Pharmacological Treatment of Rett Syndrome With Glatiramer Acetate (Copaxone)

• ClinicalTrials.gov Identifier: NCT02153723
• Recruitment Status: Completed
• First Posted: June 3, 2014
• Results First Posted: November 5, 2018
• Last Update Posted: November 5, 2018
• Sponsor: Montefiore Medical Center
• Collaborator: Rett Syndrome Research Trust
• Information provided by (Responsible Party): Aleksandra Djukic, Montefiore Medical Center

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Rett Syndrome
• Intervention: Drug: Glatiramer Acetate
• Enrollment: 10

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.
Pre-assignment Details

Arm/Group Title	Copaxone
Arm/Group Description	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
Period Title: Overall Study
Started	10
Completed	10
Not Completed	0

Baseline Characteristics

Arm/Group Title		Copaxone
Arm/Group Description		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
Overall Number of Baseline Participants		10
Baseline Analysis Population Description		All enrolled participants were female, ambulatory, and had been previously diagnosed with Rett syndrome.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	10 participants
	<=18 years	9 90.0%
	Between 18 and 65 years	1 10.0%
	>=65 years	0 0.0%
Sex: Female, Male [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	10 participants
	Female	10 100.0%
	Male	0 0.0%
		[1] Measure Description: All participants were female
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	10 participants
		10

Outcome Measures

1. Primary Outcome

Title	Gait Velocity as Measured by GAITRite System
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Copaxone
Arm/Group Description:	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
Overall Number of Participants Analyzed	10
Median (Inter-Quartile Range); Unit of Measure: cm/sec
Baseline	62.7; (42.3 to 103.2)
Final week of treatment (week 32)	84.3; (58.1 to 119.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Copaxone
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Wilcoxon signed rank sum test
Statistical Test of Hypothesis	P-Value	0.03
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	21.6
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Breath Hold Index (Number of Breath Holds Per Hour; Assessed in the Sleep Monitoring Lab)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Copaxone
Arm/Group Description:	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
Overall Number of Participants Analyzed	9
Median (Inter-Quartile Range); Unit of Measure: number of breath holds/hour
Baseline	3.8; (2.3 to 7.3)
Final week of treatment (week 32)	1.6; (0.3 to 2.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Copaxone
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Wilcoxon signed rank sum test
Statistical Test of Hypothesis	P-Value	0.03
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-2.0
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Breath Hold Time (Assessed in the Sleep Monitoring Lab)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Copaxone
Arm/Group Description:	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
Overall Number of Participants Analyzed	9
Median (Inter-Quartile Range); Unit of Measure: percentage of time
Baseline	1.8; (0.8 to 2.3)
Final week of treatment (week 32)	0.4; (0.1 to 0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Copaxone
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Wilcoxon signed rank sum test
Statistical Test of Hypothesis	P-Value	0.004
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.1
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Visual Memory Novelty Score as Assessed by TX300 Tobii Computer.
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Copaxone
Arm/Group Description:	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
Overall Number of Participants Analyzed	7
Median (Inter-Quartile Range); Unit of Measure: percentage of time
Baseline	42.4; (39.5 to 61.0)
Final week of treatment (week 32)	62.4; (55.7 to 65.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Copaxone
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Wilcoxon signed rank sum test
Statistical Test of Hypothesis	P-Value	0.08
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	15.9
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Visual Attention (Number of Fixations) Assessed by Eye-tracking TX300 Tobii Computer.
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Copaxone
Arm/Group Description:	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
Overall Number of Participants Analyzed	7
Median (Inter-Quartile Range); Unit of Measure: number of fixations
Baseline	19.4; (8.0 to 20.8)
Final week of treatment (week 32)	16.2; (11.0 to 27.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Copaxone
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Wilcoxon signed rank sum test
Statistical Test of Hypothesis	P-Value	0.86
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Visual Attention (Fixation Length) Assessed by Eye-tracking TX300 Tobii Computer.
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Copaxone
Arm/Group Description:	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
Overall Number of Participants Analyzed	7
Median (Inter-Quartile Range); Unit of Measure: seconds
Baseline	0.46; (0.26 to 0.64)
Final week of treatment (week 32)	0.35; (0.18 to 0.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Copaxone
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Wilcoxon signed rank sum test
Statistical Test of Hypothesis	P-Value	0.44
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.00
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Copaxone
Arm/Group Description	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
All-Cause Mortality
	Copaxone
	Affected / at Risk (%)
Total	0/10 (0.00%)
Serious Adverse Events
	Copaxone
	Affected / at Risk (%)	# Events
Total	0/10 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Copaxone
	Affected / at Risk (%)	# Events
Total	1/10 (10.00%)
Musculoskeletal and connective tissue disorders
laboratory result (elevated CPK) without clinical correlate, transitory † [1]	1/10 (10.00%)	1
† Indicates events were collected by systematic assessment; [1] not sympromatic

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Aleksandra Djukic
• Organization: Montefiore Medical Center
• Phone: 718 920 4378
• EMail: adjukic@montefiore.org

Publications of Results:

Djukic A, Holtzer R, Shinnar S, Muzumdar H, Rose SA, Mowrey W, Galanopoulou AS, Shinnar R, Jankowski JJ, Feldman JF, Pillai S, Moshe SL. Pharmacologic Treatment of Rett Syndrome With Glatiramer Acetate. Pediatr Neurol. 2016 Aug;61:51-7. doi: 10.1016/j.pediatrneurol.2016.05.010. Epub 2016 May 27.

• Responsible Party: Aleksandra Djukic, Montefiore Medical Center
• ClinicalTrials.gov Identifier: NCT02153723
• Other Study ID Numbers: 13-05-117
• First Submitted: May 26, 2014
• First Posted: June 3, 2014
• Results First Submitted: July 20, 2015
• Results First Posted: November 5, 2018
• Last Update Posted: November 5, 2018