Trial of Minocycline to Treat Children With Fragile X Syndrome

Study Overview
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Brief Summary
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This is a single center study at the UC Davis MIND Institute in patients age 3.5-16 years of age with fragile X syndrome (FXS), funded by a National Fragile X Foundation Grant. It is a controlled trial of minocycline, an antibiotic commonly used in children for infection or for treatment of neurodegenerative disorders. We are investigating its use in FXS because it lowers matrix metalloproteinase 9 (MMP9) levels, which are high in FXS, and it also strengthens brain connections in the animal models of FXS. We hypothesize that minocycline will likely be helpful for language, behavior and/or cognition in fragile X patients.

Detailed Description
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This is a single center study at the UC Davis MIND Institute in patients age 3.5-16 years of age with fragile X syndrome (FXS), funded by a National Fragile X Foundation Grant. It is a controlled trial of minocycline, an antibiotic commonly used in children for infection or for treatment of neurodegenerative disorders. We are investigating its use in FXS because it lowers matrix metalloproteinase 9 (MMP9) levels, which are high in FXS, and it also strengthens brain connections in the animal models of FXS. We hypothesize that minocycline will likely be helpful for language, behavior and/or cognition in fragile X patients. The aim of this study is to carry out a double-blind placebo controlled trial of minocycline treatment in children with FXS who are 3.5 to 16 years of age. At baseline, we will assess behavior and perceptual and cognitive development. After the children have been treated for 3 months with either minocycline or placebo, they undergo the same baseline testing. They will then cross over and be treated for a second 3 months. We will carry out testing again at the end of the second 3 month period. We will also assess the side effects of minocycline treatment throughout the study.

Official Title
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Randomized Double-Blind Controlled Cross Over Trial of Minocycline in Children With Fragile X Syndrome

Conditions
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Fragile X Syndrome

Intervention / Treatment
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* Drug: minocycline hydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have fragile X syndrome with molecular documentation Current pharmacological treatment regimen has been stable for at least 4 weeks Exclusion Criteria: Subjects who plan to initiate or change pharmacologic or non-pharmacologic interventions during the course of the study subjects who are unable to take oral medication subjects who have been on minocycline previously subjects who are allergic to minocycline or tetracyclines subjects who are pregnant subjects with history of lupus or hepatic dysfunction

Ages Eligible for Study
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Minimum Age: 42 Months
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo pill<br>All patients will be on placebo for 3 months in this crossover study. | Drug: Placebo<br>* Placebo will be given daily for 3 months.<br>|
| Experimental: Minocycline<br>All patients will be on minocycline for 3 months in this crossover trial. | Drug: minocycline hydrochloride<br>* Minocycline hydrochloride dosed orally once a day for 3 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression Scale (CGI) | 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. | 3 months (post first treatment) and 6 months (post second treatment) | 
| Visual Analogue Scale- Behavior 1 | 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. | Baseline, 3 months, 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analogue Scale- Behaviors 2 | 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. | Baseline, 3 months, 6 months | 
| Expressive Vocabulary Test-2 | 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. | Baseline, 3 months and 6 months | 
| Vineland Adaptive Behavior Scale-II (VABS-II)Adaptive Behavior Composite Score | 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. | Baseline, 3 months, and 6 months | 
| Aberrant Behavior Checklist-Community Edition (ABC-C)Composite Score | 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. | Baseline, 3 months, and 6 months | 
| Visual Analogue Scale Behavior 3- VAS3 | 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. | Baseline, 3 months, 6 months | 
| VAS Categorized by Behavior: Aggression/ ADHD | 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. | Baseline, 3 months, 6 months | 
| VAS Categorized by Behavior:Anxiety/ Mood | 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. | Baseline, 3 months, 6 months | 
| VAS Categorized by Behavior:Language/ Cognition | 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. | Baseline, 3 months, 6 months | 
| VAS Categorized by Behavior: Other | 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. | Baseline, 3 months, 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fragile X syndrome, minocycline, targeted treatment