Back to resultsLeucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder
Primary Purpose
Autism Spectrum Disorder
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Folinic Acid
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Autism Spectrum Disorder focused on measuring Language Impairment
Eligibility Criteria
Inclusion Criteria:
- Boys and girls ≥ 5 years and < 17 years 5 months of age;
- Weight ≥ 15 kg;
- 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 -4 (CELF)- 4 or the Second Edition of the CELF-Preschool test (CELF-P).
- Current Clinical Global Impression Severity score ≥ 4 on ASD + communication delay.
- IQ at least 40 as measured by the Leiter-3 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).
Exclusion Criteria:
- IQ below 40 as measured by the Leiter-3 or below a mental age of 18 months on the Receptive Language Scale of Mullen. (N.B. subjects who test below 18 months of age, but are otherwise eligible, may be enrolled following a case review by the Steering Committee - e.g., child's uncooperative behavior resulted in a likely underestimate of intellectual ability);
- Is within the scoreable range of the CELF-4 or CELF-P as detailed in the Language Algorithm;
- 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 by history or by physical examination or lab tests that would be incompatible with the study drug.
- Children taking anticonvulsant medication for seizures.
- Children taking Bactrim (trimethoprim + sulfamethoxazole) because Bactrim can interfere with folate metabolism. Children who discontinue use of Bactrim for 2 months may be re-evaluated for the study. Caregivers will be advised not to use any of these medications during the trial.
- Children taking valproic acid or derivatives or lamotrigine for any purpose will be excluded because these drugs can interfere with folate metabolism. Caregivers will be advised not to use any of these medications during the trial.
- Children on mineral or vitamin supplements that exceed the Recommended Daily Allowance set by the IOM.
Sites / Locations
- Southwestern Research and Resource Center
- Children's Healtcare of Atlanta
- Harvard University
- State University of New York, DownstateRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Folinic Acid
Placebo Control
Arm Description
Subjects randomized to receive Folinic Acid will take Liquid levo-leucovorin via oral route. The target dose is 1 mg/kg/day with a maximum of 25 mg/day, divided in two daily doses. A two- to four-week supply of 15 ml vials will be dispensed in line with the visit schedule. With the exception of children in the lowest weight group (≥ 15 - < 20 kg) from days 1-14, parents will administer the prescribed dose twice a day at the same time each day.
Subjects randomized to receive placebo will take placebo twice a day (Exception: children in the lowest weight group ( ≥ 15 - < 20 kg) will start once a day for Days1-13). The pattern of dose escalation will be the same as the active compound. After 12 weeks, the blind will not be broken and subjects will be offered treatment for a 12-week open-label extension phase.
Outcomes
Primary Outcome Measures
Change in Clinical Evaluation of Language Fundamentals 4 (CELF-4) Score.
The Scale title is the "Clinical Evaluation of Language Fundamentals 4" which is abbreviated as CELF-4 as indicated in the title above. Higher Scores indicate better performance. The Minimum Scaled Score is 40 and the Maximum Scaled Score is 160. The CELF-4 will be administered for participants between > 6.6 and < 12.5 years of age. The CELF-4 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.
Change in Clinical Evaluation of Language Fundamentals Preschool (CELF-P) score
The Scale title is the "Clinical Evaluation of Language Fundamentals Preschool" which is abbreviated as CELF-P as indicated in the title above. Higher Scores indicate better performance. The Minimum Scaled Score is 40 and the Maximum Scaled Score is 160. The CELF-P will be administered for participants between > 5.0 and < 6.5 years of age to obtain an estimate of expressive and receptive language skills (based on population mean of 100 +15). Administration of the Core CELF-P takes 20-30 minutes. To make the CELF-P match the CELF-4, one additional subtest on CELF-P called the Concepts and Following Directions was added (this subtest is included in the Core of the CELF-4, but not included in the Core CELF-P).
Secondary Outcome Measures
Change in Clinician Global Impression for Improvement (CGI-I) Score
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.
Full Information
NCT ID
NCT02839915
First Posted
July 19, 2016
Last Updated
October 23, 2023
Sponsor
Southwest Autism Research & Resource Center
Collaborators
Emory University, Harvard University, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), State University of New York - Downstate Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT02839915
Brief Title
Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder
Official Title
Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 13, 2020 (Actual)
Primary Completion Date
January 2025 (Anticipated)
Study Completion Date
January 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Southwest Autism Research & Resource Center
Collaborators
Emory University, Harvard University, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), State University of New York - Downstate Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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 134 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, 134 children (age 5 to 17 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autism Spectrum Disorder
Keywords
Language Impairment
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
134 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Folinic Acid
Arm Type
Experimental
Arm Description
Subjects randomized to receive Folinic Acid will take Liquid levo-leucovorin via oral route. The target dose is 1 mg/kg/day with a maximum of 25 mg/day, divided in two daily doses. A two- to four-week supply of 15 ml vials will be dispensed in line with the visit schedule. With the exception of children in the lowest weight group (≥ 15 - < 20 kg) from days 1-14, parents will administer the prescribed dose twice a day at the same time each day.
Arm Title
Placebo Control
Arm Type
Placebo Comparator
Arm Description
Subjects randomized to receive placebo will take placebo twice a day (Exception: children in the lowest weight group ( ≥ 15 - < 20 kg) will start once a day for Days1-13). The pattern of dose escalation will be the same as the active compound. After 12 weeks, the blind will not be broken and subjects will be offered treatment for a 12-week open-label extension phase.
Intervention Type
Drug
Intervention Name(s)
Folinic Acid
Other Intervention Name(s)
Liquid levo-leucovorin
Intervention Description
Liquid levo-leucovorin via oral route. L-leucovorin is the active isomer.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Inactive placebo comparator
Primary Outcome Measure Information:
Title
Change in Clinical Evaluation of Language Fundamentals 4 (CELF-4) Score.
Description
The Scale title is the "Clinical Evaluation of Language Fundamentals 4" which is abbreviated as CELF-4 as indicated in the title above. Higher Scores indicate better performance. The Minimum Scaled Score is 40 and the Maximum Scaled Score is 160. The CELF-4 will be administered for participants between > 6.6 and < 12.5 years of age. The CELF-4 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.
Time Frame
Screening, Week 12
Title
Change in Clinical Evaluation of Language Fundamentals Preschool (CELF-P) score
Description
The Scale title is the "Clinical Evaluation of Language Fundamentals Preschool" which is abbreviated as CELF-P as indicated in the title above. Higher Scores indicate better performance. The Minimum Scaled Score is 40 and the Maximum Scaled Score is 160. The CELF-P will be administered for participants between > 5.0 and < 6.5 years of age to obtain an estimate of expressive and receptive language skills (based on population mean of 100 +15). Administration of the Core CELF-P takes 20-30 minutes. To make the CELF-P match the CELF-4, one additional subtest on CELF-P called the Concepts and Following Directions was added (this subtest is included in the Core of the CELF-4, but not included in the Core CELF-P).
Time Frame
Screening, Week 12
Secondary Outcome Measure Information:
Title
Change in Clinician Global Impression for Improvement (CGI-I) Score
Description
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.
Time Frame
Up to 12 Weeks
Other Pre-specified Outcome Measures:
Title
Change in the age appropriate version of the CELF compared to the pre-treatment level in the open-label extension phase
Description
Change in the age appropriate version of the CELF compared to the pre-treatment level will be evaluated
Time Frame
Pre-treatment, and 24weeks (or early termination)
Title
Change in folate gene expression
Description
Change in folate gene expression will be assessed by blood RNA test
Time Frame
Pre-treatment, 12 weeks(optional), and 24weeks (or early termination)
Title
Change in in methylation
Description
Change in in methylation will be assessed by blood DNA test (or saliva test if the blood sample was insufficient)
Time Frame
Pre-treatment, 12 weeks (optional), and 24weeks (or early termination)
Title
Change in Aberrant Behavior Checklist (ABC) Score
Description
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.
Time Frame
Up to 12 Weeks
Title
Home Situations Questionnaire- Modified for ASD (HSQ-ASD)
Description
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
Time Frame
Up to 12 Weeks
Title
Children's Yale-Brown Obsessive-Compulsive Scales-ASD (CYBOCS-ASD)
Description
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
Time Frame
Up to 12 Weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Boys and girls ≥ 5 years and < 17 years 5 months of age;
Weight ≥ 15 kg;
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 -4 (CELF)- 4 or the Second Edition of the CELF-Preschool test (CELF-P).
Current Clinical Global Impression Severity score ≥ 4 on ASD + communication delay.
IQ at least 40 as measured by the Leiter-3 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).
Exclusion Criteria:
IQ below 40 as measured by the Leiter-3 or below a mental age of 18 months on the Receptive Language Scale of Mullen. (N.B. subjects who test below 18 months of age, but are otherwise eligible, may be enrolled following a case review by the Steering Committee - e.g., child's uncooperative behavior resulted in a likely underestimate of intellectual ability);
Is within the scorable range of the CELF-4 or CELF-P as detailed in the Language Algorithm;
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 by history or by physical examination or lab tests that would be incompatible with the study drug.
Children taking anticonvulsant medication for seizures.
Children taking Bactrim (trimethoprim + sulfamethoxazole) because Bactrim can interfere with folate metabolism. Children who discontinue use of Bactrim for 2 months may be re-evaluated for the study. Caregivers will be advised not to use any of these medications during the trial.
Children taking valproic acid or derivatives or lamotrigine for any purpose will be excluded because these drugs can interfere with folate metabolism. Caregivers will be advised not to use any of these medications during the trial.
Children on mineral or vitamin supplements that exceed the Recommended Daily Allowance set by the IOM.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Richard E Frye, MD, PhD
Phone
(321) 259-7111
Email
DrFrye@RossignolMedicalCenter.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard E Frye, MD, PhD
Organizational Affiliation
Rossignol Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Southwestern Research and Resource Center
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christopher J Smith, PhD
Phone
602-218-8192
First Name & Middle Initial & Last Name & Degree
Sophia Crisler
Phone
(480) 582-9467
First Name & Middle Initial & Last Name & Degree
Richard Frye, MD, PhD
Facility Name
Children's Healtcare of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Completed
Facility Name
Harvard University
City
Lexington
State/Province
Massachusetts
ZIP/Postal Code
02421
Country
United States
Individual Site Status
Completed
Facility Name
State University of New York, Downstate
City
Brooklyn
State/Province
New York
ZIP/Postal Code
11203
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Harris Huberman, MD
Phone
718-270-2272
Email
harris.huberman@downstate.edu
First Name & Middle Initial & Last Name & Degree
Khadija Sikriti
Phone
(718) 270-4657
Email
khadija.sikriti@downstate.edu
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
National Database for Autism Research
IPD Sharing Time Frame
Biyearly NDAR is updated
IPD Sharing Access Criteria
Registered for NDAR Access
Citations:
PubMed Identifier
32892962
Citation
Frye RE, Rossignol DA, Scahill L, McDougle CJ, Huberman H, Quadros EV. Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder. Semin Pediatr Neurol. 2020 Oct;35:100835. doi: 10.1016/j.spen.2020.100835. Epub 2020 Jun 25.
Results Reference
background
PubMed Identifier
28770615
Citation
Frye RE, Slattery JC, Quadros EV. Folate metabolism abnormalities in autism: potential biomarkers. Biomark Med. 2017 Aug;11(8):687-699. doi: 10.2217/bmm-2017-0109. Epub 2017 Aug 3.
Results Reference
background
PubMed Identifier
27752075
Citation
Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018 Feb;23(2):247-256. doi: 10.1038/mp.2016.168. Epub 2016 Oct 18.
Results Reference
background
PubMed Identifier
27013943
Citation
Frye RE, Delhey L, Slattery J, Tippett M, Wynne R, Rose S, Kahler SG, Bennuri SC, Melnyk S, Sequeira JM, Quadros E. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups. Front Neurosci. 2016 Mar 9;10:80. doi: 10.3389/fnins.2016.00080. eCollection 2016.
Results Reference
background
PubMed Identifier
22230883
Citation
Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013 Mar;18(3):369-81. doi: 10.1038/mp.2011.175. Epub 2012 Jan 10.
Results Reference
background
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Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder
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