Severe Sepsis
Conditions
Keywords
Sepsis, septic shock, Systemic Inflammatory Response Syndrome
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.
Interventions
DRUGAZD9773 (CytoFab)
intravenous infusions
OTHERPlacebo
Placebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight | 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 | 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 | 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 | 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 Bilirubin Values | 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 Haemoglobin Values | 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 White Blood Cell Values | 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 Platelet Count Values | 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 Prothrombin Time Values | 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 Troponin I | 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 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. | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| 28-Day Mortality | End of study (Day 28) | The number of patients who had died at Day 28. Safety analysis set (ie all patients who started study drug infusion). |
| Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores | Day 6 | Change in SOFA (Sequential Organ Failure Assessment) scores from baseline (pre-infusion) to Day 6 \[calculated as Day 6 mean minus baseline mean\]. The SOFA score is out of a maximum of 24 (units on a scale 0 to 24). The higher the score, the worse the organ system functioning. Safety analysis set (ie all patients who started study drug infusion). |
| 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] | AUC(0-12) for single dose AZD9773 serum total Fabs (cohorts 1 and 2). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK). |
| 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] | t1/2 of single dose AZD9773 serum total Fabs (cohorts 1 and 2). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK). |
| 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] | CL of single dose AZD9773 serum total Fabs (cohorts 1 and 2). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK). |
| 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] | AUC(0-12) of loading dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK). |
| 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] | Cinf of loading dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK). |
| 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] | tmax of loading dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK). |
| 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 | AUC(0-12) of maintenance dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK). |
| 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 | Cinf of maintenance dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK). |
| 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 | tmax of maintenance dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK). |
| Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ) | 24 hours | Number of patients below tumour necrosis factor (TNF)-alpha limit of quantification (LOQ) at 24 hours (n\< LOQ) measured by ELISA (LOQ = 1.3 pg/mL). Safety analysis set (ie all patients who started study drug infusion). |
Countries
United States
Participant flow
Recruitment details
The first patient was enrolled on January 18, 2008 and the last patient had their last visit on July 30, 2009. Patients were randomised at 17 centres in the United States of America
Pre-assignment details
70 adult patients with severe sepsis, clinical evidence of infection requiring parenteral antibiotics, meeting systemic inflammatory response syndrome criteria, and with cardiovascular/respiratory dysfunction were randomised to receive AZD9773 (2 single dose and 3 multiple dose cohorts) in a double-blind, placebo controlled, dose escalation study
Participants by arm
| Arm | Count |
|---|---|
| AZD9773 Cohort 1 (50 Units/kg) AZD9773: single infusion of 50 units/kg | 8 |
| AZD9773 Cohort 2 (250 Units/kg) AZD9773: single infusion of 250 units/kg | 9 |
| AZD9773 Cohort 3 (250/50 Units/kg) AZD9773: loading infusion of 250 units/kg then 9 maintenance doses of 50 units/kg q12hrs | 12 |
| AZD9773 Cohort 4 (500/100 Units/kg) AZD9773: loading infusion of 500 units/kg then 9 maintenance doses of 100 units/kg q12hrs | 10 |
| AZD9773 Cohort 5 (750/250 Units/kg) AZD9773: loading infusion of 750 units/kg then 9 maintenance doses of 250 units/kg q12hrs | 8 |
| Placebo Placebo | 23 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 2 | 0 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 2 | 0 | 1 | 1 |
| Overall Study | Physician discontinued drug | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Sepsis resolved | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Transferred out of Intensive Care Unit | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | AZD9773 Cohort 1 (50 Units/kg) | AZD9773 Cohort 2 (250 Units/kg) | AZD9773 Cohort 3 (250/50 Units/kg) | AZD9773 Cohort 4 (500/100 Units/kg) | AZD9773 Cohort 5 (750/250 Units/kg) | Placebo |
|---|---|---|---|---|---|---|---|
| Age Continuous | 56.1 Year STANDARD_DEVIATION 15.5 | 53 Year STANDARD_DEVIATION 11.8 | 49.7 Year STANDARD_DEVIATION 15 | 55.1 Year STANDARD_DEVIATION 10.8 | 53 Year STANDARD_DEVIATION 17.9 | 63.5 Year STANDARD_DEVIATION 16.1 | 58.9 Year STANDARD_DEVIATION 17.4 |
| Mechanical ventilation Missing | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Mechanical ventilation No | 7 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Mechanical ventilation Yes | 60 Participants | 7 Participants | 8 Participants | 9 Participants | 8 Participants | 8 Participants | 20 Participants |
| Organ failure site Cardiovascular | 19 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 7 Participants |
| Organ failure site Cardiovascular and pulmonary dysfunction | 38 Participants | 4 Participants | 5 Participants | 6 Participants | 6 Participants | 4 Participants | 13 Participants |
| Organ failure site Pulmonary dysfunction | 13 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Female | 38 Participants | 2 Participants | 4 Participants | 7 Participants | 7 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 32 Participants | 6 Participants | 5 Participants | 5 Participants | 3 Participants | 2 Participants | 11 Participants |
| Shock No | 14 Participants | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 1 Participants | 3 Participants |
| Shock Yes | 56 Participants | 5 Participants | 6 Participants | 9 Participants | 9 Participants | 7 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 8 / 9 | 11 / 12 | 7 / 10 | 7 / 8 | 22 / 23 |
| serious Total, serious adverse events | 3 / 8 | 6 / 9 | 7 / 12 | 3 / 10 | 4 / 8 | 13 / 23 |
Outcome results
Primary
Change From Baseline in Alanine Aminotransferase Values
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).
Time frame: End of study (Day 28)
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Alanine Aminotransferase Values | -0.998 μkat/L | Full Range -3.24 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Alanine Aminotransferase Values | 0.017 μkat/L | Full Range -0.25 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Alanine Aminotransferase Values | -3.133 μkat/L | Full Range -20.62 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Alanine Aminotransferase Values | -0.520 μkat/L | Full Range -2.05 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Alanine Aminotransferase Values | -0.825 μkat/L | Full Range -4.53 |
| Placebo | Change From Baseline in Alanine Aminotransferase Values | -0.111 μkat/L | Full Range -0.79 |
Primary
Change From Baseline in Aspartate Aminotransferase Values
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).
Time frame: End of study (Day 28)
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Aspartate Aminotransferase Values | -2.298 μkat/L | Full Range -5.56 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Aspartate Aminotransferase Values | -0.213 μkat/L | Full Range -0.43 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Aspartate Aminotransferase Values | -3.647 μkat/L | Full Range -21.36 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Aspartate Aminotransferase Values | -0.926 μkat/L | Full Range -3.27 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Aspartate Aminotransferase Values | -0.998 μkat/L | Full Range -3.29 |
| Placebo | Change From Baseline in Aspartate Aminotransferase Values | -0.253 μkat/L | Full Range -1.54 |
Primary
Change From Baseline in Bilirubin Values
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).
Time frame: End of study (Day 28)
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Bilirubin Values | -11.30 μmol/L | Full Range -17.1 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Bilirubin Values | -13.10 μmol/L | Full Range -34.2 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Bilirubin Values | -10.04 μmol/L | Full Range -49.6 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Bilirubin Values | -23.71 μmol/L | Full Range -71.8 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Bilirubin Values | -2.58 μmol/L | Full Range -29.1 |
| Placebo | Change From Baseline in Bilirubin Values | -10.00 μmol/L | Full Range -37.6 |
Primary
Change From Baseline in Body Weight
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).
Time frame: Day 6
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Body Weight | 1.3 kg | Full Range -2 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Body Weight | 0.2 kg | Full Range -7 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Body Weight | 4 kg | Full Range 1 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Body Weight | 7.4 kg | Full Range -10 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Body Weight | 0.2 kg | Full Range -11 |
| Placebo | Change From Baseline in Body Weight | 9.9 kg | Full Range 0 |
Primary
Change From Baseline in Calculated Mean Arterial Blood Pressure
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).
Time frame: Day 14
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Calculated Mean Arterial Blood Pressure | 20 mmHg | Full Range 3 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Calculated Mean Arterial Blood Pressure | 7.3 mmHg | Full Range 2 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Calculated Mean Arterial Blood Pressure | 5.3 mmHg | Full Range -19 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Calculated Mean Arterial Blood Pressure | 28.7 mmHg | Full Range 4 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Calculated Mean Arterial Blood Pressure | 6.8 mmHg | Full Range -9 |
| Placebo | Change From Baseline in Calculated Mean Arterial Blood Pressure | 18 mmHg | Full Range -4 |
Primary
Change From Baseline in Creatinine Values
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).
Time frame: End of study (Day 28)
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Creatinine Values | -78.6 μmol/L | Full Range -239 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Creatinine Values | -196.8 μmol/L | Full Range -681 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Creatinine Values | -25.1 μmol/L | Full Range -126 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Creatinine Values | -10.9 μmol/L | Full Range -68 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Creatinine Values | 159.0 μmol/L | Full Range -89 |
| Placebo | Change From Baseline in Creatinine Values | -57.4 μmol/L | Full Range -191 |
Primary
Change From Baseline in Haemoglobin Values
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).
Time frame: End of study (Day 28)
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Haemoglobin Values | 7 g/L | Full Range -18 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Haemoglobin Values | -16.3 g/L | Full Range -42 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Haemoglobin Values | -0.8 g/L | Full Range -31 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Haemoglobin Values | 6.5 g/L | Full Range -5 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Haemoglobin Values | -13.8 g/L | Full Range -35 |
| Placebo | Change From Baseline in Haemoglobin Values | -4.5 g/L | Full Range -47 |
Primary
Change From Baseline in Platelet Count Values
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).
Time frame: End of study (Day 28)
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Platelet Count Values | 287 10^9/L | Full Range -41 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Platelet Count Values | 117.3 10^9/L | Full Range 18 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Platelet Count Values | 162 10^9/L | Full Range -56 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Platelet Count Values | 72.3 10^9/L | Full Range -114 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Platelet Count Values | 252.5 10^9/L | Full Range 40 |
| Placebo | Change From Baseline in Platelet Count Values | 145.1 10^9/L | Full Range -232 |
Primary
Change From Baseline in Prothrombin Time Values
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).
Time frame: Day 7
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Prothrombin Time Values | -3.20 sec | Full Range -8.6 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Prothrombin Time Values | 0.53 sec | Full Range -0.8 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Prothrombin Time Values | -1.00 sec | Full Range -2.4 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Prothrombin Time Values | -5.31 sec | Full Range -14.7 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Prothrombin Time Values | 4.36 sec | Full Range -23.8 |
| Placebo | Change From Baseline in Prothrombin Time Values | 1.68 sec | Full Range -7.5 |
Primary
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.
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).
Time frame: Day 1 (end of infusion) for Cohorts 1 and 2; Day 5 (end of infusion) for Cohorts 3 to 5 and placebo
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | 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. | -9.9 msec | Full Range -37 |
| AZD9773 Cohort 2 (250 Units/kg) | 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. | 3.6 msec | Full Range -35 |
| AZD9773 Cohort 3 (250/50 Units/kg) | 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. | -21.5 msec | Full Range -43 |
| AZD9773 Cohort 4 (500/100 Units/kg) | 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. | -9.2 msec | Full Range -47 |
| AZD9773 Cohort 5 (750/250 Units/kg) | 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. | 21.4 msec | Full Range -32 |
| Placebo | 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. | -3.4 msec | Full Range -61 |
Primary
Change From Baseline in Troponin I
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).
Time frame: Day 6
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Troponin I | -16.454 μg/L | Full Range -127.37 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Troponin I | -9.523 μg/L | Full Range -28.58 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Troponin I | -0.630 μg/L | Full Range -1.61 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Troponin I | -1.434 μg/L | Full Range -7.21 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Troponin I | -0.027 μg/L | Full Range -0.07 |
| Placebo | Change From Baseline in Troponin I | -0.735 μg/L | Full Range -6.77 |
Primary
Change From Baseline in White Blood Cell Values
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).
Time frame: End of study (Day 28)
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in White Blood Cell Values | -17.552 10^9 cells/L | Full Range -46.67 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in White Blood Cell Values | -8.975 10^9 cells/L | Full Range -22.58 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in White Blood Cell Values | 0.413 10^9 cells/L | Full Range -8.11 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in White Blood Cell Values | -0.225 10^9 cells/L | Full Range -5.6 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in White Blood Cell Values | -3.482 10^9 cells/L | Full Range -13.42 |
| Placebo | Change From Baseline in White Blood Cell Values | -9.987 10^9 cells/L | Full Range -26.4 |
Secondary
28-Day Mortality
The number of patients who had died at Day 28. Safety analysis set (ie all patients who started study drug infusion).
Time frame: End of study (Day 28)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | 28-Day Mortality | 2 Participants |
| AZD9773 Cohort 2 (250 Units/kg) | 28-Day Mortality | 4 Participants |
| AZD9773 Cohort 3 (250/50 Units/kg) | 28-Day Mortality | 5 Participants |
| AZD9773 Cohort 4 (500/100 Units/kg) | 28-Day Mortality | 1 Participants |
| AZD9773 Cohort 5 (750/250 Units/kg) | 28-Day Mortality | 1 Participants |
| Placebo | 28-Day Mortality | 6 Participants |
Secondary
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)
AUC(0-12) for single dose AZD9773 serum total Fabs (cohorts 1 and 2). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK).
Time frame: 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]
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | 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) | 125.22 μg.h/mL |
| AZD9773 Cohort 2 (250 Units/kg) | 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) | 581.01 μg.h/mL |
Secondary
AUC(0-12) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
AUC(0-12) of loading dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK).
Time frame: 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]
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9773 Cohort 3 (250/50 Units/kg) | AUC(0-12) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 449.18 μg.h/mL |
| AZD9773 Cohort 4 (500/100 Units/kg) | AUC(0-12) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 691.53 μg.h/mL |
| AZD9773 Cohort 5 (750/250 Units/kg) | AUC(0-12) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 1872.73 μg.h/mL |
Secondary
AUC(0-12) of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
AUC(0-12) of maintenance dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK).
Time frame: 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
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9773 Cohort 3 (250/50 Units/kg) | AUC(0-12) of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 162.82 μg.h/mL |
| AZD9773 Cohort 4 (500/100 Units/kg) | AUC(0-12) of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 251.59 μg.h/mL |
| AZD9773 Cohort 5 (750/250 Units/kg) | AUC(0-12) of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 980.95 μg.h/mL |
Secondary
Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores
Change in SOFA (Sequential Organ Failure Assessment) scores from baseline (pre-infusion) to Day 6 \[calculated as Day 6 mean minus baseline mean\]. The SOFA score is out of a maximum of 24 (units on a scale 0 to 24). The higher the score, the worse the organ system functioning. Safety analysis set (ie all patients who started study drug infusion).
Time frame: Day 6
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores | -6 units on a scale (0 to 24) | Full Range -7 |
| AZD9773 Cohort 2 (250 Units/kg) | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores | -2 units on a scale (0 to 24) | Full Range -5 |
| AZD9773 Cohort 3 (250/50 Units/kg) | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores | -3.3 units on a scale (0 to 24) | Full Range -5 |
| AZD9773 Cohort 4 (500/100 Units/kg) | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores | -3 units on a scale (0 to 24) | Full Range -7 |
| AZD9773 Cohort 5 (750/250 Units/kg) | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores | -6 units on a scale (0 to 24) | Full Range -11 |
| Placebo | Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores | -4.3 units on a scale (0 to 24) | Full Range -8 |
Secondary
Cinf of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
Cinf of maintenance dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK).
Time frame: 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
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9773 Cohort 3 (250/50 Units/kg) | Cinf of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 28.37 μg/mL |
| AZD9773 Cohort 4 (500/100 Units/kg) | Cinf of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 42.51 μg/mL |
| AZD9773 Cohort 5 (750/250 Units/kg) | Cinf of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 151.76 μg/mL |
Secondary
Maximum (End of Infusion) Serum Concentration (Cinf) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3,4 and 5)
Cinf of loading dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK).
Time frame: 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]
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9773 Cohort 3 (250/50 Units/kg) | Maximum (End of Infusion) Serum Concentration (Cinf) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3,4 and 5) | 107.84 μg/mL |
| AZD9773 Cohort 4 (500/100 Units/kg) | Maximum (End of Infusion) Serum Concentration (Cinf) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3,4 and 5) | 160.09 μg/mL |
| AZD9773 Cohort 5 (750/250 Units/kg) | Maximum (End of Infusion) Serum Concentration (Cinf) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3,4 and 5) | 351.52 μg/mL |
Secondary
Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ)
Number of patients below tumour necrosis factor (TNF)-alpha limit of quantification (LOQ) at 24 hours (n\< LOQ) measured by ELISA (LOQ = 1.3 pg/mL). Safety analysis set (ie all patients who started study drug infusion).
Time frame: 24 hours
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ) | 1.0 Participants |
| AZD9773 Cohort 2 (250 Units/kg) | Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ) | 3.0 Participants |
| AZD9773 Cohort 3 (250/50 Units/kg) | Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ) | 5.0 Participants |
| AZD9773 Cohort 4 (500/100 Units/kg) | Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ) | 6.0 Participants |
| AZD9773 Cohort 5 (750/250 Units/kg) | Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ) | 4.0 Participants |
| Placebo | Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ) | 0.0 Participants |
Secondary
Terminal Half-life (t1/2) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2)
t1/2 of single dose AZD9773 serum total Fabs (cohorts 1 and 2). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK).
Time frame: 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]
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Terminal Half-life (t1/2) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2) | 17.97 Hours | Full Range 7.8 |
| AZD9773 Cohort 2 (250 Units/kg) | Terminal Half-life (t1/2) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2) | 19.76 Hours | Full Range 10.5 |
Secondary
Time to Reach Cinf (Tmax) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
tmax of loading dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK).
Time frame: 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]
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD9773 Cohort 3 (250/50 Units/kg) | Time to Reach Cinf (Tmax) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 0.92 Hours |
| AZD9773 Cohort 4 (500/100 Units/kg) | Time to Reach Cinf (Tmax) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 1.08 Hours |
| AZD9773 Cohort 5 (750/250 Units/kg) | Time to Reach Cinf (Tmax) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 1.12 Hours |
Secondary
Tmax of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
tmax of maintenance dose AZD9773 serum total Fabs (cohorts 3, 4 and 5). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK).
Time frame: 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
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD9773 Cohort 3 (250/50 Units/kg) | Tmax of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 0.54 Hours |
| AZD9773 Cohort 4 (500/100 Units/kg) | Tmax of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 1.00 Hours |
| AZD9773 Cohort 5 (750/250 Units/kg) | Tmax of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5) | 0.74 Hours |
Secondary
Total Apparent Clearance (CL) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2)
CL of single dose AZD9773 serum total Fabs (cohorts 1 and 2). PK analysis set (ie a subset of the safety analysis set including only those patients without important deviations that could affect the PK).
Time frame: 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]
Population: Participants analyzed relates to the number of evaluable patients at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD9773 Cohort 1 (50 Units/kg) | Total Apparent Clearance (CL) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2) | 6.11 mL/min/kg | Full Range 1.2 |
| AZD9773 Cohort 2 (250 Units/kg) | Total Apparent Clearance (CL) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2) | 7.61 mL/min/kg | Full Range 0.8 |