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Apathy in Dementia Methylphenidate Trial (ADMET)

This study has been completed.
Sponsor:
Collaborators:
Medical University of South Carolina
Johns Hopkins University
University of Toronto
Information provided by (Responsible Party):
Johns Hopkins Bloomberg School of Public Health
ClinicalTrials.gov Identifier:
NCT01117181
First received: May 4, 2010
Last updated: April 1, 2013
Last verified: November 2011
  Purpose

The Apathy in Dementia Methylphenidate Trial (ADMET) is a masked, placebo-controlled trial that will examine the efficacy and safety of methylphenidate for the treatment of clinically significant apathy in patients with Alzheimer's dementia.


Condition Intervention Phase
Apathy
Alzheimer's Disease
Drug: Methylphenidate
Drug: placebo
Other: Psychosocial intervention
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Apathy in Dementia Methylphenidate Trial (ADMET)

Resource links provided by NLM:


Further study details as provided by Johns Hopkins Bloomberg School of Public Health:

Primary Outcome Measures:
  • Apathy Evaluation Scale (AES) [ Time Frame: baseline to 6 weeks ] [ Designated as safety issue: No ]
    Change in score of Apathy Evaluation Scale from baseline to 6 weeks; the minimum score is 18; the maximum score is 72. Higher scores indicate more severe apathy.

  • Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change [ Time Frame: baseline to 6 weeks ] [ Designated as safety issue: No ]
    Proportion of individuals improving on Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change (CGIC) from baseline to 6 weeks; the CGIC is a 7-point Likert scale used to rate each patient with the following scores: "marked worsening"(7), "moderate worsening" (6), "minimal worsening"(5), "no change"(4), "minimal improvement"(3), "moderate improvement"(2), "marked improvement"(1). Ratings were based on an interview with the caregiver and an examination of the patient. The CGIC requires the clinician to consider a number of aspects of apathy, such as level of initiative, level of interest, and emotional engagement.


Secondary Outcome Measures:
  • Digit Span [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
    Change in Digit Span at baseline and 6 weeks; this assessment is used to assess auditory attention and working memory. Higher numbers indicate better functioning.

  • Mini-Mental State Exam (MMSE) [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: Yes ]
    Change in Mini-Mental State Exam score from baseline to 6 weeks; this cognitive test estimates of dementia severity. Domains included orientation, memory, working memory, naming, following verbal and written commands, spontaneously writing a sentence, and copying two overlapping pentagons. The minimum MMSE score is 0; the maximum MMSE score is 30. Lower MMSE scores indicate more severe cognitive impairment.

  • Neuropsychiatric Inventory (NPI): Apathy Subscale [ Time Frame: baseline to week 6 ] [ Designated as safety issue: Yes ]
    Change from baseline to 6 weeks in neuropsychiatric symptoms in apathy subscore. Frequency (ranges from 1=occasionally, less than once/week to 4 = very frequently, once or more/day or continuously) and severity (1=mild, 2=moderate, 3=severe) scales are scored based on responses from an informed caregiver involved in the patient's life. To obtain the NPI score, the severity score is multiplied by the frequency score. Range is 0 to 12. Larger numbers indicate more severe behavioral disturbance.

  • Vital Status [ Time Frame: vital status at 6 weeks ] [ Designated as safety issue: Yes ]
    vital status as measured by death

  • Electrolytes [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    Percent abnormal at 6 weeks as assessed by local lab

  • Electrocardiogram (ECG) [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    Abnormal electrocardiogram results at 6 weeks


Enrollment: 60
Study Start Date: June 2010
Study Completion Date: August 2012
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Methylphenidate
Methylphenidate, target dose 20 mg per day (range 10-20 mg per day) and psychosocial intervention
Drug: Methylphenidate
The target dose is 20 mg per day provided as two 10 mg doses administered orally. Patients will start by taking 10 mg daily (two 5 mg over-encapsulated tablets) for three days, at which time the dose will be increased to 20 mg per day (four 5 mg over-encapsulated tablets). In the event of significant side-effects, the dose will be reduced to a minimum of 10 mg per day. The study drug will be administered for 6 weeks.
Other Name: Ritalin
Other: Psychosocial intervention

The psychosocial intervention will consist of three components: a counseling session, the provision of education materials, and 24-hour availability for crises.

The counseling session, in which a trained study clinician will counsel the primary caregiver, lasts approximately 20-30 minutes, and consists of the following elements:

  • Review and adjustment of the patient and caregiver supportive care plans
  • Emotional support and opportunity to ventilate feelings
  • Counseling regarding specific caregiving skills
  • Assistance with problem solving of specific issues that the caregiver brings to the sessions
  • Answers for questions regarding the educational materials

The educational materials will consist of a copy of the book The 36-Hour Day

Placebo Comparator: Placebo
matching placebo and psychosocial intervention
Drug: placebo
Patients will start with two capsules of placebo for three days, at which time the dose will be increased to four capsules. The dose may be reduced to a minimum of two capsules per day if there appears to be significant side-effects. Placebo will be administered for 6 weeks.
Other Name: dummy pill
Other: Psychosocial intervention

The psychosocial intervention will consist of three components: a counseling session, the provision of education materials, and 24-hour availability for crises.

The counseling session, in which a trained study clinician will counsel the primary caregiver, lasts approximately 20-30 minutes, and consists of the following elements:

  • Review and adjustment of the patient and caregiver supportive care plans
  • Emotional support and opportunity to ventilate feelings
  • Counseling regarding specific caregiving skills
  • Assistance with problem solving of specific issues that the caregiver brings to the sessions
  • Answers for questions regarding the educational materials

The educational materials will consist of a copy of the book The 36-Hour Day


Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01117181

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21224
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29406
Canada, Ontario
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada
Sponsors and Collaborators
Johns Hopkins Bloomberg School of Public Health
Medical University of South Carolina
Johns Hopkins University
University of Toronto
Investigators
Principal Investigator: Roberta Scherer, PhD Johns Hopkins University Bloomberg School of Public Health
Study Chair: Jacobo Mintzer, MD, MBA Medical University of South Carolina
Principal Investigator: Paul Rosenberg, MD Johns Hopkins University
Principal Investigator: Krista Lanctot, PhD Sunnybrook Health Sciences Centre
  More Information

Additional Information:
No publications provided by Johns Hopkins Bloomberg School of Public Health

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Johns Hopkins Bloomberg School of Public Health
ClinicalTrials.gov Identifier: NCT01117181     History of Changes
Other Study ID Numbers: R01AG033032-01, R01AG033032-01
Study First Received: May 4, 2010
Results First Received: February 11, 2013
Last Updated: April 1, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Johns Hopkins Bloomberg School of Public Health:
Alzheimer's disease
Apathy
Methylphenidate
Dopaminergic agents
Apathy Evaluation Scale
Dementia

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Nervous System Diseases
Neurodegenerative Diseases
Tauopathies
Methylphenidate
Central Nervous System Agents
Central Nervous System Stimulants
Dopamine Agents
Dopamine Uptake Inhibitors
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014