Table 2.

Design Summary

Apathy in dementia methylphenidate trial (ADMET)

Objectives Primary objective To examine in a masked, randomized trial the efficacy of methylphenidate for the treatment of clinically significant apathy, without depression, in patients with Alzheimer’s dementia Secondary objectives To examine the effects of methylphenidate treatment on cognition of patients To examine the safety of methylphenidate To examine predictors of response to methylphenidate therapy

Type of trial Randomized, multicenter phase II clinical trial Two parallel treatment groups Double masked 1:1 assignment ratio

Setting Clinical centers Johns Hopkins School of Medicine, Baltimore Medical University of South Carolina, Charleston Sunnybrook Health Sciences Centre, Toronto Chair’s office Medical University of South Carolina, Charleston Coordinating center Johns Hopkins Bloomberg School of Public Health, Baltimore

Primary outcome measures Change in apathy from baseline to 6 weeks as measured by AES Change in apathy from baseline to 6 weeks as measured by ADCS-CGIC

Other outcomes Change in apathy from baseline to 6 weeks as measured by NPI Global cognition as assessed by MMSE Attention as assessed by Digit Span Adverse events (including delusions, hallucinations, weight loss and abnormal ECGs) Serious adverse events (requiring hospitalization)

Study population 60 patients who meet the ADMET criteria for clinically significant apathy

Power calculations AES: Power greater than 80% Two-sided alpha = 0.05 Standard deviation of AES = 4.5 Detectable difference in change in apathy severity is 3.3 ADCS-CGIC apathy: Power greater than 80% Two-sided alpha = 0.05 Assuming 20–30% of placebo patients improve Detectable difference in proportion of patients improving is 35%

Treatment groups Methylphenidate, target dose 20 mg per day (range 10–20 mg per day), given orally + standardized psychosocial intervention Placebo + standardized psychosocial intervention

Stratification of randomization By clinical center

Masking Double-masked (treatment assignment masked to participants, study partners and all clinical center personnel, including physicians, nurses, and neuropsychologists)

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 the frequency of apathy as assessed by the NPI is ‘Very frequently’, or the frequency of apathy as assessed by the NPI is ‘Frequently’ or ‘Often’ AND the severity of the apathy as assessed by the NPI is ‘Moderate’, or ‘Marked’ 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 necessary) and study partner Availability of a study partner, who spends several hours a week with the patient and supervises his/her care, to accompany the patient to study visits and to participate in the study 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 DSM-IV (TR) criteria Clinically significant agitation/aggression for which either the frequency of agitation/aggression as assessed by the NPI is ‘Very frequently’, or the frequency of agitation/aggression as assessed by the NPI is ‘Frequently’ AND the severity of the agitation/aggression as assessed by the NPI is ‘Moderate’, or ‘Marked’ Clinically significant delusions for which either the frequency of delusions as assessed by the NPI is ‘Very frequently’, or 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 the frequency of hallucinations as assessed by the NPI is ‘Very frequently’, or 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 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 a significant burden or affect neuropsychological or other 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 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 for the patient to enroll in the trial

Duration of follow-up 6 weeks

Data collection schedule Scheduled in-person visits (baseline and weeks 2, 4, and 6 after randomization) Telephone contacts (weeks 1, 3, and 5 after randomization)