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

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 DiagnosticObservational Schedule.

• A score < 80 on the Core Language score of the Clinical Evaluation of LanguageFundamentals -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 asmeasured on the Receptive Language Scale of the Mullen.

• Stable educational plan (one month) with no planned changes in the intensity oftreatment for 12 weeks. (Otherwise eligible subjects with anticipated changes intheir school program in the near term will be invited to return when the transitionhas been accomplished.

• Stable speech therapy program in the community (one month) with no planned changesfor 12 weeks.

• English is spoken in the home and at least one parent is able to read, write andspeak English.

• Stable medication (no changes in past 6 weeks and no planned changes for the next 6months (duration of the study).

Exclusion Criteria:

• IQ below 40 as measured by the Leiter-3 or below a mental age of 18 months on theReceptive 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 SteeringCommittee - e.g., child's uncooperative behavior resulted in a likely underestimateof intellectual ability);

• Is within the scorable range of the CELF-4 or CELF-P as detailed in the LanguageAlgorithm;

• Current DSM-IV diagnosis requiring alternative pharmacotherapy, e.g., MajorDepression, Bipolar Disorder, a psychotic disorder (based on clinical assessmentassisted by the Child and Adolescent Symptom Inventory);

• Presence of serious behavioral problems (tantrums, aggression, self-injury) forwhich another treatment is warranted.

• Significant medical condition by history or by physical examination or lab teststhat would be incompatible with the study drug.

• Children taking anticonvulsant medication for seizures.

• Children taking Bactrim (trimethoprim + sulfamethoxazole) because Bactrim caninterfere with folate metabolism. Children who discontinue use of Bactrim for 2months may be re-evaluated for the study. Caregivers will be advised not to use anyof these medications during the trial.

• Children taking valproic acid or derivatives or lamotrigine for any purpose will beexcluded because these drugs can interfere with folate metabolism. Caregivers willbe advised not to use any of these medications during the trial.

• Children on mineral or vitamin supplements that exceed the Recommended DailyAllowance set by the IOM.