Understanding the Isradipine trial results
Original articles: Parkinson Study Group, S.-P. D. I. I. I. I. (2020). Isradipine Versus Placebo in Early Parkinson Disease: A Randomized Trial. Ann Intern Med. doi:10.7326/M19-2534 and Maiti, B., & Perlmutter, J. S. (2020). A Clinical Trial of Isradipine: What Went Wrong? Ann Intern Med. doi:10.7326/M20-1023
Disease Neuroscience Letters : 2020
The results of the STEADY-PD III trial have now been published. There was no evidence that isradipine slowed disease progression in people with Parkinson’s.
Why is it important?
Understanding why this promising trial found no evidence of change in disease progression is essential, both for any future trials of isradipine as well as for the community’s research efforts into other disease modifying treatments.
Isradipine is a drug used to manage high blood pressure, seen as highly promising in terms of neuroprotection for Parkinson’s. The evidence base for it is broad. Isradipine was found to promote neuronal survival in animal studies, at a dose that was safe and tolerable in people. The mechanism by which it has this effect was also discovered. Large population-based studies also found that people taking isradipine and other drugs in this class were less likely to have Parkinson’s. For these reasons, isradipine was put to the test in the large multicenter STEADY-PD phase III trial.
In STEADY- PD III, 336 people across 57 sites throughout North America were recruited within 3 years of being diagnosed with Parkinson’s and before they began receiving dopaminergic medications. The trial was run in two parallel groups of participants, randomly allocated to receive either isradipine or placebo, in a double-blind manner, so that neither participants nor investigators knew who was taking which treatment until after the end of the study, which lasted for a period of 3 years. Participants were assessed with the Unified Parkinson’s Disease Rating Scale (UPDRS) every 3 months for the first year, and every 6 months over the next two.
Unfortunately, no UPDRS improvement was seen when the isradipine and placebo treated participants were compared. Other secondary measures, such as whether a different dose of dopaminergic medication was eventually required by the two groups, also did not differ.
It is important to understand why this large trial did not yield a positive result. Significant issues to consider are whether the UPDRS is a sensitive enough instrument to measure disease progression in this context, and importantly, whether isradipine did actually reach its target in the brain. At the moment, there is no method to measure target engagement for isradipine in humans. This is an essential next step before another trial of this otherwise promising candidate drug can be considered.
Parkinson Study Group, S.-P. D. I. I. I. I. (2020). Isradipine Versus Placebo in Early Parkinson Disease: A Randomized Trial. Ann Intern Med. doi:10.7326/M19-2534 and Maiti, B., & Perlmutter, J. S. (2020). A Clinical Trial of Isradipine: What Went Wrong? Ann Intern Med. doi:10.7326/M20-1023