A Study of N-Acetyl Cysteine in Children With Autism

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00627705
• Collaborator: (none)
• Enrollment: 43
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The purpose of the study is to test the tolerability and efficacy of N-Acetyl Cysteine (NAC) in children with Autism. NAC is a compound that increases the levels of Glutathione, the body's main antioxidant. Glutathione is a compound in the blood that is part of a natural defense system (the antioxidant system). Anti-oxidants protect the body from damage caused by internal toxins called "free radicals." It is possible that children with Autism tend to have lower levels of glutathione, an important compound in our bodies that helps combat the effects of toxic free radicals.

We hope that by studying the antioxidant system in more detail, we will increase our understanding of the reasons why people develop Autism so that we can design better ways to treat individuals with this condition. This study is meant to test the safety tolerability of NAC and its effectiveness in the treatment of behavioral difficulties in children with autism. It will also examine the possible benefit of this agent in improving the core deficits in autism such as social deficits.

Condition or Disease	Intervention/Treatment	Phase
Autistic Disorder	Drug: N-Acetyl Cysteine; Other: Placebo - sugar pill	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Double-blind , Randomized, Placebo Controlled Study of N-Acetyl Cysteine in Autism.
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: N-Acetyl Cysteine active compound N-Acetyl Cysteine	Drug: N-Acetyl Cysteine; Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).; Other Names: NAC
Placebo Comparator: Sugar pill Placebo or sugar pill	Other: Placebo - sugar pill; Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).; Other Names: Placebo

Outcome Measures

Primary Outcome Measures

1. Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) [4, 8, and 12 weeks]

   The Dosage Record and Treatment Emergent Symptom Scale (DOTES) provides information on the presence, frequency, and severity of side effects reported during the course of the trial.

2. The Clinical Global Rating Scale (CGRS) Improvement Subscale Score [12 weeks]

   Score range 1-7 (lower score mean more improvement compared to baseline)

3. Glutathione (GSH) Levels in Peripheral Blood, Measured by State-of-the-art High-performance Liquid Chromatography (HPLC) [12 weeks]

   Data not collected. The laboratory was not able to measure Glutathione levels.

4. Irritability Subscale of the Aberrant Behavior Checklist (ABC) [baseline and 12 weeks]

   Aberrant Behavior Checklist (ABC) Irritability Subscale Score (range 0-45); higher scores mean higher irritability

Secondary Outcome Measures

1. The Aberrant Behavior Checklist Total Score (ABC) [4, 8, and 12 weeks]

   Total score was not analyzed since we analyzed the sub scales. Additionally, the authors of the instrument do not recommend analyzing the total score.

2. Social Responsiveness Scale (SRS) [12 weeks]

   SRS total score (range 0-195); higher scores mean more social impairment

3. Sensory Profile Questionnaire (SPQ) [12 weeks]

4. Glutathione (GSH) Metabolism Intermediates in Peripheral Blood [12 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Outpatients between 3.0 and 12.11 years of age inclusive

2. Males and females who are physically healthy

3. diagnosis of autism based Diagnostic and Statistical Manual (DSM-IV-TR) criteria, the Autism Diagnostic Interview-Revised, and expert clinical evaluation

4. Clinical Global Impression Severity rating of 4

5. Care provider who can reliably bring subject to clinic visits, can provide trustworthy ratings, and interacts with subject on a regular basis

6. Ability of subject to swallow the compound

7. Stable concomitant medications for at least 2 weeks

8. No planned changes in psychosocial interventions during the open-label N-Acetyl Cysteine trial

Exclusion Criteria:

1. DSM-IV-TR diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder not otherwise specified

2. Prior adequate trial of N-Acetyl Cysteine

3. Active medical problems: unstable seizures, significant physical illness (e.g., serious liver or renal pathology)

4. Pregnancy or sexually active females

5. Subjects taking antioxidant agents and glutathione prodrugs will be excluded from the study except if they have been off these compounds for at least 4 weeks

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University

Investigators

• Principal Investigator: Antonio Hardan, MD, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Antonio Hardan, Professor, Stanford University
• ClinicalTrials.gov Identifier: NCT00627705
• Other Study ID Numbers: SU-02012008-995; 10142
• First Posted: Mar 3, 2008
• Last Update Posted: May 18, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Autistic Disorder; Acetylcysteine; N-monoacetylcystine

Study Results

Participant Flow

Recruitment Details	Recruitment started in March 2009 and ended in September 2010. This study was conducted in the Autism & Developmental Disabilities Clinic in the Division of Child & Adolescent Psychiatry, Lucile Packard Children's Hospital at Stanford University.
Pre-assignment Detail	Fifty-one potential subjects inquired about the study. Forty-three of the subjects signed a consent form. Seven subjects were excluded because they did not meet criteria for autistic disorder. Three subjects decided not to participate in the study before baseline measures were obtained. Thirty-three subjects were randomized in the study.

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
Period Title: Overall Study
STARTED	15	18
COMPLETED	13	12
NOT COMPLETED	2	6

Baseline Characteristics

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill	Total
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Total of all reporting groups
Overall Participants	15	18	33
Age (Count of Participants)
<=18 years	15 100%	18 100%	33 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 13.3%	0 0%	2 6.1%
Male	13 86.7%	18 100%	31 93.9%
Region of Enrollment (participants) [Number]
United States	15 100%	18 100%	33 100%

Outcome Measures

1. Primary Outcome

Title	Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES)
Description	The Dosage Record and Treatment Emergent Symptom Scale (DOTES) provides information on the presence, frequency, and severity of side effects reported during the course of the trial.
Time Frame	4, 8, and 12 weeks

Outcome Measure Data

Analysis Population Description

We analyzed subjects who had follow-up data available.

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
Measure Participants	14	15
Total Number of Subjects with GI adverse Events	11 73.3%	7 38.9%
Constipation	3 20%	2 11.1%
Nausea/Vomiting	6 40%	3 16.7%
Diarrhea	3 20%	1 5.6%
Increased Appetite	2 13.3%	0 0%
Decreased Appetite	2 13.3%	3 16.7%
Akathisia	1 6.7%	0 0%
Excitement/Agitation	2 13.3%	3 16.7%
Increased Motor Activity	2 13.3%	3 16.7%
Tremor	0 0%	1 5.6%
Syncope/Dizziness	0 0%	1 5.6%
Depressive Affect	1 6.7%	0 0%
Nasal Congestion	4 26.7%	6 33.3%
Increased Salivation	0 0%	2 11.1%
Sweating	0 0%	1 5.6%

2. Primary Outcome

Title	The Clinical Global Rating Scale (CGRS) Improvement Subscale Score
Description	Score range 1-7 (lower score mean more improvement compared to baseline)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

We analyzed subjects who had follow-up data available.

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
Measure Participants	14	15
Mean (Standard Deviation) [score (range 1-7)]	3.2 (0.9)	2.9 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-Acetyl Cysteine, Sugar Pill
	Comments	Cohen's d = 0.30
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.449
	Comments
	Method	mixed effects regression models
	Comments	F= 0.81

3. Primary Outcome

Title	Glutathione (GSH) Levels in Peripheral Blood, Measured by State-of-the-art High-performance Liquid Chromatography (HPLC)
Description	Data not collected. The laboratory was not able to measure Glutathione levels.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Data not collected.

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
Measure Participants	0	0

4. Primary Outcome

Title	Irritability Subscale of the Aberrant Behavior Checklist (ABC)
Description	Aberrant Behavior Checklist (ABC) Irritability Subscale Score (range 0-45); higher scores mean higher irritability
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

We analyzed subjects who had follow-up data available.

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
Measure Participants	14	15
Baseline ABC-I Score	16.9 (7.9)	14.8 (9.6)
Week 12 ABC-I Score	7.2 (5.7)	13.1 (9.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-Acetyl Cysteine, Sugar Pill
	Comments	F values were derived from the interaction of participant group (NAC vs. placebo) and time (week) in mixed effects regression models. Cohen's d was computed based on the standardized mean difference in the change from baseline to week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	Aberrant Behavior Checklist irritability subscale (F = 6.80; p = <.001; d = .96).
	Method	Mixed effects regression models
	Comments

5. Secondary Outcome

Title	The Aberrant Behavior Checklist Total Score (ABC)
Description	Total score was not analyzed since we analyzed the sub scales. Additionally, the authors of the instrument do not recommend analyzing the total score.
Time Frame	4, 8, and 12 weeks

Outcome Measure Data

Analysis Population Description

Measure not analyzed.

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
Measure Participants	0	0

6. Secondary Outcome

Title	Social Responsiveness Scale (SRS)
Description	SRS total score (range 0-195); higher scores mean more social impairment
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

We analyzed subjects who had follow-up data available.

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
Measure Participants	14	15
Baseline SRS Total Score	111.9 (28.3)	104.7 (28.1)
Week 12 SRS Total Score	93.8 (26.7)	98.5 (37.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-Acetyl Cysteine, Sugar Pill
	Comments	F-values were derived from the interaction of Participant Group (NAC vs. Placebo) and Time (Week) in mixed effects regression models.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.141
	Comments
	Method	mixed effects regression models
	Comments	degrees of freedom were 1, 22

7. Secondary Outcome

Title	Sensory Profile Questionnaire (SPQ)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Data not collected. Measure not analyzed.

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
Measure Participants	0	0

8. Secondary Outcome

Title	Glutathione (GSH) Metabolism Intermediates in Peripheral Blood
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Data not collected. The measure was not analyzed. The lab was not able to measure Glutathione for the study.

Arm/Group Title	N-Acetyl Cysteine	Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).	Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
Measure Participants	0	0

Adverse Events

Time Frame	Baseline and 4, 8 and 12 Weeks
Adverse Event Reporting Description	We analyzed all subjects who had follow-up data available.
Arm/Group Title	N-Acetyl Cysteine		Sugar Pill
Arm/Group Description	active compound N-Acetyl Cysteine N-Acetyl Cysteine: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).		Placebo or sugar pill Placebo - sugar pill: Phase 1: Oral, 900 mg daily for 4 weeks Phase 2: Oral, 900 mg twice daily 4 weeks Phase 3: Oral, 900 mg three times daily for 4 weeks Entire intervention lasts for 12 weeks (drug administration is continuous).
All Cause Mortality
	N-Acetyl Cysteine		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	N-Acetyl Cysteine		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	N-Acetyl Cysteine		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/14 (92.9%)		14/15 (93.3%)
Gastrointestinal disorders
Constipation	3/14 (21.4%)	3	2/15 (13.3%)	2
Nausea/Vomiting	6/14 (42.9%)	6	3/15 (20%)	3
Diarrhea	3/14 (21.4%)	3	1/15 (6.7%)	1
Increased Appetite	2/14 (14.3%)	2	0/15 (0%)	0
Decreased Appetite	2/14 (14.3%)	2	3/15 (20%)	3
General disorders
Akathisia	1/14 (7.1%)	1	0/15 (0%)	0
Excitement/ Agitation	2/14 (14.3%)	2	3/15 (20%)	3
Increased Motor Activity	2/14 (14.3%)	2	3/15 (20%)	3
Tremor	0/14 (0%)	0	1/15 (6.7%)	1
Syncope/Dizziness	0/14 (0%)	0	1/15 (6.7%)	1
Nasal Congestion	4/14 (28.6%)	4	6/15 (40%)	6
Increased Salivation	0/14 (0%)	0	2/15 (13.3%)	2
Sweating	0/14 (0%)	0	1/15 (6.7%)	1
Psychiatric disorders
Depressive Affect	1/14 (7.1%)	1	0/15 (0%)	0

Limitations/Caveats

The sample size was relatively small and the age range was narrow, which limits the generalizability of the findings. Most subjects were taking psychotropic medications and were receiving behavioral interventions.

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.