untreated subjects with early PD who were randomized to receive either 1 mg per day or 2 mg per day for 72 weeks (designated the “early-start” groups) or to receive placebo for 36 weeks followed by 1 mg or 2 mg rasagiline for the following 36 weeks (designated the “delayed-start” groups).¹³ The ADAGIO study included 3 primary end points. The first primary end point was change in UPDRS points per week, also known as the “slope,” which was the primary means of measuring disease progression in the 4 treatment groups. The second primary end point was a comparison between the earlystart and delayed-start groups for estimated change in UPDRS from baseline to week 76, which was intended to measure if initial benefits gained by patients in the early-start groups were sustained at the end of the study, which would also tend to indicate positive outcome modification. The third primary end point was noninferiority of slope during weeks 48 through 72 for the early- versus delayed-start group, ie, if benefits gained during the second 36-week period remained as robust in the early-start group versus the delayed-start group, this would indicate an enduring positive outcome effect resulting from the early-start strategy.¹³

The ADAGIO trial, in seeking to maintain a type I error of 0.05 across a study that involved 3 primary end points and 2 separate doses in each group, employed a hierarchical design, such that each of its primary end points had to be met for the results to be deemed positive for either of the 1 mg or 2 mg doses.^10,13 At the end of the study, early-start patients receiving 1 mg had achieved all 3 primary end points, while the 2 mg group, though it did achieve the first and third end points, did not achieve the second primary end point.¹⁰

Numerous explanations have been offered to account for the failure of the 2 mg dose to achieve the second primary end point; the results should be viewed in light of results from the TEMPO trial, which although quite different in design, showed UPDRS benefits with both 1 mg and 2 mg doses of rasagiline.¹⁴ Although the 2-mg treatment group of ADAGIO did not achieve all 3 primary end points, the 1-mg treatment group did demonstrate that outcome modification is achievable with early initiation of treatment in that patients in the early-start group experienced fewer symptoms than those in the late-start group over the course of the study.10 The benefits of early treatment are further borne out by a group of prespecified and post hoc analyses of the ADAGIO study, which found that early treatment was associated with significantly less need for, and a significant delay in the need for, other additional antiparkinsonian treatments and improved UPDRS ADL subscores at week 72.¹⁵

Importantly, from the standpoint of understanding the role of early PD treatment in achieving outcome modification, an analysis of the ADAGIO data found that the rate of UPDRS decline was significantly associated with baseline disease severity. This association may be seen in the difference in progression of UPDRS from baseline to week 36 in the highest versus lowest quartiles of UPDRS scores, which was highly statistically significant (P <.0001) (Figure 1).¹⁵ Future studies will need to incorporate this finding into their study design and randomization approach to ensure large enough sample sizes and power to detect meaningful differences in outcomes over time.

A number of preclinical studies have offered evidence of neuroprotection from dopamine agonist agents, including pramipexole, ropinirole, and rotigotine.16-18 With regard to human clinical trials, the CALM-PD study, in a substudy within the larger trial, employed SPECT to evaluate disease progression by evaluating uptake of striatal 2β-carbomethoxy-3β-(4-iodophenyl)tropane(β-CIT), a marker for dopamine neuron degeneration, in 82 subjects with early PD receiving pramipexole or levodopa/carbidopa.¹⁹ At 4-year follow-up, pramipexole-treated patients experienced significantly greater β-CIT uptake decline versus levodopa-treated patients, and β-CIT uptake decline was significantly correlated with change in UPDRS from baseline. These data point to a possible modification of dopaminergic neuronal degeneration with pramipexole that is greater than that seen with levodopa (though levodopa also exerted positive benefits), although the effects of these medications on synaptic activity and β-CIT uptake are not fully understood.¹⁹

The REAL-PET study employed PET imaging to compare the effects of ropinirole versus levodopa in 186 patients with early PD over the course of 2 years.²⁰ PET data revealed significantly slower disease progression with ropinirole treatment based on the rate of loss of dopamine-terminal function. However, motor score improvement, which was seen with both treatments, was sustained in the levodopa group but not the ropinirole group. Importantly, in terms of symptomatic effectiveness of treatment, reduced dyskinesia and longer time to dyskinesia were associated with ropinirole versus levodopa, although Clinical Global Impression scores were not significantly different between treatment groups.