Clinical trial NCT01560754: Disease-modifying Potential of Transdermal NICotine in Early Parkinson's Disease
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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Parkinson's Disease
Keywords: Randomized
Placebo-controlled
Double-blind
Multi-center
Disease-modifying potential
transdermal nicotine
Lead sponsor: University of Vermont
Sponsor class: OTHER
Collaborators: name: Michael J. Fox Foundation for Parkinson's Research
name: Parkinson Study Group (PSG)
name: International Parkinson Fonds Germany GmbH
name: German Parkinson Study Group (GPS)
name: German Parkinson Society (DPG)
name: Philipps University Marburg
First posted: 2012-03-22
Enrollment: 160
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility 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

Primary outcomes:
measure: 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).
timeFrame: From Baseline to week 60
Secondary outcomes:
measure: The change in total UPDRS I-III score between baseline and 52 weeks (12 months)
timeFrame: Baseline to 52 weeks
measure: Parkinson's Disease Questionaire - 8(PDQ-8) that is calculated as the change between baseline and 60 weeks
timeFrame: Baseline and week 60
measure: The frequency of adverse events will be analyzed
timeFrame: Baseline through week 60
measure: The 'time to initiation of a symptomatic treatment' is calculated from the date of randomization to the date that a subject initiates symptomatic therapy
timeFrame: 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
measure: 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
timeFrame: Baseline to week 52 and week 60
measure: Parkinson's Disease Questionnaire - 8 (PDQ-8), a patient completed questionaire, calculated as the change between baseline and week 52
timeFrame: Baseline and week 52
measure: Scales for Outcomes of Parkinson's disease - Cognition (SCOPA-COG), is calculated as the change between baseline and week 52
timeFrame: Baseline and week 52
measure: Beck Depression Inventory - II (BDI-II) that is calculated as the change between baseline and week 52
timeFrame: Baseline and week 52
measure: Parkinson's Disease Sleep Scale (PDSS) that is calculated as the change between baseline and week 52
timeFrame: baseline and week 52
measure: SCOPA-COG that is calculated as the change between baseline and 60 weeks
timeFrame: Baseline and week 60
measure: BDI-II that is calculated as the change between baseline and 60 weeks
timeFrame: Baseline and Week 60
measure: PDSS that is calculated as the change between baseline and week 60
timeFrame: Baseline and Week 60
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Sunnyvale
country: United States
facility: The Parkinsons Institute
state: California
city: Honolulu
country: United States
facility: Pacific Health Research & Education Institute
state: Hawaii
city: Kansas City
country: United States
facility: The University of Kansas Medical Center
state: Kansas
city: Golden Valley
country: United States
facility: Struthers Parkinson'S Center
state: Minnesota
city: Manhasset
country: United States
facility: Feinstein Institute For Medical Research, North Shore-Lij Health System
state: New York
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
city: Standort Marburg
country: Germany
facility: Universitatsklinikum Giessen U. Marburg GmbH
state: Marburg
city: Berlin
country: Germany
facility: Charite Campus Virchow Klinikum
city: Bremerhaven
country: Germany
facility: Klinikum Bremerhaven
city: Dresden
country: Germany
facility: Universitaetsklinikum CarlGustav Carus
city: Dusseldorf
country: Germany
facility: Neurologische Klinik der, Dusseldorf
city: Freiburg
country: Germany
facility: Neurologische Universitaetsklinik Freiburg
city: Hanau
country: Germany
facility: Klinikum Hanau GmbH
city: Homburg/Saar
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Kassel
country: Germany
facility: Paracelsus-Elena-Klinik Kassel
city: Kiel
country: Germany
facility: Universitaetsklinikum Schlewsig-Holstein
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig
city: Magdeburg
country: Germany
facility: Otto-von-Guericke-Universitat
city: Munchen
country: Germany
facility: Klinikum rechts der Isar
city: Tubingen
country: Germany
facility: Universitaetsklinikum Tubingen
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
Study officials:
affiliation: Philipps-University Marburg, Germany / Global and German Principal Investigator
name: Wolfgang Oertel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Vermont / United States Principal Investigator
name: James Boyd, MD
role: PRINCIPAL_INVESTIGATOR
References: