Caffeine for Motor Manifestations of Parkinson's Disease

Caffeine for Motor Manifestations of Parkinson's Disease: An Open-Label Dose-Response Study.

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.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Drug: Caffeine alkaloid

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 Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
      • Montreal General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Caffeine; 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.

Drug: Caffeine alkaloid; The following intervention will be provided for six consecutive weeks: Week 1 (100 mg BID), Week 2 (200 mg BID), Week 3 (300 mg BID), Week 4 (400 mg BID), Week 5 and 6(500 mg BID). At the conclusion of the study, patients will decrease their dose by 100 mg BID every other day, until caffeine is stopped. This gradual reduction will be to prevent withdrawal symptoms. If a patient experiences a dose-limiting event, they will be terminated from the study, and will withdraw from the medication in the same manner. If dose-limiting events occur between visits, patients will be encouraged to decrease the caffeine dose back to the previously-tolerated dose until in-person assessment can be performed.; Other Names: Wake-Ups; 100mg tabs, NPN 00533629, serial no 5503701103; 200mg tabs, NPN, 80003474, serial no 5503701105

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability	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.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Epworth Sleepiness Scale (ESS)	Will systematically track changes in ESS.	6 weeks
Unified Parkinson Disease Rating Scale(UPDRS): Part II	Systematically performing part II of the UPDRS, motor examination.	6 weeks
Timed Up and Go (TUG)	This is a measure of gait and transfer speed.	6 weeks
Clinical Global Impression of Change		6 weeks
Pittsburgh Sleep Quality Index		6 weeks
Fatigue Severity Scale		6 weeks
The Parkinson's Disease Questionnaire - PDQ-39	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.	6 weeks
Beck Depression Inventory	Self-administered questionnaire.	6 weeks
Beck Anxiety Inventory	Self-administered questionnaire.	6 weeks
UPDRS: Part I,II,IV	Systematically querying I (non-motor aspects of activities of daily living), II (motor aspects of activities of daily living) and IV (motor complications)	6 weeks

Collaborators and Investigators

• Sponsor: Ron Postuma
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Study Director: Ron Postuma, MD, Msc, McGill University Health Centre/Research Institute of the McGill University Health Centre; Principal Investigator: Robert Altman, MD, McGill University Health Centre/Research Institute of the McGill University Health Centre

Publications and helpful links

Helpful Links

• Ongoing study investigating caffeine for excessive daytime somnolence in Parkinson's Disease

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: August 26, 2010
• First Submitted That Met QC Criteria: August 27, 2010
• First Posted (Estimate): August 30, 2010

Study Record Updates

• Last Update Posted (Estimate): April 16, 2015
• Last Update Submitted That Met QC Criteria: April 15, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: Nervous System Diseases; Parkinson's Disease; Movement Disorders; Parkinson Disease; Central Nervous System Diseases; Neurodegenerative Diseases; Physiological Effects of Drugs; Central Nervous System Agents; Pharmacologic Actions; Caffeine; Brain Diseases; Therapeutic Uses; Parkinsonian Disorders; Molecular Mechanisms of Pharmacological Action; Central Nervous System Stimulants; Caffeine citrate; Basal Ganglia Diseases
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Caffeine
• Other Study ID Numbers: CIHR-219243