Confirmed: No Slowing of Parkinson’s Progression With Rasagiline
A 1-mg daily dose of rasagiline has no disease-modifying effect for patients with Parkinson’s disease (PD), new research confirms.
Results from a randomized, double-blind, placebo-controlled trial support previous observations that free-water accumulation in the posterior substantia nigra (pSN) is a valid biomarker of disease progression.
However, at 1 year, pSN free-water accumulation was the same for the patients who received rasagiline and for those who received placebo.
Dr David Vaillancourt
“We’re using an imaging biomarker of the substantia nigra as the outcome variable, which has not been done before,” corresponding investigator David E. Vaillancourt, PhD, professor and chair of applied physiology and kinesiology at the University of Florida, Gainesville, Florida, told Medscape Medical News.
“We did not find evidence that rasagiline slows down the progression of the substantia nigra over time,” Vaillancourt said.
The findings were published online November 1 in Movement Disorders.
Seeking a DMT
No available drug has been proven to slow disease progression for patients with PD. Researchers continue to seek a disease-modifying therapy (DMT), which remains an unmet need.
Previous investigators have identified rasagiline, a monoamine oxidase (MAO) type B inhibitor approved for the treatment of motor symptoms in PD, as a potential DMT.
ADAGIO trial results, published in 2009, suggested that a 1-mg/d dosage but not a 2-mg/d dosage of rasagiline could modify disease course. The US Food and Drug Administration, however, rejected the designation of the therapy as a DMT.
One of the new biomarkers of disease progression that has emerged since the ADAGIO trial is free-water pSN. Data indicate that free-water pSN increases during 1 year in patients with PD but not in a control group. This marker was later validated in various cohorts and at various sites.
Using free-water pSN as a biomarker, the current researchers examined whether 1 mg/d of rasagiline would slow PD progression.
The trial included 96 patients with PD. For all patients, disease duration was <5 years. The patients were aged 40 to 77 years, had PD of Hoehn and Yahr stage ≤2 while taking medication, and had never taken rasagiline previously.
While in the off state at baseline, patients underwent diffusion MRI with short and long repetition time (TR), secondary motor testing, and cognitive testing. The researchers then randomly assigned the participants to receive 1 mg/d of rasagiline or matching placebo.
To monitor for adverse events, participants were called via telephone every 3 months. At 1 year, they again underwent diffusion MRI and secondary motor and cognitive testing in the off state.
No Differences in Primary Outcome
In all, 90 participants were included in the final analysis. Of this group, 11 did not return to complete the 1-year follow-up visit.
In the placebo group, 29% of the participants were women, compared with 36% of the rasagiline group. The baseline age was 63 years and 65 years, respectively. These differences were not statistically significant. Baseline free-water measurements were also similar between the groups.
Absolute change in free-water accumulation in the pSN at 1 year, which was the study’s primary outcome, did not differ significantly between the groups. The estimated mean group difference was 0.0015 on short TR scans (P = .346) and -0.0015 on long TR scans (P = .228).
There were also no significant between-group differences in change in the secondary endpoints of anxiety, depression, cognition, and motor function at 1 year.
A significant increase in free-water measurements during the study period was observed on long TR scans but not on short TR scans.
There was also a positive correlation between long TR baseline free-water pSN values and the 1-year change in Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III total score (P = .004) and change in bradykinesia score (P = .04).
The current study differed from the earlier ADAGIO study in several ways, Vaillancourt noted.
One major difference was that ADAGIO included a delayed-start group that was switched from placebo to rasagiline after 36 weeks. Also, the current study used an imaging outcome (free-water pSN) rather than a clinical outcome (MDS-UPDRS), as in ADAGIO.
The current study represents the third study to indicate that free-water pSN progresses in PD, Vaillancourt said. He noted that a key finding was that long TR scans showed the progression effect but short TR scans did not, which is “relevant for future studies looking to run a clinical trial.”
Vaillancourt said that although there are currently “a lot” of medications for symptoms of PD, “the field needs a DMT.
“For that to be accepted by the field overall, there needs to be biomarker evidence and clinical evidence,” he said. A DMT would have a major impact in PD, Vaillancourt added.
Commenting on the findings for Medscape Medical News, Alfonso Fasano, MD, PhD, chair in neuromodulation and professor of neurology at the University of Toronto, Toronto, Canada, said a strength of the study was the comparison of short and long TR neuroimaging findings.
Dr Alfonso Fasano
On the other hand, the dropout rate in the long TR arm was higher than the expected 15%, he added. “It’s slightly underpowered when it comes to the long TR part of the study,” said Fasano, who was not involved with the research.
Free-water pSN “is obviously a promising biomarker,” he noted. “It’s been shown to predict long-term outcome and to correlate with the condition of the patient. More importantly, it seems to be sensitive to time.”
The results also clearly indicate that long TR is superior to short TR as a biomarker of disease progression, Fasano said, but whether the biomarker is sensitive enough to detect small changes affected by drug molecules is an open question.
In addition, the findings confirm the current consensus that the disease-modifying effect of MAO-B inhibitors such as rasagiline is minimal or nonexistent, Fasano noted.
“Unfortunately, we don’t have anything that can really slow down the progression of the disease, at least not yet,” he said.
Nevertheless, the study may inspire better-designed trials in the future ― and the use of a biomarker on neuroimaging is the study’s biggest strength, Fasano added.
“This is probably the way to go in the future, rather than using clinical scales or patient-reported outcomes,” he concluded.
The study was funded by the National Institutes of Health. Vaillancourt and Fasano reported no relevant financial relationships.
Mov Disord. Published online November 1, 2021. Abstract
Follow Erik Greb on Twitter: @MedscapeErik.
For more Medscape Neurology news, join us on Facebook and Twitter.
Source: Read Full Article