A Folinic Acid Intervention for Autism Spectrum Disorders

Study Description

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Brief Summary:

Researchers at Arkansas Children's Hospital Research Institute are conducting a study looking at the effects of Folinic Acid on language in Autism Spectrum Disorder and language impairment. The study has 3 phases. Phase 1 confirms that your child has language impairment (there is no compensation for this visit). If language impairment is verified in the phase 1 screening, then your child will be eligible for phase 2. Phase 2 consists of receiving 12 weeks of folinic acid or an inactive placebo, in addition to several evaluations of your child's abilities and a single blood test. Children that complete phase 2 will be eligible for a 12 week open-label trial of folinic acid which is phase 3.

Condition or disease	Intervention/treatment	Phase
Autism Spectrum Disorder; Autistic Disorder; Autism; Asperger's Syndrome; Pervasive Development Disorders	Drug: Folinic Acid and placebo; Drug: Folinic Acid	Phase 2

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	99 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Folinic Acid Intervention for ASD: Links to Folate Receptor-alpha Autoimmunity & Redox Metabolism
Study Start Date :	May 2012
Actual Primary Completion Date :	November 2015
Actual Study Completion Date :	November 2015

Arms and Interventions

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Arm	Intervention/treatment
No Intervention: Phase I; Baseline Visit Phase 1: The screening portion of the CELF will be administered to the child to screen for language impairment. If a child is determined to be pre-verbal they will automatically qualify,If there is no language impairment, the subject will not be eligible. If language impairment is confirmed, the participant will immediately go on to the baseline visit of Phase 2.
Phase II: 12 week Folinic Acid or Placebo intervention; The child will be consented for Phase 2 (the RCT) and undergo a blood draw (up to 20mL) for metabolic and autoantibody testing. the child will undergo language and behavioral assessment while the parent will be interviewed for the Vineland and other questionnaires (ASQ, RBS-R, SRS, and ABC). Demographic information including; age, race, gender, and ethnicity will be collected. The research pharmacist will randomize the participant to either Intervention A or B (only the research pharmacist will know which intervention has the folinic acid). The research pharmacist will distribute the drug or placebo to the parent and instruct the parent of the proper administration of the intervention. This will be considered the 12 week randomly controlled clinical trial that is investigating the safety and efficacy of folinic acis interventions in ASD and will last for approximately 12 weeks. At the end of 12 weeks, the same assessments that were conducted at baseline will be readministered	Drug: Folinic Acid and placebo; Capsules of folinic acid and placebo will be administered in 1mg/kg/day in two divided doses (0.5mg/kg/dose; 25mg/day maximum) for two weeks followed by 2 mg/kg/day with a maximum dose of 50mg/day provided the lower dose is well tolerated for 10 weeks.
Experimental: Phase III: Open Label Extension of Folinic Acid; If consent for Phase 3 is signed by parents with children who qualify for Phase 3, the research pharmacist will provide a 12 week supply of folinic acid to the parent. This arm will be offered to all clients that completed phase 2 of the trial. After consenting and 12 weeks of folinic acid dosing, the client will come back and complete the same protocol and be tested on the same measures used in phase II of the study. This will be a rolling stopping point so that new therapies can be started, if the parent/caregiver is so inclined	Drug: Folinic Acid; capsules of folinic acis will be provided. The target dose will be 1mg/kg/day in two divided doses (0.5mg/kg/dose; 25mg/day maximum) for two weeks followed by 2 mg/kg/day with a maximum dose of 50mg/day provided the lower dose is well tolerated, for 10 weeks.

Outcome Measures

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Primary Outcome Measures :

1. Language Improvement [ Time Frame: (baseline and 12 weeks ) ]
   Language (measured by the receptive and expressive CELF language index, and preschool language scale (PLS), as needed) will be the primary outcome for the study. Both preliminary studies have suggested that the folinic acid intervention will be associated with receptive and expressive language improvements.

Secondary Outcome Measures :

1. Improved Stereotyped Behavior and Improved Social Skills [ Time Frame: (baseline, 6, and 12 weeks) ]
   Stereotyped behavior (as measured by the OACIS (not at 6 weeks), ASQ, RBS-R, and ABC) and social skills (as measured by the Vineland (not at 6 weeks), ASQ, and SRS) will be the secondary outcomes.

Eligibility Criteria

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Ages Eligible for Study:	3 Years to 14 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria

• 1. Autism Spectrum Disorder (as defined by a gold standard measure for ASD diagnosis: the Autism Diagnostic Observation Schedule and/or Autism Diagnostic Interview-Revised). In an event where sufficient diagnostic information is lacking, and the PI believes that the clients meet all other inclusion criteria and a prospective diagnosis of an ASD is clinically warranted, and a formal diagnosis is scheduled to occur within a reasonable time frame from the date of study entry but before dispersing study drug/placebo, then the client may be considered as potentially eligible. Furthermore, a research-reliable rater must complete the diagnosis.
• 2. 3 years to 14 years of age
• 3. Language Impairment
• 4. Ability to maintain complementary, traditional, and/or behavioral interventions and to attempt to keep them constant during the study, when possible.
• 5. Unchanged complementary, traditional, and/or behavioral intervention for approximately 8 weeks prior to study entry, when possible.

Exclusion Criteria

• 1. Currently taking Antipsychotic medication
• 2. Vitamin or Element Supplementation that exceeds the IOM Tolerable Upper Intake Levels
• 3. Any moderate to severe positive response on that Aberrant Behavior Checklist Irritability subscale on questions: Injures self on purpose, is aggressive to other children or adults (verbally or physically), deliberately hurts himself/herself, and/or does physical violence to self.
• 4. Prematurity (<34 weeks gestation) as determined by medical history

• 5. Current uncontrolled gastroesophageal reflux or ongoing significant kidney or liver disease. The PI will determine whether any ongoing kidney or liver disease is significant.

  6. Drugs known to affect folate metabolism (e.g., methotrexate) and their derivatives.

  7. Profound sensory deficits (e.g. hearing and vision deficits) that could interfere with the interpretation of study results.

  8. Any major genetic defect, or mutation, that is known to be associated with disease or possibly related to disease that affects folate, methylation, and/or glutathione metabolism. Questions regarding eligibility concerning this criterion will be addressed with the lead site PI before enrollment into the trial.

  9. Documented current or active seizures, as defined by a clinical seizure or abnormal EEG within the past 6 months.

  10. Children with major single-gene abnormalities, such as Fragile X, Rett's Syndrome, etc., recognized chromosome syndromes, such as 15q11 microdeletion syndrome, or have been diagnosed with other well recognized syndromes, such as fetal alcohol syndrome. Children with copy number variants that represent known polymorphisms or benign changes will not be excluded. Questions regarding eligibility concerning this criterion should be addressed with the lead site PI before enrollment into the trial.

  11. Children diagnosed with congenital brain malformations, acquired brain insults, congenital or acquired microcephaly, or infection of the central nervous system.

  12. Children with major well-defined metabolic disease, such as mitochondrial disease, urea cycle disorders, succinic semialdehyde dehydrogenase deficiency, creatine deficiency syndromes, etc.

  13. Current therapies that could potentially interfere with interpretation of study results.

  14. Other conditions which, in the opinion of the study team, will place subjects at unacceptable risk or result in inability to interpret the study data.

  15. Unwillingness or inability to return for follow-up testing at specified interval.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Arkansas
Arkansas Children's Hospital Research Institute
Little Rock, Arkansas, United States, 72205

Sponsors and Collaborators

University of Arkansas

Arkansas Children's Hospital Research Institute

Investigators

Principal Investigator:	Richard E Frye, M.D./Ph.D.	Director of Autism Research

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

To see a list of current clinical Trials at Arkansas Children's Hospital, click here!! 

Responsible Party:	University of Arkansas
ClinicalTrials.gov Identifier:	NCT01602016 History of Changes
Other Study ID Numbers:	136002
First Posted:	May 18, 2012
Results First Posted:	November 7, 2016
Last Update Posted:	October 17, 2017
Last Verified:	September 2017

Keywords provided by University of Arkansas:

ASD; PDD-NOS

Additional relevant MeSH terms:

Disease; Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Asperger Syndrome; Pathologic Processes; Neurodevelopmental Disorders; Mental Disorders; Leucovorin; Levoleucovorin	Folic Acid; Antidotes; Protective Agents; Physiological Effects of Drugs; Vitamin B Complex; Vitamins; Micronutrients; Growth Substances; Hematinics