Clinical trial NCT00615017: AZD9773 Dose Escalation Study
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Severe Sepsis
Keywords: Sepsis
septic shock
Systemic Inflammatory Response Syndrome
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2008-02-14
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Change From Baseline in Creatinine Values
timeFrame: End of study (Day 28)
measure: Change From Baseline in Alanine Aminotransferase Values
timeFrame: End of study (Day 28)
measure: Change From Baseline in Aspartate Aminotransferase Values
timeFrame: End of study (Day 28)
measure: Change From Baseline in Bilirubin Values
timeFrame: End of study (Day 28)
measure: Change From Baseline in Haemoglobin Values
timeFrame: End of study (Day 28)
measure: Change From Baseline in White Blood Cell Values
timeFrame: End of study (Day 28)
measure: Change From Baseline in Platelet Count Values
timeFrame: End of study (Day 28)
measure: Change From Baseline in Prothrombin Time Values
timeFrame: Day 7
measure: Change From Baseline in Troponin I
timeFrame: Day 6
measure: 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.
timeFrame: Day 1 (end of infusion) for Cohorts 1 and 2; Day 5 (end of infusion) for Cohorts 3 to 5 and placebo
measure: Change From Baseline in Calculated Mean Arterial Blood Pressure
timeFrame: Day 14
measure: Change From Baseline in Body Weight
timeFrame: Day 6
Secondary outcomes:
measure: 28-Day Mortality
timeFrame: End of study (Day 28)
measure: Change From Baseline in Sequential Organ Failure Assessment (SOFA) Scores
timeFrame: Day 6
measure: 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)
timeFrame: 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]
measure: Terminal Half-life (t1/2) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2)
timeFrame: 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]
measure: Total Apparent Clearance (CL) of Single Dose AZD9773 Serum Total Fabs (Cohorts 1 and 2)
timeFrame: 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]
measure: AUC(0-12) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
timeFrame: 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]
measure: Maximum (End of Infusion) Serum Concentration (Cinf) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3,4 and 5)
timeFrame: 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]
measure: Time to Reach Cinf (Tmax) of Loading Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
timeFrame: 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]
measure: AUC(0-12) of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
timeFrame: 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
measure: Cinf of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
timeFrame: 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
measure: Tmax of Maintenance Dose AZD9773 Serum Total Fabs (Cohorts 3, 4 and 5)
timeFrame: 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
measure: Number of Patients Below Tumour Necrosis Factor (TNF)-Alpha Limit of Quantification (LOQ) at 24 Hours (n< LOQ)
timeFrame: 24 hours
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Research Site
state: Alabama
city: Newark
country: United States
facility: Research Site
state: Delaware
city: Bay Pines
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Oak Park
country: United States
facility: Research Site
state: Illinois
city: Peoria
country: United States
facility: Research Site
state: Illinois
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Iowa City
country: United States
facility: Research Site
state: Iowa
city: Hazard
country: United States
facility: Research Site
state: Kentucky
city: Lexington
country: United States
facility: Research Site
state: Kentucky
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Kansas City
country: United States
facility: Research Site
state: Missouri
city: Camden
country: United States
facility: Research Site
state: New Jersey
city: Newark
country: United States
facility: Research Site
state: New Jersey
city: Brooklyn
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Rochester
country: United States
facility: Research Site
state: New York
city: Durham
country: United States
facility: Research Site
state: North Carolina
city: Greensboro
country: United States
facility: Research Site
state: North Carolina
city: Winston Salem
country: United States
facility: Research Site
state: North Carolina
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Galveston
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
Study officials:
affiliation: AstraZeneca
name: Steven Simonson, MD
role: STUDY_DIRECTOR
affiliation: Parexel
name: Wayne Dankner, MD
role: STUDY_DIRECTOR
References:
citation: 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.