A Study to Assess Safety,and Tolerability of 2 Doses of AZD9773 (CytoFab™) in Japanese With Severe Sepsis/Septic Shock

A Phase II, Multicentre, Randomised, Double-Blind, Placebo-Controlled, Dose Escalation Study to Assess the Safety, Tolerability and Pharmacokinetics of Intravenous Infusions of AZD9773 (CytoFab™) in Japanese Patients With Severe Sepsis and/or Septic Shock

The two co-primary objectives of this study are to assess in Japanese patients with severe sepsis and/or septic shock: 1) the safety and tolerability of two different doses of intravenous AZD9773 and 2) the PK of AZD9773.

The secondary objective is to make a preliminary assessment of the pharmacodynamics of two different doses of intravenous AZD9773 in Japanese patients with severe sepsis and/or septic shock.

Study Overview

• Status: Completed
• Conditions: Septic Shock; Severe Sepsis
• Intervention / Treatment: Drug: AZD9773; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Osaka, Japan
    • Research Site
  • Hokkaido
    • Sapporo-shi, Hokkaido, Japan
      • Research Site
  • Hyogo
    • Kobe, Hyogo, Japan
      • Research Site
  • Kumamoto
    • Kumamoto-Shi, Kumamoto, Japan
      • Research Site
  • Osaka
    • Sumiyoshi-ku, Osaka, Japan
      • Research Site
  • Tokyo
    • Hachioji, Tokyo, Japan
      • Research Site
    • Ohta-ku, Tokyo, Japan
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Japanese adults with a first episode of sepsis during this hospitalisation and objective evidence of infection that requires parenteral antibiotics.
• At least 2 of 4 SIRS criteria in the 24 hours before organ dysfunction (must include either fever OR elevated white blood cells [WBC])
• Cardiovascular or respiratory dysfunction.

Exclusion Criteria:

• Immunocompromising comorbidities or concomitant medications:

  1. Advanced human immunodeficiency virus (HIV) infection (CD4 ≤50/mm3).
  2. Haemopoietic or lymphoreticular malignancies not in remission.
  3. Receiving radiation therapy or chemotherapy.
  4. Any organ or bone marrow transplant within the past 24 weeks.
  5. Absolute neutrophil count <500 per μL.
  6. High dose steroids or other immunocompromising drugs.

• Concomitant diseases:

  1. Deep-seated fungal infection or active tuberculosis.
  2. Severe chronic liver disease associated with portal hypertension, cirrhosis, chronic ascites or Child-Pugh class C.
  3. History of chronic hypercarbia, respiratory failure in past 6 months or use of home oxygen in the setting of severe chronic respiratory disease.
  4. Neuromuscular disorders that impact breathing/spontaneous ventilation.
  5. Quadriplegia.
  6. Cardiac arrest in the past 30 days.
  7. New York Heart Association functional Class III or IV due to heart failure or any disorder.
  8. Burns over > 30% of body surface area in the past 5 days.

• Medication and allergy disqualifications.

  1. Treatment with anti-TNF agents within the last 8 weeks.
  2. Previously received ovine derived products (CroFab™, DigiFab™).
  3. Sheep product allergy or allergy to papain, chymopapain.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2	Drug: Placebo; Intravenous infusion of a saline solution
Experimental: 1; AZD9773 250 units/kg (1 infusion) + 50 units/kg (9 infusions) (Dose Cohort 1): AZD9773 500 units/kg (1 infusion) + 100 units/kg (9 infusions) (Dose Cohort 2)	Drug: AZD9773; A single loading dose followed by 9 maintenance doses; doses to be given every 12 hours over a period of 5 days; Other Names: CytoFab™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of AZD9773	Number of patients with treatment-emergent adverse events and number of patients who died over 28 days	28 day study period
Pharmacokinetics of AZD9773	Maximum concentration at steady state (Cmax ss) for serum total and specific fabs	From first dose to last dose (Day 5/6 or at premature treatment discontinuation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic Effects of AZD9773 on TNF-alpha	TNF-alpha levels over approximately 6 days following the first dose	Levels taken at baseline, over the dosing period (up to Day 5/6)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Wayne Dankner, MD, PAREXEL International Medical Services; Study Director: Warren Botnick, MD, PAREXEL International Medical Services

Publications and helpful links

General Publications

• Aikawa N, Takahashi T, Fujimi S, Yokoyama T, Yoshihara K, Ikeda T, Sadamitsu D, Momozawa M, Maruyama T. A Phase II study of polyclonal anti-TNF-alpha (AZD9773) in Japanese patients with severe sepsis and/or septic shock. J Infect Chemother. 2013 Oct;19(5):931-40. doi: 10.1007/s10156-013-0612-y. Epub 2013 May 17.

Helpful Links

• D0620C00005 Study Report Synopsis
• redacted-CSP-D0620C00005.pdf

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: June 7, 2010
• First Submitted That Met QC Criteria: June 14, 2010
• First Posted (Estimate): June 15, 2010

Study Record Updates

• Last Update Posted (Estimate): October 6, 2014
• Last Update Submitted That Met QC Criteria: September 26, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: TNF neutralisation
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock
• Other Study ID Numbers: D0620C00005