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Trial of Minocycline to Treat Children With Fragile X Syndrome

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ClinicalTrials.gov Identifier: NCT01053156
Recruitment Status : Completed
First Posted : January 21, 2010
Results First Posted : July 30, 2014
Last Update Posted : May 30, 2017
Sponsor:
Collaborator:
The National Fragile X Foundation
Information provided by (Responsible Party):
University of California, Davis

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Fragile X Syndrome
Interventions Drug: minocycline hydrochloride
Drug: Placebo
Enrollment 66
Recruitment Details 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.
Pre-assignment Details 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or allergy to tetracyclines. 66 patients enrolled; 55 patients with any data on outcome measures analyzed (11 withdrawn).
Arm/Group Title Minocycline First, Then Placebo Second Placebo First, Minocycline Second
Hide Arm/Group Description Minocycline hydrochloride dosed orally once a day for 3 months, the switched to placebo dosed orally once a day for 3 months. Placebo will be given once daily for 3 months, then minocycline dosed once daily for 3 months
Period Title: First Intervention (Week 1-12)
Started 33 33
Completed 28 27
Not Completed 5 6
Period Title: Second Intervention (Week 13-24)
Started 28 27
Completed 26 22
Not Completed 2 5
Arm/Group Title Minocycline First, Placebo Second Placebo First, Minocycline Second Total
Hide Arm/Group Description Minocycline hydrochloride dosed orally once a day for 3 months, the switched to placebo dosed orally once a day for 3 months. Placebo will be given once daily for 3 months, then minocycline dosed once daily for 3 months Total of all reporting groups
Overall Number of Baseline Participants 28 27 55
Hide Baseline Analysis Population Description
The baseline participants are different in number from those started in the participant flow module because in our intent to treat analysis, only those who completed one or more treatment periods were included in the analysis.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 28 participants 27 participants 55 participants
<=18 years
28
 100.0%
27
 100.0%
55
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 28 participants 27 participants 55 participants
9.01  (3.76) 9.4  (3.39) 9.21  (3.57)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 28 participants 27 participants 55 participants
Female
5
  17.9%
3
  11.1%
8
  14.5%
Male
23
  82.1%
24
  88.9%
47
  85.5%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 28 participants 27 participants 55 participants
28 27 55
1.Primary Outcome
Title Clinical Global Impression Scale (CGI)
Hide Description 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.
Time Frame 3 months (post first treatment) and 6 months (post second treatment)
Hide Outcome Measure Data
Hide Analysis Population Description
Any participant who completed at least the first arm of the trial were included in the intention to treat analysis
Arm/Group Title Minocycline Placebo
Hide Arm/Group Description:
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 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.
Overall Number of Participants Analyzed 55 55
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
2.49  (0.13) 2.97  (0.13)
2.Primary Outcome
Title Visual Analogue Scale- Behavior 1
Hide Description 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.
Time Frame Baseline, 3 months, 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Any participant who completed at least the first arm of the trial were included in the intention to treat analysis
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 55 55 55
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
2.28  (0.21) 4.60  (0.31) 4.44  (0.30)
3.Secondary Outcome
Title Visual Analogue Scale- Behaviors 2
Hide Description 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.
Time Frame Baseline, 3 months, 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 55 55 55
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
2.62  (0.23) 4.91  (0.31) 4.16  (0.29)
4.Secondary Outcome
Title Expressive Vocabulary Test-2
Hide Description 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.
Time Frame Baseline, 3 months and 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 55 55 55
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
65.92  (3.61) 68.86  (1.28) 67.91  (1.20)
5.Secondary Outcome
Title Vineland Adaptive Behavior Scale-II (VABS-II)Adaptive Behavior Composite Score
Hide Description 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.
Time Frame Baseline, 3 months, and 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 55 55 55
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
69.88  (2.00) 70.85  (0.92) 71.43  (0.90)
6.Secondary Outcome
Title Aberrant Behavior Checklist-Community Edition (ABC-C)Composite Score
Hide Description 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.
Time Frame Baseline, 3 months, and 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 55 55 55
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
41.22  (3.44) 44.22  (3.02) 41.81  (2.94)
7.Secondary Outcome
Title Visual Analogue Scale Behavior 3- VAS3
Hide Description 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.
Time Frame Baseline, 3 months, 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
This behavior was not provided by all of the participating caregivers, and so the number is less than the participants analyzed for other measures.
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 50 50 50
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
2.80  (0.27) 4.88  (0.36) 4.13  (0.35)
8.Secondary Outcome
Title VAS Categorized by Behavior: Aggression/ ADHD
Hide Description 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.
Time Frame Baseline, 3 months, 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 46 46 46
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
2.38  (0.20) 4.49  (0.32) 4.26  (0.32)
9.Secondary Outcome
Title VAS Categorized by Behavior:Anxiety/ Mood
Hide Description 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.
Time Frame Baseline, 3 months, 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 26 26 26
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
2.47  (0.25) 5.26  (0.46) 4.05  (0.46)
10.Secondary Outcome
Title VAS Categorized by Behavior:Language/ Cognition
Hide Description 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.
Time Frame Baseline, 3 months, 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 37 37 37
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
2.58  (0.30) 4.99  (0.37) 4.67  (0.34)
11.Secondary Outcome
Title VAS Categorized by Behavior: Other
Hide Description 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.
Time Frame Baseline, 3 months, 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Baseline Minocycline Placebo
Hide Arm/Group Description:
Prior to any intervention being started.
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 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.
Overall Number of Participants Analyzed 12 12 12
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
3.49  (0.66) 5.84  (0.54) 3.41  (0.54)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Minocycline Placebo
Hide Arm/Group Description 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 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.
All-Cause Mortality
Minocycline Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Minocycline Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/66 (0.00%)      1/66 (1.52%)    
Nervous system disorders     
Seizure  [1]  0/66 (0.00%)  0 1/66 (1.52%)  1
Indicates events were collected by systematic assessment
[1]
The patient was on placebo when this occurred
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Minocycline Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   53/66 (80.30%)      53/66 (80.30%)    
Gastrointestinal disorders     
Diarrhea *  15/66 (22.73%)  15 15/66 (22.73%)  15
GI Upset/ Vomiting/Loss of Appetite *  9/66 (13.64%)  9 15/66 (22.73%)  15
Nervous system disorders     
Headache *  4/66 (6.06%)  4 5/66 (7.58%)  5
Psychiatric disorders     
Increased agitation, aggression, tantrums, uncooperative, irritability *  1/66 (1.52%)  1 4/66 (6.06%)  4
Respiratory, thoracic and mediastinal disorders     
Fever/Chills/URI/Sore Throat *  6/66 (9.09%)  6 11/66 (16.67%)  11
Skin and subcutaneous tissue disorders     
Skin Rash/ Itching/ Swelling *  12/66 (18.18%)  12 7/66 (10.61%)  7
Sunburn/Sun Sensitivity *  4/66 (6.06%)  4 1/66 (1.52%)  1
Blue-grey/Grey hue to teeth or other tissues *  3/66 (4.55%)  3 1/66 (1.52%)  1
*
Indicates events were collected by non-systematic assessment
Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding and preliminary efficacy analysis results known to investigators.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Randi J. Hagerman MD, Medical Director of the MIND Institute
Organization: MIND Institute, University of California Davis Medical Center
Phone: 916-703-0247
Responsible Party: University of California, Davis
ClinicalTrials.gov Identifier: NCT01053156     History of Changes
Other Study ID Numbers: 200917522
First Submitted: January 19, 2010
First Posted: January 21, 2010
Results First Submitted: February 8, 2013
Results First Posted: July 30, 2014
Last Update Posted: May 30, 2017