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| Name | Class |
|---|---|
| The National Fragile X Foundation | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo pill | Placebo Comparator | All patients will be on placebo for 3 months in this crossover study. |
|
| Minocycline | Experimental | All patients will be on minocycline for 3 months in this crossover trial. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| minocycline hydrochloride | Drug | Minocycline hydrochloride dosed orally once a day for 3 months. |
|
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Randi J Hagerman, MD | M.I.N.D. Institute at University of California at Davis, Sacramento CA | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| M.I.N.D. Institute at University of California at Davis Medical Center | Sacramento | California | 95817 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18835858 | Background | Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, Ethell IM. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet. 2009 Feb;46(2):94-102. doi: 10.1136/jmg.2008.061796. Epub 2008 Oct 3. |
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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).
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Placebo First, Minocycline Second | Placebo will be given once daily for 3 months, then minocycline dosed once daily for 3 months |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (Week 1-12) |
| |||||||||||||
| Second Intervention (Week 13-24) |
|
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.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Placebo First, Minocycline Second |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Any participant who completed at least the first arm of the trial were included in the intention to treat analysis | Posted | Least Squares Mean | Standard Error | units on a scale | 3 months (post first treatment) and 6 months (post second treatment) |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Minocycline | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Seizure | Nervous system disorders | Systematic Assessment | The patient was on placebo when this occurred |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | 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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Randi J. Hagerman MD, Medical Director of the MIND Institute | MIND Institute, University of California Davis Medical Center | 916-703-0247 | randi.hagerman@ucdmc.ucdavis.edu |
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| ID | Term |
|---|---|
| D005600 | Fragile X Syndrome |
| C562573 | cyclopia sequence |
| ID | Term |
|---|---|
| D038901 | X-Linked Intellectual Disability |
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
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| ID | Term |
|---|---|
| D008911 | Minocycline |
| ID | Term |
|---|---|
| D013754 | Tetracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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| Placebo | Drug | Placebo will be given daily for 3 months. |
|
| 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 |
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Placebo will be given once daily for 3 months, then minocycline dosed once daily for 3 months
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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. |
|
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| 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. | Any participant who completed at least the first arm of the trial were included in the intention to treat analysis | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months, 6 months |
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|
|
| 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months, 6 months |
|
|
|
| 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months and 6 months |
|
|
|
| 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months, and 6 months |
|
|
|
| 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months, and 6 months |
|
|
|
| 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. | This behavior was not provided by all of the participating caregivers, and so the number is less than the participants analyzed for other measures. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months, 6 months |
|
|
|
| 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. | 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months, 6 months |
|
|
|
| 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. | 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months, 6 months |
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|
|
| 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. | 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months, 6 months |
|
|
|
| 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. | 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. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, 3 months, 6 months |
|
|
|
| 0 |
| 66 |
| 53 |
| 66 |
| EG001 | 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. | 1 | 66 | 53 | 66 |
|
| GI Upset/ Vomiting/Loss of Appetite | Gastrointestinal disorders | Non-systematic Assessment |
|
| Skin Rash/ Itching/ Swelling | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Fever/Chills/URI/Sore Throat | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Sunburn/Sun Sensitivity | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Increased agitation, aggression, tantrums, uncooperative, irritability | Psychiatric disorders | Non-systematic Assessment |
|
| Blue-grey/Grey hue to teeth or other tissues | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
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| D009422 | Nervous System Diseases |
| D025064 | Sex Chromosome Disorders |
| D025063 | Chromosome Disorders |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D040181 | Genetic Diseases, X-Linked |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |