Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism

Study Overview
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Brief Summary
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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.

Official Title
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Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism

Conditions
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Autism Spectrum Disorder, Asperger Syndrome, Aspergers Syndrome

Intervention / Treatment
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* Drug: Milnacipran
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Milnacipran<br> | Drug: Milnacipran<br>* 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.<br>* Other names: Savella;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Week 12 scores | 
| 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. | Baseline to Endpoint - 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | screening, baseline, weeks 2,4,6,8,10,12 | 
| 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. | baseline, weeks 2,4,6,8,10,12 | 
| 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. Child faces 2 (range 0 - 100, higher values reflecting higher % of errors) Adult faces 2 (range 0 - 100, higher values reflecting higher % of errors) Child paralanguage 2 (range 0 - 100, higher values reflecting higher % of errors) 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. | baseline, weeks 2,4,6,8,10,12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASD, Autism, Autism Spectrum Disorder, Asperger Syndrome, Asperger, PDD, PDD-NOS