FINAL Management options for moderate to severe acne – pairwise comparisons GRADE tables for review question: What is the effectiveness and acceptability of interventions for the treatment of moderate to severe acne (side effects and participant reported improvement)? Oral antibiotics Table 5: Clinical evidence profile for comparison of oral antibiotic versus placebo in participants with moderate to severe acne Quality assessment No of patients Effect Importanc Quality e No of Risk of Other Oral Placeb Relative Design Inconsistency Indirectness Imprecision Absolute studies bias considerations antibiotic o (95% CI) Skin irritation - Minocycline versus placebo 11 randomised serious7 no serious no serious very serious8 none 5/119 1/55 RR 2.31 (0.28 to 24 more per 1000 (from 13 ⊕ΟΟΟ CRITICAL trials inconsistency indirectness (4.2%) (1.8%) 19.31) fewer to 333 more) VERY LOW GI side effects 51,2,3,4,5 randomised very serious10 no serious very serious8 none 82/1543 41/1177 RR 1.11 (0.62 to 4 more per 1000 (from 13 ⊕ΟΟΟ CRITICAL trials serious9 indirectness (5.3%) (3.5%) 2) fewer to 35 more) VERY LOW Thrush / candiasis - Sarecyline versus placebo 24,5 randomised serious7 no serious no serious serious11 none 4/994 0/996 Peto OR 7.44 - ⊕⊕ΟΟ CRITICAL trials inconsistency indirectness (0.4%) (0%) (1.05 to 52.86) LOW Patient reported improvement - Tetracycline versus placebo 16 randomised very no serious no serious no serious none 21/29 1/29 RR 21 (3.02 to 690 more per 1000 (from ⊕⊕ΟΟ CRITICAL trials serious9 inconsistency indirectness imprecision (72.4%) (3.4%) 145.98) 70 more to 1000 more) LOW CI: confidence interval; GI: gastrointestinal; POR: peto odds ratio; RR: risk ratio 1 Stewart 2006 Acne vulgaris: evidence reviews for management options for moderate to severe acne – pairwise comparisons FINAL (June 2021) 143 FINAL Management options for moderate to severe acne – pairwise comparisons 2 Dubertret 2003 3 Leyden 2018 4 Moore 2018 (SC1401) 5 Moore 2018 (SC1402) 6 Braathen 1984 7 Overall risk of bias judgement: serious risk of bias. 8 Evidence downgraded by 2 levels due to risk of very serious imprecision as 95% confidence interval crosses 2 default MIDs for dichotomous outcomes. 9 Overall risk of bias judgement: very serious risk of bias 10 Evidence downgraded by 1 level due to serious inconsistency. 11 Evidence downgraded by 1 level due to risk of serious imprecision as 95% confidence interval crosses 1 default MID for dichotomous outcomes. Table 6: Clinical evidence profile for comparison of oral antibiotic versus oral antibiotic in participants with moderate to severe acne Quality assessment No of patients Effect Importanc Quality e No of Risk of Other Oral Oral Relative Design Inconsistency Indirectness Imprecision Absolute studies bias considerations antibiotic antibiotic (95% CI) GI side effects - LYME vs MINO 11 randomised very no serious no serious very serious4 none 3/56 2/53 RR 1.42 (0.25 16 more per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness (5.4%) (3.8%) to 8.16) 28 fewer to 270 more) VERY LOW Thrush / candiasis - TETRA versus MINO 12 randomised very no serious no serious very serious4 none 1/21 1/23 RR 1.1 (0.07 4 more per 1000 (from 40 ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness (4.8%) (4.3%) to 16.43) fewer to 671 more) VERY LOW Patient reported improvement - LYME vs MINO 11 randomised very no serious no serious no serious none 53/66 53/68 RR 1.03 (0.87 23 more per 1000 (from ⊕⊕ΟΟ CRITICAL trials serious3 inconsistency indirectness imprecision (80.3%) (77.9%) to 1.23) 101 fewer to 179 more) LOW CI: confidence interval; LYME: lymecycline; MINO: minocycline; RR: risk ratio; TETRA: tetracycline 1 Bossuyt 2003 2 Khanna 2013 3 Overall risk of bias judgement: very serious risk of bias. 4 Evidence downgraded by 2 levels due to risk of very serious imprecision as 95% confidence interval crosses 2 default MIDs for dichotomous outcomes. Oral hormonal contraceptives and hormone-modifying agents Acne vulgaris: evidence reviews for management options for moderate to severe acne – pairwise comparisons FINAL (June 2021) 144 FINAL Management options for moderate to severe acne – pairwise comparisons Table 7: Clinical evidence profile for comparison of hormonal treatments versus hormonal treatments in participants with moderate to severe acne Quality assessment No of patients Effect Importanc Quality e No of Risk of Other Hormonal Hormonal Relative Design Inconsistency Indirectness Imprecision Absolute studies bias considerations treatments treatments (95% CI) Breast tenderness - CPA/EE (Diane 50) versus NOR/EE (Minovlar) 11 randomised very no serious no serious very none 5/26 3/24 RR 1.54 (0.41 67 more per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness serious4 (19.2%) (12.5%) to 5.76) 74 fewer to 595 more) VERY LOW Breast tenderness - CPA/EE (Diane 50) versus CPA/EE (high dose CPA) 11 randomised very no serious no serious very none 5/26 4/26 RR 1.25 (0.38 38 more per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness serious4 (19.2%) (15.4%) to 4.14) 95 fewer to 483 more) VERY LOW Sexual dysfunction - CPA/EE (Diane 50) versus CPA/EE (high dose CPA) 11 randomised very no serious no serious very none 0/26 1/24 Peto OR 0.12 37 fewer per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness serious4 (0%) (4.2%) (0 to 6.29) 42 fewer to 220 more) VERY LOW Sexual dysfunction - CPA/EE (Diane 50) versus NOR/EE (Minovlar) 11 randomised very no serious no serious very none 0/26 1/24 Peto OR 0.12 37 fewer per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness serious4 (0%) (4.2%) (0 to 6.29) 42 fewer to 220 more) VERY LOW Mood disturbance - CPA/EE (Diane 50) versus CPA/EE (high dose CPA) 11 randomised very no serious no serious very none 3/26 3/26 RR 1 (0.22 to 0 fewer per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness serious4 (11.5%) (11.5%) 4.5) 90 fewer to 404 more) VERY LOW Mood disturbance - CPA/EE (Diane 50) versus NOR/EE (Minovlar) 11 randomised very no serious no serious very none 3/26 3/24 RR 0.92 (0.21 10 fewer per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness serious4 (11.5%) (12.5%) to 4.14) 99 fewer to 392 more) VERY LOW Acne vulgaris: evidence reviews for management options for moderate to severe acne – pairwise comparisons FINAL (June 2021) 145 FINAL Management options for moderate to severe acne – pairwise comparisons Quality assessment No of patients Effect Importanc Quality e No of Risk of Other Hormonal Hormonal Relative Design Inconsistency Indirectness Imprecision Absolute studies bias considerations treatments treatments (95% CI) Breakthrough bleeding - CPA/EE (Diane 50) versus CPA/EE (Diane 35) 12 randomised very no serious no serious very none 4/33 2/40 RR 2.42 (0.47 71 more per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness serious4 (12.1%) (5%) to 12.42) 26 fewer to 571 more) VERY LOW Breakthrough bleeding - CPA/EE (Diane 50) versus NOR/EE (Minovlar) 11 randomised very no serious no serious very none 2/26 3/24 RR 0.62 (0.11 47 fewer per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness serious4 (7.7%) (12.5%) to 3.37) 111 fewer to 296 more) VERY LOW Breakthrough bleeding - CPA/EE (Diane 50) versus CPA/EE (high dose CPA) 11 randomised very no serious no serious very none 2/26 4/26 RR 0.5 (0.1 to 77 fewer per 1000 (from ⊕ΟΟΟ CRITICAL trials serious3 inconsistency indirectness serious4 (7.7%) (15.4%) 2.5) 138 fewer to 231 more) VERY LOW CI: confidence interval; CPA: cyproterone acetate; EE: ethinyl estradiol; NOR: northisterone; OR: odds ratio; RR: risk ratio 1 Miller 1986 2 Fugere 1990 3 Overall risk of bias judgement: very serious risk of bias. 4 Evidence downgraded by 2 levels due to risk of very serious imprecision as 95% confidence interval crosses 2 default MIDs for dichotomous outcomes. Oral isotretinoin Table 8: Clinical evidence profile for comparison of isotretinoin versus isotretinoin in participants with moderate to severe acne Quality assessment No of patients Effect Importanc Quality e No of Risk of Other Isotretinoi Isotretinoi Relative Design Inconsistency Indirectness Imprecision Absolute studies bias considerations n n (95% CI) mucosal / cutaneous changes - ISO≥120.Daily≥0.5 versus ISO<120.Daily<0.5 Acne vulgaris: evidence reviews for management options for moderate to severe acne – pairwise comparisons FINAL (June 2021) 146 FINAL Management options for moderate to severe acne – pairwise comparisons Quality assessment No of patients Effect Importanc Quality e No of Risk of Other Isotretinoi Isotretinoi Relative Design Inconsistency Indirectness Imprecision Absolute studies bias considerations n n (95% CI) 11 randomised very no serious no serious serious7 none 46/49 18/23 RR 1.2 (0.96 to 157 more per 1000 ⊕ΟΟΟ CRITICAL trials serious6 inconsistency indirectness (93.9%) (78.3%) 1.51) (from 31 fewer to 399 VERY LOW more) mucosal / cutaneous changes - ISO<120.Daily≥0.5 versus ISO<120.Daily<0.5 31,2,3 randomised very very serious9 no serious very serious10 none 83/106 54/89 RR 1.26 (0.72 158 more per 1000 ⊕ΟΟΟ CRITICAL trials serious6 indirectness (78.3%) (60.7%) to 2.22) (from 170 fewer to 740 VERY LOW more) mucosal / cutaneous changes - ISO<120.Daily≥0.5 versus ISO<120.Other≥0.5 14 randomised very no serious no serious serious7 none 37/38 16/22 RR 1.34 (1.03 247 more per 1000 ⊕ΟΟΟ CRITICAL trials serious6 inconsistency indirectness (97.4%) (72.7%) to 1.74) (from 22 more to 538 VERY LOW more) mucosal / cutaneous changes