Aggression Symptoms
Description	Brief qualitative reports of the patient's subjective experience will be recorded by asking "In what ways did you find the patch helpful or harmful during the past week, if at all?".
Time Frame	Baseline and 7 days

Outcome Measure Data

Analysis Population Description

Data were not collected.

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	0	0

4. Secondary Outcome

Title	Change in Frustration and Irritability Ratings During Frustration-induction Go-NoGo Task
Description	Subjects will perform a computerized frustration-induction task and complete a rating scale of irritability and frustration levels.
Time Frame	Baseline and one week

Outcome Measure Data

Analysis Population Description

Data were not collected.

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	0	0

5. Secondary Outcome

Title	Change in State/Trait Anxiety Inventory (STAI) Score
Description	The State-Trait Anxiety Inventory (STAI) is a measure of trait and state anxiety. It ranges from a score of 20 (least affected) to 80 (most affected).
Time Frame	Baseline and day 7

Outcome Measure Data

Analysis Population Description

Data were not collected.

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	0	0

6. Secondary Outcome

Title	Nightly Sleep Quality
Description	Caregivers rated nightly sleep quality from 0 (worst) to 10 (best). Average rating for each treatment week is compared.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	10 (0.2)	9 (2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-tailed

7. Post-Hoc Outcome

Title	Aberrant Behavior Checklist - Lethargy/Social Withdrawal Subscale Change From Baseline
Description	Aberrant Behavior Checklist (ABC) measures symptom subscales for individuals with neurodevelopmental disorders. The ABC-lethargy/social withdrawal subscale measures lethargy/social withdrawal and related symptoms and the subscale score range is 0 (least symptomatic) to 48 (most symptomatic). The ABC is completed by parents/caregivers.
Time Frame	Baseline and 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	-2 (3)	-7 (4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-tailed

8. Post-Hoc Outcome

Title	Aberrant Behavior Checklist - Stereotypic Behavior Subscale Change From Baseline
Description	Aberrant Behavior Checklist (ABC) measures symptom subscales for individuals with neurodevelopmental disorders. The ABC-stereotypic behavior subscale measures stereotypic behaviors and related symptoms and the subscale score range is 0 (least symptomatic) to 21 (most symptomatic). The ABC is completed by parents/caregivers.
Time Frame	Baseline and 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	-2 (3)	-4 (4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.50
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-tailed

9. Post-Hoc Outcome

Title	Aberrant Behavior Checklist - Hyperactivity Subscale Change From Baseline
Description	Aberrant Behavior Checklist (ABC) measures symptom subscales for individuals with neurodevelopmental disorders. The ABC-hyperactivity subscale measures hyperactivity and related symptoms and the subscale score range is 0 (least symptomatic) to 48 (most symptomatic). The ABC is completed by parents/caregivers.
Time Frame	Baseline and 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	-7 (6)	-6 (6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nicotine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments	P value was calculated to >0.99 and thus rounded to 1.0.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-tailed

10. Post-Hoc Outcome

Title	Aberrant Behavior Checklist - Inappropriate Speech Subscale Change From Baseline
Description	Aberrant Behavior Checklist (ABC) measures symptom subscales for individuals with neurodevelopmental disorders. The ABC-Inappropriate speech subscale measures Inappropriate speech and related symptoms and the subscale score range is 0 (least symptomatic) to 12 (most symptomatic). The ABC is completed by parents/caregivers.
Time Frame	Baseline and 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	-1 (2)	0.2 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-tailed

11. Post-Hoc Outcome

Title	Global Aggressive Behavior Improvement
Description	Caregivers asked which treatment week showed the greatest improvement in aggressive or irritable behavior
Time Frame	Baseline and 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nicotine	Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.	Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
Measure Participants	6	6
Count of Participants [Participants]	4 57.1%	2 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Binomial test
	Comments

Adverse Events

Time Frame	Duration of trial (3 weeks).
Arm/Group Title	Nicotine		Placebo
Arm/Group Description	Subject receiving transdermal nicotine in either the first or last week of the study and completing all study visits.		Subject receiving transdermal placebo in either the first or last week of the study and completing all study visits.
All Cause Mortality
	Nicotine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Serious Adverse Events
	Nicotine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Nicotine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		1/7 (14.3%)
Gastrointestinal disorders
Dyspepsia	0/7 (0%)	0	1/7 (14.3%)	1
Nervous system disorders
Nightmare	0/7 (0%)	0	1/7 (14.3%)	1

Limitations/Caveats

Unable to recruit the pre-specified number of subjects; Subjects were unable to reliably complete personal ratings (STAI and STAXI) and were unable to reliably complete the frustrative computer task.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.