Treatment of Rett Syndrome With Recombinant Human IGF-1

• ClinicalTrials.gov Identifier: NCT01777542
• Recruitment Status: Completed
• First Posted: January 29, 2013
• Results First Posted: March 26, 2018
• Last Update Posted: March 26, 2018
• Sponsor: Boston Children's Hospital
• Collaborator: International Rett Syndrome Foundation
• Information provided by (Responsible Party): Mustafa Sahin, Harvard Medical School (HMS and HSDM)

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Rett Syndrome
• Interventions: Drug: Recombinant Human Insulin Growth Factor 1 (rhIGF-1); Drug: Placebo
• Enrollment: 30

Participant Flow

Recruitment Details
Pre-assignment Details	Assessments findings during the Screening Visit that could result in ineligibility after informed consent include: Scoliosis curve > 40º by x-ray; Bone age > 11 years by x-ray; Cardiomegaly by echocardiogram; Tanner Stage II breast development by physical exam; Prolonged QTc by ECG

Arm/Group Title	Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description	One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Period Title: First Intervention (20 Weeks)
Started	15	15
Completed	15	15
Not Completed	0	0
Period Title: Washout Period (28 +/- 2 Weeks)
Started	15	15
Completed	15	15
Not Completed	0	0
Period Title: Second Intervention (20 Weeks)
Started	15	15
Completed	15	14
Not Completed	0	1
Reason Not Completed
Adverse Event	0	1

Baseline Characteristics

Arm/Group Title		All Participants
Arm/Group Description		All 30 subjects enrolled and randomized in the study
Overall Number of Baseline Participants		30
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	<=18 years	30 100.0%
	Between 18 and 65 years	0 0.0%
	>=65 years	0 0.0%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	Female	30 100.0%
	Male	0 0.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	Hispanic or Latino	26 86.7%
	Not Hispanic or Latino	3 10.0%
	Unknown or Not Reported	1 3.3%

Outcome Measures

1. Primary Outcome

Title	Rett Syndrome Behavior Questionnaire (RSBQ) - Fear/Anxiety Subscale
Description	The RSBQ is an informant/parent-completed measure of abnormal behaviors typically observed in individuals with RTT, which is completed by a parent/caregiver/LAR. Each item, grouped into eight domains/factors: General mood, Breathing problems, Body rocking and expressionless face, Hand behaviors, Repetitive face movements, Night-time behaviors, Fear/anxiety and Walking/standing), is scored on a Likert scale of 0-2, according to how well the item describes the individual's behavior. A score of "0" indicates the described item is "not true," a score of "1" indicates the described item is "somewhat or sometimes true," and a score of "2" indicates the described item is "very true or often true." The total sum of items in each subscale is reported. For the fear/anxiety subscale, the sum total could be between 0-8. The higher the sum total score, the greater the frequency of fear/anxiety behaviors.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 6.00)	5.00; (2.00 to 6.00)
Visit 2 - First Intervention	Number Analyzed	15 participants	15 participants
		5.00; (3.00 to 6.00)	3.00; (2.00 to 5.00)
Visit 3 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 5.00)	3.00; (2.00 to 5.00)
Visit 4 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (2.00 to 5.00)	3.00; (1.00 to 6.00)
Visit 5 - First Intervention	Number Analyzed	15 participants	15 participants
		3.00; (2.00 to 5.00)	3.00; (1.00 to 5.00)
Visit 6 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (2.00 to 5.00)	4.00; (2.00 to 6.00)
Visit 7 - Second Intervention	Number Analyzed	14 participants	15 participants
		4.00; (2.00 to 4.00)	3.00; (2.00 to 5.00)
Visit 8 - Second Intervention	Number Analyzed	15 participants	15 participants
		3.00; (3.00 to 5.00)	4.00; (1.00 to 5.00)
Visit 9 - Second Intervention	Number Analyzed	15 participants	15 participants
		3.00; (2.00 to 4.00)	3.00; (1.00 to 5.00)
Visit 10 - Second Intervention	Number Analyzed	14 participants	14 participants
		4.00; (2.00 to 5.00)	3.00; (2.00 to 4.00)
Follow-up	Number Analyzed	14 participants	14 participants
		3.50; (2.00 to 5.00)	3.50; (2.00 to 5.00)

2. Primary Outcome

Title	Anxiety, Depression, and Mood Scale (ADAMS) - Social Avoidance Subscale
Description	The ADAMS is completed by the parent/caregiver/LAR and consists of 29 items which are scored on a 4-point rating scale that combines frequency and severity ratings. The instructions ask the rater to describe the individual's behavior over the last six months on the following scale: "0" if the behavior has not occurred, "1" if the behavior occurs occasionally or is a mild problem, "2" if the behavior occurs quite often or is moderate problem, or "3" if the behavior occurs a lot or is a severe problem. The Social Avoidance subscale of the ADAMS will be used as a primary outcome measure for this trial. The range for this subscale is 0-21. The higher the subscale score, the more problematic the behavior.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention	Number Analyzed	15 participants	15 participants
		6.00; (5.00 to 8.00)	4.00; (2.00 to 8.00)
Visit 2 - First Intervention	Number Analyzed	15 participants	15 participants
		5.00; (3.00 to 7.00)	5.00; (3.00 to 7.00)
Visit 3 - First Intervention	Number Analyzed	15 participants	15 participants
		5.00; (4.00 to 7.00)	4.00; (2.00 to 7.00)
Visit 4 - First Intervention	Number Analyzed	15 participants	15 participants
		6.00; (3.00 to 7.00)	4.00; (3.00 to 7.00)
Visit 5 - First Intervention	Number Analyzed	15 participants	15 participants
		5.00; (2.00 to 6.00)	3.00; (2.00 to 5.00)
Visit 6 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 5.00)	4.00; (3.00 to 6.00)
Visit 7 - Second Intervention	Number Analyzed	14 participants	15 participants
		4.00; (2.00 to 7.00)	4.00; (3.00 to 5.00)
Visit 8 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (2.00 to 6.00)	4.00; (3.00 to 5.00)
Visit 9 - Second Intervention	Number Analyzed	15 participants	15 participants
		3.00; (1.00 to 7.00)	3.00; (2.00 to 5.00)
Visit 10 - Second Intervention	Number Analyzed	14 participants	14 participants
		3.50; (2.00 to 5.00)	3.50; (2.00 to 5.00)
Follow-up	Number Analyzed	14 participants	14 participants
		4.00; (2.00 to 6.00)	3.00; (2.00 to 4.00)

3. Primary Outcome

Title	Clinical Global Impression - Severity (CGI-S)
Description	This scale is used to judge the severity of the subject's disease prior to entry into the study. The clinician will rate the severity of behavioral symptoms at baseline on a 7-point scale from not impaired to the most impaired. The scores that correspond to each possible grouping are as follows: 1=Normal, not at all impaired; 2=Borderline impaired; 3=Mildly impaired; 4=Moderately impaired; 5=Markedly impaired; 6=Severely impaired; 7=The most impaired. The possible range for reported scores is 1-7.
Time Frame	Every 10 weeks during each of the two 20-week treatment periods

Outcome Measure Data

Analysis Population Description

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 4.00)	4.00; (3.00 to 4.00)
Visit 3 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 4.00)	4.00; (4.00 to 4.00)
Visit 5 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 4.00)	4.00; (4.00 to 5.00)
Visit 6 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 4.00)	4.00; (4.00 to 5.00)
Visit 8 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 4.00)	4.00; (4.00 to 5.00)
Visit 10 - Second Intervention	Number Analyzed	15 participants	14 participants
		4.00; (4.00 to 4.00)	4.50; (4.00 to 5.00)

4. Primary Outcome

Title	Clinical Global Impression - Improvement (CGI-I)
Description	Each time the patient was seen after the study intervention was initiated, the clinician compared the patient's overall clinical condition to the CGI-S score obtained at the baseline (visit 1) visit. Based on information collected, the clinician determined if any improvement occurred on the following 7-point scale: 1=Very much improved since the initiation of treatment; 2=Much improved; 3=Minimally improved; 4=No change from baseline (the initiation of treatment); 5=Minimally worse; 6=Much worse; 7=Very much worse since the initiation of treatment. The possible range for reported scores is 1-7.
Time Frame	Every 10 weeks during each of the two 20-week treatment periods

Outcome Measure Data

Analysis Population Description

Data was not collected at Visit 1 because participants had not yet been exposed to either intervention.

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 3 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 4.00)	4.00; (4.00 to 4.00)
Visit 5 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 4.00)	4.00; (4.00 to 4.00)
Visit 6 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 5.00)	4.00; (4.00 to 5.00)
Visit 8 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 4.00)	4.00; (4.00 to 5.00)
Visit 10 - Second Intervention	Number Analyzed	15 participants	14 participants
		4.00; (3.00 to 4.00)	4.00; (3.00 to 5.00)

5. Primary Outcome

Title	Parental Global Impression - Severity (PGI-S)
Description	The PGI-S is the parent version of the CGI-S. Parents/caregivers/LAR are asked to rate the severity of their child's symptoms at baseline on a 7-point scale from not at all impaired to the most impaired. The parents/caregivers/LAR will complete the PGI-S at each study visit. The scores that correspond to each possible grouping are as follows: 1=Normal, not at all impaired; 2=Borderline impaired; 3=Mildly impaired; 4=Moderately impaired; 5=Markedly impaired; 6=Severely impaired; 7=The most impaired. The possible range for reported scores is 1-7.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 4.00)	6.00; (4.00 to 6.00)
Visit 2 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 6.00)	4.00; (4.00 to 6.00)
Visit 3 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 4.00)	4.00; (4.00 to 6.00)
Visit 4 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 4.00)	4.00; (4.00 to 6.00)
Visit 5 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 6.00)	4.00; (4.00 to 6.00)
Visit 6 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 6.00)	4.00; (4.00 to 6.00)
Visit 7 - Second Intervention	Number Analyzed	14 participants	15 participants
		4.00; (3.00 to 4.00)	4.00; (4.00 to 6.00)
Visit 8 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 4.00)	6.00; (4.00 to 6.00)
Visit 9 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (4.00 to 4.00)	6.00; (4.00 to 6.00)
Visit 10 - Second Intervention	Number Analyzed	14 participants	14 participants
		4.00; (3.00 to 4.00)	5.00; (4.00 to 6.00)
Follow-up	Number Analyzed	14 participants	14 participants
		4.00; (3.00 to 4.00)	4.00; (4.00 to 6.00)

6. Primary Outcome

Title	Parental Global Impression - Improvement (PGI-I)
Description	As part of each visit after the study intervention was initiated, the parent/caregiver was asked to compare the patient's overall clinical condition to the score obtained at the baseline (visit 1) visit. Based on information collected, the clinician determined if any improvement occurred on the following 7-point scale: 1=Very much improved since the initiation of treatment; 2=Much improved; 3=Minimally improved; 4=No change from baseline (the initiation of treatment); 5=Minimally worse; 6=Much worse; 7=Very much worse since the initiation of treatment. The possible range for reported scores is 1-7.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

Data was not collected at visit 1 because participants had not yet been exposed to either intervention.

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 2 - First Intervention	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 4.00)	4.00; (4.00 to 4.00)
Visit 3 - First Intervention	Number Analyzed	15 participants	15 participants
		3.00; (3.00 to 4.00)	4.00; (3.00 to 4.00)
Visit 4 - First Intervention	Number Analyzed	15 participants	15 participants
		3.00; (3.00 to 4.00)	4.00; (3.00 to 4.00)
Visit 5 - First Intervention	Number Analyzed	15 participants	15 participants
		3.00; (3.00 to 4.00)	3.00; (3.00 to 4.00)
Visit 6 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.00; (2.00 to 4.00)	3.00; (3.00 to 4.00)
Visit 7 - Second Intervention	Number Analyzed	14 participants	15 participants
		3.00; (3.00 to 4.00)	3.00; (3.00 to 3.00)
Visit 8 - Second Intervention	Number Analyzed	15 participants	15 participants
		3.00; (3.00 to 4.00)	3.00; (3.00 to 3.00)
Visit 9 - Second Intervention	Number Analyzed	15 participants	15 participants
		3.00; (3.00 to 5.00)	3.00; (3.00 to 3.00)
Visit 10 - Second Intervention	Number Analyzed	14 participants	14 participants
		3.00; (3.00 to 3.00)	3.00; (3.00 to 3.00)
Follow-up	Number Analyzed	14 participants	14 participants
		3.00; (2.00 to 3.00)	3.00; (3.00 to 3.00)

7. Primary Outcome

Title	Parent Targeted Visual Analog Scale (PTSVAS) - Scale 1
Description	The parent or caretaker identifies the three most troublesome, RTT-specific, "target" symptoms, such as inattention or breath-holding. This allows the problems that are of concern to parents and the family to be targeted in the trial. In this study the caregiver will choose three target symptoms at baseline and then rate changes in severity of each target symptom on a visual analog scale (VAS). The VAS is a 10 cm line, where a target symptom is anchored on one end with the description "the best it has ever been" and on the other with the description "the worst it has ever been." The parent was asked to marked on the line where they felt their child's symptoms currently fit best. This mark was measured as recorded as a numeric value from 0.00-10.00 cm. The higher the value, the worse the symptom.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention	Number Analyzed	15 participants	15 participants
		6.50; (3.25 to 8.40)	8.80; (5.05 to 9.85)
Visit 2 - First Intervention	Number Analyzed	13 participants	13 participants
		4.70; (3.45 to 7.70)	4.80; (2.30 to 8.95)
Visit 3 - First Intervention	Number Analyzed	15 participants	15 participants
		5.65; (3.55 to 8.90)	5.35; (3.80 to 9.35)
Visit 4 - First Intervention	Number Analyzed	11 participants	11 participants
		5.05; (2.55 to 7.70)	5.10; (4.80 to 9.10)
Visit 5 - First Intervention	Number Analyzed	15 participants	15 participants
		4.80; (2.00 to 7.50)	5.15; (2.90 to 9.55)
Visit 6 - Second Intervention	Number Analyzed	14 participants	15 participants
		4.95; (3.75 to 8.50)	5.20; (4.70 to 9.25)
Visit 7 - Second Intervention	Number Analyzed	11 participants	13 participants
		4.55; (2.55 to 6.00)	4.65; (3.85 to 7.25)
Visit 8 - Second Intervention	Number Analyzed	15 participants	15 participants
		5.65; (3.70 to 7.55)	5.00; (3.65 to 7.45)
Visit 9 - Second Intervention	Number Analyzed	13 participants	12 participants
		4.15; (2.45 to 6.45)	5.15; (3.63 to 8.58)
Visit 10 - Second Intervention	Number Analyzed	14 participants	14 participants
		4.80; (2.50 to 6.90)	5.05; (4.20 to 8.50)
Follow-up	Number Analyzed	9 participants	12 participants
		5.60; (1.40 to 6.25)	5.08; (4.13 to 8.13)

8. Primary Outcome

Title	Parent Targeted Visual Analog Scale (PTSVAS) - Scale 2
Description	The parent or caretaker identifies the three most troublesome, RTT-specific, "target" symptoms, such as inattention or breath-holding. This allows the problems that are of concern to parents and the family to be targeted in the trial. In this study the caregiver will choose three target symptoms at baseline and then rate changes in severity of each target symptom on a visual analog scale (VAS). The VAS is a 10 cm line, where a target symptom is anchored on one end with the description "the best it has ever been" and on the other with the description "the worst it has ever been." The parent was asked to marked on the line where they felt their child's symptoms currently fit best. This mark was measured as recorded as a numeric value from 0.00-10.00 cm. The higher the value, the worse the symptom.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

Arm/Group Title	Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:	One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed	15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention	7.75; (4.80 to 9.45)	6.35; (5.20 to 9.85)
Visit 2 - First Intervention	4.50; (3.75 to 5.00)	5.25; (4.85 to 8.40)
Visit 3 - First Intervention	5.85; (4.30 to 7.25)	5.95; (4.95 to 8.90)
Visit 4 - First Intervention	5.00; (3.05 to 6.20)	5.40; (4.90 to 6.45)
Visit 5 - First Intervention	5.00; (3.30 to 6.10)	5.45; (1.40 to 7.80)
Visit 6 - Second Intervention	5.35; (4.95 to 7.85)	7.10; (4.95 to 9.25)
Visit 7 - Second Intervention	5.50; (3.85 to 6.20)	5.85; (3.40 to 6.90)
Visit 8 - Second Intervention	5.15; (3.80 to 7.20)	5.00; (3.00 to 7.60)
Visit 9 - Second Intervention	3.80; (1.70 to 6.35)	5.13; (3.43 to 7.05)
Visit 10 - Second Intervention	4.90; (2.60 to 6.80)	4.95; (2.25 to 8.15)
Follow-up	5.15; (3.85 to 6.65)	5.20; (3.60 to 7.95)

9. Primary Outcome

Title	Parent Targeted Visual Analog Scale (PTSVAS) - Scale 3
Description	The parent or caretaker identifies the three most troublesome, RTT-specific, "target" symptoms, such as inattention or breath-holding. This allows the problems that are of concern to parents and the family to be targeted in the trial. In this study the caregiver will choose three target symptoms at baseline and then rate changes in severity of each target symptom on a visual analog scale (VAS). The VAS is a 10 cm line, where a target symptom is anchored on one end with the description "the best it has ever been" and on the other with the description "the worst it has ever been." The parent was asked to marked on the line where they felt their child's symptoms currently fit best. This mark was measured as recorded as a numeric value from 0.00-10.00 cm. The higher the value, the worse the symptom.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention	Number Analyzed	15 participants	15 participants
		7.85; (5.70 to 8.70)	5.70; (4.50 to 9.65)
Visit 2 - First Intervention	Number Analyzed	12 participants	13 participants
		4.70; (4.48 to 8.30)	5.00; (2.55 to 5.40)
Visit 3 - First Intervention	Number Analyzed	15 participants	15 participants
		5.65; (3.65 to 9.00)	5.20; (3.50 to 9.40)
Visit 4 - First Intervention	Number Analyzed	11 participants	11 participants
		4.15; (2.90 to 6.05)	5.35; (3.50 to 8.65)
Visit 5 - First Intervention	Number Analyzed	15 participants	15 participants
		5.00; (4.40 to 7.40)	5.10; (4.00 to 8.20)
Visit 6 - Second Intervention	Number Analyzed	14 participants	15 participants
		6.20; (4.70 to 8.35)	5.35; (4.05 to 9.05)
Visit 7 - Second Intervention	Number Analyzed	11 participants	13 participants
		4.80; (3.15 to 7.30)	4.95; (2.95 to 7.05)
Visit 8 - Second Intervention	Number Analyzed	15 participants	15 participants
		4.85; (3.80 to 8.15)	5.15; (1.75 to 7.10)
Visit 9 - Second Intervention	Number Analyzed	13 participants	12 participants
		4.60; (3.15 to 7.90)	5.25; (3.35 to 7.10)
Visit 10 - Second Intervention	Number Analyzed	14 participants	14 participants
		4.13; (1.10 to 8.45)	4.55; (2.95 to 5.45)
Follow-up	Number Analyzed	9 participants	12 participants
		4.55; (2.20 to 7.00)	5.10; (3.20 to 8.03)

10. Primary Outcome

Title	Kerr Clinical Severity Scale
Description	The Kerr clinical severity scale (Kerr scale) is a quantitative measure of global disease severity. The Kerr scale is a summation of individual items related to Rett syndrome phenotypic characteristics. The items are based on the severity or degree of abnormality of each characteristic on a discrete scale (0, 1, 2) with the highest level corresponding to the most severe or most abnormal presentations. The possible range of scores is 0-48. The higher the score, the more severe the symptoms.
Time Frame	At the start and end of each 20-week treatment period

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention	Number Analyzed	15 participants	15 participants
		16.50; (13.00 to 20.00)	18.00; (12.00 to 22.00)
Visit 5 - First Intervention	Number Analyzed	15 participants	15 participants
		15.00; (13.00 to 21.00)	18.00; (14.00 to 22.00)
Visit 6 - Second Intervention	Number Analyzed	15 participants	15 participants
		15.00; (12.00 to 20.00)	19.00; (16.00 to 22.00)
Visit 10 - Second Intervention	Number Analyzed	15 participants	14 participants
		14.00; (13.00 to 22.00)	20.00; (17.00 to 22.00)

11. Secondary Outcome

Title	Rett Syndrome Behavior Questionnaire (RSBQ)
Description	The RSBQ is a parent-completed measure of abnormal behaviors typically observed in individuals with RTT. Each item, grouped into eight subscales, is scored on a Likert scale of 0-2, according to how well the item describes the individual's behavior. A score of "0" indicates the described item is "not true," a score of "1" indicates the described item is "somewhat or sometimes true," and a score of "2" indicates the described item is "very true or often true." The total sum of each subscale is reported. The higher the score, the more severe the symptoms of that subscale in the participant. The range for each subscale is as follows: General Mood: 0-16 Body rocking and expressionless face: 0-14 Hand behaviors: 0-12 Breathing Problems: 0-10 Repetitive Face Movements: 0-8 Night-time behaviors: 0-6 Walking Standing: 0-4 The fear/anxiety subscale was used as a primary outcome measure in this study and results can be found in that section.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1- First Intervention: General Mood	Number Analyzed	15 participants	15 participants
		7.00; (4.00 to 11.00)	4.00; (3.00 to 7.00)
Visit 2- First Intervention: General Mood	Number Analyzed	15 participants	15 participants
		5.00; (3.00 to 8.00)	3.00; (1.00 to 4.00)
Visit 3- First Intervention: General Mood	Number Analyzed	15 participants	15 participants
		6.00; (1.00 to 8.00)	2.00; (1.00 to 4.00)
Visit 4- First Intervention: General Mood	Number Analyzed	15 participants	15 participants
		5.00; (3.00 to 8.00)	2.00; (1.00 to 5.00)
Visit 5- First Intervention: General Mood	Number Analyzed	15 participants	15 participants
		5.00; (1.00 to 8.00)	3.00; (1.00 to 6.00)
Visit 6- Second Intervention: General Mood	Number Analyzed	15 participants	15 participants
		4.00; (2.00 to 8.00)	4.00; (2.00 to 6.00)
Visit 7- Second Intervention: General Mood	Number Analyzed	14 participants	15 participants
		5.50; (2.00 to 7.00)	2.00; (1.00 to 5.00)
Visit 8- Second Intervention: General Mood	Number Analyzed	15 participants	15 participants
		5.00; (2.00 to 8.00)	2.00; (1.00 to 4.00)
Visit 9- Second Intervention: General Mood	Number Analyzed	15 participants	15 participants
		6.00; (3.00 to 8.00)	1.00; (1.00 to 5.00)
Visit 10- Second Intervention: General Mood	Number Analyzed	14 participants	14 participants
		4.00; (2.00 to 8.00)	2.50; (1.00 to 6.00)
Follow-up: General Mood	Number Analyzed	14 participants	14 participants
		5.50; (3.00 to 6.00)	2.00; (1.00 to 4.00)
Visit 1- First Intervention: Body Rocking	Number Analyzed	15 participants	15 participants
		6.00; (5.00 to 10.00)	4.00; (4.00 to 6.00)
Visit 2- First Intervention: Body Rocking	Number Analyzed	15 participants	15 participants
		5.00; (4.00 to 7.00)	4.00; (3.00 to 6.00)
Visit 3- First Intervention: Body Rocking	Number Analyzed	15 participants	15 participants
		5.00; (3.00 to 8.00)	3.00; (2.00 to 6.00)
Visit 4- First Intervention: Body Rocking	Number Analyzed	15 participants	15 participants
		6.00; (4.00 to 7.00)	4.00; (2.00 to 5.00)
Visit 5- First Intervention: Body Rocking	Number Analyzed	15 participants	15 participants
		5.00; (3.00 to 8.00)	4.00; (2.00 to 5.00)
Visit 6- Second Intervention: Body Rocking	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 7.00)	4.00; (3.00 to 5.00)
Visit 7- Second Intervention: Body Rocking	Number Analyzed	14 participants	15 participants
		5.00; (3.00 to 7.00)	3.00; (3.00 to 5.00)
Visit 8- Second Intervention: Body Rocking	Number Analyzed	15 participants	15 participants
		5.00; (3.00 to 6.00)	4.00; (2.00 to 5.00)
Visit 9- Second Intervention: Body Rocking	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 7.00)	3.00; (2.00 to 5.00)
Visit 10- Second Intervention: Body Rocking	Number Analyzed	14 participants	14 participants
		5.00; (3.00 to 7.00)	4.00; (2.00 to 5.00)
Followup: Body Rocking	Number Analyzed	14 participants	14 participants
		4.50; (3.00 to 7.00)	4.00; (2.00 to 5.00)
Visit 1- First Intervention: Hand Behaviors	Number Analyzed	15 participants	15 participants
		8.00; (7.00 to 10.00)	8.00; (5.00 to 10.00)
Visit 2- First Intervention: Hand Behaviors	Number Analyzed	15 participants	15 participants
		9.00; (6.00 to 9.00)	8.00; (6.00 to 10.00)
Visit 3- First Intervention: Hand Behaviors	Number Analyzed	15 participants	15 participants
		8.00; (7.00 to 10.00)	8.00; (5.00 to 9.00)
Visit 4- First Intervention: Hand Behaviors	Number Analyzed	15 participants	15 participants
		8.00; (6.00 to 9.00)	9.00; (6.00 to 9.00)
Visit 5- First Intervention: Hand Behaviors	Number Analyzed	15 participants	15 participants
		8.00; (6.00 to 10.00)	9.00; (5.00 to 10.00)
Visit 6- Second Intervention: Hand Behaviors	Number Analyzed	15 participants	15 participants
		9.00; (6.00 to 10.00)	8.00; (7.00 to 10.00)
Visit 7- Second Intervention: Hand Behaviors	Number Analyzed	14 participants	15 participants
		8.00; (5.00 to 10.00)	9.00; (6.00 to 9.00)
Visit 8- Second Intervention: Hand Behaviors	Number Analyzed	15 participants	15 participants
		8.00; (6.00 to 9.00)	9.00; (6.00 to 9.00)
Visit 9- Second Intervention: Hand Behaviors	Number Analyzed	15 participants	15 participants
		8.00; (5.00 to 9.00)	7.00; (6.00 to 10.00)
Visit 10- Second Intervention: Hand Behaviors	Number Analyzed	14 participants	14 participants
		7.00; (6.00 to 9.00)	9.00; (6.00 to 10.00)
Follow-up: Hand Behaviors	Number Analyzed	14 participants	14 participants
		7.50; (7.00 to 9.00)	8.50; (6.00 to 10.00)
Visit 1- First Intervention: Breathing Problems	Number Analyzed	15 participants	15 participants
		6.00; (3.00 to 9.00)	4.00; (3.00 to 7.00)
Visit 2- First Intervention: Breathing Problems	Number Analyzed	15 participants	15 participants
		4.00; (2.00 to 8.00)	4.00; (2.00 to 6.00)
Visit 3- First Intervention: Breathing Problems	Number Analyzed	15 participants	15 participants
		5.00; (2.00 to 8.00)	4.00; (2.00 to 6.00)
Visit 4- First Intervention: Breathing Problems	Number Analyzed	15 participants	15 participants
		5.00; (3.00 to 7.00)	5.00; (2.00 to 7.00)
Visit 5- First Intervention: Breathing Problems	Number Analyzed	15 participants	15 participants
		5.00; (1.00 to 8.00)	4.00; (2.00 to 7.00)
Visit 6- Second Intervention: Breathing Problems	Number Analyzed	15 participants	15 participants
		6.00; (2.00 to 9.00)	4.00; (1.00 to 8.00)
Visit 7- Second Intervention: Breathing Problems	Number Analyzed	14 participants	15 participants
		4.50; (2.00 to 7.00)	3.00; (1.00 to 7.00)
Visit 8- Second Intervention: Breathing Problems	Number Analyzed	15 participants	15 participants
		6.00; (3.00 to 7.00)	3.00; (1.00 to 6.00)
Visit 9- Second Intervention: Breathing Problems	Number Analyzed	15 participants	15 participants
		5.00; (2.00 to 7.00)	3.00; (0.00 to 5.00)
Visit 10- Second Intervention: Breathing Problems	Number Analyzed	14 participants	14 participants
		6.00; (3.00 to 7.00)	4.00; (1.00 to 5.00)
Follow-up: Breathing Problems	Number Analyzed	14 participants	14 participants
		5.00; (2.00 to 7.00)	3.00; (0.00 to 4.00)
Visit 1- First Intervention: Repetitive Face Movem	Number Analyzed	15 participants	15 participants
		2.00; (1.00 to 5.00)	2.00; (2.00 to 4.00)
Visit 2- First Intervention: Repetitive Face Movem	Number Analyzed	15 participants	15 participants
		2.00; (0.00 to 4.00)	2.00; (2.00 to 4.00)
Visit 3- First Intervention: Repetitive Face Movem	Number Analyzed	15 participants	15 participants
		3.00; (1.00 to 4.00)	3.00; (2.00 to 4.00)
Visit 4- First Intervention: Repetitive Face Movem	Number Analyzed	15 participants	15 participants
		2.00; (1.00 to 5.00)	2.00; (1.00 to 4.00)
Visit 5- First Intervention: Repetitive Face Movem	Number Analyzed	15 participants	15 participants
		3.00; (0.00 to 5.00)	2.00; (0.00 to 4.00)
Visit 6- Second Intervention: Repetitive Face Mov	Number Analyzed	15 participants	15 participants
		3.00; (2.00 to 5.00)	3.00; (2.00 to 4.00)
Visit 7- Second Intervention: Repetitive Face Mov	Number Analyzed	14 participants	15 participants
		3.00; (1.00 to 5.00)	2.00; (0.00 to 4.00)
Visit 8- Second Intervention: Repetitive Face Mov	Number Analyzed	15 participants	15 participants
		3.00; (2.00 to 4.00)	2.00; (1.00 to 4.00)
Visit 9- Second Intervention: Repetitive Face Mov	Number Analyzed	15 participants	15 participants
		3.00; (1.00 to 5.00)	2.00; (0.00 to 3.00)
Visit 10- Second Intervention: Repetitive Face Mov	Number Analyzed	14 participants	14 participants
		3.00; (1.00 to 5.00)	1.50; (1.00 to 4.00)
Follow-up: Repetitive Face Movements	Number Analyzed	14 participants	14 participants
		2.00; (1.00 to 4.00)	2.00; (0.00 to 2.00)
Visit 1- First Intervention: Night time Behaviors	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 2.00)	1.00; (0.00 to 2.00)
Visit 2- First Intervention: Night time Behaviors	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 3.00)	1.00; (0.00 to 2.00)
Visit 3- First Intervention: Night time Behaviors	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 0.00)	0.00; (0.00 to 2.00)
Visit 4- First Intervention: Night time Behaviors	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 2.00)	0.00; (0.00 to 1.00)
Visit 5- First Intervention: Night time Behaviors	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 2.00)	1.00; (0.00 to 2.00)
Visit 6- Second Intervention: Night time Behavior	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 2.00)	1.00; (0.00 to 2.00)
Visit 7- Second Intervention: Night time Behavior	Number Analyzed	14 participants	15 participants
		0.00; (0.00 to 2.00)	0.00; (0.00 to 1.00)
Visit 8- Second Intervention: Night time Behavior	Number Analyzed	15 participants	15 participants
		1.00; (0.00 to 2.00)	0.00; (0.00 to 1.00)
Visit 9- Second Intervention: Night time Behavior	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 3.00)	0.00; (0.00 to 1.00)
Visit 10- Second Intervention: Night time Behavior	Number Analyzed	14 participants	14 participants
		0.00; (0.00 to 1.00)	0.00; (0.00 to 1.00)
Follow-up: Night time Behaviors	Number Analyzed	14 participants	14 participants
		0.00; (0.00 to 1.00)	0.00; (0.00 to 1.00)
Visit 1- First Intervention: Walking/Standing	Number Analyzed	15 participants	15 participants
		2.00; (2.00 to 3.00)	2.00; (1.00 to 3.00)
Visit 2- First Intervention: Walking/Standing	Number Analyzed	15 participants	15 participants
		2.00; (1.00 to 3.00)	2.00; (1.00 to 3.00)
Visit 3- First Intervention: Walking/Standing	Number Analyzed	15 participants	15 participants
		2.00; (2.00 to 2.00)	2.00; (1.00 to 3.00)
Visit 4- First Intervention: Walking/Standing	Number Analyzed	15 participants	15 participants
		2.00; (1.00 to 3.00)	2.00; (1.00 to 3.00)
Visit 5- First Intervention: Walking/Standing	Number Analyzed	15 participants	15 participants
		2.00; (1.00 to 3.00)	2.00; (1.00 to 3.00)
Visit 6- Second Intervention: Walking/Standing	Number Analyzed	15 participants	15 participants
		2.00; (2.00 to 3.00)	2.00; (1.00 to 2.00)
Visit 7- Second Intervention: Walking/Standing	Number Analyzed	14 participants	15 participants
		2.00; (2.00 to 3.00)	2.00; (1.00 to 3.00)
Visit 8- Second Intervention: Walking/Standing	Number Analyzed	15 participants	15 participants
		2.00; (1.00 to 3.00)	2.00; (1.00 to 3.00)
Visit 9- Second Intervention: Walking/Standing	Number Analyzed	15 participants	15 participants
		3.00; (1.00 to 3.00)	2.00; (1.00 to 2.00)
Visit 10- Second Intervention: Walking/Standing	Number Analyzed	14 participants	14 participants
		1.50; (1.00 to 3.00)	2.00; (1.00 to 2.00)
Follow-up: Walking/Standing	Number Analyzed	14 participants	14 participants
		2.00; (1.00 to 3.00)	2.00; (2.00 to 3.00)

12. Secondary Outcome

Title	Anxiety, Depression, and Mood Scale (ADAMS)
Description	Remaining subscales of the ADAMS that are not primary outcome measures include: Manic/hyperactive, Depressed mood, General anxiety, Obsessive/compulsive behavior. The range for each subscale is as follows: Manic/Hyperactive Behavior: 0-15 Depressed Mood: 0-21 General Anxiety: 0-21 Obsessive/Compulsive Behavior: 0-9 The higher the score for each subscale, the more problematic the behavior.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1- First Intervention: Manic/Hyperactive	Number Analyzed	15 participants	15 participants
		8.00; (5.00 to 11.00)	7.00; (5.00 to 9.00)
Visit 2- First Intervention: Manic/Hyperactive	Number Analyzed	15 participants	15 participants
		7.00; (3.00 to 10.00)	7.00; (4.00 to 9.00)
Visit 3- First Intervention: Manic/Hyperactive	Number Analyzed	15 participants	15 participants
		7.00; (3.00 to 9.00)	6.00; (4.00 to 7.00)
Visit 4- First Intervention: Manic/Hyperactive	Number Analyzed	15 participants	15 participants
		7.00; (5.00 to 9.00)	5.00; (4.00 to 7.00)
Visit 5- First Intervention: Manic/Hyperactive	Number Analyzed	15 participants	15 participants
		7.00; (4.00 to 9.00)	4.00; (3.00 to 7.00)
Visit 6- Second Intervention: Manic/Hyperactive	Number Analyzed	15 participants	15 participants
		8.00; (3.00 to 9.00)	6.00; (5.00 to 8.00)
Visit 7- Second Intervention: Manic/Hyperactive	Number Analyzed	14 participants	15 participants
		6.50; (3.00 to 9.00)	5.00; (3.00 to 7.00)
Visit 8- Second Intervention: Manic/Hyperactive	Number Analyzed	15 participants	15 participants
		6.00; (3.00 to 8.00)	5.00; (3.00 to 6.00)
Visit 9- Second Intervention: Manic/Hyperactive	Number Analyzed	15 participants	15 participants
		6.00; (4.00 to 9.00)	4.00; (1.00 to 6.00)
Visit 10- First Intervention: Manic/Hyperactive	Number Analyzed	14 participants	14 participants
		5.00; (2.00 to 7.00)	4.50; (2.00 to 7.00)
Follow-up: Manic/Hyperactive Subscale	Number Analyzed	14 participants	14 participants
		5.00; (3.00 to 9.00)	5.00; (3.00 to 7.00)
Visit 1- First Intervention: Depressed Mood	Number Analyzed	15 participants	15 participants
		2.00; (2.00 to 7.00)	4.00; (3.00 to 6.00)
Visit 2- First Intervention: Depressed Mood	Number Analyzed	15 participants	15 participants
		4.00; (1.00 to 5.00)	5.00; (2.00 to 6.00)
Visit 3- First Intervention: Depressed Mood	Number Analyzed	15 participants	15 participants
		3.00; (1.00 to 5.00)	3.00; (2.00 to 5.00)
Visit 4- First Intervention: Depressed Mood	Number Analyzed	15 participants	15 participants
		2.00; (1.00 to 4.00)	3.00; (1.00 to 5.00)
Visit 5- First Intervention: Depressed Mood	Number Analyzed	15 participants	15 participants
		2.00; (1.00 to 4.00)	4.00; (0.00 to 5.00)
Visit 6- Second Intervention: Depressed Mood	Number Analyzed	15 participants	15 participants
		2.00; (0.00 to 5.00)	4.00; (3.00 to 6.00)
Visit 7- Second Intervention: Depressed Mood	Number Analyzed	14 participants	15 participants
		3.00; (0.00 to 6.00)	3.00; (2.00 to 5.00)
Visit 8- Second Intervention: Depressed Mood	Number Analyzed	15 participants	15 participants
		2.00; (1.00 to 5.00)	3.00; (1.00 to 5.00)
Visit 9- Second Intervention: Depressed Mood	Number Analyzed	15 participants	15 participants
		3.00; (0.00 to 4.00)	2.00; (1.00 to 5.00)
Visit 10- Second Intervention: Depressed Mood	Number Analyzed	14 participants	14 participants
		2.00; (1.00 to 4.00)	3.00; (2.00 to 4.00)
Follow-up: Depressed Mood Subscale	Number Analyzed	14 participants	14 participants
		2.00; (0.00 to 5.00)	3.50; (0.00 to 4.00)
Visit 1- First Intervention: General Anxiety	Number Analyzed	15 participants	15 participants
		8.00; (5.00 to 12.00)	6.00; (5.00 to 12.00)
Visit 2- First Intervention: General Anxiety	Number Analyzed	15 participants	15 participants
		6.00; (4.00 to 12.00)	7.00; (3.00 to 10.00)
Visit 3- First Intervention: General Anxiety	Number Analyzed	15 participants	15 participants
		6.00; (3.00 to 9.00)	6.00; (3.00 to 9.00)
Visit 4- First Intervention: General Anxiety	Number Analyzed	15 participants	15 participants
		5.00; (2.00 to 11.00)	5.00; (2.00 to 8.00)
Visit 5- First Intervention: General Anxiety	Number Analyzed	15 participants	15 participants
		5.00; (2.00 to 10.00)	5.00; (3.00 to 7.00)
Visit 6- Second Intervention: General Anxiety	Number Analyzed	15 participants	15 participants
		6.00; (3.00 to 9.00)	7.00; (3.00 to 11.00)
Visit 7- Second Intervention: General Anxiety	Number Analyzed	14 participants	15 participants
		6.00; (2.00 to 8.00)	5.00; (1.00 to 7.00)
Visit 8- Second Intervention: General Anxiety	Number Analyzed	15 participants	15 participants
		6.00; (3.00 to 9.00)	4.00; (2.00 to 8.00)
Visit 9- Second Intervention: General Anxiety	Number Analyzed	15 participants	15 participants
		4.00; (2.00 to 8.00)	3.00; (1.00 to 6.00)
Visit 10- Second Intervention: General Anxiety	Number Analyzed	14 participants	14 participants
		4.00; (2.00 to 7.00)	4.00; (2.00 to 5.00)
Follow-up: General Anxiety Subscale	Number Analyzed	14 participants	14 participants
		5.50; (3.00 to 9.00)	4.00; (1.00 to 6.00)
Visit 1- First Intervention: Obsessive Compulsive	Number Analyzed	15 participants	15 participants
		4.00; (3.00 to 6.00)	3.00; (0.00 to 5.00)
Visit 2- First Intervention: Obsessive Compulsive	Number Analyzed	15 participants	15 participants
		4.00; (2.00 to 4.00)	4.00; (1.00 to 4.00)
Visit 3- First Intervention: Obsessive Compulsive	Number Analyzed	15 participants	15 participants
		4.00; (1.00 to 4.00)	4.00; (1.00 to 4.00)
Visit 4- First Intervention: Obsessive Compulsive	Number Analyzed	15 participants	15 participants
		3.00; (3.00 to 4.00)	3.00; (1.00 to 4.00)
Visit 5- First Intervention: Obsessive Compulsive	Number Analyzed	15 participants	15 participants
		3.00; (2.00 to 4.00)	3.00; (0.00 to 4.00)
Visit 6- Second Intervention: Obsessive Compulsive	Number Analyzed	15 participants	15 participants
		3.00; (1.00 to 5.00)	3.00; (1.00 to 5.00)
Visit 7- Second Intervention: Obsessive Compulsive	Number Analyzed	14 participants	15 participants
		3.00; (2.00 to 6.00)	3.00; (0.00 to 4.00)
Visit 8- Second Intervention: Obsessive Compulsive	Number Analyzed	15 participants	15 participants
		3.00; (2.00 to 4.00)	3.00; (0.00 to 4.00)
Visit 9- Second Intervention: Obsessive Compulsive	Number Analyzed	15 participants	15 participants
		3.00; (1.00 to 3.00)	2.00; (0.00 to 4.00)
Visit 10- First Intervention: Obsessive Compulsive	Number Analyzed	14 participants	14 participants
		2.00; (1.00 to 4.00)	2.50; (0.00 to 5.00)
Follow-up: Obsessive Compulsive Behavior Subscale	Number Analyzed	14 participants	14 participants
		3.50; (2.00 to 4.00)	3.00; (0.00 to 4.00)

13. Secondary Outcome

Title	Mullen Scales of Early Learning (MSEL)
Description	The MSEL is a standardized developmental test for children ages 3 to 68 months consisting of five subscales: gross motor, fine motor, visual reception, expressive language, and receptive language. The raw score is reported for each subscale domain. The potential score ranges are as follows: Visual Reception: 33 items, score range=0-50, Fine Motor: 30 items, score range= 0-49, Receptive Language: 33 items, score range= 0-48, Expressive Language: 28 items, score range= 0-50. The gross motor subscale was not included in this population. A higher raw score indicates more advanced abilities in that section.
Time Frame	At the start and end of each 20-week treatment period

Outcome Measure Data

Analysis Population Description

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

In some cases, the number of participants analyzed is less than 15 for each group due to subject's inability or unwillingness to complete the testing.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1- First Intervention: Visual Reception	Number Analyzed	15 participants	15 participants
		17.00; (15.00 to 25.00)	26.00; (18.00 to 42.00)
Visit 5- First Intervention: Visual Reception	Number Analyzed	15 participants	14 participants
		26.00; (16.00 to 33.00)	39.50; (20.00 to 49.00)
Visit 6- Second Intervention: Visual Reception	Number Analyzed	15 participants	15 participants
		23.00; (20.00 to 36.00)	42.00; (23.00 to 48.00)
Visit 10: Visual Reception Raw Score	Number Analyzed	15 participants	13 participants
		28.00; (25.00 to 41.00)	44.00; (28.00 to 48.00)
Visit 1- First Intervention: Fine Motor	Number Analyzed	15 participants	15 participants
		10.00; (7.00 to 14.00)	7.00; (6.00 to 17.00)
Visit 5- First Intervention: Fine Motor	Number Analyzed	15 participants	15 participants
		9.00; (6.00 to 13.00)	7.00; (3.00 to 15.00)
Visit 6- Second Intervention: Fine Motor	Number Analyzed	15 participants	15 participants
		11.00; (7.00 to 13.00)	10.00; (5.00 to 17.00)
Visit 10- Second Intervention: Fine Motor	Number Analyzed	15 participants	14 participants
		9.00; (6.00 to 13.00)	8.50; (4.00 to 13.00)
Visit 1- First Intervention: Receptive Language	Number Analyzed	15 participants	14 participants
		20.00; (17.00 to 31.00)	25.50; (17.00 to 40.00)
Visit 5- First Intervention: Receptive Language	Number Analyzed	15 participants	15 participants
		30.00; (19.00 to 33.00)	32.00; (25.00 to 44.00)
Visit 6- Second Intervention: Receptive Language	Number Analyzed	15 participants	15 participants
		31.00; (24.00 to 35.00)	38.00; (33.00 to 47.00)
Visit 10- Second Intervention: Receptive Language	Number Analyzed	15 participants	14 participants
		31.00; (26.00 to 38.00)	36.50; (27.00 to 44.00)
Visit 1- First Intervention: Expressive Language	Number Analyzed	15 participants	15 participants
		8.00; (5.00 to 9.00)	9.00; (6.00 to 11.00)
Visit 5- First Intervention: Expressive Language	Number Analyzed	15 participants	15 participants
		9.00; (5.00 to 11.00)	8.00; (5.00 to 11.00)
Visit 6- Second Intervention: Expressive Language	Number Analyzed	15 participants	15 participants
		6.00; (5.00 to 9.00)	10.00; (5.00 to 12.00)
Visit 10- Second Intervention: Expressive Language	Number Analyzed	15 participants	14 participants
		8.00; (5.00 to 10.00)	8.00; (6.00 to 12.00)

14. Secondary Outcome

Title	Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
Description	The VABS-II is a survey designed to assess personal and social functioning. Within each domain (Communication, Daily Living Skills, Socialization, and Motor Skills), items can given a score of "2" if the participant successfully performs the activity usually; a "1" if the participant successfully performs the activity sometimes, or needs reminders; a "0" if the participant never performs the activity, and a "DK" if the parent/caregiver is unsure of the participant's ability for an item. The raw scores in each sub-domain are reported and the ranges for these are as follows: [Communication Domain], Receptive Language=0-40, Expressive Language=0-108, Written Language=0-50; [Daily Living Skills Domain], Personal=0-82, Domestic=0-48, Community=0-88; [Socialization Domain], Interpersonal Relationships=0-76, Play and Leisure Time=0-62, Coping Skills=0-60; [Motor Skills Domain]: Gross Motor Skills=0-80, Fine Motor Skills=0-72. A higher score indicates more advanced abilities.
Time Frame	At the start and end of each 20-week treatment period

Outcome Measure Data

Analysis Population Description

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention: Receptive	Number Analyzed	15 participants	15 participants
		13.00; (9.00 to 16.00)	18.00; (13.00 to 20.00)
Visit 5 - First Intervention: Receptive	Number Analyzed	15 participants	15 participants
		15.00; (14.00 to 20.00)	21.00; (17.00 to 23.00)
Visit 6 - Second Intervention: Receptive Language	Number Analyzed	15 participants	14 participants
		18.00; (13.00 to 20.00)	22.00; (20.00 to 24.00)
Visit 10 - Second Intervention: Receptive Language	Number Analyzed	15 participants	14 participants
		20.00; (15.00 to 24.00)	24.50; (20.00 to 29.00)
Visit 1 - First Intervention: Expressive	Number Analyzed	15 participants	15 participants
		16.00; (12.00 to 17.00)	18.00; (13.00 to 25.00)
Visit 5 - First Intervention: Expressive	Number Analyzed	15 participants	15 participants
		17.00; (13.00 to 23.00)	22.00; (18.00 to 29.00)
Visit 6 - Second Intervention: Expressive Lang.	Number Analyzed	15 participants	14 participants
		18.00; (11.00 to 23.00)	25.00; (18.00 to 31.00)
Visit 10 - Second Intervention: Expressive Lang.	Number Analyzed	15 participants	14 participants
		20.00; (15.00 to 28.00)	24.00; (23.00 to 34.0)
Visit 1 - First Intervention: Written	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 1.00)	4.00; (0.00 to 7.00)
Visit 5 - First Intervention: Written	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 5.00)	5.00; (0.00 to 9.00)
Visit 6: - Second Intervention Written Language	Number Analyzed	15 participants	14 participants
		4.00; (1.00 to 7.00)	7.00; (2.00 to 9.00)
Visit 10 - Second Intervention: Written Language	Number Analyzed	15 participants	14 participants
		6.00; (0.00 to 8.00)	7.00; (4.00 to 10.00)
Visit 1 - First Intervention: Personal	Number Analyzed	15 participants	15 participants
		9.00; (7.00 to 10.00)	8.00; (6.00 to 10.00)
Visit 5 - First Intervention: Personal	Number Analyzed	15 participants	15 participants
		10.00; (8.00 to 13.00)	9.00; (7.00 to 13.00)
Visit 6 - Second Intervention: Personal	Number Analyzed	15 participants	14 participants
		9.00; (8.00 to 14.00)	8.50; (8.00 to 16.00)
Visit 10 - Second Intervention: Personal	Number Analyzed	15 participants	14 participants
		10.00; (7.00 to 14.00)	9.50; (8.00 to 10.00)
Visit 1 - First Intervention: Domestic	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 0.00)	0.00; (0.00 to 1.00)
Visit 5 - First Intervention: Domestic	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 0.00)	0.00; (0.00 to 1.00)
Visit 6 - Second Intervention: Domestic	Number Analyzed	15 participants	14 participants
		0.00; (0.00 to 0.00)	0.00; (0.00 to 2.00)
Visit 10 - Second Intervention: Domestic	Number Analyzed	15 participants	14 participants
		0.00; (0.00 to 1.00)	0.00; (0.00 to 1.00)
Visit 1 - First Intervention: Community	Number Analyzed	15 participants	15 participants
		0.00; (0.00 to 1.00)	3.00; (2.00 to 6.00)
Visit 5 - First Intervention: Community	Number Analyzed	15 participants	15 participants
		1.00; (0.00 to 2.00)	3.00; (2.00 to 4.00)
Visit 6 - Second Intervention: Community	Number Analyzed	15 participants	14 participants
		1.00; (0.00 to 3.00)	5.00; (2.00 to 7.00)
Visit 10 - Second Intervention: Community	Number Analyzed	15 participants	14 participants
		2.00; (0.00 to 5.00)	5.00; (2.00 to 7.00)
Visit 1 - First Intervention: Interpersonal Rel.	Number Analyzed	15 participants	15 participants
		18.00; (15.00 to 21.00)	21.00; (17.00 to 24.00)
Visit 5 - First Intervention: Interpersonal Rel.	Number Analyzed	15 participants	15 participants
		18.00; (15.00 to 21.00)	22.00; (17.00 to 25.00)
Visit 6 - Second Intervention: Interpersonal Rel.	Number Analyzed	15 participants	14 participants
		19.00; (15.00 to 21.00)	21.00; (20.00 to 26.00)
Visit 10 - Second Intervention: Interpersonal Rel.	Number Analyzed	15 participants	14 participants
		20.00; (16.00 to 23.00)	22.50; (19.00 to 27.00)
Visit 1 - First Intervention: Play and Leisure	Number Analyzed	15 participants	15 participants
		8.00; (7.00 to 12.00)	13.00; (11.00 to 17.00)
Visit 5 - First Intervention: Play and Leisure	Number Analyzed	15 participants	15 participants
		11.00; (9.00 to 12.00)	12.00; (11.00 to 16.00)
Visit 6 - Second Intervention: Play and Leisure	Number Analyzed	15 participants	14 participants
		12.00; (9.00 to 14.00)	13.00; (11.00 to 16.00)
Visit 10 - Second Intervention: Play and Leisure	Number Analyzed	15 participants	14 participants
		11.00; (9.00 to 15.00)	12.50; (10.00 to 16.00)
Visit 1 - First Intervention: Coping Skills	Number Analyzed	15 participants	15 participants
		3.00; (2.00 to 4.00)	3.00; (3.00 to 4.00)
Visit 5 - First Intervention: Coping Skills	Number Analyzed	15 participants	15 participants
		2.00; (2.00 to 4.00)	4.00; (2.00 to 6.00)
Visit 6 - Second Intervention: Coping Skills	Number Analyzed	15 participants	14 participants
		3.00; (3.00 to 4.00)	6.00; (3.00 to 6.00)
Visit 10 - Second Intervention: Coping Skills	Number Analyzed	15 participants	14 participants
		4.00; (3.00 to 5.00)	4.50; (3.00 to 8.00)
Visit 1 - First Intervention: Gross Motor	Number Analyzed	15 participants	15 participants
		31.00; (21.00 to 37.00)	10.00; (7.00 to 43.00)
Visit 5 - First Intervention: Gross Motor	Number Analyzed	15 participants	15 participants
		34.00; (22.00 to 42.00)	10.00; (8.00 to 36.00)
Visit 6 - Second Intervention: Gross Motor	Number Analyzed	15 participants	14 participants
		27.00; (12.00 to 45.00)	11.50; (8.00 to 34.00)
Visit 10 - Second Intervention: Gross Motor	Number Analyzed	15 participants	14 participants
		27.00; (14.00 to 46.00)	10.50; (8.00 to 30.00)
Visit 1 - First Intervention: Fine Motor	Number Analyzed	15 participants	15 participants
		6.00; (3.00 to 8.00)	2.00; (1.00 to 14.00)
Visit 5 - First Intervention: Fine Motor	Number Analyzed	15 participants	15 participants
		6.00; (4.00 to 9.00)	3.00; (2.00 to 15.00)
Visit 6 - Second Intervention: Fine Motor	Number Analyzed	15 participants	14 participants
		7.00; (3.00 to 10.00)	4.00; (2.00 to 16.00)
Visit 10 - Second Intervention: Fine Motor	Number Analyzed	15 participants	14 participants
		5.00; (2.00 to 9.00)	4.00; (2.00 to 8.00)

15. Secondary Outcome

Title	Communication and Symbolic Behavior Scales - Developmental Profile (CSBS-DP)
Description	The CSBS-DP was designed to measure early communication and symbolic skills in infants and young children (that is, functional communication skills of 6 month to 2 year olds). The CSBS-DP measures skills from three composites: (a) Social (emotion, eye gaze, and communication); (b) Speech (sounds and words); and (c) Symbolic (understanding and object use) and asks about developmental milestones. The data reported are the composite scores for these three categories. The possible scores for the three composite categories are as follows: Social Composite = 0-48; Speech Composite = 0-40; Symbolic Composite = 0-51. A higher score indicates more advanced abilities in that area.
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention: Social	Number Analyzed	15 participants	15 participants
		19.00; (16.00 to 25.00)	22.00; (19.00 to 26.00)
Visit 2: Social Composite Score	Number Analyzed	15 participants	15 participants
		20.00; (15.00 to 23.00)	24.00; (20.00 to 28.00)
Visit 3: Social Composite Score	Number Analyzed	15 participants	15 participants
		18.00; (13.00 to 25.00)	24.00; (21.00 to 30.00)
Visit 4: Social Composite Score	Number Analyzed	15 participants	15 participants
		18.00; (17.00 to 25.00)	24.00; (21.00 to 31.00)
Visit 5: Social Composite Score	Number Analyzed	15 participants	15 participants
		20.00; (15.00 to 29.00)	23.00; (21.00 to 34.00)
Visit 6 - Second Intervention: Social	Number Analyzed	15 participants	15 participants
		18.00; (15.00 to 28.00)	28.00; (22.00 to 34.00)
Visit 7 - Second Intervention: Social	Number Analyzed	14 participants	15 participants
		20.00; (16.00 to 26.00)	25.00; (21.00 to 34.00)
Visit 8 - Second Intervention: Social	Number Analyzed	15 participants	14 participants
		21.00; (17.00 to 27.00)	27.00; (25.00 to 36.00)
Visit 9 - Second Intervention: Social	Number Analyzed	15 participants	15 participants
		21.00; (17.00 to 29.00)	29.00; (25.00 to 34.00)
Visit 10 - Second Intervention: Social	Number Analyzed	14 participants	14 participants
		22.50; (19.00 to 30.00)	27.00; (23.00 to 36.00)
Follow-up: Social Composite Score	Number Analyzed	14 participants	15 participants
		22.50; (18.00 to 25.00)	28.00; (26.00 to 36.00)
Visit 1 - First Intervention: Speech	Number Analyzed	15 participants	15 participants
		4.00; (2.00 to 8.00)	7.00; (2.00 to 10.00)
Visit 2 - First Intervention: Speech	Number Analyzed	15 participants	15 participants
		3.00; (1.00 to 9.00)	5.00; (2.00 to 11.00)
Visit 3 - First Intervention: Speech	Number Analyzed	15 participants	15 participants
		5.00; (1.00 to 6.00)	8.00; (2.00 to 11.00)
Visit 4 - First Intervention: Speech	Number Analyzed	15 participants	15 participants
		5.50; (3.00 to 8.50)	5.00; (2.00 to 10.50)
Visit 5 - First Intervention: Speech	Number Analyzed	15 participants	15 participants
		6.50; (3.00 to 7.50)	8.00; (2.00 to 11.50)
Visit 6 - Second Intervention: Speech	Number Analyzed	15 participants	15 participants
		4.00; (1.00 to 6.00)	8.50; (2.00 to 11.50)
Visit 7 - Second Intervention: Speech	Number Analyzed	14 participants	15 participants
		4.00; (2.00 to 5.00)	7.00; (4.00 to 12.00)
Visit 8 - Second Intervention: Speech	Number Analyzed	15 participants	14 participants
		5.00; (1.00 to 7.00)	6.50; (2.00 to 9.00)
Visit 9 - Second Intervention: Speech	Number Analyzed	15 participants	15 participants
		5.00; (2.00 to 8.50)	5.00; (2.00 to 10.00)
Visit 10 - Second Intervention: Speech	Number Analyzed	14 participants	14 participants
		5.00; (3.00 to 7.00)	7.25; (2.50 to 11.00)
Follow-up: Speech Composite Score	Number Analyzed	14 participants	14 participants
		6.00; (2.00 to 9.50)	6.00; (2.00 to 10.50)
Visit 1 - First Intervention: Symbolic	Number Analyzed	15 participants	15 participants
		9.50; (6.50 to 12.50)	14.00; (12.50 to 19.50)
Visit 2 - First Intervention: Symbolic	Number Analyzed	15 participants	15 participants
		10.50; (6.00 to 13.50)	14.50; (11.00 to 17.00)
Visit 3 - First Intervention: Symbolic	Number Analyzed	15 participants	15 participants
		10.50; (4.00 to 13.00)	15.00; (10.00 to 21.00)
Visit 4 - First Intervention: Symbolic	Number Analyzed	15 participants	15 participants
		12.00; (5.50 to 13.50)	14.00; (11.50 to 22.00)
Visit 5 - First Intervention: Symbolic	Number Analyzed	15 participants	15 participants
		11.50; (7.00 to 17.50)	16.50; (11.50 to 23.00)
Visit 6 - Second Intervention: Symbolic	Number Analyzed	15 participants	15 participants
		13.00; (6.50 to 15.00)	18.50; (12.00 to 23.00)
Visit 7 - Second Intervention: Symbolic	Number Analyzed	14 participants	15 participants
		10.25; (6.00 to 13.00)	17.00; (10.00 to 22.00)
Visit 8 - Second Intervention: Symbolic	Number Analyzed	15 participants	14 participants
		11.50; (6.50 to 15.50)	17.00; (9.00 to 20.50)
Visit 9 - Second Intervention: Symbolic	Number Analyzed	15 participants	15 participants
		11.50; (9.00 to 18.50)	18.00; (12.50 to 20.50)
Visit 10 - Second Intervention: Symbolic	Number Analyzed	14 participants	14 participants
		13.75; (8.00 to 17.00)	17.00; (11.00 to 19.00)
Follow-up: Symbolic Composite Score	Number Analyzed	14 participants	14 participants
		14.25; (9.00 to 16.00)	18.00; (13.50 to 19.00)

16. Secondary Outcome

Title	Aberrant Behavior Checklist - Community Edition (ABC-C)
Description	The ABC-C is a global behavior checklist implemented for the measurement of drug and other treatment effects in populations with intellectual disability. Behavior based on 58 items that describe various behavioral problems. Each item is rated on the parents perceived severity of the behavior. The answer options for each item are: 0 = Not a problem; = Problem but slight in degree; = Moderately serious problem; = Severe in degree The measure is broken down into the following subscales with individual ranges as follows: Subscale I (Irritability): 15 items, score range = 0-45 Subscale II (Lethargy): 16 items, score range = 0-48 Subscale III (Stereotypy): 7 items, score range = 0-21 Subscale IV (Hyperactivity): 16 items, score range = 0-48 Subscale V (Inappropriate Speech) was not included in the breakdown because it was not applicable (no participants in the study had verbal language).
Time Frame	Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to caregiver(s) not completing the forms.

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: units on a scale
Visit 1 - First Intervention: Subscale I	Number Analyzed	15 participants	15 participants
		9.00; (6.00 to 22.00)	6.00; (3.00 to 12.00)
Visit 3 - First Intervention: Subscale I	Number Analyzed	15 participants	15 participants
		9.00; (2.00 to 15.00)	4.00; (0.00 to 7.00)
Visit 5 - First Intervention: Subscale I	Number Analyzed	15 participants	15 participants
		7.00; (0.00 to 16.00)	2.00; (0.00 to 6.00)
Visit 6 - Second Intervention: Subscale I	Number Analyzed	15 participants	15 participants
		7.00; (3.00 to 13.00)	4.00; (0.00 to 10.00)
Visit 8 - Second Intervention: Subscale I	Number Analyzed	15 participants	15 participants
		4.00; (1.00 to 17.00)	3.00; (0.00 to 10.00)
Visit 10 - Second Intervention: Subscale I	Number Analyzed	15 participants	14 participants
		5.00; (2.00 to 14.00)	5.00; (0.00 to 8.00)
Follow-up: Subscale I (Irritability)	Number Analyzed	15 participants	13 participants
		3.00; (0.00 to 9.00)	2.00; (0.00 to 7.00)
Visit 1 - First Intervention: Subscale II	Number Analyzed	15 participants	15 participants
		13.00; (5.00 to 19.00)	8.00; (4.00 to 10.00)
Visit 3 - First Intervention: Subscale II	Number Analyzed	15 participants	15 participants
		11.00; (3.00 to 17.00)	7.00; (3.00 to 8.00)
Visit 5 - First Intervention: Subscale II	Number Analyzed	15 participants	15 participants
		9.00; (5.00 to 12.00)	6.00; (4.00 to 10.00)
Visit 6 - Second Intervention: Subscale II	Number Analyzed	15 participants	15 participants
		11.00; (5.00 to 16.00)	5.00; (2.00 to 9.00)
Visit 8 - Second Intervention: Subscale II	Number Analyzed	15 participants	15 participants
		8.00; (4.00 to 11.00)	5.00; (2.00 to 9.00)
Visit 10 - Second Intervention: Subscale II	Number Analyzed	15 participants	14 participants
		6.00; (4.00 to 9.00)	4.00; (2.00 to 6.00)
Follow-up: Subscale II (Lethargy)	Number Analyzed	15 participants	13 participants
		6.00; (2.00 to 11.00)	5.00; (2.00 to 8.00)
Visit 1 - First Intervention: Subscale III	Number Analyzed	15 participants	15 participants
		13.00; (10.00 to 16.00)	12.00; (9.00 to 14.00)
Visit 3 - First Intervention: Subscale III	Number Analyzed	15 participants	15 participants
		10.00; (8.00 to 15.00)	10.00; (8.00 to 13.00)
Visit 5 - First Intervention: Subscale III	Number Analyzed	15 participants	15 participants
		11.00; (9.00 to 16.00)	9.00; (7.00 to 12.00)
Visit 6 - Second Intervention: Subscale III	Number Analyzed	15 participants	15 participants
		11.00; (7.00 to 16.00)	11.00; (9.00 to 12.00)
Visit 8 - Second Intervention: Subscale III	Number Analyzed	15 participants	15 participants
		10.00; (7.00 to 15.00)	9.00; (7.00 to 11.00)
Visit 10 - Second Intervention: Subscale III	Number Analyzed	15 participants	15 participants
		8.00; (6.00 to 12.00)	9.00; (7.00 to 12.00)
Follow-up: Subscale III (Stereotypy)	Number Analyzed	15 participants	15 participants
		8.00; (6.00 to 11.00)	9.00; (7.00 to 12.00)
Visit 1 - First Intervention: Subscale IV	Number Analyzed	15 participants	15 participants
		13.00; (8.00 to 22.00)	8.00; (6.00 to 14.00)
Visit 3 - First Intervention: Subscale IV	Number Analyzed	15 participants	15 participants
		12.00; (7.00 to 15.00)	8.00; (3.00 to 13.00)
Visit 5 - First Intervention: Subscale IV	Number Analyzed	15 participants	15 participants
		11.00; (8.00 to 26.00)	6.00; (3.00 to 6.00)
Visit 6 - Second Intervention: Subscale IV	Number Analyzed	15 participants	15 participants
		11.00; (7.00 to 22.00)	7.00; (2.00 to 17.00)
Visit 8 - Second Intervention: Subscale IV	Number Analyzed	15 participants	15 participants
		7.00; (5.00 to 16.00)	4.00; (0.00 to 11.00)
Visit 10 - Second Intervention: Subscale IV	Number Analyzed	15 participants	14 participants
		10.00; (4.00 to 20.00)	5.00; (2.00 to 10.00)
Follow-up: Subscale IV (Hyperactivity)	Number Analyzed	15 participants	13 participants
		9.00; (3.00 to 17.00)	5.00; (1.00 to 9.00)

17. Secondary Outcome

Title	Quantitative Measures of Respiration: Apnea Index
Description	Respiratory data was collected using non-invasive respiratory inductance plethysmography from a BioCapture® recording device. BioCapture® is a child-friendly measurement device that can record from 1 to 12 physiological signal transducers in a time-locked manner. It can be configured with the pediatric chest and abdominal plethysmography bands and the 3 lead ECG signals we plan to use for monitoring cardiac safety throughout the study. Each transducer is placed on the patient independently to provide a customized fit that yields the highest signal quality for each patient irrespective of body shape and proportion. The transducer signals captured by the BioCapture® are transmitted wirelessly to a laptop computer where all signals are displayed in real-time. The apnea index is given as apneas/hour. Data on apneas greater than or equal to 10 seconds are displayed below. The higher the frequency of apnea, the more severe the breathing abnormality.
Time Frame	Every 10 weeks during each of the two 20-week treatment periods

Outcome Measure Data

Analysis Population Description

In some cases, the number of participants analyzed is less than 15 for each group due to inability to complete testing session.

One participant from the "rhIGF-1 First, Then Placebo" group was removed from the study prior to Visit 10, so there is only data for 14 participants included at that time point.

Arm/Group Title		Placebo First, Then rhIGF-1	rhIGF-1 First, Then Placebo
Arm/Group Description:		One half of subjects will be randomly assigned to receive placebo during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of a saline solution (placebo).	One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) during the first arm of the study. Subjects assigned to this group will receive twice daily subcutaneous injections of IGF-1.
Overall Number of Participants Analyzed		15	15
Median (Inter-Quartile Range); Unit of Measure: Apneas/Hour
Visit 1 - First Intervention: Apnea Index	Number Analyzed	15 participants	14 participants
		7.58; (1.58 to 10.33)	4.05; (2.07 to 7.91)
Visit 3 - First Intervention: Apnea Index	Number Analyzed	15 participants	14 participants
		4.80; (0.38 to 9.20)	3.48; (2.00 to 4.19)
Visit 5 - First Intervention: Apnea Index	Number Analyzed	15 participants	14 participants
		6.93; (3.06 to 9.07)	3.07; (0.40 to 5.11)
Visit 6 - Second Intervention: Apnea Index	Number Analyzed	15 participants	14 participants
		7.90; (4.30 to 17.60)	3.62; (2.20 to 11.82)
Visit 8 - Second Intervention: Apnea Index	Number Analyzed	15 participants	14 participants
		7.28; (2.80 to 12.53)	5.55; (1.24 to 12.81)
Visit 10 - Second Intervention: Apnea Index	Number Analyzed	15 participants	14 participants
		8.91; (4.13 to 14.34)	5.56; (1.57 to 13.47)

Adverse Events

Time Frame	80 weeks (from screening visit to 12-week follow up phone call).
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo		rhIGF-1		Off Treatment
Arm/Group Description	This group includes subjects who had a reported Adverse Event (AE) while they were receiving placebo treatment.		This group includes subjects who had a reported Adverse Event (AE) while they were receiving rhIGF-1 treatment.		This group includes subjects who had a reported Adverse Event (AE) while they were not receiving any treatment. This includes the period between Screening and Baseline, the 20-week washout period between study arms, and the 12-week follow up period after study completion.
All-Cause Mortality
	Placebo		rhIGF-1		Off Treatment
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/30 (0.00%)		0/30 (0.00%)		0/30 (0.00%)
Serious Adverse Events
	Placebo		rhIGF-1		Off Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/30 (13.33%)		4/30 (13.33%)		2/30 (6.67%)
Gastrointestinal disorders
Colitis * 1	0/15 (0.00%)	0	1/15 (6.67%)	1	0/30 (0.00%)	0
General disorders
Seizure * 1	2/30 (6.67%)	2	1/30 (3.33%)	1	0/30 (0.00%)	0
Infections and infestations
Pneumonia * 1	2/30 (6.67%)	2	2/30 (6.67%)	3	1/30 (3.33%)	2
Respiratory, thoracic and mediastinal disorders
Aspiration * 1	0/30 (0.00%)	0	1/30 (3.33%)	1	1/30 (3.33%)	1
1 Term from vocabulary, CTCAE (4.0); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Placebo		rhIGF-1		Off Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/30 (53.33%)		20/30 (66.67%)		15/30 (50.00%)
Cardiac disorders
Abnormal ECG - Prolonged QT † 1	0/30 (0.00%)	0	0/30 (0.00%)	0	2/30 (6.67%)	2
Other Cardiac Disorder † 1	0/30 (0.00%)	0	0/30 (0.00%)	0	1/30 (3.33%)	1
Ear and labyrinth disorders
Otitis Media † 1	2/30 (6.67%)	2	4/30 (13.33%)	4	1/30 (3.33%)	1
Endocrine disorders
Advanced Bone Age † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Precocious Puberty † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	1/30 (3.33%)	1
Gastrointestinal disorders
Vomiting † 1	2/30 (6.67%)	2	1/30 (3.33%)	1	1/30 (3.33%)	1
Vomiting and Diarrhea * 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Constipation † 1	0/30 (0.00%)	0	2/30 (6.67%)	2	0/30 (0.00%)	0
Diarrhea † 1	1/30 (3.33%)	1	1/30 (3.33%)	1	0/30 (0.00%)	0
Dyspepsia * 1	1/30 (3.33%)	1	0/30 (0.00%)	0	0/30 (0.00%)	0
Gastroenteritis † 1	1/30 (3.33%)	1	0/30 (0.00%)	0	0/30 (0.00%)	0
General disorders
Seizures * 1	3/30 (10.00%)	4	1/30 (3.33%)	1	2/30 (6.67%)	2
Seizure and vomiting * 1	1/30 (3.33%)	1	0/30 (0.00%)	0	0/30 (0.00%)	0
Elevated Alkaline Phosphatase * 1	0/30 (0.00%)	0	0/30 (0.00%)	0	1/30 (3.33%)	1
Alopecia † 1	0/30 (0.00%)	0	2/30 (6.67%)	2	0/30 (0.00%)	0
Dysphagia * 1	1/30 (3.33%)	1	0/30 (0.00%)	0	0/30 (0.00%)	0
Productive Cough and Vomiting † 1	1/30 (3.33%)	1	0/30 (0.00%)	0	0/30 (0.00%)	0
Car Accident * 1 [1]	0/30 (0.00%)	0	0/30 (0.00%)	0	1/30 (3.33%)	1
Fall † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	1/30 (3.33%)	1
Injection Site Reaction † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Minor Head Injury † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Immune system disorders
Tonsillar Hypertrophy † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Infections and infestations
Conjunctivitis * 1	0/30 (0.00%)	0	0/30 (0.00%)	0	1/30 (3.33%)	1
Lung Infection † 1	0/30 (0.00%)	0	2/30 (6.67%)	2	0/30 (0.00%)	0
Pharyngitis * 1	2/30 (6.67%)	2	1/30 (3.33%)	1	0/30 (0.00%)	0
Pneumonia * 1	1/30 (3.33%)	1	1/30 (3.33%)	1	0/30 (0.00%)	0
Seizure and Fever * 1	0/30 (0.00%)	0	0/30 (0.00%)	0	2/30 (6.67%)	2
Sinusitis * 1	1/30 (3.33%)	1	4/30 (13.33%)	4	1/30 (3.33%)	1
Fever † 1	1/30 (3.33%)	1	1/30 (3.33%)	1	0/30 (0.00%)	0
Hand, Foot, and Mouth Disease † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Skin (Eye) Infection † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Upper Respiratory Infection * 1	1/30 (3.33%)	1	0/30 (0.00%)	0	0/30 (0.00%)	0
Metabolism and nutrition disorders
Anorexia † 1	0/30 (0.00%)	0	0/30 (0.00%)	0	1/30 (3.33%)	1
Musculoskeletal and connective tissue disorders
Fracture † 1	1/30 (3.33%)	1	1/30 (3.33%)	1	0/30 (0.00%)	0
Scoliosis † 1	1/30 (3.33%)	1	0/30 (0.00%)	0	1/30 (3.33%)	1
Unequal limb length * 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Nervous system disorders
Extrapyramidal Disorder † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Psychiatric disorders
Anxiety * 1	1/30 (3.33%)	1	0/30 (0.00%)	0	0/30 (0.00%)	0
Personality Disorder * 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Sleep Apnea † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	1/30 (3.33%)	1
Cough † 1	1/30 (3.33%)	1	0/30 (0.00%)	0	0/30 (0.00%)	0
Skin and subcutaneous tissue disorders
Eczema † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Facial Swelling * 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Rash † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Skin Abscess * 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Surgical and medical procedures
Adenoidectomy † 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
Gastrostomy Tube Replacement * 1	0/30 (0.00%)	0	1/30 (3.33%)	1	0/30 (0.00%)	0
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment; * Indicates events were collected by non-systematic assessment; [1] Participant was in car accident on way to study visit. No injuries sustained.

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Dr. Mustafa Sahin, Director of Translational Neuroscience Center
• Organization: Boston Children's Hospital
• Phone: 617-919-6258
• EMail: ResearchTNC@childrens.harvard.edu

Publications:

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• Responsible Party: Mustafa Sahin, Harvard Medical School (HMS and HSDM)
• ClinicalTrials.gov Identifier: NCT01777542
• Other Study ID Numbers: IRB-P00005610
• First Submitted: January 23, 2013
• First Posted: January 29, 2013
• Results First Submitted: November 20, 2017
• Results First Posted: March 26, 2018
• Last Update Posted: March 26, 2018