NN104 RHAPSODY

RHAPSODY (NeuroNEXT trial NN104) was a phase 2 trial in moderate to severe acute ischemic stroke. It tested 3K3A-APC, an engineered form of activated protein C, given after intravenous tPA, mechanical thrombectomy or both. Doses were escalated across four tiers (120, 240, 360 and 540 µg/kg) with a continual reassessment method and compared with placebo. The sponsor was ZZ Biotech, the network was funded by NINDS, and data were held at the University of Iowa. Trial MRI was used to measure bleeding into the brain, the main safety concern for this class of drugs. The imaging is archived at the LONI Image and Data Archive, but the archive does not accept applications for it.

Composition

Patients were enrolled between January 2015 and April 2017 at sites in the United States. Of 2814 screened patients, 110 were enrolled: 66 received 3K3A-APC and 44 placebo. 53 were men and the mean age was 64 years in both arms. About half of each arm received tPA alone and most of the others tPA plus thrombectomy.

Acquisition

MRI followed a common protocol with gradient echo (GRE) or susceptibility-weighted (SWI) sequences, acquired 7, 30 and 90 days after the stroke. Of the 80 Day-30 scans in the hemorrhage analysis, 63 were SWI and 17 GRE. FLAIR images showed the infarct, and T2-weighted images were used to outline the lesion. Field strength and scanner models are not reported.

Annotations

A central analyst blinded to treatment quantified hemorrhage volume (hematomas, petechiae and microbleeds) on the susceptibility-sensitive scans. Infarct lesions were labeled in ITK-SNAP 3.6 to compute volume. Any hemorrhage by Day 30 was seen in 61 of 80 patients and microbleeds in the infarct zone in 15. No masks are published.

Known limitations

• The archive lists the study as closed to applications, and no data use terms are public.
• The hemorrhage analysis covers the 80 patients who received at least two doses or had a dose-limiting toxicity.
• The abstract and the results text give different end dates for enrollment.