Primary outcome and cardiorespiratory secondary outcomes
| Placebo N=24* | Caffeine citrate 5mg/kg/day N=24* | Caffeine citrate 10mg/kg/day N=27* | Caffeine citrate 15 mg/kg/day N=27* | Caffeine citrate 20 mg/kg/day N=27* | Any dose of caffeine N=105* | ||||||
| Summary data | Summary data | RGM or mean difference (95% CI); p value† | Summary data | RGM or mean difference (95% CI); p value† | Summary data | RGM or mean difference (95% CI); p value† | Summary data | RGM or mean difference (95% CI); p value† | Summary data | RGM or mean difference (95% CI); p value† | |
| Primary outcome | |||||||||||
| Rate of intermittent hypoxaemia at 2 weeks; median (IQR)(geometric mean) | 4.0 (1.8, 9.8) (4.6) | 5.9 (2.8, 7.6) (4.6) | 0.97 (0.49 to 1.95); 0.94 | 2.5 (0.6, 5.7) (2.0) | 0.39 (0.20 to 0.76); 0.006 | 3.3 (2.1, 8.8) (3.8) | 0.79 (0.40 to 1.56); 0.49 | 1.8 (0.9, 4.2) (1.7) | 0.33 (0.17 to 0.68); 0.003 | 3.0 (1.3, 6.1) (2.7) | 0.56 (0.32 to 0.98); 0.043 |
| Secondary outcomes | |||||||||||
| Rate of intermittent hypoxaemia; median (IQR) (geometric mean) | |||||||||||
| Baseline | 0.9 (0.6, 1.4) | 2.0 (0.9, 3.3) | 1.1 (0.7, 2.0) | 1.9 (1.1, 2.6) | 1.5 (0.8, 4.4) | 1.5 (0.9, 2.8) | |||||
| Term | 3.0 (1.9, 6.2) (3.3) | 4.0 (1.9, 6.9) (3.4) | 1.02 (0.50 to 2.07); 0.96 | 2.5 (1.0, 6.1) (2.4) | 0.65 (0.33 to 1.32); 0.23 | 3.3 (1.5, 8.2) (3.1) | 0.82 (0.40 to 1.69); 0.59 | 2.2 (1.0, 4.7) (1.9) | 0.54 (0.26 to 1.11); 0.09 | 2.9 (1.3, 6.7) (2.7) | 0.75 (0.43 to 1.30); 0.30 |
| Mean SpO2; mean (SD) | |||||||||||
| Baseline | 96.4 (1.3) | 96.4 (1.5) | 95.6 (1.8) | 96.6 (1.4) | 95.5 (2.0) | 96.0 (1.7) | |||||
| Two weeks | 96.0 (0.8) | 96.4 (1.4) | 0.39 (−0.28 to 1.07); 0.25 | 96.7 (1.0) | 0.68 (0.04 to 1.33); 0.039 | 96.7 (1.3) | 0.66 (−0.01 to 1.33); 0.06 | 97.2 (1.0) | 1.31 (0.62 to 2.00); <0.001 | 96.8 (1.2) | 0.74 (0.21 to 1.28); 0.007 |
| Term | 97.3 (1.0) | 97.5 (0.9) | 0.13 (−0.61 to 0.87); 0.72 | 97.2 (0.8) | 0.09 (−0.64 to 0.82); 0.81 | 97.2 (1.2) | 0.05 (−0.70 to 0.81); 0.89 | 97.4 (1.7) | 0.30 (−0.46 to 1.06); 0.44 | 97.3 (1.2) | 0.14 (−0.43 to 0.71); 0.62 |
| Percentage of time SpO2 <90%; median (IQR) | |||||||||||
| Baseline | 1.1 (0.3, 1.6) | 1.2 (0.5, 2.4) | 1.2 (0.3, 1.9) | 1.0 (0.6, 1.4) | 1.5 (0.5, 3.1) | 1.2 (0.5, 2.3) | |||||
| Two weeks | 1.1 (0.6, 2.4) (1.3) | 1.0 (0.7, 2.0) (1.1) | 0.83 (0.43 to 1.60); 0.58 | 0.9 (0.3, 1.6) (0.6) | 0.40 (0.21 to 0.75); 0.005 | 0.7 (0.4, 1.6) (0.8) | 0.63 (0.33 to 1.22); 0.17 | 0.5 (0.2, 0.8) (0.4) | 0.29 (0.14 to 0.56); <0.001 | 0.7 (0.3, 1.6) (0.7) | 0.50 (0.29 to 0.85); 0.011 |
| Term | 0.6 (0.3, 1.1) (0.6) | 0.5 (0.3, 1.3) (0.6) | 0.89 (0.43 to 1.84); 0.76 | 0.4 (0.3, 1.1) (0.5) | 0.75 (0.37 to 1.53); 0.43 | 0.6 (0.4, 1.3) (0.6) | 0.84 (0.40 to 1.77); 0.65 | 0.3 (0.2, 1.7) (0.4) | 0.59 (0.28 to 1.22); 0.15 | 0.5 (0.2, 1.3) (0.5) | 0.76 (0.43 to 1.34); 0.34 |
| Mean heart rate; mean (SD) | |||||||||||
| Baseline | 130.1 (9.0) | 130.0 (6.8) | 134.0 (10.2) | 132.1 (10.4) | 130.8 (9.3) | 131.7 (9.3) | |||||
| Two weeks | 147.7 (6.8) | 150.3 (8.2) | 3.07 (−5.32 to 4.63); 0.89 | 150.8 (7.4) | 3.43 (−2.22 to 9.08); 0.23 | 156.0 (12.7) | 8.44 (2.59 to 14.30); 0.005 | 152.4 (12.4) | 3.75 (−2.28 to 9.79); 0.22 | 152.3 (10.4) | 4.63 (0.04 to 9.21); 0.048 |
| Term | 150.8 (8.6) | 150.3 (6.9) | −0.35 (−5.25 to 4.55); 0.89 | 152.3 (5.7) | 1.26 (−3.66 to 6.19); 0.61 | 155.5 (8.9) | 4.37 (−0.69 to 9.42); 0.09 | 151.1 (8.5) | 0.07 (−5.05 to 5.19); 0.98 | 152.3 (7.6) | 1.28 (−2.62 to 5.17); 0.52 |
| Percentage of time HR >180; median (IQR) | |||||||||||
| Baseline | 0.0 (0.0, 0.0) | 0.0 (0.0, 0.4) | 0.1 (0.0, 0.3) | 0.0 (0.0, 0.3) | 0.0 (0.0, 0.2) | 0.0 (0.0, 0.3) | |||||
| Two weeks | 0.9 (0.2, 5.2) (0.9) | 3.1 (2.0, 8.9) (3.8) | 4.34 (1.87 to 10.10); 0.001 | 4.3 (2.4, 9.0) (3.8) | 4.03 (1.79 to 9.08); 0.001 | 7.0 (4.0, 10.1) (5.5) | 5.94 (2.56 to 13.77); <0.001 | 7.4 (4.4, 13.9) (6.1) | 5.71 (2.40 to 13.57); <0.001 | 6.0 (2.9, 10.0) (4.7) | 4.87 (2.55 to 9.29); <0.001 |
| Term | 2.0 (0.4, 5.6) (1.6) | 4.7 (3.0, 8.0) (3.9) | 2.50 (1.07 to 5.86); 0.035 | 5.5 (2.4, 9.4) (4.6) | 2.86 (1.23 to 6.63); 0.015 | 5.6 (2.7, 9.9) (3.6) | 2.22 (0.93 to 5.27); 0.07 | 6.7 (4.4, 10.7) (5.2) | 3.19 (1.33 to 7.65); 0.010 | 5.7 (2.7, 9.0) (4.3) | 2.66 (1.39 to 5.11); 0.004 |
| Compliant‡ with administration schedule at 2 weeks | 21 (87.5%) | 18 (78.5%) | 0.33 (0.06 to 1.91); 0.22 | 23 (85.2%) | 0.54 (0.09 to 3.41); 0.51 | 19 (70.4%) | 0.20 (0.04 to 1.14); 0.07 | 18 (66.7%) | 0.21 (0.04 to 1.24); 0.09 | 78 (73.6%) | 0.28 (0.06 to 1.33); 0.11 |
| Study drug stopped due to presumed side effects§ | 2 (9.1%) | 4 (16.7%) | 2.07 (0.32 to 13.18); 0.44 | 5 (19.2%) | 2.49 (0.37 to 16.75); 0.35 | 7 (28.0%) | 4.21 (0.68 to 26.13); 0.12 | 6 (22.2%) | 2.96 (0.49 to 17.75); 0.23 | 22 (21.6%) | 2.88 (0.58 to 14.31) 0.20 |
*Number of infants with oximetry traces of usable quality (% of total remaining in study in that group) at baseline, 2 weeks and term, respectively, are: 20 (83.3%), 22 (100%), 20 (100%) in placebo group; 23 (95.8%), 20 (100%), 18 (94.7%) in 5 mg/kg/day group; 26 (96.3%), 24 (96.0%), 20 (95.2%) in 10 mg/kg/day group; 27 (100%), 21 (100%), 18 (94.7%) in 15 mg/kg/day group and 25 (89.3%), 20 (100%), 17 (85.0%) in 20 mg/kg/day group.
†Where the mean (SD) is presented the exposure effect is a mean difference; where median (IQR) and geometric mean are presented the exposure effect is the RGM. For all comparisons the reference category is the placebo group.
‡Compliant is defined as <20% of the expected study drug volume (as calculated for that child based on birth weight) remaining in the bottle when measured by the research team at the 2-week visit (ie, >80% of the study drug has been removed from the bottle). Information on compliance at 2 weeks is missing for n=4 (1 in each group except 10 mg/kg).
§Further breakdown of reasons for withdrawals is provided in the online supplemental tables.
RGM, geometric mean ratio.