- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02879136
TAME-PD - Physical Therapy, Atomoxetine and, Methylphenidate, to Enhance Gait and Balance in Parkinson's Disease (TAME-PD)
TAME-PD - Physical Therapy, Atomoxetine and, Methylphenidate, to Enhance Gait and Balance in Parkinson's Disease: A Single Center, Randomized Pilot Study
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Estimated)
Phase
- Early Phase 1
Contacts and Locations
Study Contact
- Name: Shnehal Patel, MD
- Email: patels7@ccf.org
Study Contact Backup
- Name: Jennifer Mule
- Email: mulej@ccf.org
Study Locations
-
-
Ohio
-
Cleveland, Ohio, United States, 44195
- Recruiting
- Cleveland Clinic
-
Contact:
- Shnehal Patel, MD
- Email: patels7@ccf.org
-
Contact:
- Jennifer Mule, BS
- Email: mulej@ccf.org
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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'.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / 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.
|
All Patients will have standard of care PT used for PD patients
Other Names:
|
Active Comparator: Physical Therapy plus Methylphenidate
Methylphenidate 20 mg daily in combination with PT
|
All Patients will have standard of care PT used for PD patients
Other Names:
Patient will be randomized to Methylphenidate
Other Names:
|
Active Comparator: Physical Therapy plus Atomoxetine
Atomoxetine 10 mg daily in combination with PT or PT alone.
|
All Patients will have standard of care PT used for PD patients
Other Names:
Patient will be randomized to Atomoxetine
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Balance Evaluation
Time Frame: 12 weeks
|
Change in the balance evaluation systems test, MiniBest is standard gait analysis measure conducted by physical therapists.
|
12 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in gait
Time Frame: 12 weeks
|
Stride length and gait velocity measured using "GaitRite", which is a standard gait analysis measure conducted by physical therapists.
|
12 weeks
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Motor function
Time Frame: 12 weeks
|
UPDRS part III scale
|
12 weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Shnehal Patel, The Cleveland Clinic
Publications and helpful links
General Publications
- Leentjens AF, Dujardin K, Pontone GM, Starkstein SE, Weintraub D, Martinez-Martin P. The Parkinson Anxiety Scale (PAS): development and validation of a new anxiety scale. Mov Disord. 2014 Jul;29(8):1035-43. doi: 10.1002/mds.25919. Epub 2014 May 23.
- Mendonca DA, Menezes K, Jog MS. Methylphenidate improves fatigue scores in Parkinson disease: a randomized controlled trial. Mov Disord. 2007 Oct 31;22(14):2070-6. doi: 10.1002/mds.21656.
- Boonstra TA, van der Kooij H, Munneke M, Bloem BR. Gait disorders and balance disturbances in Parkinson's disease: clinical update and pathophysiology. Curr Opin Neurol. 2008 Aug;21(4):461-71. doi: 10.1097/WCO.0b013e328305bdaf.
- Williams DR, Watt HC, Lees AJ. Predictors of falls and fractures in bradykinetic rigid syndromes: a retrospective study. J Neurol Neurosurg Psychiatry. 2006 Apr;77(4):468-73. doi: 10.1136/jnnp.2005.074070.
- Moreau C, Cantiniaux S, Delval A, Defebvre L, Azulay JP. [Gait disorders in Parkinson's disease: and pathophysiological approaches]. Rev Neurol (Paris). 2010 Feb;166(2):158-67. doi: 10.1016/j.neurol.2009.05.010. Epub 2009 Jul 18. French.
- Wielinski CL, Erickson-Davis C, Wichmann R, Walde-Douglas M, Parashos SA. Falls and injuries resulting from falls among patients with Parkinson's disease and other parkinsonian syndromes. Mov Disord. 2005 Apr;20(4):410-415. doi: 10.1002/mds.20347.
- Collomb-Clerc A, Welter ML. Effects of deep brain stimulation on balance and gait in patients with Parkinson's disease: A systematic neurophysiological review. Neurophysiol Clin. 2015 Nov;45(4-5):371-88. doi: 10.1016/j.neucli.2015.07.001. Epub 2015 Aug 28.
- Nutt JG, Horak FB, Bloem BR. Milestones in gait, balance, and falling. Mov Disord. 2011 May;26(6):1166-74. doi: 10.1002/mds.23588.
- Auriel E, Hausdorff JM, Herman T, Simon ES, Giladi N. Effects of methylphenidate on cognitive function and gait in patients with Parkinson's disease: a pilot study. Clin Neuropharmacol. 2006 Jan-Feb;29(1):15-7. doi: 10.1097/00002826-200601000-00005.
- Pollak L, Dobronevsky Y, Prohorov T, Bahunker S, Rabey JM. Low dose methylphenidate improves freezing in advanced Parkinson's disease during off-state. J Neural Transm Suppl. 2007;(72):145-8. doi: 10.1007/978-3-211-73574-9_17.
- Devos D, Krystkowiak P, Clement F, Dujardin K, Cottencin O, Waucquier N, Ajebbar K, Thielemans B, Kroumova M, Duhamel A, Destee A, Bordet R, Defebvre L. Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson's disease. J Neurol Neurosurg Psychiatry. 2007 May;78(5):470-5. doi: 10.1136/jnnp.2006.100016. Epub 2006 Nov 10.
- Espay AJ, Dwivedi AK, Payne M, Gaines L, Vaughan JE, Maddux BN, Slevin JT, Gartner M, Sahay A, Revilla FJ, Duker AP, Shukla R. Methylphenidate for gait impairment in Parkinson disease: a randomized clinical trial. Neurology. 2011 Apr 5;76(14):1256-62. doi: 10.1212/WNL.0b013e3182143537.
- Jankovic J. Atomoxetine for freezing of gait in Parkinson disease. J Neurol Sci. 2009 Sep 15;284(1-2):177-8. doi: 10.1016/j.jns.2009.03.022. Epub 2009 Apr 9.
- Mirelman A, Maidan I, Deutsch JE. Virtual reality and motor imagery: promising tools for assessment and therapy in Parkinson's disease. Mov Disord. 2013 Sep 15;28(11):1597-608. doi: 10.1002/mds.25670.
- Gisbert R, Schenkman M. Physical therapist interventions for Parkinson disease. Phys Ther. 2015 Mar;95(3):299-305. doi: 10.2522/ptj.20130334. Epub 2014 Nov 25. No abstract available. Erratum In: Phys Ther. 2015 Apr;95(4):685.
- Tomlinson CL, Patel S, Meek C, Clarke CE, Stowe R, Shah L, Sackley CM, Deane KH, Herd CP, Wheatley K, Ives N. Physiotherapy versus placebo or no intervention in Parkinson's disease. Cochrane Database Syst Rev. 2012 Jul 11;(7):CD002817. doi: 10.1002/14651858.CD002817.pub2.
- Thomas M, Jankovic J, Suteerawattananon M, Wankadia S, Caroline KS, Vuong KD, Protas E. Clinical gait and balance scale (GABS): validation and utilization. J Neurol Sci. 2004 Jan 15;217(1):89-99. doi: 10.1016/j.jns.2003.09.005.
- Williams JR, Hirsch ES, Anderson K, Bush AL, Goldstein SR, Grill S, Lehmann S, Little JT, Margolis RL, Palanci J, Pontone G, Weiss H, Rabins P, Marsh L. A comparison of nine scales to detect depression in Parkinson disease: which scale to use? Neurology. 2012 Mar 27;78(13):998-1006. doi: 10.1212/WNL.0b013e31824d587f. Epub 2012 Mar 14.
Study record dates
Study Major Dates
Study Start
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Parkinsonian Disorders
- Basal Ganglia Diseases
- Movement Disorders
- Synucleinopathies
- Neurodegenerative Diseases
- Parkinson Disease
- Physiological Effects of Drugs
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Neurotransmitter Uptake Inhibitors
- Membrane Transport Modulators
- Dopamine Agents
- Dopamine Uptake Inhibitors
- Central Nervous System Stimulants
- Adrenergic Uptake Inhibitors
- Methylphenidate
- Atomoxetine Hydrochloride
Other Study ID Numbers
- 16-277
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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