Summary of safety evaluations: adverse events and major biochemical and haematological changes—safety dataset
| Paracetamol | Ibuprofen | 1 × Combination tablet | 2 × Combination tablet | |
|---|---|---|---|---|
| No of subjects reporting an AE in the first 10 days of the study | ||||
| N | 222 | 224 | 222 | 224 |
| Any AE, n (%) | 112 (50.5) | 99 (44.2) | 103 (46.4) | 111 (49.6) |
| AE related to treatment*, n (%) | ||||
| 61 (27.5) | 47 (21.0) | 64 (28.8) | 69 (30.8) | |
| Dyspepsia | 11 (5.0) | 14 (6.3) | 26 (11.7) | 14 (6.3) |
| Diarrhoea | 10 (4.5) | 4 (1.8) | 4 (1.8) | 15 (6.7) |
| Nausea | 8 (3.6) | 8 (3.6) | 9 (4.1) | 10 (4.5) |
| No of subjects reporting an AE to study endpoint | ||||
| N | 222 | 224 | 222 | 224 |
| Any AE, n (%) | 180 (81.1) | 175 (78.1) | 173 (77.9) | 189 (84.4) |
| AE related to treatment*, n (%) | ||||
| 101 (45.5) | 93 (41.5) | 112 (50.5) | 115 (51.3) | |
| Dyspepsia | 14 (6.3) | 22 (9.8) | 38 (17.1) | 25 (11.2) |
| Diarrhoea | 13 (5.9) | 9 (4.0) | 11 (5.0) | 21 (9.4) |
| Nausea | 12 (5.4) | 12 (5.4) | 15 (6.8) | 12 (5.4) |
| Biochemistry, change from baseline, mean±SD (n) | ||||
| Alanine transaminase, IU/l | ||||
| Day 10 >2 × normal limit, n (%) | 7.6±15.5 (194)6 (3.1) | −1.5±6.6 (193)0 (0.0) | 3.2±12.1 (201)2 (1.0) | 9.1±20.0 (206)7 (3.4) |
| >3 × normal limit, n (%) | 1 (0.5) | 0 (0.0) | 0 (0.0) | 1 (0.5) |
| Week 7 | 3.4±12.8 (149) | −0.0±8.2 (175) | 3.4±10.9 (159) | 2.4±13.9 (174) |
| >2 × normal limit, n (%) | 2 (1.3) | 0 (0.0) | 3 (1.9) | 1 (0.6) |
| >3 × normal limit, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.6) |
| Week 13 | 1.5±9.2 (135) | 0.1±8.2 (162) | 0.9±11.2 (151) | 0.8±8.4 (159) |
| >2 × normal limit, n (%) | 2 (1.0) | 0 (0.0) | 3 (1.5) | 1 (0.5) |
| >3 × normal limit, n (%) | 0 (0.0) | 0 (0.0) | 2 (1.0) | 0 (0.0) |
| Endpoint (LOCF) | 2.0±9.1 (217) | −0.3±9.0 (219) | 2.1±14.9 (219) | 1.6±10.2 (215) |
| >2 × normal limit, n (%) | 1 (0.5) | 0 (0.0) | 3 (1.4) | 2 (0.9) |
| > 3 × normal limit, n (%) | 0 (0.0) | 0 (0.0) | 2 (0.9) | 0 (0.0) |
| γ Glutamyl transferase, IU/l | ||||
| Day 10 | 9.5±2.4 (194) | −4.8±9.3 (193) | 4.1±15.5 (201) | 7.1±18.0 (206) |
| >2 × normal limit, n (%) | 13 (67) | 1 (0.5) | 7 (3.5) | 7 (3.4) |
| >3 × normal limit, n (%) | 4 (2.1) | 1 (0.5) | 2 (1.0) | 3 (1.5) |
| Week 7 | 18.5±31.2 (149) | − 5.5±9.8 (175) | 9.7±25.0 (159) | 11.8±22.4 (174) |
| >2 × normal limit, n (%) | 11 (7.4) | 1 (0.6) | 9 (5.7) | 10 (5.7) |
| >3 × normal limit, n (%) | 5 (3.4) | 1 (0.6) | 3 (1.9) | 3 (1.7) |
| Week 13 | 12.7±33.5 (135) | −5.0±10.7 (162) | 5.8±18.8 (151) | 11.0±18.0 (159) |
| >2 × normal limit, n (%) | 15 (7.5) | 2 (1.0) | 7 (3.4) | 9 (4.5) |
| >3 × normal limit, n (%) | 7 (3.5) | 1 (0.5) | 6 (3.0) | 3 (1.5) |
| Endpoint (LOCF) | 12.0±29.3 (217) | −4.5±10.4 (219) | 5.9±23.5 (219) | 10.2±19.2 (215) |
| >2 × normal limit, n (%) | 15 (6.9) | 2 (0.9) | 7 (3.2) | 10 (4.7) |
| >3 × normal limit, n (%) | 6 (2.8) | 1 (0.5) | 6 (2.7) | 3 (1.4) |
| Haematology assessments, change from baseline, mean±SD (n) | ||||
| Mean cell volume, fl | ||||
| Day 10 | −0.2±3.4 (193) | −1.0±3.3 (194) | −0.2±3.0 (204) | −0.1±3.1 (206) |
| Week 7 | −0.3±3.6 (149) | −1.2±3.4 (176) | −0.3±3.4 (161) | 0.0±3.3 (174) |
| Week 13 | −0.2±3.6 (136) | −2.1±3.1 (162) | −0.9±2.9 (153) | −0.1±3.6 (160) |
| Endpoint (LOCF) | −0.1±3.5 (217) | −1.8±3.2 (219) | −0.9±2.9 (220) | −0.1±3.5 (216) |
| Platelet counts, 109/l | ||||
| Day 10 | 10.1±37.0 (193) | −5.3±37.2 (194) | −1.3±45.5 (204) | 3.6±39.1 (206) |
| Week 7 | 6.8±32.4 (149) | −0.4±31.2 (176) | 5.1±43.1 (161) | 16.0±42.4 (174) |
| Week 13 | 21.6±40.9 (136) | 8.2±31.4 (162) | 10.1±39.3 (153) | 28.5±50.8 (160) |
| Endpoint (LOCF) | 17.9±40.2 (217) | 8.0±30.4 (219) | 11.2±45.3 (220) | 22.5±50.8 (216) |
| Haemoglobin, g/dl | ||||
| Day 10 | −0.17±0.60 (193) | −0.26±0.59 (194) | −0.29±0.57 (204) | −0.34±0.67 (206) |
| Week 7 | −0.38±0.55 (149) | −0.35±0.60 (176) | −0.40±0.62 (161) | −0.66±0.72 (174) |
| Week 13 | −0.45±0.80 (136) | −0.50±0.62 (162) | −0.59±0.73 (153) | −0.90±0.79 (160) |
| Endpoint (LOCF) | −0.37±0.75 (217) | −0.47±0.60 (219) | −0.52±0.70 (220) | −0.78±0.80 (216) |
| Analysis of haemoglobin levels | ||||
| Subjects with a change in haemoglobin levels between baseline and day 10 | ||||
| Decrease ≥1 g/dl, n (%) | 14 (7.3) | 22 (11.3) | 22 (10.8) | 36 (17.5) |
| Decrease ≥2 g/dl, n (%) | 0 (0.0) | 0 (0.0) | 1 (0.5) | 0 (0.0) |
| Subjects with a change in haemoglobin levels between baseline and study endpoint (LOCF) | ||||
| Decrease ≥1 g/dl, n (%) | 44 (20.3) | 43 (19.6) | 53 (24.1) | 83 (38.4) |
| Decrease ≥2 g/dl, n (%) | 2 (0.9) | 2 (0.9) | 4 (1.8) | 15 (6.9) |
| Subjects with a change in haemoglobin levels between any successive assessments | ||||
| Decrease ≥1 g/dl, n (%) | 37 (17.1) | 49 (22.4) | 49 (22.3) | 82 (38.0) |
| Decrease ≥2 g/dl, n (%) | 15 (6.9) | 23 (10.5) | 22 (10.0) | 38 (17.6) |
↵* Investigator classed AE as definitely, probably or possibly related to treatment.
AE, adverse event; LOCF, last recorded post-baseline value.