ALPHABET.

Methods	Randomised, blinded, parallel‐group placebo‐controlled trial
Participants	Males or females over 8 years of age with PAH in NYHA functional classes II and III, including primary pulmonary hypertension, pulmonary hypertension associated with collagen vascular disease, congenital systemic‐to‐pulmonary shunts, portal hypertension and HIV infection; a baseline 6MWD between 50 metres and 500 metres, a mPAP > 25 mmHg and a pulmonary capillary wedge pressure < 15 mmHg were required for inclusion. Participants were excluded if they had received long‐term treatment with other prostacyclin analogues within one month of enrolment. Additional therapies including anticoagulants, diuretics, and calcium channel blockers were included; use of PDE‐5 inhibitors or ERAs were not reported. n = 130
Interventions	Oral beraprost sodium (n = 65) compared to placebo (n = 65) In the first six weeks participants were up‐titrated with 20 μg or matching placebo four times a day for the first week, and the dose was increased by 20 μg or matching placebo four times a day each week. The maximal dose allowed in the study was 120 μg four times a day at week 6. At the end of 12 weeks, mean dose of drug was 80 + 35 μg four times a day (median 80 μg four times a day) in the beraprost sodium group, and the hypothetical dose in the placebo group was 111 + 22μg four times a day.
Outcomes	Change in WHO functional class, 6MWD, Borg dyspnoea score, clinical worsening (hospitalisation for worsening of symptoms related to pulmonary hypertension), haemodynamics, adverse events Outcomes were measured at 6 and 12 weeks
Notes	Industry funded: Sanofi‐Adventis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated as randomised, and probably done, but no methods of randomisation were detailed
Allocation concealment (selection bias)	Unclear risk	Allocation concealment methods not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo‐controlled. Given this was an up‐titration study, number of doses between intervention and placebo were outlined.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Unclear if outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	States how missing data were dealt with, but does not state how many participants were affected. In the event that no data were available at week 12 for the primary or secondary efficacy variable, the week 6 values or, if lacking, the baseline values were carried forward and used as values at week 12 (last observation carried forward). Two additional methods for missing data imputation were prospectively planned for the primary efficacy variable to ensure robustness of the results: the "left censored data" and "worst quartile" methods.
Selective reporting (reporting bias)	Low risk	Outcomes were reported
Other bias	Low risk	Other bias unlikely