Trial Outcomes & Findings for Trial of Minocycline to Treat Children With Fragile X Syndrome (NCT NCT01053156)

NCT ID: NCT01053156

Last Updated: 2017-05-30

Results Overview

The CGI-I utilizes history from primary caregivers and incorporates it into a seven step clinical rating for follow up throughout treatment, from 1 "very much improved" to 7 "very much worse". Lower scores indicate more improvement. Scores were obtained post treatments. Scores from when the patients were on minocycline either first or second were combined and averaged to determine a least squares mean and placebo scores were obtained in the same manner.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 66 participants
• Primary outcome timeframe: 3 months (post first treatment) and 6 months (post second treatment)
• Results posted on: 2017-05-30

Participant Flow

Recruitment occurred from January 2010 to June 2011, with the last participants completing the study in December 2011. The study site was a single site, the MIND Institute at the University of California Davis Medical Center.

Inclusion criteria: FXS confirmed by FMR1 DNA, age 3.5-16 years and stable pharmacological regimen > 4 weeks prior to study. Exclusion criteria:previous minocycline treatment, plans to change pharmacological intervention or allergy to tetracyclines. 66 patients enrolled; 55 patients with any data on outcome measures analyzed (11 withdrawn).

Participant milestones

Measure	Minocycline First, Then Placebo Second Minocycline hydrochloride dosed orally once a day for 3 months, the switched to placebo dosed orally once a day for 3 months.	Placebo First, Minocycline Second Placebo will be given once daily for 3 months, then minocycline dosed once daily for 3 months
First Intervention (Week 1-12) STARTED	33	33
First Intervention (Week 1-12) COMPLETED	28	27
First Intervention (Week 1-12) NOT COMPLETED	5	6
Second Intervention (Week 13-24) STARTED	28	27
Second Intervention (Week 13-24) COMPLETED	26	22
Second Intervention (Week 13-24) NOT COMPLETED	2	5

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Trial of Minocycline to Treat Children With Fragile X Syndrome

Baseline characteristics by cohort

Measure	Minocycline First, Placebo Second n=28 Participants Minocycline hydrochloride dosed orally once a day for 3 months, the switched to placebo dosed orally once a day for 3 months.	Placebo First, Minocycline Second n=27 Participants Placebo will be given once daily for 3 months, then minocycline dosed once daily for 3 months	Total n=55 Participants Total of all reporting groups
Age, Categorical <=18 years	28 Participants n=5 Participants	27 Participants n=7 Participants	55 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	9.01 years STANDARD_DEVIATION 3.76 • n=5 Participants	9.4 years STANDARD_DEVIATION 3.39 • n=7 Participants	9.21 years STANDARD_DEVIATION 3.57 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	24 Participants n=7 Participants	47 Participants n=5 Participants
Region of Enrollment United States	28 participants n=5 Participants	27 participants n=7 Participants	55 participants n=5 Participants

PRIMARY outcome

Timeframe: 3 months (post first treatment) and 6 months (post second treatment)

Population: Any participant who completed at least the first arm of the trial were included in the intention to treat analysis

The CGI-I utilizes history from primary caregivers and incorporates it into a seven step clinical rating for follow up throughout treatment, from 1 "very much improved" to 7 "very much worse". Lower scores indicate more improvement. Scores were obtained post treatments. Scores from when the patients were on minocycline either first or second were combined and averaged to determine a least squares mean and placebo scores were obtained in the same manner.

Outcome measures

Measure	Minocycline n=55 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=55 Participants Prior to any intervention being started.
Clinical Global Impression Scale (CGI)	2.97 units on a scale Standard Error 0.13	—	2.49 units on a scale Standard Error 0.13

PRIMARY outcome

Timeframe: Baseline, 3 months, 6 months

Population: Any participant who completed at least the first arm of the trial were included in the intention to treat analysis

A VAS is used to represent a caregiver's assessment of given behaviors, which were chosen by the parents. Caregivers marked a 10 cm horizontal line representing a visual continuum of each behavior from "worst behavior" to "behavior not a problem." Greater values indicate greater improvement. This measure represents the first behavior that the caregivers noted, out of three.

Outcome measures

Measure	Minocycline n=55 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=55 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=55 Participants Prior to any intervention being started.
Visual Analogue Scale- Behavior 1	4.60 units on a scale Standard Error 0.31	4.44 units on a scale Standard Error 0.30	2.28 units on a scale Standard Error 0.21

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months

A VAS is used to represent a caregiver's assessment of given behaviors, which were chosen by the parents. Caregivers marked a 10 cm horizontal line representing a visual continuum of each behavior from "worst behavior" to "behavior not a problem." Greater values indicate greater improvement. This measure represents the second behavior that the caregivers noted, out of three.

Outcome measures

Measure	Minocycline n=55 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=55 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=55 Participants Prior to any intervention being started.
Visual Analogue Scale- Behaviors 2	4.91 units on a scale Standard Error 0.31	4.16 units on a scale Standard Error 0.29	2.62 units on a scale Standard Error 0.23

SECONDARY outcome

Timeframe: Baseline, 3 months and 6 months

The EVT-2 standard score assesses language development through a participant's one word synonym response to visual stimuli. Standard scores range from 20-160. A standard score of 100 is average, with a 15 point standard deviation. Higher values represent a better outcome.

Outcome measures

Measure	Minocycline n=55 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=55 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=55 Participants Prior to any intervention being started.
Expressive Vocabulary Test-2	68.86 units on a scale Standard Error 1.28	67.91 units on a scale Standard Error 1.20	65.92 units on a scale Standard Error 3.61

SECONDARY outcome

Timeframe: Baseline, 3 months, and 6 months

The VABS-II Adaptive Behavior Composite Score was used to assess adaptive skills. An Adaptive Behavior Composite Score may range from 20-160 with an average of 100 with a standard deviation of 15. Higher scores show improvement.

Outcome measures

Measure	Minocycline n=55 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=55 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=55 Participants Prior to any intervention being started.
Vineland Adaptive Behavior Scale-II (VABS-II)Adaptive Behavior Composite Score	70.85 units on a scale Standard Error 0.92	71.43 units on a scale Standard Error 0.90	69.88 units on a scale Standard Error 2.00

SECONDARY outcome

Timeframe: Baseline, 3 months, and 6 months

The ABC-C composite scores were used to quantify the severity of a patient's behaviors. A composite score consists of subscale scores including Irritability and Agitation, Lethargy and Social Withdrawal, Stereotypic Behavior, Hyperactivity and Noncompliance, and Inappropriate Speech. The composite score may range from 0-174. Lower scores indicate improvement.

Outcome measures

Measure	Minocycline n=55 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=55 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=55 Participants Prior to any intervention being started.
Aberrant Behavior Checklist-Community Edition (ABC-C)Composite Score	44.22 units on a scale Standard Error 3.02	41.81 units on a scale Standard Error 2.94	41.22 units on a scale Standard Error 3.44

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months

Population: This behavior was not provided by all of the participating caregivers, and so the number is less than the participants analyzed for other measures.

A VAS is used to represent a caregiver's assessment of given behaviors, which were chosen by the parents. Caregivers marked a 10 cm horizontal line representing a visual continuum of each behavior from "worst behavior" to "behavior not a problem." Greater values indicate greater improvement. This measure represents the third behavior that caregivers noted, out of three.

Outcome measures

Measure	Minocycline n=50 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=50 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=50 Participants Prior to any intervention being started.
Visual Analogue Scale Behavior 3- VAS3	4.88 units on a scale Standard Error 0.36	4.13 units on a scale Standard Error 0.35	2.80 units on a scale Standard Error 0.27

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months

Population: In this ad hoc analysis, the various behaviors captured on the VAS were categorized and any behaviors regarding ADHD or Aggression symptoms were placed into this category. As not every caregiver named a behavior related to ADHD or aggression, this number is less than the number of participants.

A VAS is used to represent a caregiver's assessment of given behaviors, which were chosen by the parents. Caregivers marked a 10 cm horizontal line representing a visual continuum of each behavior from "worst behavior" to "behavior not a problem." Greater values indicate greater improvement. This measure represents the least squares mean of all behaviors having to do with aggression or ADHD behaviors.

Outcome measures

Measure	Minocycline n=46 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=46 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=46 Participants Prior to any intervention being started.
VAS Categorized by Behavior: Aggression/ ADHD	4.49 units on a scale Standard Error 0.32	4.26 units on a scale Standard Error 0.32	2.38 units on a scale Standard Error 0.20

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months

Population: In this ad hoc analysis, the various behaviors captured on the VAS were categorized and any behaviors regarding anxiety or mood symptoms were placed into this category. As not every caregiver named a behavior related to anxiety or mood, this number is less than the number of participants.

A VAS is used to represent a caregiver's assessment of given behaviors, which were chosen by the parents. Caregivers marked a 10 cm horizontal line representing a visual continuum of each behavior from "worst behavior" to "behavior not a problem." Greater values indicate greater improvement. This measure represents the least squares mean of all behaviors having to do with anxiety or mood related behaviors.

Outcome measures

Measure	Minocycline n=26 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=26 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=26 Participants Prior to any intervention being started.
VAS Categorized by Behavior:Anxiety/ Mood	5.26 units on a scale Standard Error 0.46	4.05 units on a scale Standard Error 0.46	2.47 units on a scale Standard Error 0.25

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months

Population: In this ad hoc analysis, the various behaviors captured on the VAS were categorized and any behaviors regarding language or cognition symptoms were placed into this category. As not every caregiver named a behavior related to language or cognition, this number is less than the number of participants.

A VAS is used to represent a caregiver's assessment of given behaviors, which were chosen by the parents. Caregivers marked a 10 cm horizontal line representing a visual continuum of each behavior from "worst behavior" to "behavior not a problem." Greater values indicate greater improvement. This measure represents the least squares mean of all behaviors having to do with language or cognitive symptoms.

Outcome measures

Measure	Minocycline n=37 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=37 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=37 Participants Prior to any intervention being started.
VAS Categorized by Behavior:Language/ Cognition	4.99 units on a scale Standard Error 0.37	4.67 units on a scale Standard Error 0.34	2.58 units on a scale Standard Error 0.30

SECONDARY outcome

Timeframe: Baseline, 3 months, 6 months

Population: In this ad hoc analysis, the various behaviors captured on the VAS were categorized and any behaviors not falling into the other categories were placed into this category. As not every caregiver named a behavior unrelated to the other categories, this number is less than the number of participants.

A VAS is used to represent a caregiver's assessment of given behaviors, which were chosen by the parents. Caregivers marked a 10 cm horizontal line representing a visual continuum of each behavior from "worst behavior" to "behavior not a problem." Greater values indicate greater improvement. This measure represents the least squares mean of all behaviors having to do with other behaviors that were not able to be categorized.

Outcome measures

Measure	Minocycline n=12 Participants Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=12 Participants Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Baseline n=12 Participants Prior to any intervention being started.
VAS Categorized by Behavior: Other	5.84 units on a scale Standard Error 0.54	3.41 units on a scale Standard Error 0.54	3.49 units on a scale Standard Error 0.66

Adverse Events

Minocycline

Serious events: 0 serious events

Other events: 53 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 53 other events

Deaths: 0 deaths

Serious adverse events

Measure	Minocycline n=66 participants at risk Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=66 participants at risk Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.
Nervous system disorders Seizure	0.00% 0/66	1.5% 1/66 • Number of events 1

Other adverse events

Measure	Minocycline n=66 participants at risk Minocycline dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.	Placebo n=66 participants at risk Placebo dosage was assigned based on weight, with patients weighing up to 25 kg receiving 25mg once daily, those weighing between 25 and 45 kg receiving 50 mg once daily, and those weighing \>45 kg receiving 100 mg once daily.
Gastrointestinal disorders Diarrhea	22.7% 15/66 • Number of events 15	22.7% 15/66 • Number of events 15
Gastrointestinal disorders GI Upset/ Vomiting/Loss of Appetite	13.6% 9/66 • Number of events 9	22.7% 15/66 • Number of events 15
Skin and subcutaneous tissue disorders Skin Rash/ Itching/ Swelling	18.2% 12/66 • Number of events 12	10.6% 7/66 • Number of events 7
Respiratory, thoracic and mediastinal disorders Fever/Chills/URI/Sore Throat	9.1% 6/66 • Number of events 6	16.7% 11/66 • Number of events 11
Nervous system disorders Headache	6.1% 4/66 • Number of events 4	7.6% 5/66 • Number of events 5
Skin and subcutaneous tissue disorders Sunburn/Sun Sensitivity	6.1% 4/66 • Number of events 4	1.5% 1/66 • Number of events 1
Psychiatric disorders Increased agitation, aggression, tantrums, uncooperative, irritability	1.5% 1/66 • Number of events 1	6.1% 4/66 • Number of events 4
Skin and subcutaneous tissue disorders Blue-grey/Grey hue to teeth or other tissues	4.5% 3/66 • Number of events 3	1.5% 1/66 • Number of events 1

Additional Information

Randi J. Hagerman MD, Medical Director of the MIND Institute

MIND Institute, University of California Davis Medical Center

Phone: 916-703-0247

Email: randi.hagerman@ucdmc.ucdavis.edu

Results disclosure agreements

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