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

This study has been completed.
Sponsor:
Collaborators:
International Rett Syndrome Foundation
Autism Speaks
Information provided by (Responsible Party):
Walter Kaufmann, Children's Hospital, Boston
ClinicalTrials.gov Identifier:
NCT01253317
First received: December 2, 2010
Last updated: January 24, 2013
Last verified: January 2013
  Purpose

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. During PHASE 2, a device called BioRadio® will be used to monitor vital signs in a non-invasive way. This information will be recorded and stored on the accompanying laptop. Before starting PHASE 2, the investigators would like to "beta-test" the BioRadio® in PHASE 1. As such, the investigators may ask you to try using the BioRadio® with your child to test the fit and the performance of the equipment. Should you choose to enroll your child in PHASE 2, the investigators will then ask that your child wear the BioRadio® for two hours, on two consecutive days every four weeks.
  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. All of the tests used during these evaluations are non-invasive. the investigators will also ask you what your impressions are about her behavior and day-to-day activities through a structured parental interview and various 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 by applying a net of electrodes to her scalp. Through this we gain insight into how neural function correlates to the progression of behavioral abnormalities seen in individuals with RTT. By understanding how this electrical brain activity produces the abnormal behaviors seen in RTT, we will be better able to identify whether or not treatment with IGF-1 affects the way the brain communicates with the body.
  5. Children with Rett Syndrome are often unable to regulate their body temperature and will sometimes experience "flushing" in their cheeks or have exceptionally cold hands or feet. 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 your child's ability to regulate her body temperature. As such, we ask that your child wear the Qsensor® during each study visit. This wrist-worn sensor has been demonstrated to be safe and comfortable but may cause a slight gray discoloration where the sensor contacts your child's skin. This discoloration will go away in less than a day. The Qsensor® is not waterproof, therefore may not be worn in the shower or while your child is washing her hands. If you believe the device is broken, please contact the study team immediately.

Condition Intervention Phase
Rett Syndrome
Drug: rhIGF-1
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: PHARMACOLOGICAL TREATMENT OF RETT SYNDROME BY STIMULATION OF SYNAPTIC MATURATION WITH IGF-1

Resource links provided by NLM:


Further study details as provided by Children's Hospital Boston:

Primary Outcome Measures:
  • respiratory inductance plethysmography [ Time Frame: every five weeks during each 20-week arm ] [ Designated as safety issue: No ]
    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 five weeks during each 20-week arm ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Growth Measurements [ Time Frame: every five weeks throughout each 20-week arm ] [ Designated as safety issue: Yes ]
    measuring height, weight, head circumference

  • Clinical Assessment [ Time Frame: every five weeks during each 20-week arm ] [ Designated as safety issue: No ]
    assess severity of neurological and motor symptoms of Rett Syndrome.

  • Clinical Severity Scale [ Time Frame: every five weeks during each 20-week phase ] [ Designated as safety issue: No ]
    measures severity of clinical features of Rett Syndrome

  • Fundoscopic [ Time Frame: every five weeks during each 20 week arm ] [ Designated as safety issue: Yes ]
    Assesses cranial pressure.

  • Tonsillar and Otolaryngological Exam [ Time Frame: every five weeks during each 20 week arm ] [ Designated as safety issue: Yes ]
    Measures tonsillar growth.

  • Electroencephalogram [ Time Frame: every five weeks during each 20-week arm ] [ Designated as safety issue: No ]
    evaluates changes in epileptiform waves.

  • Scoliosis x-ray [ Time Frame: at the beginning and end of each 20-week arm ] [ Designated as safety issue: Yes ]
    determine if degree of scoliosis is affected by medication.

  • RNA profiling [ Time Frame: beginning and end of each 20-week arm ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 five weeks during each 20 week arm ] [ Designated as safety issue: No ]
    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 five weeks during each 20 week arm ] [ Designated as safety issue: No ]
  • Unified Parkinson Disease Rating Scale [ Time Frame: every five weeks during each 20 week arm ] [ Designated as safety issue: No ]
  • Child Health Questionnaire [ Time Frame: beginning and end of each 20-week arm ] [ Designated as safety issue: No ]
    Child quality of life measure.

  • Your Health and Well-Being [ Time Frame: beginning and end of each 20-week arm ] [ Designated as safety issue: No ]
    Parental quality of life measure.

  • Stereotypy Linear Analog Scale [ Time Frame: every five weeks during each 20 week arm ] [ Designated as safety issue: No ]
    Evaluates severity of stereotypical hand movements.

  • Rett Syndrome Behavior Questionnaire [ Time Frame: every five weeks during each 20 week arm ] [ Designated as safety issue: No ]
  • Aberrant Behavior Checklist [ Time Frame: every five weeks during each 20 week arm ] [ Designated as safety issue: No ]
  • Parent Targeted Symptoms Visual Analog Scales [ Time Frame: Monthly ] [ Designated as safety issue: No ]
    Parent or caregiver selected target symptoms (3) measures on linear analog scale for duration of study


Enrollment: 12
Study Start Date: December 2010
Study Completion Date: January 2013
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Saline placebo
Crossover study subjects will be randomized to receive twice daily subcutaneous injections (SC) of normal saline for a period of 20 weeks beginning with a sham dose escalation (40 µg/kg, 80 µg/kg, 120 µg/kg) over the first 3 weeks.
Drug: rhIGF-1
1) PHASE 1 (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 PHASE2.
Other Name: Mecasermin (brand name Increlex)
Active Comparator: rhIGF-1

PHASE 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 PHASE2.

PHASE 2:

  • ARM1: Crossover study subjects will be randomized to receive twice daily subcutaneous injections (SC) of IGF-1 or normal saline for a period of 20 weeks beginning with an initial or sham dose escalation (40 µg/kg, 80 µg/kg, 120 µg/kg) over the first 3 weeks. Subjects from PHASE1 will participate in every aspect of ARM1 of PHASE2; however, it will be open-label IGF-1 treatment and subjects will not participate in a placebo phase.
  • ARM2: After a 6 week wash-out period, the subjects will cross-over to the parallel arm and receive the alternate therapy (IGF-1 or normal saline) for an additional 20 week period, again beginning with an initial or sham dose escalation. Subjects enrolled in PHASE1 will not participate in ARM2.
Drug: rhIGF-1
1) PHASE 1 (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 PHASE2.
Other Name: Mecasermin (brand name Increlex)

Detailed Description:

There are two phases to the trial. Phase 1 is an intensive 6-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 Phase 1. The primary goal of Phase 1 is to determine the safety of IGF-1 therapy for girls with RS. As such, the investigators will ask that you monitor your child's blood sugar levels using a glucometer. Your child's health is our utmost concern and she will be monitored continuously to ensure her safety. At the end of Phase 1, you will have the option of enrolling your daughter in an additional 20 weeks of treatment with IGF-1 during Phase 2 of the trial. The investigators must successfully complete Phase 1 before the investigators can move to the second phase of the trial with a larger number of patients.

The second phase will be double-blinded; meaning neither the families nor the researchers will know which participants are receiving IGF-1. The cross-over design of the trial means each subject will receive 20 weeks of either placebo or IGF-1 and then, after the 6-week washout period, participants will receive another 20 weeks of the alternate treatment. All girls enrolled in Phase 2 will receive 20 weeks of treatment with IGF-1.

Girls enrolled in Phase 2 will be seen monthly for safety monitoring, developmental evaluations and lab work. The investigators will ask caregivers to fill out a number of questionnaires and answer questions regarding their daughter's health, behavior and quality of life. The investigators will also monitor your daughter's heart function (ECG) and the electrical activity in her brain (EEG) four times throughout Phase 2. The BioRadio® is a child-friendly measurement device, capable of recording heart and breathing patterns. The investigators ask that your child wear the BioRadio® and Qsensor® for 2 hours of quiet activity during each study visit, every 5 weeks. Data from the BioRadio® will demonstrate if treatment with IGF-1 improves the heart rhythm and respiratory symptoms of girls with RS. Data from the Qsensor® may indicate if your child's perspiration level and body temperature show signs of normalizing.

  Eligibility

Ages Eligible for Study:   2 Years to 12 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01253317

Locations
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Walter Kaufmann
International Rett Syndrome Foundation
Autism Speaks
Investigators
Principal Investigator: Walter Kaufmann, MD Boston Children's Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: Walter Kaufmann, Neurologist, Children's Hospital, Boston
ClinicalTrials.gov Identifier: NCT01253317     History of Changes
Other Study ID Numbers: 10-08-0403
Study First Received: December 2, 2010
Last Updated: January 24, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Children's Hospital Boston:
Rett Syndrome
IGF-1
Increlex
Mecasermin
IGF1
MECP2
RTT

Additional relevant MeSH terms:
Rett Syndrome
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Nervous System Diseases
Mental Retardation, X-Linked
Mental Retardation
Neurobehavioral Manifestations
Neurologic Manifestations
Genetic Diseases, X-Linked
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on April 15, 2014