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
Overview
- Phase
- Phase 2
- Intervention
- AZD9773 (CytoFab)
- Conditions
- Severe Sepsis
- Sponsor
- AstraZeneca
- Enrollment
- 70
- Locations
- 1
- Primary Endpoint
- Change From Baseline in Haemoglobin Values
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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.
Arms & Interventions
AZD9773 cohort 1 (50 units/kg)
AZD9773: single infusion of 50 units/kg
Intervention: AZD9773 (CytoFab)
AZD9773 cohort 2 (250 units/kg)
AZD9773: single infusion of 250 units/kg
Intervention: AZD9773 (CytoFab)
AZD9773 cohort 3 (250/50 units/kg)
AZD9773: loading infusion of 250 units/kg then 9 maintenance doses of 50 units/kg q12hrs
Intervention: AZD9773 (CytoFab)
AZD9773 cohort 4 (500/100 units/kg)
AZD9773: loading infusion of 500 units/kg then 9 maintenance doses of 100 units/kg q12hrs
Intervention: AZD9773 (CytoFab)
AZD9773 cohort 5 (750/250 units/kg)
AZD9773: loading infusion of 750 units/kg then 9 maintenance doses of 250 units/kg q12hrs
Intervention: AZD9773 (CytoFab)
Placebo
Placebo
Intervention: Placebo
Outcomes
Primary Outcomes
Change From Baseline in Haemoglobin Values
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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.
Time Frame: 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
Time Frame: 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).
Secondary Outcomes
- 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)