CALM-PD β-CIT and REAL-PET

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

CALM-PD β-CIT: the Parkinson Study Group (JAMA, April 2002), a substudy of the 301-person CALM-PD trial (JAMA 2000), 82 people at 17 sites in the US and Canada, enrolled 1996–97. REAL-PET: Alan Whone, David Brooks and the REAL-PET Study Group (Annals of Neurology, July 2003), 186 people. The n above is the 82 + 186 total across both imaging groups.

What happened

Both used a scan as a stand-in for nerve-cell loss, since the clinical scales are shaped by symptom drugs (landmark 1 explains the dopamine system they track).

• CALM-PD β-CIT. Of the main trial's patients, 82 had SPECT scans (β-CIT, which measures dopamine transporters on nerve endings). Randomised double-blind to pramipexole (n=42) or levodopa (n=40). Striatal uptake fell by 16.0% on pramipexole versus 25.5% on levodopa after 46 months (P=0.01; the main measure). Loss correlated with UPDRS change (r = −0.40, P=0.001).
• REAL-PET. 186 people with early untreated Parkinson's were randomised 1:1 to ropinirole or levodopa for 2 years; 162 were eligible for analysis. In the putamen, PET uptake of 18F-dopa fell 13.4% on ropinirole (n=68) versus 20.3% on levodopa (n=59) (P=0.022; 95% CI 0.65 to 13.06). The authors called this slower progression.
• The catch. Neither trial had a placebo arm, so the gap could mean the agonist slowed loss or that levodopa sped it up (the question left open by landmark 161); either drug could also change tracer uptake directly. Neither trial showed clinical protection.

Why it moved us toward a cure

These trials gave hope that scans could stand in for years of clinical follow-up. PROUD (landmark 165), a placebo-controlled delayed-start trial of pramipexole (535 people), found no difference in 15-month UPDRS (−0.4, 95% CI −2.2 to 1.4) or in scan loss (−15.1% vs −14.6%) and did not support disease modification.

Outcome

Superseded. The scan advantage did not translate into clinical proof, and the better-controlled PROUD trial did not support disease modification by pramipexole.

Sources

• Parkinson Study Group, JAMA 2002;287:1653–1661, doi:10.1001/jama.287.13.1653 (PMID 11926889)
• Whone et al., Ann Neurol 2003;54:93–101, doi:10.1002/ana.10609 (PMID 12838524)
• Parkinson Study Group, JAMA 2000;284:1931–1938 (main CALM-PD, 301 people) · Schapira et al. (PROUD), Lancet Neurol 2013;12:747–755, NCT00321854
• Not yet verified: the phase label (removed); REAL-PET sponsor and sites; CALM-PD clinical outcomes beyond the imaging substudy.