Asperger Syndrome, Autistic Disorder, Child Development Disorders, Pervasive
Conditions
Keywords
Autistic Disorder, Asperger's, PDD NOS, Pervasive Developmental Disorder, Autism, N-acetylcysteine, acetylcysteine, NAC, antioxidant, treatment, core symptoms, Autism Spectrum Disorders, Asperger's Disorder, Pervasive Developmental Disorder Not Otherwise Specified, Pervasive Developmental Disorders
Brief summary
The purpose of this study is to determine whether treatment with oral N-acetylcysteine (NAC) will improve behavior problems often associated with autism spectrum disorders.
Detailed description
Autism is increasingly being recognized as a common disorder with enormous public health significance. The core symptoms of autism include severe deficits in social relatedness and communication, and interfering repetitive behavior. No medications have been shown to consistently improve any of these symptoms. The central hypothesis of this study is that NAC will improve behavioral manifestations of autism which may include core or associated symptoms. We plan to test our hypothesis and complete the objectives of this project by pursuing the following specific aims: * Evaluate the efficacy of oral NAC in a 12-week, double-blind, placebo-controlled study involving 32 children and adolescents with autism spectrum disorders. * Evaluate the safety and tolerability of oral NAC in 32 children and adolescents with autism spectrum disorders.
Interventions
DRUGN-acetylcysteine
Capsules available in 300 mg or 600mg strength. Target dose of n-acetylcysteine will be 60mg/kg/day TID. Dosage will be increased to this target dose from week 1 to week 3 barring side effects. Dose reduction will be allowed at any time for adverse side effects. Maximum dose of n-acetylcysteine will be 4200mg/day.
DRUGPlacebo
Subjects randomized to placebo arm will receive placebo pill for duration of study.
Sponsors
National Alliance for Autism Research
Indiana University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
* Age 4 to 12 years. * Diagnosis of autistic disorder, Asperger's disorder, or PDD NOS. * If taking concomitant psychotropic medications, the medication must be at a constant dose for 60 days with no dose changes planned for the duration of the trial. * Able to swallow capsules.
Exclusion criteria
* Presence of any medical condition that significantly increases risk or hampers assessment (e.g., unstable hypertension or cardiac disease, unstable asthma, kidney disease, unstable seizure disorder, pregnancy or any other medical condition as determined by the investigator). * Weight \< 15 kg. * Subjects taking concomitant medications or supplements known for their glutamatergic effects (e.g., dextromethorphan, D-cycloserine, amantadine, memantine, lamotrigine, riluzole) or antioxidant properties (high dose vitamin supplements, DMG, TMG, many alternative treatments) within 30 days of the baseline visit with the exception of short term use of dextromethorphan as needed as a cough suppressant. The use of this medicine must be stopped at least 7 days prior to the baseline visit. Regular multivitamins will be allowed. * Subjects taking daily acetaminophen or nonsteroidal anti-inflammatory drugs within 30 days of the baseline visit. * Profound mental retardation as evidenced by a mental age below 18 months. * Subjects taking concomitant medications with the potential for pharmacokinetic or pharmacodynamic drug-drug interactions (e.g., carbamazepine) within 30 days of the baseline visit. * Subjects who are likely to experience significant changes in their ongoing psychosocial or medical treatments for autism over the course of the trial (e.g., initiation of new behavioral therapy, initiation of new medication or alternative treatment \[e.g., chelation\]). Minor changes in ongoing treatment (e.g., missed therapy sessions due to holiday/vacation; planned break in therapy due to school holidays) will not be considered significant. * History of prior treatment with NAC. * Evidence of hypersensitivity/allergy to NAC. * Presence of certain neurodevelopmental disorders such as Fragile X Syndrome, Tuberous Sclerosis, or other neurological disorders known to be associated with autism or autistic features. * Diagnosis of Rett's disorder, childhood disintegrative disorder, schizophrenia, bipolar disorder, another psychotic disorder, or substance abuse disorder.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression - Severity | Week 12 | The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. |
| Clinical Global Impression - Improvement | Week 12 | Clinical Global Impression - Improvement (CGI-I) is designed to take into account all factors to arrive at an assessment of response to treatment. The CGI-I scale ranges from 1 to 7 (1=very much improved; 2=much improved, 3=minimally Improved, 4=no change, 5=minimally worse, 6= much worse and 7=very much worse). Participants with a CGI-I score of 1 or 2 were classified as improved. Participants with a CGI score of 3, 4 or 5 were classified as no response. No participants scored 6 or 7. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Aberrant Behavior Checklist | Week 12 | The Aberrant Behavior Checklist (ABC) is a 58-item measure of maladaptive behaviors and is used as a measure of drug effects. Each of the 58 items are rated from 0 (not at all) to 3 (severe).The ABC has 5 subscales: Irritability (15 items) ranging from 0 (not at all) to 45 (severe), Lethargy (16 items) ranging from 0 (not at all) to 48 (severe), Stereotypy (7 items) ranging from 0 (not at all) to 21 (severe), Hyperactivity (16 items) ranging from 0 (not at all) to 48 (severe), and Inappropriate Speech (4 items) ranging from 0 (not at all) to 12 (severe). Higher scores indicate a higher level of maladaptive behavior. |
| Social Responsiveness Scale | Week 12 | The Social Responsiveness Scale (SRS) is a 65-item scale that assesses social impairment in the aspects of social awareness, social cognition, social communication, social motivation and autistic mannerisms. Each item is scored from 0 (not true) to 3 (almost always true). The total SRS raw score may range from 0-195, where higher scores indicate greater severity. |
| Pervasive Developmental Disorder Behavior Index | Week 12 | The PDD Behavior Inventory (PDDBI) is a rating scale filled out by caregivers or teachers that was designed to assess children having a Pervasive Developmental Disorder (PDD; autism, Asperger disorder, PDD-NOS, or childhood disintegrative disorder). Both adaptive and maladaptive behaviors are assessed in the scale, making it useful for treatment studies in which decreases in maladaptive behaviors and improvements in adaptive social and language skills relevant to PDD are expected. |
| Vineland Adaptive Behavior Scales-II (VABS-II) | Week 12 | The VABS-II is a semi-structured interview designed to assess adaptive functioning in the domains of communication, daily living skills and socialization. Items in each domain are rated as either 0 (does not), 1(sometimes) or 2(independently) performs a given behavior or skill. The communication domain has 99 items with scores ranging from 0-198. The daily living skills domain has 109 items with scores ranging from 0-218. The socialization domain has 99 items with scores ranging from 0-198. The domains scores are combined to form the adaptive composite score (ranging from 20-160). The raw scores from the communication, daily living skills and socialization domains along with the composite score were selected for use in this study. Higher scores indicate a higher level of adaptive functioning. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| N-acetylcysteine Target dose for n-acetylcysteine is 60 mg/kg/day. Capsules available in 300 mg and 600 mg strengths.
N-acetylcysteine: Capsules available in 300 mg or 600mg strength. Target dose of n-acetylcysteine will be 60mg/kg/day TID. Dosage will be increased to this target dose from week 1 to week 3 barring side effects. Dose reduction will be allowed at any time for adverse side effects. Maximum dose of n-acetylcysteine will be 4200mg/day. | 16 |
| Placebo Subjects randomized to placebo arm will receive capsules identical in size and appearance to those subjects receiving study drug. Placebo capsules contain inactive ingredients.
Placebo: Subjects randomized to placebo arm will receive placebo pill for duration of study. | 15 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Lost to Follow-up | 2 | 1 |
Baseline characteristics
| Characteristic | N-acetylcysteine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 16 Participants | 15 Participants | 31 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 7.6 Years STANDARD_DEVIATION 2.5 | 8.2 Years STANDARD_DEVIATION 2.9 | 7.8 Years STANDARD_DEVIATION 2.7 |
| Clinical Global Impression-Severity 1. Normal, not al all ill | 0 Participants | 0 Participants | 0 Participants |
| Clinical Global Impression-Severity 2. Borderline ill | 0 Participants | 0 Participants | 0 Participants |
| Clinical Global Impression-Severity 3..Mildly ill | 0 Participants | 0 Participants | 0 Participants |
| Clinical Global Impression-Severity 4. Moderatly ill | 6 Participants | 9 Participants | 15 Participants |
| Clinical Global Impression-Severity 5. Markedly ill | 9 Participants | 6 Participants | 15 Participants |
| Clinical Global Impression-Severity 6. Severly ill | 1 Participants | 0 Participants | 1 Participants |
| Clinical Global Impression-Severity 7. Extremly ill | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 16 participants | 15 participants | 31 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 16 | 15 / 15 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 |
Outcome results
Primary
Clinical Global Impression - Improvement
Clinical Global Impression - Improvement (CGI-I) is designed to take into account all factors to arrive at an assessment of response to treatment. The CGI-I scale ranges from 1 to 7 (1=very much improved; 2=much improved, 3=minimally Improved, 4=no change, 5=minimally worse, 6= much worse and 7=very much worse). Participants with a CGI-I score of 1 or 2 were classified as improved. Participants with a CGI score of 3, 4 or 5 were classified as no response. No participants scored 6 or 7.
Time frame: Week 12
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| N-acetylcysteine | Clinical Global Impression - Improvement | Improved | 6 Participants |
| N-acetylcysteine | Clinical Global Impression - Improvement | No Response | 7 Participants |
| Placebo | Clinical Global Impression - Improvement | Improved | 5 Participants |
| Placebo | Clinical Global Impression - Improvement | No Response | 7 Participants |
Primary
Clinical Global Impression - Severity
The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
Time frame: Week 12
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| N-acetylcysteine | Clinical Global Impression - Severity | 3.Mildly ill | 3 Participants |
| N-acetylcysteine | Clinical Global Impression - Severity | 5.Markedly ill | 5 Participants |
| N-acetylcysteine | Clinical Global Impression - Severity | 4.Moderately ill | 5 Participants |
| N-acetylcysteine | Clinical Global Impression - Severity | 2.Borderline ill | 0 Participants |
| N-acetylcysteine | Clinical Global Impression - Severity | 6.Severely ill | 0 Participants |
| N-acetylcysteine | Clinical Global Impression - Severity | 7.Extremely ill | 0 Participants |
| N-acetylcysteine | Clinical Global Impression - Severity | 1.Normal, not at all ill | 0 Participants |
| Placebo | Clinical Global Impression - Severity | 7.Extremely ill | 0 Participants |
| Placebo | Clinical Global Impression - Severity | 4.Moderately ill | 12 Participants |
| Placebo | Clinical Global Impression - Severity | 1.Normal, not at all ill | 0 Participants |
| Placebo | Clinical Global Impression - Severity | 2.Borderline ill | 0 Participants |
| Placebo | Clinical Global Impression - Severity | 3.Mildly ill | 0 Participants |
| Placebo | Clinical Global Impression - Severity | 5.Markedly ill | 0 Participants |
| Placebo | Clinical Global Impression - Severity | 6.Severely ill | 0 Participants |
Secondary
Aberrant Behavior Checklist
The Aberrant Behavior Checklist (ABC) is a 58-item measure of maladaptive behaviors and is used as a measure of drug effects. Each of the 58 items are rated from 0 (not at all) to 3 (severe).The ABC has 5 subscales: Irritability (15 items) ranging from 0 (not at all) to 45 (severe), Lethargy (16 items) ranging from 0 (not at all) to 48 (severe), Stereotypy (7 items) ranging from 0 (not at all) to 21 (severe), Hyperactivity (16 items) ranging from 0 (not at all) to 48 (severe), and Inappropriate Speech (4 items) ranging from 0 (not at all) to 12 (severe). Higher scores indicate a higher level of maladaptive behavior.
Time frame: Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-acetylcysteine | Aberrant Behavior Checklist | Lethargy | 10.0 units on a scale | Standard Deviation 7.1 |
| N-acetylcysteine | Aberrant Behavior Checklist | Hyperactivity | 17.4 units on a scale | Standard Deviation 16.4 |
| N-acetylcysteine | Aberrant Behavior Checklist | Stereotypy | 3.9 units on a scale | Standard Deviation 5.1 |
| N-acetylcysteine | Aberrant Behavior Checklist | Inappropriate Speech | 4.1 units on a scale | Standard Deviation 3.9 |
| N-acetylcysteine | Aberrant Behavior Checklist | Irritablity | 14.9 units on a scale | Standard Deviation 14 |
| Placebo | Aberrant Behavior Checklist | Inappropriate Speech | 5.14 units on a scale | Standard Deviation 3.5 |
| Placebo | Aberrant Behavior Checklist | Irritablity | 12.0 units on a scale | Standard Deviation 7.3 |
| Placebo | Aberrant Behavior Checklist | Lethargy | 7.9 units on a scale | Standard Deviation 4.7 |
| Placebo | Aberrant Behavior Checklist | Stereotypy | 5.8 units on a scale | Standard Deviation 4 |
| Placebo | Aberrant Behavior Checklist | Hyperactivity | 15.1 units on a scale | Standard Deviation 10.8 |
Secondary
Pervasive Developmental Disorder Behavior Index
The PDD Behavior Inventory (PDDBI) is a rating scale filled out by caregivers or teachers that was designed to assess children having a Pervasive Developmental Disorder (PDD; autism, Asperger disorder, PDD-NOS, or childhood disintegrative disorder). Both adaptive and maladaptive behaviors are assessed in the scale, making it useful for treatment studies in which decreases in maladaptive behaviors and improvements in adaptive social and language skills relevant to PDD are expected.
Time frame: Week 12
Population: Less than 25% of participants in each group received a score on the PDDBI due to a significant floor effect. As a result, the data for these participants are not considered reliable given the significant floor effect.
Secondary
Social Responsiveness Scale
The Social Responsiveness Scale (SRS) is a 65-item scale that assesses social impairment in the aspects of social awareness, social cognition, social communication, social motivation and autistic mannerisms. Each item is scored from 0 (not true) to 3 (almost always true). The total SRS raw score may range from 0-195, where higher scores indicate greater severity.
Time frame: Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine | Social Responsiveness Scale | 85.8 units on a scale | Standard Deviation 34.9 |
| Placebo | Social Responsiveness Scale | 89.1 units on a scale | Standard Deviation 26.3 |
Secondary
Vineland Adaptive Behavior Scales-II (VABS-II)
The VABS-II is a semi-structured interview designed to assess adaptive functioning in the domains of communication, daily living skills and socialization. Items in each domain are rated as either 0 (does not), 1(sometimes) or 2(independently) performs a given behavior or skill. The communication domain has 99 items with scores ranging from 0-198. The daily living skills domain has 109 items with scores ranging from 0-218. The socialization domain has 99 items with scores ranging from 0-198. The domains scores are combined to form the adaptive composite score (ranging from 20-160). The raw scores from the communication, daily living skills and socialization domains along with the composite score were selected for use in this study. Higher scores indicate a higher level of adaptive functioning.
Time frame: Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-acetylcysteine | Vineland Adaptive Behavior Scales-II (VABS-II) | Socialization | 71.7 units on a scale | Standard Deviation 18.7 |
| N-acetylcysteine | Vineland Adaptive Behavior Scales-II (VABS-II) | Communication | 88.5 units on a scale | Standard Deviation 32.5 |
| N-acetylcysteine | Vineland Adaptive Behavior Scales-II (VABS-II) | Adaptive Behavior Composite | 62.9 units on a scale | Standard Deviation 17.1 |
| N-acetylcysteine | Vineland Adaptive Behavior Scales-II (VABS-II) | Daily Living Skills | 99.0 units on a scale | Standard Deviation 37.1 |
| Placebo | Vineland Adaptive Behavior Scales-II (VABS-II) | Adaptive Behavior Composite | 60.5 units on a scale | Standard Deviation 18.8 |
| Placebo | Vineland Adaptive Behavior Scales-II (VABS-II) | Communication | 95.0 units on a scale | Standard Deviation 30.3 |
| Placebo | Vineland Adaptive Behavior Scales-II (VABS-II) | Socialization | 75.9 units on a scale | Standard Deviation 21 |
| Placebo | Vineland Adaptive Behavior Scales-II (VABS-II) | Daily Living Skills | 98.6 units on a scale | Standard Deviation 33.4 |