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

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.

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.

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.