AZD9773 Dose Escalation Study

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT00615017
First received: January 31, 2008
Last updated: July 19, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Severe Sepsis
Drug: AZD9773 (CytoFab)
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Change From Baseline in Creatinine Values [ Time Frame: End of study (Day 28) ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: End of study (Day 28) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: End of study (Day 28) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: End of study (Day 28) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: End of study (Day 28) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 6 ] [ Designated as safety issue: Yes ]
    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. [ Time Frame: Day 1 (end of infusion) for Cohorts 1 and 2; Day 5 (end of infusion) for Cohorts 3 to 5 and placebo ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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).

  • Change From Baseline in Body Weight [ Time Frame: Day 6 ] [ Designated as safety issue: Yes ]
    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).


Secondary Outcome Measures:
  • 28-Day Mortality [ Time Frame: End of study (Day 28) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 6 ] [ Designated as safety issue: Yes ]
    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) [ 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] ] [ Designated as safety issue: No ]
    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) [ 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] ] [ Designated as safety issue: No ]
    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) [ 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] ] [ Designated as safety issue: No ]
    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) [ 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] ] [ Designated as safety issue: No ]
    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) [ 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] ] [ Designated as safety issue: No ]
    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) [ 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] ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    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) [ 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 ] [ Designated as safety issue: No ]
    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) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    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).


Enrollment: 70
Study Start Date: January 2008
Study Completion Date: July 2009
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Placebo Comparator: Placebo
Placebo
Other: Placebo
Placebo

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00615017

  Show 26 Study Locations
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Steven Simonson, MD AstraZeneca
Study Director: Wayne Dankner, MD Parexel
  More Information

No publications provided by AstraZeneca

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT00615017     History of Changes
Other Study ID Numbers: D0620C00004
Study First Received: January 31, 2008
Results First Received: November 30, 2012
Last Updated: July 19, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by AstraZeneca:
Sepsis
septic shock
Systemic Inflammatory Response Syndrome

Additional relevant MeSH terms:
Sepsis
Toxemia
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes

ClinicalTrials.gov processed this record on April 15, 2014