Hashemian 2016.

Methods	2‐arm, double‐blind, single‐centre, parallel‐group RCT, with 8 weeks duration of treatment and follow‐up
Participants	Location: Iran, 1 site Setting of recruitment and treatment: secondary care, hospital ENT clinic Sample size: 54 Number randomised: 27 in intervention, 27 in comparison Number completed: 24 in intervention, 24 in comparison Participant (baseline) characteristics: Mean age (± SD): group 1: 38.25 (± 1.70); group 2: 39.75 (± 3.195) Gender (M/F): 34 (70.8%)/14 (29.2%) Main diagnosis: chronic rhinosinusitis (CRS) Presence of allergic fungal rhinosinusitis: not reported Presence of eosinophilic CRS: not reported Polyps status (% with polyps): 21 (43.8%) Previous sinus surgery status: not reported Other important effect modifiers, if applicable: smoking status – smoker: 5 (10.4%) Inclusion criteria: adults (age > 18 years) with CRS diagnosed according to the American Academy of Otolaryngology ‐ Head and Neck Surgery (AAO‐HNS) criteria, which had not been responsive to routine medical treatments Exclusion criteria: patients who were pregnant, lactating or suffered from a major illness (such as cardiovascular disease, acute renal or liver disease, cancer or active malignancy). Known sensitivity to fluconazole; immune compromised patients; patients with acute complication of CRS; superimposition of ARS (fever, acute pain, pressure on face); antibiotic use in recent 7 days; systemic antifungal use in recent 7 days and systemic steroid use in recent 30 days
Interventions	Intervention (n = 27): fluconazole nasal drops 0.2% (12 drops per day, 2 times a day). Total daily dose = 1.2 mg fluconazole. Treatment duration = 8 weeks. Comparator group (n = 27): placebo nasal drops (12 drops per day, 2 times a day). Treatment duration = 8 weeks. Use of additional interventions (common to both treatment arms): Fluticasone nasal spray 50 µg (2 puffs per day, 2 times a day)
Outcomes	Outcomes of interest in the review: Primary outcomes: Health‐related quality of life, disease‐specific, SNOT‐20 range: 0 to 100, lower = better quality of life, 8 weeks Secondary outcomes: Endoscopy (polyps size or overall score) (Personal communication: No evidence of disease (stage 0); Inflammatory mucosal changes confined to the middle meatus superior to the lower edge of the middle turbinate (stage 1); Polypoid changes between the lower edge of the middle turbinate and the root of the inferior turbinate (stage 2); Polypoid changes between the root of the inferior turbinate and the lower edge of the inferior turbinate (stage 3); Polypoid changes below the lower edge of the inferior turbinate (stage 4). The stages of the 2 sides were added (range, 0‐8).) CT scan (Personal communication; range 0 to 30 points: mucosal thickening scored on 0 to 3 range for each of frontal (2), maxillary (2), sphenoid (1) and ethmoid (2) sinuses, nasal passages and OMC (2)) Adverse effects (topical antifungals): local discomfort Other outcomes reported by the study: None
Funding sources	"Academic research fund was provided by Hamadan University of Medical Sciences"
Declarations of interest	"The authors declare no conflicts of interest at all."
Notes	Registered in Iranian Registry of Clinical Trials: IRCT138811063186N1
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was done by tossing a coin by an independent third party (ward secretary)." Comment: adequate randomisation
Allocation concealment (selection bias)	Low risk	Quote: "… the bottles were coded by a third party who wrote down the codes in a table and the third party himself decoded the bottles at the end of the study." Comment: randomisation completed by a 3rd party and clinicians were handed coded bottles
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "…drug and placebo were exactly identical in terms of their appearance and could not be identified neither by the clinician nor the patient." Comment: adequate details in paper to demonstrate that sufficient efforts were made to prevent the participants knowing their allocation
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "…drug and placebo were exactly identical in terms of their appearance and could not be identified neither by the clinician nor the patient." Comment: adequate details in paper to demonstrate that sufficient efforts were made to prevent the participants knowing their allocation for the outcome of SNOT‐20. For CT scan and endoscopic score it is assumed that these were completed by blinded clinician.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 6/54 (11%) of randomised participants did not complete the study. There was no difference in the number of people dropping out between the groups. The reasons for dropping out were "exacerbation of disease" (1 person) and voluntary refusal to continue study (5 people)
Selective reporting (reporting bias)	Unclear risk	Comment: although the protocol is available (IRCT138811063186N1), endoscopic score is not listed as an outcome. Furthermore, the method for reporting endoscopic score and CT scan score are not reported in the published paper. Standard deviations for the data are not given in the paper. The results for adverse effects are not well described.
Other bias (non‐validated instrument)	Unclear risk	Comment: although SNOT‐20 is a validated tool in CRS, it is unclear whether an Iranian version was used. No information on validity of the version was used with regards to translation and cultural adaptation. No details were given regarding the criteria used for endoscopic score and CT scan score and so it is not possible to say whether these were validated instruments.
Other bias	Low risk	Comment: no other bias identified