Caffeine for Motor Manifestations of Parkinson's Disease

Phase 2

Completed

• Conditions: Parkinson's Disease
• Interventions: Drug: Caffeine alkaloid

• Registration Number: NCT01190735
• Lead Sponsor: Ron Postuma

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.

Study Timeline

• Study Start: 2010-08
• Study First Submitted: 2010-08-26
• Study First Submitted QC: 2010-08-27
• Study First Posted: 2010-08-30
• Primary Completion: 2011-02
• Study Completion: 2011-02
• Status Verified: 2015-04
• Last Update Submitted: 2015-04-15
• Last Update Posted: 2015-04-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Caffeine	Caffeine alkaloid	Each patient will take pills twice per day containing 100-200 mg of caffeine (as synthetic caffeine alkaloid). Patients will be instructed to take whatever caffeine-containing beverages they are accustomed to taking, without changing their habitual schedule (note that all will be taking \<200 mg per day). Caffeine intake will be assessed at each visit. Patients will continue their usual PD medications, without change in dose or timing for the entire duration of the study. Medication will be provided in pre-packaged dosettes.

Primary Outcome Measures

Name	Time	Method
Tolerability	6 weeks	Patients will be given a structured questionnaire targeting common side effects of caffeine, as well as a series of open-ended questions for other side effects. Vital signs will be measured. Questionnaire symptoms will be selected, where available, from the common terminology criteria for adverse events, version 3.0, developed by the National Cancer Institute. A severity of 2 or greater on the 5-point scale will delineate a dose-limiting effect. Evaluations will occur in person after 2 weeks, 4 weeks, 6 weeks (at study termination) and via telephone follow-up at the end of weeks 1,3 and 5.

Secondary Outcome Measures

Name	Time	Method
Beck Anxiety Inventory	6 weeks	Self-administered questionnaire.
UPDRS: Part I,II,IV	6 weeks	Systematically querying I (non-motor aspects of activities of daily living), II (motor aspects of activities of daily living) and IV (motor complications)
Epworth Sleepiness Scale (ESS)	6 weeks	Will systematically track changes in ESS.
Unified Parkinson Disease Rating Scale(UPDRS): Part II	6 weeks	Systematically performing part II of the UPDRS, motor examination.
Clinical Global Impression of Change	6 weeks
Fatigue Severity Scale	6 weeks
Timed Up and Go (TUG)	6 weeks	This is a measure of gait and transfer speed.
The Parkinson's Disease Questionnaire - PDQ-39	6 weeks	This self-completion questionnaire addresses aspects of functioning and well-being in those affected by Parkinson's Disease (PD). Considered to be the industry 'gold standard' in the assessment of quality of life in PD patients. The 39-point PDQ provides scores on 8 scales: mobility, activities of daily living, emotions, stigma, social support, cognition, communications and bodily discomfort.
Beck Depression Inventory	6 weeks	Self-administered questionnaire.
Pittsburgh Sleep Quality Index	6 weeks

Trial Locations

Locations (1)

Montreal General Hospital; 🇨🇦 Montreal, Quebec, Canada