REPLY TO DRS. OLANOW AND RASCOL

As clinicians with active Parkinson disease (PD) practices, we took publication of the Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) study results very seriously. Should rasagiline be prescribed to all patients with PD? After carefully considering this and other relevant trials, we concluded that there are insufficient data to support this practice. This parallels the scenario that played out 2 decades ago relating to investigation of another MAO-B inhibitor, selegiline.^1,2

Our interpretation differs substantially from that of our colleagues, Drs. Olanow and Rascol. They argue that the ADAGIO statistical comparisons seemingly make other analyses “inappropriate” and “an error”; apparently this includes visual inspection of graphs and perusal of raw data. However, statistical analyses are only valid if the study design is sound and without potential confounding influences. With this drug (rasagiline), and with the delayed-start study design, the potential for confounding is substantial, as we outlined in our article. Statistics, no matter how “rigorous,” will not salvage a flawed study with faulty premises. Thus, incomplete blinding (open-label conditions in the last half of the study), sequential and perhaps unbalanced placebo effects, a partially subjective scale (Unified Parkinson's Disease Rating Scale [UPDRS]), and the potential for asymmetric practice effects could easily have influenced outcomes, especially when the measured differences were so small (1.7 UPDRS points).

Defending use of the UPDRS, Drs. Olanow and Rascol comment that “. . . this scale is used in virtually every trial in PD.” In fact, the UPDRS evolved from earlier rating scales that were developed primarily to assess the symptomatic effects of PD drugs. In that setting, where robust symptomatic responses translate into marked differences in UPDRS scores, the utility of this measure is obvious. However, adapting the UPDRS to analyze parkinsonism progression, where very small differences accrue over long periods of time, seriously challenges this scale.

The statement that “the delayed start is the best design currently available” bears on a larger issue: Are our current approaches for assessment of PD progression truly “futility trials”³? When drugs with symptomatic effects are studied for neuroprotection, current study designs seemingly are inadequate, and generate far more questions than answers. Thus, we agree with Drs. Olanow and Rascol that “a validated biomarker would obviously be helpful.”

See pages 1143 and 1149

Disclosure: Dr. Ahlskog received the Fred Springer Award from the American Parkinson's Disease Association; receives royalties from publishing The Parkinson's Disease Treatment Book (Oxford University Press, 2005) and Parkinson's Disease Treatment Guide for Physicians (Oxford University Press, 2009), Parkinson's Disease and Movement Disorders (Humana Press, 2000), and Surgical Treatment of Parkinson's Disease and other Movement Disorders (Humana Press, 2003); has received honoraria for lectures or educational activities not funded by industry; and receives research support from NIH/NINDS [P50 NS 40256-R (Co-I)]. Dr. Uitti serves as an Associate Editor of Neurology®; has received research support from Advanced Neuromodulations Systems and from the NIH/NINDS (P50NS 40256 [Co-I]); and his institution receives annual royalties from the licensing of the technology related to PARK8/LRRK2.

Address correspondence and reprint requests to Dr. J. Eric Ahlskog, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; eahlskog@mayo.edu