Disease-modifying Potential of Transdermal NICotine in Early Parkinson's Disease

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).

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.

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