Clinical trial NCT01190735: Caffeine for Motor Manifestations of Parkinson's Disease
Official title: Caffeine for Motor Manifestations of Parkinson's Disease: An Open-Label Dose-Response Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson's Disease
Keywords: Caffeine
Parkinson's Disease
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Caffeine citrate
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Central Nervous System Stimulants
Physiological Effects of Drugs
Central Nervous System Agents
Therapeutic Uses
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2010-08-30
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Numerous epidemiological studies have linked lifelong use of caffeine to a lower risk of Parkinson's disease (PD) - prospective studies have estimated that non-coffee drinkers have an approximately 1.7-2.5 fold increased risk of developing PD compared to coffee drinkers. This is an extremely important finding which deserves further more in depth investigations.

The exact pathophysiological mechanism remains elusive, but multiple hypotheses do exist: Caffeine antagonizes adenosine receptors directly yielding an improvement on motor systems and even on Levodopa serum concentrations (when on therapy). An additional explanation is that adenosine antagonism has neuroprotective properties by acting locally on basal ganglia circuits and the substantia nigra.

The current study aims to identify the optimal caffeine dose with maximal motor benefit and the least amount of undesirable adverse effects.

Detailed description: Caffeine has been in widespread use for centuries, and is the commonest psychostimulant used worldwide. In Canada, estimates of mean daily intake for a 70 kg person range from 200-450 mg. The main sources of caffeine ingestion are in beverages - depending on brewing technique a typical cup of drip-filtered coffee can contain between 100 and 150 mg of caffeine (gourmet drip coffees contain up to 300 mg and espresso preparations generally contain much less caffeine). Black tea contains between 30 and 50 mg, and lower amounts of caffeine are found in soft drinks, green teas, and chocolate. Caffeine is a substance with a well-defined effect and side-effect profile, and in general it is very well tolerated. Side effects can include irritability, insomnia, enhancement of physiologic tremor, and stomach upset. Abrupt withdrawal from caffeine can cause headache and excessive sleepiness. Caffeine can exacerbate pre-existing supraventricular tachycardia. Multiple large-scale epidemiologic studies have not found evidence for adverse health effects with long-term moderate use of caffeine. Caffeine has a T-max of approximately 1 hour and readily crosses the blood brain barrier. It has first order kinetics. Plasma half life estimates range from 3-6 hours, increased in the case of pregnancy or severe liver disease. Drug interactions are uncommon: Caffeine withdrawal may cause lithium toxicity, and caffeine increases clozapine levels.

CNS effects of caffeine are mainly due to antagonism of the A1 and A2A adenosine receptors, (A2A predominates in the striatum). Potential effects upon motor manifestations of PD are predominantly related to the antagonistic action of adenosine on dopamine release in the striatum. Partial tolerance to CNS effects is common, and begins to occur within one week (tolerance is more pronounced for the A1 receptor, suggesting that motor changes may show less tolerance). If effective for PD, caffeine has the potential to be a very important advance for patient care, for numerous reasons. First of all, it has been in widespread use for centuries, so the long-term safety has been determined. Caffeine is widely available as tablets which are very inexpensive (i.e. less than 25 cents per tablet), potentially resulting in substantial cost savings for patients and health-care planners. Caffeine also has the potential (as yet unproven) to treat non-motor manifestations of PD, particularly excessive daytime somnolence.

Eligibility criteria: Inclusion Criteria:

1. Subject has been diagnosed with idiopathic Parkinson's disease (stage I - IV Hoehn and Yahr)

Exclusion Criteria:

1. Estimated daily caffeine intake of more than 200 mg per day.
2. Subject has dementia (MMSE \< 26/30) and ADL impairment secondary to cognitive loss, inability to understand consent process.
3. Changes to antiparkinsonian medications in last 4 weeks or changes will be required during the period of the study protocol.
4. Contraindication to caffeine use:

   1. Uncontrolled hypertension (systolic bp \>170 or diastolic bp \>110 on two consecutive readings)
   2. Use of lithium or clozapine
   3. Pre-menopausal women who are not using effective methods of birth control
   4. Current use of prescribed alerting agents such as modafinil and methylphenidate
   5. Active peptic ulcer disease
   6. Supraventricular cardiac arrhythmia
   7. Previous adverse reaction to caffeine which either required admission to hospital,or after which the patient was directly advised by a physician to not use caffeine.

Primary outcomes:
measure: Tolerability
timeFrame: 6 weeks
Secondary outcomes:
measure: Epworth Sleepiness Scale (ESS)
timeFrame: 6 weeks
measure: Unified Parkinson Disease Rating Scale(UPDRS): Part II
timeFrame: 6 weeks
measure: Timed Up and Go (TUG)
timeFrame: 6 weeks
measure: Clinical Global Impression of Change
timeFrame: 6 weeks
measure: Pittsburgh Sleep Quality Index
timeFrame: 6 weeks
measure: Fatigue Severity Scale
timeFrame: 6 weeks
measure: The Parkinson's Disease Questionnaire - PDQ-39
timeFrame: 6 weeks
measure: Beck Depression Inventory
timeFrame: 6 weeks
measure: Beck Anxiety Inventory
timeFrame: 6 weeks
measure: UPDRS: Part I,II,IV
timeFrame: 6 weeks
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: Montreal General Hospital
state: Quebec
Study officials:
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Ron Postuma, MD, Msc
role: STUDY_DIRECTOR
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Robert Altman, MD
role: PRINCIPAL_INVESTIGATOR
References: