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Treatment of Rett Syndrome With rhIGF-1 (Mecasermin [rDNA]Injection)

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ClinicalTrials.gov Identifier: NCT01253317
Recruitment Status : Completed
First Posted : December 3, 2010
Results First Posted : June 22, 2017
Last Update Posted : June 22, 2017
Sponsor:
Collaborators:
International Rett Syndrome Foundation
Autism Speaks
Information provided by (Responsible Party):
Mustafa Sahin, Boston Children’s Hospital

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Rett Syndrome
Intervention Drug: rhIGF-1
Enrollment 12
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Open-label IGF-1 Treatment
Hide Arm/Group Description

Twelve girls with MECP2 mutations participated in the 4-week multiple ascending dose (MAD) period of open-label treatment with IGF-1 (mecasermin). The MAD focused on obtaining PK data, determining cerebrospinal fluid (CSF) penetration, evaluating safety and tolerability, and estimating feasibility of automated cardiorespiratory measures as biomarkers. Mecasermin was escalated over a 4-week period, beginning with twice daily injections of 40 mcg/kg the first week, 80 mcg/kg the second week, and 120 mcg/kg during the third and fourth weeks. CSF samples were obtained prior to initiating treatment and after completing the fourth week.

10 of these subjects went on to complete the open label extension (OLE). The OLE was designed to obtain additional information on safety, tolerability, and cardiorespiratory measures after 20-weeks of treatment, as well as preliminary data on neurologic and behavioral parameters. During the 20-week OLE subjects were evaluated every 5 weeks.

Period Title: Overall Study
Started 12
Completed 10
Not Completed 2
Reason Not Completed
Adverse Event             2
Arm/Group Title Open-label IGF-1 Treatment
Hide Arm/Group Description

Twelve girls with MECP2 mutations participated in the 4-week multiple ascending dose (MAD) period of open-label treatment with IGF-1 (mecasermin). The MAD focused on obtaining PK data, determining cerebrospinal fluid (CSF) penetration, evaluating safety and tolerability, and estimating feasibility of automated cardiorespiratory measures as biomarkers. Mecasermin was escalated over a 4-week period, beginning with twice daily injections of 40 mcg/kg the first week, 80 mcg/kg the second week, and 120 mcg/kg during the third and fourth weeks. CSF samples were obtained prior to initiating treatment and after completing the fourth week.

10 of these subjects went on to complete the open label extension (OLE). The OLE was designed to obtain additional information on safety, tolerability, and cardiorespiratory measures after 20-weeks of treatment, as well as preliminary data on neurologic and behavioral parameters. During the 20-week OLE subjects were evaluated every 5 weeks.

Overall Number of Baseline Participants 12
Hide Baseline Analysis Population Description
Twelve girls with MECP2 mutations participated in the 4-week MAD period; ten of them continued and completed the subsequent 20-week OLE. Nine subjects met full diagnostic criteria for RTT, all of whom continued in the OLE.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
<=18 years
12
 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 12 participants
Female
12
 100.0%
Male
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
American Indian or Alaska Native
0
   0.0%
Asian
2
  16.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
0
   0.0%
White
10
  83.3%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
Hispanic or Latino
0
   0.0%
Not Hispanic or Latino
12
 100.0%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 12 participants
12
1.Primary Outcome
Title Adverse Events
Hide Description [Not Specified]
Time Frame biweekly during the MAD and every five weeks during the OLE
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects that had the same adverse event more than once are counted only one time using the closest relationship to study medication.
Arm/Group Title 4-week Multiple Ascending Dose (MAD) 20-week Open Label Extension (OLE)
Hide Arm/Group Description:
Twelve girls with MECP2 mutations participated in the 4-week multiple ascending dose (MAD) period of open-label treatment with IGF-1 (mecasermin). The MAD focused on obtaining PK data, determining cerebrospinal fluid (CSF) penetration, and evaluating safety and tolerability of IGF-1.
10 subjects that previously participated in the MAD went on to complete the OLE and were monitoring for safety of prolonged treatment (20 weeks).
Overall Number of Participants Analyzed 12 10
Measure Type: Number
Unit of Measure: Adverse events
Unrelated adverse events 4 4
Possibly related adverse events 2 17
Probably related adverse events 2 9
2.Primary Outcome
Title Pharmacokinetic (PK) Profile - Areas Under the Curve (AUCt)
Hide Description [Not Specified]
Time Frame 60 minutes pre-dose and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 8.0, and 12.0 hours post-dose on days 1, 8, 15 and 29.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Open-label IGF-1 Treatment
Hide Arm/Group Description:

Twelve girls with MECP2 mutations participated in the 4-week multiple ascending dose (MAD) period of open-label treatment with IGF-1 (mecasermin). The MAD focused on obtaining PK data, determining cerebrospinal fluid (CSF) penetration, evaluating safety and tolerability, and estimating feasibility of automated cardiorespiratory measures as biomarkers. Mecasermin was escalated over a 4-week period, beginning with twice daily injections of 40 mcg/kg the first week, 80 mcg/kg the second week, and 120 mcg/kg during the third and fourth weeks. CSF samples were obtained prior to initiating treatment and after completing the fourth week.

10 of these subjects went on to complete the open label extension (OLE). The OLE was designed to obtain additional information on safety, tolerability, and cardiorespiratory measures after 20-weeks of treatment, as well as preliminary data on neurologic and behavioral parameters. During the 20-week OLE subjects were evaluated every 5 weeks.

Overall Number of Participants Analyzed 12
Mean (Standard Error)
Unit of Measure: ng.h/mL
Day 1: 40 mcg/kg dose 2050.0  (235.2)
Day 29: 120 mcg/kg dose 3348.9  (261.9)
3.Secondary Outcome
Title Change From Pre-MAD Apnea Index at Post-OLE
Hide Description Apnea indices were compared from pre-MAD (prior to initiating treatment) to post-OLE (after 20 weeks of IGF-1 therapy). A negative value indicates a reduction in apnea index; representing an improved outcome. Apnea Index is defined as the number of apneas (≥ 10 seconds in length) occuring within one hour. The Apnea Index is calculated by dividing the number of qualifying apneic events by the number of hours in which they occurred. An apnea index greater than or equal to 5 is considered clinically significant by the American Academy of Sleep Medicine (AASM).
Time Frame pre-MAD (baseline) to post-OLE (after 20 weeks of IGF-1 treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
Two subjects enrolled in the MAD did not continue participation in the OLE and one subject was excluded from the analysis because, upon further medical record review, she did not meet diagnostic criteria for Rett syndrome.
Arm/Group Title MAD and OLE Treatment Periods
Hide Arm/Group Description:
Twelve girls with MECP2 mutations participated in the 4-week multiple ascending dose (MAD) period of open-label treatment with IGF-1 (mecasermin). The MAD focused on obtaining PK data, determining cerebrospinal fluid (CSF) penetration, and evaluating safety and tolerability of IGF-1. Ten subjects that previously participated in the MAD went on to complete the OLE and were monitoring for safety of prolonged treatment (20 weeks).
Overall Number of Participants Analyzed 9
Mean (Standard Error)
Unit of Measure: apneas per hour
-7.12  (4.58)
4.Secondary Outcome
Title Change in Social Avoidance Subscale Scores on the ADAMS From Pre-OLE to Post-OLE
Hide Description The Anxiety Depression and Mood Scale (ADAMS) is completed by the parent/caregiver and consists of 29 items which are scored on a 4-point rating scale that combines frequency and severity ratings. The Social Avoidance subscale [0 = best; 20 = worst] of the ADAMS is reported as a secondary outcome measure. A negative value indicates a decrease in the Social Avoidance subscale; which represents an improved outcome.
Time Frame Pre-OLE (visit 1) and post-OLE (after 20 weeks of IGF-1 therapy)
Hide Outcome Measure Data
Hide Analysis Population Description
The ADAMS was not completed during the MAD.
Arm/Group Title 20-week Open Label Extension (OLE)
Hide Arm/Group Description:
10 subjects that previously participated in the MAD went on to complete the OLE and were monitored for safety of prolonged treatment (20 weeks).
Overall Number of Participants Analyzed 10
Mean (Standard Error)
Unit of Measure: units on a scale
-1.44  (0.84)
Time Frame During the MAD and OLE (approximately 1 year, 4 months)
Adverse Event Reporting Description AEs were assessed by guidelines published by the National Institutes of Health, National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010)
 
Arm/Group Title Open-label IGF-1 Treatment
Hide Arm/Group Description

Twelve girls with MECP2 mutations participated in the 4-week multiple ascending dose (MAD) period of open-label treatment with IGF-1 (mecasermin). The MAD focused on obtaining PK data, determining cerebrospinal fluid (CSF) penetration, evaluating safety and tolerability, and estimating feasibility of automated cardiorespiratory measures as biomarkers. Mecasermin was escalated over a 4-week period, beginning with twice daily injections of 40 mcg/kg the first week, 80 mcg/kg the second week, and 120 mcg/kg during the third and fourth weeks. CSF samples were obtained prior to initiating treatment and after completing the fourth week.

10 of these subjects went on to complete the open label extension (OLE). The OLE was designed to obtain additional information on safety, tolerability, and cardiorespiratory measures after 20-weeks of treatment, as well as preliminary data on neurologic and behavioral parameters. During the 20-week OLE subjects were evaluated every 5 weeks.

All-Cause Mortality
Open-label IGF-1 Treatment
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Open-label IGF-1 Treatment
Affected / at Risk (%) # Events
Total   1/12 (8.33%)    
Respiratory, thoracic and mediastinal disorders   
Respiratory distress  1 [1]  1/12 (8.33%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
[1]
During the MAD period, one serious adverse event occurred (respiratory distress) and was determined to be unrelated to the study drug.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Open-label IGF-1 Treatment
Affected / at Risk (%) # Events
Total   12/12 (100.00%)    
Endocrine disorders   
Polydipsia  1 [1]  6/12 (50.00%)  6
Gastrointestinal disorders   
Vomiting  1 [2]  2/12 (16.67%)  5
Salivary hypersecretion  1 [3]  2/12 (16.67%)  2
Reproductive system and breast disorders   
Precocious puberty  1 [4]  4/12 (33.33%)  4
Respiratory, thoracic and mediastinal disorders   
Upper respiratory tract infection  1  2/12 (16.67%)  2
Tonsillar Hypertrophy  1 [5]  2/12 (16.67%)  2
Snoring  1 [6]  5/12 (41.67%)  5
Skin and subcutaneous tissue disorders   
Nonscarring hair loss  1 [7]  2/12 (16.67%)  2
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
[1]
Increased thirst
[2]
Vomiting
[3]
Increased drooling
[4]
Signs of early pubertal development
[5]
Increased tonsil size
[6]
Snoring
[7]
Hair loss
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Walter E. Kaufmann, MD
Organization: Boston Children's Hospital
Phone: 617-355-5230
Responsible Party: Mustafa Sahin, Boston Children’s Hospital
ClinicalTrials.gov Identifier: NCT01253317     History of Changes
Other Study ID Numbers: 10-08-0403
First Submitted: December 2, 2010
First Posted: December 3, 2010
Results First Submitted: May 13, 2014
Results First Posted: June 22, 2017
Last Update Posted: June 22, 2017