Pharmacokinetics and Pharmacodynamics Study of SEG101 (Crizanlizumab) in Sickle Cell Disease (SCD) Patients With Vaso- Occlusive Crisis (VOC)
- Registration Number
- NCT03264989
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 57
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description crizanlizumab crizanlizumab SEG101 (crizanlizumab) drug at a dose of 5.0 mg/kg (or 7.5 mg/kg for exploratory group) by IV infusion.
- Primary Outcome Measures
Name Time Method 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.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)
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 Outcome Measures
Name Time Method 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 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).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).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).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.
Trial Locations
- Locations (11)
Childrens Healthcare of Atlanta .
🇺🇸Atlanta, Georgia, United States
University of Maryland Medical Ctr
🇺🇸Baltimore, Maryland, United States
East Carolina University East Carolina University
🇺🇸Greenville, North Carolina, United States
Childrens Hospital Of Philadelphia Patient Treatment
🇺🇸Philadelphia, Pennsylvania, United States
M Francisco Gonzalez MD PA .
🇺🇸Columbia, South Carolina, United States
Medical Uni of South Carolina Medical Univ of SC
🇺🇸Charleston, South Carolina, United States
Carolina Blood and Cancer Care of South Carolina
🇺🇸Rock Hill, South Carolina, United States
Novartis Investigative Site
🇺🇸Tampa, Florida, United States
Duke University Medical Center Patient Treatment
🇺🇸Durham, North Carolina, United States
Augusta University Georgia Patient Treatment
🇺🇸Augusta, Georgia, United States
Childrens Hospital at Montefiore
🇺🇸Bronx, New York, United States