Chicago—Research suggesting that dihydropyridine calcium-channel blockers could be associated with reduced risk for Parkinson’s disease (PD) had raised hopes for reducing the rate of clinical progression. 

An article in Annals of Internal Medicine discusses results of a study testing that hypothesis by assessing the effect of isradipine, a dihydropyridine calcium-channel blocker, on the rate of clinical progression of PD. Although the recent trial failed to establish an effect, it also left a glimmer of hope.

The multicenter, randomized, parallel-group, double-blind, placebo-controlled trial was led by Northwestern University Feinberg School of Medicine researchers as part of The Parkinson Study Group STEADY-PD III Investigators.

The trial was conducted at 57 Parkinson Study Group sites in North America in patients with early-stage PD, defined as less than age 3 years, who were not taking dopaminergic medications at enrollment. The 336 patients were treated with either 5 mg of immediate-release isradipine twice daily or placebo for 36 months.

Defined as 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. Researchers also tracked secondary outcomes, including time to initiation and use of anti-Parkinson medications, time to onset of motor complications, change in nonmotor disability, and quality-of-life measures.

Participants had a mean age of 62 years and mean disease duration of 0.9 year, as well as a mean UPDRS part I to III score, 23.1 (SD, 8.6). 

With several follow-up visits during the course of the study—baseline, 14 days, 28 days, and then every 3 months and later every 6 months until 36 months—participants answered questionnaires and UPDRS assessments. The UPDRS measures mental function, activities of daily living, and motor function and was the main outcome for the study. The participants also told researchers if they were having any side effects from the medication. 

With 95% of patients completing the study, the authors report that 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, 0.95-5.03) points versus 3.26 (CI, 1.25-5.26) points, respectively, with a treatment effect of -0.27 (CI,-3.02-2.48) point (P = 0.85).

Statistical adjustment for antiparkinson medication use did not change the findings, and secondary outcomes showed no effect of isradipine treatment. 

Edema and dizziness were the most common adverse effects of isradipine, according to the report.

Researchers suggest that the dose of isradipine provided might have been insufficient to engage the target calcium channels associated with neuroprotective effects, concluding, “Long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD.”

An accompanying commentary points out that Parkinson’s disease is the second most common progressive neurodegenerative disorder. The authors, Baijayanta Maiti, MD, PhD, and Joel S. Perlmutter, MD, of Washington University School of Medicine in St. Louis, add that, while treatment with levodopa or related medications provides substantial relief for most motor symptoms, especially early in the disease, therapy for most nonmotor symptoms remains inadequate. 

“Moreover, no current agents stall or even delay PD progression. The projected increase in PD prevalence (1), with the daunting socioeconomic burden that accompanies it, pushes investigators and the public to develop a disease-modifying therapy,” the commentators assert. “Industry and the federal government have supported clinical investigators in testing many drugs during the past 25 years, yet no trial has found an effective means to slow PD progression.”. 

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