Apathy in Dementia Methylphenidate Trial (ADMET)

The Apathy in Dementia Methylphenidate Trial (ADMET), funded by the National Institute of
Aging, is a Phase II, placebo-controlled, masked, 3-center randomized clinical trial. ADMET
will enroll 60 patients with Alzheimer's disease (AD) and significant apathy from outpatient,
nursing home, and assisted living facilities along with their primary caregiver. Eligible and
willing patients will be randomly assigned to methylphenidate (20 mg per day) or placebo. At
baseline and each in-person follow-up visit, all caregivers and patients will be provided
with a standardized psychosocial intervention consisting of a counseling session, provision
of educational materials, and 24-hour availability for crises. Efficacy and safety outcomes
will be measured at baseline and at in-person follow-up visits at 2, 4, and 6 weeks following
randomization. Telephone contact will take place at 1, 3, and 5 weeks after randomization.

ADMET has 80% power to detect a difference of at least 3.3 in change in the Apathy Evaluation
Scale scores between the two treatment groups. It also has 80% power to detect an absolute
difference of 35% or more in the change in the proportion of study participants improving on
te Clinical Global Impression of Change, given that 20% to 305 of participants in the placebo
group show improvement.

Inclusion criteria:

- Possible or probable Alzheimer's disease (National Institute of Neurological and
Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders
Association (NINCDS-ADRDA) criteria), with Mini-Mental State Exam (MMSE) score of
10-26 inclusive; MMSE scores above 26 in those who nevertheless meet criteria for AD
may be allowed with Steering Committee approval on a case by case basis

- Clinically significant apathy for at least four weeks for which either 1) the
frequency of apathy as assessed by the Neuropsychiatric Inventory (NPI) is 'Very
frequently', or 2) the frequency of apathy as assessed by the NPI is 'Frequently' or
'Often' AND the severity of apathy as assessed by the NPI is 'Moderate' or 'Marked'

- A medication for apathy is appropriate, in the opinion of the study physician

- Provision of informed consent for participation in the study by patient or surrogate
(if the patient is unable to provide informed consent) and caregiver

- Availability of primary caregiver, who spends greater than ten hours a week with the
patient and supervises his/her care, to accompany the patient to study visits and to
participate in the study

- Sufficient fluency, of both the patient and caregiver, in written and spoken English
to participate in study visits, physical exams, and outcome assessments

- No change to AD medications within the month preceding randomization, including
starting, stopping, or dosage modifications

- Treatment with stable doses of selective serotonin reuptake inhibitor
antidepressants(SSRIs) is appropriate if stable for 3 months prior to randomization.
Other psychotropics(with the exclusion of antipsychotics), if stable for 3 months, may
be allowed only with Steering Committee approval on a case by case basis.

Exclusion criteria:

- Meets criteria for Major Depressive Episode, by Diagnostic Statistical Manual of
Mental Disorder - IV (TR) criteria

- Clinically significant agitation /aggression for which either 1) the frequency of
agitation /aggression as assessed by the NPI is 'Very frequently', or 2) the frequency
of agitation /aggression as assessed by the NPI is 'Frequently' AND the severity of
the agitation as assessed by the NPI is 'Moderate', or 'Marked'

- Clinically significant delusions for which either 1) the frequency of delusions as
assessed by the NPI is 'Very frequently', or 2) the frequency of delusions as assessed
by the NPI is 'Frequently' AND the severity of the delusions as assessed by the NPI is
'Moderate', or 'Marked'

- Clinically significant hallucinations for which either 1) the frequency of
hallucinations as assessed by the NPI is 'Very frequently', or 2) the frequency of
hallucinations as assessed by the NPI is 'Frequently' AND the severity of the
hallucinations as assessed by the NPI is 'Moderate', or 'Marked'

- Treatment with psychotropic medications in the 2 weeks prior to randomization with the
exception of approved treatments for dementia (ChEIs and memantine), selective
serotonin reuptake inhibitor antidepressants, and trazodone (if used as an aid to
facilitate sleep and not as an antidepressant); other psychotropics (with the
exclusion of antipsychotics), if stable for 3 months, may be allowed only with
Steering Committee approval on a case by case basis. Note that antipsychotics are
expressly prohibited.

- Treatment with methylphenidate is contraindicated in the opinion of the study
physician

- Failure of treatment with methylphenidate in the past for apathy after convincing
evidence of an adequate trial as judged by study physician

- Treatment with a medication that would prohibit the safe concurrent use of
methylphenidate such as monoamine oxidase inhibitors and tricyclic antidepressants

- Need for acute psychiatric hospitalization or is suicidal

- Uncontrolled hypertension (medication non-compliance or past 3 months with a diastolic
reading of 105 as verified by compartment pressure of the rectus sheath (CPRS))

- Symptomatic coronary artery disease deemed to be significant by study physician at the
time of screening

- Lack of appetite that results in significant unintentional weight loss as determined
by the study physician in the last three months

- Significant communicative impairments

- Current participation in a clinical trial or in any study that may add significant
burden or affect study outcomes

- Hyperthyroidism, advanced arteriosclerosis, symptomatic cardiovascular disease,
serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm
abnormalities, or a family history of sudden death or death related to heart problems

- Glaucoma, pheochromocytoma, or known or suspected hypersensitivity to methylphenidate
or its excipients

- Central Nervous System (CNS) abnormalities (e.g., cerebral aneurysm) and/or other
vascular abnormalities such as vasculitis or pre-existing stroke, motor tics or a
family history or diagnosis of Tourette's syndrome, seizures (convulsions, epilepsy),
or abnormal EEGs

- Any condition that, in the opinion of the study physician, makes it medically
inappropriate or risky for the patient to enroll in the trial