The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial

Figures

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  Fig. 1. CONSORT diagram. ITT population: all patients who met the eligibility criteria and were randomized to study drug (CDR132L or placebo). mITT population: all randomized patients who received at least one dose of study drug (CDR132L or placebo). PP population: all patients from the ITT population who had completed treatments and the 6-month visit without any major protocol deviations that could affect the validity of primary and secondary efficacy assessments. Safety population: all randomized patients who received at least one dose of study drug (CDR132L or placebo) and had at least one post-dose safety assessment. Missing data for the primary endpoint were as follows: placebo, five missing; CDR132L 5 mg kg−1, nine missing; CDR132L 10 mg kg−1, seven missing. a The mITT population also served as the safety population, although one patient included in the CDR132L 10 mg kg−1 arm in the mITT population was included in the placebo arm in the safety population. b One patient included in the CDR132L 10 mg kg−1 arm in the mITT population was included in the placebo arm in the PP population.

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  Fig. 2. Concentration of miR-132 in plasma derived from patients treated with placebo, CDR132L 5 mg kg−1 or CDR132L 10 mg kg−1. Data are shown for the mITT population with each CDR132L dose analyzed separately.

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  Fig. 3. Changes in LVESVI in patients treated after MI with placebo, CDR132L 5 mg kg−1 or CDR132L 10 mg kg−1. Percentage change from baseline in LVESVI at month 6 (a), LSM difference versus placebo at month 6 (b) and absolute change from baseline in LVESVI at month 6 (c). Data are shown for the mITT population with each CDR132L dose analyzed separately. In b, LSM difference was determined using an ANCOVA model including treatment and center group, stratification factors of age group (<60 years, ≥60 years) and location of infarction (anterior, non-anterior) as fixed effects and baseline LVESVI as a covariate (comparisons shown versus placebo).

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  Fig. 4. Subgroup analyses for percentage change from baseline in LVESVI. The difference in LSM (95% CI) between treatment arms at month 6 (a) and at month 12 (b) for selected subgroups is shown. Data are shown for the mITT population with each CDR132L dose analyzed separately. The ANCOVA model (used for all displayed subgroup analyses) includes treatment and center group, stratification factors of age group (<60 years, ≥60 years) and location of infarction (anterior, non-anterior), baseline LVESVI and subgroup and treatment-by-subgroup interaction. P values are two-sided. All comparisons shown are versus placebo. CI, confidence interval; INT, intervention; NE, not estimable; PBO, placebo.

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  Extended Data Fig. 1. Baseline distributions of LVESVI (a) and NT-proBNP (b). Data are shown for the mITT population. LVESVI, left ventricular end-systolic volume index; mITT, modified intention-to-treat; NT-proBNP, N-terminal pro B-type natriuretic peptide.

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  Extended Data Fig. 2. Percentage change from baseline in LVESVI at month 6 (a) and month 12 (b). Data are shown for the PP population with each CDR132L dose analyzed separately. LVESVI, left ventricular end-systolic volume index; PP, per protocol; SEM, standard error of the mean.

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  Extended Data Fig. 3. Subgroup analyses for change from baseline in LVEF. (a, b) The difference in LSM (95% CI) between treatment arms at month 6 (a) and month 12 (b) for selected subgroups is shown. Data are shown for the mITT population with each CDR132L dose analyzed separately. The ANCOVA model (used for all displayed subgroup analyses) includes treatment and center group, stratification factors of age group (<60 years, ≥60 years) and location of infarction (anterior, non-anterior), baseline LVEF, subgroup and treatment-by-subgroup interaction. P values are 2-sided. All comparisons shown are versus placebo. ANCOVA, analysis of covariance; CI, confidence interval; INT, intervention; LSM, least squares mean; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; mITT, modified intention-to-treat; NE, not evaluable; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; PBO, placebo.

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  Extended Data Fig. 4. Subgroup analyses for NT-proBNP ratio to baseline. (a,b) The difference in LSM (95% CI) between treatment groups at month 6 (a) and month 12 (b) for selected subgroups is shown. Data are shown for the mITT population with each CDR132L dose analyzed separately. The ANCOVA model includes treatment and center group, stratification factors of age group (<60 years, ≥60 years) and location of infarction (anterior, non-anterior), baseline NT-proBNP (log transformed), subgroup and treatment-by-subgroup interaction. P values are 2-sided. All comparisons shown are versus placebo. Triangles represent estimates that fall outside the x axis range. ANCOVA, analysis of covariance; CI, confidence interval; INT, intervention; LSM, least squares mean; LVEF, left ventricular ejection fraction; mITT, modified intention-to-treat; NE, not evaluable; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; PBO, placebo.