In mechanically ventilated patients with severe community-acquired pneumonia, add-on therapy with trimodulin, a novel polyclonal antibody preparation, did not statistically significantly increase ventilator-free days (primary endpoint) vs. placebo. Exploratory post hoc analyses suggest reductions in mortality for trimodulin compared with placebo in subsets of patients with elevated C-reactive protein levels and/or reduced immunoglobulin M levels, and warrant investigation in a phase III study with a targeted patient population. |
Introduction
Methods
Study design and patient population
Efficacy assessments
Safety
Statistical analysis
Results
Characteristic | Trimodulin (n = 81) | Placebo (n = 79) | p value* |
---|---|---|---|
Sex, n (%) | 0.675 | ||
Male | 56 (69.1) | 57 (72.2) | |
Female | 25 (30.9) | 22 (27.8) |
Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | ||
---|---|---|---|---|---|
Age (years) | 63.7 (14.5) | 66 (53–75) | 65.5 (14.8) | 67 (57–77) | 0.435 |
BMI (kg/m2)a | 26.5 (5.0) | 25.7 (23.3–29.6) | 25.9 (4.7) | 25.5 (23.1–28.0) | 0.410 |
APACHE IIb | 23.1 (8.1) | 23 (18–29) | 26.2 (8.3) | 25 (20–33) | 0.036 |
SOFA | 9.7 (3.8) | 11 (7–12) | 10.8 (3.5) | 11 (8–14) | 0.071 |
CURB-65c | 2.7 (1.1) | 3 (2–4) | 2.8 (1.3) | 3 (2–4) | 0.637 |
PaO2/FiO
2
d
| 134.7 (72.5) | 110.0 (82.0–173.6) | 133.7 (72.5) | 106.5 (77.0–185.7) | 0.937 |
IgM (g/L) | 0.8 (0.79) | 0.6 (0.4–0.9) | 0.7 (0.41) | 0.6 (0.4–0.9) | 0.186 |
IgG (g/L) | 6.8 (2.73) | 6.7 (5.0–8.9) | 6.6 (3.04) | 6.4 (4.2–8.2) | 0.530 |
IgA (g/L) | 2.3 (1.14) | 2.1 (1.4–3.1) | 2.5 (1.78) | 2.0 (1.3–3.2) | 0.322 |
CRP (mg/L)e | 220 (130.8) | 217 (121.5–325.3) | 227 (147.5) | 235 (88.2–333.5) | 0.723 |
PCT (ng/mL)f | 8.3 (12.9) | 2.3 (0.7–10.4) | 23.3 (31.75) | 8.7 (1.9–30.6) | 0.0004 |
Medical history, n (%) | |||||
Cardiac disordersg | 39 (48.1) | 41 (51.9) | 0.752 | ||
Hypertensionh | 42 (51.9) | 42 (53.2) | 0.876 | ||
Diabetes mellitush | 15 (18.5) | 6 (7.6) | 0.060 | ||
Nervous system disordersg | 21 (25.9) | 22 (27.8) | 0.859 | ||
Neoplasm (benign, malignant, and unspecified)g | 22 (27.2) | 17 (21.5) | 0.463 | ||
Renal and urinary disordersg | 41 (50.6) | 40 (50.6) | 1.000 | ||
Sepsish | 13 (16.0) | 10 (12.7) | 0.654 | ||
Septic shockh | 35 (43.2) | 44 (55.7) | 0.154 | ||
Hepatic cirrhosish | 5 (6.2) | 0 (0.0) | 0.059 | ||
Medication at baseline, n (%) | |||||
Corticosteroids for systemic use | 24 (29.6) | 21 (26.6) | 0.375 | ||
Antivirals for systemic use | 11 (13.6) | 12 (15.2) | 0.824 |
Endpoint | Trimodulin | Placebo | p value | ||
---|---|---|---|---|---|
Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | ||
VFDs | n = 81 | n = 79 | |||
11.0 (9.5) | 11.0 (0–20) | 9.6 (9.4) | 8.0 (0–19) | 0.173 * | |
Duration of mechanical ventilation (days)a | n = 81 | n = 79 | |||
12.8 (8.5) | 10.0 (6–19) | 13.8 (8.6) | 11.0 (7–21) | Not calculated | |
VFDs in surviving patients | n = 63 | n = 57 | |||
14.2 (8.4) | 18.0 (8–21) | 13.3 (8.5) | 16.0 (4–20) | 0.271† | |
Vasopressor-free days | n = 81 | n = 79 | |||
13.0 (8.9) | 14.0 (6–20) | 13.7 (8.4) | 15.0 (8–20) | 0.639† | |
Discharge time from ICU (days) | n = 81b | n = 79b | |||
13.4 (5.9) | 11.0 (9–17) | 14.4 (5.8) | 13.0 (10–18) | 0.161† | |
Discharge time from hospital (days) | n = 81 | n = 79 | |||
19.5 (5.5) | 20.0 (15–24) | 19.0 (4.9) | 19.0 (15–23) | 0.479 | |
28-day all-cause mortality, n (%) | 18/81 (22.2) | 22/79 (27.8) | 0.465‡ | ||
28-day pneumonia-related mortality, n (%) | 5/81 (6.2) | 10/79 (12.7) | Not calculated | ||
Change in SOFA score from day 1 to 7 | −4.8 (7.5) | −7.0 (−10–0) | −5.4 (6.5) | −7.0 (−10 to 3.0) | Not calculated |
Trimodulin (n = 81) | Placebo (n = 79) | p value* | |
---|---|---|---|
Overall incidence | 75 (92.6) | 75 (94.9) | 0.746 |
TEAEs with onset during infusion and up to 24 h after infusion end | 67 (82.7) | 67 (84.8) | 0.831 |
Serious TEAEs | 62 (76.5) | 62 (78.5) | 0.850 |
TEAEs with fatal outcomea | 20 (24.7) | 23 (29.1) | 0.594 |
Discontinuation due to TEAEs | 2 (2.5) | 1 (1.3) | 1.000 |
TEAEs by System Organ Class (≥ 5% of patients) | |||
Blood and lymphatic system disorders | 33 (40.7) | 34 (43.0) | 0.873 |
Cardiac disorders | 31 (38.3) | 27 (34.2) | 0.624 |
Vascular disorders | 30 (37.0) | 30 (38.0) | 1.000 |
Metabolism and nutrition disorders | 29 (35.8) | 29 (36.7) | 1.000 |
Respiratory, thoracic, and mediastinal disorders | 29 (35.8) | 40 (50.6) | 0.079 |
Gastrointestinal disorders | 27 (33.3) | 36 (45.6) | 0.145 |
Infections and infestations | 27 (33.3) | 45 (57.0) | 0.004 |
General disorders and administration-site conditions | 22 (27.2) | 31 (39.2) | 0.131 |
Renal and urinary disorders | 20 (24.7) | 12 (15.2) | 0.167 |
Psychiatric disorders | 18 (22.2) | 23 (29.1) | 0.367 |
Investigations | 15 (18.5) | 13 (16.5) | 0.836 |
Skin and subcutaneous tissue disorders | 14 (17.3) | 14 (17.7) | 1.000 |
Nervous system disordersb | 13 (16.0) | 8 (10.1) | 0.350 |
Hepatobiliary disorders | 12 (14.8) | 4 (5.1) | 0.063 |
Musculoskeletal and connective tissue disorders | 9 (11.1) | 11 (13.9) | 0.639 |
Injury, poisoning, and connective tissue disorders | 8 (9.9) | 8 (10.1) | 1.000 |
Patient subset | Trimodulin | Placebo | p value* |
---|---|---|---|
VFD mean (95% CI) | VFD mean (95% CI) | ||
CRP ≥ 70 mg/L | n = 65 | n = 59 | |
12.1 (9.8–14.4) | 9.2 (6.8–11.6) | 0.044 | |
IgM ≤ 0.8 g/L | n = 56 | n = 55 | |
12.4 (10.0–14.9) | 8.9 (6.5–11.4) | 0.031 | |
CRP ≥ 70 mg/L and IgM ≤ 0.8 g/L | n = 51 | n = 41 | |
12.6 (10.1–15.2) | 8.7 (5.8–11.6) | 0.031 | |
PCT ≥ 2 ng/mL | n = 43 | n = 51 | |
11.2 (8.2–14.1) | 7.8 (5.2–10.3) | 0.047 |