NET-PD futility screens FS-1 and FS-2

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 NET-PD Investigators (the National Institute of Neurological Disorders and Stroke programme for finding neuroprotective drugs). FS-1 in Neurology 2006;66:664–671 (NCT00063193, started May 2003); FS-2 in Neurology 2007;68:20–28 (NCT00076492, started January 2004). Both Phase 2, run from the University of Rochester.

What happened

A futility trial asks a cheaper question than a full efficacy trial: is the drug so unpromising that it should not go to Phase 3? Each drug's UPDRS progression over about a year was compared with the placebo group of DATATOP (landmark 61).

• FS-1 (2006). 200 people with PD diagnosed within 5 years and not yet needing symptomatic drugs, randomised 1:1:1 to creatine 10 g a day, minocycline 200 mg a day or placebo. Main measure: change in total UPDRS over 12 months or until symptomatic treatment was needed. The bar: a 30% cut in progression, set from the DATATOP placebo/tocopherol arm. Neither drug could be called futile (creatine p=0.96, minocycline p=0.66; futility needed p≤0.1). The calibration placebo group progressed outside the DATATOP historical range, but a sensitivity analysis using it gave the same answer. The authors said both should be considered for Phase 3.
• FS-2 (2007). GPI-1485 (a nerve-growth-boosting compound) and coenzyme Q10 (CoQ10, an energy cofactor tested earlier in landmark 102). Neither failed the futility test (change in total UPDRS over 1 year, again against DATATOP placebo data), but analyses with calibration controls and newer placebo data questioned whether the threshold was too lenient and suggested a more restrictive one.
• What followed. Creatine went to NET-PD LS-1 (NCT00449865, Phase 3, 1,741 people, registry status terminated) (landmark 70). CoQ10 went to the QE3 trial (landmark 26).

Why it moved us toward a cure

It was the first systematic attempt to triage candidate drugs before Phase 3. Its weakness is also a lesson: comparing with historic placebo data is unreliable, as the FS-2 authors themselves noted. The futility design was reused for pioglitazone (landmark 105).

Outcome

Advanced as a method: the futility design was reused for pioglitazone (FS-ZONE, NCT01280123). The screens passed the drugs forward; creatine and CoQ10 then failed in Phase 3 (landmark 70, landmark 26).

Sources

• NET-PD FS-1, Neurology 2006;66:664–671, doi:10.1212/01.wnl.0000201252.57661.e1 (PMID 16481597) · ClinicalTrials.gov NCT00063193
• NET-PD FS-2, Neurology 2007;68:20–28, doi:10.1212/01.wnl.0000250355.28474.8e (PMID 17200487) · ClinicalTrials.gov NCT00076492 · NCT00449865 (LS-1)
• Not yet verified: the FS-2 sample size and arm counts (the registry lists 195 for each study; the FS-1 paper says 200); whether minocycline went to any Phase 3. No n is given because the combined size is unclear.