Patient and Clinical Experience on Concizumab Clinical Trial: A Case Study

Background: The patient is an adolescent with severe hemophilia B who was enrolled in Novo Nordisk concizumab clinical trial NCT04082429 (explorer8) following completion of the non-interventional study NCT03741881 (explorer6). At the start of the non-interventional study, the patient had three reported target joints and one target joint remaining at the time of enrollment in the clinical trial. Annualized bleed rate (ABR) in the non-interventional study was 7.5 and 50.6 during the clinical trial. Of the total bleeds, over 23 anatomical areas were reported during the clinical trial, 28.6% of the bleeds came from the known target joint. The patient's physical activities changed during the non-interventional study due to the COVID-19 lockdown, and they were possibly less active during the study period with sport activity rated as low to moderate risk. During the clinical trial, the patient was physically active, engaging in ball hockey and cross-country running. Sport activity was rated as moderate risk and moderate to high risk at baseline and week 28 of the clinical trial respectively. The patient's concizumab dose was 0.25 mg/kg. The maintenance dose was initiated on week 4 based on a concizumab exposure of 97.9 ng/mL. Prior to explorer8, the patient was intensely treated with daily BeneFIX® and Rebinyn® prophylaxis during explorer6, but both FIX standard and extended half-life treatment failed to prevent bleeding episodes. Key Clinical Question: What factors should be considered when determining whether a patient should be withdrawn from a clinical trial? Clinical Approach: Throughout the clinical trial, the investigator discussed withdrawal from the study because of an increase in the number of bleeding episodes; however, the patient remained in the clinical trial as the patient and their family preferred concizumab over previous prophylaxis regimens. The patient reported on several occasions that they felt better despite the increased number of bleeding episodes. The patient reported that while on concizumab, the bleeding episodes were easier to treat, required shorter duration of treatment, and had less impact on the patient's daily life. The patient had concizumab plasma concentrations around or below 100 ng/mL except for the first measurement after initiating treatment with concizumab and had an increase in free TFPI over time. No response in thrombin generation was observed. It was not until a biological explanation behind the increase in bleeding episodes was available that the patient and family agreed to withdraw from the clinical trial. Conclusion: This case study demonstrates a patient who was difficult to treat with limited response to both FIX and concizumab. This case also raises several questions including: 1) Should the investigator have insisted that the patient be removed from the clinical trial before the biological data became available? 2) Is there something about concizumab that made it easier to treat bleeds? This case demonstrates that we may have more to learn from our patients on why they choose to participate and/or stay on clinical trials. Disclaimer: Novo Nordisk had no influence on the content of the abstract. The studies explorer6 and 8 are sponsored by Novo Nordisk.