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

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.

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