Langer 2006.

Methods	Randomised placebo‐controlled trial
Participants	866 healthy postmenopausal women (45 to 79 years of age with a body mass index > 19 and < 32 kg/m2) who had been amenorrhoeic for ≥ 1 year (mean time since menopause 11 years), with or without intact uterus. If the date of final menstruation was unclear, the woman was to have used hormone therapy (HT) for > 2 years and had to be > 53 years old or fulfil the US Food and Drug Administration (FDA) criteria for menopause (serum oestradiol ≤ 20pg/mL [or 73 pmol/L] and follicle‐stimulating hormone ≥ 40 mIU/mL). Mean age 59 years
Interventions	Tibolone 2.5mg/d 0.625 mg continuous combined conjugated equine oestrogen and 2.5 mg medroxyprogesterone acetate (CEE/MPA) Placebo Administered for 3 years (39 cycles of 28 days) CF336 study numbers
Outcomes	Vaginal bleeding (requiring more than 1 sanitary napkin or tampon per day), vaginal spotting (requiring just 1 sanitary napkin or tampon per day), breast cancer, cardiovascular events, mortality from any cause, endometrial cancer For bleeding outcomes: reported in 97% (689/707) of women with a uterus For endometrial cancer: only 50% (351/707) of randomised women with a uterus had baseline biopsy, and only 33% had endpoint biopsy For other outcomes: 70% completed 3 years of follow‐up with treatment, but total proportion of women followed up for other adverse events unclear
Notes	Data on endometrial cancer considered in separate publication Timing: unclear Location: United States and Europe Multi‐centre: 11 sites (6 in the United States, 5 in Europe) All participants also received oral calcium (500 mg/d) 707/857 women taking ≥ 1 dose of study medication had intact uterus
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	No information provided in the published article. In a private communication, the main study author assured that study treatments were allocated through random codes generated by a central co‐ordinating group
Allocation concealment (selection bias)	Unclear risk	In another published article describing the study methods (Bots ML; Cont Clin Trials 2003;24:752‐75), it is stated: "code numbers were assigned to subjects in the order of their randomisation in the trial, that is, the first subject received the first number (the lowest), the second subject received the next number in sequence, and so on". This specification made the allocation concealment issue unclear, but in a private communication, the main study author assured that such process was concealed to investigators but provided no further details
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo‐controlled with double‐dummy technique
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not specified, but given the nature of outcomes assessed, their evaluation is likely to be "objective"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Number of women not completing the trial and with no assessment of outcomes of interest is unclear
Selective reporting (reporting bias)	Low risk	Study reported data on outcomes as indicated in the protocol. Additional data on breast and endometrial cancer, cardiovascular events and mortality from any cause available in the study publication and included in this review
Conflict of interest	High risk	Financed by the drug manufacturer. One study author was an employee of the drug manufacturer