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

• Sponsor: Boston Children’s Hospital
• Collaborators: International Rett Syndrome Foundation; Autism Speaks
• Information provided by (Responsible Party): Mustafa Sahin, Boston Children’s Hospital

Tracking Information

• First Submitted Date: December 2, 2010
• First Posted Date: December 3, 2010
• Results First Submitted Date: May 13, 2014
• Results First Posted Date: June 22, 2017
• Last Update Posted Date: June 22, 2017
• Study Start Date: December 2010
• Actual Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 20, 2017)

• Adverse Events [ Time Frame: biweekly during the MAD and every five weeks during the OLE ]
• Pharmacokinetic (PK) Profile - Areas Under the Curve (AUCt) [ 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. ]

Original Primary Outcome Measures (submitted: December 2, 2010)

• respiratory inductance plethysmography [ Time Frame: every four weeks during each 20-week arm ]
  The primary outcome measure will be the index of autonomic/respiratory dysregulation, using non-invasive respiratory inductance plethysmography. The data for index calculation are derived from a device known as the BioRadio®. The BioRadio® 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 3 lead ECG signal.
• Electrocardiogram [ Time Frame: every two weeks during each 20-week arm ]
  The BioRadio® is a child-friendly measurement device that can record from 1 to 12 physiological signal transducers in a time-locked manner. It will be configured for the pediatric chest with 3 lead ECG signals.

• Change History: Complete list of historical versions of study NCT01253317 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: June 20, 2017)

• Change From Pre-MAD Apnea Index at Post-OLE [ Time Frame: pre-MAD (baseline) to post-OLE (after 20 weeks of IGF-1 treatment) ]
  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).
• Change in Social Avoidance Subscale Scores on the ADAMS From Pre-OLE to Post-OLE [ Time Frame: Pre-OLE (visit 1) and post-OLE (after 20 weeks of IGF-1 therapy) ]
  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.

Original Secondary Outcome Measures (submitted: December 2, 2010)

• Growth Measurements [ Time Frame: every four weeks throughout each 20-week arm ]
  measuring height, weight, head circumference
• Clinical Assessment [ Time Frame: every four weeks during each 20-week arm ]
  assess severity of neurological and motor symptoms of Rett Syndrome.
• Clinical Severity Scale [ Time Frame: every four weeks during each 20-week phase ]
  measures severity of clinical features of Rett Syndrome
• Fundoscopic [ Time Frame: every four weeks during each 20 week arm ]
  Assesses cranial pressure.
• Tonsillar and Otolaryngological Exam [ Time Frame: every four weeks during each 20 week arm ]
  Measures tonsillar growth.
• Electroencephalogram [ Time Frame: every 4 weeks during each 20-week arm ]
  evaluates changes in epileptiform waves.
• Scoliosis x-ray [ Time Frame: at the beginning and end of each 20-week arm ]
  determine if degree of scoliosis is affected by medication.
• RNA profiling [ Time Frame: beginning and end of each 20-week arm ]
  The investigators will perform a genetic test to determine if the RNA profile of subjects is altered by the medication.
• Mullen Scales of Early Learning [ Time Frame: beginning and end of each 20-week arm ]
  The investigators will administer this test to assess if the medication has an effect on cognition, motor function, and language skills.
• Vineland Adaptive Behavior Scales [ Time Frame: every 4 weeks during each 20 week arm ]
  This parental interview will be administered to determine if there is any change in subjects' adaptive behavior skills during the trial.
• Clinical Global Impression Scales [ Time Frame: every 4 weeks during each 20 week arm ]
• Modified Ashworth Scale [ Time Frame: every 4 weeks during each 20 week arm ]
• Unified Parkinson Disease Rating Scale [ Time Frame: every 4 weeks during each 20 week arm ]
• Medical Research Council Grading System [ Time Frame: every 4 weeks during each 20 week arm ]
  Muscle strength scale.
• Child Health Questionnaire [ Time Frame: every 4 weeks during each 20 week arm ]
  Child quality of life measure.
• Your Health and Well-Being [ Time Frame: every 4 weeks during each 20 week arm ]
  Parental quality of life measure.
• Stereotypy Linear Analog Scale [ Time Frame: every 4 weeks during each 20 week arm ]
  Evaluates severity of Rett Syndrome stereotypies.
• Rett Syndrome Behavior Questionnaire [ Time Frame: every 4 weeks during each 20 week arm ]
• Aberrant Behavior Checklist [ Time Frame: every 4 weeks during each 20 week arm ]
• Parent Targeted Symptoms Visual Analog Scales [ Time Frame: Monthly ]
  Parent or caregiver selected target symptoms (3) measures on linear analog scale for duration of study

• Current Other Outcome Measures: Not Provided
• Original Other Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treatment of Rett Syndrome With rhIGF-1 (Mecasermin [rDNA]Injection)
• Official Title: Pharmacological Treatment of Rett Syndrome by Stimulation of Synaptic Maturation With IGF-1

Brief Summary

The investigators are recruiting children for a research study using a medication known as IGF-1 (mecasermin or INCRELEX) to see if it improves the health of children with Rett syndrome (RTT). To participate in the study your child must be female, between the ages of 2 to 12 and have a genetic diagnosis (MECP2 deletion or mutation) of Rett Syndrome. As you may know, there is no treatment for this illness. Currently, the standard management of Rett syndrome is supportive, which means attempting to prevent complications and treatment of symptoms.

This study involves testing an investigational drug, which means that even though IGF-1 is approved by the Food and Drug Administration (FDA) for use in children, it has not been used before to treat Rett syndrome specifically. Information from this research will help determine whether the drug should be approved by the FDA in the future for the treatment of Rett Syndrome.

There are five major goals to this study:

1. As one of the features of Rett Syndrome is unstable vital signs, the investigators are trying to determine if IGF-1 has any effect on normalizing your child's pulse, blood pressure and breathing pattern.
2. The safety of IGF-1 in children with Rett syndrome. The study personnel will ask you to complete a medication diary and side effect reporting form on a regular basis. They will assist you in completing this by telephone interviews. Your child will undergo 2 lumbar punctures performed at the bedside in the clinical research facility. In addition, laboratory tests will be performed throughout the study to evaluate the safety of IGF-1. These will be blood tests similar to those provided in routine clinical care. Your child will undergo regular non-invasive comprehensive physical examinations including neurological and eye examination, tonsil evaluation, electrocardiograms (ECG), measurement of height, weight and head circumference.
3. IGF-1 may improve your child's behavior, communication and speech. In order to measure this, the investigators will evaluate your child once during each month of treatment with neurodevelopmental assessments and a neurological exam. Investigators will also ask you about her behavior and day-to-day functioning through a structured parental interview and questionnaires.
4. We will examine your child's cortical function through use of electroencephalography (EEG) in conjunction with presentation of visual and auditory stimuli. EEG is a non-invasive way of recording the electrical activity of your child's brain.

5. Children with Rett Syndrome sometimes experience "flushing" in their cheeks or have exceptionally cold hands or feet and/or abnormal perspiration. The Qsensor® is a non-invasive device worn on a fabric bracelet that continually measures your child's perspiration level and body temperature. We would like to use the Qsensor® to determine whether or not IGF-1 improves these symptoms.

• Detailed Description: There are two treatment periods in the trial. The multiple ascending dose (MAD) period is an intensive 4-week pharmacokinetic study which will require 3 inpatient stays and 4 half-day outpatient visits. During in-patient sessions, an IV line will be placed for frequent blood samples. A lumbar puncture will be performed by a physician at the beginning and again at the end of the MAD. The primary goal of the MAD is to determine the safety of IGF-1 therapy for girls with RTT. As such, the investigators will ask that you monitor your child's blood sugar levels using a glucometer. At the end of the MAD, you will have the option of enrolling your daughter in an additional 20 weeks of open-label IGF-1 treatment.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Rett Syndrome

Intervention

Drug: rhIGF-1

1) Multiple ascending dose (MAD) period (4 weeks): Subjects will receive escalating twice-daily doses of IGF-1 over 4 weeks (40 µg/kg, 80 µg/kg, 120 µg/kg) and then continue treatment at 120 µg/kg BID for 20 weeks should they choose to enroll in the open-label extension period.

Other Name: Mecasermin (brand name Increlex)

Study Arms

Experimental: rhIGF-1

Subjects will receive escalating twice-daily doses of IGF-1 over 4 weeks (40 µg/kg, 80 µg/kg, 120 µg/kg) and then continue treatment at 120 µg/kg BID for 20 weeks should they choose to enroll in the OLE.

Intervention: Drug: rhIGF-1

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 24, 2013): 12
• Original Estimated Enrollment (submitted: December 2, 2010): 40
• Actual Study Completion Date: January 2013
• Actual Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• female
• with RTT (typical or variant) as defined using the internationally agreed 2010 RettSearch criteria.
• genetically defined mutation or deletion of the MECP2 gene.
• Girls will have the following prepubertal status: (1) Tanner stage 1 or 2 breast development; (2) Tanner stage 1 or 2 pubic hair development; (3) and younger than 12 years by bone age.
• Chronological age must be 2 years or older

Exclusion Criteria:

• prior therapeutic use of IGF-1, growth hormone, Lupron® or sex steroids
• allergy to the trial product
• co-morbid or chronic illness beyond that known to be associated with Rett Syndrome: diabetes mellitus, fatty acid oxidation disorder, chromosomal aneuploidy, syndromes associated with high risk of malignancy, current or previous exposure to spinal irradiation or history of malignancy.
• severe scoliosis (defined as a spinal curve of 70 degrees or more as measured on clinical and radiological examination)

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 2 Years to 12 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01253317
• Other Study ID Numbers: 10-08-0403
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Mustafa Sahin, Boston Children’s Hospital
• Study Sponsor: Boston Children’s Hospital

Collaborators

• International Rett Syndrome Foundation
• Autism Speaks

Investigators

• Principal Investigator: Mustafa Sahin, MD, PhD; Boston Children’s Hospital

• PRS Account: Boston Children’s Hospital
• Verification Date: June 2017