Trial Outcomes & Findings for Minocycline in the Treatment of Angelman Syndrome (NCT NCT01531582)

NCT ID: NCT01531582

Last Updated: 2023-04-18

Results Overview

The primary outcome measure consists of improvement in raw and standard scores on the Bayley Scales of Infant and Toddler Development when post Minocycline administration results are compared to baseline results. This is an individually administered test used to asses developmental functioning. The Bayley scales are typically used for ages 1-42 months, and can be utilized to identify developmental delay by evaluating five major areas of development: cognitive, communication, physical, social/emotional, and adaptive. The score ranges for each subscale are as follows: Cognitive, 0-91; Communication, 0-75; Receptive Language, 0-49; Expressive Language, 0-48; Gross Motor, 0-72; Fine Motor, 0-66; Self-Care, 0-72; and Self-Direction, 0-75. Fine and Gross Motor scores were summed for the Motor domain; Receptive and Expressive Language were combined for the Language domain. Increase in raw score indicates improvement in the specific subdomain for each of the listed scales.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 25 participants
• Primary outcome timeframe: Baseline, 8 weeks & 16 weeks
• Results posted on: 2023-04-18

Participant Flow

Participant milestones

Measure	Children With Angelman Syndrome Children with a molecularly confirmed diagnosis of Angelman Syndrome meeting the protocol requirements will be selected randomly. All participants will receive the study drug, minocycline, over an identical time course. Participants will undergo identical baseline, 8 and 16 week follow up assessments. Minocycline: The participant's parent or guardian will be instructed to administer minocycline caplets by mouth twice daily. Parents or guardians will be instructed to avoid dairy products, antacids, or any vitamin preparation that contains any divalent or trivalent cations (e.g. Aluminum, Calcium, Magnesium, etc.) for one hour prior to, and two hours after study medication administration.
Overall Study STARTED	25
Overall Study COMPLETED	24
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Minocycline in the Treatment of Angelman Syndrome

Baseline characteristics by cohort

Measure	Children With Angelman Syndrome n=25 Participants Children with a molecularly confirmed diagnosis of Angelman Syndrome meeting the protocol requirements will be selected randomly. All participants will receive the study drug, minocycline, over an identical time course. Participants will undergo identical baseline, 8 and 16 week follow up assessments. Minocycline: The participant's parent or guardian will be instructed to administer minocycline caplets by mouth twice daily. Parents or guardians will be instructed to avoid dairy products, antacids, or any vitamin preparation that contains any divalent or trivalent cations (e.g. Aluminum, Calcium, Magnesium, etc.) for one hour prior to, and two hours after study medication administration.
Age, Continuous	8.6 years STANDARD_DEVIATION 2.1 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants
Sex: Female, Male Male	14 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 8 weeks & 16 weeks

The primary outcome measure consists of improvement in raw and standard scores on the Bayley Scales of Infant and Toddler Development when post Minocycline administration results are compared to baseline results. This is an individually administered test used to asses developmental functioning. The Bayley scales are typically used for ages 1-42 months, and can be utilized to identify developmental delay by evaluating five major areas of development: cognitive, communication, physical, social/emotional, and adaptive.

The score ranges for each subscale are as follows: Cognitive, 0-91; Communication, 0-75; Receptive Language, 0-49; Expressive Language, 0-48; Gross Motor, 0-72; Fine Motor, 0-66; Self-Care, 0-72; and Self-Direction, 0-75.

Fine and Gross Motor scores were summed for the Motor domain; Receptive and Expressive Language were combined for the Language domain.

Increase in raw score indicates improvement in the specific subdomain for each of the listed scales.

Outcome measures

Measure	Baseline Measures n=24 Participants	8 Weeks After Treatment With Minocycline n=24 Participants	16 Weeks-After 8 Week Washout n=24 Participants
Bayley Scales of Infant and Toddler Development, 2nd Edition (BSID-II) Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Cognitive	26.4 Scores on Scale Standard Deviation 2.48	31.7 Scores on Scale Standard Deviation 1.83	30.7 Scores on Scale Standard Deviation 2.09
Bayley Scales of Infant and Toddler Development, 2nd Edition (BSID-II) Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Communication	18.9 Scores on Scale Standard Deviation 1.6	22.8 Scores on Scale Standard Deviation 1.69	23.5 Scores on Scale Standard Deviation 1.88
Bayley Scales of Infant and Toddler Development, 2nd Edition (BSID-II) Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Receptive Language	13.4 Scores on Scale Standard Deviation 0.61	13.7 Scores on Scale Standard Deviation 0.81	13.8 Scores on Scale Standard Deviation 0.68
Bayley Scales of Infant and Toddler Development, 2nd Edition (BSID-II) Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Expressive Language	10.1 Scores on Scale Standard Deviation 0.76	11.8 Scores on Scale Standard Deviation 0.75	11.2 Scores on Scale Standard Deviation 0.68
Bayley Scales of Infant and Toddler Development, 2nd Edition (BSID-II) Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Gross Motor	41.3 Scores on Scale Standard Deviation 1.69	40.5 Scores on Scale Standard Deviation 1.6	42.8 Scores on Scale Standard Deviation 1.12
Bayley Scales of Infant and Toddler Development, 2nd Edition (BSID-II) Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Fine Motor	19.4 Scores on Scale Standard Deviation 1.05	19.8 Scores on Scale Standard Deviation 1.47	22.4 Scores on Scale Standard Deviation 1.5
Bayley Scales of Infant and Toddler Development, 2nd Edition (BSID-II) Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Self-Care	37.8 Scores on Scale Standard Deviation 1.81	40.6 Scores on Scale Standard Deviation 1.84	40 Scores on Scale Standard Deviation 1.99
Bayley Scales of Infant and Toddler Development, 2nd Edition (BSID-II) Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Self-Direction	3.8 Scores on Scale Standard Deviation 2.24	38.1 Scores on Scale Standard Deviation 1.98	39.5 Scores on Scale Standard Deviation 1.94

SECONDARY outcome

Timeframe: Baseline, 8 and 16 weeks

A scoring system was used to evaluate several aspects of the EEG recordings regardless of whether or not they were a part of AS specific EEG patterns. Points were assigned when a particular characteristic was observed. For instance, when evaluating the EEG background, 1 point was assigned if primarily theta waves (mild slowing, >50%) were observed. When a mixture of theta and delta waves (moderate slowing) were observed, 2 points were assigned. When primarily delta waves (severe slowing, >50%) were recorded 3 points were assigned. Other EEG characteristics were also examined including occipital rhythm (normal-1, slow-2 and absent-3), rhythmic theta (present <50% of time-1, present >50% of time-2) rhythmic delta (present-3) and epileptiform abnormalities (present-1, focal-1, multifocal-1, generalized-1, seizure-2). The points were totaled resulting in a total score, ranging from 0 (most normal) to 24 (most abnormal).

Outcome measures

Measure	Baseline Measures n=24 Participants	8 Weeks After Treatment With Minocycline n=24 Participants	16 Weeks-After 8 Week Washout n=24 Participants
Normalization of the EEG (Electroencephalogram) Signature	9.16 Score Standard Deviation 3.47	8.76 Score Standard Deviation 2.8	8.17 Score Standard Deviation 3.47

SECONDARY outcome

Timeframe: Baseline, 8 and 16 weeks

This test is to measure the adaptive behaviors; the ability to adapt to changes in one's environment, learn new everyday skills and level of independence. It measures social and personal skills via five major domains: communication, daily living skills, socialization, motor skills, and a maladaptive behavioral index. These scales can be used to support the diagnosis of intellectual and developmental disability.

The score ranges for each subdomain are as follows: Receptive Communication, 0-108; Expressive Communication, 0-308; Fine Motor, 0-196; Gross Motor, 0-228; Personal Daily Living Skills, 0-268; Domestic Daily Living Skills, 0-184; Community Daily Living Skills, 0-348; Internalizing Maladaptive Behavior, 0-22; and Externalizing Maladaptive Behavior, 0-20. These raw scores are allocated into the five major domains, and standardized for analysis of results.Increase in raw score indicates improvement in the specific subdomain for each, except for Maladaptive Behavior Scales.

Outcome measures

Measure	Baseline Measures n=24 Participants	8 Weeks After Treatment With Minocycline n=24 Participants	16 Weeks-After 8 Week Washout n=24 Participants
Vineland Adaptive Behavior Scale, 4th Edition (Vineland-II)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Expressive Communication	41.84 Scores on Scale Standard Deviation 15.11	44.28 Scores on Scale Standard Deviation 14.95	43.79 Scores on Scale Standard Deviation 12.64
Vineland Adaptive Behavior Scale, 4th Edition (Vineland-II)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Fine Motor Ability	98.96 Scores on Scale Standard Deviation 35.60	101.2 Scores on Scale Standard Deviation 39.62	95.38 Scores on Scale Standard Deviation 38.45
Vineland Adaptive Behavior Scale, 4th Edition (Vineland-II)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Gross Motor Ability	48.28 Scores on Scale Standard Deviation 16.62	48.92 Scores on Scale Standard Deviation 16.62	49.38 Scores on Scale Standard Deviation 15.90
Vineland Adaptive Behavior Scale, 4th Edition (Vineland-II)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Daily Living Skills - Personal	53.8 Scores on Scale Standard Deviation 28.05	59.12 Scores on Scale Standard Deviation 28.73	56.38 Scores on Scale Standard Deviation 24.28
Vineland Adaptive Behavior Scale, 4th Edition (Vineland-II)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Receptive Communication	30.28 Scores on Scale Standard Deviation 8.10	36.4 Scores on Scale Standard Deviation 12.08	33.88 Scores on Scale Standard Deviation 11.00
Vineland Adaptive Behavior Scale, 4th Edition (Vineland-II)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Daily Living Skills - Domestic	2.6 Scores on Scale Standard Deviation 4.76	3.84 Scores on Scale Standard Deviation 7.46	2.67 Scores on Scale Standard Deviation 4.49
Vineland Adaptive Behavior Scale, 4th Edition (Vineland-II)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Daily Living Skills - Community	6.04 Scores on Scale Standard Deviation 9.09	7.44 Scores on Scale Standard Deviation 9.57	7.08 Scores on Scale Standard Deviation 7.92
Vineland Adaptive Behavior Scale, 4th Edition (Vineland-II)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Maladaptive Behavior - Internalizing	6.68 Scores on Scale Standard Deviation 2.23	5.48 Scores on Scale Standard Deviation 2.35	5.71 Scores on Scale Standard Deviation 2.54
Vineland Adaptive Behavior Scale, 4th Edition (Vineland-II)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Maladaptive Behavior - Externalizing	5.64 Scores on Scale Standard Deviation 2.87	4.68 Scores on Scale Standard Deviation 2.87	6.00 Scores on Scale Standard Deviation 6.12

SECONDARY outcome

Timeframe: Baseline, 8 and 16 weeks

This test is used to evaluate the development of expressive and receptive language development. It also can be used to assess behaviors considered to be language precursors. The PLS use a play-based assessment to provide a comprehensive developmental language appraisal. These scales assess auditory and expressive comprehension. The score ranges for the two subdomains of this measure depend on 16 chronological age ranges from birth - 7 years, with a score range of 0-62 in Auditory Comprehension and 0-68 for Expressive Communication in a 7 year old. Minimum range: 50 (lower language abilities) Maximum range: 150 (higher language abilities). The PLS use a play-based assessment to provide a comprehensive developmental language appraisal. Increase in raw score indicates improvement in the specific subdomain. These raw scores are standardized for analysis and comparison. Standardization does not impact the interpretation of the results

Outcome measures

Measure	Baseline Measures n=24 Participants	8 Weeks After Treatment With Minocycline n=24 Participants	16 Weeks-After 8 Week Washout n=24 Participants
Preschool Language Scale, Fourth Edition (PLS-4)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Auditory Comprehension	17.664 Scores on Scale Standard Deviation 3.43	18.25 Scores on Scale Standard Deviation 2.86	20.47 Scores on Scale Standard Deviation 3.42
Preschool Language Scale, Fourth Edition (PLS-4)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Expressive Communication	16.28 Scores on Scale Standard Deviation 5.72	16.63 Scores on Scale Standard Deviation 4.62	17.48 Scores on Scale Standard Deviation 4.69
Preschool Language Scale, Fourth Edition (PLS-4)Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up Total Language Ability	34.20 Scores on Scale Standard Deviation 7.87	34.88 Scores on Scale Standard Deviation 6.65	38.83 Scores on Scale Standard Deviation 6.43

SECONDARY outcome

Timeframe: Baseline, 8 & 16 weeks

The CGI is a brief assessment used by the clinician to describe the participants condition before and after the administration of a study medication.It is a research rating tool that physicians use to provide a timely assessment of a clinician's view of a particular patient's global functioning before and after the usage of a study medication. The CGI is used to measure the change since the initiation of treatment; both measures 10 questions on a seven-point Likert-type scale ranging from ranging from 1 to 7 points, equaling 10-70 points total, from which the mean is attained. A decrease in mean score indicates improvement in the specific sub-domain.

Outcome measures

Measure	Baseline Measures n=24 Participants	8 Weeks After Treatment With Minocycline n=24 Participants	16 Weeks-After 8 Week Washout n=24 Participants
Clinical Global Impressions Severity Scale Score at Baseline, 8 Weeks After Treatment, and at 16 Week Follow-up	5.5 Scores on Scale Standard Deviation 1.1	4.88 Scores on Scale Standard Deviation 1.03	5.08 Scores on Scale Standard Deviation 1.25

Adverse Events

Children With Angelman Syndrome Receiving Minocycline

Serious events: 3 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Measure	Children With Angelman Syndrome Receiving Minocycline n=25 participants at risk
Congenital, familial and genetic disorders Seizure	12.0% 3/25 • Events were reported to the investigator by the parents of participant throughout the 16 week trial.

Other adverse events

Measure	Children With Angelman Syndrome Receiving Minocycline n=25 participants at risk
Congenital, familial and genetic disorders Lethargy/Sleepiness	8.0% 2/25 • Events were reported to the investigator by the parents of participant throughout the 16 week trial.
Congenital, familial and genetic disorders Difficulty Ambulating	8.0% 2/25 • Events were reported to the investigator by the parents of participant throughout the 16 week trial.
Congenital, familial and genetic disorders Darkening/discoloration over the anterior tibia	4.0% 1/25 • Events were reported to the investigator by the parents of participant throughout the 16 week trial.
Congenital, familial and genetic disorders Commencement of Menstruation	4.0% 1/25 • Events were reported to the investigator by the parents of participant throughout the 16 week trial.
Congenital, familial and genetic disorders Urinary Tract Infection	4.0% 1/25 • Events were reported to the investigator by the parents of participant throughout the 16 week trial.
Congenital, familial and genetic disorders Influenza Type A	4.0% 1/25 • Events were reported to the investigator by the parents of participant throughout the 16 week trial.
Congenital, familial and genetic disorders Feminine yeast Infection	4.0% 1/25 • Events were reported to the investigator by the parents of participant throughout the 16 week trial.

Additional Information

Edwin J. Weeber, Ph.D.

University of South Florida, Morsani College of Medicine

Phone: (813) 396-9995

Email: eweeber@health.usf.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place