Introduction
Materials and methods
Study design
Patient population
Dosing
AZD9773 cohort 1 | AZD9773 cohort 2 | AZD9773 cohort 3 | AZD9773 cohort 4 | AZD9773 cohort 5 | |
---|---|---|---|---|---|
Loading dose × 1 |
50 units/kg
(over 90 minutes) |
250 units/kg
(over 225 minutes for first three patients, then 95 minutes for next nine patients) |
250 units/kg
(over 65 minutes for first three patients, then 60 minutes for next nine patients) |
500 units/kg
(over 90 minutes for first three patients, then 60 minutes for next nine patients) |
750 units/kg
(over 75 minutes for first three patients, then 60 minutes for next nine patients) |
Maintenance doses × 9 |
50 units/kg
(over 30 minutes once every 12 hours) |
100 units/kg
(over 30 minutes once every 12 hours) |
250 units/kg
(over 30 minutes once every 12 hours) |
Assessments
Pharmacokinetic and pharmacodynamic assessments
Safety
General sepsis outcomes
Human anti-sheep antibody (HASA) IgG and bridging assay
Statistical analysis
Data and safety monitoring board
Results
Patient disposition
Baseline demographics and disease characteristics
AZD9773 cohort 1 (50 U/kg) (n= 8) | AZD9773 cohort 2 (250 U/kg) (n= 9) | AZD9773 cohort 3 (250/50 U/kg) (n= 12) | AZD9773 cohort 4 (500/100 U/kg) (n= 10) | AZD9773 cohort 5 (750/250 U/kg) (n= 8) | Placebo (n= 23) | Total (n= 70) | |
---|---|---|---|---|---|---|---|
Mean age ± SD, years | 53.0 ± 11.8 | 49.7 ± 15.0 | 55.1 ± 10.8 | 53.0 ± 17.9 | 63.5 ± 16.1 | 58.9 ± 17.4 | 56.1 ± 15.5 |
Male:female, n | 6:2 | 5:4 | 5:7 | 3:7 | 2:6 | 11:12 | 32:38 |
Race, n (%) | |||||||
Caucasian/white | 7 (87.5) | 8 (88.9) | 11 (91.7) | 9 (90.0) | 7 (87.5) | 20 (87.0) | 62 (88.6) |
Black/African American | 1 (12.5) | 1 (11.1) | 1 (8.3) | 0 | 1 (12.5) | 2 (8.7) | 6 (8.6) |
Other | 0 | 0 | 0 | 1 (10.0) | 0 | 1 (4.3) | 2 (2.9) |
Shock, n (%) | |||||||
Yes | 5 (62.5) | 6 (66.7) | 9 (75.0) | 9 (90.0) | 7 (87.5) | 20 (87.0) | 56 (80.0) |
No | 3 (37.5) | 3 (33.3) | 3 (25.0) | 1 (10.0) | 1 (12.5) | 3 (13.0) | 14 (20.0) |
On ventilator, n (%)* | |||||||
Yes | 7 (87.5) | 8 (100.0) | 9 (81.8) | 8 (88.9) | 8 (100.0) | 20 (87.0) | 60 (89.6) |
No | 1 (12.5) | 0 | 2 (18.2) | 1 (11.1) | 0 | 3 (13.0) | 7 (10.4) |
Missing | 0 | 1 | 1 | 1 | 0 | 0 | 3 |
Shock + ventilator, n (%)* | 4 (50.0) | 5 (55.6) | 7 (58.3) | 7 (70.0) | 7 (87.5) | 17 (73.9) | 47 (67.1) |
Organ failures, n (%)** | |||||||
0 | 1 (12.5) | 0 | 1 (8.3) | 0 | 0 | 0 | 2 (2.9) |
1 | 0 | 0 | 2 (16.7) | 2 (20.0) | 2 (25.0) | 1 (4.3) | 7 (10.0) |
2 | 2 (25.0) | 3 (33.3) | 2 (16.7) | 1 (10.0) | 1 (12.5) | 5 (21.7) | 14 (20.0) |
3 | 3 (37.5) | 4 (44.4) | 3 (25.0) | 3 (30.0) | 1 (12.5) | 9 (39.1) | 23 (32.9) |
≥ 4 | 2 (25.0) | 2 (22.2) | 4 (33.3) | 4 (40.0) | 4 (50.0) | 8 (34.8) | 24 (34.3) |
APACHE II score |
(
n
= 8)
|
(
n
= 9)
|
(
n
= 12)
|
(
n
= 10)
|
(
n
= 7)
|
(
n
= 22)
|
(
n
= 68)
|
Mean ± SD | 28.4 ± 10.3 | 25.1 ± 7.8 | 26.3 ± 11.1 | 22.9 ± 9.0 | 25.1 ± 8.8 | 26.6 ± 8.0 | 25.9 ± 8.9 |
SOFA score |
(
n
= 7)
|
(
n
= 8)
|
(
n
= 7)
|
(
n
= 8)
|
(
n
= 6)
|
(
n
= 20)
|
(
n
= 56)
|
Mean ± SD | 11.9 ± 4.3 | 10.9 ± 3.6 | 10.4 ± 3.4 | 11.5 ± 2.6 | 10.3 ± 3.6 | 10.7 ± 3.0 | 11.0 ± 3.2 |
TNF-α concentration, pg/mL |
(
n
= 8)
|
(
n
= 8)
|
(
n
= 9)
|
(
n
= 9)
|
(
n
= 8)
|
(
n
= 23)
|
(
n
= 65)
|
Median (range) | 4.7 (1.3 to 48.8) | 9.8 (2.7 to 54.3) | 3.6 (1.3 to 14.2) | 3.7 (1.3 to 8.2) | 5.8 (1.3 to 18.3) | 5.0 (1.6 to 61.7) | 5.2 (1.3 to 61.7) |
IL-6 concentration, pg/mL |
(
n
= 7)
|
(
n
= 7)
|
(
n
= 9)
|
(
n
= 8)
|
(
n
= 7)
|
(
n
= 19)
|
(
n
= 57)
|
Median (range) | 465 (18 to 23,733) | 189 (47 to 85,183) | 215 (24 to 13,849) | 1403 (135 to 16,168) | 336 (194 to 94,207) | 454 (28 to 153,600) | 336 (18 to 153,600) |
Procalcitonin level, ng/mL |
(
n
= 8)
|
(
n
= 8)
|
(
n
= 10)
|
(
n
= 10)
|
(
n
= 6)
|
(
n
= 23)
|
(
n
= 65)
|
Median (range) | 28.5 (1.8 to 456.4) | 4.8 (0.3 to 250.9) | 4.0 (0.3 to 800.3) | 16.5 (1.3 to 89.6) | 15.1 (2.5 to 17.1) | 14.7 (0.3 to 328.5) | 14.2 (0.3 to 800.3) |
> 0.5 ng/mL, n (%) | 8 (100) | 7 (87.5) | 7 (70.0) | 10 (100) | 6 (100) | 22 (95.7) | 60 (92.3) |
Total fluid volume in 24 h prior to randomization, mL/kg |
(
n
= 8)
|
(
n
= 9)
|
(
n
= 11)
|
(
n
= 7)
|
(
n
= 8)
|
(
n
= 23)
|
(
n
= 66)
|
Median (range) | 51.7 (23.8 to 167.6) | 58.0 (6.4 to 158.6) | 40.1 (11.1 to 183.4) | 34.0 (17.2 to 196.8) | 58.5 (29.3 to 434.1) | 58.4 (8.7 to 373.5) | 56.4 (6.4 to 434.1) |
Relevant medical history, n (%)† | |||||||
Diabetes | 1 (12.5) | 4 (44.4) | 4 (33.3) | 3 (30.0) | 3 (37.5) | 7 (30.4) | 22 (31.4) |
COPD | 3 (37.5) | 2 (22.2) | 2 (16.7) | 2 (20.0) | 3 (37.5) | 4 (17.4) | 16 (22.9) |
Chronic renal failure | 1 (12.5) | 2 (22.2) | 0 | 1 (10.0) | 0 | 0 | 4 (5.7) |
Colon cancer | 0 | 0 | 0 | 0 | 1 (12.5) | 1 (4.3) | 2 (2.9) |
AZD9773 cohort 1 (50 U/kg) (n= 8) | AZD9773 cohort 2 (250 U/kg) (n= 9) | AZD9773 cohort 3 (250/50 U/kg) (n= 12) | AZD9773 cohort 4 (500/100 U/kg) (n= 10) | AZD9773 cohort 5 (750/250 U/kg) (n= 8) | Placebo (n= 23) | Total (n= 70) | |
---|---|---|---|---|---|---|---|
Infection site, n (%) | |||||||
Abdomen | 2 (25.0) | 3 (33.3) | 2 (16.7) | 1 (10.0) | 5 (62.5) | 3 (13.0) | 16 (22.9) |
Catheter/device | 1 (12.5) | 0 | 0 | 0 | 0 | 0 | 1 (1.4) |
Lung | 3 (37.5) | 4 (44.4) | 6 (50.0) | 6 (60.0) | 2 (25.0) | 12 (52.2) | 33 (47.1) |
Skin and soft tissue | 1 (12.5) | 1 (11.1) | 1 (8.3) | 1 (10.0) | 0 | 4 (17.4) | 8 (11.4) |
Unknown | 1 (12.5) | 1 (11.1) | 2 (16.7) | 2 (20.0) | 0 | 1 (4.3) | 7 (10.0) |
Urinary tract | 0 | 0 | 3 (25.0) | 0 | 1 (12.5) | 3 (13.0) | 7 (10.0) |
Time from qualifying organ failure to first antibiotic use, hours* | |||||||
(
n
= 7)
|
(
n
= 6)
|
(
n
= 9)
|
(
n
= 7)
|
(
n
= 8)
|
(
n
= 19)
|
(
n
= 56)
| |
Median (range) | -4.4 (-39.0 to 20.6) | -10.1 (-85.7 to 0.7) | -0.8 (-41.3 to 16.4) | -3.9 (-108.2 to 1.2) | -6.3 (-85.1 to 6.5) | -4.9 (-366.5 to 12.8) | -4.2 (-366.5 to 20.6) |
Pharmacokinetics of AZD9773
AZD9773 cohort 1 (50 U/kg) (n= 7) | AZD9773 cohort 2 (250 U/kg) (n= 8) | AZD9773 cohort 3 (250/50 U/kg) (n= 6)§ | AZD9773 cohort 4 (500/100 U/kg) (n= 7)§ | AZD9773 cohort 5 (750/250 U/kg) (n= 4)§ | |
---|---|---|---|---|---|
AUC0-12, μg.h/mL*‡ | 125.2 ± 79.8 | 581.0 ± 94.04 | 449.2 ± 46.8 | 691.5 ± 22.7 | 1872 ± 28.4 |
AUC0-12, μg.h/mL* | - | - | 162.8 ± 82.2 | 251.6 ± 56.0 | 981.0 ± 39.3 |
Cinf, μg/mL*‡ | 29.6 ± 112.5 | 156.2 ± 208.1 | - | - | - |
Cinf, μg/mL* | - | - | 28.4 ± 52.9 | 42.5 ± 83.5 | 151.8 ± 14.7 |
Accumulation ratio* | - | - | 1.9 ± 32.0 | 1.6 ± 79.1 | 1.6 ± 38.1 |
tmax, hours** | 1.5 (1.4 to 3.5) | 2.1 (1.0 to 4.3) | 0.5 (0 to 0.7) | 1.0 (0.4 to 8.5) | 0.7 (0.5 to 1.6) |
t1/2, hours† | 18.0 ± 7.3 | 19.8 ± 5.2 | - | - | - |
CL, mL/min/kg† | 6.1 ± 3.4 | 7.6 ± 6.0 | - | - | - |
Vss, mL/kg† | 92.6 ± 30.8 | 152.8 ± 132.8 | - | - | - |
Dose excreted, %* | 10.6 ± 69.3 | 15.0 ± 100.4 | 15.2 ± 57.1 | 11.8 ± 94.0 | 20.9 ± 223.1 |
Pharmacodynamics of AZD9773
TNF-α concentrations
IL-6 concentrations
Procalcitonin levels
Safety of AZD9773
Adverse events
AZD9773 cohort 1 (50 U/kg) (n= 8) | AZD9773 cohort 2 (250 U/kg) (n= 9) | AZD9773 cohort 3 (250/50 U/kg) (n= 12) | AZD9773 cohort 4 (500/100 U/kg) (n= 10) | AZD9773 cohort 5 (750/250 U/kg) (n= 8) | Placebo (n= 23) | |
---|---|---|---|---|---|---|
Patients with any TEAE | 8 (100.0) | 9 (100.0) | 12 (100.0) | 8 (80.0) | 7 (87.5) | 23 (100.0) |
Anemia | 1 (12.5) | 3 (33.3) | 2 (16.7) | 1 (10.0) | 2 (25.0) | 4 (17.4) |
Agitation | 2 (25.0) | 2 (22.2) | 1 (8.3) | 3 (30.0) | 1 (12.5) | 4 (17.4) |
Constipation | 2 (25.0) | 2 (22.2) | 2 (16.7) | 1 (10.0) | 0 | 6 (26.1) |
Generalized edema | 0 | 1 (11.1) | 3 (25.0) | 2 (20.0) | 3 (37.5) | 3 (13.0) |
Hypoglycemia | 1 (12.5) | 1 (11.1) | 1 (8.3) | 4 (40.0) | 3 (37.5) | 2 (8.7) |
Hypokalemia | 2 (25.0) | 1 (11.1) | 0 | 2 (20.0) | 0 | 7 (30.4) |
Hypernatremia | 1 (12.5) | 1 (11.1) | 0 | 3 (30.0) | 2 (25.0) | 2 (8.7) |
Hypophosphatemia | 2 (25.0) | 1 (11.1) | 0 | 2 (20.0) | 1 (12.5) | 2 (8.7) |
Diarrhea | 2 (25.0) | 0 | 0 | 1 (10.0) | 1 (12.5) | 4 (17.4) |
Edema peripheral | 2 (25.0) | 0 | 0 | 0 | 1 (12.5) | 4 (17.4) |
Insomnia | 1 (12.5) | 2 (22.2) | 0 | 1 (10.0) | 0 | 2 (8.7) |
Sepsis | 1 (12.5) | 0 | 3 (25.0) | 0 | 0 | 1 (4.3) |
Wheezing | 1 (12.5) | 2 (22.2) | 0 | 1 (10.0) | 0 | 1 (4.3) |
Bradycardia | 0 | 0 | 0 | 2 (20.0) | 0 | 3 (13.0) |
Feeding disorder | 1 (12.5) | 2 (22.2) | 0 | 0 | 0 | 1 (4.3) |
Decubitus ulcer | 1 (12.5) | 0 | 0 | 2 (20.0) | 1 (12.5) | 0 |
Hypertension | 0 | 1 (11.1) | 0 | 2 (20.0) | 1 (12.5) | 0 |
Scleral hemorrhage | 2 (25.0) | 0 | 0 | 0 | 0 | 0 |
AZD9773 cohort 1 (50 U/kg) (n= 8) | AZD9773 cohort 2 (250 U/kg) (n= 9) | AZD9773 cohort 3 (250/50 U/kg) (n= 12) | AZD9773 cohort 4 (500/100 U/kg) (n= 10) | AZD9773 cohort 5 (750/250 U/kg) (n= 8) | Placebo (n= 23) | |
---|---|---|---|---|---|---|
Patients with any serious TEAE | 3 (37.5) | 6 (66.7) | 7 (58.3) | 3 (30.0) | 4 (50.0) | 13 (56.5) |
Sepsis | 1 (12.5) | 0 | 3 (25.0) | 0 | 0 | 1 (4.3) |
Pneumonia | 1 (12.5) | 1 (11.1) | 0 | 0 | 0 | 2 (8.7) |
Septic shock | 0 | 1 (11.1) | 0 | 0 | 1 (12.5) | 2 (8.7) |
Respiratory failure | 0 | 0 | 0 | 2 (20.0) | 0 | 2 (8.7) |
Cardiac arrest | 1 (12.5) | 1 (11.1) | 0 | 0 | 0 | 1 (4.3) |
Pulmonary embolism | 0 | 1 (11.1) | 0 | 0 | 1 (12.5) | 1 (4.3) |
Deep vein thrombosis | 0 | 0 | 1 (8.3) | 1 (10.0) | 0 | 1 (4.3) |
Hemorrhagic shock | 0 | 0 | 1 (8.3) | 0 | 0 | 1 (4.3) |
Empyema | 0 | 0 | 1 (8.3) | 0 | 0 | 0 |
Endocarditis | 0 | 1 (11.1) | 0 | 0 | 0 | 0 |
Cellulitis | 0 | 0 | 0 | 0 | 0 | 1 (4.3) |
Acute myocardial infarction | 0 | 0 | 0 | 1 (10.0) | 0 | 0 |
Cardiac failure | 0 | 0 | 1 (8.3) | 0 | 0 | 0 |
Supraventricular tachycardia | 0 | 0 | 0 | 1 (10.0) | 0 | 0 |
Atrial fibrillation | 0 | 0 | 0 | 0 | 0 | 1 (4.3) |
Pneumonia aspiration | 0 | 0 | 0 | 1 (10.0) | 0 | 0 |
Hypoxia | 0 | 0 | 0 | 0 | 0 | 1 (4.3) |
Shock | 0 | 0 | 1 (8.3) | 0 | 0 | 0 |
Peripheral ischemia | 0 | 0 | 0 | 0 | 0 | 1 (4.3) |
Enterocutaneous fistula | 0 | 0 | 0 | 0 | 1 (12.5) | 0 |
Intestinal ischemia | 0 | 0 | 0 | 0 | 1 (12.5) | 0 |
Intestinal perforation | 0 | 0 | 0 | 0 | 0 | 1 (4.3) |
Medical device complication | 0 | 1 (11.1) | 0 | 0 | 0 | 0 |
Acidosis | 0 | 1 (11.1) | 0 | 0 | 0 | 0 |
Malignant lung neoplasm | 0 | 1 (11.1) | 0 | 0 | 0 | 0 |
Cerebral infarction | 0 | 0 | 1 (8.3) | 0 | 0 | 0 |
Intracranial hemorrhage | 0 | 0 | 0 | 0 | 0 | 1 (4.3) |
Toxic epidermal necrolysis | 1 (12.5) | 0 | 0 | 0 | 0 | 0 |
Muscle hemorrhage | 0 | 0 | 0 | 0 | 0 | 1 (4.3) |
Treatment-emergent infections
Laboratory data
Electrocardiogram assessment
Mortality
AZD9773 cohort 1 (50 U/kg) (n= 8) | AZD9773 cohort 2 (250 U/kg) (n= 9) | AZD9773 cohort 3 (250/50 U/kg) (n= 12) | AZD9773 cohort 4 (500/100 U/kg) (n= 10) | AZD9773 cohort 5 (750/250 U/kg) (n= 8) | Placebo (n= 23) | |
---|---|---|---|---|---|---|
Alive, n (%) | 6 (75.0) | 5 (55.6) | 7 (58.3) | 9 (90.0) | 7 (87.5) | 16 (69.6) |
Dead, n (%) | 2 (25.0) | 4 (44.4) | 5 (41.7) | 1 (10.0) | 1 (12.5) | 6 (26.1) |
Lost to follow-up, n (%) | 0 | 0 | 0 | 0 | 0 | 1 (4.3) |