Clinical trial NCT05669170: Methylphenidate for Apathy in Veterans With Parkinson's Disease
Official title: Evaluating Safety and Potential Benefit of Methylphenidate as a Symptomatic Treatment for Apathy in Veterans With Parkinson's Disease.
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Parkinson Disease
Apathy
Keywords: methylphenidate
apathy
Parkinson disease
Lead sponsor: Ralph H. Johnson VA Medical Center
Sponsor class: FED
First posted: 2022-12-30
Enrollment: 60
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Apathy is one of the most common behavioral symptoms of Parkinson's disease. Patients with apathy show diminution in motivation and goal-directed behaviors, which is a fundamental aspect of human functioning, affecting dependency and quality of life. Although apathy is thought to be potentially treatable currently there are no effective treatments for apathy. Given the higher incidence of medical and psychiatric comorbidities, the Veterans Affairs health system represents a unique population for which medication response may be different from the general population. This study aims to evaluate if a medication that has already been proven to be useful in Alzheimer's disease patients with apathy, could be helpful in Parkinson's disease as well as decreasing its debilitating consequences and reducing patients' dependency on caregivers, providing well-deserved relief to patients and their loved ones.

Detailed description: Apathy in Parkinson's disease (PD) is a significant public health problem with serious adverse consequences for patients and caregivers. Apathy is present in up to 70% of people with PD. Patients suffering from apathy experience decreased motivation, relying heavily on caregivers to initiate daily activities. The presence of apathy is associated with worse quality of life for patients and caregivers. Moreover, patients with apathy have a faster disease progression and increased likelihood of development of cognitive impairment.

Despite the high prevalence of apathy in PD and its serious consequences, there are no proven treatments for this condition. Dopaminergic enhancement appears as a potential mechanism as there is evidence that degeneration of the frontostriatal circuits involving the prefrontal cortex is one of the main mechanisms for the presence of apathy in PD as well as other neurodegenerative disorders, such as Alzheimer's disease (AD). This degeneration is associated with deficits in dopaminergic and noradrenergic input fibers to the prefrontal cortex.

Methylphenidate, a dopamine and noradrenaline reuptake inhibitor, has been shown to be safe and effective in PD in the treatment of motor and cognitive symptoms, and several small trials and case series reported improvement in motivation and mood. Recently, methylphenidate was shown to be safe and improve apathy in AD in a series of well-controlled studies conducted by members of our team. This represents a relevant result as similar pathophysiology for apathy has been suggested in both AD and PD.

Given the common biological pathways in the onset of apathy in both disorders, we propose that, as is the case in AD, methylphenidate will be a safe and effective treatment for apathy in PD.

The goal of the proposed study of Methylphenidate for Apathy in Veterans with Parkinson's Disease (MAV-PD) is to expand upon this encouraging preliminary work by evaluating methylphenidate for the treatment of apathy in PD Veteran patients. It is our strong belief that a trial designed specifically in Veteran population should be conducted, as reliance on data from civilian populations who differ in their level of medical and psychiatric comorbidity, which influence drug response, may not be applicable to Veterans with PD.

This study will employ a single-site, parallel, randomized, double-blind, placebo-controlled design conducted on 60 Veterans with apathy and PD. MAV-PD is designed specifically for PD patients with apathy, and as such it employs a concise battery of neuropsychological tests that have been chosen for this patient group.

This project is of great importance because it will explore the efficacy and safety of a promising dopamine agonist for treating apathy in PD, where there are no proven treatment options. Should methylphenidate be found effective, it will likely become the first-line therapy for apathy in PD.

Eligibility criteria: Inclusion Criteria:

* • Clinically established or probable Parkinson disease according to the Movement Disorders Society Clinical Diagnostic Criteria for Parkinson's Disease

  * Age 40 or older at the time of screening
  * Montreal Cognitive Assessment (MoCA) score between 17-30.
  * Clinical Dementia Rating scale (CDR) lower than 1 and CDR sum of boxes lower than 4.5. The CDR is a numeric scale used to quantify the severity of symptoms of dementia. Using a structured interview protocol, qualified raters assess the subject's cognitive and functional performance in six areas: memory, orientation, judgement, and problem solving, community affairs, home and hobbies, and personal care. Scores are combined to obtain a composite score ranging from 0 through 3. A score between 0 and 1 indicates none or mild symptoms. The individual scores can also be added up, which gives the sum of boxes score.
  * 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'
  * Provision of informed consent for participation in the study by the patient. The ability to provide consent will be determined by the Assessment of Capacity for Everyday Decision-Making (ACED). The total score must be 9 (out of 10) or higher to meet the criteria for the study.
  * 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
  * No change to PD medications within the month preceding randomization, including starting, stopping, or dosage modifications
  * Treatment with stable doses of levodopa and cholinesterase inhibitors (ChEIs) is allowable if stable for 3 months before randomization. Other psychotropics (with the exclusion of antipsychotics), if stable for 3 months, may be allowed only with PIs' approval on a case-by-case basis

Exclusion Criteria:

* • Meets criteria Major Depressive Episode according to the Diagnostic Statistical Manual of Mental Disorder 5

  * History of psychotic symptoms due to another illness (i.e., schizophrenia, psychosis in mood disorders, etc.) in the past 2 years
  * 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'
  * Clinically significant impulse control disorders as assessed by the QUIP
  * Substance use disorder in the past year as assessed by the Drug Abuse Screening Test (DAST-10).
  * Treatment with psychotropic medications in the 2 weeks prior to randomization with the exception of approved treatments for cognitive impairment (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 PI approval on a case-by-case basis. Note that antipsychotics are expressly prohibited
  * Treatment with methylphenidate is contraindicated in the opinion of the PIs
  * Failure of treatment with methylphenidate in the past for apathy
  * 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
  * Active suicidal ideation as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS).60 If any of the responses to the questionnaires are yes, the subject will be evaluated by a psychiatrist to assess the risk of suicidality.
  * Uncontrolled hypertension (medication non-compliance or past 3 months with a diastolic reading of 105 mmHg)
  * Symptomatic coronary artery disease deemed to be significant by the PIs at the time of screening
  * Unintentional weight loss as determined by the PIs in the last three months
  * Significant communicative impairments that prohibit meaningful participation in the study assessments
  * Current participation in a clinical trial
  * 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 family history or diagnosis of Tourette's syndrome, seizures (convulsions, epilepsy), or abnormal EEGs
  * Any condition that, in the opinion of the PIs, makes it medically inappropriate or risky for the patient to enroll in the trial
  * Women who are currently pregnant (methylphenidate is category D). Screening will include pregnancy test

Primary outcomes:
measure: Apathy Evaluation Scale (AES)
timeFrame: 6 weeks
measure: Clinical Global Impression of Change (CGIC)
timeFrame: 6 weeks
Secondary outcomes:
measure: Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog)
timeFrame: 6 weeks
measure: Continuous Performance Test (CPT)
timeFrame: 6 weeks
measure: Trail Making Test (TMT)
timeFrame: 6 weeks
measure: Neuropsychiatric Inventory (NPI)
timeFrame: 6 weeks
measure: Starkstein Apathy Scale (SAS)
timeFrame: 6 weeks
measure: Dementia Apathy Interview Rating (DAIR)
timeFrame: 6 weeks
measure: Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
timeFrame: 6 weeks
measure: Questionnaire for Impulsive-Compulsive Disorders in PD (QUIP)
timeFrame: 6 weeks
measure: Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) - Part III and IV
timeFrame: 6 weeks
Other outcomes:
Locations:
Study officials:
References:
citation: 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.
citation: Rosenberg PB, Lanctot KL, Drye LT, Herrmann N, Scherer RW, Bachman DL, Mintzer JE, ADMET Investigators. Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial. J Clin Psychiatry. 2013 Aug;74(8):810-6. doi: 10.4088/JCP.12m08099.
citation: Le Heron C, Holroyd CB, Salamone J, Husain M. Brain mechanisms underlying apathy. J Neurol Neurosurg Psychiatry. 2019 Mar;90(3):302-312. doi: 10.1136/jnnp-2018-318265. Epub 2018 Oct 26.
citation: Aarsland D, Larsen JP, Lim NG, Janvin C, Karlsen K, Tandberg E, Cummings JL. Range of neuropsychiatric disturbances in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 1999 Oct;67(4):492-6. doi: 10.1136/jnnp.67.4.492.
citation: Pagonabarraga J, Kulisevsky J, Strafella AP, Krack P. Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol. 2015 May;14(5):518-31. doi: 10.1016/S1474-4422(15)00019-8. Epub 2015 Apr 12.