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PROACT

PROACT: A Phase II Randomized Trial of Recombinant Pro-Urokinase by Direct Arterial Delivery in Acute Middle Cerebral Artery Stroke

Year of Publication: 1998

Authors: Gregory J. del Zoppo, MD; Randall T. Higashida, MD; Anthony J. Furlan, ..., DSc; and the PROACT Investigators

Journal: Stroke

Citation: Stroke. 1998;29:4-11.

Link: https://www.ahajournals.org/doi/pdf/10.1161/01.STR.29.1.4

Clinical Question

To test the safety and recanalization efficacy of intra-arterial delivery of recombinant pro-urokinase (rpro-UK) compared to placebo in patients with acute ischemic stroke caused by an angiographically documented M1 or M2 middle cerebral artery (MCA) occlusion, treated within 6 hours of symptom onset.

Bottom Line

Intra-arterial infusion of 6 mg of rpro-UK with concomitant heparin resulted in a significantly higher rate of MCA recanalization compared to placebo with heparin. The frequency of intracranial hemorrhage, while not statistically different for symptomatic events, was a concern and appeared to be 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 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.
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.

      

Design

Study Type: Phase II, randomized, double-blind, placebo-controlled, multicenter trial

Randomization: 1

Blinding: Double-blind (patients, investigators, examining physicians, and Core Neuroradiology Facility)

Enrollment Period: February 1994 to February 1995

Follow-up Duration: 90 days

Centers: 37

Countries: United States, Canada

Sample Size: 40

Analysis: The primary efficacy outcome was based on the 40 patients who completed treatment (26 rpro-UK, 14 placebo). Outcomes were compared using Fisher's exact test.

Inclusion Criteria

New onset of focal neurological signs in the MCA distribution
Treatment initiated within 6 hours of symptom onset
National Institutes of Health Stroke Scale (NIHSS) score of ≥4 (except for isolated aphasia or hemianopsia)
Age 18 to 85 years
Angiographically confirmed M1 or M2 MCA occlusion (TIMI grade 0 or 1)

Exclusion Criteria

NIHSS score >30 or coma
Suspected lacunar stroke or minor stroke symptoms
Seizure at stroke onset
Evidence or history of intracranial hemorrhage
Sustained blood pressure >180/100 mm Hg
Recent surgery or trauma (within 30 days)
Oral anticoagulation with an International Normalized Ratio (INR) >1.5

Arms

Field	Control	rpro-UK + Heparin
Intervention	Intra-arterial infusion of saline placebo over 120 minutes into the proximal face of the thrombus. All patients also received a 4-hour infusion of intravenous heparin.	Intra-arterial infusion of 6 mg of recombinant pro-urokinase (rpro-UK) over 120 minutes into the proximal face of the thrombus. All patients also received a 4-hour infusion of intravenous heparin.
Duration	2 hours	2 hours

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Partial (TIMI 2) or complete (TIMI 3) recanalization of the target M1 or M2 MCA at 120 minutes after initiation of infusion.	Primary	14.3% (2/14)	57.7% (15/26)	43.41%	0.017
Primary Safety Outcome: Hemorrhagic transformation causing neurological deterioration within 24 hours.	Secondary	7.1% (1/14)	15.4% (4/26)		0.64
All hemorrhagic transformation within 24h	Adverse	7.1% (1/14)	42.3% (11/26)		0.030
Mortality at 90 days	Adverse	42.9% (6/14)	26.9% (7/26)		0.48

Subgroup Analysis

The study analyzed outcomes based on heparin dose. In the rpro-UK group, a high-heparin regimen was associated with a higher recanalization rate (81.8% vs. 40.0% with low heparin) and a higher rate of any hemorrhagic transformation at 24 hours (72.7% vs. 20.0% with low heparin).

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.

Funding

Abbott Laboratories

Based on: PROACT (Stroke, 1998)