Table 1.

Clinical trials cited^a,b

Trial name	Type and location	Patient population	Outcome/endpoint	Regimen and dose	Statistical method	Outcome	Adverse event	Refs
ATBC, N01-CN-45165	Prevention, Helsinki	1862 male smokers 50–69 years old, previous MI	First major coronary event (MCE)	VitE 50 mg/day, βCA 20 mg/day, 5.3 years	Kaplan-Meier method, log-rank test, Cox’s proportional-hazards regression	No difference in MCEs	Significant MI-related death in βCA (74/461) and VitE + βCA group (67/497) compared with PB (39/438)	[17]
ATBC	Prevention, Helsinki	23 144 male smokers at risk, 1255 with pretrial MI	First-ever MCE	VitE 50 mg/day, βCA 20 mg/day, 5–8 years	Likelihood ratio test for homogeneity, Poisson regression for relative risk, generalized additive model for calendar time-specific rates		Increased MCE risk in βCA (1.13) and VitE + βCA groups (1.08)	[18]
BEAM, NCT00811889	Phase II, USA	227 moderate to severe CKD adults and type 2 diabetes, 1:1:1:1 ratio for PB, 25, 75, 150 mg/day BDXL	1st: GFR improvement in 24 weeks 2nd: 52 weeks, biomarkers of kidney function	BDXL 25, 75, 150 mg/day, 52 weeks (first 8–20 weeks dose adjust), 4 weeks follow up	Repeated-measures model for 1st and 2nd outcomes, Toeplitz structure for within-patient correlation, Kaplan-Meier method for proportion of event free	Improved GFR at 24 weeks, persisted to 52 weeks	42–61 % calf muscle spasm (18% for PB), resolved over time, 21–32% hypomagnesemia (5% for PB), 71% transient mild elevation of ALT	[72]
BEACON, NCT01351675	Phase III, international (71% USA)	2185 (1088 drug + 1097 PB) type 2 diabetes with stage 4 CKD, diverse age, sex, race, ethnicity, region of origin	1st: ESRD or death 2nd: Change in GFR; heart failure hospitalization or CV death; nonfatal MI, nonfatal stroke, hospitalization for heart failure, or death from CV causes	BDXL 20 mg/day, 3–11 months (median 7 months), PB median months, median months follow up	Kaplan-Meier product limit for cumulative incidence, hazard ratios and 95% CI with Cox proportional- hazards regression models, mixed-effects regression analyses for longitudinal analysis	27 and 19 CV deaths, 43 and 51 ESRD in BDXL and PB groups	96 and 55 had heart-failure events in BDXL and PB, 139 and 86 in BDXL and PB had nonfatal MI, stroke, hospitalization, or death from CVD	[73]
BEACON	Phase III, post-hoc data analyses	See above	See above	See above	Classification and regression tree analysis to identify baseline factors predictive of adverse events	Baseline high risk of heart failure is a compound factor of heart failure by BDXL	60% increase in heart failure with previous heart failure by BDXL, similar risk for heart failure without previous heart failure between BDXL and PB groups	[75]
MIRACL	Drug purposing expansion, international	3086 unstable angina or non-Q wave acute MI	Reduction of 1 ° end-point events: death, nonfatal acute MI, cardiac arrest, recurrent myocardial ischemia	AT, 80 mg/day or PB, 24–96 h after hospital admission, for 16 weeks	Cox proportional-hazards model for primary combined end points, Cochran-Mantel-Haenszel method for each end point	Reduction of end-point events (14.8% in AT, 17.4% in PB group), reduced cholesterol	Abnormal liver transaminases more common in AT group (2.5%) than PB group (0.6%)	[76]
PROVE IT-TIMI 22	Compare standard vs intensive dose, USA and Canada	4162 acute coronary syndrome	Death from any cause, MI, unstable angina requiring hospitalization, revascularization, stroke	PV 40 mg/day or AT 80 mg/day, 2 years	Kaplan-Meier estimates of primary end point, Cox proportional-hazards model for estimates of hazard ratios and 95% CI	Reduced primary end point: 26.3% in PV, 22.4% in AT group; hazard ratio reduction of death from any cause and MI, more LDL lowering with AT than PV	Slight increase in stroke hazard ratio	[77]

^aAll trials were randomized and double blinded with placebo control except the PRPVE IT-TIMI 22 trial, which is randomized and double blinded with double-dummy control. All trials were completed except BEACON (NCT01351675), which was terminated early, with a median 9-month follow-up, due to safety concerns.

^bAbbreviations: VitE, α-tocopherol; βCA, β-carotene; PB, placebo; BDXL, bardoxolone methyl; AT, atorvastatin; PV, pravastatin; CV, cardiovascular disease; CKD, chronic kidney disease; ESRD, end-stage renal disease; GFP, glomerular filtration rate; ALT, alanine aminotransferase.