Autistic Disorder
Conditions
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.
Interventions
DRUGN-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).
OTHERPlacebo - 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).
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Years to 12 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| The Clinical Global Rating Scale (CGRS) Improvement Subscale Score | 12 weeks | Score range 1-7 (lower score mean more improvement compared to baseline) |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Social Responsiveness Scale (SRS) | 12 weeks | SRS total score (range 0-195); higher scores mean more social impairment |
| Sensory Profile Questionnaire (SPQ) | 12 weeks | — |
| Glutathione (GSH) Metabolism Intermediates in Peripheral Blood | 12 weeks | — |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| N-Acetyl Cysteine 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). | 15 |
| Sugar Pill 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). | 18 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Unwilling to take the compound (taste) | 1 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | N-Acetyl Cysteine | Sugar Pill | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 15 Participants | 18 Participants | 33 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 15 participants | 18 participants | 33 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 13 Participants | 18 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 14 | 14 / 15 |
| serious Total, serious adverse events | 0 / 14 | 0 / 15 |
Outcome results
Primary
Glutathione (GSH) Levels in Peripheral Blood, Measured by State-of-the-art High-performance Liquid Chromatography (HPLC)
Data not collected. The laboratory was not able to measure Glutathione levels.
Time frame: 12 weeks
Population: Data not collected.
Primary
Irritability Subscale of the Aberrant Behavior Checklist (ABC)
Aberrant Behavior Checklist (ABC) Irritability Subscale Score (range 0-45); higher scores mean higher irritability
Time frame: baseline and 12 weeks
Population: We analyzed subjects who had follow-up data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetyl Cysteine | Irritability Subscale of the Aberrant Behavior Checklist (ABC) | Baseline ABC-I Score | 16.9 Score (range 0-45) | Standard Deviation 7.9 |
| N-Acetyl Cysteine | Irritability Subscale of the Aberrant Behavior Checklist (ABC) | Week 12 ABC-I Score | 7.2 Score (range 0-45) | Standard Deviation 5.7 |
| Sugar Pill | Irritability Subscale of the Aberrant Behavior Checklist (ABC) | Baseline ABC-I Score | 14.8 Score (range 0-45) | Standard Deviation 9.6 |
| Sugar Pill | Irritability Subscale of the Aberrant Behavior Checklist (ABC) | Week 12 ABC-I Score | 13.1 Score (range 0-45) | Standard Deviation 9.9 |
Comparison: 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.p-value: <0.001Mixed effects regression models
Primary
The Clinical Global Rating Scale (CGRS) Improvement Subscale Score
Score range 1-7 (lower score mean more improvement compared to baseline)
Time frame: 12 weeks
Population: We analyzed subjects who had follow-up data available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetyl Cysteine | The Clinical Global Rating Scale (CGRS) Improvement Subscale Score | 3.2 score (range 1-7) | Standard Deviation 0.9 |
| Sugar Pill | The Clinical Global Rating Scale (CGRS) Improvement Subscale Score | 2.9 score (range 1-7) | Standard Deviation 1.1 |
Comparison: Cohen's d = 0.30p-value: 0.449mixed effects regression models
Primary
Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES)
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
Population: We analyzed subjects who had follow-up data available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Increased Appetite | 2 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Increased Motor Activity | 2 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Constipation | 3 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Tremor | 0 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Decreased Appetite | 2 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Syncope/Dizziness | 0 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Diarrhea | 3 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Depressive Affect | 1 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Akathisia | 1 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Nasal Congestion | 4 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Nausea/Vomiting | 6 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Increased Salivation | 0 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Excitement/Agitation | 2 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Sweating | 0 participants |
| N-Acetyl Cysteine | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Total Number of Subjects with GI adverse Events | 11 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Sweating | 1 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Total Number of Subjects with GI adverse Events | 7 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Constipation | 2 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Nausea/Vomiting | 3 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Diarrhea | 1 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Increased Appetite | 0 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Decreased Appetite | 3 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Akathisia | 0 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Excitement/Agitation | 3 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Increased Motor Activity | 3 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Tremor | 1 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Syncope/Dizziness | 1 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Depressive Affect | 0 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Nasal Congestion | 6 participants |
| Sugar Pill | Total Number of Subjects With Reported Side Effects as Assessed by Dosage Record and Treatment Emergent Symptom Scale (DOTES) | Increased Salivation | 2 participants |
Secondary
Glutathione (GSH) Metabolism Intermediates in Peripheral Blood
Time frame: 12 weeks
Population: Data not collected. The measure was not analyzed. The lab was not able to measure Glutathione for the study.
Secondary
Sensory Profile Questionnaire (SPQ)
Time frame: 12 weeks
Population: Data not collected. Measure not analyzed.
Secondary
Social Responsiveness Scale (SRS)
SRS total score (range 0-195); higher scores mean more social impairment
Time frame: 12 weeks
Population: We analyzed subjects who had follow-up data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetyl Cysteine | Social Responsiveness Scale (SRS) | Baseline SRS Total Score | 111.9 SRS total score (range 0-195) | Standard Deviation 28.3 |
| N-Acetyl Cysteine | Social Responsiveness Scale (SRS) | Week 12 SRS Total Score | 93.8 SRS total score (range 0-195) | Standard Deviation 26.7 |
| Sugar Pill | Social Responsiveness Scale (SRS) | Baseline SRS Total Score | 104.7 SRS total score (range 0-195) | Standard Deviation 28.1 |
| Sugar Pill | Social Responsiveness Scale (SRS) | Week 12 SRS Total Score | 98.5 SRS total score (range 0-195) | Standard Deviation 37.8 |
Comparison: F-values were derived from the interaction of Participant Group (NAC vs. Placebo) and Time (Week) in mixed effects regression models.p-value: 0.141mixed effects regression models
Secondary
The Aberrant Behavior Checklist Total Score (ABC)
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
Population: Measure not analyzed.