Long-term Isradipine Use Does Not Slow Progression of Parkinson Disease, Study Shows

Long-term usage of immediate-release isradipine for treatment of Parkinson disease (PD) did not exhibit an effect on slowing the clinical progression of early-stage PD, according to study findings published today in the journal Annals of Internal Medicine.¹

Isradipine, a dihydropyridine calcium-channel blocker approved for the treatment of hypertension, has been shown in previous studies to be neuroprotective in animal models characterized by PD. While there are no proven strategies for slowing the progression of PD, several epidemiologic studies have shown a reduced risk for PD in patients receiving dihydropyridines compared with other antihypertensive agents. The study authors sought to examine this link in the early stages of PD, hypothesizing that isradipine may have the potential to slow progression of PD.

Researchers conducted a 36-month, multicenter, randomized, parallel-group, placebo-controlled trial, called STEADY-PD (Safety, Tolerability, and Efficacy Assessment of Isradipine for PD), with current results derived from its phase 3 proceedings. Participants with early-stage PD (n = 336) from 57 Parkinson Study Group sites in North America were randomly assigned (1:1 ratio) to receive either 5 milligrams of immediate-release isradipine twice daily or placebo for 36 months.

The primary outcome measured in the study was the change in Unified Parkinson's Disease Rating Scale (UPDRS) parts 1 (mental function), 2 (activities of daily living), and 3 (motor function) from baseline to 36 months. Key secondary outcomes included factors such as time to initiation of antiparkinson therapy, time to onset and severity of motor complications (motor fluctuations, dyskinesia) for patients receiving antiparkinson medications, as assessed by part 4 of the UPDRS, and the difference in use of antiparkinson medications, calculated as the levodopa equivalent doses between treatment groups.

In the study results, researchers found an insignificant difference in the change in UPDRS scores from baseline to 36 months in patients receiving isradipine twice daily (least-squares [LS] mean changes = 2.99; 95% CI, 0.95-5.03) and those receiving placebo (LS mean changes = 3.26; 95% CI, 1.25-5.26). When comparing isradipine with placebo, the estimated treatment effect was noted by the study authors as small (—0.27; CI, –3.02 to 2.48). In all of the secondary outcomes included in the analysis, none demonstrated benefit of isradipine compared with placebo.

In the accompanying editorial,² authors Joel S. Perlmutter, MD, and Baijayanta Maiti, MD, PhD, both of Washington University School of Medicine, described what may have gone wrong for isradipine in slowing the progression of early-stage PD. “One possibility is that the primary outcome measure—change in UPDRS ON score—was inadequate. Ideally, one would prefer a more direct, objective measure of disease progression, such as change in brain deposition of synuclein pathology,” said the authors.

Perlmutter and Maiti indicated that while the lack of an ideal outcome measure may have complicated the study, “a larger problem may be a lack of target engagement in the brain, which limits this study and all previous studies of potential disease-modifying agents.” They note that before any additional studies of isradipine are considered, a direct measure of target engagement should be developed.

“This isradipine trial and others have continued to hone our clinical trial skills, but we still need more reliable in vivo biomarkers of disease progression and measures of specific target engagement for future clinical trials,” said the authors.

References

1. Simuni T, Oakes D, Biglan K, et al. Isradipine versus placebo in early parkinson disease [published March 30, 2020]. Ann Intern Med. doi: 10.7326/M19-2534.

2. Perlmutter JS, Maiti B. A clinical trial of isradipine: what went wrong? [published March 30, 2020]. Ann Intern Med. doi: 10.7326/M20-1023.