A phase 3b, multicenter, open‐label, single‐arm study of roxadustat within a US dialysis organization: The DENALI study

Roxadustat is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). DENALI, a phase 3b study, evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD receiving in‐center or home dialysis.

<6 weeks).Primary efficacy endpoints were proportion of patients with mean hemoglobin (Hb) ≥10.0 g/dL averaged over Weeks 16-24, and mean Hb change from baseline to the average during Weeks 16-24.Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were assessed.
Findings: Of 281 patients screened, 203 were treated and 201 included in the full analysis set.Overall, 166 patients completed the 24-week treatment period and 126 continued into the extension period.Mean baseline Hb was 10.4 g/dL and 82.6% received in-center hemodialysis.Overall, 84.6% of patients achieved a mean Hb ≥ 10.0 g/dL averaged Weeks 16-24.Mean (standard deviation) Hb change from baseline averaged Weeks 16-24 was 0.5 (1.0) g/dL.Prespecified subgroup analyses were consistent with primary analyses.Dosing adherence Yemmie Oluwatosin was associated with AstraZeneca at the time this work was carried out.

INTRODUCTION
2][3] Anemia of CKD is related to decreased erythropoietin production-associated with worsening kidney function-and elevated hepcidin, which impairs dietary iron absorption, an essential component for hemoglobin (Hb) synthesis. 1[6][7][8][9][10] Current treatment for anemia of CKD involves erythropoiesis-stimulating agents (ESAs) such as epoetin alfa and darbepoetin alfa and third-generation ESAs.Iron supplementation is used to treat or manage iron deficiency.][17] Hypoxia-inducible factors (HIFs) are transcription factors regulating expression of genes involved in erythropoiesis and iron metabolism. 18,19HIF activity is regulated by HIF prolyl hydroxylase (HIF-PH), which targets HIFα for degradation under normal oxygen conditions. 18oxadustat is an oral HIF-PH inhibitor, approved to treat anemia of CKD in several regions, including China, Japan, the European Union, and the UK, that stabilizes HIFα, thus promoting erythropoietin synthesis, iron absorption, metabolism, and transport. 16Unlike current standard-of-care injectable ESAs, roxadustat is administered orally.[22][23] Roxadustat's safety and efficacy were evaluated in >13,000 patients with anemia of CKD.Results showed roxadustat effectively increases and maintains Hb. [24][25][26][27] However, the phase three program did not assess the operational characteristics of switching from injectable ESAs to oral roxadustat in dialysis organizations, which are fundamental in delivering dialysis care and are experienced at optimizing anemia management.Assessing the feasibility of converting patients to roxadustat is important for its safe and effective use by incenter and home dialysis providers.The DENALI study assessed the feasibility in terms of safety and efficacy of converting treatment to roxadustat in patients with anemia of CKD on dialysis in a US dialysis organization.

Trial design and oversight
This phase 3b, open-label, single-arm study (NCT04410198) was designed to evaluate roxadustat's effects in increasing and/or maintaining Hb levels inpatients with end-stage kidney disease receiving dialysis, either after conversion from a stable ESA dose or as initial anemia treatment.The study comprised a screening period of ≤6 weeks, a 24-week treatment period, a posttreatment follow-up at 4 weeks, and optional extension treatment for ≤1 year (Figure 1).
Final study protocol and informed consent forms were approved by an Independent Ethics Committee or Institutional Review Board.All patients provided written informed consent.This study was performed in accordance with the ethical principles of the Declaration of Helsinki and the International Council for Harmonization for Good Clinical Practice Guidelines.

Patients
Eligible patients were aged ≥18 years and receiving incenter or home dialysis for kidney failure at a dialysis organization (Fresenius Kidney Care, Waltham, MA, USA).Patients were classified as ESA users, receiving ESAs for ≥6 weeks with a stable dose (per investigator) during the 4 weeks prior to initiating roxadustat, or non-ESA users, with <6 weeks of ESA use prior to initiating roxadustat.Eligibility criteria included screening Hb (≤10 days before initiating roxadustat) 9.0-12.0g/dL (ESA users) or <10.0 g/dL (non-ESA users), ferritin ≥50 ng/mL, transferrin saturation (TSAT) ≥10%, and vascular access of a functioning native arteriovenous (AV) fistula or graft with adequate flow, or permanent tunneled catheter.Full criteria are in the Supplementary Materials.

Treatment
Patients received oral roxadustat tablets, administered by dialysis nurses in-center or patient-administered for home dialysis, three times a week (TIW); if patients required <60 mg/week to maintain Hb level, the frequency was reduced stepwise.For ESA users, the initial dose (range, 70-200 mg) was based on average ESA dose in the 8 weeks prior (Table S1), using a dose conversion previously assessed in the phase three program.Roxadustat was started 2 weeks after stopping ESAs.If the calculated conversion dose exceeded 3.0 mg/kg, the next lower dose was used.For non-ESA users, the initial dose was 70 mg (body weight <100 kg) or 100 mg (≥100 kg).Dose evaluations/adjustments were allowed every 4 weeks, or more frequently if Hb rise was >2.0 g/dL within 4 weeks or Hb was >13.0 g/dL (Table S2).
Oral iron supplementation was permitted.IV iron was recommended for patients with ferritin <200 ng/mL and/or TSAT <20% and was administered by the dialysis organization using standardized algorithms.Red blood cell (RBC) transfusion was permitted for rapid anemia correction.Rescue ESA therapy was allowed under specific conditions for ≤1 cycle and was stopped when Hb >9.0 g/dL was achieved or after 4 weeks, whichever came first (Supplementary Materials).Roxadustat was held during rescue ESA therapy.
Permanent roxadustat discontinuation was permitted upon patient/investigator decision, or ≥2 rescue ESA treatments.Prohibited concomitant medications are presented in the Supplementary Materials.

Endpoints
Primary efficacy endpoints were the proportion of patients with mean Hb ≥10.0 g/dL averaged over Weeks 16-24, and mean Hb change from baseline to the average during Weeks 16-24.Baseline Hb was defined as the mean of one Hb level obtained at screening and at predose Day 1. Prespecified subgroup analyses were performed on the primary efficacy endpoints.
Key exploratory efficacy endpoints included the proportion of patients with mean Hb 10.0-12.0g/dL during Weeks 16-24; the proportion of patients with Hb >12.0 or >13.0 g/dL at any time during treatment; the percentage of time with Hb 10.0-12.0g/dL during Weeks 16-24; proportion with mean Hb ≥10.0 g/dL in Weeks 1-8; time to first RBC transfusion; mean IV iron use, serum iron, ferritin, total iron binding capacity, TSAT, and reticulocyte Hb content; dose adherence and adjustments; and the proportion of patients with mean Hb ≥10.0 g/dL averaged during Weeks 16-24 in subgroups based on ESA use.
Safety analyses included the incidence of treatmentemergent adverse events (TEAEs) and treatmentemergent serious adverse events (TESAEs), proportion of F I G U R E 1 Study design.a If a patient required <60 mg/week to maintain hemoglobin (Hb) levels, dose frequency was reduced in a stepwise manner.For patients converting from an erythropoiesis-stimulating agent (ESA), the initial dose of roxadustat was based on the average prescribed ESA dose in the last 8 weeks prior to conversion.If the calculated converted initial dose was >3.0 mg/kg/dose, then the next lower dose step was chosen as the initial dose.Roxadustat treatment was started 2 weeks after stopping ESA.CKD, chronic kidney disease; TESAE, treatment-emergent serious adverse event; TIW, three times a week.
patients with a TEAE of vascular access thrombosis (VAT), proportion of patients with VAT based on vascular access type, time to VAT, laboratory parameters, and vital signs.Preferred terms for VAT are reported in the Supplementary Materials.Events collected after the first dose of study drug up to 28 days after the last dose of study drug were considered treatment emergent.During the extension period only TESAEs were collected.TEAEs were coded using Medical Dictionary for Regulatory Activities, version 24.0.

Statistical analyses
A sample size of approximately 200 patients was determined sufficient to produce a 95% confidence interval (CI) with width of 11.5%, assuming the proportion maintaining Hb ≥ 10.0 g/dL in Weeks 16-24 was ≥80%.The full analysis set (FAS) included all patients who enrolled in the study and provided baseline and ≥1 post-baseline Hb assessment, and was used for efficacy endpoints.The safety population included all patients receiving roxadustat and was used for safety endpoints and roxadustat exposure.
For primary efficacy endpoints, a multiple imputation method was used.Intermittent missing Hb data were imputed only for the FAS using the Markov chain Monte Carlo imputation model, incorporating baseline Hb and available non-missing Hb for each week.Mean Hb change from baseline to average over Weeks 16-24 was presented descriptively using imputed data.
Observed values were used to calculate the proportions of patients with mean Hb 10.0-12.0g/dL during Weeks 16-24, Hb >12.0 or >13.0 g/dL at any time, and the percentage of time with Hb 10.0-12.0g/dL during Weeks 16-24.
The proportions of patients with mean Hb ≥10.0 g/dL during Weeks 1-8 and averaged during Weeks 16-24 were analyzed considering multiple imputation as described above.Rubin's method was used to estimate the proportion of responders (patients with mean Hb ≥ 10 g/dL, following multiple imputation, averaged over Weeks 16-24) and standard errors.
Time to first RBC transfusion was analyzed using the Kaplan-Meier method.

Patients
Overall, 281 patients from nine study sites were screened and 203 enrolled; 201 were included in the FAS and 203 in the safety population.Thirty-seven patients (18.2%) prematurely discontinued, primarily due to death, kidney transplant, and patient withdrawal.Overall, 126 (62.1%) continued into the extension period (Figure 2).
Patient demographics and baseline characteristics are shown in Table 1.Overall, 166 patients (82.6%) received in-center hemodialysis and 35 (17.4%) home dialysis.Mean dialysis vintage was 197.1 weeks overall, 202.1 weeks in ESA users, and 41.1 weeks in non-ESA users.Most patients were White (51.7%) or Black/African American (41.3%), and were ESA users (97.5%), primarily using methoxy polyethylene glycol-epoetin beta (97.5%).Two patients received epoetin alfa, which was stopped ≥10 weeks prior to initiating roxadustat, and were considered non-ESA users.One patient was mis-classified as a non-ESA user and had ≥6 weeks of ESA use, but started roxadustat based on body weight and was included in the non-ESA user analyses.The mean (standard deviation [SD]) baseline Hb was 10.4 (0.8) g/dL.Most patients (55.2%) received a starting roxadustat dose of 70 mg TIW.Fourteen patients (6.9%) had histories of VAT.

Primary Hb endpoints
Roxadustat effectively increased and/or maintained Hb levels during the 24-week treatment period (Figure 3).Mean Hb remained stable for ESA users, and among non-ESA users mean Hb increased during the first 6 weeks before remaining stable.Overall, 170 patients (84.6%) achieved or maintained mean Hb ≥ 10 g/dL, averaged over Weeks 16-24, including five (100%) non-ESA users and 165 (84.2%)ESA users.Mean (SD) Hb change from baseline to average during Weeks 16-24 was 0.5 (1.0) g/dL overall, 1.9 (1.1) g/dL in non-ESA users, and 0.4 (1.0) g/dL in ESA users.

Iron use and rescue therapy
Sixty-six patients (32.8%) used IV iron during the 24 weeks.Figure S2 compares mean monthly IV iron use overall (n = 201) versus patients receiving home dialysis (n = 35).In the overall population, mean monthly IV iron use was 29.3 mg during the first 4 weeks and increased to 73.0 mg during Weeks 21-24 in all patients, but decreased in the home dialysis subgroup to 5.8 mg.Six patients (3.1%) received an RBC transfusion; the incidence rate was 7.5 events/100 patient-exposure-years (PEY; Figure S3).The proportion of patients requiring an RBC transfusion or ESA rescue during Weeks 5-24 was 8.9% (n = 17).

Iron profiles
Mean baseline serum levels were 15.4 μmol/L for iron, 37.1% for TSAT, and 1280.6 μg/L for ferritin (Table 1).Figure 4 shows changes from baseline in reticulocyte Hb content, ferritin, TSAT, and serum iron.The mean Patients who participated in the post-treatment follow-up or completed the end-of-study (EOS) visit refers to the patients who completed the main 24-week treatment or who permanently discontinued from the main 24-week treatment.Patients who participated in the extension treatment period skipped the post-treatment follow-up and EOS visit; only treatment-emergent serious adverse events were collected in the extension treatment period.AE, adverse event; FAS, full analysis set.
reticulocyte Hb content and serum iron remained relatively constant from baseline to Week 24, while mean serum ferritin and TSAT showed small decreases (5%-10%).No changes in iron parameters were statistically or clinically significant.
Twenty-one patients (10.3%) received no dose change, 132 (66.0%) had ≥1 dose increases, 141 (69.5%) had ≥1 dose reductions, and 63 (31.0%) had ≥1 dose holds.Further details are presented in the Supplementary Materials.b ESA use at baseline was defined as any ESA taken where the duration overlaps the ESA baseline window, which was between 28 days prior to enrollment and the date right before the first dose.For patients with more than one ESA type at baseline, the ESA type that was administered immediately before Day 1 was used.Two (1.0%) patients had been on prior epoetin alfa rather than methoxy polyethylene glycol-epoetin beta.These patients received starting roxadustat doses as if non-ESA users based on their baseline weight.

DISCUSSION
DENALI was an open-label, single-arm study evaluating roxadustat for achieving and/or maintaining Hb in patients with kidney failure receiving chronic dialysis in an in-center or home setting.The cohort enrolled was generally consistent with the US dialysis population regarding demographics (age and proportion of females and Black or African American patients), dialysis modality use, and other baseline characteristics, providing a F I G U R E 3 Mean hemoglobin (Hb) during the 24-week study period.Full analysis set.Intermittent missing Hb data were imputed relying on non-missing data from all patients using the Markov chain Monte Carlo imputation model, using baseline Hb and available nonmissing Hb data for each scheduled week.There were 90 and 133 imputed values for the first 8 weeks and Weeks 16-24, respectively.Hb values were censored for 4 weeks if a red blood cell transfusion was administered during the treatment period.Baseline Hb was defined as the mean of available central laboratory Hb values prior to first dose of study medication, including the pre-dose Hb value collected on Day 1.One patient was mis-classified as a non-erythropoiesis-stimulating agent (ESA) user but had a history of ≥6 weeks of ESA use and was included in the non-ESA user analyses.SD, standard deviation.representation of the real-world use of roxadustat in dialysis organizations. 28,29DENALI was unique in the fact that the majority of patients converted to roxadustat from the longer-acting ESA methoxy polyethylene glycolepoetin beta, currently the most utilized ESA in the US dialysis population.We found roxadustat effectively increased and/or maintained Hb levels during the 24-week treatment period.Overall, 85% of patients achieved or maintained mean Hb ≥ 10.0 g/dL averaged over Weeks 16-24.Additionally, 66% of patients maintained mean Hb within the 10.0-12.0g/dL target from Weeks 16-24.The percentage of patients maintaining target Hb levels with roxadustat is similar to that seen in ESA clinical trials. 30,31Dosing adherence was high at 94%.This study suggests that patients receiving dialysis can be successfully treated with roxadustat as demonstrated by maintaining Hb levels and treatment adherence, in both the in-center and home settings.
Mean change in Hb from baseline in DENALI is consistent with previous roxadustat trials. 24,32,33Importantly, comparable improvements and maintenance of Hb were observed between in-center and home dialysis subgroups.These findings suggest patients can be effectively transitioned to roxadustat in the community dialysis setting.
Roxadustat dose adherence was high and dose adjustments were manageable.The proportion of patients who had at least one dose adjustment in this study was approximately 90%, which is similar to the proportions of patients requiring dose modifications with epoetin alfa (91%) and with roxadustat (93%) in the phase three ROCKIES clinical trial (mean duration of exposure of 23.2 months and 20.6 months, respectively). 24Primary reasons for dose changes were protocol-mandated adjustments; similar proportions of patients had dose increases and decreases.Similar trends in dose adjustments were observed in patients undergoing home dialysis.In the majority of patients, the roxadustat dosing algorithm achieved and/or maintained Hb at target.The influences of Hb cycling 34 and the effects of seasonality 35 are also anticipated and can influence the need for dose titration over time.Nonetheless, when considering the time in range for Hb levels within 10-12 g/dL, roxadustat use in the present study appeared consistent with injectable ESAs reported previously.We observed during Weeks 16-24 that patients receiving roxadustat spent 68.5% of the time with Hb levels within 10.0-12.0g/dL.By comparison, in the MIRCERA PASS trial, patients receiving methoxy polyethylene glycol-epoetin beta spent on average 67% of the time with Hb levels within 10.0-12.0g/dL across up to 8 years of follow-up. 36In the phase three ROCKIES clinical trial, increased rates of thrombotic events were seen with roxadustat compared with epoetin alfa, 24 which were associated with a higher rate of Hb increase.In the DENALI study, overshoots in Hb were observed, with 53% and 14% of patients having an Hb level >12.0 or >13.0 g/dL, respectively, at any time.This was, however, not unexpected, as the dose adjustment algorithm did not require a dose hold until Hb was ≥13.0 g/dL.No new safety signals were seen related to thrombotic events with roxadustat in the DENALI study, yet it should be noted that an ESA comparator group was not included and the DENALI study was not powered to assess cardiovascular safety.Alternative roxadustat dosing strategies can be considered in future.
The design of DENALI allowed evaluation of switching patients from injectable ESA to oral roxadustat at a dialysis organization, where dialysis nurses administered roxadustat in-center and managed patient selfadministration for patients undergoing home dialysis.The switch to oral roxadustat was successful and provided suitable maintenance of Hb targets during the conversion period and up to 24 weeks.High adherence rates with roxadustat dosing, manageable dose adjustments, and achievement of Hb target levels support the operational feasibility of administering oral roxadustat in home and in-center dialysis settings.
Anemia therapy in patients with CKD on hemodialysis usually requires concomitant IV iron supplementation to prevent functional iron deficiency.While our findings of overall moderate IV iron use are not consistent with earlier roxadustat studies, 24,26,33,37 there was a substantial decrease in the percentage of patients receiving IV iron during the treatment period (32.8%) compared with baseline (50.7%), as well as a lower mean monthly IV iron dose during the treatment period compared with at baseline.In DENALI, the protocol recommended that IV iron supplementation was considered for ferritin <200 ng/mL in dialysis-dependent patients, which is higher than previous roxadustat studies in dialysis-dependent patients (<100 ng/mL). 24,33The dialysis organization utilized a standardized algorithm that recommends IV iron supplementation to achieve and maintain higher TSAT (30%-50%) and ferritin (800-1200 ng/mL) and advises discontinuation of IV iron in circumstances of high Hb levels, and re-initiation after a Hb decrease; this likely explains the trends in IV iron use observed that reflect practice patterns at the provider.Given the dialysis provider's recommendations on management of iron deficiency utilize more generous targets for IV iron dosing, the results of this study would likely be most generalizable to other dialysis practices using similar IV iron supplementation guidelines.Providers who use lower TSAT and ferritin target thresholds may observe different findings related to iron indices and IV iron dosing with the use of roxadustat.The ferritin levels observed at the central laboratory in this study were consistent with the values for the entire patient population at the dialysis organization (ca.1000 ng/mL).The reticulocyte Hb content and serum iron were maintained throughout the study, while serum ferritin and TSAT values decreased slightly in the overall population.8][39] However, the DENALI study was not specifically designed to assess the impact on iron mobilization and utilization, which are both affected by multiple factors that were not systematically captured during this study.
RBC transfusions are common in patients with anemia of CKD and carry potential risks, such as infection and allosensitization. 40In DENALI, use of transfusions was relatively low (3.1%) and was lower compared with previous roxadustat studies, 24,26,33,37 suggesting that roxadustat may be effective in reducing RBC transfusions.
A primary reason for study discontinuation was kidney transplant (4.4%), which is comparable to previous roxadustat studies. 24Another eight patients (3.9%) missed the end-of-study visit due to a kidney transplant.
Although not an aim of the study, the safety profile of roxadustat was generally consistent with previous roxadustat studies, and no new safety signals were identified. 24,26,33,37,41A number of COVID-19 cases were reported because the study was performed early in the pandemic and when vaccination was not yet widely available.The rate of COVID-19 infections was comparable to rates reported in the literature in similar populations. 42imilarly, a review of the TEAEs of special interest, including myocardial infarction, stroke, seizures, deep vein thrombosis, pulmonary embolism, hypertension, infections, and sepsis, suggested a safety profile that was generally consistent with prior studies. 24,26,27,37,41ENALI was designed to include different types of dialysis patients receiving an ESA at a dialysis organization, while having inclusion and exclusion criteria that ensured appropriate safety in a clinical trial.Despite the inclusion of incident and prevalent dialysis patients, and ESA users and non-ESA users, designed to add to the generalizability of the findings, there was only a small number of incident patients and non-ESA users enrolled, which could be viewed as a limitation.Another study limitation is that DENALI did not contain a control group receiving ESAs; as such, the two treatments could not be directly compared.Also, the use of an open-label, non-blinded design may have increased risk of bias.Nonetheless, this design mimics the real-world conversion from injectable ESA therapy to oral roxadustat.Data on the workload and preference associated with conversion to roxadustat were not collected; while these metrics could be useful, they are not commonly captured by providers in standard care and may be worthwhile considerations in a future time-and-motion trial.
In conclusion, this study demonstrated that patients with anemia of CKD receiving dialysis at home or in T A B L E 3 Overview of treatment-emergent adverse events (TEAEs)/treatment-emergent serious adverse events (TESAEs) during the main treatment period (safety population).

4
Iron parameters by visit: change from baseline in (a) reticulocyte hemoglobin (Hb) content, (b) ferritin, (c) transferrin saturation (TSAT), and (d) iron.Full analysis set.Error bars are standard deviation (SD).Baselines for (a) reticulocyte Hb content, (b) ferritin, (c) TSAT, and (d) iron were defined as the last available value obtained on or before day 1, prior to the first dose of study medication.CHr, reticulocyte hemoglobin content.
Patient demographics and baseline characteristics.
T A B L E 1Abbreviations: Hb, hemoglobin; IV, intravenous; SD, standard deviation; TIW, three times a week.a One patient was mis-classified as a non-erythropoiesis-stimulating agent (ESA) user but had a history of ≥6 weeks of ESA use and was included in the non-ESA user analyses (full analysis set).
T A B L E 2 Hemoglobin (Hb) endpoints.agent (ESA) user but had a history of ≥6 weeks of ESA use and was included in the non-ESA user analyses.The proportion of patients with a mean hemoglobin (Hb) level within 10.0-12.0g/dL from Weeks 16 to 24, the proportion of patients with an Hb level >12.0 g/dL any time during treatment, the proportion of patients with an Hb level >13.0 g/dL any time during treatment, and the percentage of time with Hb values within 10.0-12.0g/dL from Weeks 16 to 24 were analyzed using observed Hb values.For the proportion of patients with a mean Hb level ≥ 10.0 g/dL in the first 8 weeks after conversion or initiation of treatment and the proportion of patients with a mean Hb level ≥ 10.0 g/dL averaged from Weeks 16 to 24 based on baseline ESA use status (≥6 weeks and <6 weeks), the intermittent missing Hb data were imputed relying on non-missing data from all patients using the Markov chain Monte Carlo imputation model, using baseline Hb and available non-missing Hb data for each scheduled week.There were 90 and 133 imputed values for the first 8 weeks and Week 16-24, respectively.Hb values were censored for 4 weeks if a red blood cell transfusion was administered during the treatment period.Baseline Hb was defined as the mean of available central laboratory Hb values prior to first dose of study medication, including the pre-dose Hb value collected on Day 1 (full analysis set).
Abbreviation: SD, standard deviation.a One patient was mis-classified as a non-erythropoiesis-stimulating Note: An adverse event that started during the treatment period was considered a TEAE if it was not present prior to the first dose of study medication or if it was present prior to the first dose of study medication but increased in severity during the treatment.The TEAE investigation period was extended up to 28 days after the last dose for patients who did not participate in the extension treatment or cut to Week 24/end of treatment visit when patients were continuing into extension treatment.Patientexposure-year (PEY) for each patient = (last dose date À first dose date + 1)/365.25.Incidence rate/100 PEY = 100 Â number of patients with events/PEY.clinics could be effectively treated with roxadustat.The feasibility of transitioning patients from injectable ESAs to oral roxadustat, and incorporating oral roxadustat into care paradigms at US dialysis organizations, was successfully demonstrated.The safety profile of roxadustat was consistent with previous roxadustat studies, and no new safety signals were identified with extended treatment.
a Included coronavirus disease 2019, cardiac arrest, pancreatitis relapsing, death, septic shock, brain injury, and azotemia.No deaths were considered related to the study drug (safety population).bTEAEs with unknown relationship to study treatment were included as related.dialysis