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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01337700
Recruitment Status : Completed
First Posted : April 19, 2011
Results First Posted : February 27, 2020
Last Update Posted : February 27, 2020
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
Eric Hollander, Montefiore Medical Center

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Autism Spectrum Disorder
Asperger Syndrome
Aspergers Syndrome
Interventions Drug: Milnacipran
Drug: Placebo
Enrollment 10
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Milnacipran Placebo
Hide Arm/Group Description 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. Placebo: Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.
Period Title: Overall Study
Started 5 5
Completed 5 5
Not Completed 0 0
Arm/Group Title Milnacipran Placebo Total
Hide Arm/Group Description 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. Placebo: Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg. Total of all reporting groups
Overall Number of Baseline Participants 5 5 10
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 5 participants 10 participants
<=18 years
0
   0.0%
1
  20.0%
1
  10.0%
Between 18 and 65 years
5
 100.0%
4
  80.0%
9
  90.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 5 participants 5 participants 10 participants
25  (3.391) 25.2  (9.149) 25.10  (6.506)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 5 participants 10 participants
Female
1
  20.0%
2
  40.0%
3
  30.0%
Male
4
  80.0%
3
  60.0%
7
  70.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 5 participants 10 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
5
 100.0%
5
 100.0%
10
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 5 participants 10 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
5
 100.0%
5
 100.0%
10
 100.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Severity of Illness   [1] 
Mean (Full Range)
Unit of measure:  Units on a scale
Number Analyzed 5 participants 5 participants 10 participants
4
(4 to 4)
5
(5 to 5)
4.5
(4 to 5)
[1]
Measure Description: Scores are using the Clinical Global Impression Scale -Severity (CGI-S). This is a 7-point scale, from 1 (normal not at all ill) to 7 (among the most extremely ill), 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.
Aberrant Behavior Checklist - Hyperactivity Scale (ABC-H)   [1] 
Mean (Full Range)
Unit of measure:  Units on a scale
Number Analyzed 5 participants 5 participants 10 participants
19
(8.45 to 29.55)
9.8
(3.91 to 15.69)
14.4
(3.91 to 29.55)
[1]
Measure Description: ABC-H can assess problematic behavior at home, in educational and work settings, and in residential and community-based facilities specifically in regard to hyperactivity. It is a sub- scale of the larger ABC-2 which rates 58 specific symptoms, and provides comprehensive descriptions, for each assessed behavior. It is further divided into five sub-scales and the one discussed here is hyperactivity. Each question is rated on a scale from 0-3 with 0 being not problematic and 3 being most problematic.
CAARS Inattention/Memory T Score   [1] 
Mean (Full Range)
Unit of measure:  T score
Number Analyzed 5 participants 5 participants 10 participants
68.6
(53.77 to 83.43)
71.8
(65.99 to 77.6)
70.2
(53.77 to 83.43)
[1]
Measure Description: The Conners Adult ADHD Rating Scales (CAARS) are the international standard for questionnaire assessment of ADHD. The raw scores are converted to T-scores for each scale and sub-scale which are then compared against the mean. This sub-scale being assessed is inattention/ memory. 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.
CAARS Hyperactivity/Restlessness T Score   [1] 
Mean (Full Range)
Unit of measure:  T score
Number Analyzed 5 participants 5 participants 10 participants
55
(42.37 to 67.63)
50.8
(49.24 to 59.56)
52.9
(42.37 to 67.63)
[1]
Measure Description: The Conners Adult ADHD Rating Scales (CAARS) are the international standard for questionnaire assessment of ADHD. 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.This sub-scale being assessed is hyperactivity/ restlessness.
CAARS Impulsivity/Emotional Labiality T Score   [1] 
Mean (Full Range)
Unit of measure:  T score
Number Analyzed 5 participants 5 participants 10 participants
55.2
(47.54 to 62.86)
49.2
(43.31 to 55.09)
52.2
(43.31 to 62.86)
[1]
Measure Description: The Conners Adult ADHD Rating Scales (CAARS) are the international standard for questionnaire assessment of ADHD. 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.This sub-scale being assessed is impulsivity/ emotional labiality.
1.Primary Outcome
Title Change in Score on Conners Adults Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Milnacipran Placebo
Hide Arm/Group Description:
Milnacipran: Patients will receive a titrated dose of milnacipran increasing to a maximum of 200mg 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.
Placebo: Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.
Overall Number of Participants Analyzed 5 5
Mean (Standard Deviation)
Unit of Measure: T-score
Baseline: T-SCORES- Inattention/Memory 68.6  (14.83) 71.8  (5.81)
Week 12: T-SCORES- Inattention/Memory 53.4  (13.05) 57  (20.22)
Baseline: T-SCORES- Hyperactivity/Restlessness 55  (12.63) 50.8  (8.76)
Week 12:T-SCORES -Hyperactivity/Restlessness 44.8  (8.76) 39.8  (7.56)
Baseline: T-SCORES- Impulsivity/Emotional Lability 55.2  (7.66) 49.2  (5.89)
Week 12: T-SCORES- Impulsivity/Emotional Lability 47.8  (6.22) 43.6  (13.90)
2.Primary Outcome
Title Change in Hyperactivity as Measured by Aberrant Behavior Checklist - Hyperactivity Scale
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Milnacipran Placebo
Hide Arm/Group Description:
Milnacipran: Patients will receive a titrated dose of milnacipran increasing to a maximum of 200mg 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.
Placebo: Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.
Overall Number of Participants Analyzed 5 5
Mean (Standard Deviation)
Unit of Measure: units on a scale
-10.4  (12.46) -4.2  (7.26)
3.Secondary Outcome
Title Change in Autism Severity Levels Based on the Clinical Global Impressions Scale
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Milnacipran Placebo
Hide Arm/Group Description:
Milnacipran: Patients will receive a titrated dose of milnacipran increasing to a maximum of 200mg 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.
Placebo: Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.
Overall Number of Participants Analyzed 5 5
Measure Type: Count of Participants
Unit of Measure: Participants
Much Improved
1
  20.0%
1
  20.0%
Minimally Improved
1
  20.0%
1
  20.0%
No Change
3
  60.0%
2
  40.0%
Minimally Worse
0
   0.0%
1
  20.0%
Much Worse
0
   0.0%
0
   0.0%
4.Secondary Outcome
Title Change in Repetitive Behaviors Using YBOCS-Compulsion and Rigidity Subscale
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Milnacipran Placebo
Hide Arm/Group Description:
Milnacipran: Patients will receive a titrated dose of milnacipran increasing to a maximum of 200mg 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.
Placebo: Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.
Overall Number of Participants Analyzed 5 5
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline 12.2  (5.45) 12  (2.75)
Week 2 10  (6.16) 12.2  (1.32)
Week 4 11.6  (5.08) 13.2  (3.12)
Week 6 11.8  (4.12) 12  (1.79)
Week 8 10.4  (3.93) 9.8  (4.99)
Week 10 11.6  (4.03) 12.8  (1.17)
Week 12 12.4  (4.41) 12  (3.03)
5.Secondary Outcome
Title Change in Diagnostic Analysis of Nonverbal Activity-2 ADULT FACIAL EXPRESSIONS: (DANVA2-AF)
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Milnacipran Placebo
Hide Arm/Group Description:
Milnacipran: Patients will receive a titrated dose of milnacipran increasing to a maximum of 200mg 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.
Placebo: Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.
Overall Number of Participants Analyzed 5 5
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline 16.5  (2.18) 18.5  (3.5)
Week 2 19.25  (1.48) 19  (2.2)
Week 4 19.6  (3.5) 19.6  (2.06)
Week 6 19.4  (4.08) 20  (1.41)
Week 8 17  (3.74) 19.2  (1.94)
Week 10 17.25  (3.77) 20  (0.81)
Week 12 18  (2.83) 18.8  (2.78)
Time Frame Adverse event data was collected from baseline to endpoint, for 12 weeks total.
Adverse Event Reporting Description By definition, serious Adverse Events includes adverse events that result in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect.
 
Arm/Group Title Milnacipran Placebo
Hide Arm/Group Description 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. Placebo: Subjects will be given placebo tablets at dosing corresponding to the fixed schedule between 12.5mg and 100mg.
All-Cause Mortality
Milnacipran Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/5 (0.00%)   0/5 (0.00%) 
Hide Serious Adverse Events
Milnacipran Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/5 (0.00%)   0/5 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Milnacipran Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   5/5 (100.00%)   4/5 (80.00%) 
Gastrointestinal disorders     
Anal Fissure  1/5 (20.00%)  0/5 (0.00%) 
Gastroenteritis  1/5 (20.00%)  0/5 (0.00%) 
General disorders     
Fatigue   2/5 (40.00%)  0/5 (0.00%) 
Headache *  2/5 (40.00%)  2/5 (40.00%) 
Nightmares  0/5 (0.00%)  2/5 (40.00%) 
Weight loss  1/5 (20.00%)  0/5 (0.00%) 
Abdominal Cramping  1/5 (20.00%)  0/5 (0.00%) 
Dizziness  1/5 (20.00%)  0/5 (0.00%) 
Gum Pain  1/5 (20.00%)  0/5 (0.00%) 
Hemorrhoids  1/5 (20.00%)  0/5 (0.00%) 
Insomnia  1/5 (20.00%)  0/5 (0.00%) 
Lethargy  0/5 (0.00%)  1/5 (20.00%) 
Lightheadedness  0/5 (0.00%)  1/5 (20.00%) 
Menstrual Cramps  0/5 (0.00%)  1/5 (20.00%) 
Nausea  1/5 (20.00%)  0/5 (0.00%) 
Sleep Disruption  1/5 (20.00%)  0/5 (0.00%) 
Stomachache  0/5 (0.00%)  1/5 (20.00%) 
Somnolence  1/5 (20.00%)  0/5 (0.00%) 
Vomiting  0/5 (0.00%)  1/5 (20.00%) 
Infections and infestations     
Upper Respiratory Infection  3/5 (60.00%)  1/5 (20.00%) 
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Eric Hollander, MD
Organization: Montefiore Medical Center, Albert Eins
Phone: 7189204287
EMail: eholland@montefiore.org
Layout table for additonal information
Responsible Party: Eric Hollander, Montefiore Medical Center
ClinicalTrials.gov Identifier: NCT01337700    
Other Study ID Numbers: 10-09-299
First Submitted: December 27, 2010
First Posted: April 19, 2011
Results First Submitted: March 17, 2016
Results First Posted: February 27, 2020
Last Update Posted: February 27, 2020