People whose Parkinson’s disease was uncontrolled by levodopa reported better mobility by adding a monoamine oxidase type B (MAO-B) inhibitor than by adding a catechol-O-methyltransferase (COMT) inhibitor, the pragmatic PD MED trial showed.
After a median of 4.5 years, patients in the MAO-B group had a mean mobility score on the 39-item Parkinson’s Disease Questionnaire (PDQ-39) that was 4.2 points better than those in the COMT group (95% CI 0.4-7.9 points, P=0.03), reported Natalie Ives, MSc, of the University of Birmingham in England, and co-authors.
The difference in PDQ-39 mobility scores between adjunctive therapy with dopamine agonists versus the combined group of dopamine reuptake inhibitors (MAO-Bs and COMTs) was not significant (2.4 points, 95% CI -1.3 to 6.0, P=0.20), the researchers wrote in JAMA Neurology.
Most Parkinson’s patients need to add a new drug when their symptoms are no longer well controlled by their initial treatment, noted co-author Richard Gray, MSc, of the University of Oxford in England.
“There are several different drug classes that could be added at this stage,” Gray told MedPage Today. “They are all effective compared to placebo, but before PD MED, there had been no trials directly comparing the main drug classes used one versus another.”
“PD MED showed that patients reported better mobility and overall quality of life from adding a dopamine agonist or a MAO-B inhibitor than from adding a COMT inhibitor,” Gray noted. “To many people’s surprise, adding a MAO-B inhibitor was at least as effective as adding one of the more expensive dopamine agonists.”
PD MED recruited dementia-free patients with idiopathic Parkinson’s disease and motor complications uncontrolled by levodopa therapy from 64 neurology or geriatric centers, mostly in the U.K., from 2001 through 2009. The mean age of participants was 73, and 62.8% were men.
Of 500 participants, 144 were randomized to any dopamine agonist: 146 to any MAO-B inhibitor, and 210 to any COMT inhibitor, though entacapone (Comtan) was the only COMT inhibitor assessed. Patients already receiving one of these drug classes at recruitment were randomized between the other two classes.
The trial was designed to fit into routine practice. Clinicians could use the drug in each class they preferred, and most assessments were done by questionnaires mailed to patients. All treatment was open-label.
The study had two primary outcomes: functional status measured by PDQ-39 mobility scores (range 0-100), and cost effectiveness, derived from utility scores on the EuroQol 5-dimension 3-level (EQ-5D-3L; range -0.59 to 1.00 points) and other data. Cost effectiveness will be reported in a separate paper.
Primary outcome measures were assessed at baseline, 6 months, and annually for 5 years. Though a clinically meaningful difference in PDQ-39 mobility scores is defined now as a mean change of at least 3.2 points, the study was powered to detect a 6-point difference, the minimum clinically important difference when the trial started.
When PDQ-39 mobility scores for dopamine agonists were compared with those for MAO-B inhibitors only, outcomes were similar. “The MAO-B inhibitors produced disease control that was equivalent to that of dopamine agonists, which suggests that MAO-B inhibitors might be underused as adjuvant therapy for the treatment of people with Parkinson’s disease,” Ives and co-authors wrote.
No significant difference was seen in the EQ-5D-3L utility score for dopamine agonists versus the dopamine reuptake inhibitor group. However, the MAO-B group reported EQ-5D-3L scores that were 0.05 points better than the COMT group (95% CI 0.003-0.09 points, P=0.04).
In secondary outcomes, there were no significant differences. Mortality rates were 63% for dopamine agonists and 64% for dopamine reuptake inhibitors; dementia onset rates were 36% and 38%, respectively.
Nine serious adverse events were reported among nine participants, but none were considered unexpected after review. Non-elective hospital admissions during follow-up were similar in the dopamine agonist and dopamine reuptake inhibitor groups.
“In our opinion, the most important conclusion was derived from review of the data on treatment adherence, hospitalization, long-term dementia, and mortality outcomes,” observed Tanya Simuni, MD, of Northwestern University in Chicago, and Michael Okun, MD, of the University of Florida in Gainesville, in an accompanying editorial.
“The conclusions are instructive and somber; the drug withdrawal rate was in the range of 30% to 50% at 1 year and 5 years, respectively, independent of randomized treatment group,” they wrote.
Treatment discontinuation occurred largely due to adverse effects, Simuni and Okun pointed out. More than 50% of non-elective hospital admissions were Parkinson’s-related, including falls, fractures, and worsening motor function. Mortality and dementia rates were “quite unfavorable despite increasing numbers of available adjunctive therapies,” they added.
“These outcomes call into question the authors’ discussion of the superiority of MAO-B inhibitors to COMT inhibitors,” Simuni and Okun wrote. “Even if there was a marginally significant benefit in the PDQ-39 motor domain, there was certainly no benefit for the most meaningful long-term outcomes.”
Other limitations included the study’s high discontinuation rates, which restricted meaningful comparison of the drug classes, the editorialists noted. The open-label nature of the trial also may have introduced bias, Ives and co-authors acknowledged.
PD MED was supported by funding from the Health Technology Assessment Programme of the U.K. National Institute for Health Research (NIHR), the U.K. Department of Health, U.K. Medical Research Council, and Parkinson’s U.K.
Researchers reported relationships with NIHR, the Movement Disorders Research Charity, BIAL, Parkinson’s U.K., AbbVie, Britannia, Profile Pharma, Teva/Lundbeck, and UCB.
Editorialists reported relationships with Amneal Pharmaceuticals, Biogen, the Michael J. Fox Foundation, NeuroDerm, NIH, the Parkinson’s Foundation, Prevail Therapeutics, Roche, Sanofi, Sun Pharmaceutical Industries, UCB, Acadia Pharmaceuticals, BlueRock Therapeutics, Caraway Therapeutics, Critical Path for Parkinson’s Consortium, Denali Therapeutics, GE Healthcare, Sinopia Biosciences, Sunovion, Takeda, Vanqua Bio, and Voyager Therapeutics.