Septic Shock, Severe Sepsis
Conditions
Keywords
TNF neutralisation
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.
Interventions
DRUGAZD9773
A single loading dose followed by 9 maintenance doses; doses to be given every 12 hours over a period of 5 days
DRUGPlacebo
Intravenous infusion of a saline solution
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of AZD9773 | 28 day study period | Number of patients with treatment-emergent adverse events and number of patients who died over 28 days |
| Pharmacokinetics of AZD9773 | From first dose to last dose (Day 5/6 or at premature treatment discontinuation) | Maximum concentration at steady state (Cmax ss) for serum total and specific fabs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic Effects of AZD9773 on TNF-alpha | Levels taken at baseline, over the dosing period (up to Day 5/6) | TNF-alpha levels over approximately 6 days following the first dose |
Countries
Japan
Participant flow
Recruitment details
Subjects were screened and enrolled at six centres in Japan.
Participants by arm
| Arm | Count |
|---|---|
| Dose Cohort 1 AZD9773 250/50 units/kg IV | 7 |
| Dose Cohort 2 AZD9773 500/100 units/kg IV | 7 |
| Placebo Saline | 6 |
| Total | 20 |
Baseline characteristics
| Characteristic | Placebo | Total | Dose Cohort 1 | Dose Cohort 2 |
|---|---|---|---|---|
| Age, Continuous | 77.7 years STANDARD_DEVIATION 17.64 | 75.4 years STANDARD_DEVIATION 12.78 | 71.3 years STANDARD_DEVIATION 10.89 | 77.6 years STANDARD_DEVIATION 10.45 |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 9 Participants | 4 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 7 / 7 | 6 / 6 |
| serious Total, serious adverse events | 4 / 7 | 1 / 7 | 1 / 6 |
Outcome results
Primary
Pharmacokinetics of AZD9773
Maximum concentration at steady state (Cmax ss) for serum total and specific fabs
Time frame: From first dose to last dose (Day 5/6 or at premature treatment discontinuation)
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Arm 1 - Dose Cohort 1 | Pharmacokinetics of AZD9773 | Cmax ss for serum total fabs | 38.48 ug/mL |
| Arm 1 - Dose Cohort 1 | Pharmacokinetics of AZD9773 | Cmax ss for serum specific fabs | 1.823 ug/mL |
| Arm 2 - Dose Cohort 2 | Pharmacokinetics of AZD9773 | Cmax ss for serum total fabs | 71.04 ug/mL |
| Arm 2 - Dose Cohort 2 | Pharmacokinetics of AZD9773 | Cmax ss for serum specific fabs | 3.335 ug/mL |
Primary
Safety and Tolerability of AZD9773
Number of patients with treatment-emergent adverse events and number of patients who died over 28 days
Time frame: 28 day study period
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 - Dose Cohort 1 | Safety and Tolerability of AZD9773 | Number of Patients with Treatment-Emergent AEs | 7 Participants |
| Arm 1 - Dose Cohort 1 | Safety and Tolerability of AZD9773 | Number of Patients who Died over 28 days | 1 Participants |
| Arm 2 - Dose Cohort 2 | Safety and Tolerability of AZD9773 | Number of Patients with Treatment-Emergent AEs | 7 Participants |
| Arm 2 - Dose Cohort 2 | Safety and Tolerability of AZD9773 | Number of Patients who Died over 28 days | 0 Participants |
| Arm 3 - Placebo | Safety and Tolerability of AZD9773 | Number of Patients with Treatment-Emergent AEs | 6 Participants |
| Arm 3 - Placebo | Safety and Tolerability of AZD9773 | Number of Patients who Died over 28 days | 2 Participants |
Secondary
Pharmacodynamic Effects of AZD9773 on TNF-alpha
TNF-alpha levels over approximately 6 days following the first dose
Time frame: Levels taken at baseline, over the dosing period (up to Day 5/6)
Population: Safety analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 - Dose Cohort 1 | Pharmacodynamic Effects of AZD9773 on TNF-alpha | TNF-alpha level 1-2 hours post-first dose | 0.920 pg/ml |
| Arm 1 - Dose Cohort 1 | Pharmacodynamic Effects of AZD9773 on TNF-alpha | TNF-alpha level at baseline | 1.000 pg/ml |
| Arm 1 - Dose Cohort 1 | Pharmacodynamic Effects of AZD9773 on TNF-alpha | TNF-alpha level on Day 6 (pre-morning dose) | 1.710 pg/ml |
| Arm 2 - Dose Cohort 2 | Pharmacodynamic Effects of AZD9773 on TNF-alpha | TNF-alpha level at baseline | 1.690 pg/ml |
| Arm 2 - Dose Cohort 2 | Pharmacodynamic Effects of AZD9773 on TNF-alpha | TNF-alpha level 1-2 hours post-first dose | 0.990 pg/ml |
| Arm 2 - Dose Cohort 2 | Pharmacodynamic Effects of AZD9773 on TNF-alpha | TNF-alpha level on Day 6 (pre-morning dose) | 1.140 pg/ml |
| Arm 3 - Placebo | Pharmacodynamic Effects of AZD9773 on TNF-alpha | TNF-alpha level at baseline | 8.810 pg/ml |
| Arm 3 - Placebo | Pharmacodynamic Effects of AZD9773 on TNF-alpha | TNF-alpha level on Day 6 (pre-morning dose) | 1.560 pg/ml |
| Arm 3 - Placebo | Pharmacodynamic Effects of AZD9773 on TNF-alpha | TNF-alpha level 1-2 hours post-first dose | 7.425 pg/ml |