A Trial of the Drug Donepezil for Sleep Enhancement and Behavioral Change in Children With Autism

i. Objective

The objective of this study is to investigate the efficacy of donepezil to improve the
developmental trajectory for core behavioral domains specific to autism, namely reciprocal
social interaction and communication.

ii. Study population

90 children with an autism spectrum disorder between the ages of 24 to 50 months will be
screened via polysomnogram to find 45 with a relative REM deficiency. This group will then be
divided into two arms of drug versus placebo. Allowing for a 22 % drop out rate we expect 17
in each group to complete the study. Additionally, we will enroll 16 children with an ASD who
do not meet criteria for relative REM deficiency in an open label arm to ascertain whether or
not donepezil is beneficial to behavior in this group.

iii. Design

The proposal is for a 6 month treatment trial of 2.5 mg donepezil/placebo/day followed by 12
months of longitudinal follow-up. The primary study endpoint will be an examination of autism
core symptoms and sleep architecture after 12 months.

iv. Outcome measures

The primary outcome measure will be:

1. An improvement in the Expressive Language and the Receptive Language subscales of the
Mullen Scales of Early Learning (MSEL) at 12 months.

Secondary outcome measures will be:

2. We will also measure the change in REM sleep parameters after 6, 12 and 18 months in
relation to improvements in behavioral indices.

Exploratory Outcome Measures will be:

3. An improvement in the Expressive Language and the Receptive Language subscales of the
Mullen Scales at 18 months.

4. An improvement on the severity scale of the Autism Diagnostic Observation Schedule
(ADOS) at 6, 12 and 18 months.

5. An improvement on the Vineland at 3, 6, 12 and 18 months

6. An exploratory analysis will investigate whether normalization of REM parameters also
improves other measurements of sleep quality in children with autism.

- INCLUSION CRITERIA:

1. Diagnosis of an Autism Spectrum Disorder (DSM-IV diagnoses of autistic disorder
or Pervasive Developmental Disorder, Not Otherwise Specified).

2. Male or Female subjects between the ages of 24 and 50 months.

3. Language scores (from the Mullen Scales of Early Learning) that are at least 1.5
SD lower than the mean.

5. Each legal guardian must have a level of understanding sufficient to agree to all
required tests and examinations. Each legal guardian must understand the nature of the
study.

6. Each subject must be stable for at least 6 weeks on any medication or therapy
regimen prior to entry into study and must have no newly (within 6 weeks) recognized
or intolerable adverse effects from that medicine or therapy. No subjects will be
asked to discontinue any medication in order to qualify for enrollment but subjects
taking contraindicated drugs will not qualify for enrollment.

7. Demonstrated REM% two standard deviations or more below the normative values for
age for the randomized controlled trial part.

8. English language is primarily spoken at home.

EXCLUSION CRITERIA:

1. Serious, unstable illnesses including gastroenterologic, respiratory, cardiovascular
endocrinologic, immunologic, or hematologic disease.

2. Renal or hepatic dysfunction that would interfere with excretion or metabolism of
donepezil as evidenced by increase above upper limits of normal for BUN/creatinine, or
two-fold elevation of serum transaminases (ALT/SGPT, AST/SGOT) or gamma glutamate
(GGT).

3. Documented history of hypersensitivity or intolerance to donepezil or other piperidine
derivative.

4. Subjects must not be taking any medication known to affect REM sleep (or sleep

architecture in general) or that is contraindicated for co-administration with
donepezil.

5. Presence or history of other unstable neurological disorders such as seizure
disorders,

metabolic disorders, narcolepsy or movement disorders.