Aspergers Syndrome, Asperger Syndrome, Autism Spectrum Disorder
Conditions
Keywords
ASD, Autism, Autism Spectrum Disorder, Asperger Syndrome, Asperger, PDD, PDD-NOS
Brief summary
Autism Spectrum Disorders (ASD) include Autistic disorder, Asperger's syndrome and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). These are developmental disorders beginning prior to three years of age. Recent Centers for Disease Control (CDC) estimates suggest that ASD affects up to 1 in 100 individuals and up to 1 in 50 boys. There are very substantial costs associated with caring for patients with ASD, and ASD has the highest Caregiver Burden Scores of any condition. There are three core symptom domains of ASD, including social deficits, repetitive behaviors and language deficits. Patients can also have associated symptoms of attentional deficits, disruptive behaviors and intellectual disability. There is currently no Food and Drug administration (FDA) approved treatment for the core symptoms of autism, but risperidone and aripiprazole have FDA approval for disruptive behaviors associated with autism. This is a 12 week randomized double blind placebo controlled trial of Milnacipran in adults with ASD or Aspergers Syndrome. Milnacipran is said to play a role in the activation and normalization of the locus coeruleus-noradrenergic system, of which is hypothesized to play a role in behavior adaptations and performance.
Interventions
DRUGMilnacipran
Patients will receive a titrated dose of milnacipran increasing to a maximum of 100mg a day over the 12 week study period. Dosing will be based on a fixed schedule that will be monitored using a side effect profile.
DRUGPlacebo
Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.
Sponsors
Forest Laboratories
Montefiore Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Male and Female patients * Aged 18-50 years * Diagnosis of Autism Spectrum Disorder * intelligence quotient greater than 70
Exclusion criteria
* Pregnant subjects * Patients deemed by comprehensive psychiatric interview to have a significant risk of suicide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Baseline and Week 12 scores | Change will be measured in each subject's score on the Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale from baseline through study end (week 12).Higher values represent a worse outcome. The raw scores are converted to T-scores for each scale and sub-scale which are then compared against the mean. Higher values represent a worse outcome. A T-score of 50 is the mean of a relevant reference population. A T-score above 65 indicates a moderate to severe problem. For example, Row 1 is the mean of baseline T-scores for the Inattention/ Memory subscale and Row 2 is the mean of week 12 T-scores for the Inattention/ Memory subscale. The difference between these two means is used to measure the change from baseline through week 12 for both the groups. |
| Change in Hyperactivity as Measured by Aberrant Behavior Checklist - Hyperactivity Scale | Baseline to Endpoint - 12 weeks | The Aberrant Behavior Checklist is an informant-based questionnaire consisting of 58 items subdivided amongst 5 scales: irritability, lethargy and social withdrawal, stereotypic behavior, hyperactivity/non-compliance, and inappropriate speech \[34\]. A score for each item ranges from 0 indicating no problem to 3 indicating severe problem. Scale scores are calculated by summing the items within that scale. Higher scores indicate greater impairment.Reported Data is for change in ABC-H from baseline to endpoint (week 0 to week 12).This data is specifically looking at the hyperactivity scale which is 16 items with each item ranging from 0-3 making total scores 0-48. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | screening, baseline, weeks 2,4,6,8,10,12 | The CGI-I reflects the rater's impression of the subject's current autism severity on a 7-point scale ranging from Much Improved (1) to Much worse (5). |
| Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | baseline, weeks 2,4,6,8,10,12 | This scale has been shown to be a sensitive outcome measure in autism trials of repetitive behaviors. Data for secondary outcome not analyzed due to lack of significance in primary outcomes measured. * scale range: 0 - 40 total, 0 - 7 subclinical, 8-15 mild, 16 - 23 moderate, 24 - 31 severe, 32 - 40 extreme * score interpretation: Higher overall scores reflect increasing symptom severity. |
| Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | baseline, weeks 2,4,6,8,10,12 | This scale is shown to be sensitive to change in adults with autism, and related to amygdala function. Higher scores mean a better outcome.A clinical tool measuring emotion recognition through facial expression, voice and posture. 1. Child faces 2 (range 0 - 100, higher values reflecting higher % of errors) 2. Adult faces 2 (range 0 - 100, higher values reflecting higher % of errors) 3. Child paralanguage 2 (range 0 - 100, higher values reflecting higher % of errors) 4. Adult paralanguage 2 (range 0 - 100, higher values reflecting higher % of errors) Errors are counted and organized by pre-determined affect and intensity. Subtests considered separately. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Milnacipran Milnacipran: Patients will receive a titrated dose of milnacipran increasing to a maximum of 100mg a day over the 12 week study period. Dosing will be based on a fixed schedule that will be monitored using a side effect profile. | 5 |
| Placebo Placebo: Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg. | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Milnacipran | Total | Placebo |
|---|---|---|---|
| Aberrant Behavior Checklist - Hyperactivity Scale (ABC-H) | 19 units on a scale | 14.4 units on a scale | 9.8 units on a scale |
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 9 Participants | 4 Participants |
| Age, Continuous | 25 years STANDARD_DEVIATION 3.391 | 25.10 years STANDARD_DEVIATION 6.506 | 25.2 years STANDARD_DEVIATION 9.149 |
| CAARS Hyperactivity/Restlessness T Score | 55 T score | 52.9 T score | 50.8 T score |
| CAARS Impulsivity/Emotional Labiality T Score | 55.2 T score | 52.2 T score | 49.2 T score |
| CAARS Inattention/Memory T Score | 68.6 T score | 70.2 T score | 71.8 T score |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 10 Participants | 5 Participants |
| Severity of Illness | 4 units on a scale | 4.5 units on a scale | 5 units on a scale |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 5 / 5 | 4 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Change in Hyperactivity as Measured by Aberrant Behavior Checklist - Hyperactivity Scale
The Aberrant Behavior Checklist is an informant-based questionnaire consisting of 58 items subdivided amongst 5 scales: irritability, lethargy and social withdrawal, stereotypic behavior, hyperactivity/non-compliance, and inappropriate speech \[34\]. A score for each item ranges from 0 indicating no problem to 3 indicating severe problem. Scale scores are calculated by summing the items within that scale. Higher scores indicate greater impairment.Reported Data is for change in ABC-H from baseline to endpoint (week 0 to week 12).This data is specifically looking at the hyperactivity scale which is 16 items with each item ranging from 0-3 making total scores 0-48.
Time frame: Baseline to Endpoint - 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Milnacipran | Change in Hyperactivity as Measured by Aberrant Behavior Checklist - Hyperactivity Scale | -10.4 units on a scale | Standard Deviation 12.46 |
| Placebo | Change in Hyperactivity as Measured by Aberrant Behavior Checklist - Hyperactivity Scale | -4.2 units on a scale | Standard Deviation 7.26 |
Primary
Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale
Change will be measured in each subject's score on the Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale from baseline through study end (week 12).Higher values represent a worse outcome. The raw scores are converted to T-scores for each scale and sub-scale which are then compared against the mean. Higher values represent a worse outcome. A T-score of 50 is the mean of a relevant reference population. A T-score above 65 indicates a moderate to severe problem. For example, Row 1 is the mean of baseline T-scores for the Inattention/ Memory subscale and Row 2 is the mean of week 12 T-scores for the Inattention/ Memory subscale. The difference between these two means is used to measure the change from baseline through week 12 for both the groups.
Time frame: Baseline and Week 12 scores
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Baseline: T-SCORES- Inattention/Memory | 68.6 T-score | Standard Deviation 14.83 |
| Milnacipran | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Week 12: T-SCORES- Inattention/Memory | 53.4 T-score | Standard Deviation 13.05 |
| Milnacipran | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Baseline: T-SCORES- Hyperactivity/Restlessness | 55 T-score | Standard Deviation 12.63 |
| Milnacipran | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Week 12:T-SCORES -Hyperactivity/Restlessness | 44.8 T-score | Standard Deviation 8.76 |
| Milnacipran | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Baseline: T-SCORES- Impulsivity/Emotional Lability | 55.2 T-score | Standard Deviation 7.66 |
| Milnacipran | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Week 12: T-SCORES- Impulsivity/Emotional Lability | 47.8 T-score | Standard Deviation 6.22 |
| Placebo | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Baseline: T-SCORES- Impulsivity/Emotional Lability | 49.2 T-score | Standard Deviation 5.89 |
| Placebo | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Baseline: T-SCORES- Inattention/Memory | 71.8 T-score | Standard Deviation 5.81 |
| Placebo | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Week 12:T-SCORES -Hyperactivity/Restlessness | 39.8 T-score | Standard Deviation 7.56 |
| Placebo | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Week 12: T-SCORES- Inattention/Memory | 57 T-score | Standard Deviation 20.22 |
| Placebo | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Week 12: T-SCORES- Impulsivity/Emotional Lability | 43.6 T-score | Standard Deviation 13.9 |
| Placebo | Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale | Baseline: T-SCORES- Hyperactivity/Restlessness | 50.8 T-score | Standard Deviation 8.76 |
Secondary
Change in Autism Severity Levels Based on the Clinical Global Impressions Scale
The CGI-I reflects the rater's impression of the subject's current autism severity on a 7-point scale ranging from Much Improved (1) to Much worse (5).
Time frame: screening, baseline, weeks 2,4,6,8,10,12
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Milnacipran | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | No Change | 3 Participants |
| Milnacipran | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | Minimally Worse | 0 Participants |
| Milnacipran | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | Minimally Improved | 1 Participants |
| Milnacipran | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | Much Worse | 0 Participants |
| Milnacipran | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | Much Improved | 1 Participants |
| Placebo | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | Much Worse | 0 Participants |
| Placebo | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | Much Improved | 1 Participants |
| Placebo | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | Minimally Improved | 1 Participants |
| Placebo | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | Minimally Worse | 1 Participants |
| Placebo | Change in Autism Severity Levels Based on the Clinical Global Impressions Scale | No Change | 2 Participants |
Secondary
Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF)
This scale is shown to be sensitive to change in adults with autism, and related to amygdala function. Higher scores mean a better outcome.A clinical tool measuring emotion recognition through facial expression, voice and posture. 1. Child faces 2 (range 0 - 100, higher values reflecting higher % of errors) 2. Adult faces 2 (range 0 - 100, higher values reflecting higher % of errors) 3. Child paralanguage 2 (range 0 - 100, higher values reflecting higher % of errors) 4. Adult paralanguage 2 (range 0 - 100, higher values reflecting higher % of errors) Errors are counted and organized by pre-determined affect and intensity. Subtests considered separately.
Time frame: baseline, weeks 2,4,6,8,10,12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 4 | 19.6 score on a scale | Standard Deviation 3.5 |
| Milnacipran | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 8 | 17 score on a scale | Standard Deviation 3.74 |
| Milnacipran | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 2 | 19.25 score on a scale | Standard Deviation 1.48 |
| Milnacipran | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 10 | 17.25 score on a scale | Standard Deviation 3.77 |
| Milnacipran | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 6 | 19.4 score on a scale | Standard Deviation 4.08 |
| Milnacipran | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 12 | 18 score on a scale | Standard Deviation 2.83 |
| Milnacipran | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Baseline | 16.5 score on a scale | Standard Deviation 2.18 |
| Placebo | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 12 | 18.8 score on a scale | Standard Deviation 2.78 |
| Placebo | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Baseline | 18.5 score on a scale | Standard Deviation 3.5 |
| Placebo | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 2 | 19 score on a scale | Standard Deviation 2.2 |
| Placebo | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 4 | 19.6 score on a scale | Standard Deviation 2.06 |
| Placebo | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 6 | 20 score on a scale | Standard Deviation 1.41 |
| Placebo | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 8 | 19.2 score on a scale | Standard Deviation 1.94 |
| Placebo | Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF) | Week 10 | 20 score on a scale | Standard Deviation 0.81 |
Secondary
Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale
This scale has been shown to be a sensitive outcome measure in autism trials of repetitive behaviors. Data for secondary outcome not analyzed due to lack of significance in primary outcomes measured. * scale range: 0 - 40 total, 0 - 7 subclinical, 8-15 mild, 16 - 23 moderate, 24 - 31 severe, 32 - 40 extreme * score interpretation: Higher overall scores reflect increasing symptom severity.
Time frame: baseline, weeks 2,4,6,8,10,12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milnacipran | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 6 | 11.8 score on a scale | Standard Deviation 4.12 |
| Milnacipran | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 8 | 10.4 score on a scale | Standard Deviation 3.93 |
| Milnacipran | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Baseline | 12.2 score on a scale | Standard Deviation 5.45 |
| Milnacipran | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 10 | 11.6 score on a scale | Standard Deviation 4.03 |
| Milnacipran | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 4 | 11.6 score on a scale | Standard Deviation 5.08 |
| Milnacipran | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 12 | 12.4 score on a scale | Standard Deviation 4.41 |
| Milnacipran | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 2 | 10 score on a scale | Standard Deviation 6.16 |
| Placebo | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 12 | 12 score on a scale | Standard Deviation 3.03 |
| Placebo | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Baseline | 12 score on a scale | Standard Deviation 2.75 |
| Placebo | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 2 | 12.2 score on a scale | Standard Deviation 1.32 |
| Placebo | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 4 | 13.2 score on a scale | Standard Deviation 3.12 |
| Placebo | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 8 | 9.8 score on a scale | Standard Deviation 4.99 |
| Placebo | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 10 | 12.8 score on a scale | Standard Deviation 1.17 |
| Placebo | Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale | Week 6 | 12 score on a scale | Standard Deviation 1.79 |