Rett Syndrome
Conditions
Keywords
Treatment trial, Rett syndrome, Glatiramer acetate
Brief summary
A phase 2 open label trial to test a potential drug treatment for Rett syndrome, the leading known genetic cause of severe neurological impairment in girls. The drug, Copaxone (generic name - Glatiramer acetate) is medication FDA approved for the treatment of multiple sclerosis. Copaxone's high safety profile has been documented in large cohorts of patients for more than 12 years.
Detailed description
Background/rationale for the study: In Rett syndrome brain cells aren't actually lost, instead poor maturation of connections between brain cells (synapses) prevents effective neurological functioning, and is the main morphological feature of the disease. The MeCP2 gene plays a major role in transcriptional regulation of other genes, one of which is the gene encoding brain-derived neurotrophic factor (BDNF). The disease progression and severity of symptoms is directly affected by the level of BDNF expression. An increase of BDNF levels (by genetic manipulations or pharmacological agents) leads to delayed onset of Rett syndrome-like symptoms in experimental models; rescued gait/mobility, improved quality of life and increased survival rates. Copaxone treatment by subcutaneous injection caused elevation of BDNF levels. Quantitative immunofluorescence assays showed about a twofold increase in neuronal expression of BDNF following Copaxone treatment. We expect that an increase in BDNF levels with Copaxone administration will stimulate communication between brain cells (synaptic maturation), which will lead to amelioration of symptoms (motor functions/gait, cognitive functions, breathing, encephalopathy and improve quality of life) for girls with Rett syndrome.
Interventions
DRUGGlatiramer Acetate
Sponsors
Rett Syndrome Research Trust
Montefiore Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
10 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female patients with genetically confirmed Rett Syndrome (RTT) * Age: 10 or more years old. Selection of the age is based on the available evidence of the safety of Glatiramer Acetate (GA) in this group, and the relative homogeneity/stability of the phenotype, which is not expected to spontaneously change within a 6 month period at this age * Ambulatory (with our without support)
Exclusion criteria
* Prolonged Qtc (obtained within 30 days prior to enrollment) * Presence of co morbid non-Rett related disease * Presence of immunodeficiency requiring intravenous immunoglobulin 3 (IVIG 3) months prior to enrollment * Allergy/sensitivity to GA or mannitol * Inability or unwillingness of legal guardians to give written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gait Velocity as Measured by GAITRite System | Baseline and Final week of treatment (week 32) | To perform quantitative gait assessments a computerized walkway (457 × 90.2 × 0.64cm) with embedded pressure sensors (GAIT Rite system) was used. Subjects walked on the walkway for two trials, while wearing comfortable footwear. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Breath Hold Index (Number of Breath Holds Per Hour; Assessed in the Sleep Monitoring Lab) | Baseline and during final week of treatment (week 32) | Breath hold index is defined as number of breath holds/hour. Respirations were monitored with sleep monitoring equipment during the daytime at the polysomnography laboratory with additional oronasal airflow, electromyography (EMG), EEG and video monitoring to confirm wakefulness during the period of study. |
| Breath Hold Time (Assessed in the Sleep Monitoring Lab) | Baseline and Final week of treatment (week 32) | Breath Hold Time is defined as percentage of time spent holding the breath in a specific time unit. It is measured by a standard medical technique where belts are placed on the chest and abdomen to record movement and sensors are used to record nasal flow. Wake respiration was monitored with sleep monitoring equipment during the daytime at the polysomnography laboratory with additional oronasal airflow, EMG, EEG and video monitoring to confirm wakefulness during the period of study. |
| Visual Memory Novelty Score as Assessed by TX300 Tobii Computer. | Baseline and Final week of treatment (week 32) | Eye-tracking is considered an indication of visual memory. Eye-tracking data was recorded at 300 Hz sampling rate using a Tobii T300 computer (Tobii Technology, Danderyd, Sweden). The actual data given by the computer represents the percentage of time spent looking at a novel visual target - this is called the novelty score. Visual memory, as indexed by the novelty score, is the percentage of time spent looking at a novel target during the test (visual paired comparison paradigm). Duration of testing was 2 minutes. |
| Visual Attention (Number of Fixations) Assessed by Eye-tracking TX300 Tobii Computer. | Baseline and Final week of treatment (week 32) | Visual attention is indexed by duration and number of fixations on novel target on testing. The standard method of assessing visual attention in neuropsychology is by measuring: A)number of fixations (how many times the subject looks at each of the 2 visual targets). The higher number of fixations, the more attentive the subject to that visual target. B) duration of fixations in seconds (the longer the fixation the more attentive). Duration of fixations correlates with intelligence: the smarter the person is the shorter his fixations are. Eye-tracking data was recorded at 300 Hz sampling rate using a Tobii T300 (Tobii Technology AB, Danderyd, Sweden). The measured index is called the Novelty Score which indicates the percentage of time spent looking at novel visual target. Duration of testing session was 2 minutes. |
| Visual Attention (Fixation Length) Assessed by Eye-tracking TX300 Tobii Computer. | Baseline and Final week of treatment (week 32) | The standard method of assessing visual attention in neuropsychology is by measuring: A)number of fixations (how many times the subject looks at each of the 2 visual targets). The higher number of fixations, the more attentive the subject to that visual target. B) duration of fixations in seconds (the longer the fixation the more attentive). Duration of fixations correlates with intelligence: the smarter the person is the shorter his fixations are. Eye-tracking data was recorded at 300 Hz sampling rate using a Tobii T300 (Tobii Technology AB, Danderyd, Sweden). The measured index is called the Novelty Score which indicates the percentage of time spent looking at novel visual target. Visual attention is indexed by number of fixations on novel target on test. Duration of testing session was 2 minutes. |
Countries
United States
Participant flow
Recruitment details
All participants were recruited between Aug 2014-Jan 2015, from the population treated at the Rett Center at Montefiore. Of 11 screened subjects, 10 met the inclusion/exclusion criteria and completed the trial. One patient was excluded due to prolonged QTc. Data analysis was performed after the first 10 participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Copaxone Dose escalation:
Study drug will be administered once a week for 4 weeks, twice a week for 4 weeks and daily for 24 weeks. Drug is administered as a subcutaneous injection.
Glatiramer Acetate | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Copaxone |
|---|---|
| Age, Categorical <=18 years | 9 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 1 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
Gait Velocity as Measured by GAITRite System
To perform quantitative gait assessments a computerized walkway (457 × 90.2 × 0.64cm) with embedded pressure sensors (GAIT Rite system) was used. Subjects walked on the walkway for two trials, while wearing comfortable footwear.
Time frame: Baseline and Final week of treatment (week 32)
Population: All 10 patients were females with genetically confirmed Rett syndrome. All were at least 10 years old and ambulatory (walking without assistance at the time of their enrollment).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copaxone | Gait Velocity as Measured by GAITRite System | Baseline | 62.7 cm/sec |
| Copaxone | Gait Velocity as Measured by GAITRite System | Final week of treatment (week 32) | 84.3 cm/sec |
p-value: 0.03Wilcoxon (Mann-Whitney)
Secondary
Breath Hold Index (Number of Breath Holds Per Hour; Assessed in the Sleep Monitoring Lab)
Breath hold index is defined as number of breath holds/hour. Respirations were monitored with sleep monitoring equipment during the daytime at the polysomnography laboratory with additional oronasal airflow, electromyography (EMG), EEG and video monitoring to confirm wakefulness during the period of study.
Time frame: Baseline and during final week of treatment (week 32)
Population: One of the 10 enrolled patients experienced panic attack during the respiratory function testing so that session was discontinued. This left 9 participants for final analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copaxone | Breath Hold Index (Number of Breath Holds Per Hour; Assessed in the Sleep Monitoring Lab) | Baseline | 3.8 number of breath holds/hour |
| Copaxone | Breath Hold Index (Number of Breath Holds Per Hour; Assessed in the Sleep Monitoring Lab) | Final week of treatment (week 32) | 1.6 number of breath holds/hour |
p-value: 0.03Wilcoxon (Mann-Whitney)
Secondary
Breath Hold Time (Assessed in the Sleep Monitoring Lab)
Breath Hold Time is defined as percentage of time spent holding the breath in a specific time unit. It is measured by a standard medical technique where belts are placed on the chest and abdomen to record movement and sensors are used to record nasal flow. Wake respiration was monitored with sleep monitoring equipment during the daytime at the polysomnography laboratory with additional oronasal airflow, EMG, EEG and video monitoring to confirm wakefulness during the period of study.
Time frame: Baseline and Final week of treatment (week 32)
Population: One of the 10 enrolled patients experienced panic attack during the respiratory function testing so that session was discontinued. This left 9 participants for final analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copaxone | Breath Hold Time (Assessed in the Sleep Monitoring Lab) | Baseline | 1.8 percentage of time |
| Copaxone | Breath Hold Time (Assessed in the Sleep Monitoring Lab) | Final week of treatment (week 32) | 0.4 percentage of time |
p-value: 0.004Wilcoxon (Mann-Whitney)
Secondary
Visual Attention (Fixation Length) Assessed by Eye-tracking TX300 Tobii Computer.
The standard method of assessing visual attention in neuropsychology is by measuring: A)number of fixations (how many times the subject looks at each of the 2 visual targets). The higher number of fixations, the more attentive the subject to that visual target. B) duration of fixations in seconds (the longer the fixation the more attentive). Duration of fixations correlates with intelligence: the smarter the person is the shorter his fixations are. Eye-tracking data was recorded at 300 Hz sampling rate using a Tobii T300 (Tobii Technology AB, Danderyd, Sweden). The measured index is called the Novelty Score which indicates the percentage of time spent looking at novel visual target. Visual attention is indexed by number of fixations on novel target on test. Duration of testing session was 2 minutes.
Time frame: Baseline and Final week of treatment (week 32)
Population: Only 7 of the 10 recruited participants were able to complete the cognitive assessment. The remaining 3 participants could not be tested due to technical reasons.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copaxone | Visual Attention (Fixation Length) Assessed by Eye-tracking TX300 Tobii Computer. | Baseline | 0.46 seconds |
| Copaxone | Visual Attention (Fixation Length) Assessed by Eye-tracking TX300 Tobii Computer. | Final week of treatment (week 32) | 0.35 seconds |
p-value: 0.44Wilcoxon (Mann-Whitney)
Secondary
Visual Attention (Number of Fixations) Assessed by Eye-tracking TX300 Tobii Computer.
Visual attention is indexed by duration and number of fixations on novel target on testing. The standard method of assessing visual attention in neuropsychology is by measuring: A)number of fixations (how many times the subject looks at each of the 2 visual targets). The higher number of fixations, the more attentive the subject to that visual target. B) duration of fixations in seconds (the longer the fixation the more attentive). Duration of fixations correlates with intelligence: the smarter the person is the shorter his fixations are. Eye-tracking data was recorded at 300 Hz sampling rate using a Tobii T300 (Tobii Technology AB, Danderyd, Sweden). The measured index is called the Novelty Score which indicates the percentage of time spent looking at novel visual target. Duration of testing session was 2 minutes.
Time frame: Baseline and Final week of treatment (week 32)
Population: Only 7 of the 10 recruited participants were able to complete the cognitive assessment. The remaining 3 participants could not be tested due to technical reasons.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copaxone | Visual Attention (Number of Fixations) Assessed by Eye-tracking TX300 Tobii Computer. | Baseline | 19.4 number of fixations |
| Copaxone | Visual Attention (Number of Fixations) Assessed by Eye-tracking TX300 Tobii Computer. | Final week of treatment (week 32) | 16.2 number of fixations |
p-value: 0.86Wilcoxon (Mann-Whitney)
Secondary
Visual Memory Novelty Score as Assessed by TX300 Tobii Computer.
Eye-tracking is considered an indication of visual memory. Eye-tracking data was recorded at 300 Hz sampling rate using a Tobii T300 computer (Tobii Technology, Danderyd, Sweden). The actual data given by the computer represents the percentage of time spent looking at a novel visual target - this is called the novelty score. Visual memory, as indexed by the novelty score, is the percentage of time spent looking at a novel target during the test (visual paired comparison paradigm). Duration of testing was 2 minutes.
Time frame: Baseline and Final week of treatment (week 32)
Population: Only 7 of the 10 recruited participants were able to complete the cognitive assessment. The remaining 3 participants could not be tested due to technical reasons.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Copaxone | Visual Memory Novelty Score as Assessed by TX300 Tobii Computer. | Baseline | 42.4 percentage of time |
| Copaxone | Visual Memory Novelty Score as Assessed by TX300 Tobii Computer. | Final week of treatment (week 32) | 62.4 percentage of time |
p-value: 0.08Wilcoxon (Mann-Whitney)