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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 57
- 试验地点
- 11
- 主要终点
- PK: Cmax of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
crizanlizumab
SEG101 (crizanlizumab) drug at a dose of 5.0 mg/kg (or 7.5 mg/kg for exploratory group) by IV infusion.
干预措施: crizanlizumab (Drug)
结局指标
主要结局
PK: Cmax of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- 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))
- Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits(Baseine (Week 1) through approx. 45 months (median exposure to treatment))
- 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))
- Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits(Baseline (Week 1) through approx. 45 months (median exposure to treatment))
- 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))
- Annualized Rate of VOC Events (Including Both Healthcare Visit and Home Treatment)(Baseline (Week 1) through approx. 45 months (median exposure to treatment))
- Number of Participants With Immunogenicity (IG) by Any Positive Status(Baseline (Week 1), post-baseline (approx. 45 months (median exposure)))