@article{822890af1e094a40a8f1afb44e0eb41d,
title = "Re-Analysis of the STEADY-PD II Trial—Evidence for Slowing the Progression of Parkinson's Disease",
abstract = "Background: Recent examination of the STEADY-PD III isradipine clinical trial data concluded that early-stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression. Objectives: To test this hypothesis, the data from the STEADY-PD II isradipine clinical trial, in which an extended-release (ER) formulation of the drug was used, was re-examined. Methods: The re-analysis of the STEADY-PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52-week trial, rather than by last observation carried forward at the beginning of symptomatic therapy. Results: Participant cohorts were well-matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced. Conclusions: These results are consistent with the recent secondary analysis of the STEADY-PD III clinical trial—suggesting that clinically attainable brain exposure to isradipine may slow early-stage PD progression.",
keywords = "DynaCirc, L-type channel, Parkinson's disease, calcium, dihydropyridine, disease-modification",
author = "Surmeier, {D. James} and Nguyen, {Jack T.} and Nicola Lancki and Venuto, {Charles S.} and David Oakes and Tanya Simuni and Wyse, {Richard K.}",
note = "Funding Information: D.J.S. received funding for research from JPB Foundation, National Institutes of Health (NIH), The Michael J. Fox Foundation, William N. and Bernice E. Bumpus Foundation, CHDI, DoD; T.S. received funding for research from NIH; C.S.V. received funding for research from NIH. The main conclusion of our re-examination of the STEADY-PD II clinical trial with ER isradipine is that participants taking 10 mg/day had significantly smaller increases in total and part 3 UPDRS scores over the course of the 52-week trial when not adjusted for symptomatic medication. Use of an adjustment equation to correct for symptomatic medication increased the P value of the differences between groups above the 0.05 value set for rejection of the null hypothesis. The conclusion that ER isradipine treatment may be associated with slowing progression differs from that drawn in the initial analysis for two potential reasons. First, our analysis was restricted to the two groups receiving daily doses of isradipine that were tolerable (5 and 10 mg/day) and, for which there was good compliance. Second, rather than using an LOCF protocol, in which UPDRS scores at the time symptomatic therapy was initiated were carried forward for the efficacy analysis, the observed UPDRS scores at the end of the trial were used instead to better estimate disease progression. Because a large proportion of participants (more than 40%) initiated symptomatic therapy during the trial, this group constituted a significant portion of the patient pool. Although the placebo and isradipine treatment groups were similar in baseline disability, initial rate of disease progression and the time at which symptomatic therapy was initiated, it is possible that there were differences in the type or amount of medication that could account for the apparent slowing of disease progression with isradipine treatment. Although there is no widely accepted statistical methodology for undertaking a post hoc adjustment of UPDRS scores for these aspects of symptomatic treatment,15 an adjustment to the total and part 3 UPDRS scores was performed using an approach similar to that developed for the STEADY-PD III trial data.6 The adjustment for total daily dose of symptomatic medication increased projected UPDRS scores (as expected), but again did not change the ordinal relationship between total and part 3 UPDRS scores in the placebo and 10 mg/day isradipine treatment groups. Nevertheless, the P values for the differences rose above the 0.05 threshold for rejecting the null hypothesis (P = 0.08–0.1). Does this mean that the null hypothesis should be accepted? We think not for three reasons. First, the linear adjustment procedure itself is of uncertain validity in early-stage PD patients.15 Second, inspection of the linear regression data, on which LED adjustment was based, revealed that the goodness of the fits varied considerably between participants in our cohort, essentially adding a random variation term to the adjusted UPDRS scores. This added variance will increase the likelihood of making a Type II error. Third, the relatively small cohorts in the STEADY-PD II trial limit the power of the analysis. In our view, like that of many statisticians in the field, P values modestly above (or below) the common 0.05 level need to be interpreted cautiously.16 Another potential complication in the interpretation of these results is that there might be a biological interaction between isradipine and MAO-B inhibitors. Recent work in animal models by our group has shown that MAO-B inhibition with rasagiline decreases mitochondrial oxidant stress by diminishing dopamine metabolism in dopaminergic neurons.17 Isradipine also lowers mitochondrial oxidant stress, but by decreasing stimulation of the tricarboxylic acid cycle in mitochondria.4 Because of this interaction, MAO-B inhibitors may mask isradipine mediated neuroprotection. Indeed, although the sample size was small, participants given 10 mg/day isradipine, but not rasagiline or selegiline, had significantly less progression, regardless of LED-adjustment. Our observations are broadly consistent with a recently published secondary pharmacokinetic analysis of the STEADY-PD III trial data.7 STEADY-PD III tested isradipine IR because ER preparation ceased being commercially available. This modeling work revealed that there was considerable variability between participants in IR pharmacokinetics and in those participants that cleared isradipine the slowest and had the greatest drug exposure, there was separation in some outcomes. In particular, there was a significant reduction in non-tremor motor disability, total symptomatic dosing by the end of the trial, and a delay in the need for symptomatic medication.7 Although the inferences from our analysis and the secondary analysis of the STEADY-PD III data are conceptually consistent, there are two apparent discrepancies. First, in the STEADY-PD II trial there was not a significant delay in the initiation of symptomatic therapy with isradipine treatment.. Funding Information: D.J.S. received funding for research from JPB Foundation, National Institutes of Health (NIH), The Michael J. Fox Foundation, William N. and Bernice E. Bumpus Foundation, CHDI, DoD; T.S. received funding for research from NIH; C.S.V. received funding for research from NIH. Publisher Copyright: {\textcopyright} 2021 International Parkinson and Movement Disorder Society.",
year = "2022",
month = feb,
doi = "10.1002/mds.28850",
language = "English (US)",
volume = "37",
pages = "334--342",
journal = "Movement Disorders",
issn = "0885-3185",
publisher = "John Wiley and Sons Inc.",
number = "2",
}