AZD9773 Dose Escalation Study

Study 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.

Official Title
-----------------
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

Conditions
-----------------
Severe Sepsis

Intervention / Treatment
-----------------
* Drug: AZD9773 (CytoFab)
* Other: Placebo


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD9773 cohort 1 (50 units/kg)<br>AZD9773: single infusion of 50 units/kg | Drug: AZD9773 (CytoFab)<br>* intravenous infusions<br>|
| Experimental: AZD9773 cohort 2 (250 units/kg)<br>AZD9773: single infusion of 250 units/kg | Drug: AZD9773 (CytoFab)<br>* intravenous infusions<br>|
| Experimental: AZD9773 cohort 3 (250/50 units/kg)<br>AZD9773: loading infusion of 250 units/kg then 9 maintenance doses of 50 units/kg q12hrs | Drug: AZD9773 (CytoFab)<br>* intravenous infusions<br>|
| Experimental: AZD9773 cohort 4 (500/100 units/kg)<br>AZD9773: loading infusion of 500 units/kg then 9 maintenance doses of 100 units/kg q12hrs | Drug: AZD9773 (CytoFab)<br>* intravenous infusions<br>|
| Experimental: AZD9773 cohort 5 (750/250 units/kg)<br>AZD9773: loading infusion of 750 units/kg then 9 maintenance doses of 250 units/kg q12hrs | Drug: AZD9773 (CytoFab)<br>* intravenous infusions<br>|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | End of study (Day 28) | 
| 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). | End of study (Day 28) | 
| 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). | End of study (Day 28) | 
| 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). | End of study (Day 28) | 
| 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). | End of study (Day 28) | 
| 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). | End of study (Day 28) | 
| 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). | End of study (Day 28) | 
| 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). | Day 7 | 
| 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). | Day 6 | 
| 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). | Day 1 (end of infusion) for Cohorts 1 and 2; Day 5 (end of infusion) for Cohorts 3 to 5 and placebo | 
| 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). | Day 14 | 
| 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). | Day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-Day Mortality | The number of patients who had died at Day 28. Safety analysis set (ie all patients who started study drug infusion). | End of study (Day 28) | 
| 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). | 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) | 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). | 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) | 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). | 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] | 
| 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). | 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) | 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). | 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) | 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). | 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) | 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). | 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 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). | 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) | 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). | 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) | 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). | 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) | 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). | 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sepsis, septic shock, Systemic Inflammatory Response Syndrome