Phase 2, randomized, open-label study on catheter-directed thrombolysis with plasmin versus rtPA and placebo in acute peripheral arterial occlusion

Abstract

Background: Patients with acute peripheral arterial occlusion (aPAO) are candidates for operative thrombectomy, bypass, or catheter-directed thrombolysis (CDT) using a plasminogen activator. Human plasma-derived plasmin may offer another CDT option. Objectives: To evaluate the efficacy, safety, and tolerability of two intrathrombus delivery methods and two doses of plasmin compared with recombinant tissue plasminogen activator (rtPA) and placebo in patients with aPAO. Patients/methods: This was a phase 2, randomized, open-label study of intra-arterial CDT of plasmin in patients with aPAO. The study used infusion catheters with or without balloon occlusion (BOC) to evaluate 150 mg plasmin (2 and 5 h post-infusion) and 250 mg plasmin (5 h post-infusion). The efficacy of plasmin, rtPA and placebo was assessed. Results: One hundred and seventy-four subjects were enrolled. Overall, the thrombolytic efficacy (>50% thrombolysis) was 59% (58/99) for 150 mg plasmin without BOC, which is comparable to 89% (8/9) for rtPA without BOC (p = 0.149) and 40% (2/5) for placebo control (p = 0.648). The thrombolytic efficacy was 33% of the 250 mg plasmin group. There was no difference (p > 0.999) in thrombolytic efficacy with BOC (59%, 58/99) or without BOC (59%, 17/29). Plasmin-treated groups experienced treatment-emergent adverse events (TEAEs) at 71% (76/107) without BOC and 63% (24/38) with BOC; 78% (7/9) of the rtPA-treated group and 89% (8/9) of the placebo group had TEAEs. Serious AEs (SAEs) occurred in 29% (31/107) of the 150 mg plasmin group without BOC and 24% (9/38) with BOC. No SAEs occurred in the 250 mg plasmin group. Conclusions: Plasmin demonstrated less bleeding during catheter-directed administration at 150 mg and 250 mg doses compared to rtPA. BOC utilization did not improve efficacy. CDT with plasmin has a potential thrombolytic benefit in patients presenting with aPAO. ClinicalTrials.gov Identifier: NCT01222117.

Keywords: Arterial occlusive disease; ischemia; peripheral arterial disease; plasmin; thrombolytic therapy.

Figures

Figure 1.

Study schema. Abbreviations. BOC, balloon occlusion catheter; rtPA, recombinant tissue plasminogen activator. aThere was no 2-h arteriogram for blinded rtPA treatment group E or blinded placebo control group F. bThere was no 5-h arteriogram for plasmin groups D, H, or J. cPost-intervention assessments were required for all treatment groups. Post-intervention arteriograms were required post-angioplasty. Any additional post-intervention arteriograms, if performed, were collected. Treatment group A: 5-h infusion at 10 mL/h, 150 mg plasmin in 75 mL, pulse, possible repositioning after 2-h arteriogram without BOC. Treatment group B: 5-h infusion at 15 mL/h, 150 mg plasmin in 75 mL, pulse, possible repositioning after 2-h arteriogram without BOC. Treatment group C: 5-h infusion (30 mL/h), 150 mg plasmin in 150 mL, pulse, possible repositioning after 2-h arteriogram without BOC. Treatment group D: 2-h infusion at 35 mL/h, 150 mg plasmin in 75 mL, pulse, without BOC. Treatment group E: the rtPA dose, volume, and infusion rate were administered according to the clinical judgment of the investigator. Placebo control group F: the placebo volume matched the equivalent rtPA volume according to the clinical judgment of the investigator. Treatment group G: 5-h infusion at 60 mL/h, 150 mg plasmin in 300 mL, no pulse, no repositioning without BOC Treatment group H: 2-h infusion at 75 mL/h, 150 mg plasmin in 50 mL, no pulse, without BOC. Treatment group I: 5-h infusion at 30 mL/h, 150 mg plasmin in 150 mL, no pulse, with BOC. Treatment group J: 2-h infusion at 35 mL/h, 150 mg plasmin in 70 mL, no pulse, with BOC. Treatment group M: 5-h infusion at 30 mL/h, 250 mg plasmin in 150 mL, no pulse, with BOC. NOTE: Plasmin groups K (250 mg plasmin, 5-h infusion at 30 mL/h) and L (250 mg plasmin, 15-h infusion at 30 mL/h) were never implemented and, thus, not included in this study schema.

Figure 2.

Subject disposition. Abbreviations. BOC, balloon occlusion catheter; rtPA, recombinant tissue plasminogen activator. Study was conducted from December 9, 2010 through September 3, 2014 in 43 study centers located in 12 countries (Belgium, Bulgaria, Czech Republic, Germany, India, Peru, Poland, Romania, Serbia, Slovakia, Ukraine, and the US). A total of 174 subjects were randomized into the study; 67 subjects were screen failures. There were 107 subjects who received 150 mg plasmin without BOC (treatment groups A–D, G, and H), 42 subjects received 150 mg plasmin with BOC (treatment groups I and J), six subjects received 250 mg plasmin with BOC (treatment group M), nine subjects in the rtPA treatment group E, and 10 subjects in the placebo control treatment group F. aOne subject in placebo control group F was not dosed.

Figure 3.

Percentage of subjects who achieved greater than 50% thrombolysis. p-values indicate comparisons of the combined ABCDGH group (plasmin-treated) vs group E (rtPA-treated) and the combined ABCDGH group (plasmin-treated) vs group F (placebo control).

Figure 4.

Plasma fibrinogen concentrations normalized to baseline value across all visits in plasmin-treated groups without balloon occlusion catheter. p-values indicate comparisons of the combined ABCDGH group (plasmin-treated, circle symbol) vs group E (rtPA-treated, square symbol) and the combined ABCDGH group (plasmin-treated, circle symbol) vs group F (placebo control, cross symbol). The superscript letter on each p-value indicates the group to which that p-value belongs.