Sickle Cell Disease (SCD)
Conditions
Keywords
Sickle Cell Disease, SCD, SEG101, Crizanlizumab, Hydroxyurea/ Hydroxycarbamide Therapy, Vaso-Occlusive Crises, SCA, blood disorders, hemoglobin, red blood cells, sickle-like shape, mutation in hemoglobin gene, sickle-cell trait, sickle-cell crisis
Brief summary
The purpose of this study is to compare the efficacy and safety of 2 doses of crizanlizumab (5.0 mg/kg and 7.5 mg/kg) versus placebo in adolescent and adult sickle cell disease (SCD) patients with history of vaso-occlusive crisis (VOC) leading to healthcare visit.
Detailed description
Study CSEG101A2301 (STAND) is an ongoing Phase III, multicenter, randomized, double-blind study to assess efficacy and safety of two doses of crizanlizumab (5 mg/kg and 7.5 mg/kg) versus placebo, with or without hydroxyurea/ hydroxycarbamide therapy (HU/HC), in adolescent and adult patients with SCD and history of VOC leading to healthcare visit. This is a multicenter clinical trial comparing 2 doses of crizanlizumab (5 mg/kg and 7.5 mg/kg) versus placebo in addition to standard of care participants might be taking at the time of study start, in adolescent and adult participants with confirmed diagnosis of sickle cell disease (SCD) and history of vaso-occlusive crisis (VOC) leading to a healthcare visit. 240 participants (including 48 adolescents) were planned to be randomized in a 1:1:1 ratio to either 5 mg/kg, 7.5 mg/kg of crizanlizumab or placebo. Randomized participants were stratified by concomitant HU/HC usage (yes/no) and baseline rate of VOCs leading to a healthcare visit in 12 months prior to screening visit (2-4 vs. ≥ 5 VOCs) at the time of enrollment. In November 2020, a capping of 90 adult participants per strata was implemented to ensure adequate opportunity for enrollment into each of the 4 strata.
Interventions
DRUGCrizanlizumab (SEG101)
Crizanlizumab was supplied in single use 10 mL glass vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab. This is a concentrate for solution for infusion. IV.
DRUGPlacebo
Placebo was supplied in single use 10 mL glass vials at a concentration of 0 mg/mL. This is a concentrate for solution for infusion IV.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind Study
Eligibility
Sex/Gender
ALL
Age
12 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Written informed consent must be obtained prior to any screening procedures 2. Male or female patients aged 12 years and older on the day of signing informed consent. Adolescent include patients aged 12 to 17 years old and adults ≥ 18 years 3. Confirmed diagnosis of SCD by hemoglobin electrophoresis or high performance liquid chromatography (HPLC) \[performed locally\]. All SCD genotypes are eligible, genotyping is not required for study entry 4. Experienced at least 2 VOCs leading to healthcare visit within the 12 months prior to screening visit as determined by medical history. Prior VOC leading to healthcare visit must resolve at least 7 days prior to Week 1 Day 1 and must include: 1. Pain crisis defined as an acute onset of pain for which there is no other medically determined explanation other than vaso- occlusion - 2. which requires a visit to a medical facility and/or healthcare professional, 3. and receipt of oral/parenteral opioids or parenteral nonsteroidal anti-inflammatory drug (NSAID) analgesia Acute chest syndrome (ACS), priapism and hepatic or splenic sequestration will be considered VOC in this study 5. If receiving HU/HC or L-glutamine (local HA approved medicinal product), must have been receiving the drug for at least 6 months and at a stable dose for at least 3 months prior to Screening visit and plan to continue taking it at the same dose and schedule until the subject has reached one year of study treatment. Patients who have not been receiving such drug must not have received it for at least 6 months prior to Screening visit to be included. Patients must have evidence of insufficient control of acute pain, such as at least one VOC leading to healthcare visit while on HU/HC or L-Glutamine treatment. If receiving erythropoietin stimulating agent, must have been receiving the drug for at least 6 months prior to Screening visit and plan to continue taking the treatment to maintain stable Hb levels at least until the subject has reached one year of study treatment 6. Patients must meet the following central laboratory values prior to Week 1 Day 1: * Absolute Neutrophil Count ≥1.0 x 109/L * Platelet count ≥75 x 109/L * Hemoglobin: for adults (Hb) ≥4.0 g/dL and for adolescents (Hb) ≥5.5 g/dL * Glomerular filtration rate ≥ 45 mL/min/1.73 m2 using CKD-EPI formula in adults, and Shwartz formula in adolescents * Direct (conjugated) bilirubin \< 2.0 x ULN * Alanine transaminase (ALT) \< 3.0 x ULN 7. ECOG performance status ≤2.0 for adults and Karnofsky ≥ 50% for adolescents Key
Exclusion criteria
1. History of stem cell transplant. 2. Participating in a chronic transfusion program (pre-planned series of transfusions for prophylactic purposes) and/or planning on undergoing an exchange transfusion during the duration of the study; episodic transfusion in response to worsened anemia or VOC is permitted. 3. Contraindication or hypersensitivity to any drug or metabolites from similar class as study drug or to any excipients of the study drug formulation. History of severe hypersensitivity reaction to other monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction. 4. Received active treatment on another investigational trial within 30 days (or 5 half-lives of that agent, whichever is greater) prior to Screening visit or plans to participate in another investigational drug trial. 5. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant unless they are using highly effective methods of contraception during dosing and for 15 weeks after stopping treatment. 6. Concurrent severe and/or uncontrolled medical conditions which, in the opinion of the Investigator, could cause unacceptable safety risks or compromise participation in the study. 7. History or current diagnosis of ECG abnormalities indicating significant risk of safety such as: * Concomitant clinically significant cardiac arrhythmias (e.g ventricular tachycardia), and clinically significant second or third degree AV block without a pacemaker * History of familial long QT syndrome or know family history of Torsades de Pointes 8. Not able to understand and to comply with study instructions and requirements. 9. Received prior treatment with crizanlizumab or other selectin targeting agent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to a Healthcare Visit | 1 year | VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Healthcare visit is defined as any visit to a medical facility such as emergency room (ER), hospital and/or office visit, which includes pain management of VOC in situ. Annualized rate of corresponding VOC events = (Number of corresponding VOC events \* 365)/(number of days in the observation period). Observation period = time from date of randomization to 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 therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over the First-year Post Randomization (Key Secondary) | 1 year | VOCs are based on documentation by provider following contact with participant. VOC:pain crisis requiring therapy with oral/parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome, priapism and hepatic or splenic sequestration. Healthcare visit:a visit to a medical facility (ER, hospital \&/or office visit resulting in pain management of VOC. Managed at home: no visit to any medical facility \&/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice is allowed. Annualized rate of corresponding VOC events = (# of corresponding VOC events \* 365)/(# of days in observation period). Observation period = time from date of randomization to 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 \& erythropoietin therapies to treat SCD \&/or to prevent/reduce VOCs), date of randomization + 365 days) |
| Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over 5 Years Post Randomization (Key Secondary) | 5 years | To compare the efficacy of 5.0 mg/kg vs placebo \& 7.5 mg/kg vs placebo on the annualized rate of all VOCs based on documentation by provider following contact with participant. VOC is defined as pain crisis (an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) requiring therapy with oral/parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome, priapism and hepatic or splenic sequestration. Healthcare visit is defined as a visit to a medical facility (emergency room, hospital and/or office visit resulting in pain management of VOC. Managed at home is defined as no visit to any medical facility and/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice is allowed. The annualized rate of VOC leading to healthcare visit is the number of VOC leading to healthcare visit multiplied by 365 \& divided by the number of days in observation period. |
| Mean Duration of VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 1 year | To assess the duration of VOCs leading to healthcare visit in each group. Mean duration of VOC per participant is defined as the average duration of all individual episodes of VOCs leading to healthcare visits of a given participant (a VOC duration is defined as end date of the VOC - start date of the VOC + 1). Participants with no VOC leading to healthcare visits have been excluded. |
| Number of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 1 year | To assess the number of participants free from VOCs leading to healthcare visit. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. A participant is free from VOC if they do not have a VOC crisis. |
| Percentage of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 1 year | To assess the percentage of participants free from VOCs leading to healthcare visit. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. A participant is free from VOC if they do not have a VOC crisis. |
| Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 1 year | To assess the time to first and second VOC leading to healthcare visit in each group. Time to first occurrence of VOC leading to a healthcare visit is defined as the time from the date of randomization to the date of the first occurrence of the VOC. Time to second occurrence of VOC leading to a healthcare visit is defined as the time from date of randomization to the date of the second occurrence of VOC. |
| Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | 1 year | To assess Healthcare resource utilization (visits to clinic, Emergency room (ER) and hospitalizations) both overall and VOC-related in each group. Annualized rate of corresponding healthcare visits =(Number of corresponding healthcare visits \* 365)/(number of days in the observation period). Observation period = time from date of randomization to 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 therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days) |
| Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | 1 year | To assess Healthcare resource utilization (visits to clinic, Emergency room (ER) and hospitalizations) both overall and VOC-related in each group. Annualized days of corresponding healthcare visits =(Number of days =(Number of days of corresponding healthcare visits \* 365)/(number of days in the observation period). Observation period = time from date of randomization to 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 therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days). |
| Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline) | Over first year post-randomization (Baseline, Week 27 Day 1, Week 51 Day 1) | Laboratory values for parameters related to renal function (creatinine, estimated glomerular filtration rate, urine microalbumin, and urine albumin/creatinine ratio) were measured at 6-month intervals over time from baseline. |
| Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline) | Over first year post-randomization (Baseline, Week 27 Day 1, Week 51 Day 1) | Laboratory values for parameters related to renal function (creatinine, estimated glomerular filtration rate, urine microalbumin, and urine albumin/creatinine ratio) were measured at 6-month intervals over time from baseline. |
| Pharmacokinetic (PK) Profile of Crizanlizumab: AUCd15, AUCtau | AUCd15 (first-dose) was assessed at W1D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose) to W3D1; AUCtau (steady-state) was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1 | To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: Area under the (concentration-time profile) curve. |
| PK Profile of Crizanlizumab: Cmax | first-dose was assessed at W1D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose) through to W3D1; steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1 | To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: Maximum concentration. |
| PK Profile of Crizanlizumab: Tmax | first-dose was assessed at W1D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose) through to W3D1; steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1 | To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: Time to maximum concentration. |
| PK Profile of Crizanlizumab: Half-life | steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1 | To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: half life. |
| PD Parameter (P-selectin Inhibition) | AUCd15 (first dose): W1D1, W1D2, W1D4, W2D1 and W3D1; steady state: W15D1, W15D2, W15D4, W16D1, W17D1 W18D1 and W19D1 | To characterize the pharmacodynamic (PD) of crizanlizumab at 5.0 and 7.5 mg/kg: P-selectin inhibition (% inhibition multipled by hr) |
| Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | 1 year | To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the annualized rate of VOCs leading to healthcare visit. VOC is defined as pain crisis which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Healthcare visit: any visit to a medical facility such as ER, hospital and/or office visit, which includes pain management of VOC in situ. Annualized rate of corresponding VOC events = (Number of corresponding VOC events \* 365)/(number of days in the observation period). Observation period = time from date of randomization to 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 therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days). |
| Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 5 Years | 5 years | To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the annualized rate of VOCs leading to healthcare visit. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Healthcare visit is defined as any visit to a medical facility such as emergency room, hospital and/or office visit, which includes pain management of VOC in situ. The annualized rate of VOC leading to healthcare visit is the number of VOC leading to healthcare visit multiplied by 365 and divided by the number of days in the observation period. |
| Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home at 5 Years | 5 years | To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the rates of all VOCs (managed at home + leading to healthcare visit). |
| Number of VOCs Managed at Home at Year 1 | 1 year | To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the number of VOC events that were managed at home. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Managed at home is defined as no visit to any medical facility and/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice was allowed. |
| Number of VOCs Managed at Home at 5 Years | 5 years | To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the number of VOC events that were managed at home. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Managed at home is defined as no visit to any medical facility and/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice was allowed. |
| Absolute Change From Baseline in Hemoglobin | 5 years | To assess safety of crizanlizumab over the study period. |
| Growth and Sexual Maturity Assessment in Adolescents (Tanner Stage) | 5 years | To assess safety of crizanlizumab over the study period. |
| Immunogenicity: Measurement of Anti-drug Antibodies (ADA) to Crizanlizumab | 5 years | To assess immunogenicity of crizanlizumab over the study period. |
Countries
Belgium, Brazil, Canada, Colombia, Finland, France, Germany, Ghana, Greece, India, Italy, Jordan, Lebanon, Netherlands, Oman, Panama, South Africa, Spain, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
240 participants (including 48 adolescents) were planned to be randomized in a 1:1:1 ratio to either 5 mg/kg, 7.5 mg/kg of crizanlizumab or placebo. This study was conducted in 21 countries and 63 centers.
Pre-assignment details
Screening assessments were done within 1 to 28 days prior to Week 1 Day 1. Re-screening of subjects was only allowed if the subject was not randomized before.
Participants by arm
| Arm | Count |
|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg Participants received Crizanlizumab (SEG101) 5.0 mg/kg IV infusions on day 1, day 15 and every 4 weeks thereafter. | 84 |
| Crizanlizumab (SEG101) at 7.5 mg/kg Participants received Crizanlizumab (SEG101) 7.5 mg/kg IV infusions on day 1, day 15 and every 4 weeks thereafter. | 83 |
| Placebo Participants received 0.5mL/kg placebo drug by IV infusions on day 1, day 15 and every 4 weeks thereafter. | 85 |
| Total | 252 |
Baseline characteristics
| Characteristic | Crizanlizumab (SEG101) at 5.0 mg/kg | Total | Placebo | Crizanlizumab (SEG101) at 7.5 mg/kg |
|---|---|---|---|---|
| Age, Customized 18 - < 65 years | 68 participants | 196 participants | 63 participants | 65 participants |
| Age, Customized 65 - < 85 years | 0 participants | 2 participants | 2 participants | 0 participants |
| Age, Customized Adolescents, 12 - < 18 years | 16 participants | 54 participants | 20 participants | 18 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 60 Participants | 18 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 167 Participants | 57 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 25 Participants | 10 Participants | 7 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 16 Participants | 6 Participants | 7 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 19 Participants | 6 Participants | 7 Participants |
| Race/Ethnicity, Customized Black or African American | 46 Participants | 123 Participants | 43 Participants | 34 Participants |
| Race/Ethnicity, Customized Multiple (White and Black or African American) | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 9 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 27 Participants | 84 Participants | 26 Participants | 31 Participants |
| Sex: Female, Male Female | 45 Participants | 139 Participants | 49 Participants | 45 Participants |
| Sex: Female, Male Male | 39 Participants | 113 Participants | 36 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 84 | 2 / 83 | 2 / 85 |
| other Total, other adverse events | 67 / 84 | 71 / 83 | 66 / 85 |
| serious Total, serious adverse events | 35 / 84 | 22 / 83 | 26 / 85 |
Outcome results
Primary
Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to a Healthcare Visit
VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Healthcare visit is defined as any visit to a medical facility such as emergency room (ER), hospital and/or office visit, which includes pain management of VOC in situ. Annualized rate of corresponding VOC events = (Number of corresponding VOC events \* 365)/(number of days in the observation period). Observation period = time from date of randomization to 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 therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days).
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to a Healthcare Visit | 2.5 number of events per year | Standard Deviation 2.98 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to a Healthcare Visit | 1.9 number of events per year | Standard Deviation 2.3 |
| Placebo | Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to a Healthcare Visit | 2.1 number of events per year | Standard Deviation 2.81 |
p-value: >0.99995% CI: [0.76, 1.55]negative binomial regression model
p-value: >0.99995% CI: [0.62, 1.27]negative binomial regression model
Secondary
Absolute Change From Baseline in Hemoglobin
To assess safety of crizanlizumab over the study period.
Time frame: 5 years
Secondary
Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization
To assess Healthcare resource utilization (visits to clinic, Emergency room (ER) and hospitalizations) both overall and VOC-related in each group. Annualized days of corresponding healthcare visits =(Number of days =(Number of days of corresponding healthcare visits \* 365)/(number of days in the observation period). Observation period = time from date of randomization to 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 therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days).
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized days of all clinic, hospitalizations and ER visits | 17.6 number of days per year | Standard Deviation 27.8 |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized days of all VOC-related clinic, hospitalizations and ER visits | 13.8 number of days per year | Standard Deviation 18.12 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized days of all clinic, hospitalizations and ER visits | 11.3 number of days per year | Standard Deviation 14.29 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized days of all VOC-related clinic, hospitalizations and ER visits | 9.3 number of days per year | Standard Deviation 12.62 |
| Placebo | Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized days of all clinic, hospitalizations and ER visits | 12.9 number of days per year | Standard Deviation 18.32 |
| Placebo | Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized days of all VOC-related clinic, hospitalizations and ER visits | 11.3 number of days per year | Standard Deviation 18.35 |
95% CI: [0.85, 2.09]Negative binomial regression model
95% CI: [0.57, 1.38]Negative binomial regression model
95% CI: [0.77, 2.09]Negative binomial regression model
95% CI: [0.52, 1.44]Negative binomial regression model
Secondary
Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home at 5 Years
To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the rates of all VOCs (managed at home + leading to healthcare visit).
Time frame: 5 years
Secondary
Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over 5 Years Post Randomization (Key Secondary)
To compare the efficacy of 5.0 mg/kg vs placebo & 7.5 mg/kg vs placebo on the annualized rate of all VOCs based on documentation by provider following contact with participant. VOC is defined as pain crisis (an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) requiring therapy with oral/parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome, priapism and hepatic or splenic sequestration. Healthcare visit is defined as a visit to a medical facility (emergency room, hospital and/or office visit resulting in pain management of VOC. Managed at home is defined as no visit to any medical facility and/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice is allowed. The annualized rate of VOC leading to healthcare visit is the number of VOC leading to healthcare visit multiplied by 365 & divided by the number of days in observation period.
Time frame: 5 years
Secondary
Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over the First-year Post Randomization (Key Secondary)
VOCs are based on documentation by provider following contact with participant. VOC:pain crisis requiring therapy with oral/parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome, priapism and hepatic or splenic sequestration. Healthcare visit:a visit to a medical facility (ER, hospital &/or office visit resulting in pain management of VOC. Managed at home: no visit to any medical facility &/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice is allowed. Annualized rate of corresponding VOC events = (# of corresponding VOC events \* 365)/(# of days in observation period). Observation period = time from date of randomization to 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 & erythropoietin therapies to treat SCD &/or to prevent/reduce VOCs), date of randomization + 365 days)
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over the First-year Post Randomization (Key Secondary) | 4.5 number of events per year | Standard Deviation 6.49 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over the First-year Post Randomization (Key Secondary) | 3.1 number of events per year | Standard Deviation 2.89 |
| Placebo | Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over the First-year Post Randomization (Key Secondary) | 3.7 number of events per year | Standard Deviation 3.78 |
95% CI: [0.87, 1.7]negative binomial regression model
95% CI: [0.59, 1.17]negative binomial regression model
Secondary
Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year
To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the annualized rate of VOCs leading to healthcare visit. VOC is defined as pain crisis which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Healthcare visit: any visit to a medical facility such as ER, hospital and/or office visit, which includes pain management of VOC in situ. Annualized rate of corresponding VOC events = (Number of corresponding VOC events \* 365)/(number of days in the observation period). Observation period = time from date of randomization to 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 therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days).
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Acute chest syndrome | 0.2 number of events per year | Standard Deviation 1.44 |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Uncomplicated sickle cell-vaso-occlusive crisis | 2.3 number of events per year | Standard Deviation 2.74 |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Hepatic sequestration | 0.0 number of events per year | Standard Deviation 0 |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Priapism | 0.0 number of events per year | Standard Deviation 0 |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Splenic sequestration | 0.0 number of events per year | Standard Deviation 0 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Priapism | 0.0 number of events per year | Standard Deviation 0.15 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Uncomplicated sickle cell-vaso-occlusive crisis | 1.8 number of events per year | Standard Deviation 2.27 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Acute chest syndrome | 0.0 number of events per year | Standard Deviation 0.21 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Hepatic sequestration | 0.0 number of events per year | Standard Deviation 0 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Splenic sequestration | 0.0 number of events per year | Standard Deviation 0.11 |
| Placebo | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Hepatic sequestration | 0.0 number of events per year | Standard Deviation 0 |
| Placebo | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Uncomplicated sickle cell-vaso-occlusive crisis | 2.0 number of events per year | Standard Deviation 2.79 |
| Placebo | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Priapism | 0.0 number of events per year | Standard Deviation 0.11 |
| Placebo | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Acute chest syndrome | 0.1 number of events per year | Standard Deviation 0.44 |
| Placebo | Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year | Subtype of VOC: Splenic sequestration | 0.0 number of events per year | Standard Deviation 0 |
Secondary
Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 5 Years
To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the annualized rate of VOCs leading to healthcare visit. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Healthcare visit is defined as any visit to a medical facility such as emergency room, hospital and/or office visit, which includes pain management of VOC in situ. The annualized rate of VOC leading to healthcare visit is the number of VOC leading to healthcare visit multiplied by 365 and divided by the number of days in the observation period.
Time frame: 5 years
Secondary
Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization
To assess Healthcare resource utilization (visits to clinic, Emergency room (ER) and hospitalizations) both overall and VOC-related in each group. Annualized rate of corresponding healthcare visits =(Number of corresponding healthcare visits \* 365)/(number of days in the observation period). Observation period = time from date of randomization to 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 therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days)
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized rate of all clinic, hospitalizations and ER visits | 3.5 number of events per year | Standard Deviation 3.65 |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized rate of VOC-related clinic, hospitalizations and ER visits | 3.0 number of events per year | Standard Deviation 3.52 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized rate of all clinic, hospitalizations and ER visits | 2.6 number of events per year | Standard Deviation 3.21 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized rate of VOC-related clinic, hospitalizations and ER visits | 2.2 number of events per year | Standard Deviation 3.01 |
| Placebo | Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized rate of all clinic, hospitalizations and ER visits | 3.0 number of events per year | Standard Deviation 3.87 |
| Placebo | Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization | Annualized rate of VOC-related clinic, hospitalizations and ER visits | 2.5 number of events per year | Standard Deviation 3.53 |
95% CI: [0.75, 1.43]Negative binomial regression model
95% CI: [0.59, 1.14]Negative binomial regression model
95% CI: [0.77, 1.59]Negative binomial regression model
95% CI: [0.6, 1.25]Negative binomial regression model
Secondary
Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline)
Laboratory values for parameters related to renal function (creatinine, estimated glomerular filtration rate, urine microalbumin, and urine albumin/creatinine ratio) were measured at 6-month intervals over time from baseline.
Time frame: Over first year post-randomization (Baseline, Week 27 Day 1, Week 51 Day 1)
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline) | Change from baseline at Week 27 Day 1 | 0.1 g/mol |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline) | Chage from baseline at Week 51 Day 1 | 0.1 g/mol |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline) | Change from baseline at Week 27 Day 1 | -0.0 g/mol |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline) | Chage from baseline at Week 51 Day 1 | -0.1 g/mol |
| Placebo | Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline) | Change from baseline at Week 27 Day 1 | -0.1 g/mol |
| Placebo | Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline) | Chage from baseline at Week 51 Day 1 | -0.2 g/mol |
Secondary
Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline)
Laboratory values for parameters related to renal function (creatinine, estimated glomerular filtration rate, urine microalbumin, and urine albumin/creatinine ratio) were measured at 6-month intervals over time from baseline.
Time frame: Over first year post-randomization (Baseline, Week 27 Day 1, Week 51 Day 1)
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline) | Change from baseline at Week 27 Day 1 | 0.0 g/L |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline) | Change from baseline at Week 51 Day 1 | 0.0 g/L |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline) | Change from baseline at Week 27 Day 1 | 0.0 g/L |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline) | Change from baseline at Week 51 Day 1 | 0.0 g/L |
| Placebo | Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline) | Change from baseline at Week 27 Day 1 | 0.0 g/L |
| Placebo | Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline) | Change from baseline at Week 51 Day 1 | 0.0 g/L |
Secondary
Growth and Sexual Maturity Assessment in Adolescents (Tanner Stage)
To assess safety of crizanlizumab over the study period.
Time frame: 5 years
Secondary
Immunogenicity: Measurement of Anti-drug Antibodies (ADA) to Crizanlizumab
To assess immunogenicity of crizanlizumab over the study period.
Time frame: 5 years
Secondary
Mean Duration of VOCs Leading to a Healthcare Visit Over the First-year Post Randomization
To assess the duration of VOCs leading to healthcare visit in each group. Mean duration of VOC per participant is defined as the average duration of all individual episodes of VOCs leading to healthcare visits of a given participant (a VOC duration is defined as end date of the VOC - start date of the VOC + 1). Participants with no VOC leading to healthcare visits have been excluded.
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization. Participants with no VOC leading to healthcare visits are excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Mean Duration of VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 7.7 days | Standard Deviation 6.93 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Mean Duration of VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 6.0 days | Standard Deviation 4.54 |
| Placebo | Mean Duration of VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 6.6 days | Standard Deviation 5.55 |
Secondary
Number of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization
To assess the number of participants free from VOCs leading to healthcare visit. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. A participant is free from VOC if they do not have a VOC crisis.
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Number of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 25 Participants |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Number of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 31 Participants |
| Placebo | Number of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 34 Participants |
Secondary
Number of VOCs Managed at Home at 5 Years
To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the number of VOC events that were managed at home. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Managed at home is defined as no visit to any medical facility and/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice was allowed.
Time frame: 5 years
Secondary
Number of VOCs Managed at Home at Year 1
To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the number of VOC events that were managed at home. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Managed at home is defined as no visit to any medical facility and/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice was allowed.
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Number of VOCs Managed at Home at Year 1 | 163 total number of VOC events |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Number of VOCs Managed at Home at Year 1 | 106 total number of VOC events |
| Placebo | Number of VOCs Managed at Home at Year 1 | 129 total number of VOC events |
Secondary
PD Parameter (P-selectin Inhibition)
To characterize the pharmacodynamic (PD) of crizanlizumab at 5.0 and 7.5 mg/kg: P-selectin inhibition (% inhibition multipled by hr)
Time frame: AUCd15 (first dose): W1D1, W1D2, W1D4, W2D1 and W3D1; steady state: W15D1, W15D2, W15D4, W16D1, W17D1 W18D1 and W19D1
Population: The Pharmacodynamic analysis set 1 includes all participants who provided at least 1 evaluable PD profile: received planned treatment of crizanlizumab at 5 mg/kg or 7.5 mg/kg before single dose PD profile or 3 consecutive doses of planned treatment before the multiple dose PD profile; provided at least 1 PD-AUC (single dose or multiple dose) parameter; did not have any transfusion of blood product in the last 4 weeks before the first PD sample of the full PD profile or during the full PD profile
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | PD Parameter (P-selectin Inhibition) | PD-AUCd29 (steady state) | 65100 h * % | Standard Deviation 7000 |
| Crizanlizumab (SEG101) at 5.0 mg/kg | PD Parameter (P-selectin Inhibition) | PD-AUCd15 (first dose) | 32700 h * % | Standard Deviation 3830 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | PD Parameter (P-selectin Inhibition) | PD-AUCd29 (steady state) | 66100 h * % | Standard Deviation 7190 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | PD Parameter (P-selectin Inhibition) | PD-AUCd15 (first dose) | 33100 h * % | Standard Deviation 3530 |
Secondary
Percentage of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization
To assess the percentage of participants free from VOCs leading to healthcare visit. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. A participant is free from VOC if they do not have a VOC crisis.
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Percentage of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 29.8 Percentage of participants |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Percentage of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 37.3 Percentage of participants |
| Placebo | Percentage of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | 40.0 Percentage of participants |
Secondary
Pharmacokinetic (PK) Profile of Crizanlizumab: AUCd15, AUCtau
To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: Area under the (concentration-time profile) curve.
Time frame: AUCd15 (first-dose) was assessed at W1D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose) to W3D1; AUCtau (steady-state) was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1
Population: Pharmacokinetic analysis set 1 includes all participants who provided at least one evaluable PK profile: received the planned treatment at 5 mg/kg or 7.5 mg/kg before single dose PK profile or 3 consecutive doses of the planned treatment before the multiple dose PK profile for the multiple dose PK profile; provided at least one PK parameter; did not have any transfusion of blood product in the last 4 weeks before the first PK sample of the full PK profile, or during the full PK profile.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Pharmacokinetic (PK) Profile of Crizanlizumab: AUCd15, AUCtau | AUCd15 (first dose) | 11300 hr*ug/mL | Standard Deviation 2950 |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Pharmacokinetic (PK) Profile of Crizanlizumab: AUCd15, AUCtau | AUCtau (steady state) | 18800 hr*ug/mL | Standard Deviation 5470 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Pharmacokinetic (PK) Profile of Crizanlizumab: AUCd15, AUCtau | AUCd15 (first dose) | 17000 hr*ug/mL | Standard Deviation 4100 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Pharmacokinetic (PK) Profile of Crizanlizumab: AUCd15, AUCtau | AUCtau (steady state) | 30200 hr*ug/mL | Standard Deviation 8580 |
Secondary
PK Profile of Crizanlizumab: Cmax
To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: Maximum concentration.
Time frame: first-dose was assessed at W1D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose) through to W3D1; steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1
Population: Pharmacokinetic analysis set 1 includes all participants who provided at least one evaluable PK profile: received the planned treatment at 5 mg/kg or 7.5 mg/kg before single dose PK profile or 3 consecutive doses of the planned treatment before the multiple dose PK profile for the multiple dose PK profile; provided at least one PK parameter; did not have any transfusion of blood product in the last 4 weeks before the first PK sample of the full PK profile, or during the full PK profile.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | PK Profile of Crizanlizumab: Cmax | Cmax (first dose) | 95.9 ug/mL | Standard Deviation 29.4 |
| Crizanlizumab (SEG101) at 5.0 mg/kg | PK Profile of Crizanlizumab: Cmax | Cmax (steady state) | 108 ug/mL | Standard Deviation 60.2 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | PK Profile of Crizanlizumab: Cmax | Cmax (first dose) | 143 ug/mL | Standard Deviation 45.3 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | PK Profile of Crizanlizumab: Cmax | Cmax (steady state) | 162 ug/mL | Standard Deviation 57.4 |
Secondary
PK Profile of Crizanlizumab: Half-life
To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: half life.
Time frame: steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1
Population: Pharmacokinetic analysis set 1 includes all participants who provided at least one evaluable PK profile: received the planned treatment at 5 mg/kg or 7.5 mg/kg before single dose PK profile or 3 consecutive doses of the planned treatment before the multiple dose PK profile for the multiple dose PK profile; provided at least one PK parameter; did not have any transfusion of blood product in the last 4 weeks before the first PK sample of the full PK profile, or during the full PK profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | PK Profile of Crizanlizumab: Half-life | 9.51 day | Standard Deviation 3.67 |
| Crizanlizumab (SEG101) at 7.5 mg/kg | PK Profile of Crizanlizumab: Half-life | 11.2 day | Standard Deviation 3.55 |
Secondary
PK Profile of Crizanlizumab: Tmax
To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: Time to maximum concentration.
Time frame: first-dose was assessed at W1D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose) through to W3D1; steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1
Population: Pharmacokinetic analysis set 1 includes all participants who provided at least one evaluable PK profile: received the planned treatment at 5 mg/kg or 7.5 mg/kg before single dose PK profile or 3 consecutive doses of the planned treatment before the multiple dose PK profile for the multiple dose PK profile; provided at least one PK parameter; did not have any transfusion of blood product in the last 4 weeks before the first PK sample of the full PK profile, or during the full PK profile.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | PK Profile of Crizanlizumab: Tmax | Tmax (first dose) | 2.08 hr |
| Crizanlizumab (SEG101) at 5.0 mg/kg | PK Profile of Crizanlizumab: Tmax | Tmax (steady state) | 2.00 hr |
| Crizanlizumab (SEG101) at 7.5 mg/kg | PK Profile of Crizanlizumab: Tmax | Tmax (first dose) | 2.08 hr |
| Crizanlizumab (SEG101) at 7.5 mg/kg | PK Profile of Crizanlizumab: Tmax | Tmax (steady state) | 3.58 hr |
Secondary
Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization
To assess the time to first and second VOC leading to healthcare visit in each group. Time to first occurrence of VOC leading to a healthcare visit is defined as the time from the date of randomization to the date of the first occurrence of the VOC. Time to second occurrence of VOC leading to a healthcare visit is defined as the time from date of randomization to the date of the second occurrence of VOC.
Time frame: 1 year
Population: The FAS comprises all participants to whom study treatment has been assigned by randomization. The estimated time to first and second VOC using Kaplan-Meier analyzed all participants, including those who experienced first (n=59, 52, 51) and second (n=41, 33, 33) events in 5mg/kg, 7.5mg/kg and placebo arms, respectively, those who were at risk, and those who were censored.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab (SEG101) at 5.0 mg/kg | Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | Time to first occurrence of VOC | 3.9 Months |
| Crizanlizumab (SEG101) at 5.0 mg/kg | Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | Time to second occurrence of VOC | 10.6 Months |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | Time to first occurrence of VOC | 6.2 Months |
| Crizanlizumab (SEG101) at 7.5 mg/kg | Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | Time to second occurrence of VOC | NA Months |
| Placebo | Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | Time to first occurrence of VOC | 6.2 Months |
| Placebo | Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization | Time to second occurrence of VOC | NA Months |
95% CI: [0.92, 1.97]Cox Model
95% CI: [0.72, 1.58]Cox Model
95% CI: [0.81, 2.04]Cox Model
95% CI: [0.59, 1.54]Cox Model