A Multidisciplinary Approach to Manage Gait Difficulty in Parkinson Patients

NCT02857244 | Withdrawn Phase 2

• 1 other identifier: IRB15-1577
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Parkinson's Disease

Keywords

Freezing of Gait

Outcome Measures

Primary Outcomes (2)

• Freezing of Gait

  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

  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 Outcomes (5)

• Change in anxiety

  From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)

• Change in cognition

  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

  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

  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

  From baseline to completion of drug regiment (4 weeks of duloxetine, 2 weeks of duloxetine & donepezil, 2 weeks & 3 days modafinil)

Study Arms (1)

Open-Label Treatment Arm

OTHER

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; Drug: Donepezil; Drug: Modafinil

Interventions

Duloxetine DRUG

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.

Open-Label Treatment Arm

Donepezil DRUG

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.

Also known as: Aricept

Open-Label Treatment Arm

Modafinil DRUG

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.

Open-Label Treatment Arm

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• University of Chicago: lead

Study Sites (1)

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Related Publications (13)

• 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.

  PMID: 21777828 BACKGROUND

• 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.

  PMID: 24142148 BACKGROUND

• 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.

  PMID: 25757831 BACKGROUND

• 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.

  PMID: 24078735 BACKGROUND

• 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.

  PMID: 23211006 BACKGROUND

• 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.

  PMID: 25224676 BACKGROUND

• 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.

  PMID: 21135389 BACKGROUND

• 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.

  PMID: 19085345 BACKGROUND

• 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.

  PMID: 25540305 BACKGROUND

• 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.

  PMID: 16272872 BACKGROUND

• 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.

  PMID: 16272871 BACKGROUND

• 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.

  PMID: 21597312 BACKGROUND

• 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.

  PMID: 23044219 BACKGROUND

MeSH Terms

Conditions

Parkinson Disease

Interventions

Duloxetine Hydrochloride; Donepezil; Modafinil

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indans; Indenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperidines; Polycyclic Compounds; Benzhydryl Compounds; Benzene Derivatives

Study Officials

• Tao Xie, MD, PhD

  University of Chicago

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 25, 2016
• First Posted: August 5, 2016
• Study Start: November 1, 2016
• Primary Completion: November 1, 2017
• Study Completion: November 1, 2017
• Last Updated: December 12, 2017

Record last verified: 2017-12

Locations

US (1)