A Multidisciplinary Approach to Manage Gait Difficulty in Parkinson Patients

December 8, 2017 updated by: University of Chicago

The study team proposes to treat Parkinson's patients with gait difficulty with multidisciplinary approach of medications. Single medication treatment, such as the use of cholinergic-boosting anti-dementia medication targeting cholinergic deficiency to improve executive dysfunction and attention deficit, or the use of medication boosting the norepinephrine system, have not proven effective so far in treating the gait difficulty. Anti-anxiety medications, particularly the SNRI (serotonin and norepinephrine reuptake inhibitor) medications, which also ameliorate the norepinephrinergic deficiency, have not been studied except for one successful case report using duloxetine to treat primary progressive freezing of gait.

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

The study team proposes to treat parkinsonian patients with gait difficulty of FOG with the SNRI anti-anxiety medication duloxetine for 4 weeks, followed by an additional anti-dementia medication donepezil for 2 weeks to determine whether antianxiety treatment alone or in combination with the anti-dementia medication can improve gait. Another medication with GABA antagonist property targeting the gait controlling area PPNa (and improving anxiety and cognition as well), modafinil, will be tried for 2 weeks after a 4-week washout period of the previous medications.

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.

Study Type

Interventional

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Chicago, Illinois, United States, 60637
        • University of Chicago Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 96 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Parkinsonian patient with Parkinson's disease per UK brain bank criteria 15,
  • or PSP per SPSP-NINDS criteria 16,
  • FOG at off or on dopaminergic medication or both.

Exclusion Criteria:

  • Patients with psychosis,
  • unable to walk without assistance,
  • seizures,
  • or allergy to any of these three medications on trial.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 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.
Drug: 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.
Drug: 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.
Other Names:
  • Aricept
Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Freezing of Gait
Time Frame: From baseline to completion of drug regimen (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Changes in score of the stand-walk-sit test, compared to the baseline, at on and off PD medications status.
From baseline to completion of drug regimen (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Freezing of Gait
Time Frame: From baseline to completion of drug regimen (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Changes in the score of the FOG questionnaire compared to the baseline, at on and off PD medications status.
From baseline to completion of drug regimen (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in anxiety
Time Frame: From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Change in anxiety as measured by GDA-7 score compared to the baseline, at on and off PD medications status.
From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Change in cognition
Time Frame: From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Change in cognition as measured by MoCA score compared to the baseline, at on and off PD medications status.
From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Change in symptom score/severity
Time Frame: From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Change in symptom as measured by UPDRS or PSPRS score compared to the baseline, at on and off PD medications status.
From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Change in sleep quality
Time Frame: From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Change in reported sleep quality as measured by the Epworth score compared to the baseline, at on and off PD medications status.
From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Change in quality of life
Time Frame: From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)
Change in reported quality of life as measured by QoL - PDQ-39 compared to the baseline, at on and off PD medications status.
From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Chicago

Investigators

  • Principal Investigator: Tao Xie, MD, PhD, University of Chicago

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2016

Primary Completion (Anticipated)

November 1, 2017

Study Completion (Anticipated)

November 1, 2017

Study Registration Dates

First Submitted

July 25, 2016

First Submitted That Met QC Criteria

August 4, 2016

First Posted (Estimate)

August 5, 2016

Study Record Updates

Last Update Posted (Actual)

December 12, 2017

Last Update Submitted That Met QC Criteria

December 8, 2017

Last Verified

December 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB15-1577

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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