1. In this phase three open-label randomized trial, concizumab prophylaxis reduced the annualized bleeding rate in patients with hemophilia with inhibitors as compared to placebo control.
2. While overall and serious adverse events were not significantly different between control and concizumab groups, the trial was temporarily suspended due to nonfatal thromboembolic events in three patients receiving concizumab and then restarted with protocol modifications.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Hemophilia A and B are commonly treated with intravenous clotting factor concentrates. This approach is associated with several challenges in children, as it requires repeated venipuncture or central venous access that can lead to complications such as infections and thrombosis. Additionally, patients can develop neutralizing antibodies against clotting factors that limit treatment effectiveness. Concizumab is a bypass agent that directly targets coagulation pathways independent of clotting factors. In this phase three open-label randomized trial, patients over the age of 12 with hemophilia A or B with inhibitors and a prescription for a bypass agent were split into randomized and nonrandomized groups. The randomized group was randomized in a 1:2 ratio to control (group one; no prophylaxis) and concizumab prophylaxis for at least 32 weeks (group two; prophylaxis). The nonrandomized group consisted of patients who were already receiving concizumab (group three) as well as patients already with a prescription for a bypass agent with patients receiving on-demand treatment (group four). For the primary outcome of the number of treated spontaneous and traumatic bleeding episodes, group two had significantly lower annualized rates compared to group one. For safety, the most frequently reported adverse events include arthralgia, injection-site erythema, and upper respiratory tract infection. The rate of serious adverse events was not significantly different between groups. Patient-reported outcomes of bodily pain and physical functioning were not significantly different between groups. As a limitation, the trial uses an open-label design that can introduce biases. The effect of treatment pause cannot be entirely accounted for.
Click to read the study in NEJM
In-Depth [randomized controlled trial]: In this phase three open-label randomized trial, bleeding prophylaxis with concizumab was evaluated in patients with hemophilia A or B with inhibitors over the age of 12 who had a prescription for a bypass agent. Patients were randomly assigned to receive no prophylaxis (group one; n=19) or prophylaxis with concizumab (n=33). Group three were patients transferred from another clinical trial who were already receiving concizumab (n = 27) and group four were additional patients who were receiving prophylaxis treatment at screening (n=60). Because of safety concerns, the trial was paused and subsequently restarted with an altered protocol consisting of a loading dose and dose-adjustment period. For the primary outcome, group two had significantly lower estimated mean annualized rates of treated spontaneous and traumatic bleeding episodes compared to group one (rate ratio, 0.14; 95% Confidence Interval [CI], 0.07 to 0.29). In all groups that received concizumab prophylaxis (groups two, three, and four), the median annualized rate of the primary outcome was zero (interquartile range, 0.0 to 3.3), and they were more likely to occur within the first 24 weeks. Patients (26%) developed antibodies to concizumab and most were at low titers. Groups two, three, and four were included in the safety analysis. The most frequently occurring adverse events were arthralgia, injection-site erythema, and upper respiratory tract infection (all≤10%). Two patients receiving concizumab died during the treatment pause. Two hypersensitivity-type reactions occurred in patients receiving concizumab, leading to permanent discontinuation. For patient-reported outcomes, there were no significant differences between groups one and two for bodily pain or physical functioning scores 36-Item Short-Form Health Survey, version 2, but patients preferred concizumab treatment compared to their previous treatment (93%). In summary, this study suggests that concizumab prophylaxis reduces the bleeding rate in patients with hemophilia with inhibitors.
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