A Multidisciplinary Approach to Manage Gait Difficulty in Parkinson Patients
NCT ID: NCT02857244
Last Updated: 2017-12-12
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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WITHDRAWN
PHASE2
INTERVENTIONAL
2016-11-30
2017-11-30
Brief Summary
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Targeting multiple mechanisms at same time, such as the combination of a SNRI antianxiety medication (also boosting the norepinephrine system, such as duloxetine) with an anti-dementia medication correcting the cholinergic deficiency (such as donepezil), or targeting a new mechanism, such as the use of anti-GABAergic medication targeting the area responsible for gait and sleep cycle (pedunculopontine nucleus area, PPNa) should be tried.
Therefore, a collaboration of multidisciplinary teams among the neurology movement disorder team and cognition and sleep team, and psychiatry team is essential, which has not been tried before in studying and treating the challenging gait difficulty in Parkinson patients.
Detailed Description
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Specifically, the investigators will propose an open label prospective pilot study using duloxetine to treat 22 parkinsonian patients with FOG, aiming for estimated 80% power of detecting 50%. Each patient will take duloxetine 30mg for 1 week, followed by 60mg qam for 1 week, 90mg qam for 1 week, and 120mg qam for 1 week, if tolerated. The patient will be taking duloxetine for a total of 4 weeks, as described above. The dose of duloxetine will be reduced if the patient cannot tolerate a higher rank dose as designated. This principle will apply to the other two medications used in the study as well. Donepezil will then be added to duloxetine 120mg qam (or the highest dose the patient can tolerate if it is lower than 120mg) by 5mg qd for 1 week, followed by 10mg qd for 1 week. Each patient will visit us 3 times (baseline and at the end of each medication, namely 4 weeks after the duloxetine and 2 weeks after the donepezil), checking UPDRS-III (and PSP scale as well for PSP patients), stand-walk-sit, freezing of gait questionnaire, Montreal cognitive scale (MoCA) for patients before and after Donepezil treatment, and anxiety scale for patients before and after duloxetine treatment (if the patient is on dopaminergic medication). Daily falls, freezing of gait (by the questionnaire) and quality of life (by PDQ-39 scale) over the past week prior to the clinical visit will also be checked.
After a 4-week washout period, each patient will take modafinil 100mg qam for 1 week, followed by 200mg qam for 1 week. Each patient will visit us twice (baseline at the end of the 4-week washout period, and at the end of the 2-week modafinil treatment), checking UPDRS (and PSP scale as well if for PSP patient), stand-walk-sit, freezing of gait questionnaire, MoCA, anxiety scale and Epworth sleep scale at each visit before and 1 hour after the dopaminergic medication(s) (if the patient is on dopaminergic medication). Daily falls, freezing of gait and quality of life (by PDQ-39) over the past week prior to the clinical visit will also be checked.
A paired t-test will be used to compare the changes under each regimen with that at baseline, with primary outcome on gait difficulty of FOG frequency and severity, and secondary outcome on anxiety, cognition, UPDRS-III (plus PSP scale for PSP patients), and Epworth sleep scale (for modafinil trial) at dopaminergic medication off (after staying off the dopaminergic medication for over night) and on (1 hour after taking dopaminergic medication) state and quality of life assessment. The investigators want to see if the medications of different working mechanism, along or in combination, could improve the FOG and other motor symptoms, through the improvement of anxiety, cognitive dysfunction and wakening state at dopaminergic medications (for parkinsonism) off state and on state.
Conditions
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Keywords
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Open-Label Treatment Arm
Each patient will take Duloxetine 30mg for 1 week, followed by 60mg qam for 1 week, 90mg qam for 1 week, and 120mg qam for 1 week, if tolerated. The patient will be taking Duloxetine for a total of 4 weeks. The dose of Duloxetine will be reduced if the patient cannot tolerate. Donepezil will then be added to Duloxetine 120mg qam (or the highest dose the patient can tolerate) by 5mg qd for 1 week, followed by 10mg qd for 1 week.
After a 4-week washout period, each patient will take Modafinil 100mg qam for one week, followed by 200mg qam for 1 week.
Patients will come into the medical center on 5 occasions, 1 for screening/baseline, 1 after completion of duloxetine, 1 after completion of duloxetine+donepezil, 1 after four-week washout, 1 after completion of modafinil.
Duloxetine
Patients will first receive Duloxetine for 4 weeks starting at 30mg, 60mg, 90mg then 120mg (if tolerated). Increases in dosage amounts will occur every week.
Donepezil
Patients will receive Donepezil after 4 weeks of dosing with Duloxetine. Patients will receive Donepezil in combination with the highest dose of Duloxetine that was tolerated. Patients will remain on this for 2 weeks with increasing doses at each week. One week of 5mg, one week of 10mg.
Modafinil
Patients will receive Modafinil after a 4 week washout period (after dosing with donepezil \& duloxetine in combination). Patients will receive Modafinil for two weeks with increasing doses at each week. One week at 100mg, one week at 200mg.
Interventions
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Duloxetine
Patients will first receive Duloxetine for 4 weeks starting at 30mg, 60mg, 90mg then 120mg (if tolerated). Increases in dosage amounts will occur every week.
Donepezil
Patients will receive Donepezil after 4 weeks of dosing with Duloxetine. Patients will receive Donepezil in combination with the highest dose of Duloxetine that was tolerated. Patients will remain on this for 2 weeks with increasing doses at each week. One week of 5mg, one week of 10mg.
Modafinil
Patients will receive Modafinil after a 4 week washout period (after dosing with donepezil \& duloxetine in combination). Patients will receive Modafinil for two weeks with increasing doses at each week. One week at 100mg, one week at 200mg.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* or PSP per SPSP-NINDS criteria 16,
* FOG at off or on dopaminergic medication or both.
Exclusion Criteria
* unable to walk without assistance,
* seizures,
* or allergy to any of these three medications on trial.
18 Years
100 Years
ALL
No
Sponsors
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University of Chicago
OTHER
Responsible Party
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Principal Investigators
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Tao Xie, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Chicago
Locations
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University of Chicago Medical Center
Chicago, Illinois, United States
Countries
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References
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Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A. Freezing of gait: moving forward on a mysterious clinical phenomenon. Lancet Neurol. 2011 Aug;10(8):734-44. doi: 10.1016/S1474-4422(11)70143-0.
Shine JM, Matar E, Ward PB, Frank MJ, Moustafa AA, Pearson M, Naismith SL, Lewis SJ. Freezing of gait in Parkinson's disease is associated with functional decoupling between the cognitive control network and the basal ganglia. Brain. 2013 Dec;136(Pt 12):3671-81. doi: 10.1093/brain/awt272. Epub 2013 Oct 18.
Fasano A, Herman T, Tessitore A, Strafella AP, Bohnen NI. Neuroimaging of Freezing of Gait. J Parkinsons Dis. 2015;5(2):241-54. doi: 10.3233/JPD-150536.
Bohnen NI, Frey KA, Studenski S, Kotagal V, Koeppe RA, Scott PJ, Albin RL, Muller ML. Gait speed in Parkinson disease correlates with cholinergic degeneration. Neurology. 2013 Oct 29;81(18):1611-6. doi: 10.1212/WNL.0b013e3182a9f558. Epub 2013 Sep 27.
Lewitt PA. Norepinephrine: the next therapeutics frontier for Parkinson's disease. Transl Neurodegener. 2012 Jan 13;1(1):4. doi: 10.1186/2047-9158-1-4.
Pagano G, Rengo G, Pasqualetti G, Femminella GD, Monzani F, Ferrara N, Tagliati M. Cholinesterase inhibitors for Parkinson's disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2015 Jul;86(7):767-73. doi: 10.1136/jnnp-2014-308764. Epub 2014 Sep 15.
Morgante F, Fasano A. Improvement with duloxetine in primary progressive freezing gait. Neurology. 2010 Dec 7;75(23):2130-2. doi: 10.1212/WNL.0b013e318200d7a3. No abstract available.
Nandi D, Jenkinson N, Stein J, Aziz T. The pedunculopontine nucleus in Parkinson's disease: primate studies. Br J Neurosurg. 2008;22 Suppl 1:S4-8. doi: 10.1080/02688690802448350.
Xie T, Vigil J, MacCracken E, Gasparaitis A, Young J, Kang W, Bernard J, Warnke P, Kang UJ. Low-frequency stimulation of STN-DBS reduces aspiration and freezing of gait in patients with PD. Neurology. 2015 Jan 27;84(4):415-20. doi: 10.1212/WNL.0000000000001184. Epub 2014 Dec 24.
Plaha P, Gill SS. Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson's disease. Neuroreport. 2005 Nov 28;16(17):1883-7. doi: 10.1097/01.wnr.0000187637.20771.a0.
Mazzone P, Lozano A, Stanzione P, Galati S, Scarnati E, Peppe A, Stefani A. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson's disease. Neuroreport. 2005 Nov 28;16(17):1877-81. doi: 10.1097/01.wnr.0000187629.38010.12.
Acar F, Acar G, Bir LS, Gedik B, Oguzhanoglu A. Deep brain stimulation of the pedunculopontine nucleus in a patient with freezing of gait. Stereotact Funct Neurosurg. 2011;89(4):214-9. doi: 10.1159/000326617. Epub 2011 May 20.
Garcia-Rill E, Kezunovic N, Hyde J, Simon C, Beck P, Urbano FJ. Coherence and frequency in the reticular activating system (RAS). Sleep Med Rev. 2013 Jun;17(3):227-38. doi: 10.1016/j.smrv.2012.06.002. Epub 2012 Oct 6.
Other Identifiers
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IRB15-1577
Identifier Type: -
Identifier Source: org_study_id