Efficacy of Transdermal Nicotine, on Motor Symptoms in Advanced Parkinson’s Disease

Brief Summary

Official Title: “Efficacy of Transdermal Nicotine, on Motor Symptoms in Advanced Parkinson’s Disease(One Daily Administration).A Controlled Randomised Study, in Two Parallel Groups and Single Blind in 40 Patients.”

Medical treatment of idiopathic Parkinson disease motor symptoms requires dopaminergic drugs, with long term disabling side effects. (fluctuations, dyskinesia, ON/OFF phenomena). Use of nicotine in Parkinson's disease has been suggested by the lowest prevalence of smokers among Parkinsonian patients. However, controlled studies provided conflicting results. One of our patients showed a substantial decrease of his parkinsonian symptoms under transdermal nicotine-therapy. Currently, this patient has been treated since 8 years with an excellent safety, especially on cardiovascular level. Otherwise, the investigators performed an open pilot safety and feasibility study in 6 patients, which demonstrated the possibility of a controlled study. In this study, all patients received daily doses during several months until 105 mg/day and could, in parallel, decrease their L-Dopa and agonists doses, improving their motor scores.

The investigators now propose a phase II, controlled, single blind and randomised efficacy study (n=40) in 2 parallel groups. (1 group transdermal nicotine-therapy / 1 control group without additional therapy) The main objective is to verify the correlation between UPDRS (score III) motor score and the administrated nicotine dose. This study will also allow the evaluation of nicotine neuroprotective effect. The incrementation phase by weekly steps of 5 mg until 20 mg, then 10 mg to reach 90 mg/j or the maximal tolerated dose, will last on 11 weeks and will be followed by a 28 weeks phase at this stable dose. After this maximal dose "plateau phase", treatment will be progressively decreased by 15 mg weekly steps, over a de 6-week period followed by a five-week wash out phase.

Taking into account results from the pilot study, a long-term high doses treatment, seems to be liable to improve patients who deeply suffer from their disease. This is why the investigators now propose this monocentric institutional project.

  • Study Type: Interventional
  • Study Design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
  • Study Primary Completion Date: December 2012

Detailed Clinical Trial Description

Experimental plan

Phase II controled study, in 40 patients, randomised in single blind, and in 2 groups:

- One group treated by transdermal nicotine-therapy (N= 20),

- One group without additional therapy (N= 20).

This study will consist in :

- One phase of weekly incrementations of dose during 11 weeks,

- Steps of 5 mg until 20 mg

- Then steps of 10 mg until the dose of 90mg or the maximal tolerated dose

- One stable dose phase, (90 mg or maximal tolerated dose) during 28 weeks,

- One phase of decrementing: treatment will be progressively decreased in a 6 weeks period,

Interventions Used in this Clinical Trial

  • Drug: Transdermal nicotine
    • Steps of 5 mg until 20 mg Then steps of 10 mg until the dose of 90mg or the maximal tolerated dose One stable dose phase, (90 mg or maximal tolerated dose) during 28 weeks
  • Other: Usual drug treatment of Parkinson’s disease
    • Usual drug treatment of Parkinson’s disease

Arms, Groups and Cohorts in this Clinical Trial

  • Experimental: 1
    • Experimental drug
  • Active Comparator: 2
    • Usual treatment

Outcome Measures for this Clinical Trial

Primary Measures

  • Comparison of motor scores in defined off condition : UPDRS III motor score assessed in “defined OFF” condition in comparison with control group.
    • Time Frame: after 20/39 weeks of treatment at maximal administered dose of nicotine
      Safety Issue?: Yes

Secondary Measures

  • Evaluation of UPDRS III motor score assessed in “defined OFF” condition
    • Time Frame: after 20 weeks of treatment in comparison with control group
      Safety Issue?: No
  • Improvement of UPDRS III motor score assessed in “defined ON” condition
    • Time Frame: after a 12 hours discontinuation of antiparkinsonian treatments after 11, 20 and 39 weeks of treatment
      Safety Issue?: No
  • Evaluation of motor benefit (UPDRS “OFF” and “ON”)
    • Time Frame: after a 28 weeks treatment period at stable dose of 90 mg
      Safety Issue?: No
  • Evaluation of neuroprotection, (SPECT DaTSCAN and UPDRS “OFF”)
    • Time Frame: after 5 weeks of study treatment discontinuation
      Safety Issue?: No
  • Persistence of motor benefit (UPDRS “OFF” and “ON”)
    • Time Frame: after 5 weeks of study treatment discontinuation
      Safety Issue?: No
  • Decrease of total daily L-Dopa dose (or calculated equivalent in case of polytherapy)
    • Time Frame: after 20 and 39 weeks of treatment
      Safety Issue?: No
  • Improvement of quality of life (ADL and PDQ 39 scales)
    • Time Frame: after 20 and 39 weeks of treatment
      Safety Issue?: No
  • Decrease of daily percentage of “OFF” phase
    • Time Frame: after 20 and 39 weeks of treatment
      Safety Issue?: No
  • Improvement of dyskinesia score, (UPDRS IV)
    • Time Frame: during the study
      Safety Issue?: No
  • Relation dose / effect of nicotine
    • Time Frame: end of the study
      Safety Issue?: No
  • Estimation of the most effective and tolerated dose of nicotine per kg
    • Time Frame: end of the study
      Safety Issue?: No
  • Improvement of cognitive functions assessed by Mattis scale
    • Time Frame: after 39 weeks of treatment
      Safety Issue?: No
  • Comparison of all parameters between the 2 groups of patients
    • Time Frame: after study treatment discontinuation, (Week 50)
      Safety Issue?: No
  • Compliance to nicotine treatment
    • Time Frame: during treatment
      Safety Issue?: No
  • Tolerance of transdermal nicotine
    • Time Frame: during the treatment
      Safety Issue?: Yes

Criteria for Participation in this Clinical Trial

Inclusion Criteria

  • Patients with idiopathic Parkinson's disease according to the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB), since at least three years,or treated by L-dopa for 2 years minimum with motor fluctuations (amendment 12/10/2010)
  • Patients aged between 35 and 70 years inclusive,
  • L-Dopa responders: L-Dopa test with an improvement of over 30 % of UPDRS-III motor score,
  • L-Dopa treatment since at least three years,
  • Patients with Parkinson's disease stage maximum IV ("OFF" state) according to the modified Hoehn and Yahr classification (without treatment since at least 12 hours), and III maximum in "ON" state,
  • Non smoker,
  • Signed Informed Consent

Exclusion Criteria

  • Previous neurosurgery for Parkinson's disease,
  • Weight < 45 kg or > 100 kg,
  • Previous Parkinson's disease treatment by transdermal nicotine-therapy discontinued less than 6 months before inclusion,
  • History of allergy to Nicotine,
  • History of allergy to transdermal device,
  • Cutaneous disorders wich could disturb use of transdermal device,
  • Cognitive disorders, (Mattis score < 125)
  • History or detection at inclusion of cardiac arrhythmia,
  • History of coronary failure,
  • History of cardiac failure, (NYHA from II to IV & ejection fraction (EF) < 40%)
  • Severe arterial hypertension (diastolic > 100 mmHg) or uncontrolled,
  • Symptomatic orthostatic hypotension, (2 points of differential in standing position and systolic <100mm Hg or clinical evidence)
  • History of stroke or occlusive peripheral vascular disease,
  • History of hyperthyroid,
  • History or detection at inclusion of type I or II diabetes, (HbA1c < 11%)
  • History of pulmonary disease: asthma, chronic obstructive pulmonary disease (COPD),
  • History of auto-immune disease,
  • Progressive depression, suicide attack, acute psychosis, invasive hallucinations, psychiatrist opinion harmful for a correct compliance to experimentation,
  • History or recent gastroduodenal ulcer, (< 3 months)
  • History or detection at inclusion of hepatobiliary or renal failure, (clearance< 60 mL/min)
  • Pregnancy, breast-feeding,
  • Absence of effective contraception in women in childbearing potential,
  • Treatment by nifedipine, beta-blockers, diuretics, insulin and H2 antihistaminics for potential side effects in combination with nicotine,
  • Patients unlikely to be compliant or to fully cooperate during the study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 35 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

  • Lead Sponsor
    • Assistance Publique – H├┤pitaux de Paris
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Pierre CESARO, PUPH, Principal Investigator, Groupe Hospitalier Albert Chenevier Henri Mondor

Citations Reporting on Results

Villafane G, Cesaro P, Rialland A, Baloul S, Azimi S, Bourdet C, Le Houezec J, Macquin-Mavier I, Maison P. Chronic high dose transdermal nicotine in Parkinson's disease: an open trial. Eur J Neurol. 2007 Dec;14(12):1313-6. Epub 2007 Oct 17.

Source

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The URL of this page is:
http://clinicaltrialsfeeds.org/clinical-trials/show/NCT00873392