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

• Sponsor: University of California, Davis (Other)
• Overall Status: Completed
• CT.gov ID: NCT02642653
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 30
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Fragile X Syndrome; Genetic Diseases	Drug: Lovastatin; Other: Placebo	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Combining Lovastatin and a Parent-Implemented Language Intervention in a Multimodal Treatment for Fragile X Syndrome
• Actual Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Jul 1, 2018
• Actual Study Completion Date: Jul 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lovastatin and PILI Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin.	Drug: Lovastatin; Once per day dosing; Other Names: Mevacor
Placebo Comparator: Placebo and PILI Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo.	Other: Placebo; Once per day dosing

Outcome Measures

Primary Outcome Measures

1. Expressive Language Sample Composite Score in the Home [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).

2. Expressive Language Sample Composite Score in the Home [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).

Secondary Outcome Measures

1. FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale [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.

2. FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale [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.

3. FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale [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.

4. Clinical Global Impression- Severity (CGI-S) [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.

5. Clinical Global Impression-Improvement (CGI-I) Scale [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.

6. Clinical Global Impression-Improvement (CGI-I) Scale [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.

7. Visual Analog Scale (VAS) - Spoken Language Impairment [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.

8. Visual Analog Scale (VAS) - Spoken Language Impairment [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.

9. Visual Analog Scale (VAS) - Spoken Language Impairment [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.

10. Visual Analog Scale (VAS) - Social Impairment [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.

11. Visual Analog Scale (VAS) - Social Impairment [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.

12. Visual Analog Scale (VAS) - Social Impairment [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC Davis MIND Institute	Sacramento	California	United States	95817

Sponsors and Collaborators

• University of California, Davis

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 7, 2017

More Information

Publications

None provided.

• Responsible Party: University of California, Davis
• ClinicalTrials.gov Identifier: NCT02642653
• Other Study ID Numbers: 520144
• First Posted: Dec 30, 2015
• Last Update Posted: Sep 11, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of California, Davis: Fra(X) Syndrome; Trinucleotide Repeat Expansion; Fragile X Syndrome; Fragile X Mental Retardation Syndrome; Intellectual Disability; Parent Implemented Language Intervention (PILI); FXS; Mental Retardation, X-linked; Genetic Diseases, X-linked; Neurobehavioral Manifestations; Chromosome Disorders
• Additional relevant MeSH terms: Fragile X Syndrome; Genetic Diseases, Inborn; Syndrome; Lovastatin; L 647318; Dihydromevinolin

Study Results

Participant Flow

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Period Title: Overall Study
STARTED	14	16
COMPLETED	12	16
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Lovastatin and PILI	Placebo and PILI	Total
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing	Total of all reporting groups
Overall Participants	14	16	30
Age (Count of Participants)
<=18 years	14 100%	16 100%	30 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.86 (2.14)	13.17 (2.54)	13.52 (2.34)
Sex: Female, Male (Count of Participants)
Female	2 14.3%	0 0%	2 6.7%
Male	12 85.7%	16 100%	28 93.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	4 25%	4 13.3%
Not Hispanic or Latino	14 100%	12 75%	26 86.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 6.3%	1 3.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 6.3%	1 3.3%
White	14 100%	10 62.5%	24 80%
More than one race	0 0%	4 25%	4 13.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%	16 100%	30 100%
Intelligence Quotient (IQ) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	44.00 (9.22)	43.13 (6.24)	43.57 (7.73)
Cognitive growth score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	461.4 (13.32)	462.3 (8.57)	461.85 (10.95)
Autism Diagnostic Observation Scale (ADOS) severity score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.85 (2.54)	6.75 (2.05)	6.80 (2.30)

Outcome Measures

1. Primary Outcome

Title	Expressive Language Sample Composite Score in the Home
Description	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).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [score on a scale]	39.63 (32.41)	42.47 (18.60)

2. Secondary Outcome

Title	FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [score on a scale]	2.5 (2.84)	4.31 (3.66)

3. Secondary Outcome

Title	FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale
Description	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.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [score on a scale]	2.5 (2.11)	3.53 (3.68)

4. Secondary Outcome

Title	FXS- Normed Aberrant Behavior Checklist (ABC) Social Avoidance Subscale
Description	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.
Time Frame	20 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [score on a scale]	2.42 (2.84)	3.38 (3.34)

5. Secondary Outcome

Title	Clinical Global Impression- Severity (CGI-S)
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [units on a scale]	4.58 (0.67)	4.50 (0.63)

6. Secondary Outcome

Title	Clinical Global Impression-Improvement (CGI-I) Scale
Description	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.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [units on a scale]	2.92 (0.79)	3.00 (0.73)

7. Secondary Outcome

Title	Clinical Global Impression-Improvement (CGI-I) Scale
Description	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.
Time Frame	20 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [units on a scale]	2.42 (0.67)	2.38 (0.72)

8. Secondary Outcome

Title	Visual Analog Scale (VAS) - Spoken Language Impairment
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [centimeters]	4.06 (2.43)	1.94 (1.41)

9. Secondary Outcome

Title	Visual Analog Scale (VAS) - Spoken Language Impairment
Description	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.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [centimeters]	5.28 (2.69)	3.09 (1.14)

10. Secondary Outcome

Title	Visual Analog Scale (VAS) - Spoken Language Impairment
Description	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.
Time Frame	20 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [centimeters]	5.66 (1.99)	4.18 (1.53)

11. Secondary Outcome

Title	Visual Analog Scale (VAS) - Social Impairment
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [centimeters]	3.73 (1.74)	2.55 (1.36)

12. Secondary Outcome

Title	Visual Analog Scale (VAS) - Social Impairment
Description	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.
Time Frame	10-weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [centimeters]	4.57 (2.15)	3.41 (1.61)

13. Secondary Outcome

Title	Visual Analog Scale (VAS) - Social Impairment
Description	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.
Time Frame	20-weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [centimeters]	5.18 (1.70)	3.99 (2.06)

14. Primary Outcome

Title	Expressive Language Sample Composite Score in the Home
Description	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).
Time Frame	20 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin and PILI	Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
Measure Participants	12	16
Mean (Standard Deviation) [score on a scale]	59.32 (22.81)	54.81 (16.04)

Adverse Events

Time Frame	From baseline to follow-up (20-weeks)
Arm/Group Title	Lovastatin and PILI		Placebo and PILI
Arm/Group Description	Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with study medication Lovastatin. Lovastatin: Once per day dosing		Subjects will receive the Parent Implemented Language Intervention (PILI) in combination with placebo. Placebo: Once per day dosing
All Cause Mortality
	Lovastatin and PILI		Placebo and PILI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/16 (0%)
Serious Adverse Events
	Lovastatin and PILI		Placebo and PILI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Lovastatin and PILI		Placebo and PILI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)		13/16 (81.3%)
Blood and lymphatic system disorders
Epistaxis	1/12 (8.3%)	1	1/16 (6.3%)	1
Eye disorders
Eye Infection	0/12 (0%)	0	1/16 (6.3%)	2
Gastrointestinal disorders
Decreased Appetite	0/12 (0%)	0	3/16 (18.8%)	3
Diarrhea	1/12 (8.3%)	1	2/16 (12.5%)	3
Gastrointestinal issues	2/12 (16.7%)	2	4/16 (25%)	5
Vomiting	1/12 (8.3%)	1	0/16 (0%)	0
General disorders
Fatigue	0/12 (0%)	0	1/16 (6.3%)	1
Fever	1/12 (8.3%)	2	0/16 (0%)	0
Hepatobiliary disorders
Elevated Bilirubin	0/12 (0%)	0	1/16 (6.3%)	1
Infections and infestations
Ear infection	0/12 (0%)	0	1/16 (6.3%)	1
Sinus Infection	0/12 (0%)	0	1/16 (6.3%)	1
Skin_Infection	1/12 (8.3%)	2	2/16 (12.5%)	2
Upper Respiratory Infection	7/12 (58.3%)	10	8/16 (50%)	12
Injury, poisoning and procedural complications
Musculoskeletal injury	0/12 (0%)	0	1/16 (6.3%)	1
Sprain	0/12 (0%)	0	1/16 (6.3%)	1
Skin abrasion	1/12 (8.3%)	1	0/16 (0%)	0
Metabolism and nutrition disorders
Weight Loss	0/12 (0%)	0	1/16 (6.3%)	1
Nervous system disorders
Dizziness	0/12 (0%)	0	1/16 (6.3%)	1
Dry Mouth	0/12 (0%)	0	1/16 (6.3%)	1
Headache	1/12 (8.3%)	1	2/16 (12.5%)	2
Sedation	0/12 (0%)	0	1/16 (6.3%)	1
Psychiatric disorders
Abnormal vocalizations	1/12 (8.3%)	1	1/16 (6.3%)	1
Agitation	0/12 (0%)	0	1/16 (6.3%)	1
Anxiety	1/12 (8.3%)	1	1/16 (6.3%)	1
Disruptive behavior	1/12 (8.3%)	1	0/16 (0%)	0
Emotional Lability	0/12 (0%)	0	2/16 (12.5%)	2
Hyperactivity	2/12 (16.7%)	2	0/16 (0%)	0
Insomnia	0/12 (0%)	0	1/16 (6.3%)	1
Irritability	0/12 (0%)	0	1/16 (6.3%)	1
Obsessive compulsive behavior	0/12 (0%)	0	1/16 (6.3%)	1
Self-injurious behavior	0/12 (0%)	0	1/16 (6.3%)	1
Sleep Disturbance	1/12 (8.3%)	1	1/16 (6.3%)	1
Renal and urinary disorders
Incontinence	1/12 (8.3%)	1	0/16 (0%)	0
Reproductive system and breast disorders
Menstrual Cramps	1/12 (8.3%)	1	0/16 (0%)	0
Respiratory, thoracic and mediastinal disorders
Rhinorrhea	0/12 (0%)	0	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Itchiness	0/12 (0%)	0	2/16 (12.5%)	3
Rash	3/12 (25%)	3	1/16 (6.3%)	1

Limitations/Caveats

The study did not have a cohort treated only with lovastatin without the parent-implemented language intervention (PILI). The efficacy of the study medication alone compared to placebo can't be evaluated.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.