Apathy in Dementia Methylphenidate Trial 2

NCT ID: NCT02346201

Last Updated: 2023-06-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-31
• Study Completion Date: 2020-07-15

Brief Summary

Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is a Phase III, placebo-controlled, masked, 6 month, multi-center randomized clinical trial sponsored by National Institutes of Aging involving 200 participants with Alzheimer's disease (AD). ADMET 2 is designed to examine the efficacy and safety of methylphenidate as treatment for clinically significant apathy in AD participants. ADMET 2 will enroll participants from real world settings such as outpatient, nursing home, and assisted living facilities and will examine the effects of methylphenidate on apathy and cognition. ADMET 2 will also conduct careful safety monitoring.

Detailed Description

ADMET 2 will examine in a masked, randomized trial the efficacy of methylphenidate for the treatment of clinically significant apathy in participants with Alzheimer's dementia. Efficacy will be assessed as the change in Neuropsychiatric Inventory Apathy subscale (NPI apathy) from baseline to 6 months and score on the Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (CGIC) scale at 6 months.

ADMET 2 will also examine the safety of methylphenidate for the treatment of clinically significant apathy in participants with Alzheimer's disease by measuring vital signs, electrolyte panels, adverse event reports, and electrocardiograms. Safety will also be measured by examining neuropsychiatric symptoms other than apathy using the Neuropsychiatric Inventory (NPI).

Changes from baseline to 6 months in other neuropsychological assessments as measured using the Dementia Apathy Interview and Rating (DAIR) scale will also be assessed.

Cost-effectiveness will be measured by assessing quality of life and economic assessment and cognitive changes using a cognitive battery that includes the Mini Mental State Exam (MMSE) and other scales.

A biomarker sub-study initiated part-way through the main trial will collect information on blood-based biomarkers, including microRNA, markers of oxidative stress, inflammation, neuronal loss and lipidomics.

Conditions

Apathy; Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Methylphenidate

Methylphenidate, target dose 20 mg per day (range 10-20 mg per day), in 5 mg over-capsulated tablets, and psychosocial intervention

Group Type: ACTIVE_COMPARATOR

Methylphenidate

Intervention Type: DRUG

Two 5mg methylphenidate over-encapsulated drug taken twice a day for 6 months (total of 20 mg methylphenidate per day), and psychosocial intervention

Placebo

Matching over-encapsulated placebo and psychosocial intervention

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Two over-encapsulated placebo taken twice a day for 6 months and psychosocial intervention

Interventions

Methylphenidate

Two 5mg methylphenidate over-encapsulated drug taken twice a day for 6 months (total of 20 mg methylphenidate per day), and psychosocial intervention

Intervention Type: DRUG

Placebo

Two over-encapsulated placebo taken twice a day for 6 months and psychosocial intervention

Intervention Type: DRUG

Other Intervention Names

Ritalin

Eligibility 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 10-28 inclusive
• Clinically significant apathy for at least four weeks for which either

• the frequency of apathy as assessed by the Neuropsychiatric Inventory (NPI) is 'Very frequently', or
• 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 potential participant or surrogate (with participant assent if the potential participant is unable to provide informed consent) and caregiver
• Availability of primary caregiver, who spends greater than ten hours a week with the potential participant and supervises his/her care, to accompany the potential participant to study visits and to participate in the study
• Sufficient fluency, of both the potential participant and caregiver, in written and spoken English to participate in study visits, physical exams, and outcome assessments
• If female, woman must be post-menopausal for at least 2 years or have had a hysterectomy

Exclusion Criteria

• Currently meets criteria for Major Depressive Episode, by Diagnostic Statistical Manual of Mental Disorder - 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 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'
• Change to AD medications within the month preceding randomization, including starting, stopping, or dosage modifications
• Change in anti-depressant (except for trazodone used for sleeping difficulties as described below) use within the 30 days preceding randomization or a period of time equal to 5 half-lives of drug, whichever period of time is longer
• Use of trazodone > 50mg or lorazepam > 0.5mg or for indications other than sleeping difficulties within the 30 days preceding randomization or a period of time equal to 5 half-lives of drug, whichever period of time is longer. Other benzodiazepines are prohibited in the past 30 days or within 5 half-lives, whichever period of time is longer.
• Failure of treatment with methylphenidate in the past for apathy after convincing evidence of an adequate trial as judged by study physician
• Currently taking any amphetamine product, an antipsychotic, bupropion, or any medication that would prohibit the safe concurrent use of methylphenidate, including but not limited to monoamine oxidase inhibitors and tricyclic antidepressants within the 30 days preceding randomization or a period of time equal to 5 half-lives of drug, whichever period of time is longer
• Need for acute psychiatric hospitalization or is suicidal in the opinion of the study physician
• Significant communicative impairments that would affect participation in clinical trial
• Central nervous system abnormalities (e.g., cerebral aneurysm), seizures (convulsions, epilepsy), Tourette's syndrome or presence of motor tics, or abnormal electroencephalograms
• Lack of appetite that results in significant unintentional weight loss as determined by the study physician in the last three months
• Uncontrolled hyperthyroidism
• Any cardiovascular or cerebrovascular abnormality deemed to be clinically significant by the study physician, tachycardia (heart rate > 100 beats per minute), or uncontrolled hypertension (defined as medication non-compliance or past 3 months with a diastolic reading > 105 mm Hg), at the time of screening
• Closed angle glaucoma or pheochromocytoma
• Women with childbearing potential
• Current participation in a clinical trial or study that may add significant burden or affect study outcomes
• Any condition that, in the opinion of the study physician, makes it medically inappropriate or risky for the potential participant to enroll in the trial, including, but not limited to, contraindication to treatment with methylphenidate.

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Johns Hopkins Bloomberg School of Public Health

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jacobo Mintzer, MD

Role: STUDY_CHAIR

Medical University of South Carolina

Locations

Banner Alzheimer's Institute

Phoenix, Arizona, United States

University of Arkansas

Little Rock, Arkansas, United States

Yale Alzheimer's Disease Research Unit

New Haven, Connecticut, United States

Emory

Atlanta, Georgia, United States

Johns Hopkins University

Baltimore, Maryland, United States

University of Rochester

Rochester, New York, United States

Wake Forest

Winston-Salem, North Carolina, United States

University Hospitals- Case Medical Center

Cleveland, Ohio, United States

Roper-St. Francis Healthcare

Charleston, South Carolina, United States

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Countries

United States; Canada

References

Lanctot KL, Chen C, Mah E, Kiss A, Li A, Shade D, Scherer RW, Vieira D, Coulibaly H, Rosenberg PB, Lerner AJ, Padala PR, Brawman-Mintzer O, van Dyck CH, Porsteinsson AP, Craft S, Levey A, Burke WJ, Mintzer J, Herrmann N. Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2). Int Psychogeriatr. 2023 Nov;35(11):664-672. doi: 10.1017/S1041610223000327. Epub 2023 Apr 17.

Reference Type: DERIVED

PMID: 37066690 (View on PubMed)

Mintzer J, Lanctot KL, Scherer RW, Rosenberg PB, Herrmann N, van Dyck CH, Padala PR, Brawman-Mintzer O, Porsteinsson AP, Lerner AJ, Craft S, Levey AI, Burke W, Perin J, Shade D; ADMET 2 Research Group. Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial. JAMA Neurol. 2021 Nov 1;78(11):1324-1332. doi: 10.1001/jamaneurol.2021.3356.

Reference Type: DERIVED

PMID: 34570180 (View on PubMed)

Scherer RW, Drye L, Mintzer J, Lanctot K, Rosenberg P, Herrmann N, Padala P, Brawman-Mintzer O, Burke W, Craft S, Lerner AJ, Levey A, Porsteinsson A, van Dyck CH; ADMET 2 Research Group. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): study protocol for a randomized controlled trial. Trials. 2018 Jan 18;19(1):46. doi: 10.1186/s13063-017-2406-5.

Reference Type: DERIVED

PMID: 29347996 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

R01AG046543

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ADMET2

Identifier Type: -

Identifier Source: org_study_id