AZD9773 Dose Escalation Study

Phase 2

Completed

• Conditions: Severe Sepsis
• Interventions: Drug: AZD9773 (CytoFab); Other: Placebo

• Registration Number: NCT00615017
• Lead Sponsor: AstraZeneca

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2008-01
• Study First Submitted: 2008-01-31
• Study First Submitted QC: 2008-02-01
• Study First Posted: 2008-02-14
• Primary Completion: 2009-07
• Study Completion: 2009-07
• Results First Submitted: 2012-11-30
• Status Verified: 2013-07
• Results First Submitted QC: 2013-07-19
• Last Update Submitted: 2013-07-19
• Results First Posted: 2013-08-22
• Last Update Posted: 2013-08-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 70

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
AZD9773 cohort 2 (250 units/kg)	AZD9773 (CytoFab)	AZD9773: single infusion of 250 units/kg
AZD9773 cohort 1 (50 units/kg)	AZD9773 (CytoFab)	AZD9773: single infusion of 50 units/kg
AZD9773 cohort 3 (250/50 units/kg)	AZD9773 (CytoFab)	AZD9773: loading infusion of 250 units/kg then 9 maintenance doses of 50 units/kg q12hrs
AZD9773 cohort 4 (500/100 units/kg)	AZD9773 (CytoFab)	AZD9773: loading infusion of 500 units/kg then 9 maintenance doses of 100 units/kg q12hrs
Placebo	Placebo	Placebo
AZD9773 cohort 5 (750/250 units/kg)	AZD9773 (CytoFab)	AZD9773: loading infusion of 750 units/kg then 9 maintenance doses of 250 units/kg q12hrs

Primary Outcome Measures

Name	Time	Method
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 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 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 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 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 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 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 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 Outcome Measures

Name	Time	Method
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).
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).
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).
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).

Trial Locations

Locations (1)

Research Site; 🇺🇸 Houston, Texas, United States