Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial.

ABSTRACT: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871.

Lower risk of severe hypoglycaemia with insulin glargine 300 U/mL versus glargine 100 U/mL in participants with type 1 diabetes: A meta-analysis of 6-month phase 3 clinical trials.

Severe hypoglycaemia (SH) remains a challenge to people with type 1 diabetes (T1DM), and new-generation basal insulins may improve patient outcomes. This post hoc meta-analysis explored the risk of SH with insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100) in a pooled population with T1DM from three randomized, multicentre, 6-month similarly designed phase 3 trials: EDITION 4, EDITION JP 1 and EDITION JUNIOR. Endpoints included incidence and time to first occurrence of SH. Among 629 and 626 participants randomized to Gla-300 and Gla-100, respectively, glycated haemoglobin reductions were similar. Fewer participants experienced ≥1 SH event with Gla-300 (6.2%) than with Gla-100 (9.3%). From baseline to month 6, the risk of a first SH event was lower with Gla-300: hazard ratio 0.65 [95% confidence interval (CI) 0.44-0.98; stratified log-rank test P = 0.038]. SH event rates were numerically lower with Gla-300 versus Gla-100 from baseline to month 6 [relative risk (RR) 0.80 (95% CI 0.49-1.29); P = 0.356] and baseline to week 8 [RR 0.73 (95% CI 0.37-1.44); P = 0.369]. Thus, Gla-300 demonstrated similar glycaemic control with lower risk of SH versus Gla-100, particularly during the titration period.

Influence of SPECT attenuation correction on the quantification of hibernating myocardium as derived from combined myocardial perfusion SPECT and ¹8F-FDG PET.

BACKGROUND: To evaluate the influence of SPECT attenuation correction on the quantification of hibernating myocardium derived from perfusion SPECT and (18)F-FDG PET. METHODS AND RESULTS: 20 patients underwent rest (99m)Tc-tetrofosmin perfusion SPECT/CT and (18)F-FDG PET/CT. Perfusion images were reconstructed without attenuation correction (NC), with attenuation correction based on the CT from the SPECT/CT (AC_SPECT), and with attenuation correction based on the CT from the PET/CT (AC_PET). Another 56 patients had rest (99m)Tc-tetrofosmin perfusion SPECT and (18)F-FDG PET/CT. Perfusion images were reconstructed as NC and AC_PET. The amounts of hibernating myocardium and scar were quantified with QPS and corresponding AC and NC normative databases. In both cohorts, perfusion in the inferior wall was higher in the AC scans than without AC. Global and regional values for total perfusion deficit (TPD), hibernation and scar areas did not differ between NC, AC_SPECT, and AC_PET scans. In a retrospective evaluation with 7% cut-off of hibernating myocardium as a condition for revascularization, the therapeutic approach would have been altered in 5 of 56 patients, if the AC_PET approach had been used. CONCLUSIONS: AC of SPECT perfusion scans with an attenuation map derived from PET/CT scans is feasible. If AC is unavailable, perfusion scans should be compared to NC normative databases for assessing TPD, hibernation, and mismatch. It should be taken into account that in approximately 10% of the patients, a therapeutic recommendation based on published thresholds for hibernating myocardium would be altered if NC scans were used as compared to AC scans.