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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 : March 28, 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

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.

Condition or disease Intervention/treatment Phase
Autism Spectrum Disorder Drug: Folinic Acid Other: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 162 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : January 1, 2022
Estimated Study Completion Date : January 1, 2023


Arm Intervention/treatment
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.
Drug: Folinic Acid
Capsule form, taken twice a day with a max dose of 50 mg
Other Name: Leucovorin

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.
Other: Placebo
Inactive placebo comparator




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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

  4. 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



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Ages Eligible for Study:   5 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02839915


Contacts
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Contact: Nichole Evans, MS 404-785-9345 Andrea.Evans@choa.org
Contact: Lawrence Scahill, MSN, PhD 404-785-9400 lawrence.scahill@emory.edu

Locations
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United States, Arizona
Phoenix Children's Hospital Not yet recruiting
Phoenix, Arizona, United States, 85016
Contact: Richard Frye, MD, PhD    602-933-1000      
Principal Investigator: Richard Frye, MD, PhD         
United States, Georgia
Children's Healtcare of Atlanta Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Nichole Evans, MS    404-785-9345    Andrea.Evans@choa.org   
Contact: Lawrence Scahill, PhD    404-785-9400    Lawrence.scahill@emory.edu   
Principal Investigator: Lawrence Scahill, PhD         
United States, Massachusetts
Harvard University Not yet recruiting
Lexington, Massachusetts, United States, 02421
Contact: Jennifer Mullett, RN    781-860-1700    JMULLETT@mgh.harvard.edu   
Contact: Christopher Christopher, MD    781-860-1700    CMCDOUGLE@mgh.harvard.edu   
Principal Investigator: Christopher Christopher, MD         
Sponsors and Collaborators
Emory University
Phoenix Children's Hospital
Harvard University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Richard Frye, MD, PhD Phoenix Children's Hospital

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Responsible Party: Lawrence Scahill, MSN, PhD, Director of Clinical Trials, Marcus Autism Center, Emory University
ClinicalTrials.gov Identifier: NCT02839915     History of Changes
Other Study ID Numbers: IRB00089662
R01HD088528 ( U.S. NIH Grant/Contract )
First Posted: July 21, 2016    Key Record Dates
Last Update Posted: March 28, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: National Database for Autism Research

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

Keywords provided by Lawrence Scahill, MSN, PhD, Emory University:
Language Impairment

Additional relevant MeSH terms:
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Child Development Disorders, Pervasive
Disease
Autistic Disorder
Autism Spectrum Disorder
Language Disorders
Pathologic Processes
Neurodevelopmental Disorders
Mental Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Leucovorin
Levoleucovorin
Folic Acid
Antidotes
Protective Agents
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Hematinics