The delayed-start trial design is one approach to separating symptomatic improvement from a true effect on disease progression. In this design, one group receives active treatment and another group receives placebo during the first period of the trial, and both groups receive active treatment during the second period of the trial. The results in the second period may show whether an effect is long term and disease modifying or short term and symptomatic.17 Figure 117 presents a schematic of the delayed trial design.
Figure 1. Schematic of the Delayed-Start Clinical Trial Design17
The delayed-start trial has the potential to demonstrate disease modification based on the following logic: improvements in the active treatment group during the first trial period could be due to disease modification or symptomatic improvement. During the second trial period, however, when both groups are receiving the active treatment, a sustained benefit in the early-start group as compared with the delayed-start group would represent evidence for disease modification. If the effect of the experimental treatment was due solely to symptomatic improvement, then both groups would show similar improvement from baseline during the second stage of the trial when both are receiving the same treatment.18
When designing a delayed-start trial, there is the problem of deciding how long a delay to useâie, how long the first trial stage needs to be in order for the drug to exert its putative disease-modifying effects. A delay of 6 months has been used in some trials, but there is no evidence that this delay is long enough for a putative neuroprotective agent to have a measurable effect. Holford and Nutt19 argue that actual time of complete wash-in and wash-out of symptomatic effects is not finite, and that a major limitation of delayed-start trials is the inherent assumption that some finite timing of these events can be prespecified. They suggest that this could be overcome by designing a trial with quantitative modeling of the entire time course of responses to clinical trial interventions, using data from every study visit rather than the first and last study visit.19
Ideally, one would like each of the stages of the delayed-start trial to be as long as possible, but if the stages are too long, a high or disproportionate dropout rate could compromise the results.20 Patients with highly symptomatic disease are also more likely to leave the study early, thereby limiting delayed-start trials largely to patient populations with mild early PD with slow progressionâa population in whom it is difficult to show measurable change.13
Delayed-start trials do not address the mechanism of disease modification, nor do they evaluate the full magnitude of benefit derived from the study drug over the course of an illness; they merely provide evidence that observed benefits are not the result of symptomatic relief alone.20
The delayed-start trials presented here investigated the effects of rasagiline (a monoamine oxidase-B inhibitor) on subjects with early PD.
The TEMPO Trial
The TVP-1012 in Early Monotherapy for Parkinson's disease Outpatients (TEMPO) trial21 randomly assigned 404 subjects to receive blinded treatment with rasagiline 1 mg/day for 1 year, 2 mg/day for 1 year, or placebo for 6 months followed by rasagiline 2 mg/day for 6 months. Some subjects continued in an open-label extension22 in which all patients, regardless of initial randomization, received rasagiline. In the extension phase, 177 subjects received rasagiline for 5 years or longer (as well as other PD medications as needed) and were assessed using the UPDRS. The authors concluded that early initiation of rasagiline, when compared with delayed start, provided long-term clinical benefit that might reflect enduring benefits due to neuroprotection or effects on compensatory mechanisms.
The ADAGIO Trial
The ADAGIO Trial23 is another example of a delayed-start trial. ADAGIO prospectively examined the effects of rasagiline in 1176 patients with untreated PD. Subjects in the early-start group received rasagiline (1 or 2 mg/day) for 72 weeks, and subjects in the delayed-start group received placebo for 36 weeks followed by rasagiline (1 or 2 mg/day) for 36 weeks, with the UPDRS used for assessment. The authors concluded that early treatment with rasagiline 1 mg/day, but not 2 mg/day, provided benefits that were consistent with a possible neuroprotective effect.
Thus, these two delayed-start trials of rasagiline provide suggestive evidence that this drug may have neuroprotective or disease-modifying effects in early PD. However, the ADAGIO trial did not replicate the TEMPO results for rasagiline 2 mg, and the results are therefore inconclusive. Results and limitations of this trial are discussed further in Chapter 3.
The PROUD Trial
This study used the delayed-start design to investigate the effects of the dopamine agonist pramipexole 1.5 mg/day on symptoms and disease progression in 535 patients with early, untreated PD. The results, presented to date only as an abstract,24 confirm the utility of pramipexole as monotherapy in early PD but do not support a disease-modifying effect of this drug. Change from baseline in UPDRS and PDQ-39 scores significantly favored pramipexole at the end of the placebo-controlled phase, but there was no significant difference between groups at the end of the second stage of the trial when both arms were receiving pramipexole. Neither was there a significant difference between groups in the change in striatal DaTSCAN uptake.
8/13Results of the PROUD trial are now published in Lancet Neurology.
11/28/12GM1 ganglioside showed possible disease-modifying effect in placebo-controlled delayed-start trial.
Long-Term Simple Trial
Agents that show success in delayed-start studies should be considered for further evaluation in a long-term simple study in which patients are randomized to active treatment or placebo and followed for a long duration (eg, 5â8 years) while concurrently receiving any other needed PD medication.20 Such trials can use composite endpoints, including measures such as change in UPDRS and quality of life, as well as nondopaminergic features, such as gait and cognitive function. Such trials can also provide information about the effect of a treatment on long-term cumulative disability, but do not provide information about the mechanism of any disease-modifying effects.20 Some ongoing trials using this design include the PD-MED trial and the NET-PD study of creatine.