Early Rasagiline May Have Disease-Modifying Effect in Parkinson's

Allison Gandey

September 24, 2008

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Dr. Warren Olanow discusses the ADAGIO delayed-start study.

September 24, 2008 (Salt Lake City, Utah) — Results from the Attenuation of Disease Progression With Azilect Given Once-Daily (ADAGIO) delayed-start study show that early treatment offered benefits not obtained with later initiation of the drug. Presenting at the American Neurological Association (ANA) 133rd Annual Meeting, researchers showed that rasagiline (Azilect, Teva Neuroscience) 1 mg slowed the progression of Parkinson's disease. Yet the 2-mg dose failed to meet the primary end point for the trial.

"Why did the 1-mg dose work and 2-mg fail? I don't have an answer for that," lead investigator Warren Olanow, MD, from the Mount Sinai School of Medicine in New York, said during his presentation. "Many questions remain."

First results from the ADAGIO study were presented in August at the 12th Congress of the European Federation of Neurological Societies, in Madrid, Spain.

The randomized, multicenter, double-blind, placebo-controlled study prospectively examined 1176 patients with untreatable Parkinson's disease. Investigators point out this is 1 of the largest studies to date in this area.

During the discussion period after the ANA presentation, a delegate congratulated the investigators and called this a "beautifully presented and exciting study."

Others were less enthusiastic, and more than 1 attendee asked by Medscape Neurology & Neurosurgery to comment on the work declined. They criticized the delayed-start study design as overly complex and, to some, incomprehensible.

Attendee Emmanuelle Waubant, MD, from the University of California, San Francisco, was willing to be interviewed about the work. "We have to remember that this is a relatively short-term study, and we will need longer follow-up to assess safety," she said.

Still, Dr. Waubant calls the findings "intriguing" and says they suggest a possible neuroprotective effect.

Rasagiline is a selective, irreversible, second-generation monoamine oxidase-B inhibitor. It is used as monotherapy or as adjunct to levodopa in moderate or advanced Parkinson's disease.

Delayed-Start Trial

Dr. Olanow says the delayed-start study design was developed to address the limitations of previous designs and was intended to separate disease-modifying effects from symptomatic effects.

The ADAGIO study was composed of 2 phases:

  • A 36-week double-blind, placebo-controlled phase.

  • A 36-week double-blind, active-treatment phase in which all patients received rasagiline.

Patients were randomized in a 1:1:1:1 ratio into 4 treatment groups. Patients received rasagiline 1 or 2 mg per day or placebo followed by doses of rasagiline.

The primary analysis included 3 hierarchal end points based on the unified Parkinson's disease rating scale. End points included:

  • Superiority of slopes between weeks 12 to 36.

  • Superiority in change from baseline to week 72.

  • Noninferiority of slopes during weeks 48 to 72.

The researchers found that early treatment with rasagiline 1 mg met all 3 end points compared with delayed-start or 2-mg rasagiline:

  • Superiority of slope: -0.05 (P = .013; 95% CI, -0.08 to -0.01).

  • Change from baseline: -1.7 units (P = .25; 95% CI, -3.15 to -0.21).

  • Noninferiority of slope: 0.0 (90% CI, -0.04 to 0.04).

"These results are consistent with the possibility that rasagiline 1 mg per day has a disease-modifying effect," Dr. Olanow suggests. "Rasagiline is well tolerated with minimal side effects."

The study was funded by Teva. The authors have served as consultants to the company.

American Neurological Association 133rd Annual Meeting: Derek Denny-Brown New Member Symposium. Presented September 23, 2008.

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