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 Description

Brief Summary:

Investigators are recruiting children for a clinical trial using the medication recombinant human IGF-1 (a.k.a. mecasermin or INCRELEX) to see if it improves the health of children with Rett syndrome (RTT). While IGF-1 is approved by the Food & Drug Administration (FDA) for certain use in children, it is considered an investigational drug in this trial because it has not previously been used to treat RTT. Information from this study will help determine if IGF-1 effectively treats RTT but will not necessarily lead to FDA approval of IGF-1 as a treatment for RTT.

Condition or disease	Intervention/treatment	Phase
Rett Syndrome	Drug: Recombinant Human Insulin Growth Factor 1 (rhIGF-1); Drug: Placebo	Phase 2

Detailed Description:

Enrolled subjects will complete five study periods: screening, two 20-week long treatment periods, a 28-week break between treatment periods ("washout"), and a follow-up phone call 4 weeks after all treatment ends. Subjects will be chosen at random to receive either IGF-1 or placebo during the first treatment period and then switch to the alternate medication for the second treatment period. Therefore, by completion of the trial, all subjects will have received treatment with IGF-1 for 20 weeks. The study will be double-blinded; meaning, neither subjects' families nor study investigators will know who is receiving IGF-1 or placebo at any time. Treatment must be administered by the caregiver twice daily through subcutaneous (just underneath the skin) injections. Caregivers will be trained by research nurses in how to administer the medication. Participation in this study will last approximately eighteen months.

Throughout the course of the trial, investigators will collect information to assess the effects of IGF-1 and monitor for safety. Families must attend study visits at Boston Children's Hospital a total of seven times (including the screening visit) over the course of 18 months. These visits cannot be completed at any other hospital. Parents will fill out questionnaires and undergo a structured interview reporting on their child's health, behavior, and mood. Subjects will undergo clinical and physical examinations by a study doctor. Non-invasive devices and cameras will also be used to monitor things like breathing, hand movements, heart rate, and body temperature. Blood and urine will be collected for routine laboratory tests to monitor for safety. Investigators will also monitor safety by asking parents to complete a medication diary and side effect reporting form on a regular basis. Between trips to Boston Children's Hospital, parents will complete a set of online questionnaires and undergo a structured interview over the phone.

The cost of travel and lodging during research-related visits to and from the hospital will not be covered by the study. If a condition or illness is identified during the trial (and is determined to be unrelated to study treatments), referrals to outside medical care will be made. Study medications and all research-related materials and services will be provided at no cost to participants. Parking vouchers will be provided for all study-related hospital visits.

The study is investigating 5 potential effects:

1. IGF-1 may improve subjects' behavior, communication and/or mood. In order to measure this, investigators will evaluate subjects every 5 weeks throughout each treatment period with behavioral and psychological assessments. All of the tests used during these evaluations are non-invasive. Investigators will ask parents what their impressions are about their child's behavior and day-to-day activities through a structured parental interview and various questionnaires.
2. Investigators will examine subjects' brain function through use of a brain- monitoring device known as electroencephalography (EEG). The EEG measurements will be taken while investigators present subjects with exercises to stimulate their vision and hearing. EEG is a non-invasive way of recording the electrical activity of a subject's brain by applying a net of monitors (electrodes) to their scalp. Through this method investigators gain insight into how brain processes visual and auditory stimulus.
3. As one of the features of RTT is unstable vital signs, investigators are trying to determine if IGF-1 has any effect on normalizing subjects' heart rate and breathing patterns. To measure this, investigators will ask subjects to wear a non-invasive device that includes three electrocardiogram connectors and two stretchy bands that wrap around her chest and abdomen to measure heart rate and respiratory patterns.
4. The safety of IGF-1 in children with RTT is very important. Investigators will ask parents to complete a medication diary and side effect reporting form on a regular basis. In addition, laboratory tests will be performed every 10 weeks throughout each treatment period to evaluate the safety of IGF-1. These will be blood tests similar to those provided in typical clinical care. Subjects will undergo regular non-invasive comprehensive physical and neurological examinations, tonsil evaluation, electrocardiogram (ECG), echocardiogram, scoliosis x-ray, bone age x-ray, ophthalmological exam, and measurements of height, weight and head circumference.
5. Children with RTT often experience unintended, stereotyped hand movements. The Qsensor® is a non-invasive device worn on a fabric bracelet that continually measures subjects' movement. Investigators will use the Qsensor® to determine whether or not IGF-1 affects the presentation of stereotyped hand movements. As such, investigators will ask subjects to wear the Qsensor® during study visits every 10 weeks throughout each treatment period and occasionally at home.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Pharmacological Treatment of Rett Syndrome by Stimulation of Synaptic Maturation With Recombinant Human IGF-1(Mecasermin [rDNA] Injection)
• Study Start Date: January 2013
• Actual Primary Completion Date: July 2016
• Actual Study Completion Date: November 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Treatment Period 1; One half of subjects will be randomly assigned to receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1) , and the other half of subjects will be randomly assigned to receive placebo.	Drug: Recombinant Human Insulin Growth Factor 1 (rhIGF-1); Subjects will receive twice daily subcutaneous injections of IGF-1.; Other Names: mecasermin [rDNA] injection; Increlex; Drug: Placebo; Subjects will receive twice daily subcutaneous injections of a saline solution (placebo).; Other Name: saline
Placebo Comparator: Treatment Period 2; Subjects that initially received Recombinant Human Insulin Growth Factor 1 (rhIGF-1) will now receive placebo, and subjects that initially received placebo will now receive Recombinant Human Insulin Growth Factor 1 (rhIGF-1).	Drug: Recombinant Human Insulin Growth Factor 1 (rhIGF-1); Subjects will receive twice daily subcutaneous injections of IGF-1.; Other Names: mecasermin [rDNA] injection; Increlex; Drug: Placebo; Subjects will receive twice daily subcutaneous injections of a saline solution (placebo).; Other Name: saline

Outcome Measures

Primary Outcome Measures :

1. Rett Syndrome Behavior Questionnaire (RSBQ) - Fear/Anxiety Subscale [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

2. Anxiety, Depression, and Mood Scale (ADAMS) - Social Avoidance Subscale [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

3. Clinical Global Impression - Severity (CGI-S) [ Time Frame: Every 10 weeks during each of the two 20-week treatment periods ]

   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.

4. Clinical Global Impression - Improvement (CGI-I) [ Time Frame: Every 10 weeks during each of the two 20-week treatment periods ]

   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.

5. Parental Global Impression - Severity (PGI-S) [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

6. Parental Global Impression - Improvement (PGI-I) [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

7. Parent Targeted Visual Analog Scale (PTSVAS) - Scale 1 [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

8. Parent Targeted Visual Analog Scale (PTSVAS) - Scale 2 [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

9. Parent Targeted Visual Analog Scale (PTSVAS) - Scale 3 [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

10. Kerr Clinical Severity Scale [ Time Frame: At the start and end of each 20-week treatment period ]

    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.

Secondary Outcome Measures :

1. Rett Syndrome Behavior Questionnaire (RSBQ) [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

2. Anxiety, Depression, and Mood Scale (ADAMS) [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

3. Mullen Scales of Early Learning (MSEL) [ Time Frame: At the start and end of each 20-week treatment period ]

   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.

4. Vineland Adaptive Behavior Scales, Second Edition (VABS-II) [ Time Frame: At the start and end of each 20-week treatment period ]

   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.

5. Communication and Symbolic Behavior Scales - Developmental Profile (CSBS-DP) [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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.

6. Aberrant Behavior Checklist - Community Edition (ABC-C) [ Time Frame: Every 5 weeks during each of the two 20-week treatment periods, and once 4 weeks after final treatment ends ]

   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

   1. = Problem but slight in degree
   2. = Moderately serious problem
   3. = 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).

7. Quantitative Measures of Respiration: Apnea Index [ Time Frame: Every 10 weeks during each of the two 20-week treatment periods ]

   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.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 10 Years (Child)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of "classic" (or "typical") Rett Syndrome
• Genetic documentation of MECP2 mutation
• Subject must be post-regression (Hagberg Stage 2)
• Subject and caregiver's primary language must be English
• Subject must reside in North America (US and Canada)
• Caregiver must have internet access and be able to complete questionnaires online and communicate via email
• Subject is stable on current medications for at least 4 weeks
• Subject's regimen of non-pharmacological interventions (physical therapy, speech therapy, etc.) is stable for at least 90 days

Exclusion Criteria:

• Severe scoliosis (curvature >40 degrees)
• Bone-age greater than 11 years
• Cardiomegaly (enlarged heart)
• Tanner stage 2 or higher breast development
• Allergy to IGF-1
• Prior use of IGF-1, growth hormone, or sex steroids

Contacts and Locations

Locations

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02215

Sponsors and Collaborators

Boston Children's Hospital

International Rett Syndrome Foundation

Investigators

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

More Information

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• Responsible Party: Mustafa Sahin, Associate Professor of Neurology, Harvard Medical School (HMS and HSDM)
• ClinicalTrials.gov Identifier: NCT01777542
• Other Study ID Numbers: IRB-P00005610
• First Posted: January 29, 2013
• Results First Posted: March 26, 2018
• Last Update Posted: March 26, 2018
• Last Verified: March 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mustafa Sahin, Harvard Medical School (HMS and HSDM):

Rett syndrome; RTT; IGF-1; autism spectrum disorder

Additional relevant MeSH terms:

Rett Syndrome; Syndrome; Disease; Pathologic Processes; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Insulin; Insulin, Globin Zinc; Mitogens; Mecasermin; Hypoglycemic Agents; Physiological Effects of Drugs; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Growth Substances