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Study of Oxytocin in Autism to Improve Reciprocal Social Behaviors (SOARS-B)

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ClinicalTrials.gov Identifier: NCT01944046
Recruitment Status : Completed
First Posted : September 17, 2013
Results First Posted : January 5, 2021
Last Update Posted : January 5, 2021
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Linmarie Sikich, Duke University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Autism Spectrum Disorders
Interventions Drug: Double blind phase Placebo Nasal Spray
Drug: double Blind Oxytocin Nasal Spray
Drug: Open Label intranasal oxytocin
Enrollment 290
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Period Title: Randomized to DB
Started 146 144
Completed 125 125
Not Completed 21 19
Reason Not Completed
Adverse Event             5             2
Clinical Worsening             3             2
Lost to Follow-up             3             3
Withdrawal by Subject             2             4
Physician Decision             1             2
Did not have baseline ABC-SW             2             0
Did not have a postbaseline ABC SW             5             6
Period Title: Open Label Eligible and Consented
Started [1] 124 124
Completed 110 116
Not Completed 14 8
Reason Not Completed
Lost to Follow-up             3             5
Adverse Event             6             1
Clinical Worsening             4             2
Withdrawal by Subject             1             0
[1]
1 from each treatment group declined to consent for openlabel
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray Total
Hide Arm/Group Description

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Total of all reporting groups
Overall Number of Baseline Participants 139 138 277
Hide Baseline Analysis Population Description
Double-Blind Full Analysis Set (FAS). The DB FAS was defined as having both baseline and at least one post-baseline ABC-SW assessment. The DB-FAS excludes 7 participants randomized to oxytocin (2 with no baseline ABC-SW and 5 with no post-baseline ABC-SW) and 6 participants assigned to placebo who had no post-baseline ABC-SW.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 139 participants 138 participants 277 participants
10.4  (4.06) 10.4  (3.99) 10.4  (4.04)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 139 participants 138 participants 277 participants
Female
17
  12.2%
18
  13.0%
35
  12.6%
Male
122
  87.8%
120
  87.0%
242
  87.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 139 participants 138 participants 277 participants
Hispanic or Latino
13
   9.4%
15
  10.9%
28
  10.1%
Not Hispanic or Latino
126
  90.6%
123
  89.1%
249
  89.9%
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 139 participants 138 participants 277 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
11
   7.9%
12
   8.7%
23
   8.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
9
   6.5%
14
  10.1%
23
   8.3%
White
104
  74.8%
100
  72.5%
204
  73.6%
More than one race
14
  10.1%
9
   6.5%
23
   8.3%
Unknown or Not Reported
1
   0.7%
3
   2.2%
4
   1.4%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 139 participants 138 participants 277 participants
139
 100.0%
138
 100.0%
277
 100.0%
Aberrant Behavior Checklist Social Withdrawal Subscale Score (ABC-SW) abc-SW (mean   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 139 participants 138 participants 277 participants
11.0  (6.9) 11.6  (7.8) 11.3  (7.4)
[1]
Measure Description: the Aberrant Behavior Scale Social withdrawal score assesses reciprocal social behaviors. It is composed of 13 questions from the Aberrant Behavior Scale Lethargy subscale that consists of 16 questions. The ABC-SW does not include the 3 questions (i.e. 3,32,53) of the Lethargy subscale that refer to sedentary behaviors. Score for each item ranges from 0 (not at all a problem) to 3 (a serious problem). Items are summed to give a minimal score of 0 and a maximal score of 39. Lower Scores are better
1.Primary Outcome
Title Change in Aberrant Behavior Checklist-Social Withdrawal Subscale ABC-SW, a Measure of Reciprocal Social Behavior
Hide Description The primary outcome is Change in Aberrant Behavior Checklist-Social Withdrawal subscale- a measure ofreciprocal social behaviors. ABC-SW is a modification of the ABC-Lethargy subscale. The ABC-SW consists of the sum of questions 5,12,16, 20, 23, 26, 30, 37, 40, 42, 43, 55, and 58. In contrast to the ABC-Lethargy subscale it eliminates question 3 (listless, sluggish, inactive), question 32 (sits or stands in one position for a long time), and question 53 (inactive, never moves spontaneously). Thirteen individual items are scored 0-3, therefore the range is 0-39. Higher score indicates higher level of social withdrawal.
Time Frame Double-blind phase: baseline, weeks 4, 8, 12, 16, 20, 24
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Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Mean (Standard Error)
Unit of Measure: score on a scale
Double-blind baseline to w4 8.81  (0.39) 8.68  (0.39)
Double-blind baseline to w8 8.97  (0.45) 8.68  (0.45)
Double-blind baseline-w12 7.48  (0.43) 8.13  (0.43)
DB w0- w16 7.99  (0.46) 8.04  (0.46)
DB w0- w20 7.81  (0.05) 7.75  (0.45)
DB w0-w24 7.75  (0.46) 8.05  (0.46)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oxytocin Nasal Spray, Placebo Nasal Spray
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.503
Comments not adjusted primary outcome
Method Mixed Models Analysis
Comments adjusted for baseline, age category, functionality category
2.Primary Outcome
Title ABC-SW (Aberrant Behavior Checklist-Social Withdrawal) Subscale - Reciprocal Social Behavior
Hide Description The ABC-SW is described above and involves 13 items reflecting lack of reciprocal interaction. Each item is scored from 0 (never shows behavior) to 3 (behavior is a major problem). The range is 0-39. Higher scores indicate worse reciprocal social functioning.
Time Frame Least mean squares for Open Label: weeks 24 -48
Hide Outcome Measure Data
Hide Analysis Population Description
Open Label phase participants in OLE FAS excluding 2 participants without usable ABC-sws (either w24 or at least one pw24 ABC-sw.
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 125 122
Least Squares Mean (95% Confidence Interval)
Unit of Measure: score on a scale
Open Label week 24
7.83
(7.11 to 8.55)
7.81
(7.09 to 8.52)
Open Label week 48
6.99
(6.10 to 7.89)
6.78
(5.89 to 7.67)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oxytocin Nasal Spray, Placebo Nasal Spray
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.61
Comments not adjusted primary outcome, p threshold 0.05
Method Mixed Models Analysis
Comments adjustment for value at week 24,
3.Primary Outcome
Title Change in Sociability Factor (SF)
Hide Description The Sociability Factor (SF) is a summed measure of the13 items of the ABC-SW and the 18 items of the Pervasive Development Disorders Behavior Inventory-Screening Version (PDDBI-SV).The PDDBI-SV assesses both adaptive social behaviors and social problems typical of ASD. The adaptive behaviors are reverse scored so that all the analyzed scores range from 0-performing in a neurotypical fashion to 3 typically performs in a way associated with ASD. the total # of items on this summed measure is 31 with a range from 0 to 93. More impaired social functioning indicated by higher scores. NOTE THIS MEASURE WAS ELIMINATED FROM FINAL SAP'S
Time Frame Double-blind phase: change in least means squares between week 0 & 24.
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
DB w0 35.8  (1.24) 36.1  (1.28)
DB w0-w4 -5.57  (0.69) -5.81  (0.69)
DB w0-w8 -5.99  (0.66) -6.30  (0.66)
DB w0-w12 -6.40  (0.66) -6.79  (0.66)
DB w0-w16 -6.82  (0.70) -7.28  (0.71)
DB w0-w20 -7.24  (0.88) -7.77  (0.88)
DB w0-w24 -7.66  (0.78) -8.27  (0.88)
4.Secondary Outcome
Title Change in Social Reciprocity Scale-2 (SRS-2) Social Motivation Subscale Score
Hide Description The SRS-Social Motivation subscale was developed to provide a quantitative measure of social impairments typically observed in ASD in children 3-18 years. Reported as T-score with a range of 38-90 for both boys and girls. Higher score indicates more severe clinical condition. Lower value in change indicates more improvement.
Time Frame Double-blind phase: baseline, weeks 12, 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Mean (Standard Deviation)
Unit of Measure: T-score
Double-blind baseline to week 12 -4.58  (0.68) -5.72  (0.69)
Double-blind baseline to week 24 -4.49  (0.70) -5.42  (0.70)
5.Secondary Outcome
Title Social Reciprocity Scale-2 (SRS-2) Social Motivation Subscale Score
Hide Description The SRS-Social Motivation subscale was developed to provide a quantitative measure of social impairments typically observed in ASD in children 3-18 years. Reported as T-score with a range of 38-90 for both boys and girls. Higher score indicates more severe clinical condition. Lower value in change indicates more improvement.
Time Frame Open Label: weeks 24, 48
Hide Outcome Measure Data
Hide Analysis Population Description
Open Label phase participants
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 127 122
Mean (Standard Error)
Unit of Measure: T-score
Open Label week 24 88.5  (1.37) 86.6  (1.37)
Open Label week 48 87.9  (1.83) 83.0  (1.81)
6.Secondary Outcome
Title Change in Stanford Binet-5th Edition (SB-5) IQ Score
Hide Description Cognitive skills will be assessed using the Stanford Binet-5th Edition (SB-5) (Roid). Acceptable IQ range is 47-153, with higher score being better. Higher change scores indicate more improvement.
Time Frame Double-blind phase: baseline to week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with scores collected at baseline and week 24.
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 94 98
Mean (Standard Deviation)
Unit of Measure: score on a scale
0.40  (11.64) 1.0  (10.84)
7.Secondary Outcome
Title Change in Vineland II Adaptive Behavior Scales (VABS-II) Composite Score
Hide Description Functional skills including communication will be assessed using the VABS-II Adaptive Behavior Composite Score. Uses standard score with a mean of 100 and SD of 15 with a range of 20-160. Higher score is better. Higher value in change indicates more improvement.
Time Frame Double-blind phase: baseline, week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Mean (Standard Deviation)
Unit of Measure: score on a scale
2.61  (1.26) 1.50  (1.27)
8.Secondary Outcome
Title Change in Vineland II Adaptive Behavior Scales (VABS-II) Socialization Domain Score
Hide Description Functional skills will be assessed using the VABS-II Socialization Domain Score. Uses standard score with a mean of 100 and SD of 15 with a range of 20-160. Higher score is better. Higher value in change indicates more improvement.
Time Frame Double-blind phase: baseline, week 24; Open Label: week 48
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Mean (Standard Error)
Unit of Measure: score on a scale
Double-blind baseline to week 24 Number Analyzed 139 participants 138 participants
4.45  (1.27) 4.87  (1.25)
Open Label week 24 to week 48 Number Analyzed 127 participants 122 participants
1.59  (1.11) 0.54  (1.10)
9.Secondary Outcome
Title Change in Vineland II Adaptive Behavior Scales (VABS-II) Daily Living Domain Score
Hide Description Functional skills will be assessed using the VABS-II Daily Living Domain Score. Uses standard score with a mean of 100 and SD of 15 with a range of 20-160. Higher score is better. Higher value in change indicates more improvement.
Time Frame Double-blind phase: baseline, week 24; Open Label: week 48
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Mean (Standard Error)
Unit of Measure: score on a scale
Double-blind baseline to week 24 Number Analyzed 139 participants 138 participants
2.50  (1.10) 1.24  (1.14)
Open Label week 24 to week 48 Number Analyzed 127 participants 122 participants
1.76  (1.19) 0.62  (0.11)
10.Secondary Outcome
Title Change in Vineland II Adaptive Behavior Scales (VABS-II) Communication Domain Score
Hide Description Functional skills will be assessed using the VABS-II Communication Domain Score. Uses standard score with a mean of 100 and SD of 15 with a range of 20-160. Higher score is better. Higher value in change indicates more improvement.
Time Frame Double-blind phase: baseline, week 24; Open Label: week 48
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Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
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Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Mean (Standard Error)
Unit of Measure: score on a scale
Double-blind baseline to week 24 Number Analyzed 139 participants 138 participants
3.88  (0.89) 2.27  (0.90)
Open Label week 24 to week 48 Number Analyzed 127 participants 122 participants
4.06  (1.35) 5.98  (1.41)
11.Secondary Outcome
Title Change in Caregiver Strain Questionnaire (CSQ) Subjective Internalizing Subscale Score
Hide Description Caregiver questionnaire that assesses the impact of caring for the proband on caregiver and family. CSQ subscale scores are ranged from 1 to 5. with each item of the subscale having the same range, the sum of the items within the subscale are summed, and the mean score is determined (I.e. a single # between 1 and 5) and reported. Higher scores indicate more caregiver strain. Lower value in change indicates more improvement.
Time Frame Double-blind phase: baseline, week 24
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Full Analysis Set
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
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Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Mean (Standard Error)
Unit of Measure: score on a scale
-0.16  (0.07) -0.29  (0.07)
12.Secondary Outcome
Title Caregiver Strain Questionnaire (CSQ) Subjective Internalizing Subscale Mean Score
Hide Description Caregiver questionnaire that assesses the impact of caring for the proband on caregiver and family. Each item on the subjective internalizing CSQ subscale is rated from 1 to 5. Then all items within the subscale are summed and the mean is determined based on the number of items in the subscale. Higher score indicates more caregiver strain. Lower value in change indicates more improvement.
Time Frame Open Label: weeks 24, 48
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Full Analysis Set participants who entered double blind and have values at week 24 AND 48
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 110 119
Mean (Standard Deviation)
Unit of Measure: mean score on a scale
Open Label week 24 2.96  (0.99) 2.85  (1.00)
Open Label week 48 2.97  (0.99) 2.85  (0.97)
13.Secondary Outcome
Title Change in Caregiver Strain Questionnaire (CSQ) Subjective Externalizing Subscale Score
Hide Description Caregiver questionnaire that assesses the impact of caring for the proband on caregiver and family. CSQ subscale scores are ranged from 1 to 5. Higher score indicates more caregiver strain. Lower value in change indicates more improvement.
Time Frame Double-blind phase: baseline, week 24; Open Label: week 48
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Full Analysis Set
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
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Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Mean (Standard Error)
Unit of Measure: score on a scale
Double-blind baseline to week 24 Number Analyzed 139 participants 138 participants
-0.08  (0.04) -0.04  (0.04)
Open Label week 24 to week 48 Number Analyzed 110 participants 119 participants
0.01  (0.07) 0  (0.08)
14.Secondary Outcome
Title Change in Caregiver Strain Questionnaire (CSQ) Objective Subscale Score
Hide Description Caregiver questionnaire that assesses the impact of caring for the proband on caregiver and family. CSQ subscale scores are ranged from 1 to 5. Higher score indicates more caregiver strain. Lower value in change indicates more improvement. The analysis directions for the instrument that are used in these analyses are the mean of all the responses in the scale or subscale.
Time Frame Double-blind phase: baseline, week 24; Open Label: week 48
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Full Analysis Set
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 139 138
Mean (Standard Error)
Unit of Measure: score on a scale
Double-blind baseline to week 24 Number Analyzed 139 participants 138 participants
-0.16  (0.06) -0.22  (0.06)
Open Label week 24 to week 48 Number Analyzed 110 participants 119 participants
0.13  (0.06) 0.44  (0.08)
15.Other Pre-specified Outcome
Title Changes in Biologic Outcome Measures
Hide Description Investigators will obtain blood, urine and vital signs from participants at regular intervals in order to assess the safety of oxytocin. In addition,the blood samples will also be used to assess oxytocin levels, OTXR differential methylation status and to assess mRNA expression. Investigators will obtain saliva at the same time points to perform salivary oxytocin levels.
Time Frame Double blind phase: change from Baseline to week 8, and week 24. Open label phase change from week 24 to week 36.
Outcome Measure Data Not Reported
16.Other Pre-specified Outcome
Title Change in Clinical Global Impressions -Improvement Score (CGI-I)
Hide Description The Clinical Global Impressions - Improvement score and Severity score, which is routinely used in pharmacologic clinical trials, will capture the study physician's global impression of response. scores of 1 and 2 are considered as a percentage of total subjects in arm
Time Frame Double blind phase: change from Baseline to week 12, and week 24. Open label phase change from week 24 to week 48
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full analysis set
Arm/Group Title Placebo Nasal Spray Oxytocin Nasal Spray
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Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except oxytocin will NOT be added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Overall Number of Participants Analyzed 138 139
Measure Type: Number
Unit of Measure: percentage of participants in arm
64 53
17.Other Pre-specified Outcome
Title Reading Mind in the Eyes Test is an Objective Measures of the Extent to Which Verbal Participants With Rudimentary Knowledge of Emotion Names Are Able to Correctly Identify the Emotion Shown in a Black and White Picture of the Eyes and Nose of an Actor.
Hide Description This computerized task consists of a series of pictures of eyes in which the participant needs to determine which emotion the eyes are expressing from 4 emotions listed along with the picture. The outcome is the % of pictures with correct emotion identified. The range is 0 to 100%. The larger percent identified correctly indicates better ability to perceive emotions. An increase or positive change indicates better ability to identify emotions since baseline.
Time Frame Double blind phase: change from Baseline and week 24. Note: only those who demonstrated understanding of these concepts were included in sample.
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only subjects who could define feelings from fluently verbal subgroup
Arm/Group Title Oxytocin Nasal Spray Placebo Nasal Spray
Hide Arm/Group Description:

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Overall Number of Participants Analyzed 69 64
Mean (Standard Deviation)
Unit of Measure: percentage of correct responses
DB w0 51.1  (18.76) 48.2  (18.61)
DB w24 54.9  (14.02) 49.92  (13.84)
Time Frame Through post-treatment follow-up, approximately 55 weeks.
Adverse Event Reporting Description Adverse events collected on Safety Population (subjects who started each phase).
 
Arm/Group Title Oxytocin Nasal Spray: Double-blind Phase Placebo Nasal Spray: Double-blind Phase Oxytocin Nasal Spray: Open Label Phase Placebo Nasal Spray: Open Label Phase
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Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

Oxytocin

Oxytocin Nasal Spray: Each insufflation will deliver 8 IU or 24 IU of oxytocin. A maximum of 3 insufflations at a time will be required. Dosing will be flexible between 8 IU/day and 80 IU/day, typically in two divided doses delivered in the morning and in the afternoon. Doses will typically increase by 8 IU twice daily (BID) at week 2 and weeks 4 and 8 until achieving the target dose of 24 IU BID at week 8. Subsequently doses may be increased in 8 IU BID increments ONLY at each visit until a maximum dose of 40 IU BID is achieved.Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. During the open label phase after approximately March 2019 the study used only the 24 IU /0.10 ml formulation and the maximum dose was 72 IU per day.

Placebo

Placebo Nasal Spray: This nasal spray will contain all of the ingredients that are in the active oxytocin spray in the same quantities, except there will be no oxytocin added to the solution. It will be packaged using the same container system as the active oxytocin nasal spray. Each bottle's label will have its own unique nonsequential randomly assigned number and not a lot number to facilitate masking. Dose titration will occur using exactly the same criteria and procedures as for active study drug.

All-Cause Mortality
Oxytocin Nasal Spray: Double-blind Phase Placebo Nasal Spray: Double-blind Phase Oxytocin Nasal Spray: Open Label Phase Placebo Nasal Spray: Open Label Phase
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/146 (0.00%)   0/144 (0.00%)   1/127 (0.79%)   0/122 (0.00%) 
Hide Serious Adverse Events
Oxytocin Nasal Spray: Double-blind Phase Placebo Nasal Spray: Double-blind Phase Oxytocin Nasal Spray: Open Label Phase Placebo Nasal Spray: Open Label Phase
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/146 (1.37%)   1/144 (0.69%)   4/127 (3.15%)   0/122 (0.00%) 
Gastrointestinal disorders         
Constipation * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
General disorders         
Appendicitis * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Nervous system disorders         
Seizures * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Sedation * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Psychiatric disorders         
Dysphoria * 1  0/146 (0.00%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Irritability * 1  0/146 (0.00%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Aggression * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Anxiety * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
1
Term from vocabulary, MedDRA
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Oxytocin Nasal Spray: Double-blind Phase Placebo Nasal Spray: Double-blind Phase Oxytocin Nasal Spray: Open Label Phase Placebo Nasal Spray: Open Label Phase
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   120/146 (82.19%)   120/144 (83.33%)   91/127 (71.65%)   92/122 (75.41%) 
Blood and lymphatic system disorders         
Increased Tendency To Bruise * 1  0/146 (0.00%)  3/144 (2.08%)  0/127 (0.00%)  0/122 (0.00%) 
Lymphadenopathy * 1  3/146 (2.05%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Cardiac disorders         
Dizziness * 1  1/146 (0.68%)  2/144 (1.39%)  1/127 (0.79%)  2/122 (1.64%) 
Cardiac Rhythm Abnormality * 1  0/146 (0.00%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Palpitations * 1  1/146 (0.68%)  0/144 (0.00%)  2/127 (1.57%)  0/122 (0.00%) 
Ear and labyrinth disorders         
Ear Ache * 1  7/146 (4.79%)  9/144 (6.25%)  2/127 (1.57%)  2/122 (1.64%) 
Ear Congestion * 1  4/146 (2.74%)  4/144 (2.78%)  0/127 (0.00%)  3/122 (2.46%) 
Tinnitus * 1  1/146 (0.68%)  1/144 (0.69%)  2/127 (1.57%)  0/122 (0.00%) 
Hypoacusis * 1  0/146 (0.00%)  0/144 (0.00%)  0/127 (0.00%)  1/122 (0.82%) 
Endocrine disorders         
Precocious Puberty * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Eye disorders         
Blepharospasm * 1  2/146 (1.37%)  3/144 (2.08%)  0/127 (0.00%)  1/122 (0.82%) 
Dry Eye * 1  3/146 (2.05%)  1/144 (0.69%)  2/127 (1.57%)  1/122 (0.82%) 
Eye Discomfort * 1  1/146 (0.68%)  1/144 (0.69%)  1/127 (0.79%)  0/122 (0.00%) 
Visual Acuity Reduced * 1  1/146 (0.68%)  1/144 (0.69%)  2/127 (1.57%)  1/122 (0.82%) 
Gastrointestinal disorders         
Diarrhea * 1  13/146 (8.90%)  15/144 (10.42%)  6/127 (4.72%)  3/122 (2.46%) 
Abdominal Pain Or Discomfort * 1  6/146 (4.11%)  14/144 (9.72%)  6/127 (4.72%)  7/122 (5.74%) 
Vomiting Or Nausea * 1  6/146 (4.11%)  12/144 (8.33%)  7/127 (5.51%)  8/122 (6.56%) 
Constipation * 1  7/146 (4.79%)  9/144 (6.25%)  4/127 (3.15%)  6/122 (4.92%) 
Stomatitis * 1  3/146 (2.05%)  7/144 (4.86%)  0/127 (0.00%)  0/122 (0.00%) 
Tooth Disorder * 1  3/146 (2.05%)  5/144 (3.47%)  3/127 (2.36%)  3/122 (2.46%) 
Encopresis * 1  3/146 (2.05%)  4/144 (2.78%)  2/127 (1.57%)  1/122 (0.82%) 
Dry Mouth * 1  1/146 (0.68%)  2/144 (1.39%)  1/127 (0.79%)  0/122 (0.00%) 
Salivary Hypersecretion * 1  0/146 (0.00%)  1/144 (0.69%)  1/127 (0.79%)  0/122 (0.00%) 
Anorectal Discomfort * 1  0/146 (0.00%)  0/144 (0.00%)  0/127 (0.00%)  1/122 (0.82%) 
Flatulence * 1  0/146 (0.00%)  0/144 (0.00%)  0/127 (0.00%)  1/122 (0.82%) 
Dysphagia * 1  0/146 (0.00%)  0/144 (0.00%)  0/127 (0.00%)  1/122 (0.82%) 
General disorders         
Energy Increased * 1  14/146 (9.59%)  5/144 (3.47%)  4/127 (3.15%)  4/122 (3.28%) 
Fatigue * 1  8/146 (5.48%)  8/144 (5.56%)  1/127 (0.79%)  6/122 (4.92%) 
Pyrexia * 1  9/146 (6.16%)  7/144 (4.86%)  2/127 (1.57%)  6/122 (4.92%) 
Swelling * 1  3/146 (2.05%)  2/144 (1.39%)  0/127 (0.00%)  1/122 (0.82%) 
Asthenia * 1  2/146 (1.37%)  2/144 (1.39%)  0/127 (0.00%)  0/122 (0.00%) 
Chest Pain Or Discomfort * 1  2/146 (1.37%)  1/144 (0.69%)  3/127 (2.36%)  0/122 (0.00%) 
Night Sweats * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Enamel Discoloration * 1  0/146 (0.00%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Immune system disorders         
Allergic Hypersensitivity * 1  14/146 (9.59%)  15/144 (10.42%)  10/127 (7.87%)  2/122 (1.64%) 
Infections and infestations         
Infection * 1  53/146 (36.30%)  67/144 (46.53%)  33/127 (25.98%)  33/122 (27.05%) 
Injury, poisoning and procedural complications         
Injury * 1  8/146 (5.48%)  6/144 (4.17%)  13/127 (10.24%)  7/122 (5.74%) 
Intentional Self-Injury * 1  5/146 (3.42%)  6/144 (4.17%)  1/127 (0.79%)  1/122 (0.82%) 
Fracture * 1  0/146 (0.00%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Sunburn * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Investigations         
Pituitary Analyses Anterior * 1  0/146 (0.00%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Abnormal Urinalysis * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Thrombocytopenia * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Metabolism and nutrition disorders         
Increased Appetite * 1  23/146 (15.75%)  14/144 (9.72%)  9/127 (7.09%)  10/122 (8.20%) 
Decreased Appetite * 1  9/146 (6.16%)  13/144 (9.03%)  7/127 (5.51%)  5/122 (4.10%) 
Abnormal Weight Gain * 1  11/146 (7.53%)  9/144 (6.25%)  8/127 (6.30%)  8/122 (6.56%) 
Abnormal Weight Loss * 1  10/146 (6.85%)  5/144 (3.47%)  2/127 (1.57%)  4/122 (3.28%) 
Thirst * 1  8/146 (5.48%)  4/144 (2.78%)  10/127 (7.87%)  3/122 (2.46%) 
Musculoskeletal and connective tissue disorders         
Myalgia * 1  5/146 (3.42%)  1/144 (0.69%)  1/127 (0.79%)  1/122 (0.82%) 
Arthralgia * 1  2/146 (1.37%)  1/144 (0.69%)  2/127 (1.57%)  0/122 (0.00%) 
Growing Pains * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Specific Muscle Pain * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Skeletal Pain * 1  0/146 (0.00%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Nervous system disorders         
Agitation * 1  19/146 (13.01%)  16/144 (11.11%)  11/127 (8.66%)  11/122 (9.02%) 
Headache * 1  11/146 (7.53%)  22/144 (15.28%)  6/127 (4.72%)  8/122 (6.56%) 
Initial Insomnia * 1  14/146 (9.59%)  19/144 (13.19%)  5/127 (3.94%)  12/122 (9.84%) 
Sedation * 1  19/146 (13.01%)  12/144 (8.33%)  5/127 (3.94%)  8/122 (6.56%) 
Stereotypy * 1  13/146 (8.90%)  8/144 (5.56%)  3/127 (2.36%)  5/122 (4.10%) 
Terminal Insomnia * 1  10/146 (6.85%)  11/144 (7.64%)  1/127 (0.79%)  4/122 (3.28%) 
Middle Insomnia * 1  6/146 (4.11%)  12/144 (8.33%)  1/127 (0.79%)  4/122 (3.28%) 
Restlessness * 1  11/146 (7.53%)  3/144 (2.08%)  4/127 (3.15%)  3/122 (2.46%) 
Hypersomnia * 1  3/146 (2.05%)  3/144 (2.08%)  1/127 (0.79%)  1/122 (0.82%) 
Confusional State * 1  1/146 (0.68%)  2/144 (1.39%)  2/127 (1.57%)  0/122 (0.00%) 
Speech Disorder * 1  2/146 (1.37%)  1/144 (0.69%)  1/127 (0.79%)  1/122 (0.82%) 
Dyskinesia * 1  1/146 (0.68%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Dystonia * 1  1/146 (0.68%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Paresthesia * 1  2/146 (1.37%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Ganglion Cyst * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Photophobia * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  1/122 (0.82%) 
Tremor * 1  1/146 (0.68%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Seizure Or Convulsion * 1  0/146 (0.00%)  0/144 (0.00%)  2/127 (1.57%)  0/122 (0.00%) 
Coordination Abnormal * 1  0/146 (0.00%)  0/144 (0.00%)  0/127 (0.00%)  1/122 (0.82%) 
Sleep Walking * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Psychiatric disorders         
Negativism * 1  24/146 (16.44%)  23/144 (15.97%)  10/127 (7.87%)  10/122 (8.20%) 
Aggression Or Hostility * 1  23/146 (15.75%)  20/144 (13.89%)  10/127 (7.87%)  6/122 (4.92%) 
Anger Or Irritability * 1  20/146 (13.70%)  20/144 (13.89%)  14/127 (11.02%)  6/122 (4.92%) 
Frustration * 1  15/146 (10.27%)  18/144 (12.50%)  7/127 (5.51%)  9/122 (7.38%) 
Crying * 1  13/146 (8.90%)  17/144 (11.81%)  10/127 (7.87%)  10/122 (8.20%) 
Inappropriate Affect * 1  13/146 (8.90%)  13/144 (9.03%)  5/127 (3.94%)  4/122 (3.28%) 
Psychomotor Hyperactivity * 1  11/146 (7.53%)  10/144 (6.94%)  3/127 (2.36%)  7/122 (5.74%) 
Impulse-Control Disorder * 1  9/146 (6.16%)  9/144 (6.25%)  8/127 (6.30%)  5/122 (4.10%) 
Anxiety * 1  6/146 (4.11%)  8/144 (5.56%)  2/127 (1.57%)  5/122 (4.10%) 
Disturbance In Attention * 1  9/146 (6.16%)  4/144 (2.78%)  3/127 (2.36%)  4/122 (3.28%) 
Mood Swings * 1  3/146 (2.05%)  10/144 (6.94%)  4/127 (3.15%)  3/122 (2.46%) 
Obsessive Rumination * 1  4/146 (2.74%)  6/144 (4.17%)  3/127 (2.36%)  3/122 (2.46%) 
Apathy Or Boredom * 1  4/146 (2.74%)  5/144 (3.47%)  5/127 (3.94%)  4/122 (3.28%) 
Depressed Mood * 1  3/146 (2.05%)  5/144 (3.47%)  3/127 (2.36%)  3/122 (2.46%) 
Perseveration * 1  2/146 (1.37%)  6/144 (4.17%)  1/127 (0.79%)  3/122 (2.46%) 
Tic * 1  3/146 (2.05%)  4/144 (2.78%)  5/127 (3.94%)  4/122 (3.28%) 
Nightmares * 1  3/146 (2.05%)  3/144 (2.08%)  2/127 (1.57%)  2/122 (1.64%) 
Insomnia * 1  1/146 (0.68%)  2/144 (1.39%)  0/127 (0.00%)  1/122 (0.82%) 
Suicidal Ideation * 1  1/146 (0.68%)  2/144 (1.39%)  2/127 (1.57%)  1/122 (0.82%) 
Delusion * 1  0/146 (0.00%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Hallucination * 1  0/146 (0.00%)  1/144 (0.69%)  0/127 (0.00%)  0/122 (0.00%) 
Mania Or Hypomania * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Pressure Of Speech * 1  1/146 (0.68%)  0/144 (0.00%)  2/127 (1.57%)  1/122 (0.82%) 
Renal and urinary disorders         
Enuresis * 1  3/146 (2.05%)  16/144 (11.11%)  7/127 (5.51%)  8/122 (6.56%) 
Pollakiuria * 1  5/146 (3.42%)  6/144 (4.17%)  0/127 (0.00%)  1/122 (0.82%) 
Dysuria * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  0/122 (0.00%) 
Hematuria * 1  0/146 (0.00%)  0/144 (0.00%)  0/127 (0.00%)  1/122 (0.82%) 
Micturition Frequency Decreased * 1  0/146 (0.00%)  0/144 (0.00%)  0/127 (0.00%)  1/122 (0.82%) 
Reproductive system and breast disorders         
Libido Increased * 1  7/146 (4.79%)  6/144 (4.17%)  6/127 (4.72%)  5/122 (4.10%) 
Breast Pain * 1  2/146 (1.37%)  0/144 (0.00%)  0/127 (0.00%)  1/122 (0.82%) 
Menstrual Disorder * 1  0/146 (0.00%)  2/144 (1.39%)  0/127 (0.00%)  1/122 (0.82%) 
Respiratory, thoracic and mediastinal disorders         
Cough * 1  26/146 (17.81%)  18/144 (12.50%)  9/127 (7.09%)  13/122 (10.66%) 
Asthma * 1  2/146 (1.37%)  7/144 (4.86%)  0/127 (0.00%)  1/122 (0.82%) 
Dyspnea * 1  1/146 (0.68%)  4/144 (2.78%)  0/127 (0.00%)  1/122 (0.82%) 
Nasal Discomfort * 1  3/146 (2.05%)  2/144 (1.39%)  0/127 (0.00%)  0/122 (0.00%) 
Nasal Congestion * 1  1/146 (0.68%)  0/144 (0.00%)  0/127 (0.00%)  2/122 (1.64%) 
Rhinitis Nos * 1  1/146 (0.68%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Sore Throat * 1  1/146 (0.68%)  0/144 (0.00%)  2/127 (1.57%)  0/122 (0.00%) 
Skin and subcutaneous tissue disorders         
Rash * 1  16/146 (10.96%)  14/144 (9.72%)  15/127 (11.81%)  9/122 (7.38%) 
Acne * 1  5/146 (3.42%)  12/144 (8.33%)  4/127 (3.15%)  6/122 (4.92%) 
Eczema * 1  7/146 (4.79%)  4/144 (2.78%)  7/127 (5.51%)  7/122 (5.74%) 
Wart * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
Vascular disorders         
Epistaxis * 1  11/146 (7.53%)  10/144 (6.94%)  6/127 (4.72%)  4/122 (3.28%) 
Hypertension * 1  0/146 (0.00%)  0/144 (0.00%)  1/127 (0.79%)  0/122 (0.00%) 
1
Term from vocabulary, MedDRA
*
Indicates events were collected by non-systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Linmarie Sikich, M.D.
Organization: Duke University
Phone: 919-681-0026
EMail: linmarie.sikich@duke.edu
Layout table for additonal information
Responsible Party: Linmarie Sikich, Duke University
ClinicalTrials.gov Identifier: NCT01944046    
Other Study ID Numbers: Pro00063950
1U01HD073984 ( U.S. NIH Grant/Contract )
13-0593 ( Other Identifier: UNC )
First Submitted: June 13, 2013
First Posted: September 17, 2013
Results First Submitted: July 31, 2020
Results First Posted: January 5, 2021
Last Update Posted: January 5, 2021