Lester 1985.

Methods	Parallel design, randomised controlled trial
Participants	30 participants from two centres, Departments of Dermatology of Sunnybrook Medical Center and Women’s College Hospital, at Toronto, Canada Inclusion criteria: presence of 10 or more deep dermal inflamed cystic nodules, which measured 4 mm or more on their longest diameter; past of minimal responses to treatment with tetracycline; failure to respond to other oral and topic agents, including antibiotics, topical tretinoin, benzoyl peroxide, and prednisone, as well as many other conventional forms of acne therapy. Exclusion criteria: pregnant and women of childbearing potential; significant ocular, hepatic, renal, or hematologic diseases or abnormalities; superficial x‐ray therapy within 6 months prior to the study; history of hypersensitivity to tetracycline or to vitamin A and its derivatives Age: for all participants, ranged from 17.1 to 37.7 years Age: by group, mean ± standard deviation/range (years) Group 1: 24.3 ± 5.9/17.1‐35.4 Group 2: 26.5 ± 7.2/18.1‐37.7 Gender: male/female Group 1: 15/0 Group 2: 14/1 Duration of acne: mean ± standard deviation (years)/range Group 1: 8.3 ± 5.9/2‐20 Group 2: 8.9 ± 6.3/2‐22 Acne severity: 100% severe
Interventions	Group 1 (n = 15): oral isotretinoin 1.0 to 2.0 mg/kg/day, taken in divided doses for 16 weeks. Increments of 0.5 mg/kg/day to the maximal dosage permitted at biweekly intervals Group 2 (n = 15): tetracycline hydrochloride 500 mg/day to 1 g/day, given for 16 weeks. Increments of 250 mg/day to reach the maximal dosage were permitted at biweekly intervals
Outcomes	Clinical efficacy assessments: Changes from baseline in the number of cysts of 4 mm or greater*, the sum of their longest diameters and the number of comedones and pustules in face, back, and chest Signs and symptoms associated with the acne condition, including erythema and pain of the acne lesions, oiliness of the skin, rate of development of new lesions, and healing time of the lesions Clinical and laboratory safety assessments Frequency of abnormalities in routine haematology, blood chemistry, urinalysis, ophthalmic examination, and spermatogenesis evaluations* Frequency of adverse reactions related to the test medications according to organ system* The ophthalmic examination was done at the end of the treatment period and spermatogenesis evaluations were performed at 12, 20, and 24 weeks. All other outcomes measurements were made at 2, 4, 8, 12, and 16 weeks during drug administration, and at 20 and 24 weeks during the follow‐up period. * Indicates outcomes which matched those prespecified for this review
Funding body	Hoffman‐La Roche Ltd
Notes	Authors declared being from the Clinical Research Unit of Hoffman‐La Roche Ltd., Toronto, Ontario, Canada
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: The trial did not provide any information about random sequence generation
Allocation concealment (selection bias)	Unclear risk	Comment: There was no statement regarding methods of allocation concealment in the study
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: “The double‐blind condition of the trial was preserved by the pharmacists, who dispensed the appropriate test medication at the dosage level prescribed by the investigator. In addition, the objective cyst evaluations were performed by a research nurse independent of consultation with the investigator ”. Comment: It was not clear if the term "double‐blind" was a reference to participants and personnel or to investigators (personnel) and independent research nurse (outcome assessor)
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: “...the objective cyst evaluations were performed by a research nurse independent of consultation with the investigator”. Comment: There was no description of blinding assessment for all outcomes reported in the study
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: “Two patients in the tetracycline‐treatment group withdrew from the study prematurely due to poor control of their disease". Comment: There was an imbalance in missing outcome data due to ‘inefficacy’ across the two intervention groups
Selective reporting (reporting bias)	Low risk	Comment: No protocol available; however, there was an adequate report of outcomes listed in methods section
Other bias	Unclear risk	Comment: The study might be at risk of inappropriate influence of funders, as it was sponsored and promoted by a pharmaceutical company