Effects of HDL Mimetic Agent CER-001 on Atherosclerosis in ACS
Effects of HDL Mimetic Agent CER-001 on Atherosclerosis in ACS
Five hundred and seven patients were randomized (Figure 1) and baseline patient characteristics were similar among groups ( Table 1 ). There were 417 and 461 patients with paired IVUS and QCA measurements, respectively. The main reasons for the lack of IVUS analysis were early study termination and inability to obtain a matched coronary segment at both time points (Figure 1). The percentages of patients who received all six planned study drug infusions in the primary analysis (modified intent-to-treat) population were 97.5, 100, 96.7, and 91.4% in the placebo, CER-001 3, 6, and 12 mg/kg groups (P = 0.004).
(Enlarge Image)
Figure 1.
Disposition of patients in the trial.
Intravascular ultrasonography images were traced over a mean arterial segment length of 48 ± 15 mm ( Table 2 ). The mean total atheroma volume at baseline was 155.24 ± 67.99 mm. The adjusted means for change in the total atheroma volume were −2.71, −3.13, −1.50, and −3.05 mm in the placebo, CER-001 3, 6, and 12 mg/kg groups (P = 0.81 for the pre-specified primary analysis of 12 mg/kg vs. placebo). There were also no differences compared with placebo for the CER-001 6 mg/kg (nominal P = 0.45) and 3 mg/kg (nominal P = 0.77) groups. The change in per cent atheroma volume was similar among all study groups [0.02, −0.02, 0.01, and 0.19% in the placebo, CER-001 3 mg/kg (P = 0.86), 6 mg/kg (P = 0.95), and 12 mg/kg (P = 0.53) groups (nominal P-values vs. placebo)]. A sensitivity analysis conducted on the per-protocol population, which had 97% power to detect the target difference given the observed standard deviation, yielded similar results ( Table 2 ).
Quantitative coronary angiography results are described in Table 4 . The change from baseline to follow-up in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm in the placebo and CER-001 3, 6, and 12 mg/kg groups, respectively (vs. placebo, nominal P = 0.25, 0.99, 0.55, respectively). The change from baseline to follow-up in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% in the placebo and CER-001 3, 6, and 12 mg/kg groups (nominal P = 0.01 for 3 mg/kg vs. placebo).
The number of patients with at least one major adverse cardiovascular event was 10 (8.3%) in the placebo group, and 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the CER-001 groups, without statistically significant differences (Table 5).
CER-001 was generally well tolerated during the study (Table 6). There were a few infusion-type reactions during the study, which led to the temporary halting of patient recruitment (without interrupting ongoing study drug administration) to allow updating of the informed consent document as per the recommendation of the safety monitoring committee following its periodic review which included all subjects from the first two study cohorts and 128 subjects from the third cohort. Drug-related hypersensitivity reported as a serious adverse event occurred in 0, 1, 3, and 2 patients in the placebo and CER-001 groups. Treatment-emergent infusion-type reactions (with rigors, chills, nausea, and/or hypotension) occurred in 0, 0, 3, and 3 patients of the placebo, CER-001 3, 6, and 12 mg/kg groups, respectively. None of these patients had anti-apoA-I antibodies.
Treatment-emergent elevations in ALT (three times the ULN) occurred in 2, 2, 2, and 1 patients in the four study groups.
At the end of the study, the sponsor requested a post hoc re-analysis of the IVUS recordings by a separate group, which also showed that the primary endpoint was not met (Table 3). The adjusted means for change in the total atheroma volume were −2.85, −4.76, −3.34, and −2.61 mm in the placebo, CER-001 3 mg/kg (P = 0.28), 6 mg/kg (P = 0.78), and 12 mg/kg (P = 0.89) groups (nominal P-values vs. placebo). A sensitivity analysis performed on the per-protocol population of these post hoc re-analysed data yielded similar results (Table 3).
Results
Baseline Demographics
Five hundred and seven patients were randomized (Figure 1) and baseline patient characteristics were similar among groups ( Table 1 ). There were 417 and 461 patients with paired IVUS and QCA measurements, respectively. The main reasons for the lack of IVUS analysis were early study termination and inability to obtain a matched coronary segment at both time points (Figure 1). The percentages of patients who received all six planned study drug infusions in the primary analysis (modified intent-to-treat) population were 97.5, 100, 96.7, and 91.4% in the placebo, CER-001 3, 6, and 12 mg/kg groups (P = 0.004).
(Enlarge Image)
Figure 1.
Disposition of patients in the trial.
Imaging Efficacy Results
Intravascular ultrasonography images were traced over a mean arterial segment length of 48 ± 15 mm ( Table 2 ). The mean total atheroma volume at baseline was 155.24 ± 67.99 mm. The adjusted means for change in the total atheroma volume were −2.71, −3.13, −1.50, and −3.05 mm in the placebo, CER-001 3, 6, and 12 mg/kg groups (P = 0.81 for the pre-specified primary analysis of 12 mg/kg vs. placebo). There were also no differences compared with placebo for the CER-001 6 mg/kg (nominal P = 0.45) and 3 mg/kg (nominal P = 0.77) groups. The change in per cent atheroma volume was similar among all study groups [0.02, −0.02, 0.01, and 0.19% in the placebo, CER-001 3 mg/kg (P = 0.86), 6 mg/kg (P = 0.95), and 12 mg/kg (P = 0.53) groups (nominal P-values vs. placebo)]. A sensitivity analysis conducted on the per-protocol population, which had 97% power to detect the target difference given the observed standard deviation, yielded similar results ( Table 2 ).
Quantitative coronary angiography results are described in Table 4 . The change from baseline to follow-up in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm in the placebo and CER-001 3, 6, and 12 mg/kg groups, respectively (vs. placebo, nominal P = 0.25, 0.99, 0.55, respectively). The change from baseline to follow-up in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% in the placebo and CER-001 3, 6, and 12 mg/kg groups (nominal P = 0.01 for 3 mg/kg vs. placebo).
Cardiovascular Events
The number of patients with at least one major adverse cardiovascular event was 10 (8.3%) in the placebo group, and 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the CER-001 groups, without statistically significant differences (Table 5).
Safety Results
CER-001 was generally well tolerated during the study (Table 6). There were a few infusion-type reactions during the study, which led to the temporary halting of patient recruitment (without interrupting ongoing study drug administration) to allow updating of the informed consent document as per the recommendation of the safety monitoring committee following its periodic review which included all subjects from the first two study cohorts and 128 subjects from the third cohort. Drug-related hypersensitivity reported as a serious adverse event occurred in 0, 1, 3, and 2 patients in the placebo and CER-001 groups. Treatment-emergent infusion-type reactions (with rigors, chills, nausea, and/or hypotension) occurred in 0, 0, 3, and 3 patients of the placebo, CER-001 3, 6, and 12 mg/kg groups, respectively. None of these patients had anti-apoA-I antibodies.
Treatment-emergent elevations in ALT (three times the ULN) occurred in 2, 2, 2, and 1 patients in the four study groups.
Post hoc Re-analysis
At the end of the study, the sponsor requested a post hoc re-analysis of the IVUS recordings by a separate group, which also showed that the primary endpoint was not met (Table 3). The adjusted means for change in the total atheroma volume were −2.85, −4.76, −3.34, and −2.61 mm in the placebo, CER-001 3 mg/kg (P = 0.28), 6 mg/kg (P = 0.78), and 12 mg/kg (P = 0.89) groups (nominal P-values vs. placebo). A sensitivity analysis performed on the per-protocol population of these post hoc re-analysed data yielded similar results (Table 3).