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Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder

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ClinicalTrials.gov Identifier: NCT02839915
Recruitment Status : Not yet recruiting
First Posted : July 21, 2016
Last Update Posted : August 20, 2019
Sponsor:
Collaborators:
Phoenix Children's Hospital
Harvard University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Lawrence Scahill, MSN, PhD, Emory University

Tracking Information
First Submitted Date  ICMJE July 19, 2016
First Posted Date  ICMJE July 21, 2016
Last Update Posted Date August 20, 2019
Estimated Study Start Date  ICMJE October 2019
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 7, 2016)
Change in Core-Clinical Evaluation of Language Fundamentals (Core-CELF) Score [ Time Frame: Screening, Week 12 ]
The Core-CELF is comprised of 4 subtests intended to identify language problems and can be used to track progress over time. Administration of the CELF takes 30-45 minutes. The Core-CELF score is a composite that includes receptive and expressive language. Using the tables in the manual, raw scores from the four subtests are compared to normative data by age. The population mean = 100 + 15.
Original Primary Outcome Measures  ICMJE
 (submitted: July 19, 2016)
Core-Clinical Evaluation of Language Fundamentals (Core-CELF) [ Time Frame: 12 Weeks ]
Change History Complete list of historical versions of study NCT02839915 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 7, 2016)
  • Change in Clinician Global Impression for Improvement (CGI-I) Score [ Time Frame: Up to 12 Weeks ]
    The CGI-I is a 7-point measure of overall symptomatic change compared to baseline that will be used as a key secondary outcome measure. Scores range from 1 (Very Much Improved) through 4 (Unchanged) to 7 (Very Much Worse). The CGI-I will be rated by a clinician who is blind to treatment assignment, and will not engage in discussion of adverse events and medication dose. Ratings of "Much Improved" or "Very Much Improved" on the CGI-I will be used to define positive response. Subjects who drop out will be rated as non-responders.
  • Change in Aberrant Behavior Checklist (ABC) Score [ Time Frame: Up to 12 Weeks ]
    The ABC is a 58-item consisting five subscales: hyperactivity, irritability, social withdrawal, stereotypic behavior and inappropriate speech in children with developmental disabilities. A higher score indicates more frequent aberrant behaviors.
  • Home Situations Questionnaire- Modified for ASD (HSQ-ASD): [ Time Frame: Up to 12 Weeks ]
    The HSQ-ASD is a parent-rated scale of child noncompliance. The parent reports on the child's difficulties with compliance in 24 everyday situations. Questions answered affirmatively are then rated on a 1 to 9 Likert scale, with higher scores indicating more severe noncompliance. The scale yields a count of "yes" responses (0 to 27) and a severity score (total of 1 through 9 for all "yes" responses, for a range of 0 to 216
  • Children's Yale-Brown Obsessive-Compulsive Scales-ASD (CYBOCS-ASD) [ Time Frame: Up to 12 Weeks ]
    The CYBOCS-ASD is a modified version of the CYBOCS developed for use in children with Obsessive-Compulsive Disorder. Each item is scored from 0 (least symptomatic) to 4 (most symptomatic), yielding a Total score from 0 to 20. It has established reliability and validity65 and is sensitive to change.66
Original Secondary Outcome Measures  ICMJE
 (submitted: July 19, 2016)
  • Clinician Global Impression for Improvement (CGI-I) [ Time Frame: 12 Weeks ]
  • Aberrant Behavior Checklist (ABC) - Irritability and Social Withdrawal subscales [ Time Frame: 12 Weeks ]
  • Children's Yale-Brown Obsessive-Compulsive Scales-ASD (CYBOCS-ASD) [ Time Frame: 12 Weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder
Official Title  ICMJE Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder
Brief Summary The purpose of this study is to determine the effectiveness of folinic acid in the treatment of language problems in children with autism spectrum disorder. Folinic acid, also known as leucovorin, is approved by the U.S. Food and Drug Administration (FDA) to decrease side effects during cancer chemotherapy. Folinic acid may be helpful in treating language problems in children with autism spectrum disorder, but this is not known. Therefore, folinic acid is an investigational new drug for this study. Investigators will enroll a total of 162 participants across all three centers, over a 5 year period and participation will last between 12 and 24 weeks.
Detailed Description

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder often with life-long consequences that affects young children during critical developmental periods. The Centers for Disease Control estimates that ASD affects as many as 14.7 per 1000 children (1 in 68). Despite the dramatic rise in the detected prevalence of ASD over the past two decades, no effective medical treatment has been developed to address core ASD symptoms (social communication and repetitive behavior), the closely associated problem of language impairment, or the underlying pathophysiology of ASD. Currently, the only accepted treatment for core ASD symptoms is behavior therapy, which may entail intensive one-on-one treatment over several years.

The purpose of this study is to determine the effectiveness of folinic acid in the treatment of language problems in children with autism spectrum disorder. Folinic acid, also known as leucovorin, is approved by the U.S. Food and Drug Administration (FDA) to decrease side effects during cancer chemotherapy. Folinic acid may be helpful in treating language problems in children with autism spectrum disorder, but this is not known. Therefore, folinic acid is an investigational new drug for this study.

The primary aims of this study are to evaluate the efficacy and tolerability of high-dose folinic acid for improving the closely associated symptoms of language impairment in children with autism spectrum disorder (ASD). Improvement in delayed language may also benefit the core ASD problem of social communication. The study will also focus on identification of biomarkers in pre-specified subgroups of children with ASD that may moderate positive response to folinic acid. The study model is that high-dose folinic acid will improve language and set the stage for improved social communication in children with ASD and moderate language impairment. To test whether folinic acid is superior to placebo, 162 children (age 5 to 12 yrs 6 months, inclusive) with ASD and moderate language will be randomly assigned to folinic acid or placebo for 12 weeks under double-blind conditions. The study team will also test whether abnormalities in folate-dependent pathways, such as dysfunctional transport of folate across the blood-brain barrier, will moderate positive response to folinic acid treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Autism Spectrum Disorder
Intervention  ICMJE
  • Drug: Folinic Acid
    Capsule form, taken twice a day with a max dose of 50 mg
    Other Name: Leucovorin
  • Other: Placebo
    Inactive placebo comparator
Study Arms  ICMJE
  • Experimental: Folinic Acid
    Subjects randomized to receive Folinic Acid will take one capsule, twice a day. Once in the morning and once in the evening (Exception: children in the lowest weight group ( ≥ 15 - < 20 kg) will start with 10 mg capsule once a day for Days1-13). Dosing will start at 10-20 mg/day, based on subject's weight, and increase to 30-50 mg/day over four weeks. Primary caregiver will be contacted by telephone on Weeks 2, 6 and 10. Follow up visits at Weeks 4, 8 and 12 (end of Double-blind phase). After 12 weeks, the blind will not be broken and subjects will be offered treatment for a 12-week open-label extension phase.
    Intervention: Drug: Folinic Acid
  • Placebo Comparator: Placebo Control
    Subjects randomized to receive placebo will take one capsule, twice a day (Exception: children in the lowest weight group ( ≥ 15 - < 20 kg) will start with capsule once a day for Days1-13). The pattern of dose escalation will be the same as the active compound. Primary caregiver will be contacted by telephone on Weeks 2, 6 and 10. Follow up visits at Weeks 4, 8 and 12 (end of Double-blind phase). After 12 weeks, the blind will not be broken and subjects will be offered treatment for a 12-week open-label extension phase.
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 6, 2018)
162
Original Estimated Enrollment  ICMJE
 (submitted: July 19, 2016)
160
Estimated Study Completion Date  ICMJE January 1, 2023
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Boys and girls ≥ 5 years of age < 12 years 6 months of age
  • Weight ≥ 15 kg
  • Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 diagnosis of Autism Spectrum Disorder as established by clinical assessment, corroborated by the Social Communication Questionnaire and the Autism Diagnostic Observational Schedule
  • A score ≤ 80 on the Core Language score of the Clinical Evaluation of Language Fundamentals, fourth edition (CELF- 4)
  • Current Clinical Global Impression Severity score ≥ 4 on ASD + communication delay
  • Intelligence quotient (IQ) at least 40 as measured by the Leiter or mental age at least 18 months as measured on the Receptive Language Scale of the Mullen
  • Stable educational plan (one month) with no planned changes in the intensity of treatment for 12 weeks (otherwise eligible subjects with anticipated changes in their school program in the near term will be invited to return when the transition has been accomplished)
  • Stable speech therapy program in the community (one month) with no planned changes for 12 weeks
  • English is spoken in the home and at least one parent is able to read, write and speak English
  • Stable medication (no changes in past 6 weeks and no planned changes for the next 6 months (duration of the study)
  • Able to swallow pills whole, as reported by parent or demonstrated by child

Exclusion Criteria:

  • IQ below 40 as measured by the Leiter or below a mental age of 18 months on the Receptive Language Scale of Mullen
  • A score of 40 on the Core CELF- 4
  • Current DSM-IV diagnosis requiring alternative pharmacotherapy, e.g., Major Depression, Bipolar Disorder, a psychotic disorder (based on clinical assessment assisted by the Child and Adolescent Symptom Inventory)
  • Presence of serious behavioral problems (tantrums, aggression, self-injury) for which another treatment is warranted
  • Significant medical condition (determined by history or by physical examination or lab tests) that would be incompatible with the study drug
  • Children taking anticonvulsant medication for seizures
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 12 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nichole Evans, MS 404-785-9345 Andrea.Evans@choa.org
Contact: Lawrence Scahill, MSN, PhD 404-785-9400 lawrence.scahill@emory.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02839915
Other Study ID Numbers  ICMJE IRB00089662
R01HD088528 ( U.S. NIH Grant/Contract )
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  ICMJE
Plan to Share IPD: Yes
Plan Description: National Database for Autism Research
Responsible Party Lawrence Scahill, MSN, PhD, Emory University
Study Sponsor  ICMJE Emory University
Collaborators  ICMJE
  • Phoenix Children's Hospital
  • Harvard University
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators  ICMJE
Principal Investigator: Richard Frye, MD, PhD Phoenix Children's Hospital
PRS Account Emory University
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP