Isradipine (STEADY-PD III)

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

The Parkinson Study Group STEADY-PD III Investigators, at 57 North American sites (led by Tanya Simuni, Northwestern; the University of Rochester is the registered sponsor). Funded by the National Institute of Neurological Disorders and Stroke. Published in Annals of Internal Medicine, 2020.

What happened

Surmeier's lab found that dopamine neurons of the substantia nigra use L-type calcium channels (Cav1.3) to keep firing, and that isradipine, which blocks them, protected these neurons in mice (landmark 57).

• Design. Phase 3, placebo-controlled, 36 months. 336 people with early Parkinson's (168 per arm), mean age 62, mean time since diagnosis 0.9 years. Immediate-release isradipine 5 mg twice daily (10 mg a day) by mouth, or placebo (NCT02168842; started Nov 2014). 95% completed the study.
• Main measure. Change in MDS-UPDRS Parts I–III on medication. It rose 2.99 points on isradipine and 3.26 on placebo, a treatment effect of −0.27 points (95% CI −3.02 to 2.48, p=0.85; a negative value means slightly less worsening on isradipine, not a significant one). No secondary measure favoured the drug. Oedema (swelling) and dizziness were the commonest side effects. The authors noted the dose may have been too low to engage the target calcium channels.

Earlier dose-finding study (STEADY-PD, Phase 2, 2013). Before Phase 3, 99 people with early Parkinson's who did not yet need dopamine drugs were randomised to isradipine controlled-release 5, 10 or 20 mg a day or placebo for 52 weeks. The aim was to find a dose people could tolerate. Staying on the assigned dose: placebo 25 of 26 (96%), 5 mg 19 of 23 (83%), 10 mg 19 of 26 (73%), 20 mg 9 of 24 (37%). Leg swelling (30 cases) and dizziness (24) were the commonest side effects. UPDRS change did not differ between doses. 10 mg a day was chosen as the highest tolerable dose for Phase 3. It was a safety and dose study, not an efficacy test.

Why it moved us toward a cure

It was a clean test of a specific hypothesis about why nigral neurons die, and it was negative at that dose. It does not disprove the mechanism: isradipine may not reach brain cells in enough amounts at doses people can tolerate, or treatment may be too late. It also fed the shift toward other explanations of vulnerability, such as mitochondrial and dopamine-chemistry stress (landmark 58).

Outcome

Dead end for isradipine. The vulnerability idea stays open.

Sources

• Simuni et al., "Isradipine versus placebo in early Parkinson disease," Ann Intern Med 2020, DOI 10.7326/M19-2534, PMID 32227247 (abstract read via Europe PMC; AJMC summary)
• NeurologyLive, AAN 2019 presentation · NINDS PDBP summary
• STEADY-PD Phase 2: Mov Disord 2013;28:1823-1831, DOI 10.1002/mds.25639, PMID 24123224 (abstract read via Europe PMC)
• Not yet verified: the full Phase 3 paper (only the abstract was read); the STEADY-PD Phase 2 figures were not rechecked on 19 Oct.