Background Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Methods In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disease characterized by hemolysis and thrombosis. Many patients with PNH use C5-inhibitors (i.e., eculizumab/ravulizumab) to control their symptoms. Although C5-inhibition prevents intravascular hemolysis (IVH), it fails to prevent extravascular hemolysis (EVH). Because of persistent EVH, up to 72% of eculizumab-treated patients remain anemic, and up to 36% require at least one transfusion per year. Pegcetacoplan (PEG), a C3-inhibitor recently approved by the US FDA to treat adults with PNH, controls IVH and prevents EVH. Studies of PEG treatment in patients with PNH that remained anemic despite eculizumab treatment demonstrated that PEG was superior to eculizumab in achieving improvements in hemoglobin (Hb) levels (Hillmen P, et al., N Engl J Med, 2021 384 (11):1028-1037). Additionally, two early phase open-label trials demonstrated the efficacy of PEG in complement-inhibitor naïve patients with PNH (Wong RS, et al., Blood, 2020 136 [Supplement 1]). Aims: To present results from the Phase 3 PRINCE study (NCT04085601), a multicenter, randomized, open-label, controlled study evaluating the efficacy and safety of PEG compared to standard of care (SOC; excluding complement-inhibitors) in complement-inhibitor naïve patients with PNH. Methods: Fifty-three adult (≥18 years old), complement-inhibitor naïve (no complement-inhibitor treatment [i.e., eculizumab/ravulizumab] within 3 months prior to screening) patients with PNH and Hb levels below the lower limits of normal (males: ≤13.6 g/dL; females: ≤12.0 g/dL), and lactate dehydrogenase (LDH) levels ≥1.5 times the upper limit of normal (1.5x ULN; ≥339 U/L) were enrolled. Patients were randomized 2:1 to receive PEG (1080 mg subcutaneously twice weekly [n=35]) or SOC (excluding complement-inhibitors eculizumab/ravulizumab [n=18]) through Week 26. Patients on SOC had the option to switch to the PEG group if their Hb decreased by ≥2 g/dL from baseline. Co-primary endpoints were Hb stabilization (avoidance of a >1 g/dL decrease in Hb levels in the absence of transfusions) and change from baseline (CFB) in LDH level from baseline to Week 26. Secondary endpoints included CFB in Hb levels, transfusion avoidance (defined as the proportion of subjects who did not require a transfusion through Week 26), and the incidence of adverse events (AEs). Statistical analyses were performed using the Cochran-Mantel-Haenszel test and ANCOVA model. Results: PEG was superior to SOC in both co-primary endpoints. Hb stabilization was achieved by 85.7% (n=30) of PEG-treated patients and 0.0% of SOC patients through Week 26 (p<0.0001). PEG-treated patients demonstrated superior reductions in mean LDH levels from baseline to Week 26 compared to SOC patients (least-squares mean CFB: PEG, -1870.5 U/L; SOC, -400.1 U/L; p<0.0001), and mean LDH levels in PEG-treated patients at Week 26 (mean level: 204.6 U/L) were below the ULN for LDH (226.0 U/L). PEG was also superior to SOC in the secondary endpoints: mean CFB in Hb levels (least-squares mean CFB: PEG, 2.9 g/dL; SOC, 0.3 g/dL; p=0.0019; Week 26 mean Hb: PEG, 12.8 g/dL; SOC, 9.8 g/dL) (Figure) and transfusion avoidance (PEG, 91.4%, n=32; SOC, 5.6%, n=1; p<0.0001). Serious AEs were reported by 8.7% (n=4) of PEG-treated patients and 16.7% (n=3) of SOC patients through Week 26. Two deaths (PEG, 2.9%, n=1, septic shock related to medullary aplasia; SOC, 5.6%, n=1, respiratory failure), both deemed unrelated to treatment, occurred. No events of meningitis or thrombosis were reported in either group. The most common AEs reported during the study were injection site reaction (PEG, 30.4%, n=14; SOC, 0.0%), hypokalemia (PEG, 13.0%, n=6; SOC, 11.1%, n=2), and fever (PEG, 8.7%, n=4; SOC, 0.0%). There were no AEs leading to discontinuation of PEG. Conclusions: Patients with PNH that were naïve to complement-inhibitor treatment demonstrated meaningful hematological and clinical improvements following 26 weeks of PEG treatment. The safety profile of PEG was similar to previous study results and represent a favorable risk-benefit profile. These results provide evidence for the safety and efficacy of PEG treatment in complement-inhibitor naïve patients with PNH. Figure 1 Figure 1. Disclosures Wong: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis Pharmaceuticals: Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Al-Adhami: Apellis Pharmaceuticals: Current Employment. Ajayi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Alvarenga: Apellis Pharmaceuticals: Consultancy. Deschatelets: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Francois: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Grossi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response to or intolerance of a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for 3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate efficacy and safety of pegcetacoplan versus control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor-naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomized and stratified based on their number of transfusions (<4, ≥4) 12 months before screening. Patients received pegcetacoplan 1080 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary endpoints were hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n=35) or control (n=18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1% [95% CI: 57.2, 89.0]; P <0.0001) and change from baseline in LDH (least-square mean change: pegcetacoplan, -1870.5 U/L; control -400.1 U/L; difference, -1470.4 U/L [95% CI: -2113.4, -827.3]; P <0.0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor-naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT04085601.

No abstract

No abstract