Table 3.
Key secondary and secondary end points (mITT population)
| Resmetirom 100 mg OL (n = 169) | Resmetirom 100 mg DB (n = 314) | Resmetirom 80 mg DB (n = 320) | Placebo DB (n = 309) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Least squares mean %CFB or CFB (s.e.m.) | 95% CI | Least squares mean %CFB or CFB (s.e.m.) | Least squares mean difference (97.5% CI) | P value | Least squares mean %CFB or CFB (s.e.m.) | Least squares mean difference (97.5% CI) | P value | Least squares mean %CFB or CFB (s.e.m.) | |
| LDL-C, mg dl−1 | |||||||||
| Week 24 | −19.4 (2.6) | −24.5 to −14.3 | −13.9 (2.0) | −12.6 (−16.7 to −8.6) | <0.0001 | −12.4 (2.0) | −11.1 (−15.0 to −7.2) | <0.0001 | −1.3 (1.9) |
| Week 48 | −20.5 (2.5) | −25.4 to −15.6 | −13.4 (2.4) | −12.0 (−16.8 to −7.2) | <0.0001 | −10.6 (2.1) | −9.2 (−14.2 to −4.3) | 0.0004 | −1.4 (2.4) |
| LDL-C, mg dl−1 (baseline LDL-C ≥ 100 mg dl−1) | |||||||||
| N | 103 | 181 | 194 | 162 | |||||
| Baseline, mean (s.d.) | 137.2 (35.5) | 133.9 (25.6) | 134.2 (28.7) | 133.8 (26.3) | |||||
| Week 24 | −22.2 (3.0) | −28.1 to −16.3 | −22.0 (2.4) | −15.9 (−20.1 to −11.7) | <0.0001 | −19.0 (2.3) | −12.9 (−17.1 to −8.7) | <0.0001 | −6.1 (2.4) |
| Week 48 | −22.6 (2.9) | −28.2 to −16.9 | −21.9 (3.0) | −15.6 (−20.6 to −10.7) | <0.0001 | −17.3 (2.8) | −11.0 (−15.9 to −6.2) | <0.0001 | −6.2 (2.8) |
| ApoB, mg dl−1 | |||||||||
| Week 24 | −21.3 (2.1) | −25.4 to −17.2 | −16.5 (1.6) | −16.5 (−19.5 to −13.4) | <0.0001 | −14.3 (1.6) | −14.3 (−17.4 to −11.3) | <0.0001 | 0.0 (1.5) |
| Week 48 | −22.4 (2.1) | −26.4 to −18.4 | −16.3 (1.8) | −15.1 (−18.7 to −11.6) | <0.0001 | −13.8 (1.6) | −12.5 (−16.4 to −8.7) | <0.0001 | −1.2 (1.8) |
| ApoB, mg dl−1 (baseline LDL-C ≥ 100 mg dl−1) | |||||||||
| N | 103 | 181 | 194 | 162 | |||||
| Baseline, mean (s.d.) | 115.1 (25.3) | 110.4 (19.4) | 112.8 (20.0) | 114.2 (20.5) | |||||
| Week 24 | −23.6 (2.7) | −28.8 to −18.4 | −22.3 (2.1) | −18.0 (−21.7 to −14.4) | <0.0001 | −19.9 (2.1) | −15.6 (−19.3 to −12.0) | <0.0001 | −4.2 (2.2) |
| Week 48 | −21.7 (2.7) | −27.0 to −16.5 | −23.2 (2.7) | −17.5 (−21.8 to −13.3) | <0.0001 | −19.4 (2.2) | −13.8 (−18.0 to −9.6) | <0.0001 | −5.6 (2.5) |
| MRI-PDFF, % fat fraction | |||||||||
| n | 152 | 268 | 255 | 268 | |||||
| Week 16 | −47.8 (3.1) | −53.8 to −41.8 | −44.8 (2.6) | −38.6 (−44.6 to −32.6) | <0.0001 | −41.2 (2.6) | −34.9 (−41.0 to −28.9) | <0.0001 | −6.2 (2.6) |
| Week 52 | −51.8 (3.5) | −58.6 to −45.0 | −43.8 (2.9) | −33.9 (−40.7 to −27.1) | <0.0001 | −38.6 (2.9) | −28.8 (−35.6 to −21.9) | <0.0001 | −9.9 (2.9) |
| TG, mg dl−1 (baseline TG > 150 mg dl−1) | |||||||||
| n | 97 | 169 | 166 | 163 | |||||
| Baseline, mean (s.d.) | 232.2 (82.0) | 228.3 (97.1) | 236.5 (97.3) | 254.0 (133.3) | |||||
| Week 24 | −27.5 (4.5) | −36.3 to −18.8 | −23.4 (5.0) | −20.4 (−30.2 to −10.6) | <0.0001 | −18.4 (4.8) | −15.4 (−24.9 to −5.9) | 0.0015 | −3.0 (4.9) |
| Week 48 | −34.7 (4.6) | −43.8 to −25.5 | −22.5 (4.5) | −22.8 (−31.0 to −14.5) | <0.0001 | −22.6 (4.7) | −22.9 (−31.3 to −14.5) | <0.0001 | 0.3 (4.6) |
| Lp(a), nmol l−1 (baseline Lp(a) > 10 nmol l−1) | |||||||||
| n | 130 | 246 | 244 | 220 | |||||
| Baseline, mean (s.d.) | 61.1 (79.6) | 72.4 (82.9) | 78.0 (82.6) | 64.8 (76.2) | |||||
| Week 24 | −28.4 (3.7) | −35.6 to −21.2 | −19.7 (4.2) | −28.3 (−37.2 to −19.4) | <0.0001 | −4.8 (4.1) | −13.3 (−22.3 to −4.3) | 0.0037 | 8.5 (4.1) |
| Week 48 | −18.7 (3.5) | −25.6 to −11.8 | -33.6 (4.0) | −29.2 (−37.3 to −21.1) | <0.0001 | −24.0 (4.1) | −19.6 (−27.6 to −11.6) | <0.0001 | −4.4 (4.1) |
| ApoCIII, mg dl−1 | |||||||||
| n | 162 | 286 | 278 | 289 | |||||
| Baseline, mean (s.d.) | 11.3 (4.8) | 10.6 (4.5) | 10.9 (4.5) | 11.0 (4.8) | |||||
| Week 24 | −18.1 (3.0) | −23.9 to −12.3 | −17.6 (2.5) | -18.5 (−24.3 to −12.6) | <0.0001 | −11.5 (2.4) | −12.5 (−18.3 to −6.6) | <0.0001 | 0.9 (2.4) |
| Week 48 | −13.6 (3.1) | −19.6 to −7.6 | −14.4 (2.6) | −22.2 (−28.3 to −16.0) | <0.0001 | −9.7 (2.6) | −17.5 (−23.7 to −11.2) | <0.0001 | 7.7 (2.6) |
| FibroScan CAP, dBm | |||||||||
| n | 147 | 270 | 260 | 260 | |||||
| Week 52 CFB | −46.0 (4.8) | −55.3 to −36.6 | −42.8 (4.0) | −24.4 (−33.8 to −15.1) | <0.0001 | −36.7 (3.9) | −18.3 (−27.8 to −8.9) | <0.0001 | −18.4 (3.9) |
| FibroScan VCTE, kPa (baseline VCTE ≥ 7.2 kPa) | |||||||||
| n | 50 | 102 | 83 | 107 | |||||
| Baseline, mean (s.d.) | 9.1 (2.4) | 8.4 (1.6) | 8.5 (1.3) | 8.5 (1.8) | |||||
| Week 52 CFB | −2.09 (0.5) | −3.0 to −1.2 | −1.70 (0.4) | −0.50 (−1.3 to 0.3) | 0.1710 | −1.02 (0.4) | 0.17 (−0.7 to 1.0) | 0.6614 | −1.19 (0.4) |
| Liver enzymes, U l−1 (baseline ALT ≥ 30 IU l−1) | |||||||||
| n | 83 | 157 | 169 | 156 | |||||
| ALT | |||||||||
| Baseline, mean (s.d.) | 52.5 (25.3) | 51.1 (23.2) | 51.9 (22.4) | 55.5 (31.2) | |||||
| Week 52 CFB | −14.3 (3.0) | −20.2 to −8.4 | −11.9 (2.6) | −10.8 (−16.8 to −4.8) | <0.0001 | −10.8 (2.5) | −9.6 (−15.7 to −3.6) | 0.0004 | −1.1 (2.6) |
| AST | |||||||||
| Baseline, mean (s.d.) | 33.9 (13.9) | 32.0 (12.5) | 32.0 (13.2) | 34.9 (17.2) | |||||
| Week 52 CFB | −3.5 (2.2) | −7.9 to 0.9 | −3.1 (1.9) | −4.3 (−8.7 to 0.2) | 0.0341 | −3.9 (1.9) | −5.0 (−9.5 to −0.4) | 0.0141 | 1.1 (1.9) |
| GGT | |||||||||
| Baseline, mean (s.d.) | 58.5 (66.4) | 53.0 (38.1) | 58.4 (50.8) | 68.8 (83.0) | |||||
| Week 52 CFB | −16.5 (3.9) | −24.2 to −8.7 | −11.5 (3.4) | −10.0 (−17.9 to −2.0) | 0.0049 | −10.1 (3.3) | −8.6 (−16.5 to −0.6) | 0.0157 | −1.5 (3.4) |
| NASH biomarkers | |||||||||
| CK-18/M30, U l−1 | |||||||||
| n | 150 | 250 | 238 | 250 | |||||
| Baseline, mean (s.d.) | 664.8 (399.4) | 601.1 (357.3) | 601.7 (358.4) | 609.0 (410.8) | |||||
| Week 52 CFB | −174.2 (31.6) | −236.2 to −112.3 | −78.4 (27.1) | −82.6 (−146.8 to −18.4) | 0.0040 | −87.2 (26.8) | −91.4 −156.4 to −26.3) | 0.0017 | 4.15 (26.6) |
| Adiponectin, μg ml−1 | |||||||||
| n | 126 | 175 | 173 | 178 | |||||
| Baseline, mean (s.d.) | 4.9 (2.8) | 4.7 (2.7) | 4.7 (3.0) | 4.4 (2.7) | |||||
| Week 52 CFB | 1.61 (0.2) | 1.2 to 2.0 | 0.90 (0.2) | 0.48 (0.02 to 0.9) | 0.0195 | 1.12 (0.2) | 0.70 (0.24 to 1.2) | 0.0007 | 0.42 (0.2) |
| Reverse T3, ng dl−1 | |||||||||
| n | 152 | 265 | 250 | 257 | |||||
| Baseline, mean (s.d.) | 18.1 (5.5) | 16.3 (4.6) | 17.8 (5.1) | 16.8 (4.6) | |||||
| Week 52 CFB | −3.34 (0.4) | −4.1 to −2.6 | −3.21 (0.3) | −3.94 (−4.7 to −3.2) | <0.0001 | −2.70 (0.3) | −3.43 (−4.2 to −2.7) | <0.0001 | 0.73 (0.3) |
Lipids and lipoproteins are evaluated at week 24 and week 48 as least squares mean %CFB; other analytes as week 52 least squares mean CFB. This trial was designed to maintain an overall study-wise type I error rate of α = 0.05 for the key secondary end points only. The error rate was controlled by first splitting the overall two-sided α = 0.05 into two partitions via the Bonferroni method and then the key secondary end points tested in a prespecified hierarchical order. For the primary analysis of key secondary lipid end points, an analysis of covariance (ANCOVA) model was used to analyze each set of ten imputed datasets. The ANCOVA models for each lipid outcome included percent change from baseline to week 24 (and all other end point visits) as the dependent variable; treatment and stratification factors (presence of type 2 diabetes and ASCVD) as independent variables; and baseline lipid values as a covariable. The statistical method of estimating the treatment effect and testing for apoB and TG was similar to the LDL-C end point; a similar ANCOVA model was used whereby the baseline value of the dependent variable was included as covariate instead of LDL-C. CFB, change from baseline; %CFB, percentage change from baseline.