Isradipine Versus Placebo in Early Parkinson Disease: A Randomized Trial

Abstract

Background: Studies suggest that dihydropyridine calcium-channel blockers may be associated with reduced risk for Parkinson disease (PD).

Objective: To assess the effect of isradipine, a dihydropyridine calcium-channel blocker, on the rate of clinical progression of PD.

Design: Multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT02168842).

Setting: 57 Parkinson Study Group sites in North America.

Participants: Patients with early-stage PD (duration <3 years) who were not taking dopaminergic medications at enrollment.

Intervention: 5 mg of immediate-release isradipine twice daily or placebo for 36 months.

Measurements: The primary outcome was change in the Unified Parkinson's Disease Rating Scale (UPDRS) parts I to III score measured in the antiparkinson medication "ON" state between baseline and 36 months. Secondary outcomes included time to initiation and use of antiparkinson medications, time to onset of motor complications, change in nonmotor disability, and quality-of-life measures.

Results: 336 patients were randomly assigned (mean age, 62 years [SD, 9]; 68% men; disease duration, 0.9 year [SD, 0.7]; mean UPDRS part I to III score, 23.1 [SD, 8.6]); 95% of patients completed the study. Adjusted least-squares mean changes in total UPDRS score in the antiparkinson medication ON state over 36 months for isradipine and placebo recipients were 2.99 (95% CI, 0.95 to 5.03) points versus 3.26 (CI, 1.25 to 5.26) points, respectively, with a treatment effect of -0.27 (CI, -3.02 to 2.48) point (P = 0.85). Statistical adjustment for antiparkinson medication use did not change the findings. Secondary outcomes showed no effect of isradipine treatment. The most common adverse effects of isradipine were edema and dizziness.

Limitation: The isradipine dose may have been insufficient to engage the target calcium channels associated with neuroprotective effects.

Conclusion: Long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD.

Primary funding source: National Institute of Neurological Disorders and Stroke.

Figure 1.. Study flow diagram.

Patients were included in the primary analysis if they received a total score on parts I to III of the UPDRS in the “ON” state at both the baseline visit and the last visit on the study drug at 3 y. UPDRS = Unified Parkinson’s Disease Rating Scale.

Figure 2.. Primary and key secondary outcomes.

UPDRS = Unified Parkinson’s Disease Rating Scale. A. Mean UPDRS parts I to III score calculated in the ON state for patients receiving antiparkinson medications, by study visit. The baseline, 2-wk, and 1-mo visits are separated for clarity. The plot shows observed means and 95% CIs. Adjusted values were adjusted for current and cumulative levodopa equivalent doses. B. Mean UPDRS part III score for all patients. The plot shows observed means and 95% CIs. Patients receiving antiparkinson therapy at any visit were evaluated in the OFF state at that visit. C. Mean total UPDRS score for all patients before initiation of antiparkinson therapy. The plot shows observed means and 95% CIs. Data from patients receiving antiparkinson therapy at any visit were excluded in the calculations for that visit. D. Time to antiparkinson therapy, calculated in days from enrollment but shown in months. The P value was calculated using the log-rank test with stratification by site.