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

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

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).

Study Overview

• Status: Unknown
• Conditions: Parkinson's Disease
• Intervention / Treatment: Drug: nicotine transdermal patch

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 Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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	From Baseline to week 60

Secondary Outcome Measures

Outcome Measure	Time Frame
The change in total UPDRS I-III score between baseline and 52 weeks (12 months)	Baseline to 52 weeks
Parkinson's Disease Questionaire - 8(PDQ-8) that is calculated as the change between baseline and 60 weeks	Baseline and week 60
The frequency of adverse events will be analyzed	Baseline through week 60
The 'time to initiation of a symptomatic treatment' is calculated from the date of randomization to the date that a subject initiates symptomatic therapy	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
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	Baseline to week 52 and week 60
Parkinson's Disease Questionnaire - 8 (PDQ-8), a patient completed questionaire, calculated as the change between baseline and week 52	Baseline and week 52
Scales for Outcomes of Parkinson's disease - Cognition (SCOPA-COG), is calculated as the change between baseline and week 52	Baseline and week 52
Beck Depression Inventory - II (BDI-II) that is calculated as the change between baseline and week 52	Baseline and week 52
Parkinson's Disease Sleep Scale (PDSS) that is calculated as the change between baseline and week 52	baseline and week 52
SCOPA-COG that is calculated as the change between baseline and 60 weeks	Baseline and week 60
BDI-II that is calculated as the change between baseline and 60 weeks	Baseline and Week 60
PDSS that is calculated as the change between baseline and week 60	Baseline and Week 60

Collaborators and Investigators

• Sponsor: James BOYD MD
• Collaborators: Michael J. Fox Foundation for Parkinson's Research; Philipps University Marburg Medical Center; German Parkinson Study Group (GPS); Parkinson Study Group (PSG); International Parkinson Fonds Germany GmbH; German Parkinson Society (DPG)
• 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

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Anticipated): August 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: March 9, 2012
• First Submitted That Met QC Criteria: March 21, 2012
• First Posted (Estimate): March 22, 2012

Study Record Updates

• Last Update Posted (Estimate): September 29, 2015
• Last Update Submitted That Met QC Criteria: September 28, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Placebo-controlled; Randomized; Double-blind; Multi-center; Disease-modifying potential; transdermal nicotine
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Nicotine
• Other Study ID Numbers: KKS-135