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.
Brief Title
Pharmacokinetics and Pharmacodynamics Study of SEG101 (Crizanlizumab) in Sickle Cell Disease (SCD) Patients With Vaso- Occlusive Crisis (VOC)
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.
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.
Completion Date
Completion Date Type
Actual
Conditions
Sickle Cell Disease (SCD)
Eligibility Criteria
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
* 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
Inclusion Criteria
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
* 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
Gender
All
Gender Based
false
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
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
70 Years
Minimum Age
16 Years
NCT Id
NCT03264989
Org Class
Industry
Org Full Name
Novartis
Org Study Id
CSEG101A2202
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 2, Multicenter, Open-Label Study to Assess PK/PD of SEG101 (Crizanlizumab), With or Without Hydroxyurea/Hydroxycarbamide, in Sickle Cell Patients With Vaso-Occlusive Crisis
Primary Outcomes
Outcome Description
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)
Outcome Measure
Pharmacokinetic (PK): AUCd15 and AUCtau of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
Outcome 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
Outcome Description
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).
Outcome Measure
PK: Cmax of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
Outcome Time Frame
After the starting dose (Week 1) and after multiple doses (steady state, Week 15)
Outcome Description
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.
Data was collected prior to each study drug dose; From Week 3 (loading dose), pre-dose (trough) concentrations were obtained every 4 weeks.
Outcome Measure
Pre-dose Concentrations Prior to Each Study Drug Dose
Outcome Time Frame
Pre-dose at Day 1 on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51
Outcome Description
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.
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.
Outcome Measure
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
Outcome 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
Outcome Description
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.
Outcome Measure
Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
Outcome 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)
Secondary Outcomes
Outcome Description
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).
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).
Outcome Time Frame
Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Outcome Measure
Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic/Emergency Room (ER)/Hospital
Outcome Description
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).
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).
Outcome Time Frame
Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Outcome Measure
Annualized Rate of VOC Events Treated at Home (Based on Documentation by Health Care Provider Following Phone Contact With Patient)
Outcome Description
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).
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).
Outcome Time Frame
Baseine (Week 1) through approx. 45 months (median exposure to treatment)
Outcome Measure
Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits
Outcome Description
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).
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).
Outcome Time Frame
Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Outcome Measure
Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits
Outcome Description
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).
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).
Outcome Time Frame
Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Outcome Measure
Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs))
Outcome Description
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).
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).
Outcome Time Frame
Baseline (Week 1) through approx. 45 months (median exposure to treatment)
Outcome Measure
Annualized Rate of VOC Events (Including Both Healthcare Visit and Home Treatment)
Outcome Description
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.
Outcome Time Frame
Baseline (Week 1), post-baseline (approx. 45 months (median exposure))
Outcome Measure
Number of Participants With Immunogenicity (IG) by Any Positive Status
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Locked Fields
Render the field
Maximum Age Number (converted to Years and rounded down)
70
Minimum Age Number (converted to Years and rounded down)
16
Investigators
Investigator Type
Principal Investigator
Investigator Name
Deepa Manwani
Investigator Email
dmanwani@montefiore.org
Investigator Phone
718-741-2342