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TAME-PD - Physical Therapy, Atomoxetine and, Methylphenidate, to Enhance Gait and Balance in Parkinson's Disease

Sponsor
Hubert Fernandez (Other)
Overall Status
Recruiting
CT.gov ID
NCT02879136
Collaborator
(none)
42
Enrollment
1
Location
3
Arms
96
Duration (Months)
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Gait and balance problems are a significant source of disability in patients with Parkinson disease. Physical therapy remains one of the main treatments. On the other hand some medications, such as methyphenidate and atomoxetine, have been tried with promising results. The outcomes in gait and balance in Parkinson disease after a combination of physical therapy and the medications mentioned above have not been explored yet. The investigators want to evaluate whether the addition of medication, either low dose of methylphenidate or atomoxetine, to physical therapy will achieve improvement in gait and balance in Parkinson disease more than physical therapy alone. The investigators propose a pilot, single center, rater blind, prospective randomized trial. 2-arm-parallel group, intention-to-treat analysis.

Condition or Disease Intervention/Treatment Phase
Early Phase 1

Detailed Description

Gait impairment and postural instability constitute major sources of disability in Parkinson disease (PD). Increased level of dependence in activities of daily living and augmented risk of falling are the main consequences. About 87% of patients experience at least one fall during their illness, 65% an injury that requires evaluation in an emergency room, and up to 33% sustain one or more fractures.

Pedunculopontine nucleus, locus ceruleus, frontal brain cortex, and striatum play a critical role in gait and balance, with dopamine, noradrenaline and acetylcholine as the main neurotransmitters. Therefore, increased availability of dopamine in the nigrostriatal pathway, and enhanced disposal of central noradrenaline and acetylcholine in the locus ceruleus can in theory, contribute to improvement .

Methylphenidate and atomoxetine are dopamine and noradrenaline reuptake inhibitors approved for the treatment of attention disorders. Interestingly, growing literature suggests a promising role of these medications in gait and balance in PD. Three open-label studies reported efficacy of methylphenidate in gait impairment in patients with PD. Auriel et al used a single 20 mg dose of methylphenidate in 23 patients and found an improvement in gait speed, stride time variability, and timed gait. In a second study, 5 patients received a single 10-mg dose of methylphenidate and improvements were noted in total walking time, total freezing time, number of freezing episodes, and nonfreezing walking time. Another study, which evaluated a 50 to 80 mg dose of methylphenidate over 3 months in 17 patients undergoing concomitant deep brain stimulation, found an improvement in both timed gait and in the number of freezing episodes.

However, the only randomized clinical trial with methylphenidate showed a different result. Twenty-three subjects with PD and moderate gait impairment were screened for this 6- month, placebo-controlled, double-blind study. Subjects were randomly assigned to high dose of methylphenidate (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score obtained through GAITrite (a system that was developed to measure and record temporal and spatial parameters of gait by using a walkway approximately 3 meters long with grids of embedded, pressure-sensitive sensors connected to a personal computer). Seventeen patients completed the trial. There was no change in the gait composite score or any of the secondary or exploratory variables such as fatigue, freezing, depression and daily sleepiness at 12 weeks; however, some improvement was noted in the early phase of the study.

The discrepancy between the results of the open label studies and the randomized study may be explained by dose of methylphenidate substantially higher in the RCT compared to the first two open-label studies. Whereas patients in the RCT received at least 65 mg/day, patients in the first two open-label studies received 10-20 mg/day. It is been suggested that the efficacy of methylphenidate and atomoxetine varies according to the dose administrated. The complex pharmacodynamic of dopamine and noradrenaline reuptake inhibitors in the presence of other dopaminergic therapies such as Levodopa or dopamine agonist, can elicit differences in response regarding the administered dose . During the early phase of the RCT when a trend improvement was noted, smaller doses of methylphenidate were being used as the patients were being titrated to their final dose. Low chronic doses of methylphenidate have not been tested to improve gait and balance in PD in any trial.

In the one pilot study thus far evaluating atomoxetine for gait freezing, a trend towards improvement in the gait and balance scale (GABS) was noted. However, this study was underpowered as only five patients participated in the study .

Simultaneously, diverse modalities of physical therapy (PT) have shown improvement in gait and balance in PD. A systematic review from Cochrane database concluded that different physiotherapy interventions were better than placebo over three months, in terms of velocity, two- or six-minute walk test, step length, Timed Up & Go, Functional Reach Test, Berg Balance Scale and clinician-rated UPDRS. The grade of improvement varied depending on the intervention and outcome measure, ranging from 10 to 30%.

To the best of the investigators' knowledge, the combination of medication and physical therapy has never been evaluated previously in gait and balance in PD.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
42 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Investigator)
Primary Purpose:
Treatment
Official Title:
TAME-PD - Physical Therapy, Atomoxetine and, Methylphenidate, to Enhance Gait and Balance in Parkinson's Disease: A Single Center, Randomized Pilot Study
Study Start Date :
Dec 1, 2016
Anticipated Primary Completion Date :
Dec 1, 2023
Anticipated Study Completion Date :
Dec 1, 2024

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Physical Therapy

Physical Therapy (PT) will consist of two weekly sessions over a 12 week period using the Mellen center protocol PT for PD.

Other: Physical Therapy
All Patients will have standard of care PT used for PD patients
Other Names:
  • PT

    		•
    Active Comparator: Physical Therapy plus Methylphenidate

    Methylphenidate 20 mg daily in combination with PT

    Drug: Methylphenidate
    Patient will be randomized to Methylphenidate
    Other Names:
  • Ritalin

    • Other: Physical Therapy
    All Patients will have standard of care PT used for PD patients
    Other Names:
  • PT

    		•
    Active Comparator: Physical Therapy plus Atomoxetine

    Atomoxetine 10 mg daily in combination with PT or PT alone.

    Other: Physical Therapy
    All Patients will have standard of care PT used for PD patients
    Other Names:
  • PT

    • Drug: Atomoxetine
    Patient will be randomized to Atomoxetine
    Other Names:
  • Straterra

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Balance Evaluation [12 weeks]

      Change in the balance evaluation systems test, MiniBest is standard gait analysis measure conducted by physical therapists.

    Secondary Outcome Measures

    1. Change in gait [12 weeks]

      Stride length and gait velocity measured using "GaitRite", which is a standard gait analysis measure conducted by physical therapists.

    Other Outcome Measures

    1. Motor function [12 weeks]

      UPDRS part III scale

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 90 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients with PD having significant balance or gait disorder with a score ≥2 in the Unified Parkinson Disease Rating Scale (UPDRS) 3.10 item 'independent walking but with substantial gait impairment; not related to off periods' occurring despite satisfactory motor control by dopaminergic therapy, with a medication regimen unlikely to change in the next 30 days.
    Exclusion Criteria:

    • Previous participation in PD-specific PT.

    • Presence of signs and symptoms suggestive of atypical parkinsonism.

    • Concomitant conditions that may affect significantly the evaluation of balance or gait, including orthopedic, rheumatologic or other neurological diseases.

    • Contraindication for physical therapy

    • Comorbidities that contraindicate the use of the methylphenidate or atomoxetine: history of substance abuse, current severe anxiety, depression or psychosis, epilepsy, hyperthyroidism, glaucoma, cardiac arrhythmia, history of Tourette syndrome, hepatic disease, allergy to methylphenidate or atomoxetine.

    • Concurrent use of MAO inhibitors, or use in the last two weeks.

    • Previous deep brain stimulation procedure.

    • Punctuation of 5 in Hoehn and Yard modified scale: 'Wheelchair bound or bedridden unless aided'.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Cleveland Clinic Cleveland Ohio United States 44195

    Sponsors and Collaborators

    • Hubert Fernandez

    Investigators

    • Principal Investigator: Shnehal Patel, The Cleveland Clinic

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Hubert Fernandez, Principal Investigator, The Cleveland Clinic
    ClinicalTrials.gov Identifier:
    NCT02879136
    Other Study ID Numbers:
    • 16-277
    First Posted:
    Aug 25, 2016
    Last Update Posted:
    Feb 17, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Hubert Fernandez, Principal Investigator, The Cleveland Clinic
    Gait
    Balance
    PD
    Additional relevant MeSH terms:
    Parkinson Disease
    Methylphenidate
    Atomoxetine Hydrochloride

    Study Results

    No Results Posted as of Feb 17, 2022