Fragile X Syndrome
Conditions
Keywords
Fragile X syndrome, minocycline, targeted treatment
Brief summary
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
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.
Interventions
Minocycline hydrochloride dosed orally once a day for 3 months.
DRUGPlacebo
Placebo will be given daily for 3 months.
Sponsors
The National Fragile X Foundation
University of California, Davis
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
42 Months to 16 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression Scale (CGI) | 3 months (post first treatment) and 6 months (post second treatment) | 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. |
| Visual Analogue Scale- Behavior 1 | 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 first behavior that the caregivers noted, out of three. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Vineland Adaptive Behavior Scale-II (VABS-II)Adaptive Behavior Composite Score | 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. |
| Aberrant Behavior Checklist-Community Edition (ABC-C)Composite Score | 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. |
| Visual Analogue Scale Behavior 3- VAS3 | 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 third behavior that caregivers noted, out of three. |
| Visual Analogue Scale- Behaviors 2 | 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. |
| VAS Categorized by Behavior:Anxiety/ Mood | 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 least squares mean of all behaviors having to do with anxiety or mood related behaviors. |
| VAS Categorized by Behavior:Language/ Cognition | 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 least squares mean of all behaviors having to do with language or cognitive symptoms. |
| VAS Categorized by Behavior: Other | 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 least squares mean of all behaviors having to do with other behaviors that were not able to be categorized. |
| VAS Categorized by Behavior: Aggression/ ADHD | 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 least squares mean of all behaviors having to do with aggression or ADHD behaviors. |
| Expressive Vocabulary Test-2 | 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. |
Countries
United States
Participant flow
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).
Participants by arm
| Arm | Count |
|---|---|
| Minocycline First, Placebo Second Minocycline hydrochloride dosed orally once a day for 3 months, the switched to placebo dosed orally once a day for 3 months. | 28 |
| Placebo First, Minocycline Second Placebo will be given once daily for 3 months, then minocycline dosed once daily for 3 months | 27 |
| Total | 55 |
Baseline characteristics
| Characteristic | Placebo First, Minocycline Second | Minocycline First, Placebo Second | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 27 Participants | 28 Participants | 55 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 9.4 years STANDARD_DEVIATION 3.39 | 9.01 years STANDARD_DEVIATION 3.76 | 9.21 years STANDARD_DEVIATION 3.57 |
| Region of Enrollment United States | 27 participants | 28 participants | 55 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 24 Participants | 23 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 53 / 66 | 53 / 66 |
| serious Total, serious adverse events | 0 / 66 | 1 / 66 |
Outcome results
Primary
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.
Time frame: 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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Clinical Global Impression Scale (CGI) | 2.49 units on a scale | Standard Error 0.13 |
| Placebo | Clinical Global Impression Scale (CGI) | 2.97 units on a scale | Standard Error 0.13 |
Primary
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.
Time frame: 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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Visual Analogue Scale- Behavior 1 | 2.28 units on a scale | Standard Error 0.21 |
| Placebo | Visual Analogue Scale- Behavior 1 | 4.60 units on a scale | Standard Error 0.31 |
| Placebo | Visual Analogue Scale- Behavior 1 | 4.44 units on a scale | Standard Error 0.3 |
Secondary
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.
Time frame: Baseline, 3 months, and 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Aberrant Behavior Checklist-Community Edition (ABC-C)Composite Score | 41.22 units on a scale | Standard Error 3.44 |
| Placebo | Aberrant Behavior Checklist-Community Edition (ABC-C)Composite Score | 44.22 units on a scale | Standard Error 3.02 |
| Placebo | Aberrant Behavior Checklist-Community Edition (ABC-C)Composite Score | 41.81 units on a scale | Standard Error 2.94 |
Secondary
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.
Time frame: Baseline, 3 months and 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Expressive Vocabulary Test-2 | 65.92 units on a scale | Standard Error 3.61 |
| Placebo | Expressive Vocabulary Test-2 | 68.86 units on a scale | Standard Error 1.28 |
| Placebo | Expressive Vocabulary Test-2 | 67.91 units on a scale | Standard Error 1.2 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | VAS Categorized by Behavior: Aggression/ ADHD | 2.38 units on a scale | Standard Error 0.2 |
| Placebo | VAS Categorized by Behavior: Aggression/ ADHD | 4.49 units on a scale | Standard Error 0.32 |
| Placebo | VAS Categorized by Behavior: Aggression/ ADHD | 4.26 units on a scale | Standard Error 0.32 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | VAS Categorized by Behavior:Anxiety/ Mood | 2.47 units on a scale | Standard Error 0.25 |
| Placebo | VAS Categorized by Behavior:Anxiety/ Mood | 5.26 units on a scale | Standard Error 0.46 |
| Placebo | VAS Categorized by Behavior:Anxiety/ Mood | 4.05 units on a scale | Standard Error 0.46 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | VAS Categorized by Behavior:Language/ Cognition | 2.58 units on a scale | Standard Error 0.3 |
| Placebo | VAS Categorized by Behavior:Language/ Cognition | 4.99 units on a scale | Standard Error 0.37 |
| Placebo | VAS Categorized by Behavior:Language/ Cognition | 4.67 units on a scale | Standard Error 0.34 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | VAS Categorized by Behavior: Other | 3.49 units on a scale | Standard Error 0.66 |
| Placebo | VAS Categorized by Behavior: Other | 5.84 units on a scale | Standard Error 0.54 |
| Placebo | VAS Categorized by Behavior: Other | 3.41 units on a scale | Standard Error 0.54 |
Secondary
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.
Time frame: Baseline, 3 months, and 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Vineland Adaptive Behavior Scale-II (VABS-II)Adaptive Behavior Composite Score | 69.88 units on a scale | Standard Error 2 |
| Placebo | Vineland Adaptive Behavior Scale-II (VABS-II)Adaptive Behavior Composite Score | 70.85 units on a scale | Standard Error 0.92 |
| Placebo | Vineland Adaptive Behavior Scale-II (VABS-II)Adaptive Behavior Composite Score | 71.43 units on a scale | Standard Error 0.9 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Visual Analogue Scale Behavior 3- VAS3 | 2.80 units on a scale | Standard Error 0.27 |
| Placebo | Visual Analogue Scale Behavior 3- VAS3 | 4.88 units on a scale | Standard Error 0.36 |
| Placebo | Visual Analogue Scale Behavior 3- VAS3 | 4.13 units on a scale | Standard Error 0.35 |
Secondary
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.
Time frame: Baseline, 3 months, 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Minocycline | Visual Analogue Scale- Behaviors 2 | 2.62 units on a scale | Standard Error 0.23 |
| Placebo | Visual Analogue Scale- Behaviors 2 | 4.91 units on a scale | Standard Error 0.31 |
| Placebo | Visual Analogue Scale- Behaviors 2 | 4.16 units on a scale | Standard Error 0.29 |