Ravulizumab in Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplant

The Kaplan-Meier method was used to measure overall survival estimate. For Day 100 and Week 26, overall survival was calculated from randomization to death (due to any cause), up to Day 100/Week 26. Participants who survived were censored at the earliest of an additional hematopoietic stem cell transplant (HSCT), Day 100/Week 26, or their last known date alive. For Week 52, overall survival was calculated from randomization to death (due to any cause), up to Week 52. Participants who survived were censored at the earlier of an additional HSCT, or their last known date alive up to Week 52.

Cumulative incidence for each group was estimated using a competing risks model. Non-relapse mortality was defined as a participant's death due to any cause during the study, with the exception of death due to underlying disease (malignant or non-malignant reason for HSCT) progression or relapse.

The TMA response parameters included: platelet response, normalization of LDH and absence of schistocytes, and renal response. A participant could have met 0, 1, 2, or 3 TMA response criteria during the 26-week Treatment Period. If the participants met more than 1 TMA response criterion, the number of responses overlapping for at least 24 hours was counted. Least squares mean determined from a general linear model adjusted by acute GVHD status and geographic region, assuming normal data distribution.

Clinical laboratory assessments were performed according to the protocol and assessed against the following predetermined criteria for hematologic response: if baseline platelet count was ≤50000/cubic millimeter (mm^3), then the absolute platelet count had to be >50000/mm^3 without platelet transfusion support during the prior 7 days; if the baseline platelet count had to be >50000/mm^3, then there must be a ≥50% increase in platelet count compared to baseline value without platelet transfusion support during the prior 7 days; normalization of LDH and absence of schistocytes (defined as ≤1% or a result of "none", per the International Council for Standardization in Hematology recommendations for schistocyte counting).

The eGFR was calculated based on serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula. Serum creatinine was collected according to the protocol. Data reported as milliliters/minute/1.73 square meters (mL/min/1.73 m^2).

The criteria for TMA response included a hematological response and a renal response. Hematological Response: if baseline platelet count was ≤50000/mm^3, then the absolute platelet count had to be >50000/mm^3 without platelet transfusion support during the prior 7 days; if the baseline platelet count was >50000/mm^3, then there had to be a ≥50% increase in platelet count compared to baseline value without platelet transfusion support during the prior 7 days; normalization of LDH and absence of schistocytes. Renal response: at least 50% reduction of proteinuria from baseline. Participants must have met each of the response criteria, with each parameter meeting the requirements at 2 separate assessments obtained at least 24 hours apart, and any measurement in between. A participant could meet 0, 1, 2, or 3 TMA response criteria during the treatment period. If the participant met more than 1 TMA response criterion, the number of responses overlapping for at least 24 hours was counted.

Cumulative proportion of participants who experienced a complete TMA response was estimated using a competing risks model based on the time (days) to complete TMA response. Time to complete TMA response was defined as the days from randomization to the first day during the 26-week Treatment Period on which a participant met all criteria for a complete TMA response. The date of complete TMA response was defined as the first date on which all individual response criteria were met simultaneously.

Cumulative proportion of participants experiencing individual TMA components included those for platelet count, LDH, and protein/creatinine ratio. For platelet count: if baseline platelet count was ≤50000/mm^3, then the absolute platelet count had to be >50000/mm^3 without platelet transfusion support during the prior 7 days; if the baseline platelet count was >50000/mm^3, then there had to be a ≥50% increase in platelet count compared to baseline value without platelet transfusion support during the prior 7 days. For LDH: normalization of LDH and absence of schistocytes. For protein/creatinine ratio: at least 50% reduction of proteinuria from baseline.

Clinical laboratory assessments were performed according to the protocol and assessed against the following predetermined criteria for hematologic response: if baseline platelet count was ≤50000/mm^3, then the absolute platelet count had to be >50000/mm^3 without platelet transfusion support during the prior 7 days; if the baseline platelet count was >50000/mm^3, then there had to be a ≥50% increase in platelet count compared to baseline value without platelet transfusion support during the prior 7 days.

Hemoglobin response was defined as the ability to maintain hemoglobin ≥10 grams/deciliter (g/dL) without any support. The criterion had to be met at 2 separate assessments obtained at least 24 hours apart, and any measurement in between, and without any support during the prior 7 days.

Platelet response was defined as: if baseline platelet count was ≤50000/mm^3, then the absolute platelet count had to be >50000/mm^3 without platelet transfusion support during the prior 7 days; if the baseline platelet count was >50000/mm^3, then there had to be a ≥50% increase in platelet count compared to baseline value without platelet transfusion support during the prior 7 days. The criteria had to be met at 2 separate assessments obtained at least 24 hours apart, and any measurement in between.

The criteria for TMA response included a hematological response and a renal response. Hematological response: if baseline platelet count was ≤50000/mm^3, then the absolute platelet count had to be >50000/mm^3 without platelet transfusion support during the prior 7 days; if the baseline platelet count was >50000/mm^3, then there had to be a ≥50% increase in platelet count compared to baseline value without platelet transfusion support during the prior 7 days; normalization of LDH and absence of schistocytes. Renal response: at least 50% reduction of proteinuria from baseline. Partial response occurred when the participant met ≥1, but not all, criteria for TMA response.

For participants that met the criteria for TMA response during the 26-week Treatment Period, loss of TMA response was defined as when the participant failed to meet the criteria for 1 or more components of TMA response at a subsequent visit during the 26-week Treatment Period. At least 1 parameter must have failed to meet the response criteria at 2 separate assessments obtained at least 24 hours apart, and any measurement in between.

This analysis includes data for each participant after achieving TMA response under the composite strategy through Weeks 26 and 52. The criteria for TMA response included a hematological response and a renal response. Time was calculated as the number of days from TMA response under the composite strategy to first loss of response or intercurrent event in the treatment period, or TMA relapse in the follow-up period. Participants must have met each of the response criteria, with each parameter meeting the requirements at 2 separate assessments obtained at least 24 hours apart, and any measurement in between. Participants with TMA response who did not experience these events were censored at their end of study date. The estimate is calculated based on the Kaplan-Meier method. Non-responders were counted as an event with a duration of zero day.

Protocol-specified blood samples were taken for the analysis of haptoglobin in plasma at designated time points. Results are reported as grams/liter (g/L).

Protocol-specified blood samples were taken for the analyses of platelets in plasma at designated time points.

Protocol-specified blood samples were taken for the analyses of LDH in plasma at designated time points. Results are reported as units/liter (U/L).

Protocol-specified blood samples were taken for the analyses of hemoglobin in plasma at designated time points.

The modified criteria for TMA response included a hematological response and a renal response. Hematological Response: if baseline platelet count ≤50000/mm^3, then the absolute platelet count had to be >50000/mm^3 without platelet transfusion support during the prior 7 days; if baseline platelet count >50000/mm^3, then there had to be a ≥50% increase in platelet count compared to baseline value without platelet transfusion support during the prior 7 days; at least 50% reduction of LDH from baseline and absence of schistocytes or normalization of LDH and absence of schistocytes. Renal response: at least 50% reduction of proteinuria from baseline. Participants must have met each response criterion, with each parameter meeting the requirement at 2 separate assessments obtained at least 24 hours apart, and any measurement in between.

Renal dysfunction was defined as doubling of serum creatinine from baseline or requirement of dialysis. Requirements for dialysis included: at the baseline visit, if there was any dialysis within 5 days prior to the first dose of study treatment; at the post-baseline visit, if there was any dialysis within 5 days prior to the visit. Participants categorized as those experiencing no symptoms at baseline and those experiencing symptoms at baseline.

Cardiopulmonary dysfunction was defined as the presence of cardiopulmonary symptoms (excluding hypertension) or use of any mechanical ventilation. Cardiopulmonary symptoms included, but were not limited to, pleural effusion, pulmonary edema, pericardial effusion, and serositis. The presence of cardiopulmonary symptoms at baseline and post-baseline visits were assessed and recorded on the electronic case report form (eCRF). Use of any ventilatory or respiratory support, including mechanical ventilation, was reported on the participant's Nonpharmacologic Therapies and Procedures eCRF page. Participants categorized as those experiencing no symptoms at baseline and those experiencing symptoms at baseline.

Central nervous system dysfunction was defined as confirmed posterior reversible encephalopathy syndrome, or any signs of headache, confusion, visual loss, or seizures at baseline and post-baseline visits, as recorded on the eCRF. Participants categorized as those experiencing no symptoms at baseline and those experiencing symptoms at baseline.

Gastrointestinal dysfunction was defined as presence of signs and symptoms of gastrointestinal involvement at baseline and post-baseline visits, including diarrhea, vomiting, pain, and bleeding as recorded on the eCRF. Participants categorized as those experiencing no symptoms at baseline and those experiencing symptoms at baseline.

For participants that met the criteria for TMA response during the 26-week Treatment Period, TMA relapse was defined as evidence of worsening hematologic and renal dysfunction due to TMA during the post-treatment Follow-up Period and required treatment intervention, as determined by the investigator.