Heart Failure With Preserved Ejection Fraction
Conditions
Keywords
heart failure, HFpEF, preserved ejection fraction, IMR-687, PDE9
Brief summary
This study is to evaluate whether 16 weeks of treatment with IMR-687 is a safe and effective treatment for patients with Heart Failure with Preserved Ejection Fraction (HFpEF). The primary objective is to evaluate whether IMR-687 reduces NT-proBNP compared to placebo in these patients.
Interventions
DRUGIMR-687
150 mg and 200 mg tablets
OTHERIMR-687 Placebo
Matching placebo to IMR-687
Sponsors
Imara, Inc.
Cardurion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females ≥45 years * Weight 60 to 160 kg, inclusive * LVEF ≥45% by echo within 6 months prior to Screening Visit * Symptoms of HFpEF requiring treatment with a diuretic(s) for at least 30 days prior to Screening * NYHA class II to IV at the time of Screening * LV hypertrophy, by echo within 6 months of screening, defined by either LV mass/BSA \>95 g/m² for females and 115 g/m² for males or LV mass/m² for males \>44 g/m2.7 for females and 48 g/m2.7 for males * NT-proBNP criteria either ≥300 pg/mL if in sinus rhythm or ≥700 pg/mL if in atrial fibrillation at screening * Elevated LV filling pressure criteria are defined as ONE OR MORE of the following: 1. HF hospitalization within 12 months prior to screening 2. LA enlargement (LA width (diameter) ≥3.8 cm, LA length ≥5.0 cm, LA area ≥20 cm² , LA volume ≥55 mL, or LA volume index \>29 mL/m²) within 6 months of screening for a participant in sinus rhythm 3. Cardiac catheterization with at least one of the following in the 12 months prior to screening: rest LVEDP or PCWP ≥15 mm Hg, exercise PCWP ≥25 mm Hg, or fluid challenge PCWP ≥18 mm Hg 4. Echocardiogram criteria of one or more within 6 months of screening for a participant in sinus rhythm: E/e' (mean of lateral and septal) \>13, E/e' lateral \>12, or E/e' septal \>14; or for a participant in atrial fibrillation: E/e' septal \>11 * For WOCBP: Two negative pregnancy tests and the use of highly effective contraception up to 3 months following end of study
Exclusion criteria
* Any prior echocardiographic imaging measurement of LVEF \<40% * Six-minute walk test (6MWT) distance \<100 m or \>450 m at Screening Visit * Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score of \>80 * Major cardiovascular surgery, or urgent percutaneous coronary intervention (PCI) within the 3 months prior to Screening Visit, or an elective PCI within 30 days prior to Screening Visit * Any clinical event within 6 months prior to Screening Visit that could have reduced the LVEF (eg, myocardial infarction, coronary artery bypass graft) unless an echocardiographic measurement was performed at least 1 month after the event confirming the LVEF to be ≥45%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in NT-proBNP | Baseline to Week 16 | Calculated as the percent change from Baseline to Week 16 in NT-proBNP |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Baseline to Week 16 in the Kansas City Cardiomyopathy Questionnaire overall summary score | Baseline to Week 16 | The Kansas City Cardiomyopathy Questionnaire is a self-administered questionnaire. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and quality of life, each with different Likert scale wording, including limitations, frequency, bother, change in condition, understanding, levels of enjoyment, and satisfaction. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A positive change from baseline indicates improvement. |
| NYHA Classification | Baseline to Week 16 | Change from Baseline to Week 16 in NYHA classification |
| Change in Baseline to Week 16 in Clinical Composite Score | Baseline to Week 16 | The clinical composite score is defined as follows: Improved = participant improved in KCCQ score questionnaire with no major adverse cardiovascular event. Worsened = participant worsened (markedly or moderately) in KCCQ score or experienced a major adverse cardiovascular event. Unchanged = participant had no worsening in KCCQ score with no major adverse cardiovascular event. |
| Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. |
| Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. |
| Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. |
| Change From Baseline in Echocardiography Parameters: Left Ventricular Mass | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. |
| Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. |
| Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. |
| To evaluate the safety and tolerability in IMR-687 versus placebo (TEAEs: Treatment-emergent adverse events | Baseline to Week 16 | An adverse event (AE) is an untoward medical occurrence in a subject who received study drug without regard to the possibility of a causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; and any other medically important serious event as judged by the investigator. AEs are considered treatment-emergent if they have started or worsened after the first application of study drug up to 30 days after end of treatment with study drug. |
| Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A ratio \< 1 indicates improvement. |
| Change in Echocardiography Parameters: Isovolumic Relaxation Time | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. |
| Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. |
| Exercise Capacity | Baseline to Week 16 | Change from Baseline to Week 16 in 6MWT |
| Body Composition and Biomarker Measures | Baseline to Week 16 | Change from Baseline to Week 16 for body composition by waist-to-hip ratio, BMI, and Tissue Inhibitor of Metalloproteinases (TIMP) Evaluation of TIMP will be performed by central laboratory assessment. A negative change from baseline indicates improvement. |
| Change from Baseline to Week 16 for Estimated Glomerular Filtration Rate (eGFR) | Baseline to Week 16 | eGFR will be calculated from the serum creatinine concentration determined by central laboratory assessment. A positive change from baseline indicates improvement. |
| Change from Baseline to Week 16 for Interferon-gamma (Ifn-gamma) | Baseline to Week 16 | Evaluation of serum Ifn-gamma will be performed by central laboratory. A negative change from baseline indicates improvement. |
| Change from Baseline to Week 16 in body composition quantification by dual-energy X-ray absorptiometry scan (at selected sites) | Baseline to Week 16 | A dual-energy X-ray absorptiometry scan will be done to assess body composition parameters. A negative change indicates improvement |
| Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus | Baseline to Week 16 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. |
Outcome results
None listed