Patients aged 30 to 80 years with idiopathic PD as determined by an Oregon Health & Science University (OHSU) movement disorder specialist (M.A.B.) based on London Brain Bank criteria8
enrolled in the study. Patients were excluded if they had atypical features of parkinsonism, had a Mini-Mental State Examination score less than 25, or had unstable cardiovascular disease or active pepticulcer disease. They gave informed consent to a protocol approved by the OHSU institutional review board and General Clinical Research Center (GCRC) Scientific Advisory Committee.
Patients were undergoing long-term levodopa therapy and had motor fluctuations and dyskinesia as determined during screening. Patients were screened using finger tapping in the practically defined OFF motor state, having been without levodopa overnight, and in the practically defined ON motor state, approximately 1 hour after taking their usual levodopa dose. To qualify, they had to have a minimum of 10% improvement in finger-tapping speed in the ON state.
The trial was a double-blind, randomized, placebo-controlled, crossover study with patients taking a stable dose of pramipexole for 4 weeks and an identical-appearing placebo for 4 weeks. Responses to 2-hour levodopa infusions at 0.5 mg/kg/h (threshold) and 1.0 mg/kg/h (suprathreshold) were examined at the end of each 4-week treatment period.
The primary outcome was change in finger-tapping speed, a surrogate marker of bradykinesia,9–11
as measured by the area under the curve (AUC) for finger taps per minute across time. Secondary outcomes included the AUC for dyskinesia, peak finger-tapping speed, duration of response as measured by finger tapping, time to ON (defined as a 10% increase in finger-tapping speed above baseline), walking speed, effects of levodopa infusion on the motor score of the Unified Parkinson’s Disease Rating Scale (mUPDRS) (Part III), and effects of levodopa infusion on patients’ perceived mood, anxiety, and fatigue.
Patients were randomized to receive either pramipexole or placebo for the initial 5 weeks of the study. The pramipexole or placebo was titrated up for 9 days to a target dose of 1.0 mg 3 times daily and was maintained at that dose for 28 days. If they had been taking a DA, it was tapered and discontinued while the study medication was titrated upward. Levodopa therapy, and any other antiparkinson medications they were taking, was continued according to each patient’s normal schedule during each study phase. The daily oral levodopa dose was adjusted according to each patient’s need.
After a maintenance phase of 4 weeks of study medication (pramipexole, 1.0 mg 3 times daily, or placebo 3 times daily), patients were admitted in the evening to the inpatient GCRC at OHSU. Their last levodopa dose was given no later than at 10 PM, and all other PD medications were withheld after 10 PM. They practiced finger-tapping scoring 3 times on the evening of admission. At 7 AM the next morning, a dose of the study drug was given, and an intravenous line was placed.
Levodopa powder was prepared for intravenous administration as reported elsewhere.12
An intravenous levodopa infusion was administered continuously for 2 hours starting at 9 AM at a constant rate of 0.5 mg/kg/h (threshold rate) or 1.0 mg/kg/h (therapeutic rate). The infusion rate was blinded and randomized. The infusion was stopped at 11 AM. After 2 PM and when patients were deemed to be OFF, the usual antiparkinson medications were reinstituted.
Finger-tapping speed, walking speed (timed and number of steps), and dyskinesia were measured by blinded research nurses, and patients completed visual analog scales for anxiety, fatigue, and mood every 30 minutes from 7 AM until 2 PM. Finger-tapping tests measured the number of times per minute that patients could alternately tap 2 manual counters located 20 cm apart in 60 seconds using the more affected hand13
as an index of bradykinesia.9–11
Baseline finger-tapping scores were calculated as the mean of the 7:30, 8, 8:30, and 9 AM scores when patients went overnight without antiparkinson medications, except for placebo or pramipexole at 7 AM, but before levodopa infusions started at 9 AM.
Dyskinesia was graded on a scale from 0 to 4 points (0 indicating none; 1, mild; 2, definite/mild to moderate; 3, moderate, may interfere with some activities; and 4, severe, markedly impairs voluntary activities) in the face, neck, and trunk and each of the 4 limbs, and a total score (range, 0–28) was assigned. Ambulation was assessed by measuring the time it took the patient to stand up from a chair, walk 6 m, turn around, return to the chair, and sit. An mUPDRS was collected at 9 AM, just before the levodopa infusion was started, and at 11 AM, at peak levodopa concentration.
After their first stay in the GCRC, patients were switched from pramipexole to placebo or vice versa, and the doses were simultaneously titrated down from one study medication while being titrated up on the other study medication for 9 days. The patients were then maintained on study medication for 4 weeks and were readmitted for 2 days to the GCRC for levodopa infusion and analysis.
A randomized, double-blinded, placebo-controlled crossover design was used to examine the effect of oral DA therapy and levodopa infusion. Because a crossover design has the advantage of eliminating individual patient differences from the overall treatment effect, it provides more statistical power. Demographic and clinical characteristics were summarized using descriptive statistics. To compare the pramipexole effect and the infusion effect, the interaction between pramipexole and infusion, and the carryover effect due to the study design, we used the mixed model. The Bayesian information criterion was used to determine a covariance structure for the model. All analyses were performed using SAS version 9.1 (SAS Institute Inc, Cary, North Carolina), and P<.05 was considered statistically significant.
Change in the total finger-tapping score was calculated as the total finger-tapping score from 9:30 AM to 2 PM minus the baseline finger-tapping score from 7:30 to 9 AM. The AUC was calculated from the scores from 9:30 AM until 2 PM minus the mean baseline scores from 7:30 to 9 AM, setting any negative scores to zero. The peak score was the single fastest finger-tapping time or dyskinesia score. Onset of clinical response was measured as the time to a 10% increase in the finger-tapping score, and time to ON was defined as the time point after the start of the infusion at which a 10% improvement in the finger-tapping score above the mean baseline score was attained in patients who had an ON response. Duration of ON time was determined as the total time that finger tapping was at least 10% faster than the mean baseline value.