Examining Adjuvant Therapies in PD When Levodopa Wanes

Levodopa is standard of care for individuals with Parkinson disease (PD), but many patients develop complications whereby the motor symptoms become worse as the disease progresses and is no longer controlled by the therapy.

A study published in JAMA Neurology reported the results of a randomized clinical trial, conducted mostly in the United Kingdom, that looked at patient quality of life (QOL) when adding different adjuvant therapies to levodopa to help control dyskinesia and a flaring of symptoms during OFF periods or as the disease progresses.

Other drug classes are then typically added to the patient regimen, namely dopamine agonists and dopamine reuptake inhibitors (DRIs), which include catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase type B (MAO-B) inhibitors.

It is unknown, however, which drug class is preferred by patients, the researchers wrote. To date, indirect comparisons have suggested that dopamine agonists have greater efficacy and that the efficacy of COMT or MAO-B inhibitors are comparable. Without direct comparisons, the authors cautioned, that idea is misleading.

The current study stemmed from Parkinson Disease Medication, a randomized clinical trial (RCT) that compared drug classes used as initial and adjuvant PD treatment. A multicenter open-label pragmatic semifactorial (2 × 1) RCT then looked at adjuvant treatment only. Patients with idiopathic PD were included if they developed motor complications that were uncontrolled by levodopa, either alone or in combination with either a dopamine agonist or an MAO-B inhibitor, and there was uncertainty about which drug class to add next. Patients with dementia were excluded.

Investigators first wanted to determine if a DRI (either an MAO-B or COMT inhibitor) or a dopamine agonist was more effective as an adjuvant treatment with levodopa, taking into account QOL. Secondly, they wanted to know if a DRI was more effective, which drug class is preferable for patient-reported QOL for motor complications—COMT or MAO-B inhibitors?

The study recruited patients with late-stage PD from 64 neurology and geriatric practices (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009; data were analyzed between 2017 and 2020.

Five hundred patients with uncontrolled motor complications were randomly assigned on a 1:1:1 basis to receive a dopamine agonist, a COMT inhibitor, or an MAO-B inhibitor, within the following constraints:

• Patients who were on a dopamine agonist when uncontrolled motor complications occurred could be randomized only between a COMT or an MAO-B inhibitor
• Patients receiving an MAO-B inhibitor when the motor complications began and patients for whom the clinician considered an MAO-B inhibitor to be contraindicated could be randomized only between a COMT inhibitor or a dopamine agonist

Due to the nature of the study, blinding was not possible. During the study, providers could adjust the medications within the same drug class and, if symptoms were not controlled, could add or substitute a new therapy from a different drug class.

Nearly 63% of the participants were male, with a mean (SD) age of 73.0 (8.2) years, and the median follow-up was 4.5 years (range, 0-13.3 years).

Primary outcomes, which were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter, were scores on the 39-item Parkinson’s Disease Questionnaire (PDQ-39) mobility domain, which ranges from 0 to 100 points, with higher scores indicating greater difficultly.

Secondary outcomes included the EuroQol 5-dimension 3-level (EQ-5D-3L) generic QOL measure (score range, −0.59 to 1.00 points, with higher scores indicating better health-related QOL).

Statistical analysis included repeated-measures and log rank analyses in an intention-to-treat approach.

The most notable finding in the study was that MAO-B group participants had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P = .03) higher than those of the COMT group.

In addition, MAO-B group participants had EQ-5D-3L utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P = .04) better than the COMT group.

These results were consistent with previous indirect comparisons, the authors noted, and there was no advantage when looking at dopamine agonists compared with MAO-B and COMT together.

The dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, −1.3 to 6.0 points) higher than that of the combined MAO-B and COMT groups, but the difference was not statistically significant (P = .20). The researchers theorized this might be because there were fewer participants randomized to this group.

Comparing MAO-B inhibitors with COMT inhibitors yielded only nonsignificant improvements 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.

Although a cost-effectiveness analysis still has to be performed, the authors noted that MAO-B inhibitors are less expensive than COMT inhibitors.

The study had several strengths, such as the fact that it used a national hospital registry database with a nearly 5-year median follow-up. As for limitations, the study was open label, but the authors said the performance and reporting biases that sometimes occur in these studies would have been more likely to reduce, not increase, treatment differences in this case.

Reference

Gray R, Oatek S, Ives N, et al; PD MED Collaborative Group. Long-term effectiveness of adjuvant treatment with catechol-o-methyltransferase or monoamine oxidase b inhibitors compared with dopamine agonists among patients with Parkinson disease uncontrolled by levodopa therapy: the PD MED randomized clinical trial. JAMA Neurol. 2022;79(2):131–140. doi:10.1001/jamaneurol.2021.4736