Isradipine did not slow Parkinson's disease progression in randomized trial
The researchers suggested that the studied dose might have been too low to be effective, while an accompanying editorial called for caution as research in this area moves forward.
Long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage Parkinson's disease, a study found.
To assess the effect of isradipine, a dihydropyridine calcium-channel blocker, on clinical progression of Parkinson's, researchers conducted a multicenter, randomized, parallel-group, double-blind, placebo-controlled trial at 57 sites in North America. Patients with early-stage disease (less than three years since diagnosis) who were not taking dopaminergic medications received 5 mg of immediate-release isradipine twice daily or placebo for 36 months.
The primary outcome was change in the Unified Parkinson's Disease Rating Scale (UPDRS) at 36 months. The UPDRS includes subscales for mental function, activities of daily living, and motor function. Scores range from 0 to 176, with higher scores indicating greater disability. In patients receiving therapy, the scale is routinely administered in the OFF state (≥12 hours after the last dose) to assess disability without the medications and in the ON state (approximately 1 hour after a dose) to assess the effect of medications. The primary outcome measure was assessed in the medication ON state, but OFF scores were collected and assessed as a secondary outcome measure. Secondary outcomes included time to start and use of anti-Parkinson's medications, time to onset of motor complications, change in nonmotor disability, and quality-of-life measures.
Researchers randomly assigned 336 patients with disease duration of 0.9 year and a mean UPDRS part I to III score of 23.1 (SD, 8.6) to the intervention group (n=170) or the placebo group (n=166). Sixty-eight percent of patients were men, and the mean age was 62 years. The study was funded by the National Institute of Neurological Disorders and Stroke. Results were published March 31 by Annals of Internal Medicine.
Adjusted least-squares mean changes in total UPDRS score in the medication ON state were 2.99 (95% CI, 0.95 to 5.03) points in the treatment group compared to 3.26 (95% CI, 1.25 to 5.26) points in the placebo group, an effect of −0.27 point (95% CI, −3.02 to 2.48 points; P=0.85). Secondary outcomes showed no effect of isradipine treatment. Sixty-eight adverse events occurred, and of these, six (four in the intervention group and two in the placebo group) were considered to be possibly related to the study intervention. Three fatal events occurred, two in the intervention group and one in the placebo group, but all were considered unrelated to the study intervention. Edema and dizziness were the most commonly reported adverse effects.
The researchers concluded that long-term isradipine treatment did not appear to affect clinical progression in early-stage Parkinson's disease. They noted, however, that the isradipine dose may have been too low to engage the target calcium channels associated with neuroprotective effects. An editorial described the outcome as a “carefully designed and meticulously executed study” and called for developing a direct measure of efficacy before conducting any more studies of isradipine.
“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,” the editorial stated. “Pressures from our patients and families afflicted with PD [Parkinson's disease] push us to move faster, and we have to balance that with degree of scientific rigor. If we do not, then we may continue to fail.”