Human plasma-derived alpha1 -proteinase inhibitor in patients with new-onset type 1 diabetes mellitus: A randomized, placebo-controlled proof-of-concept study.

BACKGROUND: While circulating levels of alpha1 -proteinase inhibitor (alpha1 -PI) are typically normal, antiprotease activity appears to be compromised in patients with Type 1 diabetes mellitus (T1DM). Because alpha1 -PI [human] (alpha1 -PI[h]) therapy can inhibit pro-inflammatory mediators associated with ß-cell destruction and reduced insulin production, it has been proposed for T1DM disease prevention. The aim of this study was to evaluate safety, tolerability, and efficacy of intravenous (IV) alpha1 -PI[h] in preserving C-peptide production in newly diagnosed T1DM patients. PARTICIPANTS: Seventy-six participants (aged 6-35 years) were randomized at 25 centers within 3 months of T1DM diagnosis. METHODS: A Phase II, multicenter, partially blinded, placebo-controlled, proof-of-concept study evaluating four dosing regimens of alpha1 -PI[h] (NCT02093221, GTI1302): weekly IV infusions of either 90 or 180 mg/kg, each for either 13 or 26 weeks. Safety and efficacy were monitored over 52 weeks with an efficacy evaluation planned at 104 weeks. The primary efficacy endpoint was change from baseline in the 2-h area-under-the-curve C-peptide level from a mixed-meal tolerance test at 52 weeks. A battery of laboratory tests, including inflammatory biomarkers, constituted exploratory efficacy variables. RESULTS: Infusions were well tolerated with no new safety signals. All groups exhibited highly variable declines in the primary outcome measure at 52 weeks with no statistically significant difference from placebo. Interleukin-6 (IL-6) was reduced from baseline in all alpha1 -PI treatment groups but not the placebo group. CONCLUSION: Pharmacologic therapy with alpha1 -PI[h] is safe, well tolerated, and able to reduce IL-6 levels; however, due to variability in the efficacy endpoint, its effects on preservation of C-peptide production were inconclusive.

Immune globulin subcutaneous, human - klhw 20% for primary humoral immunodeficiency: an open-label, Phase III study.

Aim: This prospective, Phase III study assessed the pharmacokinetics (PK), safety and tolerability of immune globulin subcutaneous, human - klhw 20% solution (IGSC-C 20%) in participants with primary humoral immunodeficiency (PI), compared with immune globulin injection (human), 10% caprylate/chromatography purified (IGIV-C 10%). Patients & methods: About 53 participants enrolled. Total 44 received IGIV-C 10% in the run-in phase and then entered the IV phase (with an additional nine who were already receiving IGIV-C 10% and entered the IV phase directly) for steady-state IV PK assessments. Total 49 entered the SC phase (weekly doses of IGSC-C 20% for ∼24 weeks). The PK profiles of IGIV-C 10% and IGSC-C 20% and their safety and tolerability parameters were compared. Results: At a dose adjustment factor of 1.37, IGSC-C 20% provided comparable (noninferior and bioequivalent) overall total immunoglobulin G exposure to IGIV-C 10% over an equal time interval. About 33 participants reported 79 adverse events during run-in + IV phases; 41 participants reported 141 adverse events during the SC phase, with most being local infusion site reactions. The majority of infusion site reactions were mild to moderate in severity. Conclusion: IGSC-C 20% was bioequivalent to IGIV-C 10% and was well tolerated, with a safety profile comparable with IGIV-C 10%, in this study. Trial registration: ClinicalTrials.gov identifier: NCT02604810.

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

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.

Plasmin (Human) Administration in Acute Middle Cerebral Artery Ischemic Stroke: Phase 1/2a, Open-Label, Dose-Escalation, Safety Study.

BACKGROUND: This phase 1/2a, open-label, multicenter, dose-escalation, safety study describes the first evaluation of plasmin as an intracranial thrombolytic treatment for acute ischemic stroke in the middle cerebral artery. The rationale for intrathrombus administration is that plasmin would bind fibrin inside the targeted clot, protecting it from circulating inhibitors. METHODS: Plasmin was given in escalating doses within 9 hours of stroke onset, and treatment efficacy was determined in 5 patient cohorts (N = 40): cohort 1 (20 mg, .5 mL/min), cohort 2a (40 mg, .05 mL/min), cohort 2b (40 mg, .33 mL/min), cohort 3a (80 mg, .67 mL/min), and cohort 3b (80 mg, .33 mL/min). RESULTS: Plasmin was generally safe at doses as high as 80 mg. No symptomatic intracranial hemorrhage was observed, and the rate of asymptomatic intracranial hemorrhage (12.5%) was consistent with that expected under supportive care. No relationship was observed between the plasmin dose and the incidence or severity of bleeding events, any particular serious adverse events, nor death. Changes in clinical chemistry, hematology, and coagulation parameters following plasmin treatment were unremarkable and unrelated to the dose. Plasmin administration resulted in successful reperfusion of the occluded vessel in 25% of patients across all cohorts, with no relationship between successful perfusion and total plasmin dose but a potential increase in reperfusion with slower infusion rates. CONCLUSIONS: Plasmin treatment of the occluded middle cerebral artery within 9 hours of stroke onset was well tolerated and did notincrease adverse outcomes; however, successful recanalization was achieved in only a limited number of patients.