Abstract

Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug class is more effective as adjuvant therapy. To compare the long-term effects on patient-rated quality of life of adding a dopamine agonist vs a dopamine reuptake inhibitor (DRI), either a monoamine oxidase type B (MAO-B) inhibitor or a catechol-O-methyltransferase (COMT) inhibitor, to levodopa therapy for the treatment of patients with motor complications of PD. This pragmatic semifactorial (2 × 1) randomized clinical trial recruited from 64 neurology and geriatric clinics (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009. A total of 500 patients with idiopathic PD who developed uncontrolled motor complications and did not have dementia were randomly assigned on a 1:1:1 basis using a computerized minimization program. Data were analyzed between 2017 and 2020. Open-label dopamine agonist, MAO-B inhibitor, or COMT inhibitor. Primary outcomes were scores on the 39-item Parkinson's Disease Questionnaire (PDQ-39) mobility domain and cost-effectiveness. Outcomes were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter. Repeated-measures and log rank analyses were used in an intention-to-treat approach. Among 500 participants, the mean (SD) age was 73.0 (8.2) years; 314 participants (62.8%) were men. Over a median of 4.5 years (range, 0-13.3 years) of follow-up, the participants in the dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, -1.3 to 6.0 points) better than that of the combined MAO-B and COMT groups; however, this difference was not significant (P=.20). With regard to DRIs, participants in the MAO-B group had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P=.03) better than those of the COMT group and EuroQol 5-dimension 3-level (EQ-5D-3L) utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P=.04) better than the COMT group. Nonsignificant improvements were found in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 to 4.5 points; P=.07) along with nonsignificant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P = .07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P=.07). When dopamine agonists were compared with MAO-B inhibitors only, the outcomes were similar. In this study, patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists among people with PD who experienced motor complications that were uncontrolled by levodopa therapy. The MAO-B inhibitors produced equivalent disease control, suggesting that these agents may be underused as adjuvant therapy. isrctn.org Identifier: ISRCTN69812316; EU Clinical Trials Register Identifier: 2005-001813-16.

Highlights

  • MethodsStudy Design and Participants The Parkinson disease (PD) MED clinical trial has compared drug classes used as initial[1] and adjuvant treatment among people with PD; the present study was a multicenter open-label pragmatic semifactorial (2 × 1) randomized clinical trial that addressed adjuvant treatment only

  • A total of 264 participants were entered in the 2-way randomizations, with 134 participants randomized to receive either an monoamine oxidase type B (MAO-B) inhibitor or a COMT inhibitor and 130 participants randomized to receive either a dopamine agonist or a COMT inhibitor

  • The results were consistent with indirect comparisons between placebo-controlled clinical trials, which suggested that entacapone, the only COMT inhibitor assessed in the Parkinson disease (PD) MED study, was a relatively weak adjuvant agent compared with dopamine agonists and MAO-B inhibitors with regard to off time and levodopa dose reduction.[2,3]

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Summary

Methods

Study Design and Participants The PD MED clinical trial has compared drug classes used as initial[1] and adjuvant treatment among people with PD; the present study was a multicenter open-label pragmatic semifactorial (2 × 1) randomized clinical trial that addressed adjuvant treatment only. Patients were ineligible if they had dementia (as defined by the medical team responsible) or were unable to provide informed consent for participation or complete study questionnaires. All participants provided written informed consent before randomization. Study approval was obtained from the West Midlands Research Ethics Committee, the UK Medicines and Healthcare products Regulatory Agency, local

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