Introduction
Patients and methods
Setting
Endpoints
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All AEs: all AEs in any system organ class (SOC) and any preferred term (PT),
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All GI AEs: all AEs with SOC “Gastrointestinal disorders” and any PT,
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Dyspepsia: all AEs with PTs “Dyspepsia,” “Epigastric discomfort,” and “Eructation,”
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Minor GI AEs: all AEs with PTs “Heartburn,” “Nausea,” “Vomiting,” and “Abdominal pain,”
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GI bleeding: all AEs with PT “Haematemesis,”, “Haematochezia,” and “Melaena.”
Treatments considered for the analysis
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1.aspirin mono which included all available galenic formulations of aspirin alone or in combination with vitamin C, caffeine, calcium, etc.
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2. aspirin + pseudoephedrine (PSE) oral granules which is used for the treatment of swelling of the nasal mucosa and paranasal sinuses during common cold in combination with pain and fever (Bayer Vital GmbH 2021),
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3. aspirin FR tablets,
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4. aspirin mono without (w/o) FR tablets and only plain tablets, and
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5. placebo.
Data extraction and management
Statistics
Descriptive statistics
Results
Clinical study database pool and demographics
Aspirin mono | Aspirin + PSE | Placebo | Total | |
---|---|---|---|---|
Gender [N (%)] | ||||
Total | 5202 (100.0%) | 827 (100.0%) | 3259 (100.0%) | 9288 (100.0%) |
Male | 2152 (41.4%) | 410 (49.6%) | 1129 (34.6%) | 3691 (39.7%) |
Female | 3050 (58.6%) | 417 (50.4%) | 2130 (65.4%) | 5597 (60.3%) |
Race [N (%)] | ||||
Total | 5202 (100.0%) | 827 (100.0%) | 3259 (100.0%) | 9288 (100.0%) |
Missing | 835 (16.1%) | 2 (0.2%) | 294 (9.0%) | 1131 (12.2%) |
Caucasian | 3832 (73.7%) | 738 (89.2%) | 2659 (81.6%) | 7229 (77.8%) |
Black | 259 (5.0%) | 47 (5.7%) | 152 (4.7%) | 458 (4.9%) |
Asian | 76 (1.5%) | 6 (0.7%) | 31 (1.0%) | 113 (1.2%) |
American Indian | 1 (0.0%) | 1 (0.1%) | 1 (0.0%) | 3 (0.0%) |
Hispanic | 122 (2.3%) | 7 (0.8%) | 77 (2.4%) | 206 (2.2%) |
Other | 77 (1.5%) | 26 (3.1%) | 45 (1.4%) | 148 (1.6%) |
Age [year] | ||||
N | 5152 | 827 | 3209 | 9188 |
Mean | 32.1 | 21.4 | 31.4 | 30.9 |
SD | 12.5 | 5.6 | 12.7 | 12.5 |
Range | 15–75 | 18–54 | 15–72 | 15–75 |
Weight [kg] | ||||
N | 4136 | 827 | 2900 | 7863 |
Mean | 73.0 | 70.2 | 71.2 | 72.0 |
SD | 15.4 | 14.2 | 15.2 | 15.2 |
Range | 35–158.8 | 41–167.0 | 40–157.9 | 35–167.0 |
BMI [kg/m2] | ||||
N | 4136 | 827 | 2900 | 7863 |
Mean | 25.2 | 23.3 | 24.7 | 24.8 |
SD | 4.8 | 3.5 | 4.7 | 4.7 |
Range | 14.5–60.6 | 16.6–47.3 | 12.5–56.2 | 12.5–60.6 |
Comparison of the risk of adverse events between regular aspirin and aspirin FR
Event of interest | Comparison | Incidence (%) (response/total) | Odds ratio with 95% CI | ||
---|---|---|---|---|---|
Aspirin group | Control group | ||||
All AEs | Aspirin mono vs. placebo | 14.1 (611/4346) | 14.4 (404/2802) | 1.05 [0.91, 1.20] | |
Aspirin + PSE vs. placebo | 11.3 (81/716) | 10.2 (37/363) | 1.23 [0.82, 1.86] | ||
Aspirin mono (plain only, w/o FR) vs. placebo | 13.5 (377/2794)/ | 13.6 (242/1773) | 1.11 [0.93, 1.33] | ||
Aspirin FR vs. placebo | 14.4 (98/681) | 20.4 (70/343) | 0.65 [0.48, 0.90] | ||
Aspirin mono (plain only, w/o FR) vs. aspirin FR | 14.7 (62/421) | 15.4 (68/441) | 0.93 [0.64, 1.36] | ||
All GI AEs | Aspirin mono vs. placebo | 5.5 (238/4346) | 6.1 (171/2802) | 1.00 [0.81, 1.23] | |
Aspirin + PSE vs. placebo | 3.5 (25/716) | 3.9 (14/363) | 1.04 [0.53, 2.05] | ||
Aspirin mono (plain only, w/o FR) vs. placebo | 3.9 (108/2794) | 4.1 (73/1773) | 0.97 [0.72, 1.30] | ||
Aspirin FR vs. placebo | 5.9 (40/681) | 8.7 (30/343) | 0.65 [0.41, 1.03] | ||
Aspirin mono (plain only, w/o FR) vs. aspirin FR | 4.8 (20/421) | 5.4 (24/441) | 0.87 [0.47, 1.61] | ||
Dyspepsia | Aspirin mono vs. placebo | 1.5 (64/4346) | 1.7 (49/2802) | 1.24 [0.83, 1.85] | |
Aspirin + PSE vs. placebo | 0.3 (2/716) | 0.8 (3/363) | 0.61 [0.07, 5.37] | ||
aspirin mono (plain only, w/o FR) vs. placebo | 0.8 (22/2794) | 0.5 (9/1773) | 1.72 [0.80, 3.71] | ||
Aspirin FR vs. placebo | 0.3 (2/681) | 0.6 (2/343) | 0.50 [0.08, 3.02] | ||
Aspirin mono (plain only, w/o FR) vs. aspirin FR | 0.2 (1/421) | 0.5 (2/441) | 0.54 [0.05, 5.76] | ||
Minor GI AEs | Aspirin mono vs. placebo | 2.7 (118/4346) | 3.2 (89/2802) | 0.81 [0.61, 1.07] | |
aspirin + PSE vs. placebo | 1.4 (10/716) | 1.9 (7/363) | 0.79 [0.30, 2.11] | ||
Aspirin mono (plain only, w/o FR) vs. placebo | 2.1 (59/2794) | 2.7 (48/1773) | 0.77 [0.53, 1.13] | ||
Aspirin FR vs. placebo | 4.7 (32/681/) | 6.7 (23/343) | 0.68 [0.41, 1.15] | ||
Aspirin mono (plain only, w/o FR) vs. aspirin FR | 3.8 (16/421) | 4.5 (20/441) | 0.83 [0.42, 1.63] | ||
GI bleeding | Aspirin mono vs. placebo | 0.0 (1/4346) | 0.1 (3/2802) | 0.23 [0.03, 1.70] | |
Aspirin + PSE vs. placebo | 0.1 (1/716) | 0.6 (2/363) | 0.26 [0.03, 2.23] | ||
Aspirin mono (plain only, w/o FR) vs. placebo | 0.0 (1/2794) | 0.1 (2/1773) | 0.30 [0.04, 2.39] | ||
Aspirin FR vs. placebo | 0.1 (1/681) | 0.3 (1/343) | 0.50 [0.04, 6.75] | ||
Aspirin mono (plain only, w/o FR) vs. aspirin FR | 0.2 (1/421) | 0.2 (1/441) | 1.05 [0.06, 17.08] |
Event of interest | Comparison | Incidence (%) (response/total) | Odds ratio with 95% CI | |
---|---|---|---|---|
Aspirin group | Control group | |||
All AEs | Aspirin mono vs. placeboa | 7.8 (337/4346) | 7.7 (216/2802) | 1.34 [1.11, 1.62] |
Aspirin + PSE vs. placebo | 5.7 (41/716) | 5.8 (21/363) | 1.12[0.65, 1.94] | |
Aspirin mono (plain only, w/o FR) vs. placebo | 8.4 (235/2794) | 7.7 (137/1773) | 1.43 [1.13, 1.80] | |
Aspirin FR vs. placebob | 1.9 (13/681) | 4.7 (16/343) | 0.39 [0.20, 0.79] | |
Aspirin mono (plain only, w/o FR) vs. aspirin FRb | 3.0 (12/403) | 3.0(12/406) | 1.01 [0.45, 2.28] | |
All GI AEs | Aspirin mono vs. placeboa | 3.5 (150/4346) | 3.9 (109/2802) | 1.14 [0.88, 1.48] |
Aspirin + PSE vs. placebo | 2.1 (15/716) | 3.0 (11/363) | 0.83 [0.37, 1.87] | |
Aspirin mono (plain only, w/o FR) vs. placebo | 2.6 (72/2794) | 2.4 (43/1773) | 1.14 [0.78, 1.67] | |
Aspirin FR vs. placebob | 1.0 (7/681) | 2.3 (8/343) | 0.43 [0.17, 1.13] | |
Aspirin mono (plain only, w/o FR) vs. aspirin FRb | 2.0 (8/403) | 1.5 (6/406) | 1.35 [0.46, 3.92] | |
Dyspepsia | Aspirin mono vs. placeboa | 1.3 (58/4346) | 1.6 (45/2802) | 1.24 [0.82, 1.88] |
Aspirin + PSE vs. placebo | 0.1 (1/716) | 0.8 (3/363) | 0.32 [0.02, 4.91] | |
Aspirin mono (plain only, w/o FR) vs. placebo | 0.8 (22/2794) | 0.5 (8/1773) | 1.98 [0.88, 4.46] | |
Aspirin FR vs. placebob | 0.1 (1/681) | 0.3 (1/343) | 0.50 [0.04, 6.75]c | |
Aspirin mono (plain only, w/o FR) vs. aspirin FRb | 0.2 (1/403) | 0.2 (1/406) | 1.01 [0.06, 16.20]c | |
Minor GI AEs | Aspirin mono vs. placeboa | 1.4 (62/4346) | 1.6 (45/2802) | 0.93 [0.63, 1.38] |
Aspirin + PSE vs. placebo | 0.7 (5/716) | 1.7 (6/363) | 0.47 [0.14, 1.56] | |
Aspirin mono (plain only, w/o FR) vs. placebo | 1.4 (38/2794) | 1.5 (26/1773) | 0.93 [0.57, 1.51] | |
Aspirin FR vs. placebob | 1.0 (7/681) | 2.3 (8/343) | 0.43 [0.17, 1.13] | |
Aspirin mono (plain only, w/o FR) vs. aspirin FRb | 2.0 (8/403) | 1.5 (6/406) | 1.35 [0.46, 3.92] | |
GI bleeding | Aspirin mono vs. placeboa | 0.0 (1/4346) | 0.1 (3/2802) | 0.23 [0.03, 1.70] |
Aspirin + PSE vs. placebo | – | – | Not estimated | |
Aspirin mono (plain only, w/o FR) vs. placebo | – | – | Not estimated | |
Aspirin FR vs. placebob | – | – | Not estimated | |
Aspirin mono (plain only, w/o FR) vs. aspirin FRb | – | – | Not estimated |
Impact of two doses of regular aspirin and aspirin FR on the incidence of adverse events in all subjects
Aspirin mono | Aspirin + PSE | Aspirin mono, plain only, w/o FR | Aspirin FR | Placebo | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | Total | |
Number of subjects treated | 1324 | 3878 | 5202 | 467 | 360 | 827 | 1027 | 2064 | 3091 | 74 | 722 | 796 | 3259 |
Number of subjects with at least 1 AE | 179 (13.52) | 490 (12.64) | 669 (12.86) | 55 (11.78) | 41 (11.39) | 96 (11.61) | 151 (14.70) | 241 (11.68) | 392 (12.68) | 11 (14.86) | 99 (13.71) | 110 (13.82) | 443 (13.59) |
Drug-unrelated | |||||||||||||
All AEs | 56 (4.23) | 285 (7.35) | 341 (6.56) | 33 (7.07) | 20 (5.56) | 53 (6.41) | 38 (3.70) | 129 (6.25) | 167 (5.40) | 9 (12.16) | 89 (12.33) | 98 (12.31) | 227 (6.97) |
All GI AEs | 8 (0.60) | 96 (2.48) | 104 (2.00) | 6 (1.28) | 5 (1.39) | 11 (1.33) | 6 (0.58) | 36 (1.74) | 42 (1.36) | 2 (2.70) | 34 (4.71) | 36 (4.52) | 67 (2.06) |
Dyspepsia | 0 (0.00) | 11 (0.28) | 11 (0.21) | 1 (0.21) | 0 (0.00) | 1 (0.12) | 0 (0.00) | 1 (0.05) | 1 (0.03) | 0 (0.00) | 1 (0.14) | 1 (0.13) | 4 (0.12) |
Minor GI AEs | 3 (0.23) | 58 (1.50) | 61 (1.17) | 2 (0.43) | 3 (0.83) | 5 (0.60) | 2 (0.19) | 22 (1.07) | 24 (0.78) | 1 (1.35) | 26 (3.60) | 27 (3.39) | 46 (1.41) |
Drug-related | |||||||||||||
All AEs | 125 (9.44) | 236 (6.09) | 361 (6.94) | 24 (5.14) | 21 (5.83) | 45 (5.44) | 115 (11.20) | 126 (6.10) | 241 (7.80) | 2 (2.70) | 12 (1.66) | 14 (1.76) | 239 (7.33) |
All GI AEs | 16 (1.21) | 140 (3.61) | 156 (3.00) | 11 (2.36) | 5 (1.39) | 16 (1.93) | 14 (1.36) | 60 (2.91) | 74 (2.39) | 1 (1.35) | 6 (0.83) | 7 (0.88) | 116 (3.56) |
Dyspepsia | 5 (0.38) | 52 (1.34) | 57 (1.10) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 5 (0.49) | 16 (0.78) | 21 (0.68) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 44 (1.35) |
Minor GI AEs | 6 (0.45) | 58 (1.50) | 64 (1.23) | 2 (0.43) | 3 (0.83) | 5 (0.60) | 6 (0.58) | 32 (1.55) | 38 (1.23) | 0 (0.00) | 6 (0.83) | 6 (0.75) | 49 (1.50) |
Effect of two doses of regular aspirin and aspirin FR on the incidence of adverse events in subjects with different kinds of pain and healthy volunteers
Aspirin mono | Aspirin + PSE | Aspirin mono, plain only, w/o FR | Aspirin FR | Placebo | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | Total | |
Number of subjects treated | 272 | 280 | 552 | 164 | 165 | 329 | 272 | 206 | 478 | 0 | 71 | 71 | 574 |
Number of subjects with at least 1 AE | 99 (36.40) | 15 (5.36) | 114 (20.65) | 8 (4.88) | 17 (10.30) | 25 (7.60) | 99 (36.40) | 1 (0.49) | 100 (20.91) | 0 (0.00) | 13 (18.31) | 13 (18.31) | 96 (16.72) |
Drug-unrelated | |||||||||||||
All AEs | 3 (1.10) | 14 (5.00) | 17 (3.08) | 3 (1.83) | 5 (3.03) | 8 (2.43) | 3 (1.10) | 1 (0.49) | 4 (0.84) | 0 (0.00) | 13 (18.31) | 13 (18.31) | 21 (3.66) |
All GI AEs | 0 (0.00) | 4 (1.43) | 4 (0.72) | 2 (1.22) | 2 (1.21) | 4 (1.22) | 0 (0.00) | 1 (0.49) | 1 (0.21) | 0 (0.00) | 3 (4.23) | 3 (4.23) | 5 (0.87) |
Dyspepsia | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) |
Minor GI AEs | 0 (0.00) | 2 (0.71) | 2 (0.36) | 0 (0.00) | 1 (0.61) | 1 (0.30) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 2 (2.82) | 2 (2.82) | 1 (0.17) |
Drug-related | |||||||||||||
All AEs | 96 (35.26) | 1 (0.36) | 97 (17.57) | 5 (3.05) | 12 (7.27) | 17 (5.17) | 96 (35.29) | 0 (0.00) | 96 (20.08) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 75 (13.07) |
All GI AEs | 3 (1.10) | 1 (0.36) | 4 (0.72) | 2 (1.22) | 4 (2.42) | 6 (0.74) | 3 (1.10) | 0 (0.00) | 3 (0.63) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 13 (2.26) |
Dyspepsia | 3 (1.10) | 1 (0.36) | 4 (0.72) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 3 (1.10) | 0 (0.00) | 3 (0.63) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 4 (0.70) |
Minor GI AEs | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 3 (1.82) | 3 (0.91) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 5 (0.87) |
Aspirin mono | Aspirin + PSE | Aspirin mono, plain only, w/o FR | Aspirin FR | Placebo | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | Total | |
Number of subjects treated | 0 | 1065 | 1065 | 0 | 0 | 0 | 0 | 455 | 455 | 0 | 610 | 610 | 359 |
Number of subjects with at least 1 AE | 0 (0.00) | 156 (14.65) | 156 (14.65) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 71 (15.60) | 71 (15.60) | 0 (0.00) | 85 (13.93) | 85 (13.93) | 70 (19.50) |
Drug-unrelated | |||||||||||||
All AEs | 0 (0.00) | 129 (12.11) | 129 (12.11) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 54 (11.87) | 54 (11.87) | 0 (0.00) | 75 (12.30) | 75 (12.30) | 52 (14.48) |
All GI AEs | 0 (0.00) | 43 (4.04) | 43 (4.04) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 12 (2.64) | 12 (2.64) | 0 (0.00) | 31 (5.08) | 31 (5.08) | 25 (6.96) |
Dyspepsia | 0 (0.00) | 1 (0.09) | 1 (0.09) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 1 (0.16) | 1 (0.16) | 1 (0.28) |
Minor GI AEs | 0 (0.00) | 32 (3.00) | 32 (3.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 8 (1.76) | 8 (1.76) | 0 (0.00) | 24 (3.93) | 24 (3.93) | 20 (5.57) |
Drug-related | |||||||||||||
All AEs | 0 (0.00) | 32 (3.00) | 32 (3.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 20 (4.40) | 20 (4.40) | 0 (0.00) | 12 (1.97) | 12 (1.97) | 22 (6.13) |
All GI AEs | 0 (0.00) | 14 (1.31) | 14 (1.31) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 8 (1.76) | 8 (1.76) | 0 (0.00) | 6 (0.98) | 6 (0.98) | 7 (1.95) |
Dyspepsia | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) |
Minor GI AEs | 0 (0.00) | 14 (1.31) | 14 (1.31) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 8 (1.76) | 8 (1.76) | 0 (0.00) | 6 (0.98) | 6 (0.98) | 7 (1.95) |
Aspirin mono | Aspirin + PSE | Aspirin mono, plain only, w/o FR | Aspirin FR | Placebo | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | 0–500 mg | 501–1000 mg | Total | Total | |
Number of subjects treated | 557 | 502 | 1059 | 108 | 0 | 108 | 273 | 163 | 436 | 74 | 41 | 115 | 281 |
Number of subjects with at least 1 AE | 44 (7.90) | 105 (20.92) | 149 (14.07) | 16 (14.81) | 0 (0.00) | 16 (14.81) | 16 (5.89) | 36 (22.09) | 52 (11.93) | 11 (14.86) | 1 (2.44) | 12 (10.43) | 90 (32.03) |
Drug-unrelated | |||||||||||||
All AEs | 28 (5.03) | 59 (11.75) | 87 (8.22) | 12 (11.11) | 0 (0.00) | 12 (11.11) | 10 (3.66) | 32 (19.63) | 42 (9.63) | 9 (12.16) | 1 (2.44) | 10 (8.70) | 47 (16.73) |
All GI AEs | 3 (0.54) | 21 (4.18) | 24 (2.27) | 1 (0.93) | 0 (0.00) | 1 (0.93) | 1 (0.37) | 9 (5.52) | 10 (2.29) | 2 (2.70) | 0 (0.00) | 2 (1.74) | 10 (3.56) |
Dyspepsia | 0 (0.00) | 8 (1.59) | 8 (0.76) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 3 (1.07) |
Minor GI AEs | 1 (0.18) | 11 (2.19) | 12 (1.13) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 9 (5.52) | 9 (2.06) | 1 (1.35) | 0 (0.00) | 1 (0.87) | 8 (2.85) |
Drug-related | |||||||||||||
All AEs | 16 (2.87) | 57 (11.35) | 73 (6.89) | 5 (4.63) | 0 (0.00) | 5 (4.63) | 6 (2.20) | 8 (4.91) | 14 (3.21) | 2 (2.70) | 0 (0.00) | 2 (1.74) | 49 (17.44) |
All GI AEs | 5 (0.90) | 50 (9.96) | 55 (5.19) | 2 (1.85) | 0 (0.00) | 2 (1.85) | 3 (1.10) | 6 (3.68) | 9 (2.06) | 1 (1.35) | 0 (0.00) | 1 (0.87) | 45 (16.01) |
Dyspepsia | 0 (0.00) | 28 (5.58) | 28 (2.64) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 29 (10.32) |
Minor GI AEs | 1 (0.18) | 11 (2.19) | 12 (1.13) | 1 (0.93) | 0 (0.00) | 1 (0.93) | 1 (0.37) | 6 (3.68) | 7 (1.61) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 8 (2.85) |