Table 2. Primary and Secondary Outcomes (Modified Intention-to-Treat Population).*.
| Outcome | Doxycycline (N = 265) | Azithromycin (N =263) | Combination Therapy (N = 266) | Treatment Effect (95% Cl)† | ||
|---|---|---|---|---|---|---|
| Combination Therapy vs. Doxycycline | Combination Therapy vs. Azithromycin | Azithromycin vs. Doxycycline | ||||
| Primary outcome | ||||||
| Composite of death at day 28, persistent complications at day 7, and persistent fever at day 5 — no. (%)‡ | −13.3 (−21.6 to −5.1) | −14.8 (−23.1 to−6.5) | 1.5 (−7.0 to 10.0) | |||
| No. of patients (%) | 124 (47) | 127 (48) | 89 (33) | |||
| 95% Cl — percentage points | 41 to 53 | 42 to 55 | 28 to 39 | — | — | — |
| P value | 0.002 | <0.001 | 0.73 | |||
| Secondary outcomes | ||||||
| Death at day 28 — no. (%) | 29 (11) | 32 (12) | 35 (13) | 1.22 (0.74 to 1.99) | 1.09 (0.67 to 1.76) | 0.90 (0.54 to 1.48) |
| Fever defervescence | ||||||
| Patients — no./total no. (%) | 249/254 (98) | 238/251 (95) | 242/252 (96) | |||
| Median no. of days (IQR)§ | 4 (4–20) | 4 (4–28) | 4 (4–24) | 0.90 (0.75 to 1.07) | 1.00 (0.84 to 1.20) | 0.90 (0.75 to 1.07) |
| Mechanical ventilation | ||||||
| Patients — no. (%) | 108 (41) | 118 (45) | 112 (42) | |||
| Median duration (IQR) — hr | 69 (36–128) | 78 (37–132) | 70 (37–128) | — | — | — |
| Inotropic support | ||||||
| Patients — no. (%) | 69 (26) | 79 (30) | 80 (30) | |||
| Median duration (IQR) — hr | 41 (20–59) | 41 (17–76) | 48 (25–73) | — | — | — |
| Dialysis | ||||||
| Patients — no. (%) | 14 (5) | 12 (5) | 8(3) | |||
| Median no. of days (IQR) | 2 (1–3) | 2 (1–5) | 1.5 (1–3) | — | — | — |
| ICU stay | ||||||
| Patients — no. (%) | 93 (35) | 105 (40) | 98 (37) | |||
| Median no. of days (IQR) | 4 (2–7) | 5 (2–7) | 4 (2–7) | — | — | — |
| Median duration of hospital stay (IQR) — days | 8(7–10) | 8(7–10) | 8 (7–10) | — | — | — |
| Recovery to normal sensorium | ||||||
| Within 7 days— no./total no. (%) | 49/75 (65) | 45/78 (58) | 42/69 (61) | |||
| Median no. of days (IQR) | 3 (1–4) | 3 (1–4) | 2 (2–4) | — | — | — |
| O. tsutsugamushi negativity on PCR | ||||||
| Patients — no./total no. (%) | 192/226 (85) | 196/240 (82) | 203/235 (86) | |||
| Median no. of days (IQR) | 3 (3–7) | 1 (3–3) | 1 (3–3) | 1.33 (1.09 to 1.62) | 1.03 (0.85 to 1.26) | 1.28 (1.05 to 1.57) |
A dash indicates that the calculation was not performed. ICU denotes intensive care unit.
For the primary outcome, the treatment effect is a risk difference, reported in percentage points. For the secondary outcomes, the treatment effect is reported as a hazard ratio. The widths of the 95% confidence intervals have not been adjusted for multiplicity and may not be used in place of hypothesis testing.
A total of 10 patients (3 in the doxycycline group, 4 in the azithromycin group, and 3 in the combination-therapy group) discontinued the study before day 5 or day 7 but were known to have been discharged alive. Among these patients, the outcome was imputed on the basis of the severity of their complications at the time of discharge.
The time until fever defervescence was not applicable in 37 patients because of death, loss to follow-up, or withdrawal of consent before 24 hours after the temperature had been recorded at less than 37.5°C (99.5°F).