Evidence Table TxMN2Are dopamine agonists vs. placebo or levodopa effective in reducing the rate of progression of early Parkinson’s disease?

Bibliographic referenceLees, A. J., Katzenschlager, R., Head, J., & Ben Shlomo, Y. 2001, "Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial.[see comment]", Neurology, vol. 57, no. 9, pp. 1687–1694.
Study typeRandomised open trial
Evidence level1+
Study ObjectiveTo report the results of a ten-year follow-up of bromocriptine, L-dopa and L-dopa/selegiline treated PD patients
Number of patientsN=782 de novo PD patients
 N=249 levodopa alone group
 N=271 levodopa/selegiline
 N=262 bromocriptine

Location: United Kingdom
Sites: 93
Patient characteristicsInclusion criteria:
All patients fulfilled the criteria for a clinical diagnosis of PD
Untreated patients required dopaminergic treatment were included
Patients with co morbid conditions could be included
Patients on anticholinergics and amantadine were included
Exclusion criteria:
Patients who were known to have failed to respond to dopaminergic drugs
Patients with incapacitating cognitive impairment
Characteristics:
Baseline characteristics of three treatment groups were similar in age, sex, duration of PD, disability scores
InterventionBromocriptine alone (arm 3)
ComparisonLevodopa and decarboxylase inhibitor (arm 1); Levodopa/decarboxylase inhibitor & selegiline (arm 2)
Length of follow-up10 years
Outcome measuresMortality and disability
Effect size➢ 49 patients (16 arm1, 16 arm2, 17 arm3) had diagnosis revised during course of trial Mortality
➢ Average follow-up 9.2 years
➢ Standardized mortality ratio (SMR) for patients in the study compared to the general population of United Kingdom was 1.78 (95%CI, 1.62 to 1.96)
Statistical significance of difference among 3 arms in first 5 years of study; p=0.27
Hazard ratio of bromocriptine versus levodopa was 1.15 (95%CI, 0.90 to 1.47)
➢ After adjustment for age, sex, duration of disease before randomisation, hazard ratio 1.12
Hazard ratio for arms 2 vs. 3: 1.06 (95%CI, 0.84 to 1.34)
Hazard ratio for arms 2 vs. 1: 1.22 (95%CI, 0.95 to 1.55)
Hazard ratio (mortality attributed to PD arm 3 vs. arm 1) was 1.63 (95%CI, 1.0 to 2.7)

Disability
Table: difference (95%CI) in mean Webster disability scores
Time in trialsArm 3 vs. 1Arm 3 vs. 2Arm 1 vs. 2
Year 1, n=6700.9 (0.3 to 1.5)1.3 (0.6 to 1.9)0.3 (−0.3 to 1.0)
Year 3, n=6881.3 (0.4 to 2.2)1.4 (0.6 to 2.3)0.2 (−0.7 to 1.1)
Year 5, n=5731.0 (−0.2 to 2.1)1.4 (0.3 to 2.5)0.4 (−0.7 to 1.6)
Year 9, n=2700.2 (−1.5 to 1.5)1.0 (0.6 to 2.5)0.8 (−0.8 to 2.4)
➢ Adjusted for baseline disability score. A positive difference indicates worse average disability in arm 1.
➢ Difference in disability between arm 1 and 3 diminishes after 5th year of follow-up
➢ The ‘final’ disability scores based on the average of the most recent two ratings before death or the end of 1999- adjusted difference of 0.8 (95%CI 0.3 to 1.9) between arm 1 and 3
➢ Similar findings obtained from an analysis of Northwestern University disability scale
➢ On average patients in bromocriptine arm returned to baseline disability after 3 years, 1 year before levodopa group (arm 1)
➢ Significantly lower incidence of dyskinesia in the group initially randomised to bromocriptine than levodopa (arm 1) (rate ratio: 0.73 (95%CI 0.57 to 0.93)
Incidence rate for dystonia was slightly lower in the bromocriptine group (rate ratio: 0.84, 95%CI 0.65 to 1.09, p=0.17)
➢ Slightly lower incidence of on/off fluctuations in the group initially randomised to bromocriptine (difference was not significant; 0.90 (95%CI 0.72 to 1.13)
Source of FundingNon-profit organization and pharmaceutical company
Additional commentsRandomisation was carried out by independent coordinator methods listed
➢ Intention-to-treat analysis
➢ No blinding of investigators –possible bias in result interpretation
➢ If patents did not improve they could be re-randomised to another group
➢ Additional antiparkinsonian drugs were allowed during the trial
➢ Comparability of results from different sites not stated
➢ Trial took place between 1985 to 1990- where selegiline arm was terminated
Citation
NCC CC ID (Ref Man)2309
Bibliographic referenceWeiner WJ, Factor SA, Sanchez-Ramos JR, Singer C, Sheldon C, Cornelius L et al. Early combination therapy (bromocriptine and levodopa) does not prevent motor fluctuations in Parkinson’s disease.[see comment]. Neurology 1993;43:21–7.
Study typeDouble-blind, randomised, parallel group study
Study objectiveTo compare the effects of early combination therapy, LD monotherapy, and Br monotherapy on PD patients previously untreated with dopaminergic medications, with particular attention to late complications and efficacy.
Evidence level+
Number of patientsN=25 PD patients
 N=8 bromocriptine monotherapy (Br)
 N=10 levodopa monotherapy (LD)
 N=7 levodopa plus bromocriptine combination therapy (Br/LD)

Location: USA
Sites
Patient characteristicsNone of the patients had been previously treated with bromocriptine or levodopa. 12 were receiving anticholinergic medications, and 5 were receiving amantadine. These medications were continued if necessary.
BrLDBR/LD
Mean age60.365.757.6
Mean duration of PD (mo)3411.613.9
Hoehn and Yahr stage2.02.12.4
Mean duration in study43.738.440.9
Motor fluctuations n, (%)1 (17)3 (33)5 (71)
Dystonia2 (33) *9 (100)5 (71)
Chorea1 (17)5 (56)4 (57)
Freezing5 (83)2 (22)4 (57)
* Statistically significant difference (p<0.02)
No significant differences for age or PD baseline measures. A longer disease duration in Br group because one patient had PD for 105 months. Other patients in this group had a range similar to the other two groups (difference was not significant).
InterventionBr initiated at 1.25 mg per day and could be advanced to 30 mg per day
Br/LD: patients started on 2.5 mg Br- the next dose was the addition of carbidopa/levodopa 25/100 which occurred after 2 weeks. Gradually increased to max Br dose of 18 mg and carbidopa/levodopa dose of 300/1200
ComparisonLD: carbidopa/levodopa initiated at 12.5/50 and could be increased to a max dose of 300/1200
Length of follow-upStudy duration of 4 years
Outcome measuresDoses, Motor scores, activities of daily living, complications scores, adverse events, withdrawal rates
Effect sizeDoses
➢ Br dose ranged from 6.25 to 30 mg- with a mean of 18 mg per day at the end of the study
LD monotherapy dose ranged from 150–700 mg, with a mean of 417 mg per day at end of study
➢ Br/LD group the LD dose ranged from 200 to 800 mg (mean, 386 mg per day) and the Br dose ranged from 9 to 20 mg (mean, 14 mg per day)
➢ Comparison of LD doses in LD monotherapy and combination group were not significantly different
➢ Comparison of Br doses also did not show significant difference
Motor examination (modified Columbia rating scale)
➢ Br group score decreased maximally by one month-improvement not significant compared to baseline
Motor scores then became progressively worse despite increasing doses and exceeded baseline scores after 15 mo
➢ At no time did Br monotherapy result in significant improvement of motor examination scores
LD group achieved statistically significant improvement at 3 months (p<0.03) and peak improvement at 6 months (p<0.0001)
Motor examination score remained below baseline throughout study
➢ Br/LD group reached peak improvement in motor examination score at 3 months-but degree of improvement never reached significance compared with baseline
➢ Three groups tended to parallel each other: Br group had worst motor examinations score and LD group the best with Br/LD inbetween
➢ No significant difference was found between the 3 groups at any time
Activities of daily living
➢ All 3 groups reached maximal improvement at 6 months
➢ The degree of improvement within each group was significant (p<0.02 for Br, p=0.007 for group LD, p=0.05 for Br/LD)
➢ There were no differences between the groups throughout the study-with the exception of scoring at 48 months (LD group had lowest score p<0.03)
Complications scores
➢ No difference was seen between the three groups for motor fluctuations, dystonia, freezing and chorea
➢ During the last year LD group had the lowest complication scores and Br/LD group the highest
➢ There was a trend towards earlier onset of complications in the combination group
Adverse events
➢ Uncommon in study-only one patient in each group experienced hallucinations at some point during the course of the study
Withdrawals
➢ 3 patients dropped-out early and were not included in final evaluation
➢ One Br patient never returned after baseline visit
➢ Another Br patient dropped-out at 4 mo because of orthostatic hypotension
LD patient dropped-out after being diagnosed with progressive supranuclear palsy within 1st year of trial
➢ Duration of therapy for Br patients (mo): 36, 39, 42, 2x 45, 48
➢ One patient stopped therapy prior to end because of loss of efficacy (45 mo)
➢ Duration of therapy for LD patients (mo): 15, 2x 36, 39, 2x 45, 3x 48
➢ One patient dropped out because of liver enzymes (at 15 mo)
➢ None of these patients dropped out due to lack of efficacy
➢ Duration of therapy for Br/LD patients (mo): 21, 30, 42, 4x 48
➢ One patient dropped out because of lack of efficacy (21 mo) and one because of hospitalization secondary to depression (30 mo)
➢ Duration of therapy in the 3 groups was not significantly different
Source of fundingPharmaceutical, non-profit, University grant
Additional comments➢ Methods of randomisation and allocation concealment not stated
➢ Small sample size-lack of power calculations
➢ Not intention-to-treat analysis
Activities of daily living outcome?? Validated scale??
NCC CC ID (Ref Man)2718

From: Evidence Tables

Cover of Parkinson's Disease
Parkinson's Disease: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care.
NICE Clinical Guidelines, No. 35.
National Collaborating Centre for Chronic Conditions (UK).
Copyright © 2006, Royal College of Physicians of London.

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