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

Phase 2

• Conditions: Parkinson's Disease
• Interventions: Drug: nicotine transdermal patch

• Registration Number: NCT01560754
• Lead Sponsor: James BOYD MD

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).

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 Timeline

• Study First Submitted: 2012-03-09
• Study First Submitted QC: 2012-03-21
• Study First Posted: 2012-03-22
• Study Start: 2012-10
• Status Verified: 2015-09
• Last Update Submitted: 2015-09-28
• Last Update Posted: 2015-09-29
• Primary Completion: 2016-08
• Study Completion: 2016-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 160

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Transdermal nicotine patch	nicotine transdermal 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.
Transdermal placebo patch	nicotine transdermal patch	Subjects will apply a combination of 7 or 14 mg placebo transdermal patches until reaching their highest well tolerated dose.

Primary Outcome Measures

Name	Time	Method
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).	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

Name	Time	Method
Parkinson's Disease Questionaire - 8(PDQ-8) that is calculated as the change between baseline and 60 weeks	Baseline and 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 Sleep Scale (PDSS) that is calculated as the change between baseline and week 52	baseline and week 52
The change in total UPDRS I-III score between baseline and 52 weeks (12 months)	Baseline to 52 weeks
Parkinson's Disease Questionnaire - 8 (PDQ-8), a patient completed questionaire, 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
The frequency of adverse events will be analyzed	Baseline through week 60
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
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

Trial Locations

Locations (24)

Neurologische Klinik der, Dusseldorf; 🇩🇪 Dusseldorf, Germany

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Charite Campus Virchow Klinikum; 🇩🇪 Berlin, Germany

University of Southern California; 🇺🇸 Los Angeles, California, United States

Feinstein Institute For Medical Research, North Shore-Lij Health System; 🇺🇸 Manhasset, New York, United States

Pennsylvania Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

University of Vermont; 🇺🇸 Burlington, Vermont, United States

Paracelsus-Elena-Klinik Kassel; 🇩🇪 Kassel, Germany

Universitaetsklinikum Leipzig; 🇩🇪 Leipzig, Germany

The Parkinsons Institute; 🇺🇸 Sunnyvale, California, United States

The University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

Struthers Parkinson'S Center; 🇺🇸 Golden Valley, Minnesota, United States

Pacific Health Research & Education Institute; 🇺🇸 Honolulu, Hawaii, United States

Universitatsklinikum Giessen U. Marburg GmbH; 🇩🇪 Standort Marburg, Marburg, Germany

Klinikum Bremerhaven; 🇩🇪 Bremerhaven, Germany

Otto-von-Guericke-Universitat; 🇩🇪 Magdeburg, Germany

Universitaetsklinikum CarlGustav Carus; 🇩🇪 Dresden, Germany

Universitaetsklinikum Schlewsig-Holstein; 🇩🇪 Kiel, Germany

Universitaetsklinikum des Saarlandes; 🇩🇪 Homburg/Saar, Germany

Klinikum Hanau GmbH; 🇩🇪 Hanau, Germany

Klinikum rechts der Isar; 🇩🇪 Munchen, Germany

Universitaetsklinikum Tubingen; 🇩🇪 Tubingen, Germany

Universitaetsklinikum Ulm; 🇩🇪 Ulm, Germany

Neurologische Universitaetsklinik Freiburg; 🇩🇪 Freiburg, Germany