Septic Shock, Severe Sepsis
Conditions
Keywords
severe sepsis, TNF neutralisation, septic shock patients
Brief summary
The primary purpose of this study to evaluate the effect of two different doses of AZD9773 (CytoFab™) versus placebo on ventilator free days (VFDs) over the first 28 days after the start of dosing with AZD9773 in patients with severe sepsis and/or septic shock, who are already receiving appropriate standard of care treatment for sepsis.
Interventions
DRUGAZD9773
A single loading dose following by up to 9 maintenance doses; doses to be given every 12 hours over a period of 5 days
DRUGPlacebo
Placebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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. Stage III or IV cancer. 3. Haemopoietic or lymphoreticular malignancies not in remission. 4. Receiving radiation therapy or chemotherapy. 5. Stem cell, organ or bone marrow transplant in the past 6 months. 6. Absolute neutrophil count \<500 per μL. 7. High dose steroids or other immunocompromising drugs. * Concomitant diseases: 1. Deep seated fungal infection or active tuberculosis. 2. Cirrhosis with portal hypertension or Childs-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 IV due to heart failure or any disorder. 8. Burns over \> 30% of body surface area. * 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 latex, papain, chymopapain.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ventilator-free Days (VFDs) Over 28 Days | Over 28 days following first dose | Number of ventilator-free days (VFDs) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 7-day Mortality | Over 7 days following first dose | Number of patients who died over 7 days |
| 28-day Mortality | Over 28 days following first dose | Number of patients who died over 28 days |
| Safety and Tolerability | All study visits (over 90 days following first dose) | Number of patients with treatment-emergent adverse events |
Countries
Australia, Belgium, Canada, Czechia, Finland, France, Spain
Participant flow
Recruitment details
Subjects were screened and enrolled from approximately 100 centres worldwide.
Participants by arm
| Arm | Count |
|---|---|
| AZD9773 250/50 Units/kg AZD9773 250/50 units/kg IV | 100 |
| AZD9773 500/100 Units/kg AZD9773 500/100 units/kg IV | 100 |
| Placebo Saline | 100 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Accidental unblinding of study treatment | 0 | 1 | 0 |
| Overall Study | False insurance information | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 |
| Overall Study | No study drug by 24h after organ failure | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 |
| Overall Study | Withdrawal of therapy | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | AZD9773 250/50 Units/kg | AZD9773 500/100 Units/kg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 15.76 | 66.6 years STANDARD_DEVIATION 14.61 | 64.1 years STANDARD_DEVIATION 15.25 | 65.0 years STANDARD_DEVIATION 15.21 |
| Sex: Female, Male Female | 40 Participants | 40 Participants | 32 Participants | 112 Participants |
| Sex: Female, Male Male | 60 Participants | 60 Participants | 68 Participants | 188 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 | 74 / 100 | 71 / 97 | 68 / 99 |
| serious Total, serious adverse events | 28 / 100 | 27 / 97 | 31 / 99 |
Outcome results
Primary
Ventilator-free Days (VFDs) Over 28 Days
Number of ventilator-free days (VFDs)
Time frame: Over 28 days following first dose
Population: Intention-to-treat analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD9773 250/50 Units/kg | Ventilator-free Days (VFDs) Over 28 Days | 21.0 Days |
| AZD9773 500/100 Units/kg | Ventilator-free Days (VFDs) Over 28 Days | 17.5 Days |
| Placebo | Ventilator-free Days (VFDs) Over 28 Days | 19.0 Days |
Secondary
28-day Mortality
Number of patients who died over 28 days
Time frame: Over 28 days following first dose
Population: Intention-to-treat analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9773 250/50 Units/kg | 28-day Mortality | 15 Participants |
| AZD9773 500/100 Units/kg | 28-day Mortality | 27 Participants |
| Placebo | 28-day Mortality | 20 Participants |
Secondary
7-day Mortality
Number of patients who died over 7 days
Time frame: Over 7 days following first dose
Population: Intention-to-treat analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9773 250/50 Units/kg | 7-day Mortality | 9 Participants |
| AZD9773 500/100 Units/kg | 7-day Mortality | 9 Participants |
| Placebo | 7-day Mortality | 10 Participants |
Secondary
Safety and Tolerability
Number of patients with treatment-emergent adverse events
Time frame: All study visits (over 90 days following first dose)
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9773 250/50 Units/kg | Safety and Tolerability | 86 Participants |
| AZD9773 500/100 Units/kg | Safety and Tolerability | 87 Participants |
| Placebo | Safety and Tolerability | 92 Participants |