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PD MED

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

Year of Publication: 2022

Authors: Richard Gray, Smitaa Patel, Natalie Ives, ..., for the PD MED Collaborative Group

Journal: JAMA Neurology

Citation: Gray R, Patel S, Ives N, et al. Long-term Effectiveness of Adjuvant Treatment... JAMA Neurol. 2022;79(2):131-140. doi:10.1001/jamaneurol.2021.4736

Link: https://doi.org/10.1001/jamaneurol.2021.4736

Clinical Question

Among patients with PD and motor complications uncontrolled by levodopa, which adjuvant class (dopamine agonist, MAO-B inhibitor, or COMT inhibitor) offers better long-term quality of life and functional outcomes?

Bottom Line

MAO-B inhibitors were superior to COMT inhibitors in patient-rated mobility and quality of life. Dopamine agonists and MAO-B inhibitors showed similar effectiveness, suggesting that MAO-B inhibitors may be underused as adjuvant therapy.

        Major Points
        500 patients with PD and uncontrolled motor complications were randomized to dopamine agonist, MAO-B, or COMT inhibitors
Primary outcome was PDQ-39 mobility domain; secondary outcomes included EQ-5D, dementia, death, and institutionalization
No significant difference between dopamine agonist and reuptake inhibitors overall
MAO-B inhibitors had significantly better outcomes than COMT: PDQ-39 mobility +4.2 (P=0.03), EQ-5D +0.05 (P=0.04)
Dementia, mortality, and institutionalization were lower with MAO-B than COMT, but differences were not significant

      

Design

Study Type: Pragmatic randomized clinical trial

Randomization: 1

Blinding: Open-label; patients and clinicians not blinded

Enrollment Period: February 2001 to December 2009

Follow-up Duration: Median 4.5 years (range 0–13.3 years)

Centers: 64

Countries: UK, Czech Republic, Russia

Sample Size: 500

Analysis: Intention-to-treat; mixed-effects repeated measures, log-rank, and negative binomial regression models

Inclusion Criteria

Idiopathic Parkinson disease (UK Brain Bank criteria)
Motor complications uncontrolled by levodopa
Need for adjuvant therapy with uncertainty about class
No dementia

Exclusion Criteria

Dementia
Inability to provide informed consent
Inability to complete questionnaires

Arms

Field	Dopamine Agonist	MAO-B Inhibitor	Control
Intervention	Open-label dopamine agonist (ropinirole, pramipexole, etc.) added to levodopa	MAO-B inhibitor (selegiline, rasagiline) added to levodopa	COMT inhibitor (entacapone) added to levodopa
Duration	Up to 13.3 years follow-up	Up to 13.3 years follow-up	Up to 13.3 years follow-up

Outcomes

Outcome	Type	Control	Intervention	P-value
PDQ-39 mobility domain score (0–100 scale, higher worse)	Primary	COMT group mean baseline ~50.1, no significant improvement	MAO-B group mean improvement +4.2 over COMT	0.03
EQ-5D-3L utility score	Secondary	COMT group 0.51	MAO-B group 0.54	0.04
PDQ-39 Summary Index	Secondary			0.07
Psychiatric AEs	Adverse	24 (MAO-B), 45 (dopamine agonists)	Main in dopamine agonists
Gastrointestinal AEs	Adverse	27 (COMT)

Subgroup Analysis

MAO-B inhibitors outperformed COMT in several PDQ-39 domains (mobility, ADL, emotional well-being, social support). Dopamine agonists vs MAO-B were similar. Age ≥70 was associated with higher dropout.

Criticisms

Open-label design introduces potential bias
Adherence was only ~50% at 5 years
COMT group used only entacapone; results may not generalize to other COMT inhibitors

Funding

Health Technology Assessment Programme of the UK National Institute for Health Research (project number 98/03/02), Medical Research Council, Parkinson’s UK

Based on: PD MED (JAMA Neurology, 2022)

Authors: Richard Gray, Smitaa Patel, Natalie Ives, ..., for the PD MED Collaborative Group

Citation: Gray R, Patel S, Ives N, et al. Long-term Effectiveness of Adjuvant Treatment... JAMA Neurol. 2022;79(2):131-140. doi:10.1001/jamaneurol.2021.4736

Content summarized and formatted by NeuroTrials.ai.

PD MED

(2022)

Objective

PD MED compared the long-term effectiveness of dopamine agonists, MAO-B inhibitors, and COMT inhibitors as adjuvant therapy in Parkinson's disease patients with motor complications uncontrolled by levodopa.

Study Summary

• No difference in mobility or quality of life between dopamine agonists and reuptake inhibitors
• MAO-B inhibitors were superior to COMT inhibitors in mobility and EQ-5D scores

Intervention

Patients with PD and motor complications uncontrolled by levodopa were randomized to open-label treatment with dopamine agonists, MAO-B inhibitors, or COMT inhibitors. Follow-up was median 4.5 years, in 64 centers across the UK, Czech Republic, and Russia.

Inclusion Criteria

Patients with idiopathic Parkinson disease with uncontrolled motor complications requiring adjuvant therapy; no dementia

Study Design

Arms: Dopamine agonist, MAO-B inhibitor, COMT inhibitor

Patients per Arm: Dopamine agonist (144), MAO-B inhibitor (146), COMT inhibitor (210)

Outcome

• MAO-B vs COMT: PDQ-39 mobility better by 4.2 points (P=0.03), EQ-5D-3L utility better by 0.05 (P=0.04)
• Dopamine agonist vs DRI: nonsignificant differences in PDQ-39 mobility (+2.4), summary index (+1.5)
• Trends toward lower dementia and mortality in MAO-B vs COMT group, but not significant

Bottom Line

Major Points

500 patients with PD and uncontrolled motor complications were randomized to dopamine agonist, MAO-B, or COMT inhibitors
Primary outcome was PDQ-39 mobility domain; secondary outcomes included EQ-5D, dementia, death, and institutionalization
No significant difference between dopamine agonist and reuptake inhibitors overall
MAO-B inhibitors had significantly better outcomes than COMT: PDQ-39 mobility +4.2 (P=0.03), EQ-5D +0.05 (P=0.04)
Dementia, mortality, and institutionalization were lower with MAO-B than COMT, but differences were not significant

Study Design

Study Type: Pragmatic randomized clinical trial
Randomization: Yes
Blinding: Open-label; patients and clinicians not blinded
Sample Size: 500
Follow-up: Median 4.5 years (range 0–13.3 years)
Centers: 64
Countries: UK, Czech Republic, Russia

Primary Outcome

Definition: PDQ-39 mobility domain score (0–100 scale, higher worse)

Control	Intervention	HR/OR	P-value
COMT group mean baseline ~50.1, no significant improvement	MAO-B group mean improvement +4.2 over COMT	- (0.4 to 7.9)	0.03

Limitations & Criticisms

Open-label design introduces potential bias
Adherence was only ~50% at 5 years
COMT group used only entacapone; results may not generalize to other COMT inhibitors

Citation

Gray R, Patel S, Ives N, et al. Long-term Effectiveness of Adjuvant Treatment... JAMA Neurol. 2022;79(2):131-140. doi:10.1001/jamaneurol.2021.4736

View Original Publication →

PD MED

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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