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
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
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.
Exercise Targeting Cognitive Impairment in Parkinson's Disease
Mild cognitive impairment (MCI), particularly of the executive function (EF) subtype, is
common in Parkinson's disease (PD) and transitions to dementia, increased fall risk, and poor
quality of life. EF is a set of processes that include mental flexibility and attention that
are needed to learn and optimize performance of complex cognitive and motor skills. Such
skills include the ability to generalize task performance under different conditions (context
processing) and to perform two tasks simultaneously termed dual-task (DT) performance.
Deficits in EF lead to problems in daily functioning and loss of independence and create
psychosocial and economic burdens on patients and caregivers and stakeholders including
health care providers. There is currently no effective treatment in PD to address EF
deficits. Our animal and clinical studies in PD demonstrate that skilled exercise facilitates
neuroplasticity of the basal ganglia (BG), a brain region sub-serving EF and supports the
hypothesis that exercise will reverse EF deficits in PD. Furthermore, recent studies in
healthy aging support that skill-based exercise that specifically promotes motor skill
fitness (MSF), compared with aerobic exercise that promotes cardiovascular fitness (CF), has
a greater impact on EF and related BG circuits. The aim of this application is to compare and
elucidate the effects of skill-based versus aerobic exercise versus control on MCI of the EF
subtype in PD; we hypothesize that skill-based exercise will result in the greatest
improvement in EF and lead to modification of underlying neural substrates.