PDF: PROACT
(1998)Objective
To test the safety and recanalization efficacy of intra-arterial recombinant pro-urokinase (rpro-UK) versus placebo in patients with acute M1 or M2 middle cerebral artery (MCA) occlusion treated within 6 hours of symptom onset.
Study Summary
• Symptomatic hemorrhage at 24 hours was not significantly different (15.4% vs. 7.1%), but was a concern and appeared to be driven by a high-dose heparin regimen used in the initial part of the trial.
Intervention
6 mg of recombinant pro-urokinase (rpro-UK) or placebo was infused intra-arterially over 2 hours into an occluded MCA within 6 hours of symptom onset. All patients received IV heparin. Clinical follow-up was for 90 days.
Study Design
Arms: Array
Outcome
• Primary safety outcome (symptomatic intracranial hemorrhage at 24 hours) occurred in 15.4% of the rpro-UK group vs. 7.1% of the placebo group (p=0.64).
• Mortality at 90 days was numerically lower with rpro-UK but not statistically significant (26.9% vs. 42.9%; p=0.48).
Bottom Line
Intra-arterial infusion of 6 mg of rpro-UK (mechanical disruption proscribed) with concomitant IV heparin produced a significantly higher rate of MCA recanalization than placebo with heparin. The frequency of intracranial hemorrhage, while not statistically different for symptomatic events, was a concern and appeared strongly influenced by the dose of adjunctive heparin.
Major Points
- PROACT was a phase II, randomized, double-blind, placebo-controlled, multicenter trial designed to assess the safety and recanalization efficacy of intra-arterial rpro-UK.
- Patients with angiographically confirmed M1 or M2 MCA occlusion within 6 hours of onset were randomized 2:1 to receive a 2-hour intra-arterial infusion of 6 mg rpro-UK or placebo delivered to the proximal face of the thrombus; mechanical disruption of the clot was proscribed.
- All patients in both groups received a 4-hour infusion of intravenous heparin.
- The primary efficacy outcome, recanalization at 2 hours, was significantly higher in the rpro-UK group than the placebo group (57.7% vs. 14.3%; P=0.017).
- The primary safety outcome, symptomatic intracranial hemorrhage causing neurological deterioration within 24 hours, occurred in 15.4% of the rpro-UK group and 7.1% of the placebo group, a difference that was not statistically significant (P=0.64).
- A high-dose heparin regimen used early in the trial was associated with higher rates of both recanalization and hemorrhage, leading to a protocol change to a lower heparin dose.
Study Design
- Study Type
- Phase II, randomized, double-blind, placebo-controlled, multicenter trial
- Randomization
- Yes
- Blinding
- Double-blind (patients, investigators, examining physicians, and Core Neuroradiology Facility)
- Sample Size
- 46 randomized (5 rpro-UK and 1 placebo were not treated); 40 treated (rpro-UK n=26; placebo n=14)
- Follow-up
- 90 days
- Centers
- 37
- Countries
- United States, Canada
Primary Outcome
Definition: Partial (TIMI 2) or complete (TIMI 3) recanalization of the target M1 or M2 MCA at 120 minutes after initiation of infusion.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 14.3% (2/14) | 57.7% (15/26) | - | 0.017 |
Limitations & Criticisms
- The trial was terminated early by the sponsor, resulting in a small sample size that was underpowered to detect differences in clinical outcomes or definitively assess safety.
- The confounding effect of the concomitant intravenous heparin, particularly the high-dose regimen used initially, complicated the interpretation of both efficacy and safety results.
- The patient population was highly selected due to stringent inclusion/exclusion criteria; only 46 of 1314 screened patients were randomized, which may limit the generalizability of the findings.
Citation
Stroke. 1998;29:4-11.