Hashkes 2012.

Study characteristics
Methods	RCT (single participant alternating treatment), treated as cross‐over design for the first 2 phases (no washout period) Location: USA Conducted from October 2008 to January 2011 Randomization occurred at the beginning of the study to 1 of the 4 treatment sequences: rilonacept‐placebo‐rilonacept‐placebo, placebo‐rilonacept‐placebo‐rilonacept, rilonacept‐placebo‐placebo‐rilonacept, placebo‐rilonacept‐rilonacept‐placebo. So, we treated the first 2 courses as a cross‐over study
Participants	14 people with FMF diagnosed according to the Tel‐Hashomer clinical criteria, with ≥ 1 mutation on the MEFV gene, experienced an estimated mean of ≥ 1 attacks per month for 3 months before screening and ≥ 1 attacks per month during screening despite receiving adequate colchicine treatment Age: 4–47 years Gender: 6 females, 8 males
Interventions	Intervention: rilonacept 2.2 mg/kg/week subcutaneous injection (maximum 160 mg/week) for 3 months Control: matching placebo Administration: intervention for 3 months, then cross‐over for the other 3 courses, a total of 12 months. No washout period between each 2 treatment phase, nor assessment of carryover effect Co‐interventions: both groups received adequate colchicine treatment at participants' usual dose
Outcomes	Number of participants experiencing an attack (phase I outcome data available) Timing of FMF attacks Adverse events, including: digestive system, circulatory system, nervous system, respiratory system, injection site reactions and herpes Acute‐phase response, including: ESR, CRP, SAA, fibrinogen concentration Frequency of attacks Proportion of treatment courses with no attacks Proportion of courses with a decrease in attacks > 50% Composite evaluation score Global disease assessment Health‐related quality of life Outcomes measured at 12 months
Notes	The outcome data, except "number of patients experiencing an attack", could not be distinguished among each phase Funding Source: U.S. Food and Drug Administration, Office of Orphan Products Development
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Blocked randomization, using computer‐generated code."
Allocation concealment (selection bias)	Low risk	Quote: "Blocked randomization not stratified by center was done at the study coordination center by the unblinded statistician using a computer‐generated code to ensure equal allocation of participants into treatment group sequences. After confirming eligibility, the unblinded statistician called the site pharmacist with the participant number and treatment assignments."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Double‐blind", "Rilonacept and placebo vials were labelled by the pharmacist and were identical in appearance, including after preparation."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind; however, we do not know whether outcome assessment was blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	In the first treatment course: 1 participant in the control group lost to follow‐up. In the whole treatment process: 3 participants withdrew: 1 lost to follow‐up, 1 with travel difficulties; 1 with lack of efficacy. ITT analysis was performed.
Selective reporting (reporting bias)	Low risk	No selective reporting bias according to the protocol.
Other bias	Low risk	No other source of bias identified.