Van Seters 2008.

Methods	Placebo‐controlled, double‐blind, parallel‐arm RCT 52 women randomised; 26 to each study group
Participants	Age: intervention group: median 39 years, range 22 to 56; placebo group: median 44 years, range 31 to 71 (P value = 0.08) VIN grade: VIN 2 (n = 4; 2 versus 2), VIN 3 (n = 47; 23 versus 24), not reported (n = 1) Smoking status: smokers (n = 46; 23 versus 23) and non‐smokers (n = 6; 3 versus 3) HPV status: positive (n = 50; 25 versus 25), negative (n = 2) Immunocompetence: excluded women with immunodeficiency Recurrent disease (previous surgical treatment): (n = 37; 18 versus 19) Focality: 100% multifocal
Interventions	Imiquimod versus placebo for 16 weeks (twice weekly)
Outcomes	Primary: clinical response at 20 weeks defined as a reduction in lesion size of more than 25% Secondary: histological regression to a lower grade at 20 weeks, clearance of HPV, relief of clinical symptoms QoL Side effects of treatment Response to treatment was assessed at 20 weeks (biopsy), 7 months and 12 months (+/‐ repeat biopsy) Investigators also reported progression to invasive SCC
Notes	Women were advised to use sulphur precipitate 5% in zinc oxide ointment the day after application to avoid superinfection 4‐weekly review with biopsy if suspicion of progression Complete responders were followed up for more than 5 years. At 5‐year follow‐up, 3 women in the imiquimod group had developed SCC, 2 with initially a partial response and 1 non‐responder.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was carried out by 3M Pharmaceuticals in blocks of four (with a two‐by‐two design) without stratification."
Allocation concealment (selection bias)	Low risk	"Except for cases of serious side effects, the randomization code was not broken until all women had been seen at 12 months."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Double‐blind, randomized clinical trial". Clinical response was evaluated by 2 gynaecologists with the use of photographs to avoid bias relating to awareness of side effects of imiquimod.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"All biopsy evaluations were reviewed independently by two experienced gynecologic pathologists who were unaware of the clinical data"
Incomplete outcome data (attrition bias) All outcomes	Low risk	100% analysed at 20 weeks All but 3 women were followed up for 12 months
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Among complete responders in the imiquimod arm, 1 woman's VIN lesions disappeared spontaneously after the initial biopsy and, after histological review, another woman had VIN 1 not VIN2/3. This may have biased the complete responder outcome in favour of imiquimod. There was also a slight imbalance in age between the 2 groups (P value = 0.08).
Overall risk	Low risk	A well‐conducted RCT