Disease-modifying Potential of Transdermal NICotine in Early Parkinson's Disease (NIC-PD)

Study Description

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Brief Summary:

The primary objective of this study is to demonstrate that transdermal nicotine treatment retards disease progression as measured by change in total Unified Parkinson's Disease Rating Scale (UPDRS)(part I, II, III)score between baseline and after 52 weeks of study treatment plus two more months wash out (60 weeks).

Condition or disease	Intervention/treatment	Phase
Parkinson's Disease	Drug: nicotine transdermal patch	Phase 2

Detailed Description:

In order to prove the disease-modifying potential of transdermal nicotine treatment, an explanatory design with a 2 months wash-out phase before endpoint assessment will be performed. The primary objective is to demonstrate superiority measured by the difference between the nicotine arm and the placebo arm in the change in total UPDRS score (part I-III) between baseline and end of month 14 (12 months treatment and 2 months wash-out, see 3.1). The total UPDRS score will be determined by an independent rater, who is not involved in any other study-related procedure (e.g. reporting of adverse events). Change in total UPDRS score is the most widely applied measure in similar clinical trials assessing long-term beneficial effects of drugs. The investigators will also determine whether the slope of the curves for the total UPDRS score in active- and placebo-treated subjects show a tendency to converge over time. For this purpose the UPDRS will be determined three times after placebo/nicotine withdrawal at the end of the study during Visit 7,8, and 9 (i.e. four times including Visit 6).

Approximately 250 subjects will be screened at 25-30 centers in Germany and the USA. The recruitment period will be 18 months. In the screening phase, subjects will be evaluated for eligibility for enrolment into the treatment phase. The investigators expect that screening of 250 subjects will result in 160 eligible subjects who will be randomly assigned 1:1 to treatment with either transdermal nicotine or transdermal placebo patch.

The treatment phase consists of a titration period (16 weeks, to find the highest dosage tolerated by the subject with a target of 28 mg) and a maintenance period (week 17 to week 52 with the highest tolerated dosage of nicotine).

The treatment phase will be followed by an 8 week wash-out phase (3 weeks down titration and 5 weeks run out).

Dose adjustments are permitted for adverse events and have to be documented thoroughly.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	160 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	A Randomized, Placebo-controlled, Double-blind, Multi-center Trial to Assess the Disease-modifying Potential of Transdermal Nicotine in Early Parkinson's Disease in Germany and the USA
Study Start Date :	October 2012
Estimated Primary Completion Date :	August 2016
Estimated Study Completion Date :	December 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Transdermal nicotine patch; Subjects will apply a combination of 7 or 14 mg nicotine transdermal patches until reaching their highest well tolerated dose of 7 to 28 mg/day.	Drug: nicotine transdermal patch; Transdermal patches containing 7 or 14 mg nicotine or placebo with subjects titrating up until reaching their highest tolerated dose of 7 to 28mg/day.; Other Names: Habitrol Transdermal patch (US); Nicotinell Transdermal patch (Germany)
Placebo Comparator: Transdermal placebo patch; Subjects will apply a combination of 7 or 14 mg placebo transdermal patches until reaching their highest well tolerated dose.	Drug: nicotine transdermal patch; Transdermal patches containing 7 or 14 mg nicotine or placebo with subjects titrating up until reaching their highest tolerated dose of 7 to 28mg/day.; Other Names: Habitrol Transdermal patch (US); Nicotinell Transdermal patch (Germany)

Outcome Measures

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Primary Outcome Measures :

1. The primary endpoint is calculated as the difference between the nicotine arm and the placebo arm in the change in total UPDRS I-III score between baseline and 60 weeks (14 months) (52 weeks treatment plus 8 weeks wash-out). [ Time Frame: From Baseline to week 60 ]
   The primary objective is to demonstrate superiority measured by the difference between the nicotine arm and the placebo arm in the change in total UPDRS score (part I-III) between baseline and end of month 14 (12 months treatment and 2 months wash-out

Secondary Outcome Measures :

1. The change in total UPDRS I-III score between baseline and 52 weeks (12 months) [ Time Frame: Baseline to 52 weeks ]
2. Parkinson's Disease Questionaire - 8(PDQ-8) that is calculated as the change between baseline and 60 weeks [ Time Frame: Baseline and week 60 ]
3. The frequency of adverse events will be analyzed [ Time Frame: Baseline through week 60 ]
4. The 'time to initiation of a symptomatic treatment' is calculated from the date of randomization to the date that a subject initiates symptomatic therapy [ Time Frame: Baseline to initiation of symptomatic therapy, this timeframe will vary from subject to subject based on duration of disease and how well their PD is currently being managed ]
5. Determine whether the slope of the curves for the total UPDRS score in active- and placebo-treated subjects show a tendency to converge over time [ Time Frame: Baseline to week 52 and week 60 ]
6. Parkinson's Disease Questionnaire - 8 (PDQ-8), a patient completed questionaire, calculated as the change between baseline and week 52 [ Time Frame: Baseline and week 52 ]
7. Scales for Outcomes of Parkinson's disease - Cognition (SCOPA-COG), is calculated as the change between baseline and week 52 [ Time Frame: Baseline and week 52 ]
8. Beck Depression Inventory - II (BDI-II) that is calculated as the change between baseline and week 52 [ Time Frame: Baseline and week 52 ]
9. Parkinson's Disease Sleep Scale (PDSS) that is calculated as the change between baseline and week 52 [ Time Frame: baseline and week 52 ]
10. SCOPA-COG that is calculated as the change between baseline and 60 weeks [ Time Frame: Baseline and week 60 ]
11. BDI-II that is calculated as the change between baseline and 60 weeks [ Time Frame: Baseline and Week 60 ]
12. PDSS that is calculated as the change between baseline and week 60 [ Time Frame: Baseline and Week 60 ]

Eligibility Criteria

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Ages Eligible for Study:	30 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Written informed consent
2. Capability and willingness to comply with the study related procedures
3. Age >/= 30 y
4. Usage of effective contraception (see below) in fertile pre-menopausal female participants (from inclusion until end of wash out) Acceptable forms of effective contraception include established use of oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS), barrier methods of contraception (condom or occlusive cap /diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository or male / female sterilization / or true abstinence.
5. Diagnosis of PD according to the UK Brain Bank Diagnostic Criteria
6. Early PD subjects within 18 months of diagnosis
7. Hoehn and Yahr stage ≤ 2
8. Patients not receiving or needing dopamine agonist or levodopa therapy presently or for the next year
9. Stable treatment (>2 months) with MAO-B inhibitor (selegiline up to 10 mg/d or rasagiline up to 1 mg/d) allowable

Exclusion Criteria:

1. Clinical signs indicating a Parkinson syndrome other than idiopathic PD e.g.:

   • Supranuclear gaze palsy
   • Signs of frontal dementia
   • History of repeated strokes with stepwise progression of Parkinsonian features
   • History of repeated head injury or history of definite encephalitis
   • Cerebellar signs
   • Early severe autonomic involvement
   • Babinski's sign
2. History of exposure to or current treatment with neuroleptic drugs or anticraving substances
3. History of nicotine use within five years of the baseline visit
4. Previous history of allergic response to nicotine application or any of the patch excipients (see protocol sec. 10.2)
5. Previous history of allergic response to transdermal patches
6. Pre-existing dermatological disorder that could disturb transdermal patch application in the opinion of the investigator (e.g. generalized / systemic or local neurodermatitis, psoriasis, chronic dermatitis, urticaria, etc.)
7. Previous treatment with antiparkinsonian drugs (e.g. levodopa, dopamine agonists, etc.) other than MAO-B inhibitors

8. History of unstable or serious cardiovascular diseases

   • Unstable or worsening angina pectoris,
   • History of recent myocardial infarction or cardiac failure (NYHA from II to IV), myocardial insufficiency
   • History at inclusion of serious cardiac arrhythmia,
   • History of recent stroke or occlusive peripheral vascular disease, vasospasm
9. History of structural brain disease, cerebrovascular diseases
10. History of severe uncontrolled arterial hypertension
11. History of severe pulmonary disease (asthma, COPD)
12. History of auto-immune disease
13. History of Hyperthyroidism
14. History of Pheochromocytoma
15. History of seizures / epilepsy
16. History of amyosthenia / myasthenia gravis, pseudo-myasthenic syndrome
17. Dementia defined as Mini Mental State Examination (MMSE) score ≤ 24
18. Moderate depression (BDI-II score >24)
19. Suicide or suicide ideation
20. History or presence of specific psychiatric disorders, acute psychosis, hallucinations, pathologic gambling, alcohol or substance abuse
21. Patients under treatment with dihydropyridines (e.g. nifedipine, nicardipine, amlodipine)
22. History of uncontrolled diabetes
23. History of recent gastroduodenal ulcer (< 3 months) or presence of severe (acute and chronic) gastritis
24. History of known hepatobiliary or renal insufficiency
25. Pregnancy or lactation period
26. Simultaneous participation or previous participation within 60 days before screening in another clinical drug or medical device study. Other Trials that do not affect the NIC-PD Study (NIT, health economics evaluations, questionnaires, genetic studies) could be allowed, but have to be approved and documented by the steering committee

Contacts and Locations

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Locations

United States, California
University of Southern California
Los Angeles, California, United States, 90033
The Parkinsons Institute
Sunnyvale, California, United States, 94085
United States, Hawaii
Pacific Health Research & Education Institute
Honolulu, Hawaii, United States, 96819
United States, Kansas
The University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Minnesota
Struthers Parkinson`S Center
Golden Valley, Minnesota, United States, 55427
United States, New York
Feinstein Institute For Medical Research, North Shore-Lij Health System
Manhasset, New York, United States, 11030
United States, Pennsylvania
Pennsylvania Hospital
Philadelphia, Pennsylvania, United States, 19107
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
United States, Vermont
University of Vermont
Burlington, Vermont, United States, 05405
Germany
Universitatsklinikum Giessen U. Marburg GmbH
Standort Marburg, Marburg, Germany
Charite Campus Virchow Klinikum
Berlin, Germany
Klinikum Bremerhaven
Bremerhaven, Germany
Universitaetsklinikum CarlGustav Carus
Dresden, Germany
Neurologische Klinik der, Dusseldorf
Dusseldorf, Germany
Neurologische Universitaetsklinik Freiburg
Freiburg, Germany
Klinikum Hanau GmbH
Hanau, Germany
Universitaetsklinikum des Saarlandes
Homburg/Saar, Germany
Paracelsus-Elena-Klinik Kassel
Kassel, Germany
Universitaetsklinikum Schlewsig-Holstein
Kiel, Germany
Universitaetsklinikum Leipzig
Leipzig, Germany
Otto-von-Guericke-Universitat
Magdeburg, Germany, D-39120
Klinikum rechts der Isar
Munchen, Germany
Universitaetsklinikum Tubingen
Tubingen, Germany
Universitaetsklinikum Ulm
Ulm, Germany

Sponsors and Collaborators

James BOYD MD

Michael J. Fox Foundation for Parkinson's Research

Parkinson Study Group (PSG)

International Parkinson Fonds Germany GmbH

German Parkinson Study Group (GPS)

German Parkinson Society (DPG)

Philipps University Marburg Medical Center

Investigators

Principal Investigator:	Wolfgang Oertel, MD	Philipps-University Marburg, Germany / Global and German Principal Investigator
Principal Investigator:	James Boyd, MD	University of Vermont / United States Principal Investigator

More Information

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Responsible Party:	James BOYD MD, United States Principal Investigator, University of Vermont
ClinicalTrials.gov Identifier:	NCT01560754 History of Changes
Other Study ID Numbers:	KKS-135
First Posted:	March 22, 2012
Last Update Posted:	September 29, 2015
Last Verified:	September 2015

Keywords provided by James BOYD MD, University of Vermont:

Randomized; Placebo-controlled; Double-blind	Multi-center; Disease-modifying potential; transdermal nicotine

Additional relevant MeSH terms:

Parkinson Disease; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Neurodegenerative Diseases; Nicotine	Ganglionic Stimulants; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Nicotinic Agonists; Cholinergic Agonists; Cholinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action