Pioglitazone (FS-ZONE)

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 NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE investigators, at 35 US sites. FS-ZONE was a Phase 2 trial.

What happened

Pioglitazone activates PPAR-gamma, a switch that influences inflammation and mitochondria, and had protected dopamine neurons in animal models. In the trial (NCT01280123), 210 people with early Parkinson's, on a stable dose of rasagiline or selegiline, were enrolled between May 2011 and July 2013 and randomised 1:1:1 to 15 mg, 45 mg or placebo for 44 weeks. The measure was change in total UPDRS (a clinician's scale; higher is worse). The analysis groups were 72, 67 and 71 people. Mean worsening was 4.42 (15 mg), 5.13 (45 mg) and 6.25 (placebo). A "futility" design asks whether a drug is so unpromising that a larger trial is not worthwhile. Here the null hypothesis was that each dose cut worsening by 3 UPDRS points relative to placebo, rejected in favour of futility at a one-sided alpha of 0.10 (a deliberately lenient threshold). The 45 mg dose was rejected as futile (P = 0.09); the 15 mg dose was not (P = 0.19), though two sensitivity analyses suggested it too was futile (P = 0.09 each) while the same analyses did not reject 45 mg (P = 0.12 and 0.19). Serious adverse events: 6, 9 and 3, none judged related to the drug.

Why it moved us toward a cure

It used the futility-screen design first applied in NET-PD (landmark 164). It showed that a screening design could cheaply drop weak candidates before an expensive Phase 3. It belongs to the same NINDS NET-PD programme as the creatine trial in landmark 70, where a candidate that did pass screening still failed in a large trial.

Outcome

Dead end for early Parkinson's at these doses. The authors concluded pioglitazone is unlikely to modify progression and did not recommend a larger trial. A futility result speaks to this drug and these doses, not to every drug of its type.

Sources

• NET-PD FS-ZONE Investigators, Lancet Neurol 2015;14(8):795–803, DOI 10.1016/S1474-4422(15)00144-1
• Michael J. Fox Foundation summary, Jul 2015
• PubMed 26116315 (abstract: design, thresholds, results; flagged with an erratum, not read) · ClinicalTrials.gov NCT01280123
• Not yet verified: the animal-model citations; the final enrolled numbers by arm (only analysed numbers seen); what the PubMed-listed erratum corrects.