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FINAL Management options for people with moderate to severe vulgaris - network meta-analyses

Evidence tables for review question: For people with moderate to severe acne vulgaris what are the most effective treatment options?

Table 7: Clinical evidence tables (for data extraction see supplement 8) Outcomes and Study details Participants Interventions results Comments Study details N=134 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Bossuyt, L. B., J.,Richert, Sex 12 discontinuation for Some concerns;no information B.,Cromphaut, P.,Mitchell, mixed Treatment duration category any reason provided T.,Al Abadie, M.,Henry, age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from I.,Bewley, A.,Poyner, T.,Mann, 18.6 Number of arms Treatment intervention N.,Czernielewski, age (min/max) 2 discontinuation Some concerns;not reported if J. in the treatment 12/29 Split face design due to side effects participants were blinded; ITT of acne: An efficacious, safe See supplement 8 analysis was done; 8% age (other information) No and cost-effective alternative to protocol deviations in LYME LYME mean age 18.6 (range Intervention: arm 1 Clinician rated . 2003. European arm vs 1.5% in MINO arm 13 - 29), MINO mean age 18.6 LYME-oral 300mg improvement in Journal of Dermatology acne 3. Missing outcome data (range 12 - 29) Intervention: arm 2 Trial ID See supplement 8 (efficacy) Inclusion/exclusion criteria MINO-oral 100mg Bossuyt 2003 Some concerns;22% Used validated acne scale Country Coded intervention: arm 1 withdrawals / loss to follow-up - no Europe LYME-oral balanced between arms; 1.5% Acne scale Study type Coded intervention: arm 2 due to lack of efficacy; ITT Leeds Grading Scale, Cunliffe RCT MINO-oral used; Inclusion details Source of funding 4. Outcome measurement Males or females aged Galderma Belgilux N.V./S.A. (efficacy) between 12 and 30 years. and Galderma UK Limited. Low;investigator-masked Participants with at least 15 5. Selective reporting Analysis method and at most 120 inflammatory Some concerns;not reported if Intention to treat or facial lesions (papules, trial protocol was registered completers analysis pustules, nodules) including at ITT most 2 facial nodules 6. Overall bias Method of ITT imputation (diameter >1 cm), a maximum Some concerns LOCF of 60 non-inflammatory facial

97 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments lesions (open and closed comedones) and an acne severity grade between 1 and 5 (Leeds grading scale). Women of childbearing age were required to use contraception during the study and for 1 month after completing the trial. Women on oral contraceptives were to have been using the same method for 3 months prior to enrolment, or for at least 12 months for contraceptive pills constraining . Use of cosmetics was permitted during the course of the study, but contraceptives and cosmetics had to be listed as concomitant . Exclusion details Pregnancy or lactating women. Participants with acne conglobata, acne fulminans or secondary acne. Participants using topical anti-acne or anti- inflammatory drugs or , with the exception of short-courses of penicillin during the previous 6 months. Number included Number randomised: arm 1 66 Number randomised: arm 2 68 Number completed: arm 1 52

98 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Number completed: arm 2 52 Study details N=na Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Braathen, L. R.Topical Sex 8 improvement in Some concerns;no information versus oral mixed Treatment duration category acne provided and placebo in age (mean±SD) 6 to <12 weeks See supplement 8 2. Deviation from acne vulgaris. 1984. 20 Number of arms intervention Scandinavian Journal of age (min/max) 3 Some concerns;double-blinded Infectious Diseases 16/35 Split face design but not clear who was blinded; Trial ID no ITT analysis Inclusion/exclusion criteria No Braathen 1984 Used validated acne scale Intervention: arm 1 3. Missing outcome data Country no CLIND-topical 1% + PLC-oral (efficacy) Norway High;12% excluded from Acne scale Intervention: arm 2 analysis for unclear reasons - Study type None TETRA-oral 500mg bid + not clear if balanced between RCT Vehicle Inclusion details arms; no ITT Source of funding Participants with moderate to Intervention: arm 3 4. Outcome measurement Not reported. severe acne vulgaris. PLC-oral + Vehicle (efficacy) Analysis method Coded intervention: arm 1 Some concerns;not reported if Intention to treat or CLIND-topical + PLC-oral assessment of outcome was completers analysis Coded intervention: arm 2 blinded completers Exclusion details TETRA-oral + Vehicle 5. Selective reporting Participants with a history of Coded intervention: arm 3 Some concerns;not reported if gastrointestinal disease. PLC-oral + Vehicle trial protocol was registered Participants who had received systemic or topical antibiotics, 6. Overall bias systemic or topical steroids, or High androgenic drugs within 30 days of entering the study.

.Females who were pregnant, or had been on oral contraceptives for less than 3 months, or had changed oral

99 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments contraceptive within the previous 3 months. Number included Number randomised: arm 1 na Number randomised: arm 2 na Number randomised: arm 3 na Number completed: arm 1 29 Number completed: arm 2 29 Number completed: arm 3 29 Study details N=50 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Chen, X. S., H.,Chen, Sex 3 discontinuation for Some concerns;no information S.,Zhang, J.,Niu, G.,Liu, mixed Treatment duration category any reason provided X.Clinical efficacy of 5- age (min/max) 0 to <6 weeks See supplement 8 2. Deviation from aminolevulinic acid 18/33 Treatment intensity intervention photodynamic therapy in the age (other information) Total 4 sessions, once every Some concerns;no information treatment of moderate to ALA-PDT mean age=23.57; week provided; not reported if ITT severe facial acne vulgaris. control=24.12 Number of arms analysis was done 2015. Experimental and 2 3. Missing outcome data Therapeutic Medicine Inclusion/exclusion criteria Used validated acne scale Split face design (efficacy) Trial ID no No Low;1 patient withdrew for Chen 2015 unreported reason Acne scale Intervention: arm 1 Country None 5ALA 5% photodynamic 4. Outcome measurement China (efficacy) Inclusion details therapy Study type Some concerns;not reported if Participants with moderate Intervention: arm 2 RCT assessment of outcome was (acne with inflammatory Sham treatment Source of funding blinded papules and pustules) to Coded intervention: arm 1 Not reported. 5. Selective reporting severe (acne with inflammatory 5ALA-RED-PDT Some concerns;not reported if trial protocol was registered

100 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Analysis method papules, nodules, cysts and Coded intervention: arm 2 6. Overall bias Intention to treat or scars) facial acne vulgaris. PLC-physical Some concerns completers analysis Exclusion details completers Use of topical antibiotics within 2 weeks of the study or intake of systemic oral antibiotics within 4 weeks of the study.Use of systemic within 6 months of the study. Porphyria or facial atopic dermatitis. Pregnancy or lactation. History of keloid or photosensitivity disorders. Photosensitive eczema or autoimmune diseases. Use of anti-acne medication such as prophylactics, glucocorticoid and photosensitisers. Number included Number randomised: arm 1 25 Number randomised: arm 2 25 Number completed: arm 1 24 Number completed: arm 2 23 Study details N=242 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Cunliffe, W. J. M., J.,Alirezai, Sex 12 discontinuation for Some concerns;no information M.,George, S. A.,Coutts, mixed Treatment duration category any reason provided I.,Roseeuw, D. I.,Hachem, J. age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from P.,Briantais, P.,Sidou, F.,Soto, 18.9±4.7 Number of arms Treatment intervention P.Is combined oral and topical age (min/max) 2 discontinuation Some concerns;not reported if therapy better than oral 12/45 Split face design due to side effects participants were blinded; ITT therapy alone in patients with No See supplement 8 analysis was done moderate to moderately severe

101 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments acne vulgaris? A comparison age (other information) Intervention: arm 1 Clinician rated 3. Missing outcome data of the efficacy and safety of LYME+ADAP=19.3 (5.4); LYME 300mg + ADAP 0.1% improvement in (efficacy) lymecycline plus gel LYME+VEH=18.6 (4) gel acne Some concerns;more than 5% 0.1%, versus lymecycline plus Inclusion/exclusion criteria Intervention: arm 2 See supplement 8 withdrawals - balanced gel vehicle. 2003. Journal of Used validated acne scale LYME 300 mg + Vehicle gel between arms the American Academy of yes Coded intervention: arm 1 4. Outcome measurement Dermatology Acne scale LYME-oral + ADAP-topical (efficacy) Trial ID Leeds Revised Grading Scale Coded intervention: arm 2 Low;investigator-blinded Cunliffe 2003 Inclusion details LYME-oral + Vehicle 5. Selective reporting Country Males and females aged 12 to Some concerns;not reported if Europe 30 years with moderate to trial protocol was registered Study type moderately severe 6. Overall bias RCT inflammatory acne vulgaris. Some concerns Source of funding Global severity grade ranging Galderma International from 4 to 10 on the Leeds (conflicts of interest reported). Revised Acne Grading System Analysis method and at least 15 inflammatory Intention to treat or facial lesions (no more than 3 completers analysis nodules) and at least 20 non- ITT inflammatory facial lesions. Participants taking certain Method of ITT imputation topical and systemic LOCF treatments were required to complete specified washout periods before entering the study. Exclusion details Participants with acne conglobata, acne fulminans, secondary acne, severe nodulocystic acne requiring treatment with , or other dermatologic conditions requiring interfering topical or systemic treatment. Pregnancy or women planning pregnancy or nursing. Men with beards or

102 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments other facial hair likely to interfere with study assessments. Number included Number randomised: arm 1 118 Number randomised: arm 2 124 Number completed: arm 1 106 Number completed: arm 2 111 Study details N=105 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Degreef, H. V., B. G.Double- Sex 12 discontinuation for Some concerns;no information blind evaluation of miconazole- mixed Treatment duration category any reason provided combination age group 12 to <24 weeks See supplement 8 2. Deviation from for the topical treatment of =25 years Number of arms intervention acne vulgaris. 1982b. age (median) 2 Low;double-blinded; it looks Dermatologica 15 Split face design like participants were blinded; Trial ID no ITT analysis age (min/max) No Degreef 1982b 12/24 Intervention: arm 1 3. Missing outcome data Country (efficacy) Inclusion/exclusion criteria BPO 5%/MICO 2% cream Belgium Low;less than 5% withdrawals Used validated acne scale Intervention: arm 2 - balanced between arms Study type no BPO 5% cream RCT 4. Outcome measurement Acne scale Coded intervention: arm 1 (efficacy) Source of funding Unknown, 5-point scale BPO-topical + MICO-topical Not reported. Some concerns;not reported if Inclusion details Coded intervention: arm 2 Analysis method assessment of outcome was Participants with moderate to BPO-topical blinded Intention to treat or severe facial acne. completers analysis 5. Selective reporting Exclusion details Some concerns;not reported if completers Not reported. trial protocol was registered Number included 6. Overall bias Number randomised: arm 1 Some concerns 52

103 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Number randomised: arm 2 53 Number completed: arm 1 51 Number completed: arm 2 51 Study details N=40 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Dhawan, S. S. G., Sex 12 improvement in Some concerns;insufficient J.Clindamycin phosphate mixed Treatment duration category acne information provided on 1.2%-benzoyl peroxide (5% or age (mean±SD) 12 to <24 weeks See supplement 8 allocation concealment 2.5%) plus cream 21.9±8.34 Number of arms 2. Deviation from 0.1% for the treatment of acne. age (min/max) 2 intervention 2013. Cutis 12.3/45.9 Split face design Low;likely participants were Trial ID blinded; ITT analysis was Inclusion/exclusion criteria No Dhawan 2013 done Used validated acne scale Intervention: arm 1 Country no BPO 5%/CLIND 1.2% gel + 3. Missing outcome data United States (efficacy) Acne scale TAZ 0.1% cream Some concerns;12.5% Study type Investigator's Static Global Intervention: arm 2 withdrawals/lost to FU unclear RCT Assessment BPO 2.5%/CLIND 1.2% gel + reasons - not clear if balanced Source of funding (ISGA)/Investigator's global TAZ 0.1% cream between arms; ITT done Stiefel, a GlaxoSmithKline severity Assessment Coded intervention: arm 1 4. Outcome measurement company (conflicts of interest Inclusion details BPO-topical + CLIND-topical + (efficacy) reported). Males and females aged 12 to TAZ-topical Some concerns;not reported if Analysis method 45 years. Participants with Coded intervention: arm 2 assessment of outcome was Intention to treat or grade 3 or higher according to BPO-topical + CLIND-topical + blinded completers analysis the investigator static global TAZ-topical ITT assessment (ISGA) 5. Selective reporting Method of ITT imputation (3=moderate; 4=severe; Low not reported 5=very severe). 20 to 50 6. Overall bias papules and pustules Some concerns (inflammatory lesions), 30 to 100 open and closed comedones (non-inflammatory lesions), 1 or fewer small

104 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments nodular lesions, no facial cystic lesions. Exclusion details

Number included Number randomised: arm 1 20 Number randomised: arm 2 20 Number completed: arm 1 na Number completed: arm 2 na Study details N=60 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Dhir, R. G., N. P.,Agarwal, Sex 24 discontinuation for Some concerns;no information R.,More, Y. E.Oral isotretinoin mixed Treatment duration category any reason provided is as effective as a age (other information) 24+ weeks See supplement 8 2. Deviation from combination of oral isotretinoin 10-15 yrs-old, n=3 Number of arms intervention and topical anti-acne agents in 2 High;participants and nodulocystic acne. 2008. Split face design personnel were not blinded; Indian Journal of Dermatology, 16-20, n=23 No no ITT analysis Venereology & Leprology Intervention: arm 1 3. Missing outcome data Trial ID ISO=120.Daily=0.5 + CLIND (efficacy) Dhir 2008 21-25, n=26 1% during daytime + ADAP High;17% withdrawals unclear Country 0.1% at bed time reasons (not A.E.s)- balanced India between arms; no ITT Intervention: arm 2 26-30, n=5 Study type ISO=120.Daily=0.5 4. Outcome measurement RCT (efficacy) Coded intervention: arm 1 Some concerns;not reported if Source of funding ISO=120.Daily=0.5-oral + >30, n=3 assessment of outcome was None (no conflicts of interest). CLIND-topical + ADAP-topical Inclusion/exclusion criteria blinded Analysis method Coded intervention: arm 2 Used validated acne scale 5. Selective reporting Intention to treat or ISO=120.Daily=0.5-oral completers analysis no Some concerns;not reported if trial protocol was registered completers

105 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Acne scale 6. Overall bias Unclear, type of lesion x High counts scale Inclusion details Participants with nodulocystic acne. Exclusion details Pregnant and lactating females. Participants with abnormal lipid profiles, significant hepatic dysfunction and an underlying psychiatric disorder. Number included Number randomised: arm 1 30 Number randomised: arm 2 30 Number completed: arm 1 25 Number completed: arm 2 25 Study details N=253 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Dobson, R. L. B., B. S.Topical Sex 12 discontinuation for Some concerns;no information solution in acne. mixed Treatment duration category any reason provided Results of a multiclinic trial. age (other information) 12 to <24 weeks See supplement 8 2. Deviation from 1980. Journal of the American no age info reported Number of arms Clinician rated intervention Academy of Dermatology Inclusion/exclusion criteria 2 improvement in Some concerns;double-blinded Trial ID Used validated acne scale Split face design acne but not clear who was blinded; Dobson 1980 no No See supplement 8 no ITT analysis Country Acne scale Intervention: arm 1 3. Missing outcome data United States None ERYTH 1.5% solution (efficacy) High;21% withdrawals - Study type Inclusion details Intervention: arm 2 imbalanced between arms & RCT Participants with moderate to Vehicle due to lack of efficacy (2 X

106 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Source of funding severe acne vulgaris of the Coded intervention: arm 1 more in the vehicle arm); no Not reported. face (at least 10 papules or ERYTH-topical ITT Analysis method pustules, one or more Coded intervention: arm 2 4. Outcome measurement comedones, and not more than Intention to treat or Vehicle (efficacy) completers analysis 5 nodulocystic lesions). Some concerns;double-blinded

completers but not clear who was blinded 5. Selective reporting No concurrent illness and not Some concerns;not reported if receiving any anti-acne trial protocol was registered treatment (topical or systemic) 6. Overall bias for at least 2 weeks prior to High study entry. Exclusion details Not reported. Number included Number randomised: arm 1 127 Number randomised: arm 2 126 Number completed: arm 1 109 Number completed: arm 2 90 Study details N=750 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Dogra, S., Sumathy, T. K., Sex 12 discontinuation for Some concerns;random Nayak, C., Ravichandran, G., mixed Treatment duration category any reason allocation software used - but Vaidya, P. P., Mehta, S., Mittal, age (mean±SD) 12 to <24 weeks See supplement 8 no further information given R., Mane, A., Charugulla, S. 21.2 Number of arms Clinician rated 2. Deviation from N.Efficacy and safety age (median) 3 improvement in intervention comparison of combination of 20 Split face design acne Low;double-blinded but not 0.04% microspheres See supplement 8 clear who was blinded; ITT age (min/max) No plus 1% clindamycin versus analysis was done 12/48 Intervention: arm 1 their monotherapy in patients 3. Missing outcome data Inclusion/exclusion criteria Fixed dose tretinoin 0.04% with acne vulgaris: a phase 3, (efficacy) randomized, double-blind Used validated acne scale (microsphere) + clindamycin no 1.0% gel, o.d.

107 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments study. 2020. Journal of Acne scale Intervention: arm 2 Some concerns;10% Dermatological Treatment Investigator's Static Global Tretinoin gel 0.025%, o.d. discontinued in total Trial ID Assessment Intervention: arm 3 4. Outcome measurement Dogra 2020 (ISGA)/Investigator's global Clindamycin gel 1.0%, o.d. (efficacy) Country severity Assessment Coded intervention: arm 1 Some concerns;not reported if India Inclusion details TRET-topical+CLIND-topical assessment of outcome was blinded Study type Participants aged >/=12 Coded intervention: arm 2 RCT years.Facial acne TRET-topical 5. Selective reporting (inflammatory lesion count Low Source of funding Coded intervention: arm 3 [papulesþpustules] count Dr. Reddy’s Laboratories Ltd, CLIND-topical 6. Overall bias between >20 to <50; non- India. Some concerns inflammatory lesion count Analysis method [openþclosed comedones] Intention to treat or between >20 to <100, and completers analysis nodules [inflammatory lesion ITT 5mm in diameter] 2) and Method of ITT imputation Investigator’s Static Global LOCF Assessment (ISGA) score of 3 (moderate) or 4 (severe) Exclusion details Patients with a known allergy or sensitivity to study drug, or who were concomitantly using any potentially irritating over- the-counter products that contained benzoyl peroxide, a- hydroxy acids, , retinol or glycolic acids, or who required concurrent use of topical (antimicrobials, anti- acne drugs, anti-inflammatory agents, corticosteroids, retinoids) or systemic (corticosteroids, antimicrobials, retinoids) medication and not willing to undergo the specified washout period

108 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Number included Number randomised: arm 1 300 Number randomised: arm 2 300 Number randomised: arm 3 150 Number completed: arm 1 277 Number completed: arm 2 267 Number completed: arm 3 133 Study details N=378 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Dreno, B. K., R.,Talarico, Sex 12 discontinuation for Some concerns;no information S.,Torres Lozada, mixed Treatment duration category any reason provided V.,Rodríguez-Castellanos, M. age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from A.,Gómez-Flores, M.,De 18.9±4.5999999999999996 Number of arms Treatment intervention Maubeuge, J.,Berg, M.,Foley, age (min/max) 2 discontinuation Low;double-blinded; ITT P.,Sysa-Jedrzejowska, A.,et 12/35 Split face design due to side effects analysis was done al.,Combination therapy with See supplement 8 Inclusion/exclusion criteria No 3. Missing outcome data adapalene-benzoyl peroxide Clinician rated (efficacy) and oral lymecycline in the Used validated acne scale Intervention: arm 1 no ADAP 0·1%/BPO 2·5% gel + improvement in Some concerns;more than 5% treatment of moderate to acne withdrawals - balanced Acne scale LYME 300 mg severe acne vulgaris: a See supplement 8 between arms multicentre, randomized, Investigator's Global Intervention: arm 2 4. Outcome measurement double-blind controlled study. Assessment scale (IGA) LYME 300 mg + Vehicle (efficacy) 2011. British journal of Inclusion details Coded intervention: arm 1 Low;investigators blinded dermatology Participants of any race or sex ADAP-topical + BPO-topical + 5. Selective reporting Trial ID and aged between 12 and 35 LYME-oral Some concerns;not reported if Dreno 2011 years. Coded intervention: arm 2 trial protocol was registered Country Vehicle + LYME-oral 6. Overall bias Europe/Maxico/Brazil/Australia .Moderate to severe acne Some concerns Study type vulgaris (defined by the RCT

109 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Source of funding Investigator's Global Galderma (conflicts of interest Assessment: IGA score of 3 or reported). 4 on a scale from 0 to 5). Analysis method Minimum of 20 inflammatory Intention to treat or lesions, between 30 and 120 completers analysis non-inflammatory lesions, and ITT no more than 3 nodulocystic lesions on the face excluding Method of ITT imputation the nose area. Females of LOCF childbearing potential had to have a negative urine pregnancy test before and during the study. Exclusion details Participants with acne conglobata, acne fulminans (secondary acne) or other dermatological conditions which could interfere with treatment or evaluation. Number included Number randomised: arm 1 191 Number randomised: arm 2 187 Number completed: arm 1 178 Number completed: arm 2 174 Study details N=218 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Dubertret, L. A., M.,Rostain, Sex 12 discontinuation for Some concerns;no information G.,Lahfa, M.,Forsea, mixed Treatment duration category any reason provided D.,Dimitrie Niculae, B.,Simola, age (min/max) 12 to <24 weeks See supplement 8 2. Deviation from M.,Horvath, A.,Mizzi, F.The 14/39 Number of arms Treatment intervention use of lymecycline in the 3 discontinuation Low;double-blinded; treatment of moderate to

110 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments severe acne vulgaris: A age (other information) Split face design due to side effects participants likely blinded; ITT comparison of the efficacy and mean age was 20.4, 21.2 & No See supplement 8 analysis was done safety of two dosing regimens. 20.5 yrs for LYME 300mg, Intervention: arm 1 Clinician rated 3. Missing outcome data 2003. European Journal of LYME 150mg and PLC groups LYME-oral 300mg od + PLC- improvement in (efficacy) Dermatology Inclusion/exclusion criteria oral acne Some concerns;12% Trial ID Used validated acne scale Intervention: arm 2 See supplement 8 withdrawals (unclear reasons) Dubertret 2003 yes LYME-oral 150mg bid - imbalanced between arms (more in lymecycline arm); ITT Country Acne scale Intervention: arm 3 used Europe Leeds Revised Grading Scale PLC-oral bid 4. Outcome measurement Study type Inclusion details Coded intervention: arm 1 RCT Males and females aged LYME-oral + PLC-oral (efficacy) Source of funding between 16 and 40 years. Some concerns;not reported if Coded intervention: arm 2 assessment of outcome was Not reported. Acne vulgaris with a minimum LYME-oral of 15 inflammatory facial blinded Analysis method Coded intervention: arm 3 Intention to treat or lesions and a global severity of 5. Selective reporting PLC-oral completers analysis at least grade 3 on the Leeds Some concerns;not reported if ITT Revised Acne Grading trial protocol was registered System. Method of ITT imputation 6. Overall bias Exclusion details Some concerns LOCF

Number included Number randomised: arm 1 111 Number randomised: arm 2 107 Number randomised: arm 3 53 Number completed: arm 1 105 Number completed: arm 2 88 Number completed: arm 3 45

111 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Study details N=1075 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Eichenfield, L.F., Jarratt, Sex 12 discontinuation for Some concerns;no information M.,Schlessinger, J.,Kempers, mixed Treatment duration category any reason about allocation sequence S.,Manna, V.,Hwa, J.,Liu, age (mean±SD) 12 to <24 weeks See supplement 8 provided Y.,Graeber, M.Adapalene 19.1487441860465±6.89 Number of arms Treatment 2. Deviation from 0.1% lotion in the treatment of age (min/max) 2 discontinuation intervention acne vulgaris: Results from 12/63.9 Split face design due to side effects Low;double-blinded; ITT two placebo-controlled, See supplement 8 analysis was done age (other information) No multicenter, randomized Clinician rated 3. Missing outcome data double-blind, clinical studies. mean (SD) combines study 1 Intervention: arm 1 and study 2, article reports ADAP 0.1% lotion improvement in (efficacy) 2010b. Journal of Drugs in acne Some concerns;13% Dermatology combined data for both studies Intervention: arm 2 by group: ADAP age=19.3 See supplement 8 withdrawals (both trials Trial ID Vehicle (6.9), median=16.7, range 12- combined) - balanced between Eichenfield 2010b Coded intervention: arm 1 arms; ITT used 53.8, <18, n=665, 18-64, ADAP-topical Country n=403 ; Veh age=19 (6.9), 4. Outcome measurement Coded intervention: arm 2 United States median=16.8, range 12-63.9, (efficacy) Vehicle Study type <19, n=679, 18-64, n=394 Some concerns;not reported if RCT Inclusion/exclusion criteria assessment of outcome was Source of funding Used validated acne scale blinded Galderma Research & no 5. Selective reporting Development (conflicts of Acne scale Some concerns;not reported if interest were reported). Investigator's Global trial protocol was registered Analysis method Assessment scale (IGA) 6. Overall bias Intention to treat or Inclusion details Some concerns completers analysis Males and females of any ITT race/ethnicity aged 12 years or Method of ITT imputation older. Minimum of 20, but not LOCF more than 50, papules and pustules in total on the face and a minimum of 30, but not more than 100, non- inflammatory lesions (open comedones and closed comedones) on the face (excluding the nose).

112 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Participants with an Investigator's Global Assessment (IGA) of 3 (moderate; more than half of the face involved. Many comedones, papules and pustules. One small nodule may be present) or 4 (severe; entire face is involved. Covered with comedones, numerous papules and pustules. Few nodules/cysts may or may not be present). Exclusion details

Number included Number randomised: arm 1 533 Number randomised: arm 2 542 Number completed: arm 1 471 Number completed: arm 2 460 Study details N=744 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Feldman, S. R. W., C. P.,Alio Sex 12 discontinuation for Low Saenz, A. B.The efficacy and mixed Treatment duration category any reason 2. Deviation from tolerability of tazarotene foam, age (mean±SD) 12 to <24 weeks See supplement 8 intervention 0.1%, in the treatment of acne 18.400269179004±6.0598000 Number of arms Treatment Low;double-blinded; study vulgaris in 2 multicenter, 000000001 2 discontinuation center, randomized, vehicle-controlled, age (min/max) Split face design due to side effects double-blind studies. 2013. 12/44 No See supplement 8 Journal of Drugs in study monitors, sponsor age (other information) Intervention: arm 1 Clinician rated Dermatology: JDD personnel were blinded to the TAZ: 12-17, n=223, 18-25, TAZ 0.1% foam improvement in n=104, 26-35, n=38, 36-45,

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Trial ID n=6; VEH: 12-17, n=227, 18- Intervention: arm 2 acne treatment assignments. ITT Feldman 2013;Trial 1 25, n=99, 26-35, n=33, 36-45, Vehicle See supplement 8 analysis was done Country n=13 Coded intervention: arm 1 3. Missing outcome data North America Inclusion/exclusion criteria TAZ-topical (efficacy) Study type Used validated acne scale Coded intervention: arm 2 Some concerns;14% no discontinued (unclear how RCT Vehicle many due to inefficacy)- Source of funding Acne scale imbalanced between arms Stiefel, a GlaxoSmithKline Investigator's Static Global (more in tazarotene foam arm) company (conflicts of interest Assessment were reported). (ISGA)/Investigator's global 4. Outcome measurement severity Assessment (efficacy) Analysis method Low Intention to treat or Inclusion details completers analysis Males and females aged 5. Selective reporting ITT between 12 and 45 years, in Low good general health and Method of ITT imputation 6. Overall bias agreed to use a medically- LOCF Some concerns acceptable form of contraception throughout the study.

.Moderate to severe acne vulgaris: Investigator's Static Global Assessment (ISGA) score =3 at baseline; lesion counts of 25 to 50 facial inflammatory lesions (papules plus pustules), including nasal lesions, with no more than one facial nodular lesion (<5 mm) and no cystic lesions, and 30 to 125 facial non-inflammatory lesions (open and closed comedones), excluding nasal lesions. Provide consent. Exclusion details History of suspected

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Outcomes and Study details Participants Interventions results Comments intolerance to tazarotene or any of the ingredients of the study products. Participants taking certain topical and systemic treatments were required to undergo specified washout periods. Number included Number randomised: arm 1 372 Number randomised: arm 2 372 Number completed: arm 1 307 Number completed: arm 2 333 Study details N=742 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Feldman, S. R. W., C. P.,Alio Sex 12 discontinuation for Low Saenz, A. B.The efficacy and mixed Treatment duration category any reason 2. Deviation from tolerability of tazarotene foam, age (mean±SD) 12 to <24 weeks See supplement 8 intervention 0.1%, in the treatment of acne 19.2±6.6463999999999999 Number of arms Treatment Low;double-blinded; study vulgaris in 2 multicenter, age (min/max) 2 discontinuation center, randomized, vehicle-controlled, 12/45 Split face design due to side effects double-blind studies. 2013. See supplement 8 age (other information) No Journal of Drugs in study monitors, sponsor TAZ: 12-17, n=205, 18-25, Intervention: arm 1 Clinician rated Dermatology: JDD personnel were blinded to the n=117, 26-35, n=35, 36-45, TAZ 0.1% foam improvement in Trial ID acne treatment assignments. ITT n=16; VEH: 12-17, n=205, 18- Intervention: arm 2 Feldman 2013;Trial 2 See supplement 8 analysis was done 25, n=108, 26-35, n=37, 36-45, Vehicle Country n=19 3. Missing outcome data North America Coded intervention: arm 1 (efficacy) Inclusion/exclusion criteria TAZ-topical Study type Some concerns;14% Used validated acne scale Coded intervention: arm 2 discontinued (unclear how RCT no Vehicle many due to inefficacy)- Source of funding Acne scale Stiefel, a GlaxoSmithKline imbalanced between arms Investigator's Static Global (more in tazarotene foam arm) Assessment

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Outcomes and Study details Participants Interventions results Comments company (conflicts of interest (ISGA)/Investigator's global 4. Outcome measurement were reported). severity Assessment (efficacy) Analysis method Inclusion details Low Intention to treat or Males and females aged 5. Selective reporting completers analysis between 12 and 45 years, in Low ITT good general health and 6. Overall bias agreed to use a medically- Method of ITT imputation Some concerns acceptable form of LOCF contraception throughout the study.

.Moderate to severe acne vulgaris: Investigator's Static Global Assessment (ISGA) score =3 at baseline; lesion counts of 25 to 50 facial inflammatory lesions (papules plus pustules), including nasal lesions, with no more than one facial nodular lesion (<5 mm) and no cystic lesions, and 30 to 125 facial non-inflammatory lesions (open and closed comedones), excluding nasal lesions. Provide consent. Exclusion details History of suspected intolerance to tazarotene or any of the ingredients of the study products. Participants taking certain topical and systemic treatments were required to undergo specified washout periods.

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Outcomes and Study details Participants Interventions results Comments Number included Number randomised: arm 1 373 Number randomised: arm 2 369 Number completed: arm 1 307 Number completed: arm 2 334 Study details N=58 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Fluckiger, R. F., H. J.,Rufli, Sex 12 discontinuation for Some concerns;no information T.Efficacy and tolerance of a mixed Treatment duration category any reason provided miconazole-benzoyl peroxide age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from cream combination versus a 18 Number of arms Clinician rated intervention benzoyl peroxide gel in the age (min/max) 2 improvement in Low;single-blinded - topical treatment of acne 15/30 Split face design acne participants; no ITT analysis vulgaris. 1988. Dermatologica See supplement 8 age (other information) No 3. Missing outcome data Trial ID BPO mean age=18.8; BPO + Intervention: arm 1 (efficacy) Fluckiger 1988 MICO mean age =17.7 BPO 5% cream High;12% discontinued - Country imbalanced between arms Inclusion/exclusion criteria Intervention: arm 2 Switzerland (more in BPO-MCZ arm) Used validated acne scale BPO 5%/MICO 2% cream Study type 4. Outcome measurement no Coded intervention: arm 1 RCT (efficacy) Acne scale BPO-topical Source of funding Some concerns;not reported if None Coded intervention: arm 2 Not reported. assessment of outcome was Inclusion details BPO-topical + MICO-topical blinded Analysis method Participants with moderately 5. Selective reporting Intention to treat or severe to severe forms of acne Some concerns;not reported if completers analysis vulgaris. Participants not trial protocol was registered completers receiving any treatment 4 weeks prior to study entry. 6. Overall bias High Exclusion details Any accompanying treatment.

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Outcomes and Study details Participants Interventions results Comments Number included Number randomised: arm 1 29 Number randomised: arm 2 29 Number completed: arm 1 27 Number completed: arm 2 25 Study details N=73 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Fugere, P. P.-S., R. K.,Lussier- Sex 48 discontinuation for Some concerns;no information Cacan, S.,Davignon, female Treatment duration category any reason provided J.,Farquhar, D.Cyproterone age (mean±SD) 24+ weeks See supplement 8 2. Deviation from acetate/ethinyl in the 22.9260273972603±3.263999 Number of arms intervention treatment of acne. A 9999999998 2 Low;double-blinded - clear that comparative dose-response age (min/max) Split face design participants were blinded; no study of the 17/35 No ITT analysis component. 1990. 3. Missing outcome data Contraception Inclusion/exclusion criteria Intervention: arm 1 Used validated acne scale CPA 2mg + EE 0.035 mg (efficacy) Trial ID no (Diane-35) High;23% withdrawals - not Fugere 1990 clear if balanced between Acne scale Intervention: arm 2 Country arms; no ITT used Cook CPA 2mg + EE 0.05 mg Canada 4. Outcome measurement Inclusion details (Diane-50) Study type (efficacy) Women in good health aged Coded intervention: arm 1 RCT Some concerns;not reported if between 18 and 35 years. CPA-oral + EE-oral assessment of outcome was Source of funding Moderate to severe androgen- Coded intervention: arm 2 blinded Not reported. dependent acne vulgaris CPA-oral + EE-oral Analysis method (defined as presence of 5. Selective reporting Intention to treat or comedones, papules and Some concerns;not reported if completers analysis macules on at least half of the trial protocol was registered completers face. Previous treatment 6. Overall bias withdrawn within 6 weeks of High starting study treatments.

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Outcomes and Study details Participants Interventions results Comments Exclusion details Not reported. Number included Number randomised: arm 1 40 Number randomised: arm 2 33 Number completed: arm 1 37 Number completed: arm 2 25 Study details N=85 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Gollnick, H. P. G., K.,Zaumseil, Sex 26 improvement in Some concerns;no information R. P.Comparison of combined male Treatment duration category acne provided cream plus oral age (mean±SD) 24+ weeks See supplement 8 2. Deviation from minocycline with oral 19 Number of arms intervention isotretinoin in severe acne. age (min/max) 2 High;open-labeled 2001. European Journal of 15/31 Split face design 3. Missing outcome data Dermatology Inclusion/exclusion criteria No (efficacy) Trial ID Used validated acne scale Intervention: arm 1 Some concerns;more than 5% Gollnick 2001 no AZE-topical 20% cream + withdrawals - imbalanced Country between arms (more in Acne scale MINO-oral 50mg bid Germany AA/Mino arm); all participants Leeds Grading Scale, Cunliffe Intervention: arm 2 Study type were included in the efficacy Inclusion details ISO<120.Daily=0.5 RCT analysis Males over the age of 16 Coded intervention: arm 1 4. Outcome measurement Source of funding years. Participants with severe AZE-topical + MINO-oral (efficacy) Not reported. inflammatory facial acne (at Coded intervention: arm 2 High;open-labeled Analysis method least grade 4 using the ISO<120.Daily=0.5-oral Intention to treat or Cunliffe's classification (Leeds 5. Selective reporting completers analysis scale)); at least 2 deep Some concerns;not reported if ITT inflammatory lesions (nodes, trial protocol was registered Method of ITT imputation cysts or nodules) and other 6. Overall bias High not reported papules and pustules. No treatment with any systemic treatment for at least 4 weeks

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Outcomes and Study details Participants Interventions results Comments prior to the start of the study (or for isotretinoin, 12 months), use of topical treatment had to have been discontinued at least 2 weeks prior to the start of the study. For inclusion in phase II of the study, participants must have achieved a decrease of at least 75% in the number of deep inflammatory lesions in phase I of the study and in whom the efficacy of treatment had been rated as 'very good'. Exclusion details Women. Participants with milder (comedonal or papulopustular acne) or more severe (acne fulminans, acne tetrade) forms of acne. Photosensitivity. Participants with contraindications to isotretinoin or minocycline and hypersensitivity to the substances contained in the study treatment. Number included Number randomised: arm 1 50 Number randomised: arm 2 35 Number completed: arm 1 44 Number completed: arm 2 33

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Outcomes and Study details Participants Interventions results Comments Study details N=245 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Gratton, D. R., G. P.,Guertin- Sex 8 discontinuation for Some concerns;no information Larochelle, S.,Maddin, S. mixed Treatment duration category any reason provided W.,Leneck, C. M.,Warner, age (min/max) 6 to <12 weeks See supplement 8 2. Deviation from J.,Collins, J. P.,Gaudreau, 18/35 Number of arms Treatment intervention P.,Bendl, B. J.Topical Inclusion/exclusion criteria 3 discontinuation Low;double-blinded; likely that clindamycin versus systemic Used validated acne scale Split face design due to side effects participants were blinded; no tetracycline in the treatment of no No See supplement 8 ITT analysis acne. Results of a multiclinic Clinician rated 3. Missing outcome data trial. 1982. Journal of the Acne scale Intervention: arm 1 None CLIND 1% solution + PLC improvement in (efficacy) American Academy of acne High;17% discontinued - Inclusion details capsule Dermatology See supplement 8 imbalanced between arms Participants with moderate to Intervention: arm 2 Trial ID (more in placebo arm); no ITT Gratton 1982 severe acne (defined as PLC capsule + PLC solution presence of a minimum of 12 4. Outcome measurement Country Coded intervention: arm 1 to 70 inflammatory papules (efficacy) Canada CLIND-topical + PLC-oral and pustules, and a maximum Some concerns;not reported if Study type Coded intervention: arm 2 assessment of outcome was of 6 nodulocystic lesions on PLC-oral + PLC-topical RCT the face above the jawline). blinded Source of funding 5. Selective reporting Not reported. Some concerns;not reported if Analysis method trial protocol was registered Intention to treat or Exclusion details 6. Overall bias completers analysis Participants with a history of High completers gastrointestinal disease. Participants who had received systemic or topical antibiotics, systemic or topical steroids, or androgenic drugs within 30 days of starting study medication.

.Females who had been on oral contraceptives for 3 months, or made a change in

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Outcomes and Study details Participants Interventions results Comments oral contraceptives within the previous 3 months; pregnancy. Number included Number randomised: arm 1 121 Number randomised: arm 2 124 Number completed: arm 1 105 Number completed: arm 2 97 Study details N=92 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Greenwood, R. B., L.,Burke, Sex 26 discontinuation for Some concerns;no information B.,Cunliffe, W. J.Acne: Double female Treatment duration category any reason provided blind clinical and laboratory age (min/max) 24+ weeks See supplement 8 2. Deviation from trial of tetracycline, oestrogen- 16/30 Number of arms Treatment intervention cyproterone acetate, and Inclusion/exclusion criteria 3 discontinuation Low;double-blinded; likely that combined treatment. 1985. Used validated acne scale Split face design due to side effects participants were blinded; not British Medical Journal no No See supplement 8 clear if ITT analysis was done Trial ID Acne scale Intervention: arm 1 3. Missing outcome data Greenwood 1985 Leeds Grading Scale, Cunliffe CPA 2mg/EE 0.05 mg + (efficacy) Country High;33% withdrawals - Inclusion details TETRA 500 mg bid United Kingdom balanced between arms. 3% Women with moderate or Intervention: arm 2 due to inefficacy; No ITT Study type moderately severe acne who CPA 2mg/EE 0.05 mg + PLC RCT had already tried antibiotics for capsule 4. Outcome measurement (efficacy) Source of funding their acne. Intervention: arm 3 Some concerns;not reported if Not reported. Exclusion details TETRA 500 mg bid + PLC assessment of outcome was Analysis method Not reported. capsule blinded Intention to treat or Number included Coded intervention: arm 1 5. Selective reporting completers analysis Number randomised: arm 1 CPA-oral + EE-oral + TETRA- Some concerns;not reported if completers 37 oral trial protocol was registered Number randomised: arm 2 Coded intervention: arm 2 6. Overall bias 30 CPA-oral + EE-oral + PLC-oral High

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Outcomes and Study details Participants Interventions results Comments Number randomised: arm 3 Coded intervention: arm 3 25 TETRA-oral + PLC-oral Number completed: arm 1 25 Number completed: arm 2 21 Number completed: arm 3 16 Study details N=32 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Gruber, D. M. S., M. O.,Joura, Sex 13 discontinuation for Some concerns;no information E. A.,Kokoschka, E. female Treatment duration category any reason provided M.,Heinze, G.,Huber, J. age group 12 to <24 weeks See supplement 8 2. Deviation from C.Topical cyproterone acetate >25 years Number of arms Clinician rated intervention treatment in women with acne: age (mean±SD) 2 improvement in Some concerns;not reported if A placebo- controlled trial. 30.3 Split face design acne participants/personnel were 1998a. Archives of See supplement 8 blinded; no ITT analysis was age (min/max) No Dermatology done 26/38 Intervention: arm 1 Trial ID 3. Missing outcome data age (other information) CPA 2mg/EE 0.035 mg Gruber 1998a (efficacy) Oral CPA age=29.4 (range 26- Intervention: arm 2 Country High;11% withdrawals - 37); Topical CPA age 31.3 PLC-lotion Austria balanced between arms; no (range 26-38); PLC topical Coded intervention: arm 1 Study type ITT age=30.3 (range26-38) CPA-oral + EE-oral RCT 4. Outcome measurement Inclusion/exclusion criteria Coded intervention: arm 2 (efficacy) Source of funding Used validated acne scale PLC-topical Some concerns;not reported if Supported by Schering Wien no Ges. M.b.H. (manuscript assessment of outcome was Acne scale translation) and Schering blinded Leeds Grading Scale, Cunliffe Berlin (provision of cyproterone 5. Selective reporting acetate assays). Inclusion details Some concerns;not reported if Women with moderate to Analysis method trial protocol was registered severe acne who consulted the Intention to treat or 6. Overall bias endocrinology outpatient completers analysis High department for a hormonal completers evaluation and treatment of their acne. Using barrier

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Outcomes and Study details Participants Interventions results Comments contraception during study treatment. Acne treatment had been stopped 6 weeks prior to study commencement. Exclusion details Participants with medical contraindications to the study treatment or unwilling to smoke less than 5 cigarettes daily. Number included Number randomised: arm 1 14 Number randomised: arm 2 18 Number completed: arm 1 12 Number completed: arm 2 16 Study details N=44 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Hong, J. S. J., J. Y.,Yoon, J. Sex 8 improvement in Some concerns;Unit of Y.,Suh, D. H.Acne treatment mixed Treatment duration category acne randomisation was side of by methyl aminolevulinate age (min/max) 6 to <12 weeks See supplement 8 face; no information provided photodynamic therapy with red 19/35 Treatment intensity about randomisation method or light vs. intense pulsed light. allocation concealement Inclusion/exclusion criteria Total 3 sessions, once every 2 2013. International Journal of Used validated acne scale weeks. Endpoint 4-wks after 2. Deviation from Dermatology no last session. intervention Trial ID Some concerns;investigator/ Acne scale Number of arms Hong 2013 participant blinding not Leeds Grading Scale, Cunliffe 2 reported; no ITT; unlikely there Country Split face design Inclusion details was a carry over effect of Korea, Republic of Yes Males and females with active treatment Study type acne lesions and Fitzpatrick Intervention: arm 1 3. Missing outcome data RCT skin phototypes IV to V; acne MAL 16%-RED PDT (efficacy) Source of funding grade at least grade 2 (Cunliffe Intervention: arm 2 Some concerns;10% Not reported. acne grading system). MAL 16%-IPL-PDT withdrawals - balanced

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Outcomes and Study details Participants Interventions results Comments Analysis method Exclusion details Coded intervention: arm 1 between arms; withdrawals not Intention to treat or History of keloid, MAL-RED-PDT related to efficacy completers analysis photosensitive disorders. Coded intervention: arm 2 4. Outcome measurement completers Taking medication such as oral MAL-IPL-PDT (efficacy) contraceptives, oral antibiotics, Low;assessment of outcome and topical agents within 4 was blinded weeks, treatment with oral 5. Selective reporting isotretinoin within the past 6 Some concerns;not reported if months. Pregnant and/or trial protocol was registered lactating women. 6. Overall bias Number included Some concerns Number randomised: arm 1 22 Number randomised: arm 2 22 Number completed: arm 1 20 Number completed: arm 2 20 Study details N=60 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment intensity Clinician rated 1. Randomisation Horfelt, C. F., J.,Frohm- Sex Total 2 sessions, once every 2 improvement in Some concerns;Unit of Nilsson, M.,Wiegleb Edstrom, mixed weeks. Endpoint 4-wks after acne randomisation was side of D.,Wennberg, A. M.Topical age (median) last session. See supplement 8 face; no information provided methyl aminolaevulinate 18 Number of arms about randomisation method or photodynamic therapy for allocation concealement age (min/max) 2 treatment of facial acne 15/28 Split face design 2. Deviation from vulgaris: Results of a Yes intervention randomized, controlled study. age (other information) Intervention: arm 1 Low;investigator/ participant 2006. British Journal of MAL-PDT median age=18 MAL 16%-PDT blinding; ITT used Dermatology (range 15-28). Intervention: arm 2 3. Missing outcome data Trial ID PL (efficacy) Horfelt 2006 Some concerns;10% PL median age=18 (range 15- Coded intervention: arm 1 Country withdrawals - balanced 28) MAL-RED-PDT Sweden between arms; withdrawals not related to efficacy

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Outcomes and Study details Participants Interventions results Comments Study type Inclusion/exclusion criteria Coded intervention: arm 2 4. Outcome measurement RCT Used validated acne scale PLC-physical (efficacy) Source of funding no Low;assessment of outcome PhotoCure ASA, Norway Acne scale was blinded (conflicts of interest reported). Leeds Grading Scale, Cunliffe 5. Selective reporting Analysis method Inclusion details Some concerns;not reported if Intention to treat or Participants with moderate to trial protocol was registered completers analysis severe inflammatory facial 6. Overall bias ITT acne; moderate defined as at Some concerns Method of ITT imputation least 10 inflammatory lesions (papules and pustules) and 15 LOCF to 100 non-inflammatory lesions (open and closed comedones), excluding the nose. Acne treatments discontinued up to 3 months prior to the study. Exclusion details Not stated. Number included Number randomised: arm 1 30 Number randomised: arm 2 30 Number completed: arm 1 27 Number completed: arm 2 27 Study details N=80 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Ioannides, D. R., Sex 12 discontinuation for Low D.,Katsambas, A.Topical mixed Treatment duration category any reason 2. Deviation from adapalene gel 0.1% vs. age (min/max) 12 to <24 weeks See supplement 8 intervention isotretinoin gel 0.05% in the 15/35 Number of arms Treatment High;open label; no ITT treatment of acne vulgaris: A 2 discontinuation analysis was done randomized open-label clinical

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Outcomes and Study details Participants Interventions results Comments trial. 2002. British Journal of Inclusion/exclusion criteria Split face design due to side effects 3. Missing outcome data Dermatology Used validated acne scale No See supplement 8 (efficacy) Trial ID no Intervention: arm 1 High;9% discontinued - Ioannides 2002 Acne scale ADAP 0.1% gel balanced between arms; 6% Country Unclear, lesion type x severity Intervention: arm 2 due to inefficacy; no ITT Greece scale 0-100 ISO 0.05% gel 4. Outcome measurement Study type Inclusion details Coded intervention: arm 1 (efficacy) RCT Participants with 15 to 80 facial ADAP-topical High;open-labeled Source of funding non-inflammatory lesions Coded intervention: arm 2 5. Selective reporting Not reported. (open and closed comedones), ISO-topical Some concerns;not reported if 10 to 50 inflammatory lesions trial protocol was registered Analysis method (papules and pustules) and no Intention to treat or 6. Overall bias more than 3 nodulocystic completers analysis High lesions. No other cutaneous completers disease on the face. No use of any other topical treatment for 14 days, systemic antibiotics for 30 days, or systemic retinoids for at least 6 months prior to start of study treatment. Women who were not pregnant or lactating, and had discontinued oral contraception at least 3 months before study entry. Exclusion details Not reported. Number included Number randomised: arm 1 40 Number randomised: arm 2 40 Number completed: arm 1 36 Number completed: arm 2 31

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Outcomes and Study details Participants Interventions results Comments Study details N=54 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Jackson, J. M. F., J. Sex 16 discontinuation for Some concerns;no information J.,Almekinder, J. L.A mixed Treatment duration category any reason provided randomized, investigator- age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from blinded trial to assess the 16.9±5.9 Number of arms intervention antimicrobial efficacy of a age (IQR) 2 Some concerns;participants benzoyl peroxide 5%/ BPO/CLIND, median age=15.8 Split face design not blinded; ITT analysis was clindamycin phosphate 1% gel (IQR=13.5-18.5. No done compared with a clindamycin 3. Missing outcome data phosphate 1.2%/tretinoin Intervention: arm 1 BPO 5%/CLIND 1% gel (efficacy) 0.025% gel in the topical Some concerns;more than 5% CLIND/TRET=13.9-17 Intervention: arm 2 treatment of acne vulgaris. withdrawals 2010. Journal of Drugs in age (other information) CLIND 1%/TRET 0.025% gel 4. Outcome measurement Dermatology: JDD BPO/CLIND median age=15.8 Coded intervention: arm 1 (IQR 13.5-18.5). (efficacy) Trial ID BPO-topical + CLIND-topical Low;Assessors blinded Jackson 2010 Coded intervention: arm 2 5. Selective reporting CLIND-topical + TRET-topical Country CLIND/TRET median Low;All the outcomes listed in United States age=15.6 (IQR 13.9-17). the registered protocol were all Study type reported RCT 6. Overall bias

Source of funding Some concerns Not reported (conflicts of Inclusion/exclusion criteria interest reported). Used validated acne scale Analysis method no Intention to treat or Acne scale completers analysis Investigator's Global ITT Assessment scale (IGA) Method of ITT imputation Inclusion details not reported Males and females of any race, aged 12 years or older. Moderate to moderately severe and stable facial acne vulgaris characterised by 15 to 100 facial inflammatory lesions; 15 to 100 facial non-inflammatory

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Outcomes and Study details Participants Interventions results Comments lesions, and =2 facial nodules and/or cysts. P. acnes counts of =104 colony-forming units per square centimetre of skin (CFU/cm2) of which no more than 104 CFU/cm2 were erythromycin or clindamycin resistant. Women of childbearing age were required to have a negative urine pregnancy test prior to study enrolment and practice a reliable method of contraceptive during the study. Women taking oestrogens/oral contraceptives =90 days before study baseline could continue with this during the study provided they did not discontinue or alter use during the study. Washout periods and restrictions adhered to for topical and systemic treatments: topical facial treatments, including retinoids, anti-acne products and corticosteroids (2 weeks); topical antibiotics and systemic corticosteroids (4 weeks); systemic antibiotics (6 weeks) and systemic retinoids (6 months). Exclusion details Women taking oestrogens/oral contraceptives =90 days before study baseline.

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Outcomes and Study details Participants Interventions results Comments Number included Number randomised: arm 1 27 Number randomised: arm 2 27 Number completed: arm 1 25 Number completed: arm 2 24 Study details N=175 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Jones, E. L. C., A. F.Topical Sex 12 discontinuation for Some concerns;no information erythromycin vs blank vehicle mixed Treatment duration category any reason provided in a multiclinic acne study. age (other information) 12 to <24 weeks See supplement 8 2. Deviation from 1981. Archives of Dermatology ERYTH 13-20, n=31; 21-30, Number of arms Treatment intervention Trial ID n=46; 31-40, n=3; 41+, n=1; 2 discontinuation Some concerns;double-blinded Jones 1981 not known=0. Split face design due to side effects but not clear who was blinded; Country No See supplement 8 not clear if ITT analysis was done United States Intervention: arm 1 Study type Vehicle 13-20, n=29; 21-30, BPO 5%/ERYTH 3% gel 3. Missing outcome data n=39; 31-40, n=6; 41+, n=0; (efficacy) RCT Intervention: arm 2 not known=1. Some concerns;more than 5% Source of funding Vehicle Inclusion/exclusion criteria withdrawals - balanced Not reported. Coded intervention: arm 1 Used validated acne scale between arms Analysis method BPO-topical + ERYTH-topical no 4. Outcome measurement Intention to treat or Coded intervention: arm 2 Acne scale (efficacy) completers analysis Vehicle Unclear, type of lesion x Some concerns;not clear if completers counts scale blinded Inclusion details 5. Selective reporting Males and females aged 12 Some concerns;not reported if years or older, seeking trial protocol was registered medical care for acne or 6. Overall bias recruited volunteers, but High otherwise in good general health. Facial acne grades 2 or 3 on the severity scale (grade

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments 2: a moderate number of comedones, papules, and small cysts, occasional pustules, and inflammation; grade 3: a great number of lesions with deeper and larger cysts and minimal scarring). Minimum of 10 papular inflammatory acne lesions in the facial area. Participants could be pregnant or of childbearing age. Unresponsive to treatment with oral tetracycline hydrochloride, topical benzoyl peroxide, and tretinoin. Exclusion details Children aged <12 years of age. Participants could not be planning to move within 12 weeks. Use of concomitant antibiotics given for systemic effect or another topical acne treatment, unless it was possible to discontinue such treatment 3 weeks before the start of the study. Number included Number randomised: arm 1 90 Number randomised: arm 2 85 Number completed: arm 1 81 Number completed: arm 2 75

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Outcomes and Study details Participants Interventions results Comments Study details N=223 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Jones, T. M., L.,Monroe, Sex 8 discontinuation for Some concerns;no information E.,Weiss, J.,Levy, S.A mixed Treatment duration category any reason provided multicentre, double-blind, age (mean±SD) 6 to <12 weeks See supplement 8 2. Deviation from parallel-group study to 18.5±5.8 Number of arms Clinician rated intervention evaluate 3% erythromycin/5% Inclusion/exclusion criteria 2 improvement in Low;double-blinded & ITT benzoyl peroxide dual-pouch Used validated acne scale Split face design acne analysis pack for acne vulgaris. 2002. no No See supplement 8 3. Missing outcome data Clinical Drug Investigation Acne scale Intervention: arm 1 (efficacy) Trial ID Physician's Global BPO 5%/ERYTH 3% gel (dual Some concerns;Unclear how Jones 2002 Assessment (PGA)/Physician’s pouch pack) many discontinued during the Country trial Global Acne Severity Score Intervention: arm 2 United States Inclusion details Vehicle 4. Outcome measurement Study type (efficacy) Male and females aged =13 Coded intervention: arm 1 RCT Low;Assessors blinded years. Moderate to moderately BPO-topical + ERYTH-topical Source of funding 5. Selective reporting severe acne vulgaris (overall Coded intervention: arm 2 Dermick Laboratories, US. Some concerns;not reported if acne severity score =1.5 on Vehicle Analysis method the Physician’s Global Acne trial protocol was registered Intention to treat or Severity Scale, 15 to 80 6. Overall bias completers analysis inflammatory lesions, 20 to 140 Some concerns ITT comedones, and =2 nodules or Method of ITT imputation cysts measuring greater than 5mm. The comedo not reported

count did not include the nasal and nasolabial fold area). Treatment with systemic antibiotics known to affect acne and systemic corticosteroids should be discontinued 4 weeks prior to study commencement, and 6 months for oral retinoids. A 2- week washout period was required for topical antibiotics

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments and/or anti-acne medication, topical corticosteroids, and topical retinoids. Exclusion details Pregnant or lactating women. Participants with beards or long sideburns. Participants with cystic acne or any other diseases affecting their condition or interfering with treatment evaluation. Number included Number randomised: arm 1 112 Number randomised: arm 2 111 Number completed: arm 1 112 Number completed: arm 2 110 Study details N=44 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Khanna, N.Treatment of acne Sex 12 discontinuation for Some concerns;No detials on vulgaris with oral tetracylines. mixed Treatment duration category any reason methods 1993. Indian journal of age group 12 to <24 weeks See supplement 8 2. Deviation from dermatology, venerology and =25 years Number of arms Treatment intervention leprology age (min/max) 2 discontinuation High;No blinding; no ITT Trial ID 14/24 Split face design due to side effects 3. Missing outcome data Khanna 1993 See supplement 8 Inclusion/exclusion criteria No (efficacy) Country Used validated acne scale Intervention: arm 1 High;Withdrawals of 23% - India no TETRA 500 mg po bid some due to lack of efficacy & imbalanced between groups Study type Acne scale Intervention: arm 2 RCT Unclear, type of lesion x MINO 50 mg po bid 4. Outcome measurement (efficacy) Source of funding counts scale Coded intervention: arm 1 High;not blinded None (no conflicts of interest). TETRA-oral

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Analysis method Inclusion details Coded intervention: arm 2 5. Selective reporting Intention to treat or Males and females with MINO-oral Some concerns;not reported if completers analysis moderately severe acne trial protocol was registered completers (defined when acne lesion 6. Overall bias score (ALS) was 30 to 70) and Method of ITT imputation High severe acne (defined as ALS not reported score of more than 70). Participants who had taken oral antibiotics were included in the study after 1 month discontinuation of the antibiotics. Exclusion details Participants with acne conglobata. Pregnant women or women using oral contraceptives. Participants with obvious endocrinopathy. Number included Number randomised: arm 1 21 Number randomised: arm 2 23 Number completed: arm 1 15 Number completed: arm 2 19 Study details N=32 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Kim, T. I. A., H. J.,Kang, I. Sex 16 discontinuation for Some concerns;no information H.,Jeong, K. H.,Kim, N. I.,Shin, mixed Treatment duration category any reason about allocation concealment M. K.Nonablative fractional age (mean±SD) 12 to <24 weeks See supplement 8 provided laser-assisted daylight 24.75±3.5999999999999996 Treatment intensity Clinician rated 2. Deviation from photodynamic therapy with age (min/max) Total 2 sessions, once every 2 improvement in intervention topical methyl aminolevulinate 19/45 weeks. FU visits at 2, 6, 10 acne Some concerns;Not reported if for moderate to severe facial and 14 wks after last session. See supplement 8 participants were blinded; not

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments acne vulgaris: Results of a Inclusion/exclusion criteria Number of arms reported if ITT analysis was randomized and comparative Used validated acne scale 2 done study. 2017. Photodermatology no Split face design 3. Missing outcome data Photoimmunology and Acne scale No (efficacy) Photomedicine Investigator's Global Intervention: arm 1 High;more than 5% Trial ID Assessment scale (IGA) MAL 16%-DL PDT withdrawals - balanced Kim 2017 between arms Inclusion details Intervention: arm 2 Country Participants aged between 19 NAFL + MAL 16%-DL PDT 4. Outcome measurement Korea, Republic of and 45 years. Active acne Coded intervention: arm 1 (efficacy) Study type lesions and Fitzpatrick skin MAL-DL-PDT Low RCT phototypes III to IV; acne 5. Selective reporting Coded intervention: arm 2 Source of funding severity grade 3 or 4 according Some concerns;not reported if NAFL + MAL-DL-PDT Galderma Research & to the IGA. trial protocol was registered Development (no conflicts of Exclusion details 6. Overall bias interest). History of photosensitive High Analysis method disorders. Use of Intention to treat or such as oral isotretinoin for 3 completers analysis months and oral contraceptives or antibiotics for completers 4 weeks, topical treatments or facial procedures for 4 weeks. Pregnant or lactating women. Participants were prohibited from using oral or topical medications for treatment of acne during the study. Number included Number randomised: arm 1 16 Number randomised: arm 2 16 Number completed: arm 1 14 Number completed: arm 2 14

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Study details N=353 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Kircik, L.Community-based trial Sex 12 improvement in Some concerns;no information results of combination mixed Treatment duration category acne provided clindamycin 1 %-benzoyl age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from peroxide 5% topical gel plus 20.4±na Treatment intensity intervention tretinoin microsphere Gel Inclusion/exclusion criteria 3 Some concerns;not reported if 0.04% or 0.1% or adapalene Used validated acne scale Number of arms participants were blinded gel 0.1 % in the treatment of no 2 3. Missing outcome data moderate to severe acne. (efficacy) 2007. Cutis Acne scale Split face design Investigator's Static Global No Low;No withrawals / loss to Trial ID Assessment follow-up Kircik 2007 Intervention: arm 1 (ISGA)/Investigator's global BPO 5%/CLIND 1% gel + 4. Outcome measurement Country severity Assessment TRET 0.04% gel (efficacy) United States Low Inclusion details Intervention: arm 2 Study type Participants with moderate to BPO 5%/CLIND 1% gel + 5. Selective reporting RCT severe acne. ADAP 0.1% gel Some concerns;not reported if Source of funding trial protocol was registered Exclusion details Intervention: arm 3 Stiefel Laboratories (conflicts Not reported. BPO 5%/CLIND 1% gel + 6. Overall bias of interest reported). Number included TRET 0.1% gel Some concerns Analysis method Number randomised: arm 1 Coded intervention: arm 1 Intention to treat or 118 BPO-topical + CLIND-topical + completers analysis Number randomised: arm 2 TRET-tropical ITT 118 Coded intervention: arm 2 Method of ITT imputation Number randomised: arm 3 BPO-topical + CLIND -topical + not reported 117 ADAP-topical Number completed: arm 1 Coded intervention: arm 3 118 BPO-topical + CLIND-topical + Number completed: arm 2 TRET-tropical 118 Number completed: arm 3 117 Study details N=147 Interventions Results Cochrane RoB Tool v2.0 Reference Treatment duration (weeks) Treatment 1. Randomisation Kircik, L. G., L.,Thiboutot, 12 discontinuation for

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments D.,Tanghetti, E.,Wilson, Characteristics Treatment duration category any reason Some concerns;no information D.,Dhawan, S.,Parr, Sex 12 to <24 weeks See supplement 8 provided L.Comparing a novel mixed Number of arms 2. Deviation from solubilized benzoyl peroxide age (mean±SD) 2 intervention gel with benzoyl 21.4±8.4 Split face design Some concerns;not reported if peroxide/clindamycin: Final Inclusion/exclusion criteria No participants were blinded; ITT data from a multicenter, analysis was done Used validated acne scale Intervention: arm 1 investigator-blind, randomized no 3. Missing outcome data study. 2009a. Journal of Drugs BPO 5%/CLIND 1% gel + Acne scale TRET 0.04% gel (efficacy) in Dermatology Some concerns;more than 5% Investigator's Global Intervention: arm 2 Trial ID withdrawals - balanced Assessment scale (IGA) CLIND 1.2%/TRET 0.025% gel Kircik 2009a between arms Inclusion details + BPO 5% wash Country Males or females of any race, 4. Outcome measurement United States Coded intervention: arm 1 aged 12 years or older. BPO-topical + CLIND-topical + (efficacy) Study type Moderate to severe stable, TRET-tropical Low RCT non-rapidly progressing facial Coded intervention: arm 2 5. Selective reporting Source of funding acne vulgaris characterised by BPO-topical + CLIND-topical + Some concerns;not reported if Not reported (conflicts of 20 to 60 facial inflammatory trial protocol was registered TRET-tropical interest reported). lesions; 20 to 60 facial non- 6. Overall bias Analysis method inflammatory lesions and =2 Some concerns Intention to treat or facial nodules and/or cysts. completers analysis Women of childbearing ITT potential were required to have Method of ITT imputation a negative urine pregnancy test at baseline and use a not reported reliable method of contraceptive during the study period. Exclusion details Pregnancy, nursing or lack of contraceptive use. Known sensitivity to any of the test medications or their components, potentially complicating medical histories (such as history of enteritis, especially pseudomembranous

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments colitis or -associated colitis). Non-compliance with washout periods for treatments such as topical and systemic acne medications, antibiotics, retinoids, BPO and corticosteroids). Skin conditions that might interfere with the diagnosis or evaluation of acne, procedures complementary to treatment of facial acne within 14 days of baseline and compliance issues. Number included Number randomised: arm 1 73 Number randomised: arm 2 74 Number completed: arm 1 59 Number completed: arm 2 65 Study details N=na Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Kuhlman, D. S. C., J. P.A Sex 12 improvement in Some concerns;no information comparison of clindamycin mixed Treatment duration category acne provided phosphate 1 percent topical age (min/max) 12 to <24 weeks See supplement 8 2. Deviation from lotion and placebo in the 12/30 Number of arms intervention treatment of acne vulgaris. Inclusion/exclusion criteria 2 Some concerns;double-blinded 1986. Cutis Used validated acne scale Split face design but not clear who was blinded Trial ID no No 3. Missing outcome data Kuhlman 1986 Acne scale Intervention: arm 1 (efficacy) Country None CLIND 1% lotion High;not reported how many United States participants were randomised Inclusion details Intervention: arm 2 Men and women aged 12 to 30 Vehicle

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Study type years. Moderate to severe Coded intervention: arm 1 to each arm; not reported how RCT acne vulgaris defined as 12 to CLIND-topical many withdrew Source of funding 70 inflammatory papules and Coded intervention: arm 2 4. Outcome measurement no more than 6 cystic lesions Not reported. Vehicle (efficacy) on the face above the jawline. Analysis method Some concerns;not reported if Intention to treat or Exclusion details assessment of outcome was completers analysis Participants sensitive to blinded clindamycin. Pregnant or completers 5. Selective reporting nursing women. Participants Some concerns;not reported if with chronic bowel disease or trial protocol was registered frequent periodic diarrhoea. 6. Overall bias Participants requiring High additional acne treatment, those who had received systemic antibiotics, steroids, or androgens within the past 30 days or topical acne medications within the past 14 days, and participants who had started or stopped using oral contraceptives in the past 60 days. Number included Number randomised: arm 1 na Number randomised: arm 2 na Number completed: arm 1 21 Number completed: arm 2 14 Study details N=na Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Leyden, J. B., W.,Drake, Sex 13 improvement in Some concerns;no information L.,Dunlap, F.,Goldman, M. mixed Treatment duration category acne provided P.,Gottlieb, A. B.,Heffernan, M. 12 to <24 weeks See supplement 8 P.,Hickman, J. G.,Hordinsky,

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments M.,Jarrett, M.,et al.,A systemic age (other information) Number of arms 2. Deviation from type I 5 alpha-reductase no age nor sex data reported 2 intervention inhibitor is ineffective in the Inclusion/exclusion criteria Split face design Low;Participant & investigator treatment of acne vulgaris. Used validated acne scale No blinded; no ITT 2004. Journal of the american no Intervention: arm 1 3. Missing outcome data academy of dermatology Acne scale MINO 100 mg + PL (efficacy) Trial ID None Intervention: arm 2 High;not reported how many Leyden 2004 Inclusion details PL participants withdrew (only results for completers). 269 Country Participants with moderately Coded intervention: arm 1 included in safety analysis - United States severe acne with a minimum of MINO-oral + PLC-oral Study type only 182 in efficacy analysis 20 inflammatory lesions. Coded intervention: arm 2 RCT 4. Outcome measurement Exclusion details PLC-oral Source of funding Not reported. (efficacy) Low;Assessor blinded Merck Research Laboratories Number included (conflicts of interest reported). Number randomised: arm 1 5. Selective reporting Analysis method na High;Some of the specified outcomes not reported Intention to treat or Number randomised: arm 2 completers analysis na 6. Overall bias completers High Number completed: arm 1 34 Number completed: arm 2 37 Study details N=41 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment intensity Clinician rated 1. Randomisation Mei, X. S., W.,Piao, Sex Total 4 sessions, once every improvement in High;Allocation not concealed Y.Effectiveness of mixed week. Assessments 1-wk after acne 2. Deviation from photodynamic therapy with age (mean±SD) each session so have See supplement 8 intervention topical 5-aminolevulinic acid 24 assumed endpoint is at 4th Low;Participants & and intense pulsed light in treatment (see table1) Inclusion/exclusion criteria investigators blinded Chinese acne vulgaris Number of arms 3. Missing outcome data patients. 2013. Used validated acne scale no 2 (efficacy) Photodermatology Acne scale Split face design Low;No withrawals / loss to Photoimmunology and No follow-up. Photomedicine Global Acne Severity Scale (GEA Scale) Intervention: arm 1 Trial ID 5ALA 10%-IPL-PDT Mei 2013

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Country Inclusion details Intervention: arm 2 4. Outcome measurement China Chinese people aged over 18 IPL-PT + Vehicle (efficacy) Study type years. Participants with II–IV Coded intervention: arm 1 Low;Assessor blinded RCT facial acne according to 5ALA-IPL-PDT 5. Selective reporting Source of funding Pillsbury grade and Fitzpatrick Coded intervention: arm 2 Some concerns;not reported if skin type II–IV. trial protocol was registered Not reported (no conflicts of IPL + Vehicle interest). Exclusion details 6. Overall bias Participants exposed to Analysis method High Intention to treat or systemic treatment in completers analysis the last 6 months, systemic ITT antibiotics treatment or contraceptive and Method of ITT imputation photosensitive drugs in the not reported previous month, local acne drug treatment in the last 2 weeks. Participants with a tendency to form keloids or with a history of photosensitivity. Pregnant or breastfeeding women. Number included Number randomised: arm 1 21 Number randomised: arm 2 20 Number completed: arm 1 21 Number completed: arm 2 20 Study details N=90 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Miller, J. A. W., F. T.,Dowd, P. Sex 26 discontinuation for Some concerns;no information M.Anti-androgen treatment in female Treatment duration category any reason provided women with acne: A controlled age (min/max) 24+ weeks See supplement 8 2. Deviation from trial. 1986b. British Journal of 16/36 Number of arms Treatment intervention Dermatology 3 discontinuation Some concerns;double-blinded

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Trial ID age (other information) Split face design due to side effects but not clear who was blinded; Miller 1986b CPA/EE mean age=24.2 No See supplement 8 not reported if ITT analysis Country (range 18-34); NOR/EE mean Intervention: arm 1 was done United Kingdom age 24.2 (range 18-36); CPA CPA 2mg/EE 0.05 mg (days 5- 3. Missing outcome data Study type mean age=22.8 (range 16-30) 25) + PL (days 5-14) (efficacy) RCT Inclusion/exclusion criteria Intervention: arm 2 High;Withdrawal imbalanced between groups (more in Source of funding Used validated acne scale NOR 1mg/EE 0.05mg (days 5- Diane and placebo arm) and Schering Chemicals Ltd. no 25) + PL (days 5-14) more than 5% Analysis method Acne scale Intervention: arm 3 4. Outcome measurement Intention to treat or Leeds Grading Scale, Cunliffe CPA 50mg (days 5-14), then (efficacy) completers analysis Inclusion details EE 0.05 mg (days 5-25) Some concerns;not reported if completers Women aged between 16 and Coded intervention: arm 1 assessment of outcome was 36 years. Moderate to severe CPA-oral + EE-oral + PLC-oral blinded acne (graded according to Coded intervention: arm 2 Burke & Cunliffe, 1984). Any NOR-oral + EE-oral + PLC-oral 5. Selective reporting acne medication (other than Some concerns;not reported if Coded intervention: arm 3 contraceptive pill) stopped 6 trial protocol was registered CPA-oral + EE-oral weeks prior to study 6. Overall bias participation. Oral High contraception was continued until the commencement of the trial. Exclusion details Participants with medical contraindications to the study treatment. Current smokers (more than 5 cigarettes daily). Number included Number randomised: arm 1 28 Number randomised: arm 2 32 Number randomised: arm 3 30 Number completed: arm 1 24

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Number completed: arm 2 26 Number completed: arm 3 26 Study details N=46 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Nicklas, C. R., R.,Cardenas, Sex 6 discontinuation Some concerns;no information C.,Hasson, A.Comparison of mixed Treatment duration category due to side effects about allocation concealment efficacy of aminolaevulinic acid age (other information) 6 to <12 weeks See supplement 8 provided photodynamic therapy vs. 5ALA-PDT median age=21 Treatment intensity Clinician rated 2. Deviation from adapalene gel plus oral (IQR 18-21); ADAP+DOXY Total 2 sessions of 5ALA-PDT, improvement in intervention for treatment of median age=21 (IQR 18-25) once every 2 weeks acne Some concerns;not reported if moderate acne vulgaris-A Inclusion/exclusion criteria Number of arms See supplement 8 participants were blinded simple, blind, randomized, and Used validated acne scale 2 3. Missing outcome data controlled trial. 2019. no (efficacy) Photodermatology Split face design Acne scale No Low;all participants completed Photoimmunology and the study Photomedicine None Intervention: arm 1 Inclusion details 5ALA 20%-PDT 4. Outcome measurement Trial ID (efficacy) Nicklas 2019 Participants with moderately Intervention: arm 2 severe inflammatory acne Low Country ADAP 0.1% gel + DOXY 100 vulgaris defined by Leeds mg 5. Selective reporting Chile Some concerns;not reported if revised acne grading system Coded intervention: arm 1 Study type trial protocol was registered with modifications as 5ALA-RED-PDT RCT numerous papules and 6. Overall bias Coded intervention: arm 2 Source of funding pustules (40 to 100) usually Some concerns ADAP-topical + DOXY-oral Research Department, with many comedones (40 to Universidad Catolica de Chile. 100) and occasional (up to 5) Analysis method larger, deeper nodular Intention to treat or inflamed lesions on the face. completers analysis Males and females aged 18 to ITT 30 years. Phototype according Method of ITT imputation to Fitzpatrick skin type I to IV with facial acne vulgaris. No not reported other acne treatments permitted during study.

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Exclusion details Participants with photosensitivity disorder, autoimmune

diseases, infectious diseases (HIV, herpes, TB), allergy or intolerance to , taking topical medication within 3 months and/or systemic treatment within the past 6 months. Pregnant or lactating women Number included Number randomised: arm 1 23 Number randomised: arm 2 23 Number completed: arm 1 23 Number completed: arm 2 23 Study details N=48 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment intensity Clinician rated 1. Randomisation Paithankar DY, Sakamoto FH, Sex Total 3 treatments, at 2 week improvement in Some concerns;methods not Farinelli WA, et al.Acne mixed intervals acne reported Treatment Based on Selective age (mean±SD) Number of arms See supplement 8 2. Deviation from Photothermolysis of 21.2 2 intervention Sebaceous Follicles with age (min/max) Split face design Some concerns;Unclear Topically Delivered Light- 16/30 No whether blinded; no ITT Absorbing Gold Microparticles. Intervention: arm 1 3. Missing outcome data 2015. J Invest Dermatol. Inclusion/exclusion criteria Used validated acne scale GOLDMP + PDL (efficacy) Trial ID no Intervention: arm 2 High;Withdrawal imbalanced Paithankar 2015;Trial 1 No treatment between groups, &>5%,

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Country Acne scale Coded intervention: arm 1 unclear reasons for missing Poland Investigator's Global GOLDMP data; no ITT Study type Assessment scale (IGA) Coded intervention: arm 2 4. Outcome measurement RCT Inclusion details No treatment (efficacy) Source of funding Males and females aged 16 to High;Assessor blinded scores Sebacia, Duluth, GA (conflicts 35 years of age. Moderate-to- pooled with unblinded scores of interest reported). severe inflammatory facial 5. Selective reporting Analysis method acne; IGA scores 3 to 4 with at Low;Trial protocol was Intention to treat or least 25 total papules and registered (both trials 1 & 2 completers analysis pustules present on face under the same number) completers Fitzpatrick skin phototype I to 6. Overall bias III. High Exclusion details Use of systemic medications for acne, oral retinoid treatment, or treatment with Intense Pulsed Lights or lasers within the past 12 months. Number included Number randomised: arm 1 23 Number randomised: arm 2 25 Number completed: arm 1 21 Number completed: arm 2 25 Study details N=214 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Pariser, D. M. T., D. M.,Clark, Sex 12 discontinuation for Some concerns;reported only S. D.,Jones, T. M.,Liu, mixed Treatment duration category any reason that medication was dispensed Y.,Graeber, M.The efficacy age (mean±SD) 12 to <24 weeks See supplement 8 by a third party to protect and safety of adapalene gel 17.3±5.07 Number of arms Treatment blinding 0.3% in the treatment of acne age (median) 3 discontinuation 2. Deviation from vulgaris: A randomized, 16 Split face design due to side effects intervention multicenter, investigator- No See supplement 8 Some concerns;not reported if

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments blinded, controlled comparison age (min/max) Intervention: arm 1 Clinician rated participants were blinded; ITT study versus adapalene gel 12/45 ADAP 0.3% gel improvement in analysis was done 0.1% and vehicle. 2005. Cutis Inclusion/exclusion criteria Intervention: arm 2 acne 3. Missing outcome data Trial ID Used validated acne scale ADAP 0.1% gel See supplement 8 (efficacy) Pariser 2005 yes Intervention: arm 3 Some concerns;Withdrawal Country Acne scale Vehicle imbalanced between groups (21% in the adapalene gel United States Leeds Revised Grading Scale Coded intervention: arm 1 0.3% arm, only 7% in the Study type Inclusion details ADAP-topical adapalene 0.1% gel arm ) RCT Participants aged 12 to 40 Coded intervention: arm 2 Source of funding years. Moderate to moderately ADAP-topical 4. Outcome measurement (efficacy) Galderma Research & severe acne vulgaris; minimum Coded intervention: arm 3 Development (conflicts of of 20 inflammatory facial Low;investigator-blinded Vehicle interest reported). lesions (not >2 nodules/cysts), 5. Selective reporting Analysis method 20 non-inflammatory facial Some concerns;not reported if Intention to treat or lesions; global facial severity trial protocol was registered completers analysis grade 4 to 10 according to the 6. Overall bias ITT Leeds Revised Acne Grading High System. Washout periods for Method of ITT imputation certain topical and systemic baseline assigned? treatments were required. Negative urine pregnancy test results required at screening and at the final visit for women of childbearing potential. Exclusion details Not reported. Number included Number randomised: arm 1 70 Number randomised: arm 2 70 Number randomised: arm 3 74 Number completed: arm 1 55

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Number completed: arm 2 65 Number completed: arm 3 62 Study details N=498 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Pariser, D. M. R., P.,Cook- Sex 12 discontinuation for Some concerns;insufficient Bolden, F. E.,Korotzer, A.An mixed Treatment duration category any reason information provided on aqueous gel fixed combination age (mean±SD) 12 to <24 weeks See supplement 8 allocation concealment of clindamycin phosphate 1.2% 18.7±5.82 Number of arms Treatment 2. Deviation from and benzoyl peroxide 3.75% age (median) 2 discontinuation intervention for the once-daily treatment of 17 Split face design due to side effects Low;double-blinded & ITT moderate to severe acne No See supplement 8 analysis vulgaris. 2014. Journal of age (min/max) 12/40 Intervention: arm 1 Clinician rated 3. Missing outcome data Drugs in Dermatology improvement in (efficacy) age (other information) BPO 3.75%/CLIND 1.2% gel Trial ID acne Some concerns;Withdrawal Sig. diff (p=0.02) between age Intervention: arm 2 Pariser 2014 See supplement 8 imbalanced between groups, of groups Vehicle Country &>5% Inclusion/exclusion criteria Coded intervention: arm 1 United States 4. Outcome measurement Used validated acne scale BPO-topical + CLIND-topical Study type (efficacy) no RCT Coded intervention: arm 2 Low Acne scale Vehicle Source of funding 5. Selective reporting Evaluator's Global Severity Valeant Pharmaceuticals North Some concerns;not reported if Scale (EGSS) America LLC. trial protocol was registered Inclusion details Analysis method 6. Overall bias Males and females of any race Intention to treat or Some concerns and ethnicity, aged 12 to 40 completers analysis years. Moderate to severe ITT acne vulgaris (a score of 3 or 4 Method of ITT imputation on the Global Severity Score MI MCMC (EGSS), presenting with 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 non- inflammatory lesions (open and closed comedones), and =2 nodules. Women of

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments childbearing age were required to have a negative urine pregnancy test and to agree to use an effective form of contraception during the study period. A washout period of up to 1 month was required for participants who used previous prescription and over-the- counter acne treatments (including, topical (face) and systemic treatments: topical astringents and abrasives (1 week); topical anti-acne products, including soaps containing antimicrobials, and known comedogenic products (2 weeks); topical retinoids, retinol, and systemic acne treatments (4 weeks); and systemic retinoids (6 months). Exclusion details Not reported. Number included Number randomised: arm 1 253 Number randomised: arm 2 245 Number completed: arm 1 234 Number completed: arm 2 213 Study details N=153 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment intensity Treatment 1. Randomisation Pariser, D. M. E., L. Sex Total 4 sessions, once every 2 discontinuation for Low F.,Bukhalo, M.,Waterman, mixed G.,Jarratt, M.,Bhatia,

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Outcomes and Study details Participants Interventions results Comments A.,Greenstein, D.,Hamzavi, age (min/max) weeks. Endpoint is 6-wks after any reason 2. Deviation from F.,Kantor, J.,Speelman, P. 12/36 last treatment. See supplement 8 intervention N.,Murakawa, G. J.,Tichy, age (other information) Number of arms Treatment Low;double-blinded; according E.,Zaengelin, A.,Frankel, MAL-PDT median age=17 2 discontinuation to the study protocol it is E.,Werschler, W.Photodynamic (range 12-36), <18 years-old, Split face design due to side effects quadruple-blinded (participant, therapy with methyl n=59; Vehicle median age=17 No See supplement 8 care provider, investigator, aminolaevulinate 80 mg outcomes assessor); ITT (range 12-35), <18 years-old, Intervention: arm 1 Clinician rated g-1 for severe analysis was done n=31 MAL 8%-RED-PDT improvement in facial acne vulgaris: A Inclusion/exclusion criteria acne 3. Missing outcome data randomized vehicle-controlled Intervention: arm 2 Used validated acne scale See supplement 8 (efficacy) study. 2016. British Journal of Vehicle-RED-PDT no Some concerns;16% Dermatology Coded intervention: arm 1 withdrawals - imbalanced Acne scale MAL-RED-PDT Trial ID Investigator's Global between arms as 12 out of 17 Pariser 2016 Coded intervention: arm 2 Assessment scale (IGA) in the active arm discontinued Vehicle + RED due to adverse events and Country Inclusion details none in the other arm United States Males and females aged 12 to Study type 35 years. Severe facial acne 4. Outcome measurement RCT vulgaris (defined by an IGA (efficacy) Source of funding rating score of 4); 27 to 75 Low Photocure ASA, Norway inflammatory lesions (papules, 5. Selective reporting (conflicts of interest reported). pustules and no more than 3 Low Analysis method nodules) and 20 to 100 non- 6. Overall bias Intention to treat or inflammatory lesions (open Some concerns completers analysis and closed comedones) on the ITT face; Fitzpatrick skin types I to Method of ITT imputation VI. Confirmed using standardised clinical LOCF photographs. Females of childbearing potential were required to use appropriate contraception (same product and dose if using an oral contraceptive) for at least 14 days before the first treatment and during the study. Exclusion details Participants with acne

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Outcomes and Study details Participants Interventions results Comments conglobata, acne fulminans, secondary acne, melanoma or dysplastic naevi in the treatment area. Facial har that might interfere with study assessments. Participants with porphyria, cutaneous photosensitivity or known allergy to methyl aminolaevulinate, components of the cream or similar photosensitisers. Participants with moderate-to-very-severe facial acne scarring. Pregnant or nursing females. Systemic acne treatment (oral antibiotics within 1 month or oral isotretinoin within 6 months); topical treatments (other than medicated cleansers) within 14 days; facial procedures (for example, dermabrasion, chemical or laser peels); exposure to ultraviolet radiation (other than sunlight) within 1 month and concomitant hormonal therapy for acne were prohibited. Number included Number randomised: arm 1 100 Number randomised: arm 2 53 Number completed: arm 1 83 Number completed: arm 2 46

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Outcomes and Study details Participants Interventions results Comments Study details N=na Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Peacock, C. E. P., C.,Ryan, B. Sex 12 improvement in Some concerns;insufficient E.,Mitchell, A. D.Topical mixed Treatment duration category acne information provided on clindamycin (Dalacin T) age (mean±SD) 12 to <24 weeks See supplement 8 allocation concealment compared to oral minocycline 21 Number of arms 2. Deviation from (Minocin 50) in treatment of age (min/max) 2 intervention acne vulgaris. A randomized 18/34 Split face design Some concerns;Participants observer-blind controlled trial were blinded but the Inclusion/exclusion criteria No in three university student dispensing nurses were not; no Used validated acne scale Intervention: arm 1 health centres. 1990. Clinical ITT no CLIND-topical 1% bid Trials Journal 3. Missing outcome data Acne scale Intervention: arm 2 Trial ID (efficacy) None MINO-oral 50mg bid Peacock 1990 Some concerns;>10% did not Country Inclusion details Coded intervention: arm 1 complete - unclear how many United Kingdom Males and females aged 16 to CLIND-topical due to lack of efficacy 35 years of age attending Study type Coded intervention: arm 2 4. Outcome measurement student health centres at 4 RCT MINO-oral (efficacy) universities. Moderate to Low;"observers" were blinded Source of funding severe acne, defined as having Not reported. a minimum of 12 and a 5. Selective reporting Analysis method maximum of 100 inflammatory Some concerns;not reported if Intention to treat or lesions, with no more than 6 trial protocol was registered completers analysis nodulocystic lesions above the 6. Overall bias completers jawline. Some concerns Exclusion details Participants taking prescribed treatment for acne within 14 days of study start, receiving systemic antibiotics, corticosteroids or androgens within 14 days of the start of study treatment; participants who had started or stopped oral contraception within 31 days of study treatment. Participants in any other trial or

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Outcomes and Study details Participants Interventions results Comments previously enrolled in the study. Participants with known allergy to or clindamycin.

.Participants with a history of chronic bowel disease, diarrhoea or a past history of antibiotic associated colitis, participants with any serious or uncontrolled illness. Pregnant or nursing women, or women not using reliable contraceptive methods. Number included Number randomised: arm 1 na Number randomised: arm 2 na Number completed: arm 1 42 Number completed: arm 2 38 Study details N=33 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Peck, G. L. O., T. G.,Butkus, Sex 4 improvement in Low D.Isotretinoin versus placebo mixed Treatment duration category acne 2. Deviation from in the treatment of cystic acne. age (mean±SD) 0 to <6 weeks See supplement 8 intervention 1982a. Journal of the 23 Number of arms Low;double-blinded - likely that American Academy of age (other information) 2 participants were blinded; not Dermatology 32 of the 33 included Split face design reported if ITT analysis was Trial ID participants had a mean age of No done Peck 1982a 23 Intervention: arm 1 3. Missing outcome data Country ISO<120.Daily=0.5 (efficacy) United States

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Outcomes and Study details Participants Interventions results Comments Study type Inclusion/exclusion criteria Intervention: arm 2 Some concerns;not clear how RCT Used validated acne scale PLC-oral many participants discontinued Source of funding no Coded intervention: arm 1 4. Outcome measurement Not reported. Acne scale ISO<120.Daily=0.5-oral (efficacy) Analysis method None Coded intervention: arm 2 Some concerns;not reported if assessment of outcome was Intention to treat or Inclusion details PLC-oral completers analysis Volunteers with at least 10 blinded completers inflamed deep dermal or 5. Selective reporting subcutaneous acne cysts or Some concerns;not reported if nodules of at least 4 mm trial protocol was registered diameter. History of minimal 6. Overall bias response to treatment with oral Some concerns and topical antibiotics, oral vitamin A, topical vitamin A acid, topical benzoyl peroxide, x-irradiation, oral contraceptives, oral , intralesional injections of corticosteroids, oral prednisone, surgical drainage, applications of liquid nitrogen, photochemotherapy with psoralen and long-wave ultraviolet light, and other acne treatments. Discontinuation of conventional acne treatment for at least 1 month prior to study entry. No other acne treatment (topical or systemic) permitted during 4-month study treatment period. Exclusion details Pregnant women and women of childbearing potential refusing use of birth control methods. Use of oral contraceptives.

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Outcomes and Study details Participants Interventions results Comments Number included Number randomised: arm 1 16 Number randomised: arm 2 17 Number completed: arm 1 16 Number completed: arm 2 17 Study details N=45 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Sami, N. A. A., A. T.,Badawi, Sex 4 improvement in Some concerns;methods not A. M.Phototherapy in the mixed Treatment duration category acne reported treatment of acne vulgaris. age (mean±SD) 0 to <6 weeks See supplement 8 2. Deviation from 2008. Journal of drugs in 29 Treatment intensity intervention dermatology : JDD age (min/max) Trial continued until 90% lesion Some concerns;Not reported if Trial ID 20/38 clearance observed but 1-mo participants were blinded Sami 2008 Inclusion/exclusion criteria data available. Total sessions 3. Missing outcome data Country Used validated acne scale at 1-mo are 4, 4 and 8, (efficacy) Egypt no respectively, for PDL (1 Some concerns;not clear session, once a week), IPL (1 if/how many participants Study type Acne scale session, once a week) and BR- discontinued RCT Burton LED (2 sessions every week) 4. Outcome measurement Source of funding Inclusion details groups (efficacy) Not reported. Males and females with Number of arms Low Analysis method moderate to severe facial acne 3 Intention to treat or according to Burton 5. Selective reporting completers analysis classification. Split face design Some concerns;not reported if No trial protocol was registered ITT Exclusion details Participants with a history of Intervention: arm 1 6. Overall bias topical acne treatment or 595 nm PDL PT Some concerns systemic antibiotics within the Intervention: arm 2 past 2 weeks, or use of 550 nm-1200 nm IPL PT systemic steroids, systemic Intervention: arm 3 retinoids, or anti-inflammatory BR-LED PT drugs within the past 6 months.

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Outcomes and Study details Participants Interventions results Comments History of photosensitivity. Coded intervention: arm 1 Pregnancy. PDL Number included Coded intervention: arm 2 Number randomised: arm 1 IPL 15 Coded intervention: arm 3 Number randomised: arm 2 BR-LED 15 Number randomised: arm 3 15 Number completed: arm 1 15 Number completed: arm 2 15 Number completed: arm 3 15 Study details N=2010 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Schmidt, N. G., E. Sex 12 discontinuation for Some concerns;no information H.Clindamycin 1.2% tretinoin mixed Treatment duration category any reason about allocation concealment 0.025% gel versus clindamycin age (mean±SD) 12 to <24 weeks See supplement 8 provided gel treatment in acne patients: 19.0501492537313±7.250747 Number of arms Treatment 2. Deviation from A focus on fitzpatrick skin 0119521908 2 discontinuation intervention types. 2011. Journal of Clinical Inclusion/exclusion criteria Split face design due to side effects Some concerns;double-blinded and Aesthetic Dermatology Used validated acne scale No See supplement 8 but not clear who was blinded; Trial ID ITT analysis was done no Intervention: arm 1 Clinician rated Schmidt 2011 Acne scale CLIND 1.2%/TRET 0.025% gel improvement in 3. Missing outcome data Country acne (efficacy) Evaluator's Global Severity Intervention: arm 2 United States See supplement 8 Some concerns;16% Scale (EGSS) CLIND 1.2% gel Study type withdrawals - balanced Inclusion details Coded intervention: arm 1 RCT between arms (unclear how Males and females aged over CLIND-topical + TRET-topical Source of funding many due to inefficacy); ITT 12 years. Facial acne vulgaris Coded intervention: arm 2 Not reported (conflicts of used with 20 to 50 inflammatory CLIND-topical interest reported). lesions (papules and pustules), 4. Outcome measurement Analysis method 20 to 100 non-inflammatory (efficacy) Intention to treat or lesions (open and closed Some concerns;not reported if

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Outcomes and Study details Participants Interventions results Comments completers analysis comedones), and not more assessment of outcome was ITT than 2 nodules; Evaluators blinded Method of ITT imputation Global Severity Score (EGSS) 5. Selective reporting of moderate or severe. Willing LOCF Some concerns;not reported if to undergo the specified trial protocol was registered washout periods for topical 6. Overall bias antibiotics and other topical High antibacterial drugs (2 weeks); facial anti-inflammatory agents and corticosteroids (4 weeks); retinoids, including retinol (4 weeks). Had undergone the specified washout periods of systemic treatments including corticosteroids and intramuscular injections (4 weeks); antibiotics (4 weeks); other systemic acne treatments (4 weeks); systemic retinoids (6 months). Exclusion details Participated in a similar study within 30 days of enrolment or participating in another study. Facial dermatological conditions that could hinder or obstruct clinical evaluations. Use of other non-acne topical medication that could interfere with study treatment. Pregnant, nursing, planning a pregnancy, or became pregnant during the trial. Non-compliance with washout criteria for topical or systemic treatment.

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Outcomes and Study details Participants Interventions results Comments Number included Number randomised: arm 1 1008 Number randomised: arm 2 1002 Number completed: arm 1 859 Number completed: arm 2 838 Study details N=76 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Shalita, A. R. S., J. G.,Parish, Sex 8 discontinuation for Some concerns;no information L. C.,Sofman, M. S.,Chalker, mixed Treatment duration category any reason provided D. K.Topical age (mean±SD) 6 to <12 weeks See supplement 8 2. Deviation from compared with clindamycin gel 21.3 Number of arms Treatment intervention in the treatment of age (min/max) 2 discontinuation Some concerns;double-blinded inflammatory acne vulgaris. 13/35 Coded intervention: arm 1 due to side effects but not clear who was blinded; 1995. International Journal of NICO-topical See supplement 8 no ITT analysis was done Dermatology Inclusion/exclusion criteria Used validated acne scale Coded intervention: arm 2 Clinician rated 3. Missing outcome data Trial ID no CLIND-topical improvement in (efficacy) Shalita 1995 acne High;22% withdrawals - Acne scale Country See supplement 8 balanced between arms None United States (unclear how many due to Inclusion details Study type inefficacy); no ITT Men and women aged 13 to 35 RCT 4. Outcome measurement years. Moderate inflammatory (efficacy) Source of funding acne vulgaris (defined by the Some concerns;not reported if Supported in part by Genderm presence of at least 15 assessment of outcome was Corporation, Lincolnshire, IL. papules and/or pustules on the blinded Analysis method face); severity grade according Intention to treat or to Allen and Smith's 5. Selective reporting completers analysis modification of the Cook et al. Some concerns;not reported if trial protocol was registered completers procedure. Withdrawal of treatments, including topical 6. Overall bias acne preparations, topical High antimicrobial agents, medicated cosmetics, soaps or

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Outcomes and Study details Participants Interventions results Comments shampoos, and radiation therapy, topical corticosteroids, and investigational drugs at least 2 weeks before study enrolment; systemic antimicrobials corticosteroids at least 12 weeks before study; and oral isotretinoin at least 2 years prior to study enrolment. Oral contraceptives were permitted as long as they had been used continuously for at least 3 months prior to study and the dosage schedule was not expected to change during the study. Exclusion details Participants with primarily comedonal acne. Pregnant or lactating women. Participants with more than 3 nodular lesions on the face; active skin disease other than inflammatory acne vulgaris. History of allergy to study treatments. Previous history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis. Number included Number randomised: arm 1 38 Number randomised: arm 2 38 Number completed: arm 1 29

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Outcomes and Study details Participants Interventions results Comments Number completed: arm 2 30 Study details N=94 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Sklar, J. L. J., C.,Rizer, Sex 13 discontinuation for Some concerns;no information R.,Gans, E. H.Evaluation of mixed Treatment duration category any reason provided Triaz 10% Gel and age (min/max) 12 to <24 weeks See supplement 8 2. Deviation from Benzamycin in acne vulgaris. 16/30 Number of arms Clinician rated intervention 1996. Journal of Inclusion/exclusion criteria 3 improvement in Some concerns;participants dermatological treatment Used validated acne scale Split face design acne not blinded; ITT not used Trial ID no No See supplement 8 3. Missing outcome data Sklar 1996 Acne scale Intervention: arm 1 (efficacy) Country None BPO-topical 5%/ ERYTH- Some concerns;5% United States discontinued Inclusion details topical 3% Study type Males and females aged 16 to Intervention: arm 2 4. Outcome measurement RCT 30 years. Moderate to BPO-topical 10% (efficacy) Low;Investigator blinded Source of funding moderately severe, papular- Intervention: arm 3 Not reported. pustular, facial acne vulgaris Vehicle 5. Selective reporting Some concerns;not reported if Analysis method with a minimum number of Coded intervention: arm 1 trial protocol was registered Intention to treat or inflamed lesions. Willingness BPO-topical + ERYTH-topical completers analysis to co-operate and adhere to 6. Overall bias Coded intervention: arm 2 completers study criteria. Absence of Some concerns BPO-topical interfering medical and dermatological conditions and Coded intervention: arm 3 medications. Absence of Vehicle pregnancy and avoidance of interference from oral contraceptives. Exclusion details Not reported. Number included Number randomised: arm 1 30 Number randomised: arm 2 32

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Outcomes and Study details Participants Interventions results Comments Number randomised: arm 3 32 Number completed: arm 1 28 Number completed: arm 2 30 Number completed: arm 3 28 Study details N=201 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Stein Gold, L. ,. C., L. Sex 12 improvement in Some concerns;no information E.,Johnson, L. A.,Gottschalk, mixed Treatment duration category acne provided R. W.Is switching retinoids a age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from sound strategy for the 19 Number of arms intervention treatment of acne vulgaris?. age (other information) 2 Some concerns;not reported if 2008. Journal of drugs in ADAP mean age=18.5; ADAP Split face design participants were blinded; ITT dermatology : JDD then TAZ, mean age=19.4. No analysis was done Trial ID Inclusion/exclusion criteria Intervention: arm 1 3. Missing outcome data Stein Gold 2008 Used validated acne scale ADAP 0.1% gel (efficacy) Country High;more than 5% no Intervention: arm 2 United States withdrawals; not clear how Acne scale ADAP 0.1% gel for 6 weeks balanced between arms; no Study type None then TAZ 0.1% cream for 6 RCT reasons reported Inclusion details weeks 4. Outcome measurement Source of funding Males and females aged Coded intervention: arm 1 (efficacy) Not reported (conflicts of between 12 and 35 years. ADAP-topical interest reported). Low Coded intervention: arm 2 Analysis method 5. Selective reporting ADAP-topical / TAZ-topical Intention to treat or .15 to 100 non-inflammatory Some concerns;not reported if completers analysis lesions, at least 20 trial protocol was registered ITT inflammatory lesions, and no 6. Overall bias Method of ITT imputation more than 3 nodules. High LOCF Exclusion details Participants with severe nodulocystic acne. Pregnant, nursing, or planning a pregnancy during the study.

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Outcomes and Study details Participants Interventions results Comments Participants with facial hair that would interfere with study assessments. Washout periods <4 weeks for topical acne treatments or <6 months for systemic treatment. Participants with other dermatologic conditions requiring interfering treatment. Number included Number randomised: arm 1 101 Number randomised: arm 2 100 Study details N=459 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Stein Gold, L.,, C., Sex 12 discontinuation for Some concerns;no information A.,Eichenfield, L.,Tan, mixed Treatment duration category any reason provided J.,Jorizzo, J.,Kerrouche, age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from N.,Dhuin, J. C.Effective and 18.4±5.41 Number of arms Treatment intervention safe combination therapy for age (min/max) 2 discontinuation Low;double-blinded - likely that severe acne vulgaris: a 12/39 Split face design due to side effects participants wer eblinded; ITT randomized, vehicle-controlled, See supplement 8 analysis was done Inclusion/exclusion criteria No double-blind study of Clinician rated 3. Missing outcome data adapalene 0.1%-benzoyl Used validated acne scale Intervention: arm 1 no ADAP 0.1%/BPO 2.5% gel + improvement in (efficacy) peroxide 2.5% fixed-dose acne Some concerns;more than 5% Acne scale DOXY 100 mg combination gel with See supplement 8 withdrawals; balanced Investigator's Global Intervention: arm 2 doxycycline hyclate 100 mg. between arms 2010. Cutis; cutaneous Assessment scale (IGA) DOXY 100 mg + Vehicle 4. Outcome measurement medicine for the practitioner Inclusion details Coded intervention: arm 1 (efficacy) Males and females of any ADAP-topical + BPO-topical + Trial ID Some concerns;not reported if race, aged 12 to 35 years. DOXY-oral Stein Gold 2010 assessment of outcome was Severe facial acne vulgaris Country Coded intervention: arm 2 blinded (IGA score of 4); minimum of North America DOXY-oral + Vehicle 20 inflammatory lesions, 30 to 5. Selective reporting Study type 120 non-inflammatory lesions, Some concerns;not reported if RCT and no more than 3 trial protocol was registered

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Outcomes and Study details Participants Interventions results Comments Source of funding nodulocystic lesions. Specified 6. Overall bias Galderma Research & washout periods were required Some concerns Development (conflicts of for participants using topical interest reported). and oral acne treatments. Analysis method Exclusion details Intention to treat or Participants with acne completers analysis conglobata, acne fulminans ITT (secondary acne), or other Method of ITT imputation dermatologic conditions that interfere with treatment. not reported Pregnancy, breastfeeding or women planning a pregnancy during the study. Number included Number randomised: arm 1 232 Number randomised: arm 2 227 Number completed: arm 1 211 Number completed: arm 2 201 Study details N=434 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Stein Gold, L., Weiss, J., Sex 12 discontinuation for Low Rueda, M.J., Liu, H. and mixed Treatment duration category any reason 2. Deviation from Tanghetti, E., 2016. Moderate age (mean±SD) 12 to <24 weeks See supplement 8 intervention and severe inflammatory acne 19.5785288270378±6.996407 Number of arms Treatment Low;double-blinded; ITT vulgaris effectively treated with 1856287422 3 discontinuation analysis was done single-agent therapy by a new age (min/max) Split face design due to side effects 3. Missing outcome data fixed-dose combination 12/57 No See supplement 8 (efficacy) adapalene 0.3%/benzoyl Clinician rated Some concerns;10% peroxide 2.5% gel: a age (other information) Intervention: arm 1 ADAP 0.3%, range 12-57; ADAP 0.3%/BPO 2.5% gel improvement in withdrawals - balanced randomized, double-blind, acne between arms; ITT used parallel-group, controlled ADAP 0.1%, range 12-49; Intervention: arm 2 See supplement 8 4. Outcome measurement study. American Journal of Vehicle, range=12-36 ADAP 0.1%/BPO 2.5% gel (efficacy)

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Outcomes and Study details Participants Interventions results Comments Clinical Dermatology, 2016, Inclusion/exclusion criteria Intervention: arm 3 Some concerns;not reported if 17(3), 293-303 Used validated acne scale Vehicle assessment of outcome was Trial ID no Coded intervention: arm 1 blinded Stein Gold 2016 Acne scale ADAP-topical + BPO-topical 5. Selective reporting Country Investigator's Global Coded intervention: arm 2 Low United States Assessment scale (IGA) ADAP-topical + BPO-topical 6. Overall bias Study type Inclusion details Coded intervention: arm 3 Some concerns Males and females. Moderate RCT Vehicle Source of funding to severe inflammatory facial Galderma Research & acne, that is a score of 3 Development (conflicts of (moderate) or 4 (severe) on interest reported). the IGA, the presence of 20 to 100 inflammatory lesions, 30 to Analysis method 150 non-inflammatory lesions Intention to treat or (including the nose), and up to completers analysis 2 nodules on the face. A urine ITT pregnancy test was required Method of ITT imputation for females at baseline and MI (no other details reported) throughout the study. Exclusion details Participants with acne conglobata, acne fulminans, nodulocystic acne, or acne requiring systemic treatment. Number included Number randomised: arm 1 217 Number randomised: arm 2 217 Number randomised: arm 3 69 Number completed: arm 1 197 Number completed: arm 2 192

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Outcomes and Study details Participants Interventions results Comments Number completed: arm 3 61 Study details N=174 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Stewart, D. M. T., H. M.,Weiss, Sex 12 discontinuation Some concerns;methods not J. S.,Plott, R. T.Dose-ranging mixed Treatment duration category due to side effects reported efficacy of new once-daily age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from extended-release minocycline 17.7 Number of arms Clinician rated intervention for acne vulgaris. 2006. Cutis; age (min/max) 3 improvement in Low;double-blind;ITT cutaneous medicine for the 17/19 Split face design acne 3. Missing outcome data practitioner See supplement 8 Inclusion/exclusion criteria No (efficacy) Trial ID Used validated acne scale Intervention: arm 1 High;>20% discontinued - Stewart 2006 no MINO-oral 2mg/kg/day unclear how many were due to Country lack of efficacy - or which arm Acne scale Intervention: arm 2 United States they were in None MINO-oral 3mg/kg/day Study type 4. Outcome measurement Inclusion details Intervention: arm 3 RCT (efficacy) Participants aged 12 to 30 PLC-oral Source of funding Low;described as double-blind, years, weighing between 39.1 Coded intervention: arm 1 Not reported (conflicts of without further details kg and 102.3 kg (86 to 225 Ib). MINO-oral interest reported). 5. Selective reporting Diagnosed with moderate to Coded intervention: arm 2 Analysis method Some concerns;not reported if severe facial acne vulgaris; at MINO-oral Intention to treat or least 20 and no more than 100 trial protocol was registered Coded intervention: arm 3 completers analysis inflammatory facial lesions and 6. Overall bias PLC-oral ITT <5 facial nodules or cysts. High Method of ITT imputation Females of childbearing LOCF potential must have had a negative urine pregnancy test result (25 µg/mL sensitivity), be using contraception and will to continue on contraception during the study. Participants or parent/guardian consent provided.

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Outcomes and Study details Participants Interventions results Comments Exclusion details Participants sensitive to minocycline or any of the components. Pregnancy. Males with facial hair. Use of supplements containing aluminium, calcium, iron, or magnesium, or vitamin A. Prior history of complicating illnesses or medications. Number included Number randomised: arm 1 59 Number randomised: arm 2 60 Number randomised: arm 3 55 Number completed: arm 1 na Number completed: arm 2 na Number completed: arm 3 na Study details N=na Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Strauss, J. S. R., R. P.,Shalita, Sex 20 improvement in Some concerns;no information A. R.,Konecky, E.,Pochi, P. mixed Treatment duration category acne about allocation concealment E.,Comite, H.,Exner, J. age (other information) 12 to <24 weeks See supplement 8 provided H.Isotretinoin therapy for acne: Mean age 23.3,23.1 & 22.2 in Number of arms 2. Deviation from Results of a multicenter dose- the 3 groups (no SDs reported) 3 intervention response study. 1984a. Inclusion/exclusion criteria Split face design High;study was double-blinded Journal of the American Used validated acne scale No in the beginning; then "The Academy of Dermatology protocol design allowed no Intervention: arm 1 Trial ID participating people to be Acne scale ISO<120.Daily<0.5 (0.1 mg/kg Strauss 1984a retreated with isotretinoin in an None daily for 140 days) open study beginning at least 8

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Outcomes and Study details Participants Interventions results Comments Country Inclusion details Intervention: arm 2 weeks after the completion of United States Participants with treatment- ISO<120.Daily=0.5 (0.5 mg/kg the first course of therapy if Study type resistant, severe nodulocystic daily for 140 days) optimal improvement (less RCT acne; minimum of 10 Intervention: arm 3 than a 95% reduction in lesions) had not been achieved Source of funding inflammatory nodulocystic ISO=120.Daily=0.5 (1 mg/kg in the first course." No ITT Not reported. acne lesions at least 4 mm in daily for 140 days) diameter on the face, back, or analysis was done Analysis method Coded intervention: arm 1 chest. Off all treatment for at 3. Missing outcome data Intention to treat or ISO<120.Daily<0.5-oral least 1 month. Female (efficacy) completers analysis Coded intervention: arm 2 participants were required to Some concerns;6% Completers ISO<120.Daily=0.5-oral have negative pregnancy test withdrawals in 2 out of 3 arms; within 2 weeks prior to starting Coded intervention: arm 3 no reasons provided; no ITT ISO=120.Daily=0.5-oral treatment. 4. Outcome measurement Exclusion details (efficacy) Not reported. Some concerns;not reported if Number included assessment of outcome was Number randomised: arm 1 blinded na 5. Selective reporting Number randomised: arm 2 Some concerns;not reported if na trial protocol was registered Number randomised: arm 3 6. Overall bias na High Number completed: arm 1 46 Number completed: arm 2 46 Number completed: arm 3 49 Study details N=266 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Tan, J. H., S.,Vender, Sex 20 discontinuation for Low R.,Barankin, B.,Gooderham, mixed Treatment duration category any reason 2. Deviation from M.,Kerrouche, N.,Audibert, age (mean±SD) 12 to <24 weeks See supplement 8 intervention F.,Lynde, C.A treatment for 19.4±4.8 Number of arms Treatment Some concerns;not reported if severe nodular acne: A 2 discontinuation participants were blinded; ITT randomized investigator- analysis was done

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Outcomes and Study details Participants Interventions results Comments blinded, controlled, age (min/max) Split face design due to side effects 3. Missing outcome data noninferiority trial comparing 12/41 No See supplement 8 (efficacy) fixed-dose adapalene/benzoyl Inclusion/exclusion criteria Intervention: arm 1 Clinician rated Some concerns;13% peroxide plus doxycycline vs. Used validated acne scale DOXY 200 mg + ADAP improvement in withdrawals (2% due to oral isotretinoin. 2014. British no 0.1%/BPO 2.5% gel acne inefficacy) balanced between Journal of Dermatology Acne scale Intervention: arm 2 See supplement 8 arms Trial ID Investigator's Global ISO=120.Daily=0.5 (wk 1-4 0.5 4. Outcome measurement Tan 2014 Assessment scale (IGA) mg), then ISO=120.Daily=0.5 (efficacy) Country Inclusion details (wk 5-20 1.0 mg) Low Canada Participants of any race, aged Coded intervention: arm 1 5. Selective reporting Study type 12 to 35 years. DOXY-oral + ADAP-topical + Low RCT BPO-topical 6. Overall bias Source of funding Coded intervention: arm 2 Some concerns

Galderma (conflicts of interest ISO=120.Daily=0.5-oral reported). Exclusion details Analysis method Pregnancy. Intention to treat or Number included completers analysis Number randomised: arm 1 ITT 133 Method of ITT imputation Number randomised: arm 2 LOCF 133 Number completed: arm 1 105 Number completed: arm 2 116 Study details N=1208 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Tan, J. T., D.,Popp, Sex 12 discontinuation for Some concerns;no information G.,Gooderham, M.,Lynde, mixed Treatment duration category any reason about allocation concealment C.,Del Rosso, J.,Weiss, age (mean±SD) 12 to <24 weeks See supplement 8 provided J.,Blume-Peytavi, 19.4±6.41 Number of arms Treatment 2. Deviation from U.,Weglovska, J.,Johnson, age (median) 2 discontinuation intervention S.,Parish, L.,Witkowska, 18 Split face design due to side effects Low;double-blinded; ITT D.,Sanchez Colon, N.,Alio No See supplement 8 analysis was done Saenz, A.,Ahmad, F.,Graeber, age (min/max) 9/58 Clinician rated 3. Missing outcome data M.,Stein Gold, L.Randomized improvement in (efficacy)

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments phase 3 evaluation of age (other information) Intervention: arm 1 acne Some concerns;11% 50 mug/g cream <18, n=592; =18, n=616. data TRIF 0.05 mg/g See supplement 8 withdrawals (reasons unclear)- treatment of moderate facial for groups also reported Intervention: arm 2 balanced between arms; ITT and truncal acne. 2019. Inclusion/exclusion criteria Vehicle used Journal of the American Used validated acne scale Coded intervention: arm 1 4. Outcome measurement Academy of Dermatology no TRIF-topical (efficacy) Trial ID Low;likely blinded Acne scale Coded intervention: arm 2 Tan 2019;Trial 1 Investigator's Global 5. Selective reporting Vehicle Country Assessment scale (IGA) Low US/Canada/Europe/Russia Inclusion details 6. Overall bias Study type Participants aged 9 years and Some concerns RCT older. Moderate facial acne Source of funding (defined as IGA score of 3 on Nestle Skin Health Care, the face [=20 inflammatory Galderma Research & lesions and =25 non- Development, LLC, US inflammatory lesions]), and (conflicts of interest reported). moderate truncal acne (defined Analysis method as a Physician’s Global Intention to treat or Assessment [PGA] score of 3 completers analysis at screening and baseline [=20 ITT

Method of ITT imputation inflammatory lesions and 20 to MI (no further details reported) <100 non-inflammatory

lesions on the areas of the trunk within reach for

self-application]). For participants aged 9 to 11 years, the inclusion criteria relating to truncal acne were optional owing to the relative rarity of this (compared with

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments facial involvement) in this age group. Exclusion details Participants with severe forms of acne; more than 1 nodule o the face; more than 1 nodule on the trunk; presence of acne cysts. Beards or facial hair that could interfere with study evaluations. Presence of tattoos that could interfere with study assessments. Uncontrolled or serious disease or medical condition; clinically significant abnormal laboratory values; known or suspected allergies or sensitivities to the planned study treatments. Lactating women or women planning pregnancy during the study. Prohibited treatments and washout periods of 1 to 4 weeks were specified for use of antiacne treatments (prescription and over-the counter), non-steroidal anti- inflammatory drugs, corticosteroids, and antibiotics (but 6 months for use of oral retinoids and immunomodulators). Number included Number randomised: arm 1 612 Number randomised: arm 2 596

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Outcomes and Study details Participants Interventions results Comments Number completed: arm 1 540 Number completed: arm 2 535 Study details N=121 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Tanghetti, E. A., W.,Solomon, Sex 12 discontinuation for Some concerns;no information B.,Loven, K.,Shalita, mixed Treatment duration category any reason provided A.Tazarotene versus age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from tazarotene plus 20 Number of arms Clinician rated intervention clindamycin/benzoyl peroxide age (min/max) 2 improvement in Some concerns;Double blind in the treatment of acne 12 Split face design acne but not clear if participants vulgaris: a multicenter, double- See supplement 8 were blinded; no ITT Inclusion/exclusion criteria No blind, randomized parallel- 3. Missing outcome data group trial. 2006. Journal of Used validated acne scale Intervention: arm 1 no TAZ 0.1% cream + Vehicle gel (efficacy) drugs in dermatology : JDD High;Around 20% discontinued Acne scale Intervention: arm 2 Trial ID - insufficient information on None BPO 5%/CLIND 1% gel + TAZ Tanghetti 2006 reasons Inclusion details 0.1% cream Country 4. Outcome measurement Participants aged at least 12 Coded intervention: arm 1 United States (efficacy) years of age. Stable moderate TAZ-topical + Vehicle Study type Some concerns;not clear to severe facial inflammatory Coded intervention: arm 2 RCT 5. Selective reporting acne vulgaris (defined as 15 to BPO-topical + CLIND-topical + Source of funding 60 papules plus pustules, 10 to Some concerns;not reported if TAZ Not reported (conflicts of 100 comedos, and no more trial protocol was registered interest reported). than 2 nodulocystic lesions 6. Overall bias Analysis method with a maximum diameter of 5 High Intention to treat or mm). Washout periods completers analysis required: 2 weeks for topical ITT acne treatments, 30 days for Method of ITT imputation systemic antibiotics and not reported investigational drugs, 12 weeks for oestrogens/birth control pills if previously used for <12 weeks, and 6 months for oral retinoids.

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Outcomes and Study details Participants Interventions results Comments Exclusion details Participants with acne known to be resistant to oral antibiotics. Pregnancy, breastfeeding or of childbearing potential and not using reliable contraception. Number included Number randomised: arm 1 61 Number randomised: arm 2 60 Number completed: arm 1 50 Number completed: arm 2 52 Study details N=150 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Tanghetti, E. D., S.,Torok, Sex 12 discontinuation Some concerns;no information H.,Kircik, L.Tazarotene 0.1 mixed Treatment duration category due to side effects provided percent cream plus age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from clindamycin 1 percent gel 21 Number of arms Clinician rated intervention versus tretinoin 0.025 percent age (min/max) 2 improvement in Some concerns;not reported if gel plus clindamycin 1 percent 12/58 Split face design acne participants were blinded; ITT gel in the treatment of facial See supplement 8 analysis was done Inclusion/exclusion criteria No acne vulgaris. 2007. 3. Missing outcome data Dermatology Online Journal Used validated acne scale Intervention: arm 1 no CLIND 1% gel + TAZ 0.1% (efficacy) Trial ID cream Some concerns;10% Tanghetti 2007 Acne scale withdrawals - not clear if None Intervention: arm 2 Country balanced between arms Inclusion details CLIND 1% gel + TRET 0.025% United States 4. Outcome measurement Participants aged at least 12 gel Study type (efficacy) years old. Coded intervention: arm 1 RCT Low CLIND-topical + TAZ-topical Source of funding 5. Selective reporting Coded intervention: arm 2 Allergan Inc, US. .Facial acne vulgaris; 15 to 60 Some concerns;not reported if CLIND-topical + TRET-topical papules plus pustules, 10 to trial protocol was registered

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Outcomes and Study details Participants Interventions results Comments Analysis method 100 comedones, and no more 6. Overall bias Intention to treat or than 2 nodulocystic lesions High completers analysis (with a diameter no more than ITT 5 mm). Washout periods Method of ITT imputation required: 14 days for topical antibiotics and anti-acne not reported treatments, 30 days for systemic antibiotics and investigational drugs, 12 weeks for oestrogens/birth control pills if used for <12 weeks before study entry, and 12 months for oral retinoids. Exclusion details Known resistance to oral antibiotics; known hypersensitivity to lincomycin. History of enteritis; recent alcohol or drug abuse; any skin disorder that might interfere with the diagnosis or evaluation of acne vulgaris; any uncontrolled systemic disease. Any cosmetic or surgical procedures complementary to the treatment of acne in the preceding 15 days; participation in an investigational drug study in the preceding 30 days. Pregnancy or breastfeeding, and not using a reliable method of contraception. Number included Number randomised: arm 1 75

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Outcomes and Study details Participants Interventions results Comments Number randomised: arm 2 75 Study details N=46 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Tanghetti, E. K., L.,Wilson, Sex 4 improvement in Some concerns;no information D.,Dhawan, S.Solubilized mixed Treatment duration category acne provided benzoyl peroxide versus age (mean±SD) 0 to <6 weeks See supplement 8 2. Deviation from benzoyl peroxide/clindamycin 21 Number of arms intervention in the treatment of moderate age (min/max) 2 Some concerns;not reported if acne. 2008. Journal of drugs in 11/45 Split face design participants were blinded dermatology: JDD Inclusion/exclusion criteria Yes 3. Missing outcome data Trial ID Used validated acne scale Intervention: arm 1 (efficacy) Tanghetti 2008 no BPO 5% gel Low;all participants completed Country the study Acne scale Intervention: arm 2 United States None BPO 5%/CLIND 1% gel 4. Outcome measurement Study type (efficacy) Inclusion details Coded intervention: arm 1 RCT Low;investigator-blinded Participants aged between 11 BPO-topical Source of funding 5. Selective reporting to 45 years of age. Moderate Coded intervention: arm 2 Supported by Obagi Medical facial acne vulgaris; 25 to 100 Some concerns;not reported if BPO-topical + CLIND-topical Products Inc. (conflicts of non-inflammatory lesions, 25 trial protocol was registered interest reported). to 100 inflammatory lesions, up 6. Overall bias Analysis method to 2 nodulocystic lesions. Some concerns Intention to treat or Willing to refrain from using completers analysis non-study acne medications, ITT moisturisers, sunscreens, Method of ITT imputation fragrances, aftershaves, and not reported make-up on the face (oil-free non-comedogenic make-up, mascara, eyeshadow, and lipstick were allowed). Willing to avoid excessive exposure to the sun and the use of tanning booths. Washout periods required: 1 week for medicated facial cleansers; 2 weeks for topical alpha-hydroxy acids,

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Outcomes and Study details Participants Interventions results Comments anti-acne medications, topical retinoids, topical and systemic antibiotics, and topical and systemic steroids; 3 months for oestrogens/birth control pills (unless used for at least 3 months); and 6 months for systemic retinoids. Exclusion details Participants who had undergone a facial cosmetic procedure in the past 6 months. Allergic to BPO, clindamycin, lincomycin, salicylic acid, sunscreens or other ingredients in the study products. Papulopustular rosacea or other skin diseases on the face (other than acne) that could interfere with study assessments; facial sunburn at study baseline. Males with facial hear that could interfere with study assessments. Uncontrolled systemic disease or infection with HIV; history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis. Concurrent facial use of other medicated products. Participation in an investigational study in the previous 30 days. Number included Number randomised: arm 1 23

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FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Number randomised: arm 2 23 Number completed: arm 1 23 Number completed: arm 2 23 Study details N=210 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Tanghetti, E. A. K., L. Sex 12 discontinuation for Some concerns;no information H.,Green, L. J.,Guenin, mixed Treatment duration category any reason provided E.,Harris, S.,Martin, G.,Pillai, age (mean±SD) 12 to <24 weeks See supplement 8 2. Deviation from R.A Phase 2, Multicenter, 22.1332857142857±9.200576 Number of arms Treatment intervention Double-Blind, Randomized, 9230769214 3 discontinuation Low;double-blinded; ITT Vehicle-Controlled Clinical age (min/max) Split face design due to side effects analysis was done Study to Compare the Safety 12 No See supplement 8 3. Missing outcome data and Efficacy of a Novel Clinician rated (efficacy) Tazarotene 0.045% Lotion and Inclusion/exclusion criteria Intervention: arm 1 Used validated acne scale TAZ 0.045% lotion improvement in Some concerns;10% Tazarotene 0.1% Cream in the acne withdrawals - imbalanced no Intervention: arm 2 Treatment of Moderate-to- See supplement 8 between arms Severe Acne Vulgaris. 2019. Acne scale TAZ 0.1% cream 4. Outcome measurement Journal of drugs in Evaluator's Global Severity Intervention: arm 3 (efficacy) dermatology : JDD Scale (EGSS) Lotion vehicle or cream vehicle Low;likely blinded Trial ID Inclusion details (arms combined) 5. Selective reporting Tanghetti 2019 Participants of any gender, Coded intervention: arm 1 Some concerns;not reported if race and ethnicity, aged 12 TAZ-topical Country trial protocol was registered United States years or older. Participants Coded intervention: arm 2 with moderate to severe acne; 6. Overall bias Study type TAZ-topical EGSS score of 3 (moderate) or Some concerns RCT Coded intervention: arm 3 4 (severe); 20 to 40 Vehicle Source of funding inflammatory lesions (papules, Ortho Dermatologics funded pustules, and nodules), 20 to Konic Limited's activities 100 non-inflammatory lesions relating to the manuscript (open and closed comedones), (conflicts of interest reported). and 2 nodules or less. Women Analysis method of childbearing potential were Intention to treat or required to have a negative urine pregnancy test at and

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Outcomes and Study details Participants Interventions results Comments completers analysis agree to use a reliable method ITT of contraceptive during the Method of ITT imputation study period. Washout period of 1 month required for LOCF participants who previously used prescription and over-the- counter acne treatments, and 6 months for systemic retinoids. Exclusion details Not reported. Number included Number randomised: arm 1 69 Number randomised: arm 2 72 Number randomised: arm 3 69 Number completed: arm 1 65 Number completed: arm 2 63 Number completed: arm 3 61 Study details N=245 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Thiboutot, D. J., M.,Rich, Sex 8 discontinuation for Some concerns;insufficient P.,Rist, T.,Rodriguez, D.,Levy, mixed Treatment duration category any reason information provided S.A randomized, parallel, age (mean±SD) 6 to <12 weeks See supplement 8 2. Deviation from vehicle-controlled comparison 19.9 Number of arms Clinician rated intervention of two erythromycin/benzoyl age (min/max) 4 improvement in Low;Double blind; ITT peroxide preparations for acne 12/46 Split face design acne 3. Missing outcome data vulgaris. 2002. Clinical No See supplement 8 (efficacy) Therapeutics Inclusion/exclusion criteria Used validated acne scale Intervention: arm 1 Low Trial ID no BPO 5%/ERYTH 3% gel 4. Outcome measurement Thiboutot 2002 (efficacy) Low

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Outcomes and Study details Participants Interventions results Comments Country Acne scale Intervention: arm 2 5. Selective reporting United States Physician's Global BPO 5%/ERYTH 3% jar Some concerns;not reported if Study type Assessment (PGA)/Physician’s Intervention: arm 3 trial protocol was registered RCT Global Acne Severity Score Vehicle gel 6. Overall bias Source of funding Inclusion details Intervention: arm 4 Some concerns Dermik Laboratories, US. Males and females aged >12 Vehicle Jar Analysis method years of age. Moderate to Coded intervention: arm 1 Intention to treat or moderately severe acne; 15 to BPO-topical + ERYTH-topical 80 facial inflammatory lesions, completers analysis Coded intervention: arm 2 20 to 140 facial comedones ITT BPO-topical + ERYTH-topical (not including the nose or Method of ITT imputation nasolabial area), <2 nodules or Coded intervention: arm 3 Unclear cysts >5 mm, and a minimum Vehicle Physician's Global Acne Coded intervention: arm 4 Severity score of 1.5. Vehicle Exclusion details Not reported. Number included Number randomised: arm 1 124 Number randomised: arm 2 121 Number randomised: arm 3 42 Number randomised: arm 4 40 Number completed: arm 1 115 Number completed: arm 2 110 Number completed: arm 3 33 Number completed: arm 4 35

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Outcomes and Study details Participants Interventions results Comments Study details N=467 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Thiboutot, D. M. S., A. Sex 12 discontinuation for Some concerns;no information R.,Yamauchi, P. S.,Dawson, mixed Treatment duration category any reason about allocation sequence C.,Arsonnaud, S.,Kang, age (mean±SD) 12 to <24 weeks See supplement 8 provided S.Combination therapy with 17.8471092077088±4.361806 Number of arms Treatment 2. Deviation from adapalene gel 0.1% and 451612904 2 discontinuation intervention doxycycline for severe acne age (min/max) Split face design due to side effects Some concerns;not reported if vulgaris: a multicenter, 12/36 No See supplement 8 participants were blinded; ITT investigator-blind, randomized, analysis was done Inclusion/exclusion criteria Intervention: arm 1 Clinician rated controlled study. 2005. improvement in 3. Missing outcome data Skinmed Used validated acne scale ADAP 0.1% gel + DOXY 100 no mg acne (efficacy) Trial ID See supplement 8 Some concerns;18% Acne scale Intervention: arm 2 Thiboutot 2005 withdrawals - imbalanced Global Acne Severity Scale DOXY 100 mg + Vehicle Country between arms; ITT used; <1% (GEA Scale) United States Coded intervention: arm 1 due to inefficacy Inclusion details ADAP-topical + DOXY-oral Study type 4. Outcome measurement Males and females with severe RCT Coded intervention: arm 2 (efficacy) facial acne (global severity DOXY-oral + Vehicle Low Source of funding score of at least 4 on a scale Galderma Research & ranging from 0 [clear] to 5 [very 5. Selective reporting Development, US (conflicts of severe]); minimum of 15 Some concerns;not reported if interest reported). inflammatory lesions and 15 to trial protocol was registered Analysis method 100 non-inflammatory facial 6. Overall bias Intention to treat or lesions. Washout periods were High completers analysis required for participants taking ITT certain topical and systemic Method of ITT imputation treatments. not reported Exclusion details Acne requiring isotretinoin treatment or other dermatologic conditions requiring interfering treatment. Pregnancy, nursing or planning a pregnancy. Men with facial hair that would interfere with evaluations.

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Outcomes and Study details Participants Interventions results Comments Number included Number randomised: arm 1 238 Number randomised: arm 2 229 Number completed: arm 1 186 Number completed: arm 2 196 Study details N=925 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Webster, G. F., Leyden, J. J., Sex 20 improvement in Some concerns;no information & Gross, J. A.Results of a mixed Treatment duration category acne about allocation sequence Phase III, double-blind, age (mean±SD) 12 to <24 weeks See supplement 8 provided randomized, parallel-group, 20.8±7.2 Number of arms 2. Deviation from non-inferiority study evaluating age (min/max) 2 intervention the safety and efficacy of 12/52 Split face design Low;ITT analysis was done isotretinoin-Lidose in patients Inclusion/exclusion criteria No 3. Missing outcome data with severe recalcitrant nodular (efficacy) acne. 2014. Journal of Drugs Used validated acne scale Intervention: arm 1 no Isotretinoin-(lidose formulation) Some concerns;14% in Dermatology discontinued -balanced Acne scale ISO<120.Daily=0.5 Trial ID between arms. ITT used. None Intervention: arm 2 Webster 2014 Unclear how many related to ISO<120.Daily=0.5 Country Inclusion details efficacy Participants with severe Coded intervention: arm 1 North America 4. Outcome measurement calcitrant nodular acne, ISO<120.Daily=0.5-oral Study type (efficacy) compatible with isotretinoin RCT Coded intervention: arm 2 Low treatment; 10 or more facial ISO<120.Daily=0.5-oral Source of funding and/or truncal nodular lesions. 5. Selective reporting Cipher Pharmaceuticals Inc, No prior exposure to systemic Low Canada (conflicts of interest isotretinoin or other retinoids. 6. Overall bias reported). Aged between 12 and 54 years Some concerns and weighing between 40 and 110 kg. Exclusion details Pregnancy, breastfeeding, or high risk of becoming pregnant

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Outcomes and Study details Participants Interventions results Comments or considering breastfeeding during study treatment. Concurrent or history of GI disease, skin conditions that may interfere with study assessments, psychosis or psychotic symptoms, reported suicidal behaviour, carcinoma, liver or kidney disease, pseudotumour cerebri, rheumatoid arthritis or vitamin D depletion disease, and paediatric participants with 25- hydroxyvitamin D levels <20 ng/ml. Number included Number randomised: arm 1 464 Number randomised: arm 2 461 Number completed: arm 1 394 Number completed: arm 2 401 Study details N=95 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Clinician rated 1. Randomisation Xu, X. Z., Y.,Zhao, Z.,Zhang, Sex 4 improvement in Some concerns;no information X.,Liu, P.,Li, C.Efficacy of mixed Treatment duration category acne about allocation sequence photodynamic therapy age (median) 0 to <6 weeks See supplement 8 provided combined with minocycline for 24 Treatment intensity 2. Deviation from treatment of moderate to age (min/max) Total 4 sessions, once every intervention severe facial acne vulgaris and 15/35 week. Endpoint 4 wks after last Some concerns;not reported if influence on quality of life. investigators/participants were age (other information) session 2017. Medicine (United States) blinded MINO + PDT median age=24 Number of arms Trial ID (range 16-35); MINO median 2 3. Missing outcome data Xu 2017 age 24 (range 15-35) (efficacy)

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Outcomes and Study details Participants Interventions results Comments Country Inclusion/exclusion criteria Split face design High;not reportedif/how many China Used validated acne scale No participants discontinued Study type no Intervention: arm 1 4. Outcome measurement RCT Acne scale MINO 100 mg + 5ALA 5%- (efficacy) Source of funding Investigator's Global RED LED-PDT Some concerns;not reported if Not reported (no conflicts of Assessment scale (IGA) Intervention: arm 2 assessment of outcome was interest). Inclusion details MINO 100 mg blinded Analysis method Males and females aged 15 to Coded intervention: arm 1 5. Selective reporting Intention to treat or 35 years attending a MINO-oral + 5ALA-RED-PDT Some concerns;not reported if trial protocol was published completers analysis Department of Dermatology, Coded intervention: arm 2 ITT China. Moderate to severe 6. Overall bias MINO-oral Method of ITT imputation facial acne vulgaris defined by High not reported IGA scale of 3 or 4; =10 inflammatory lesions (papules, pustules, or nodules) and =10 non-inflammatory lesions (open and closed comedones) on the face. Exclusion details Participants with acne fulminans, acne conglobata, secondary acne, or dysplastic naevi in the treatment area. Systemic acne treatment with oral isotretinoin within 6

months or oral antibiotics in the past 1 month; history of facial procedures such as dermabrasion, chemical, or laser peels; phototherapy within 1 month; topical treatments other than medicated cleansers within 14 days. Pregnant or nursing females. History of

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Outcomes and Study details Participants Interventions results Comments photosensitive diseases, porphyria, or porphyrin sensitivity. Number included Number randomised: arm 1 48 Number randomised: arm 2 47 Number completed: arm 1 48 Number completed: arm 2 47 Study details N=180 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Yin, R. H., F.,Deng, J.,Yang, X. Sex 4.29 discontinuation Some concerns;no information C.,Yan, H.Investigation of mixed Treatment duration category due to side effects provided optimal aminolaevulinic acid age (mean±SD) 0 to <6 weeks See supplement 8 2. Deviation from concentration applied in topical 24.975±6.85 Treatment intensity intervention aminolaevulinic acid- age (min/max) Total 4 sessions, once every Some concerns;"single-blind": photodynamic therapy for 18/38 10 days. Fu at 2, 4, 12 and 24 not clear if investigators or treatment of moderate to participants were blinded; not Inclusion/exclusion criteria wks after last session, severe acne: A pilot study in reported if ITT analysis was Used validated acne scale assumed 2 wks to be Chinese subjects. 2010. British done no appropriate FU Journal of Dermatology 3. Missing outcome data Acne scale Number of arms Trial ID 5 (efficacy) Yin 2010 None Split face design Low;1 participant dropped out Country Inclusion details due to a severe adverse event Chines participants attending a No China 4. Outcome measurement Department of Dermatology in Intervention: arm 1 Study type (efficacy) China. Facial inflammatory 5ALA 5%-PDT RCT Some concerns;not reported if acne vulgaris (moderate to Intervention: arm 2 assessment of outcome was Source of funding severe grade according to 5ALA 10%-PDT Not reported (no conflicts of blinded Pillsbury et al.); Fitzpatrick skin Intervention: arm 3 interest). 5. Selective reporting type III and IV. Underwent 5ALA 15%-PDT Analysis method Some concerns;not reported if aminolaevulinic acid- Intervention: arm 4 Intention to treat or trial protocol was published photodynamic therapy 5ALA 20%-PDT treatment and following up

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Outcomes and Study details Participants Interventions results Comments completers analysis from June 2007 to January Coded intervention: arm 1 6. Overall bias completers 2009. 5ALA-RED-PDT Some concerns Exclusion details Coded intervention: arm 2 Participants who had used 5ALA-RED-PDT topical retinoic acid, Coded intervention: arm 3 glucocorticosteroids, antibiotics 5ALA-RED-PDT and other drugs within 2 Coded intervention: arm 4 weeks. Use of medication that 5ALA-RED-PDT may exacerbate or alleviate acne. Planned pregnancy, pregnancy or lactating women. History of photosensitivity disorder. Participants planning prolonged exposure to sunlight. Participants with herpes simplex outbreak. Number included Number randomised: arm 1 45 Number randomised: arm 2 45 Number randomised: arm 3 45 Number randomised: arm 4 45 Number completed: arm 1 45 Number completed: arm 2 45 Number completed: arm 3 45 Number completed: arm 4 44 Study details N=24 Interventions Results Cochrane RoB Tool v2.0 Reference Treatment intensity Clinician rated 1. Randomisation Zhang, L. W., Y.,Zhang, Y.,Liu, Total 3 sessions, once every 2 improvement in Some concerns;no information

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Outcomes and Study details Participants Interventions results Comments X.,Wang, B.,Wang, P.,Zhang, Characteristics weeks. FU at 4 and 8 wks after acne about allocation concealment G.,Wang, X.Topical 5- Sex last session. Assumed See supplement 8 provided aminolevulinic photodynamic mixed endpoint is 4 wks FU. 2. Deviation from therapy with red light vs age (mean±SD) Number of arms intervention intense pulsed light for the 21.75±2.9889999999999999 2 Some concerns;not reported if treatment of acne vulgaris: A age (min/max) Split face design investigators/participants were spilit face, randomized, 18/27 Yes blinded; carry over effects prospective study. 2017. Intervention: arm 1 unlikely Dermato-endocrinology Inclusion/exclusion criteria Used validated acne scale 5ALA 5%-RED LED-PDT 3. Missing outcome data Trial ID no Intervention: arm 2 (efficacy) Zhang 2017 High;not reported if/how many Acne scale 5ALA 5%-IPL-PDT Country participants discontinued EU Acne Guidelines Coded intervention: arm 1 China Inclusion details 5ALA-RED-PDT 4. Outcome measurement Study type (efficacy) Males and females aged Coded intervention: arm 2 RCT Some concerns;not reported if between 18 and 40 years. 5ALA-IPL-PDT assessment of outcome was Source of funding Acne lesions on the forehead blinded Shanghai Municipal and on both sides of the face Commission of Health and and clinically diagnosed with 5. Selective reporting Family Planning and Guide acne vulgaris and grade 3 to 4 Some concerns;not reported if support project in western according to the European trial protocol was registered medicine of Shanghai Guidelines Group. 6. Overall bias Municipal Science and Exclusion details High Technology Commission. Pregnant and lactating Analysis method females, or women planning to Intention to treat or become pregnant during the completers analysis study. History of cutaneous completers hypersensitisation, porphyria, or photodermatosis; any ongoing skin conditions (such as psoriasis, seborrheic dermatitis or allergic dermatitis) that could interfere with assessments; a severe systemic condition and unsafe for participants to participate. History of systemic retinoids within 6 months or history of

184 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments systemic steroids and antibiotics within 1 month or history of any topical treatment of acne within 2 weeks. Number included Number randomised: arm 1 12 Number randomised: arm 2 12 Number completed: arm 1 12 Number completed: arm 2 12 Study details N=56 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment intensity Clinician rated 1. Randomisation Zhang, J. Z., X.,He, Y.,Wu, Sex Total 4 sessions, once every improvement in Some concerns;no information X.,Huang, J.,Huang, H.,Lu, mixed 10 days. Fu at 4-wks and 12- acne provided C.Photodynamic therapy for age (mean±SD) wks after last session, See supplement 8 2. Deviation from severe facial acne vulgaris with 24±4.0999999999999996 assumed 4-wks as endpoint. intervention 5% 5-aminolevulinic acid vs Inclusion/exclusion criteria Number of arms Low;double-blinded ("Neither 10% 5-aminolevulinic acid: A Used validated acne scale 2 patients nor the operator knew split-face randomized no Split face design the treatment allocation"); controlled study. 2019. Journal carry over effects unlikely; it Acne scale Yes of Cosmetic Dermatology. appears that no ITT analysis Pillsbury Intervention: arm 1 Trial ID was done Inclusion details 5ALA 5%-PDT Zhang 2019 3. Missing outcome data Chinese adult participants Intervention: arm 2 Country (efficacy) attending an outpatient 5ALA 10% PDT China High;18% discontinued - department. Symmetrically Coded intervention: arm 1 unclear why; no ITT Study type distributed severe facial acne 5ALA-RED-PDT RCT 4. Outcome measurement (Pillsbury III and IV) and Coded intervention: arm 2 (efficacy) Source of funding Fitzpatrick skin type III and IV. 5ALA-RED-PDT Some concerns;not reported if National Natural Science Exclusion details assessment of outcome was Foundation of China (no Pregnant or lactating women. blinded conflicts of interest). Exposure to systemic isotretinoin during the past 6

185 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Analysis method months; exposed to systemic 5. Selective reporting Intention to treat or antibiotics, contraceptives or Some concerns;not reported if completers analysis photosensitive drugs during trial protocol was registered completers the past month; exposed to 6. Overall bias topical acne drugs 2 weeks High prior to study. Participants with other facial diseases, a history of photosensitivity disorders or keloids. Participants with diabetes or severe heart, lung, liver or renal diseases. Number included Number randomised: arm 1 28 Number randomised: arm 2 28 Number completed: arm 1 23 Number completed: arm 2 23 Study details N=209 Interventions Results Cochrane RoB Tool v2.0 Reference Characteristics Treatment duration (weeks) Treatment 1. Randomisation Zouboulis Ch, C. D., Sex 12 discontinuation for Some concerns;No information L.,Decroix, J.,Maciejewska- mixed Treatment duration category any reason provided Udziela, B.,Cambazard, age group 12 to <24 weeks See supplement 8 2. Deviation from F.,Stuhlert, A.A multicentre, =25 years Number of arms Treatment intervention single-blind, randomized age (mean±SD) 2 discontinuation Low;patients were blinded; ITT comparison of a fixed 18.6±3.2 Split face design due to side effects used clindamycin No See supplement 8 3. Missing outcome data phosphate/tretinoin gel age (median) 18 Intervention: arm 1 Clinician rated (efficacy) formulation (Velac) applied improvement in Some concerns;Withdrawal age (min/max) CLIND 1%/TRET 0.025% gel once daily and a clindamycin acne imbalanced between 14/26 Intervention: arm 2 lotion formulation (Dalacin T) See supplement 8 groups,(5% vs 13%) - mostly CLIND 1% lotion applied twice daily in the Inclusion/exclusion criteria due to patient request. topical treatment of acne Used validated acne scale Coded intervention: arm 1 4. Outcome measurement vulgaris. 2000. British Journal no CLIND-topical + TRET-topical (efficacy) of Dermatology

186 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Trial ID Acne scale Coded intervention: arm 2 Some concerns;Investigator Zouboulis 2000 Cook CLIND-topical not blinded Country Inclusion details 5. Selective reporting Europe Participants aged between 14 Some concerns;not reported if Study type and 26 years. Moderate to trial protocol was registered RCT severe acne vulgaris; scoring 6. Overall bias Source of funding =3 on the Cook acne scale. Some concerns Yamanouchi Europe BV, The Exclusion details Netherlands. Use of tretinoin or antibiotic Analysis method treatments for acne during the Intention to treat or 4 weeks prior to study; use of completers analysis irritants such as salicylic acid completers and benzoyl peroxide during the 2 weeks prior to study; required other medical interventions within 5 days of the study. Participants with skin disorders likely to compromise drug absorption, known or suspected hypersensitivity to lincomycin, clindamycin or vitamin A derivatives. Participants who had changed or started use of contraceptives or use of Diane® within 3 months of the study. Those who had participated in another clinical trial within 3 months of the study. Number included Number randomised: arm 1 104 Number randomised: arm 2 105 Number completed: arm 1 90

187 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)

FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses

Outcomes and Study details Participants Interventions results Comments Number completed: arm 2 100 ADAP: adapalene; ALA-PDT: aminolevulinic acid photodymanic therapy; ALA-RED-PDT: aminolevulinic acid using red light photodymanic therapy; AZITH: azithromycin; BPO: benzoyl peroxide; CLIND: clindomycin; CPA: cyproterone acetate; DAPS: dapsone; DOXY: doxycycline; EE: ; ERYTH: erythromycin; FU: follow up; ISO: isotretinoin; IPL: intense pulsed light; ITT: intention to treat analysis; LOCF: last observation carried forward; LYME: lymecycline; MAL DL: methyl aminolevulinate using daylight; MICO: miconazole nitrate; MINO: minocycline; MOT: motretinide; NAFL: fractional erbium glass laser; NOR: norfloxacin; PDL: pulsed dye laser; PLC: placebo; PDT: photodynamic; PT: photochemical; RCT: randomised controlled trial; SAR/SARE: sarecycline; SD: standard deviation; TAZ: tazarotene; TETRA: tetracycline; TRET: tretinoin

188 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL (June 2021)