AZD9773 Dose Escalation Study

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

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.

Study Overview

• Status: Completed
• Conditions: Severe Sepsis
• Intervention / Treatment: Other: Placebo; Drug: AZD9773 (CytoFab)

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States
      • Research Site
  • Delaware
    • Newark, Delaware, United States
      • Research Site
  • Florida
    • Bay Pines, Florida, United States
      • Research Site
    • Miami, Florida, United States
      • Research Site
  • Illinois
    • Chicago, Illinois, United States
      • Research Site
    • Oak Park, Illinois, United States
      • Research Site
    • Peoria, Illinois, United States
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States
      • Research Site
  • Iowa
    • Iowa City, Iowa, United States
      • Research Site
  • Kentucky
    • Hazard, Kentucky, United States
      • Research Site
    • Lexington, Kentucky, United States
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States
      • Research Site
  • Missouri
    • Kansas City, Missouri, United States
      • Research Site
  • New Jersey
    • Camden, New Jersey, United States
      • Research Site
    • Newark, New Jersey, United States
      • Research Site
  • New York
    • Brooklyn, New York, United States
      • Research Site
    • New York, New York, United States
      • Research Site
    • Rochester, New York, United States
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States
      • Research Site
    • Greensboro, North Carolina, United States
      • Research Site
    • Winston Salem, North Carolina, United States
      • Research Site
  • Ohio
    • Columbus, Ohio, United States
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States
      • Research Site
  • Texas
    • Galveston, Texas, United States
      • Research Site
    • Houston, Texas, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Steven Simonson, MD, AstraZeneca

Publications and helpful links

General Publications

• Yates JW, Das S, Mainwaring G, Kemp J. Population pharmacokinetic/pharmacodynamic modelling of the anti-TNF-alpha polyclonal fragment antibody AZD9773 in patients with severe sepsis. J Pharmacokinet Pharmacodyn. 2012 Dec;39(6):591-9. doi: 10.1007/s10928-012-9270-4. Epub 2012 Sep 23.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: January 31, 2008
• First Submitted That Met QC Criteria: February 1, 2008
• First Posted (Estimate): February 14, 2008

Study Record Updates

• Last Update Posted (Estimate): August 22, 2013
• Last Update Submitted That Met QC Criteria: July 19, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: septic shock; Sepsis; Systemic Inflammatory Response Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis
• Other Study ID Numbers: D0620C00004