Sickle Cell Disease (SCD)
Conditions
Keywords
Sickle cell disease, SCD, sickle cell anemia, vaso-occlusive crisis, P-selectin, SEG101, crizanlizumab, monoclonal antibody, Anemia, Sickle Cell, HbS Disease, Hemoglobin SC Disease, Sickle Cell Disorders, Sickling Disorder Due to Hemoglobin S
Brief summary
The purpose of the CSEG101A2202 study was to characterize the Pharmacokinetic (PK) and Pharmacodynamic (PD) of SEG101/crizanlizumab and to evaluate the safety and efficacy of SEG101/crizanlizumab in sickle cell disease (SCD) patients.
Detailed description
Study CSEG101A2202 was designed as a Phase II, multicenter, open-label study. The first 45 patients (to identify 27 evaluable patients) were enrolled to the treatment group crizanlizumab 5.0 mg/kg to complete full Pharmacokinetic/Pharmacodynamic (PK/PD) sampling at week 1 and week 15. In all patients, trough PK/PD samples were collected prior to each dose. In addition, throughout the study (and when possible), all patients had blood drawn for serum to assess PK and PD drawn at times of onset and resolution of each VOC event, fever, or infection. Once the up to 45 patients were enrolled, 12 additional patients were enrolled to the exploratory treatment group and began at 7.5 mg/kg of crizanlizumab. The study was initiated on 19-Dec-2017. This study provides five years follow up data that fully characterizes the safety, tolerability and treatment effect of the 5.0 mg/kg and 7.5 mg/kg doses of crizanlizumab along with the initially planned PK and PD data. At the time of study closure, crizanlizumab 5.0 mg/kg was an FDA approved treatment in the United States (US) for patients with sickle-cell disease. Therefore, the patients treated with crizanlizumab 5.0 mg/kg dose were encouraged to transition to commercial supply of crizanlizumab. The patients treated with the not currently approved dose of crizanlizumab 7.5 mg/kg were allowed to join a multi-center, multi-national, rollover clinical trial (Study SEG101A2401B), for continued access to treatment with crizanlizumab.
Interventions
DRUGcrizanlizumab
Crizanlizumab was administered IV infusion over 30 minutes at the assigned dose on Week 1 Day 1, Week 3 Day 1, and then Day 1 of every 4-week cycle. Cycle = 28 days
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male and non-pregnant female patients 16-70 years of age (inclusive) * Confirmed diagnosis of sickle cell disease by hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) \[performed locally\]. All sickle cell disease genotypes are eligible. * Experienced at least 1 VOC within the preceding 12 months prior to Screening, as determined by medical history. * If receiving HU/HC or erythropoietin stimulating agent, must have been receiving the drug for at least 6 months prior to Screening * Hemoglobin ≥4.0 g/dL. Absolute neutrophil count ≥1.0 x 109/L and platelet count ≥75 x 109/L * Adequate renal and hepatic function as defined: * GFR ≥45 mL/min/1.73 m2 calculated by CKD-EPI * ALT ≤3 x ULN * Direct (conjugated) bilirubin ≤2 x ULN * ECOG performance status ≤2 * Written informed consent (or assent/ parental consent for minor subjects) prior to any screening procedures
Exclusion criteria
* History of stem cell transplant. * Acute VOC ending 7 days prior to first dosing * Ongoing hospitalization prior to Screening * Received blood products within 30 days to first dosing * Participating in a chronic transfusion program (pre-planned series of transfusions for prophylactic purposes) * History of severe hypersensitivity reactions to other monoclonal antibodies * Received a monoclonal antibody or immunoglobulin -based agent within 1 year of Screening, or has documented immunogenicity to a prior biologic. * Received active treatment on another investigational trial within 30 days (or 5 half-lives of that agent, whichever is greater) prior to Screening * Significant active infection or immune deficiency (including chronic use of immunosuppressive drugs) * Resting QTcF ≥470 msec at pretreatment (baseline) or other cardiac or cardiac repolarization abnormality
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK): AUCd15 and AUCtau of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | 1st dose: Day 1: (pre-dose, 0.5, 1, 2, 4, 6 & 24 hours post dose, Days 4, 8 & 15; 5th dose: Day 1 (pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose), Days 4, 8, 15, 22 & 29 | To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients. AUCd15: The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) after single dose AUCtau: The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1) |
| PK: Cmax of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | After the starting dose (Week 1) and after multiple doses (steady state, Week 15) | To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients. Cmax: The maximum (peak) observed serum drug concentration after dose administration (mass x volume-1). |
| Pre-dose Concentrations Prior to Each Study Drug Dose | Pre-dose at Day 1 on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51 | To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients, by serum concentrations by treatment group. Data was collected prior to each study drug dose; From Week 3 (loading dose), pre-dose (trough) concentrations were obtained every 4 weeks. |
| Percentage of P-selectin Inhibition After the Starting Dose (PD-AUCd15), After Multiple Doses (PD-AUCd29) of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | 1st dose: Day 1: (pre-dose, 0.5, 1, 2, 4, 6 & 24 hours post dose, Days 4, 8, 15; 5th dose: Day 1(pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose), Days 4, 8, 15, 22 & 29 | PD-AUCd15 and PD-AUCd29 were derived from the P-selectin inhibition data of week 1 and week 15, respectively. To characterize PD of crizanlizumab at 5.0 mg/kg in SCD patients The area under the curve (AUC) of percentage of P-selectin inhibition versus time profile after the starting dose (PD-AUCd15) and after multiple doses (PD-AUCd29) is being reported. |
| Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | Pre-dose on Day 1 for Weeks 3, 7, 11, 15, 19, 23, 27, 31,35, 39, 43, 47, 51 (at 0 hr or pre-dose) | To characterize the PD effect of crizanlizumab in terms of Percentage of P-selectin inhibition prior to study drug dose at 5 mg/kg in CSD patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of VOC Events (Including Both Healthcare Visit and Home Treatment) | Baseline (Week 1) through approx. 45 months (median exposure to treatment) | Assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date -date of first dose of study treatment+1). End date is defined as th e minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date). |
| Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic/Emergency Room (ER)/Hospital | Baseline (Week 1) through approx. 45 months (median exposure to treatment) | To assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in Sickle cell disease (SCD) patients. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date - date of first dose of study treatment+1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date). |
| Number of Participants With Immunogenicity (IG) by Any Positive Status | Baseline (Week 1), post-baseline (approx. 45 months (median exposure)) | Assess safety and tolerability of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients by the percentage of participants with any positive status. Immunogenicity is the measurement of anti-drug antibodies (ADA) to crizanlizumab. |
| Annualized Rate of VOC Events Treated at Home (Based on Documentation by Health Care Provider Following Phone Contact With Patient) | Baseline (Week 1) through approx. 45 months (median exposure to treatment) | To assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date - date of first dose of study treatment+1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date). |
| Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Baseine (Week 1) through approx. 45 months (median exposure to treatment) | To assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. Annualized rate of hospitalizations and ER visits = number of hospitalizations and ER visits reported until end date × 365.25/(End date - treatment start date + 1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date). |
| Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Baseline (Week 1) through approx. 45 months (median exposure to treatment) | Assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients for hospitalizations and ER visits. Annualized days of all hospitalizations and ER visits = Number of days of all hospitalizations and ER visits × 365.25/(End date - treatment start date + 1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and to treat SCD and or to prevent/reduce VOCs, cut-off date). |
| Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | Baseline (Week 1) through approx. 45 months (median exposure to treatment) | Assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. The baseline (BL) annualized rate of VOC is defined as the number of VOCs reported in the last 12 months in the eCRF. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date - date of first dose of study treatment+1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date). |
Countries
United States
Participant flow
Recruitment details
57 patients were enrolled sequentially to study the at 5 mg/kg arm and at 7.5 mg/kg.
Pre-assignment details
This study was conducted in 12 centers in the United States only.
Participants by arm
| Arm | Count |
|---|---|
| Crizanlizumab 5.0 mg/kg Participants were administered crizanlizumab at a dose of 5.0 mg/kg by IV infusion. | 45 |
| Crizanlizumab 7.5 mg/kg Participants were administered crizanlizumab at a dose of 7.5 mg/kg by IV infusion. | 12 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 1 | 1 |
| Overall Study | End of Study | 19 | 5 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | New Therapy for study Indication | 1 | 0 |
| Overall Study | Patient decision | 13 | 0 |
| Overall Study | Physician Decision | 6 | 4 |
| Overall Study | Pregnancy | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Crizanlizumab 5.0 mg/kg | Crizanlizumab 7.5 mg/kg | Total |
|---|---|---|---|
| Age, Continuous | 32.3 years STANDARD_DEVIATION 12.71 | 26.8 years STANDARD_DEVIATION 12.25 | 31.2 years STANDARD_DEVIATION 12.71 |
| Age, Customized 16 - < 18 years | 1 participants | 2 participants | 3 participants |
| Age, Customized 18 - < 65 years | 43 participants | 10 participants | 53 participants |
| Age, Customized 65 - < 70 years | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 44 participants | 12 participants | 56 participants |
| Race/Ethnicity, Customized White and Black or African American | 1 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 25 Participants | 6 Participants | 31 Participants |
| Sex: Female, Male Male | 20 Participants | 6 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 45 | 1 / 12 | 2 / 57 |
| other Total, other adverse events | 42 / 45 | 11 / 12 | 53 / 57 |
| serious Total, serious adverse events | 22 / 45 | 6 / 12 | 28 / 57 |
Outcome results
Primary
Percentage of P-selectin Inhibition After the Starting Dose (PD-AUCd15), After Multiple Doses (PD-AUCd29) of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
PD-AUCd15 and PD-AUCd29 were derived from the P-selectin inhibition data of week 1 and week 15, respectively. To characterize PD of crizanlizumab at 5.0 mg/kg in SCD patients The area under the curve (AUC) of percentage of P-selectin inhibition versus time profile after the starting dose (PD-AUCd15) and after multiple doses (PD-AUCd29) is being reported.
Time frame: 1st dose: Day 1: (pre-dose, 0.5, 1, 2, 4, 6 & 24 hours post dose, Days 4, 8, 15; 5th dose: Day 1(pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose), Days 4, 8, 15, 22 & 29
Population: PDS1 included all patients who provided at least 1 evaluable PD profile. The P-selectin inhibition analysis was done on all participants including those starting dose (n = 36) and steady state (n = 33).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition After the Starting Dose (PD-AUCd15), After Multiple Doses (PD-AUCd29) of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | Starting dose (Week 1): PD-AUCd15 | 33200 hours*% of P-selectin inhibition | Standard Deviation 1830 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition After the Starting Dose (PD-AUCd15), After Multiple Doses (PD-AUCd29) of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | Steady state (Week 15): PD-AUCd29 | 66900 hours*% of P-selectin inhibition | Standard Deviation 5540 |
Primary
Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
To characterize the PD effect of crizanlizumab in terms of Percentage of P-selectin inhibition prior to study drug dose at 5 mg/kg in CSD patients.
Time frame: Pre-dose on Day 1 for Weeks 3, 7, 11, 15, 19, 23, 27, 31,35, 39, 43, 47, 51 (at 0 hr or pre-dose)
Population: Patients in the PD analysis set 2 (PDS2) with an available value for the outcome measure. PDS2 included all patients who received at least one planned treatment of 5.0 mg/kg and provided at least one corresponding evaluable PD assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | Week (W) 3 Day (D) 1: 0 hrs pre-dose | 97.3 percentage of P-selectin inhibition | Standard Deviation 7.49 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W7D1: 0 hrs pre-dose | 93.0 percentage of P-selectin inhibition | Standard Deviation 17.1 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W11D1: 0 hrs pre-dose | 87.8 percentage of P-selectin inhibition | Standard Deviation 22.6 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W15D1: 0 hrs pre-dose | 94.1 percentage of P-selectin inhibition | Standard Deviation 12.8 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | WD19: 0 hrs pre-dose | 91.7 percentage of P-selectin inhibition | Standard Deviation 18.5 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W23D1: 0 hrs pre-dose | 93.2 percentage of P-selectin inhibition | Standard Deviation 14.9 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W27D1: 0 hrs pre-dose | 94.3 percentage of P-selectin inhibition | Standard Deviation 13 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W31D1: 0 hrs pre-dose | 92.4 percentage of P-selectin inhibition | Standard Deviation 18.9 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W35D1: 0 hrs pre-dose | 91.7 percentage of P-selectin inhibition | Standard Deviation 14.7 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W39D1: 0 hrs pre-dose | 88.5 percentage of P-selectin inhibition | Standard Deviation 21.2 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W43D1: 0 hrs pre-dose | 86.1 percentage of P-selectin inhibition | Standard Deviation 24.8 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W47D1: 0 hrs pre-dose | 92.1 percentage of P-selectin inhibition | Standard Deviation 16.8 |
| Crizanlizumab 5.0 mg/kg | Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | W51D1: 0 hrs pre-dose | 91.5 percentage of P-selectin inhibition | Standard Deviation 17.6 |
Primary
Pharmacokinetic (PK): AUCd15 and AUCtau of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients. AUCd15: The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) after single dose AUCtau: The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)
Time frame: 1st dose: Day 1: (pre-dose, 0.5, 1, 2, 4, 6 & 24 hours post dose, Days 4, 8 & 15; 5th dose: Day 1 (pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose), Days 4, 8, 15, 22 & 29
Population: The PK analysis set 1 (PAS1) included all patients who provided at least one evaluable PK profile in the 5.0 mg/kg arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | Pharmacokinetic (PK): AUCd15 and AUCtau of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | Starting dose (Week 1): AUCd15 | 13100 hr*μg/mL | Standard Deviation 2810 |
| Crizanlizumab 5.0 mg/kg | Pharmacokinetic (PK): AUCd15 and AUCtau of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | Steady State (Week 15): AUCtau | 20800 hr*μg/mL | Standard Deviation 5030 |
Primary
PK: Cmax of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients. Cmax: The maximum (peak) observed serum drug concentration after dose administration (mass x volume-1).
Time frame: After the starting dose (Week 1) and after multiple doses (steady state, Week 15)
Population: The PK analysis set 1 (PAS1) included all patients who provided at least one evaluable PK profile in the 5.0 mg/kg arm. The Cmax analysis was done on all participants including those for at starting dose (n =42) and steady state (n = 36).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | PK: Cmax of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | Starting dose (Week 1) | 102 μg/mL | Standard Deviation 29.8 |
| Crizanlizumab 5.0 mg/kg | PK: Cmax of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients | Steady State (Week 15) | 123 μg/mL | Standard Deviation 36.4 |
Primary
Pre-dose Concentrations Prior to Each Study Drug Dose
To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients, by serum concentrations by treatment group. Data was collected prior to each study drug dose; From Week 3 (loading dose), pre-dose (trough) concentrations were obtained every 4 weeks.
Time frame: Pre-dose at Day 1 on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51
Population: PK Analysis set 2 (PAS2): Included all patients who received at least one planned treatment of 5 mg/kg and provided at least one corresponding evaluable PK concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | Week (W) 3 Day 1 (D)1: 0 hrs pre-dose | 18.0 μg/mL | Standard Deviation 6.42 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W7 D1: 0 hrs pre-dose | 10.8 μg/mL | Standard Deviation 5.21 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W11 D1: 0 hrs pre-dose | 9.04 μg/mL | Standard Deviation 5.04 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W15 D1: 0 hrs pre-dose | 10.0 μg/mL | Standard Deviation 5.39 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W19 D1: 0 hrs pre-dose | 9.37 μg/mL | Standard Deviation 4.95 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W23 D1: 0 hrs pre-dose | 9.91 μg/mL | Standard Deviation 5.09 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W27 D1: 0 hrs pre-dose | 9.65 μg/mL | Standard Deviation 4.03 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W31 D1: 0 hrs pre-dose | 9.75 μg/mL | Standard Deviation 4.66 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W35 D1: 0 hrs pre-dose | 9.48 μg/mL | Standard Deviation 4.6 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W39 D1: 0 hrs pre-dose | 9.54 μg/mL | Standard Deviation 5.47 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W43 D1: 0 hrs pre-dose | 8.53 μg/mL | Standard Deviation 5.24 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W47 D1: 0 hrs pre-dose | 8.96 μg/mL | Standard Deviation 4.31 |
| Crizanlizumab 5.0 mg/kg | Pre-dose Concentrations Prior to Each Study Drug Dose | W51 D1: 0 hrs pre-dose | 8.45 μg/mL | Standard Deviation 4.88 |
Secondary
Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits
Assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients for hospitalizations and ER visits. Annualized days of all hospitalizations and ER visits = Number of days of all hospitalizations and ER visits × 365.25/(End date - treatment start date + 1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and to treat SCD and or to prevent/reduce VOCs, cut-off date).
Time frame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Population: The Full analysis set (FAS) consisted of all patients to whom crizanlizumab had been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Annualized days (total) | 11.95 number of days per year |
| Crizanlizumab 5.0 mg/kg | Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Annualized days (VOC related) | 9.03 number of days per year |
| Crizanlizumab 5.0 mg/kg | Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Hospitalizations/ER Annualized days (total) | 10.31 number of days per year |
| Crizanlizumab 5.0 mg/kg | Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Hospitalizations/ER Annualized days (VOC related) | 7.27 number of days per year |
| Crizanlizumab 7.5 mg/kg | Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Hospitalizations/ER Annualized days (VOC related) | 0.60 number of days per year |
| Crizanlizumab 7.5 mg/kg | Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Annualized days (total) | 3.17 number of days per year |
| Crizanlizumab 7.5 mg/kg | Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Hospitalizations/ER Annualized days (total) | 2.57 number of days per year |
| Crizanlizumab 7.5 mg/kg | Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Annualized days (VOC related) | 1.57 number of days per year |
Secondary
Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs))
Assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. The baseline (BL) annualized rate of VOC is defined as the number of VOCs reported in the last 12 months in the eCRF. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date - date of first dose of study treatment+1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date).
Time frame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Population: The Full analysis set (FAS) consisted of all patients to whom crizanlizumab had been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | BL annualized rate of VOC: ACS | 0.00 number of events per year |
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | BL annualized rate of VOC: Priapism | 1.00 number of events per year |
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | Annualized rate of VOC on treatment: Priapism | 1.58 number of events per year |
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | BL annualized rate of VOC: Uncomplicated SC-VOCs | 3.00 number of events per year |
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | Annualized rate of VOC on treatment: Uncomplicated SC-VOCs | 2.58 number of events per year |
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | Annualized rate of VOC on treatment: ACS | 0.62 number of events per year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | BL annualized rate of VOC: ACS | 0.00 number of events per year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | BL annualized rate of VOC: Uncomplicated SC-VOCs | 2.00 number of events per year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | Annualized rate of VOC on treatment: ACS | 0.25 number of events per year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) | Annualized rate of VOC on treatment: Uncomplicated SC-VOCs | 1.04 number of events per year |
Secondary
Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits
To assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. Annualized rate of hospitalizations and ER visits = number of hospitalizations and ER visits reported until end date × 365.25/(End date - treatment start date + 1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date).
Time frame: Baseine (Week 1) through approx. 45 months (median exposure to treatment)
Population: The Full analysis set (FAS) consisted of all patients to whom crizanlizumab had been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Annualized rate (total) | 3.42 number of events per participant-year |
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Annualized rate (VOC related) | 3.34 number of events per participant-year |
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Hospitalizations/ER Annualized rate (total) | 2.46 number of events per participant-year |
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Hospitalizations/ER Annualized rate (VOC related) | 2.27 number of events per participant-year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Hospitalizations/ER Annualized rate (VOC related) | 0.48 number of events per participant-year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Annualized rate (total) | 2.47 number of events per participant-year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Hospitalizations/ER Annualized rate (total) | 1.44 number of events per participant-year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits | Annualized rate (VOC related) | 0.86 number of events per participant-year |
Secondary
Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic/Emergency Room (ER)/Hospital
To assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in Sickle cell disease (SCD) patients. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date - date of first dose of study treatment+1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date).
Time frame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Population: The Full analysis set (FAS) consisted of all patients to whom crizanlizumab had been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic/Emergency Room (ER)/Hospital | Baseline annualized rate of VOC | 4.00 number of events per year |
| Crizanlizumab 5.0 mg/kg | Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic/Emergency Room (ER)/Hospital | Annualized rate of VOC on treatment | 2.75 number of events per year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic/Emergency Room (ER)/Hospital | Baseline annualized rate of VOC | 2.00 number of events per year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic/Emergency Room (ER)/Hospital | Annualized rate of VOC on treatment | 0.97 number of events per year |
Secondary
Annualized Rate of VOC Events (Including Both Healthcare Visit and Home Treatment)
Assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date -date of first dose of study treatment+1). End date is defined as th e minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date).
Time frame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Population: The Full analysis set (FAS) consisted of all patients to whom crizanlizumab had been assigned and who received at least one dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Crizanlizumab 5.0 mg/kg | Annualized Rate of VOC Events (Including Both Healthcare Visit and Home Treatment) | 3.42 number of events per year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of VOC Events (Including Both Healthcare Visit and Home Treatment) | 1.65 number of events per year |
Secondary
Annualized Rate of VOC Events Treated at Home (Based on Documentation by Health Care Provider Following Phone Contact With Patient)
To assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date - date of first dose of study treatment+1). End date is defined as the minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-glutamine or other therapies such as voxelotor and erythropoietin to treat SCD and or to prevent/reduce VOCs, cut-off date).
Time frame: Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Population: The Full analysis set (FAS) consisted of all patients to whom crizanlizumab had been assigned and who received at least one dose of study treatment. The annualized rate of VOC events treated at home analyzed all participants including those who had a VOC event treated at home in the Crizanlizumab 5.0 mg/kg arm and in the Crizanlizumab 7.5 mg/kg arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Crizanlizumab 5.0 mg/kg | Annualized Rate of VOC Events Treated at Home (Based on Documentation by Health Care Provider Following Phone Contact With Patient) | 0.68 number of events per participant-year |
| Crizanlizumab 7.5 mg/kg | Annualized Rate of VOC Events Treated at Home (Based on Documentation by Health Care Provider Following Phone Contact With Patient) | 0.71 number of events per participant-year |
Secondary
Number of Participants With Immunogenicity (IG) by Any Positive Status
Assess safety and tolerability of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients by the percentage of participants with any positive status. Immunogenicity is the measurement of anti-drug antibodies (ADA) to crizanlizumab.
Time frame: Baseline (Week 1), post-baseline (approx. 45 months (median exposure))
Population: The Full analysis set (FAS) consisted of all patients to whom crizanlizumab had been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Crizanlizumab 5.0 mg/kg | Number of Participants With Immunogenicity (IG) by Any Positive Status | Baseline: Positive | 0 Participants |
| Crizanlizumab 5.0 mg/kg | Number of Participants With Immunogenicity (IG) by Any Positive Status | Post-Baseline: Any Positive | 0 Participants |
| Crizanlizumab 7.5 mg/kg | Number of Participants With Immunogenicity (IG) by Any Positive Status | Baseline: Positive | 0 Participants |
| Crizanlizumab 7.5 mg/kg | Number of Participants With Immunogenicity (IG) by Any Positive Status | Post-Baseline: Any Positive | 0 Participants |
| All Participants | Number of Participants With Immunogenicity (IG) by Any Positive Status | Baseline: Positive | 0 Participants |
| All Participants | Number of Participants With Immunogenicity (IG) by Any Positive Status | Post-Baseline: Any Positive | 0 Participants |