Combining Lovastatin and a Parent-Implemented Language Intervention for Fragile X Syndrome

• ClinicalTrials.gov Identifier: NCT02642653
• Recruitment Status: Completed
• First Posted: December 30, 2015
• Results First Posted: September 11, 2019
• Last Update Posted: September 11, 2019
• Sponsor: University of California, Davis
• Information provided by (Responsible Party): University of California, Davis

Tracking Information

• First Submitted Date: December 21, 2015
• First Posted Date: December 30, 2015
• Results First Submitted Date: July 23, 2019
• Results First Posted Date: September 11, 2019
• Last Update Posted Date: September 11, 2019
• Actual Study Start Date: January 2016
• Actual Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 22, 2019)

• 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).
• 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).

Original Primary Outcome Measures (submitted: December 28, 2015)

Change from baseline in the participant and mother Expressive Language Sample composite score [ Time Frame: Baseline, 20 weeks ]

The expressive language sample is collected from shared interactions around a digital wordless picture book involving the participant with fragile X syndrome and his mother. The composite is created from separate measures of the number of different words used by the participant and the mean length of his communication units measured in morphemes. Samples are collected pre- and post-treatment using different digital books on each occasion, with improvement in the composite expected from pre to post.

Current Secondary Outcome Measures (submitted: August 22, 2019)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: December 28, 2015)

• Change from baseline in the participant and examiner Expressive Language Sample composite score [ Time Frame: Baseline, 20 weeks ]
  The expressive language sample is collected from shared interactions around a wordless picture book involving the participant with fragile X syndrome and an examiner. The composite is created from separate measures of the number of different words used by the participant and the mean length of his communication units measured in morphemes. Samples are collected pre- and post-treatment using different books on each occasion, with improvement in the composite expected from pre to post.
• Change from baseline in the FXS- normed Aberrant Behavior Checklist (ABC) social avoidance subscale [ Time Frame: Baseline, 10 weeks, 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, agitation, crying; (2) lethargy, social withdrawal; (3) stereotypic behavior (4) hyperactivity, noncompliance; and (5) inappropriate speech. The social avoidance subscale will be analyzed utilizing the Sansone et al. (2011) FXS-normed ABC scoring measures.
• Improvement of Symptoms in Fragile X using the Clinical Global Impression-Improvement (CGI-I) scale [ Time Frame: Baseline, 10 weeks, 20 weeks ]
  A clinician rated scale utilizing history from the parents or caregiver and incorporating it into a clinical rating, first for severity, and then for clinical follow-up. The CGI-S will be used at the pre-treatment assessment to judge symptom severity and the CGI- I will be used at the 10 week and 20 week visits.
• Change from baseline in the Visual Analog Scale (VAS) [ Time Frame: Baseline, 10 weeks, 20 weeks ]
  The measure will be 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combining Lovastatin and a Parent-Implemented Language Intervention for Fragile X Syndrome
• Official Title: Combining Lovastatin and a Parent-Implemented Language Intervention in a Multimodal Treatment for Fragile X Syndrome
• Brief Summary: The purpose of the study is to test the efficacy of a 20 week multi-modal treatment comprised of lovastatin or placebo, and the Parent-implemented Language Intervention (PILI) in children with fragile X syndrome (FXS). Children will be randomized to drug or placebo in a double-blind design with all participating in the PILI. The primary endpoint will be to measure improvements in spoken language and behavior among lovastatin-treated than placebo treated participants.

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: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Fragile X Syndrome
• Genetic Diseases

Intervention

• Drug: Lovastatin
  Once per day dosing
  Other Name: Mevacor
• Other: Placebo
  Once per day dosing

Study Arms

• Active Comparator: Lovastatin and PILI
  Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin.
  Intervention: Drug: Lovastatin
• Placebo Comparator: Placebo and PILI
  Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo.
  Intervention: Other: Placebo

• Publications *: Thurman AJ, Potter LA, Kim K, Tassone F, Banasik A, Potter SN, Bullard L, Nguyen V, McDuffie A, Hagerman R, Abbeduto L. Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome. J Neurodev Disord. 2020 Apr 22;12(1):12. doi: 10.1186/s11689-020-09315-4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 14, 2018): 30
• Original Estimated Enrollment (submitted: December 28, 2015): 104
• Actual Study Completion Date: July 2018
• Actual Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 10 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02642653
• Other Study ID Numbers: 520144
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: University of California, Davis
• Study Sponsor: University of California, Davis
• Collaborators: Not Provided

Investigators

• Principal Investigator: Randi J Hagerman, MD; UC Davis

• PRS Account: University of California, Davis
• Verification Date: August 2019