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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Severe Sepsis, Septic Shock

Intervention / Treatment
-----------------
* Drug: AZD9773
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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: Advanced human immunodeficiency virus (HIV) infection (CD4 ≤50/mm3). Haemopoietic or lymphoreticular malignancies not in remission. Receiving radiation therapy or chemotherapy. Any organ or bone marrow transplant within the past 24 weeks. Absolute neutrophil count <500 per μL. High dose steroids or other immunocompromising drugs. Concomitant diseases: Deep-seated fungal infection or active tuberculosis. Severe chronic liver disease associated with portal hypertension, cirrhosis, chronic ascites or Child-Pugh class C. History of chronic hypercarbia, respiratory failure in past 6 months or use of home oxygen in the setting of severe chronic respiratory disease. Neuromuscular disorders that impact breathing/spontaneous ventilation. Quadriplegia. Cardiac arrest in the past 30 days. New York Heart Association functional Class III or IV due to heart failure or any disorder. Burns over > 30% of body surface area in the past 5 days. Medication and allergy disqualifications. Treatment with anti-TNF agents within the last 8 weeks. Previously received ovine derived products (CroFab™, DigiFab™). Sheep product allergy or allergy to papain, chymopapain.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>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<br>* A single loading dose followed by 9 maintenance doses; doses to be given every 12 hours over a period of 5 days<br>* Other names: CytoFab™;|
| Placebo Comparator: 2<br> | Drug: Placebo<br>* Intravenous infusion of a saline solution<br>|

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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TNF neutralisation