A Placebo-controlled, Double-blind, Dose-escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics and Pharmacodynamics of Single and Multiple Intravenous Infusions of CytoFab (AZD9773) in Patients With Severe Sepsis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Change From Baseline in Haemoglobin Values
研究概览
简要总结
This is a double-blind, placebo-controlled, multi-center, dose-escalation study to assess the safety, tolerability, Pharmacokinetics and Pharmacodynamics of single and multiple ascending intravenous infusions of CytoFab (AZD9773) in adult patients with severe sepsis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Clinical evidence of infection requiring treatment with parenteral antibiotics
- •Patients must meet multiple Systemic Inflammatory Response Syndrome (SIRS) criteria
- •Patients must meet criteria for cardiovascular and/or respiratory dysfunction
- •Sepsis (infection plus SIRS criteria) must be present prior to organ dysfunction
排除标准
- •Moribund and death is considered imminent, or patient not expected to survive 90 days because of underlying medical condition, or classified as Do Not Resuscitate or Do Not Treat
- •Patient cannot attain a MAP >60 mmHg when measured via an arterial line and/or a Systolic Blood Pressure (SBP) >80 mmHg in the presence of vasopressors and iv fluids for a period of ≥2 hours
- •Receiving immunosuppressants, or high dose steroids within 2 months of provision of informed consent
- •Any history of hypersensitivity reaction to sheep products, latex, papain or papaya, or chymopapain or previously administered antivenom manufactured using ovine serum, digoxin immune fab (DigiFab™ , DIGIBIND® ), crotalidae polyvalent immune fab (ovine) (CroFab™ ), or other sheep derived product.
- •Treatment with anti Tumor-Necrosis-Factor (anti-TNF) antibodies within 8 weeks before provision of written informed consent.
研究组 & 干预措施
AZD9773 cohort 1 (50 units/kg)
AZD9773: single infusion of 50 units/kg
干预措施: AZD9773 (CytoFab) (Drug)
AZD9773 cohort 2 (250 units/kg)
AZD9773: single infusion of 250 units/kg
干预措施: AZD9773 (CytoFab) (Drug)
AZD9773 cohort 3 (250/50 units/kg)
AZD9773: loading infusion of 250 units/kg then 9 maintenance doses of 50 units/kg q12hrs
干预措施: AZD9773 (CytoFab) (Drug)
AZD9773 cohort 4 (500/100 units/kg)
AZD9773: loading infusion of 500 units/kg then 9 maintenance doses of 100 units/kg q12hrs
干预措施: AZD9773 (CytoFab) (Drug)
AZD9773 cohort 5 (750/250 units/kg)
AZD9773: loading infusion of 750 units/kg then 9 maintenance doses of 250 units/kg q12hrs
干预措施: AZD9773 (CytoFab) (Drug)
Placebo
Placebo
干预措施: Placebo (Other)
结局指标
主要结局
Change From Baseline in Haemoglobin Values
时间窗: End of study (Day 28)
Change in haemoglobin values from baseline (pre-infusion) to follow-up (28 days after the start of study drug administration) \[calculated as Day 28 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in Prothrombin Time Values
时间窗: Day 7
Change in prothrombin time values from baseline (pre-infusion) to Day 7 \[calculated as Day 7 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in Body Weight
时间窗: Day 6
Change in body weight from baseline (pre-infusion) to Day 6 \[calculated as Day 6 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in Creatinine Values
时间窗: End of study (Day 28)
Change in creatinine values from baseline (pre-infusion) to follow-up (28 days after the start of study drug administration) \[calculated as Day 28 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in Alanine Aminotransferase Values
时间窗: End of study (Day 28)
Change in alanine aminotransferase values from baseline (pre-infusion) to follow-up (28 days after the start of study drug administration) \[calculated as Day 28 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in Aspartate Aminotransferase Values
时间窗: End of study (Day 28)
Change in aspartate aminotransferase values from baseline (pre-infusion) to follow-up (28 days after the start of study drug administration) \[calculated as Day 28 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in Platelet Count Values
时间窗: End of study (Day 28)
Change in platelet count values from baseline (pre-infusion) to follow-up (28 days after the start of study drug administration) \[calculated as Day 28 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in Troponin I
时间窗: Day 6
Change in troponin I values from baseline (pre-infusion) to Day 6 \[calculated as Day 6 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in Bilirubin Values
时间窗: End of study (Day 28)
Change in bilirubin values from baseline (pre-infusion) to follow-up (28 days after the start of study drug administration) \[calculated as Day 28 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in White Blood Cell Values
时间窗: End of study (Day 28)
Change in white blood cell values from baseline (pre-infusion) to follow-up (28 days after the start of study drug administration) \[calculated as Day 28 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in QT With Fridericia Correction (QTcF), Where QT is Measured by ECG, and is the Time Interval Between the Start of the Q Wave and the End of the T Wave in the Heart's Electrical Cycle.
时间窗: Day 1 (end of infusion) for Cohorts 1 and 2; Day 5 (end of infusion) for Cohorts 3 to 5 and placebo
Change in QTcF from baseline (pre-infusion) to Day 1 (end of infusion) for Cohorts 1 and 2 \[calculated as Day 1 mean minus baseline mean\] and Day 5 (end of infusion) for Cohorts 3 to 5 and placebo \[calculated as Day 5 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
Change From Baseline in Calculated Mean Arterial Blood Pressure
时间窗: Day 14
Change in calculated mean arterial pressure from baseline (pre-infusion) to Day 14 \[calculated as Day 14 mean minus baseline mean\]. Safety analysis set (ie all patients who started study drug infusion).
次要结局
- 28-Day Mortality(End of study (Day 28))
- Total Apparent Clearance (CL) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2)(Day 1 [PK samples taken pre-dose, the end of each infusion rate and then at 0.5, 1, 2, 8, 12, 24, 48, and 72 h post-(last) infusion])
- AUC(0-12) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)(Day 1 [PK samples taken pre-dose, the end of each infusion rate and then at 0.5, 1, 2, 8 and 12 h post-(last) infusion])
- Maximum (End of Infusion) Serum Concentration (Cinf) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3,4 and 5)(Day 1 [PK samples taken pre-dose, the end of each infusion rate and then at 0.5, 1, 2, 8 and 12 h post-(last)infusion])
- Time to Reach Cinf (Tmax) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)(Day 1 [PK samples taken pre-dose, the end of each infusion rate and then at 0.5, 1, 2, 8 and 12 h post-(last)infusion])
- Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores(Day 6)
- Area Under the Serum Concentration-time Curve From 0 to 12 Hours (AUC(0-12)) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2)(Day 1 [PK samples taken pre-dose, the end of each infusion rate and then at 0.5, 1, 2, 8, and 12h post-(last) infusion])
- Terminal Half-life (t1/2) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2)(Day 1 [PK samples taken pre-dose, the end of each infusion rate and then at 0.5, 1, 2, 8, 12, 24, 48, and 72 h post-(last) infusion])
- AUC(0-12) of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)(PK samples taken pre-dose of Doses 5,7 and 9, then at 0, 0.5, 1, 2, 8 and 12 h post dose 9 infusion)
- Cinf of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)(PK samples taken pre-dose of Doses 5,7 and 9, then at 0, 0.5, 1, 2, 8 and 12 h post dose 9 infusion)
- Tmax of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)(PK samples taken pre-dose of Doses 5,7 and 9, then at 0, 0.5, 1, 2, 8 and 12 h post dose 9 infusion)
- Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ)(24 hours)