Efficacy and Safety of Rivipansel (GMI-1070) in the Treatment of Vaso-Occlusive Crisis in Hospitalized Subjects With Sickle Cell Disease

Time to readiness-for-discharge from hospital was defined as the difference (in hours) between the time and date when all criteria for readiness-for-discharge were met and the start time and date of the first infusion (loading dose) of study drug. Criteria for readiness-for-discharge were met when all of the applicable 6 criteria (in relation to treatment of VOC and complications related to the VOC) were documented to have occurred. The six criteria were: 1) only oral pain medication was required, 2) acute complications related to the VOC (such as acute chest syndrome, stroke, priapism) had resolved to the extent that management could be in an outpatient setting, 3) IV opioids had been discontinued, 4) IV hydration had been discontinued, 5) IV antibiotics had been discontinued and 6) red blood cell (RBC) transfusion was no longer required for treatment of this VOC.

Time frame: Day 1 up to the latest day when all 6 criteria of readiness-for-discharge were met (up to an average of Day 8)

Population: Full analysis set population included all participants who were randomized in the study. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population in alignment with the primary study objective.

Cumulative IV opioid consumption was reported as cumulative IV opioid use (standardized using morphine equivalent units \[MEU\]), from the start of the first infusion (loading dose) of study drug until hospital discharge.

Time frame: Day 1 up to the latest day when IV opioid was discontinued (up to an average of Day 8)

Population: Full analysis set population included all participants who were randomized in the study. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population in alignment with the primary study objective.

Cumulative IV opioid consumption (standardized using MEU) was reported as IV opioid use in the first 24 hours from the start time of the first IV infusion (loading dose) of study drug.

Time frame: 24 hours post first IV infusion of loading dose of study drug on Day 1

Population: Full analysis set population included all participants who were randomized in the study. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population in alignment with the primary study objective.

Percentage of participants who were re-hospitalized for a vaso-occlusive crisis (VOC) within 3 days of discharge from hospital are reported.

Time frame: Within 3 days of discharge from hospital, where discharge from hospital was any day from Day 1 to an average of Day 8

Population: Full analysis set population included all participants who were randomized in the study. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population in alignment with the primary study objective.

Time to discharge from hospital was defined as the difference (in hours) between the time and date of the hospital discharge order from a qualified healthcare provider and the start time and date of the first infusion (loading dose) of study drug.

Time frame: Day 1 up to the latest day when the order of hospital discharge was issued by a qualified healthcare provider (up to an average of Day 8)

Population: Full analysis set population included all participants who were randomized in the study. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population in alignment with the primary study objective.

Time to discontinuation of IV opioids was defined as the difference (in hours) between the stop time and date of the latest IV opioid dose and the start time and date of the first infusion (loading dose) of study drug.

Time frame: Day 1 up to the latest day when IV opioid was discontinued (up to an average of Day 8)

Population: Full analysis set population included all participants who were randomized in the study. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population in alignment with the primary study objective.

Hematology: hemoglobin, hematocrit, erythrocytes \<0.8\*lower limit of normal (LLN), reticulocytes \<0.5\*LLN \>1.5\*ULN, platelets\<0.5\*LLN\>1.75\*upper limit of normal (ULN), reticulocytes/erythrocytes\<0.5\*LLN\>1.5\*ULN, leukocytes \<0.6\*LLN \>1.5\*ULN, lymphocytes, lymphocytes/leukocytes, neutrophils, neutrophils/leukocytes \<0.8\*LLN \>1.2\*ULN, basophils, basophils/leukocytes, eosinophils, eosinophils/leukocytes, monocytes monocytes/leukocytes \>1.2\*ULN. Clinical chemistry: bilirubin, direct, bilirubin, indirect bilirubin\>1.5\*ULN, aspartate aminotransferase (AT), alanine AT, lactate dehydrogenase, alkaline phosphatase\>3.0\*ULN, urea nitrogen, urea, creatinine \>1.3\*ULN, sodium\<0.95\*LLN\>1.05\*ULN, potassium, chloride, bicarbonate\<0.9\*LLN\>1.1\*ULN, glucose\<0.6\*LLN\>1.5\*ULN, estimated glomerular filtration rate \<=60. Urinalysis: urine glucose, ketones, urine protein, urine hemoglobin, nitrite, leukocyte esterase \>=1.

Time frame: Day 1 up to the 35-day post discharge visit (up to an average of Day 43)

Population: Safety analysis set population included all participants who received at least 1 infusion of study drug. Here 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population.

Physical examination included assessment of the general appearance and the skin, head, ears, eyes, nose, mouth, throat, spine, neck, thyroid, chest, extremities, lymph nodes and abdomen (including liver and kidneys) plus the respiratory, cardiovascular, musculoskeletal, neurological and genitourinary systems. Clinical significance was assessed by the Investigator.

Time frame: From Post-screening up to end of treatment (up to an average of Day 8), From Post-discharge up to 35 days post-discharge (up to an average of Day 43)

Population: Safety analysis set population included all participants who received at least 1 infusion of study drug. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population.

Hemoglobin(grade \[G\] 0:\>11g/dl,G1:\>9-11g/dl,G2:\>7-9g/dl,G3:5-7g/dl,G4:\<5g/dl),reticulocytes count(G0:\<1%,G1:1-5%,G2:\>5-10%,G3:\>10-20%,G4:\>20%),leukocytes(G0:\<=upper limit of normal \[ULN\],G1:\>ULN-15,000/mm\^3,G2:\>15,000- 20,000/mm\^3,G3:\>20,000- 50,000/mm\^, G4:\>50,000/mm\^3),neutrophils(G0:\>=LLN, G1:\<LLN-1,500/mm\^3, G2:\<1,500-1,000/mm\^3, G3:\<1,000-500/mm\^3, G4:\<500/mm\^3),blood urea nitrogen, creatinine(G0:\<=ULN, G1:\>ULN-1.5\*UL, G2:\>1.5-3.0\*ULN, G3:\>3.0\*ULN, G4:\>6.0\*ULN), lactate dehydrogenase, alanine transaminase, aspartate aminotransferase(G0:\<=ULN, G1:\>ULN-3.0\*ULN, G2:\>3.0-5.0\*ULN, G3:\>5.0-20.0\*ULN, G4:\>20.0\*ULN), bilirubin(G0:\<=ULN, G1:\>ULN-1.5\*ULN, G2:\>1.5-3.0\*ULN, G3:\>3.0-10.0\*ULN, G4:\>10.0\*ULN), urine protein(G0:0-15mg/dL, G1:\>15-30mg/dL, G2:\>30-100mg/dL, G3:\>100-300mg/dL, G4:\>300mg/dL), platelet(G0:\>=150K, G1:\>=100K-\<150K, G2:\>=50K \<100K, G3:\<50K), eGFR (G0:\>=90 mL/min/1.73m\^2, G1:\>=60-\<90mL/min/1.73m\^2, G2:\>=30-\<60mL/min/1.73m\^2, G3:\>=15-\<30mL/min/1.73m\^2, G4:\<15 mL/min/1.73m\^2)

Time frame: Baseline up to the 35-day post discharge visit (up to an average of Day 43)

Population: Safety analysis set population included all participants who received at least 1 infusion of drug. Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure; Number Analyzed signifies participants evaluable for specific rows. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population.

AE: any untoward medical occurrence in a participant who received investigational product without regard to possibility of a causal relationship. AEs were classified according to the severity in 3 categories a) mild - AEs did not interfere with participant's usual function, b) moderate - AEs interfered to some extent with participant's usual function, c) severe - AEs interfered significantly with participant's usual function.

Time frame: Day 1 up to the 35-day post discharge visit (up to an average of Day 43)

Population: Safety analysis set population included all participants who received at least 1 infusion of study drug. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population.

AE: any untoward medical occurrence in a participant who received investigational product without regard to possibility of a causal relationship. SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. An adverse event was considered a treatment-emergent adverse event (TEAE) if the event started during the effective duration of treatment (all events that started on or after the first dosing). AEs included both serious and non-serious adverse events. Participants with AEs and SAEs were categorized by genotype categories. Category 1= participants with hemoglobin SS, hemoglobin S beta0 thalassemia and hemoglobin SD; category 2= participants with hemoglobin SC, hemoglobin S beta+ thalassemia and hemoglobin S-Variant (other than HbSD).

Time frame: Day 1 up to the 35-day post discharge visit (up to an average of Day 43)

Population: Safety analysis set population included all participants who received at least 1 infusion of study drug. Here, Number Analyzed signifies number of participants evaluable for specified rows. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population.

Vital signs included temperature, respiratory rate, pulse rate and systolic and diastolic blood pressure. Relatedness to treatment was assessed by the Investigator.

Time frame: Baseline (Day 1) up to the 35-day post discharge visit (up to an average of Day 43)

Population: Safety analysis set population included all participants who received at least 1 infusion of study drug. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population.

Percentage of participants re-hospitalized for VOC within 7, 14 and 30 days of hospital discharge.

Time frame: Within 7 days of discharge; Within 14 days of discharge; Within 30 days of discharge, where discharge from hospital was any day from Day 1 to an average of Day 8

Population: Safety analysis set population included all participants who received at least 1 infusion of study drug. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population.

Investigator reported events of Acute Chest Syndrome (ACS) and other reported respiratory events were sent for adjudication by the Acute Chest Syndrome Safety Endpoint Adjudication Committee. The committee, which consisted of physicians with relevant SCD expertise, evaluated these events and determined whether they were consistent with cases of ACS.

Time frame: Day 1 up to the 35-day post discharge visit (up to an average of Day 43)

Population: Safety analysis set population included all participants who received at least 1 infusion of study drug. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population.

Investigator reported cutaneous events were sent for adjudication by the Cutaneous Manifestations Safety Endpoint Adjudication Committee. The committee, which consisted of dermatologists, evaluated these events and determined whether they were cases of severe and/or generalized cutaneous manifestations and specifically whether any event was consistent with Acute Generalized Exanthematous Pustulosis.

Time frame: Day 1 up to the 35-day post discharge visit (up to an average of Day 43)

Population: Safety analysis set population included all participants who received at least 1 infusion of study drug. Participants aged 12 years and above were identified as Cohort 1 and participants aged 6-11 years were identified as Cohort 2; however, the primary analysis and study conclusions were based on the full study population.