First-in-Human Phase 1 Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of DISC-0974, an Anti-Hemojuvelin Antibody, in Healthy Participants.

Pathologic elevations in hepcidin, a key regulator of iron homeostasis, contribute to anemia of inflammation in chronic disease. DISC-0974 is a monoclonal antibody that binds to hemojuvelin and blocks bone morphogenetic protein signaling, thereby suppressing hepcidin production. Reduction of systemic hepcidin levels is predicted to increase iron absorption and mobilize stored iron into circulation, where it may be utilized by red blood cell (RBC) precursors in the bone marrow to improve hemoglobin levels and to potentially alleviate anemia of inflammation. We conducted a first-in-human, double-blind, placebo-controlled, single-ascending dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of DISC-0974 in healthy participants. Overall, 42 participants were enrolled and received a single dose of placebo or DISC-0974 at escalating dose levels (7-56 mg), administered intravenously (IV) or subcutaneously (SC). DISC-0974 was well tolerated, with a safety profile comparable to that of placebo. Pharmacokinetic data was dose and route related, with a terminal half-life of approximately 7 days. The bioavailability of SC dosing was ∼50%. Pharmacodynamic data showed dose-dependent decreases in serum hepcidin, with reductions of nearly 75% relative to baseline at the highest dose level tested, and corresponding increases in serum iron in response to DISC-0974 administration. Dose-dependent changes in serum ferritin and hematology parameters were also observed, indicating mobilization of iron stores and downstream effects of enhanced hemoglobinization and production of RBCs. Altogether, these data are consistent with the mechanism of action of DISC-0974 and support the selection of a biologically active dose range for evaluation in clinical trials for individuals with anemia of inflammation.

Development and Content Validation of Novel Patient-Reported Outcome Measures to Assess Disease Severity and Change in Patients with Erythropoietic Protoporphyria: The EPP Impact Questionnaire (EPIQ).

Purpose: Erythropoietic protoporphyria (EPP), a rare inherited disorder, presents in early childhood with severe, painful phototoxicity, with significant impacts on health-related quality of life (HRQoL). Previous studies have not captured all concepts important to patients. Therefore, this study sought to develop a novel, comprehensive, and content valid patient-reported outcome (PRO) measure to assess the efficacy of new therapies. Patients and Methods: Qualitative interviews were conducted with EPP participants and clinical experts to obtain views on concepts relevant to patients. Results informed the development of novel PROs, which were debriefed during subsequent combined concept elicitation and cognitive debriefing interviews. Results: Twenty-three interviews were conducted with 17 adults and 6 adolescents with EPP. Concept elicitation revealed that participants experienced many symptoms with significant variability. The most common were burning, pain, swelling, and tingling. Tingling was the most common prodromal symptom, while burning was the most bothersome, and pain was the worst full reaction symptom. Participants reported being negatively impacted in their ability to do daily activities, and social and emotional functioning. Many reported impacted ability to work and be productive at their job. Participants reviewed and completed the newly developed PRO measures assessing full reactions and ability to do activities, as well as items to assess severity and change in severity of prodromal symptoms, full reactions, and EPP overall. All measures were found to be comprehensive, clear, and relevant. Conclusion: PRO measures are needed to assess important aspects of HRQoL and evaluate therapeutic response. These PRO measures are unique in assessing overall severity and change in EPP.

Development and content validation of a sunlight exposure diary in patients with erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria is a rare, inherited disorder presenting in early childhood with severe, painful phototoxicity. EPP has significant impacts on health-related quality of life, though there is variable disease severity. Accurately capturing how much time individuals with EPP can spend outdoors before they develop symptoms is critical to understanding HRQoL and measuring therapeutic response. Therefore, the goal of this study was to develop a comprehensive and content valid sun exposure diary to assess the efficacy of new therapies in individuals with EPP. METHODS: Qualitative interviews were conducted with adult and adolescent EPP participants, as well as five clinical experts, to obtain their input on the content of an existing sun exposure diary. Revisions to the diary were made based on evidence generated in cognitive debriefing interviews analyzed in eight consecutive groups of EPP participant. RESULTS: Interviews were conducted with 17 adults and 6 adolescents with EPP. The average age of adults was 40 years and of adolescents was 14 years. Clinical experts thought the original diary needed clarification on the description of symptoms, how time outdoors was captured, and the distinction between direct vs. indirect sunlight. Participants with EPP also noted these items needed revision, and that the distinction between prodromal symptoms and full reaction symptoms should be clarified. In the final diary version, participants with EPP found most items to be clear and easy to complete/think about. Seventy-six percent of participants (13/17) asked thought the diary was easy to complete. The remainder thought the majority of the diary was easy to complete with the exception of select questions. CONCLUSIONS: Evaluating a new treatment for EPP requires accurately capturing time in sunlight and symptoms in this unique disorder. The newly developed sun exposure diary is content valid and can be used to assess important aspects of symptoms and daily life and therefore evaluate clinically meaningful therapeutic response.

Clinical predictors of postoperative hemoglobin drift.

BACKGROUND: The decision to transfuse red blood cells in surgical patients should be based on multiple clinical variables, rather than on isolated hemoglobin (Hb) measurements alone. An important but often unrecognized clinical variable is the postoperative downward drift in Hb concentration (Hb drift), but the etiology, predictors, and time course of Hb drift are not well understood. STUDY DESIGN AND METHODS: Data were retrospectively collected for patients who did not receive postoperative transfusion. Initially, 11 common surgical procedures from one institution (n=3179) were compared to assess clinical predictors of Hb drift. Data were analyzed in detail for two procedures associated with a large Hb drift (Whipple [n=82] and lumbar spinal fusion [n=74]), to determine the clinical predictors and temporal pattern of postoperative Hb drift. RESULTS: Surgical procedures with greater intraoperative intravenous (IV) fluid and blood requirements had greater postoperative Hb drift. The maximum Hb drifts after the Whipple and spinal fusion procedures were -2.5 ± 1.1 g/dL (occurring on Day 4, p<0.0001) and -1.8 ± 2 g/dL (on Day 3, p<0.0001), respectively. After the nadir, a 0.6 g/dL upward Hb drift (p<0.0001) occurred after both procedures, resulting in a total drift after Whipple and spinal fusion of -1.9 ± 1.2 g/dL (p<0.0001) and -1.3 ± 1.2 g/dL (p<0.0001), respectively. Type of surgery (p=0.03), intraoperative blood loss (p=0.003), and a positive perioperative fluid balance (p=0.0008) were independent predictors of Hb drift. CONCLUSIONS: Postoperative Hb drift was greater after surgical procedures with greater intraoperative IV fluid and blood requirements. Recognition of Hb drift may be an important facet of perioperative patient blood management.

Optimizing preoperative blood ordering with data acquired from an anesthesia information management system.

BACKGROUND: The maximum surgical blood order schedule (MSBOS) is used to determine preoperative blood orders for specific surgical procedures. Because the list was developed in the late 1970s, many new surgical procedures have been introduced and others improved upon, making the original MSBOS obsolete. The authors describe methods to create an updated, institution-specific MSBOS to guide preoperative blood ordering. METHODS: Blood utilization data for 53,526 patients undergoing 1,632 different surgical procedures were gathered from an anesthesia information management system. A novel algorithm based on previously defined criteria was used to create an MSBOS for each surgical specialty. The economic implications were calculated based on the number of blood orders placed, but not indicated, according to the MSBOS. RESULTS: Among 27,825 surgical cases that did not require preoperative blood orders as determined by the MSBOS, 9,099 (32.7%) had a type and screen, and 2,643 (9.5%) had a crossmatch ordered. Of 4,644 cases determined to require only a type and screen, 1,509 (32.5%) had a type and crossmatch ordered. By using the MSBOS to eliminate unnecessary blood orders, the authors calculated a potential reduction in hospital charges and actual costs of $211,448 and $43,135 per year, respectively, or $8.89 and $1.81 per surgical patient, respectively. CONCLUSIONS: An institution-specific MSBOS can be created, using blood utilization data extracted from an anesthesia information management system along with our proposed algorithm. Using these methods to optimize the process of preoperative blood ordering can potentially improve operating room efficiency, increase patient safety, and decrease costs.

A novel method of data analysis for utilization of red blood cell transfusion.

BACKGROUND: A necessary component of an effective blood management program is the accurate and comprehensive collection and analysis of blood utilization data. This study describes innovative methods for analyzing and presenting data for red blood cell (RBC) utilization that compare hemoglobin (Hb) transfusion triggers and targets to those representing the restrictive transfusion strategy advocated by previous large outcome studies. STUDY DESIGN AND METHODS: From one institution, blood utilization data for 134,456 patients, 23,559 of whom were transfused with RBCs, were analyzed. Hb triggers and targets for transfused patients were plotted and graphically compared to the trigger and target ranges from previously published randomized clinical trials. RESULTS: Nine hospital services with the highest transfusion rates were selected for analysis. The service with the highest Hb trigger and target was further analyzed by comparing transfusion thresholds for individual providers. Differences among services and among individual providers for mean Hb transfusion triggers and targets were significant (up to 1.5 g/dL, p < 0.0001). The variation between the 10th and 90th percentiles for both trigger and target was also significant (up to 3 g/dL, p < 0.0001). If a restrictive transfusion strategy were implemented, the need for transfusion would be reduced or eliminated in 10% to 50% of patients, depending on the service and the individual provider. CONCLUSION: By using these methods for analyzing and presenting RBC utilization data, opportunities can be identified for blood conservation, and educational efforts can be directed toward the appropriate individual hospital services and providers.

Variability in blood and blood component utilization as assessed by an anesthesia information management system.

BACKGROUND: Data can be collected for various purposes with anesthesia information management systems. The authors describe methods for using data acquired from an anesthesia information management system to assess intraoperative utilization of blood and blood components. METHODS: Over an 18-month period, data were collected on 48,086 surgical patients at a tertiary care academic medical center. All data were acquired with an automated anesthesia recordkeeping system. Detailed reports were generated for blood and blood component utilization according to surgical service and surgical procedure, and for individual surgeons and anesthesiologists. Transfusion hemoglobin trigger and target concentrations were compared among surgical services and procedures, and between individual medical providers. RESULTS: For all patients given erythrocytes, the mean transfusion hemoglobin trigger was 8.4 ± 1.5, and the target was 10.2 ± 1.5 g/dl. Variation was significant among surgical services (trigger range: 7.5 ± 1.2-9.5 ± 1.1, P = 0.0001; target range: 9.1 ± 1.2-11.3 ± 1.4 g/dl, P = 0.002), surgeons (trigger range: 7.2 ± 0.7-9.8 ± 1.0, P = 0.001; target range: 8.8 ± 0.9-11.8 ± 1.3 g/dl, P = 0.001), and anesthesiologists (trigger range: 7.2 ± 0.8-9.6 ± 1.2, P = 0.001; target range: 9.0 ± 0.9-11.7 ± 1.3 g/dl, P = 0.0004). The use of erythrocyte salvage, fresh frozen plasma, and platelets varied threefold to fourfold among individual surgeons compared with their peers performing the same surgical procedure. CONCLUSIONS: The use of data acquired from an anesthesia information management system allowed a detailed analysis of blood component utilization, which revealed significant variation among surgical services and surgical procedures, and among individual anesthesiologists and surgeons compared with their peers. Incorporating these methods of data acquisition and analysis into a blood management program could reduce unnecessary transfusions, an outcome that may increase patient safety and reduce costs.