- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02642653
Combining Lovastatin and a Parent-Implemented Language Intervention for Fragile X Syndrome
Combining Lovastatin and a Parent-Implemented Language Intervention in a Multimodal Treatment for Fragile X Syndrome
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This is the first multi-modal treatment to combine a targeted treatment for FXS, lovastatin, with an innovative parent-implemented intervention (PILI) targeting language and challenging behavior delivered through telehealth technology.The hypothesis is that targeted treatments will be more effective when applied in combination with PILI. Examination of whether changes in the activity of key pathways/proteins influenced by fragile X mental retardation protein (FMRP) (the mitogen-activated protein kinase (ERK) and MMP-9) are biomarkers of treatment responsiveness. Because lovastatin is also an anti-inflammatory, characterization of MEK/ERK signaling in peripheral immune cells both pre- and post- treatment will be carried out to determine whether levels of these signaling molecules are predictive biomarkers of treatment response. It is hypothesized that those individuals with elevated inflammatory cytokine profiles will be most responsive to lovastatin treatment. Once modeled in FXS, results from these studies can then be applied to other neurodevelopmental disorders including RASopathies.
The behavioral component of the proposed multi-modal treatment will be a Parent-implemented Intervention (PILI) that targets improvements in spoken language and challenging behavior for 10- to 17-year-olds with FXS by increasing parental verbal responsiveness (PVR) within picture-book based story-telling episodes. Parents will be encouraged to use the targeted strategies in other everyday interactions with their child. The intervention will be delivered to parents in their homes by way of video teleconferencing (VTC). Participants will be randomly assigned to receive the behavioral intervention alone or in combination with Lovastatin.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
California
-
Sacramento, California, United States, 95817
- UC Davis MIND Institute
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Documentation of a full mutation with absence or deficient FMRP levels.
- Males and females ages 10 through 17 years
- Willingness of potential study participant as well as a parent or caretaker to participate in the protocol.
- Speech is the primary means of communication with three-word or longer utterances used on a daily basis.
- Intelligence quotient (IQ) ≤70 as measured by the Leiter- R.
- Sexually active women of childbearing potential (WCBP) must be using a medically acceptable method of birth control and have a negative qualitative serum β-human chorionic growth hormone (β-HCG) or urine pregnancy test collected at the initial screening visit.
Exclusion Criteria:
- Persons who do not speak English.
- Changes in any medications (including investigational medications) within the last month (4 weeks). All concomitant medications must have been on a stable course for at least 4 weeks prior to enrollment into the study and maintain stability throughout the course of the study.
- Changes in behavioral therapy or educational programming during the study. This does not include scheduled school holidays.
- Have any disease or condition (medical or surgical) at screening that might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the investigational product, or would place the subject at increased risk.
- Patients who, in the opinion of the investigator, are unsuitable in any other way to participate in this study, including being unable to comply with the requirements of the study or displaying clinically significant abnormalities in safety assessments at screening.
- Patients on prohibited medications
- History of recurrent status epilepticus.
- Inability to withhold grapefruit and grapefruit juice from diet during the entire clinical trial.
- Subjects unwilling to abstain from alcoholic beverages during the trial.
- Subjects who are actively suicidal.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Lovastatin and PILI
Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin.
|
Once per day dosing
Other Names:
|
Placebo Comparator: Placebo and PILI
Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo.
|
Once per day dosing
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Expressive Language Sample Composite Score in the Home
Time Frame: Baseline
|
The primary outcome reflects the diversity of vocabulary used.
Higher scores reflect more skill.
The lowest possible value is zero.
No theoretical maximum can be defined because the wordless picture books can lead to a large and indeterminate set of options for the amount of talk and the vocabulary used.
In a previous study of a nonpharmacological intervention, the range at baseline was 9-177, and at post-treatment, the range for the combined treated and nontreated groups was 23-214, although these values were not corrected for the number of C-units produced (McDuffie at el. 2018 Developmental Neurorehabilitation).
|
Baseline
|
Expressive Language Sample Composite Score in the Home
Time Frame: 20 weeks
|
The primary outcome reflects the diversity of vocabulary used.
Higher scores reflect more skill.
The lowest possible value is zero.
No theoretical maximum can be defined because the wordless picture books can lead to a large and indeterminate set of options for the amount of talk and the vocabulary used.
In a previous study of a nonpharmacological intervention, the range at baseline was 9-177, and at post-treatment, the range for the combined treated and nontreated groups was 23-214, although these values were not corrected for the number of C-units produced (McDuffie at el. 2018 Developmental Neurorehabilitation).
|
20 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale
Time Frame: Baseline
|
The ABC-C is a 58-item caregiver-rated behavior scale used to examine treatment effects on challenging behaviors for individuals with FXS in the following domains: (1) irritability; (2) lethargy/social withdrawal; (3) stereotypic behavior; (4) hyperactivity; and (5) inappropriate speech.
Caregiver rates the subject's behavior as follows: 0 = not a problem, l = the behavior is a problem but slight in degree, 2 = the problem is moderately serious, 3 = the problem is severe in degree.
Sansone et al. (2012) further subdivided social withdrawal to rate social avoidance in FXS.
The subscale includes 4 items which were originally part of the Lethargy/Withdrawal subscale.
This subscale captures core aspects of the FXS phenotype related to gaze avoidance, social ''escape'' behaviors, and social anxiety.
Subscale score ranges from 0 to 12, higher scores reflect a more problematic behavior.
|
Baseline
|
FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale
Time Frame: 10 weeks
|
The ABC-C is a 58-item caregiver-rated behavior scale used to examine treatment effects on challenging behaviors for individuals with FXS in the following domains: (1) irritability; (2) lethargy/social withdrawal; (3) stereotypic behavior; (4) hyperactivity; and (5) inappropriate speech.
Caregiver rates the subject's behavior as follows: 0 = not a problem, l = the behavior is a problem but slight in degree, 2 = the problem is moderately serious, 3 = the problem is severe in degree.
Sansone et al. (2012) further subdivided social withdrawal to rate social avoidance in FXS.
The subscale includes 4 items which were originally part of the Lethargy/Withdrawal subscale.
This subscale captures core aspects of the FXS phenotype related to gaze avoidance, social ''escape'' behaviors, and social anxiety.
Subscale score ranges from 0 to 12, higher scores reflect a more problematic behavior.
Shown here are the ABC social avoidance subscale mean scores from the 10-weeks follow-up visit.
|
10 weeks
|
FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale
Time Frame: 20 weeks
|
The ABC-C is a 58-item caregiver-rated behavior scale used to examine treatment effects on challenging behaviors for individuals with FXS in the following domains: (1) irritability; (2) lethargy/social withdrawal; (3) stereotypic behavior; (4) hyperactivity; and (5) inappropriate speech.
Caregiver rates the subject's behavior as follows: 0 = not a problem, l = the behavior is a problem but slight in degree, 2 = the problem is moderately serious, 3 = the problem is severe in degree.
Sansone et al. (2012) further subdivided social withdrawal to rate social avoidance in FXS.
The subscale includes 4 items which were originally part of the Lethargy/Withdrawal subscale.
This subscale captures core aspects of the FXS phenotype related to gaze avoidance, social ''escape'' behaviors, and social anxiety.
Subscale score ranges from 0 to 12, higher scores reflect a more problematic behavior.
Shown are the ABC social avoidance subscale mean scores from the 20-weeks end-of-study visit.
|
20 weeks
|
Clinical Global Impression- Severity (CGI-S)
Time Frame: Baseline
|
A clinician rated scale utilizing history from the parents or caregiver and incorporating it into a clinical rating for severity.
The CGI-S was used at the pre-treatment assessment to judge symptom severity.
The 7-point scale ranges from: 1 = Normal; 2 = Borderline Ill; 3 = Mildly Ill; 4 = Moderately Ill; 5 = Markedly Ill; 6 = Severely Ill; and 7 = Extremely Ill.
Therefore, the higher the score, the greater the severity of the patient's illness.
Shown here are the CGI-S mean scores from the baseline visit.
|
Baseline
|
Clinical Global Impression-Improvement (CGI-I) Scale
Time Frame: 10 weeks
|
A clinician rated scale utilizing history from the parents or caregiver and incorporating it into a clinical rating to assess for overall therapeutic response.
The 7-point scale ranges from: 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; and 7 = Very much worse.
Therefore, the lower the score, the greater the overall improvement as rated by the clinician.
The CGI-I was used at the 10 week and 20 week visits.
Shown here are the CGI-I mean scores from the 10-weeks end-of-study visit.
|
10 weeks
|
Clinical Global Impression-Improvement (CGI-I) Scale
Time Frame: 20 weeks
|
A clinician rated scale utilizing history from the parents or caregiver and incorporating it into a clinical rating to assess for overall therapeutic response.
The 7-point scale ranges from: 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; and 7 = Very much worse.
Therefore, the lower the score, the greater the overall improvement as rated by the clinician.
The CGI-I was used at the 10 week and 20 week visits.
Shown here are the CGI-I mean scores from the 20-weeks end-of-study visit.
|
20 weeks
|
Visual Analog Scale (VAS) - Spoken Language Impairment
Time Frame: Baseline
|
The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment.
The distance of the mark from one end is used as the outcome variable for analysis.
Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm.
For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits.
The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much.
Shown here is the mean distance in cm from the "worst behavior" side for the Spoken Language Impairment scale, at baseline.
The smaller the value, the worse the behavior.
The range is minimum 0 cm to maximum 10 cm.
|
Baseline
|
Visual Analog Scale (VAS) - Spoken Language Impairment
Time Frame: 10 weeks
|
The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment.
The distance of the mark from one end is used as the outcome variable for analysis.
Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm.
For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits.
The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much.
Shown here is the mean distance in cm from the "worst behavior" side for the Spoken Language Impairment scale, at 10-weeks.
The smaller the value, the worse the behavior.
The range is minimum 0 cm to maximum 10 cm.
|
10 weeks
|
Visual Analog Scale (VAS) - Spoken Language Impairment
Time Frame: 20 weeks
|
The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment.
The distance of the mark from one end is used as the outcome variable for analysis.
Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm.
For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits.
The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much.
Shown here is the mean distance in cm from the "worst behavior" side for the Spoken Language Impairment scale, at 20-weeks.
The smaller the value, the worse the behavior.
The range is minimum 0 cm to maximum 10 cm.
|
20 weeks
|
Visual Analog Scale (VAS) - Social Impairment
Time Frame: Baseline
|
The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment.
The distance of the mark from one end is used as the outcome variable for analysis.
Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm.
For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits.
The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much.
Shown here is the mean distance in cm from the "worst behavior" side for the Social Impairment scale, at baseline.
The smaller the value, the worse the behavior.
The range is minimum 0 cm to maximum 10 cm.
|
Baseline
|
Visual Analog Scale (VAS) - Social Impairment
Time Frame: 10-weeks
|
The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment.
The distance of the mark from one end is used as the outcome variable for analysis.
Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm.
For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits.
The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much.
Shown here is the mean distance in cm from the "worst behavior" side for the Social Impairment scale, at 10-weeks.
The smaller the value, the worse the behavior.
The range is minimum 0 cm to maximum 10 cm.
|
10-weeks
|
Visual Analog Scale (VAS) - Social Impairment
Time Frame: 20-weeks
|
The measure was used to assess parental impressions of progress in two key symptoms: spoken language impairment and social impairment.
The distance of the mark from one end is used as the outcome variable for analysis.
Caregivers mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm.
For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 10-weeks and 20-weeks visits.
The calculated distance in cm between the marks drawn at the baseline and follow-up visits thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much.
Shown here is the mean distance in cm from the "worst behavior" side for the Social Impairment scale, at 20-weeks.
The smaller the value, the worse the behavior.
The range is minimum 0 cm to maximum 10 cm.
|
20-weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Randi J Hagerman, MD, UC Davis
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Neurologic Manifestations
- Neurobehavioral Manifestations
- Disease
- Congenital Abnormalities
- Genetic Diseases, X-Linked
- Mental Retardation, X-Linked
- Intellectual Disability
- Heredodegenerative Disorders, Nervous System
- Chromosome Disorders
- Sex Chromosome Disorders
- Syndrome
- Fragile X Syndrome
- Genetic Diseases, Inborn
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites
- Anticholesteremic Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Lovastatin
- L 647318
- Dihydromevinolin
Other Study ID Numbers
- 520144
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Fragile X Syndrome
-
University of California, DavisNational Institute of Mental Health (NIMH)CompletedFragile X PremutationUnited States
-
University of California, DavisNational Institute on Aging (NIA); Forest LaboratoriesCompletedFragile X-Associated Tremor/Ataxia Syndrome | Fragile X Premutation CarriersUnited States
-
Ovid Therapeutics Inc.CompletedFragile X Syndrome (FXS)United States
-
Guido A. Davidzon, MD, SMWithdrawn
-
Marinus PharmaceuticalsUniversity of California, Davis; U.S. Army Medical Research and Development...Completed
-
RTI InternationalEunice Kennedy Shriver National Institute of Child Health and Human Development...CompletedFragile X Syndrome (FXS)United States
-
Novartis PharmaceuticalsTerminated
-
Sheba Medical CenterElMindA LtdRecruitingFragile X Associated Tremor-ataxia Syndrome | FXTASIsrael
-
University of California, DavisUniversity of Alberta; St. Justine's HospitalRecruitingNeurobehavioral Manifestations | Genetic Diseases, X-Linked | Intellectual Disability | Fragile X Syndrome | Sex Chromosome Disorders | Fragile X Mental Retardation Syndrome | Trinucleotide Repeat Expansion | Fra(X) Syndrome | FXS | Mental Retardation, X LinkedUnited States, Canada
-
University of AlbertaSt. Justine's HospitalRecruitingNeurobehavioral Manifestations | Genetic Diseases, X-Linked | Mental Retardation, X-Linked | Intellectual Disability | Fragile X Syndrome | Sex Chromosome Disorders | Fragile X Mental Retardation Syndrome | Trinucleotide Repeat Expansion | Fra(X) Syndrome | FXSCanada
Clinical Trials on Lovastatin
-
Université de SherbrookeFRAXA Research FoundationCompletedFragile X SyndromeCanada
-
Medical University of South CarolinaCompletedActinic PorokeratosisUnited States
-
Mutual Pharmaceutical Company, Inc.Completed
-
Mitchell S ElkindNational Institute of Neurological Disorders and Stroke (NINDS)CompletedStroke | Jaundice | RhabdomyolysisUnited States
-
Mutual Pharmaceutical Company, Inc.Completed
-
National Cancer Institute (NCI)CompletedPrecancerous Condition | Stage II Melanoma | Stage 0 Melanoma | Stage I MelanomaUnited States
-
National Heart, Lung, and Blood Institute (NHLBI)CompletedMyocardial Ischemia | Heart Diseases | Cardiovascular Diseases | Coronary Disease | Atherosclerosis | Hypercholesterolemia
-
Merck Sharp & Dohme LLCCompletedCoronary Artery Disease | AtherosclerosisUnited States
-
Columbia UniversityCompletedStrokeUnited States
-
National Taiwan University HospitalUnknownParkinson DiseaseTaiwan