Selective PDE9 Inhibition With IMR-687 in Adults With Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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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.

Official Title
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Selective PDE9 Inhibition With IMR-687 in Adults With Heart Failure With Preserved Ejection Fraction: a Safety and Efficacy Phase 2 Randomized Clinical Study (SP9In-HFpEF)

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: IMR-687
* Other: IMR-687 Placebo


Participation Criteria
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Eligibility Criteria
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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: HF hospitalization within 12 months prior to screening 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 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 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%

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMR-687<br>Participants randomly assigned to this arm will take IMR-687 orally with food BID for 16 weeks. IMR-687 dosing will be 300 mg BID for participants weighing less than 100 kg and 400 mg BID for participants weighing 100 kg or more. | Drug: IMR-687<br>* 150 mg and 200 mg tablets<br>|
| Placebo Comparator: Placebo<br>Participants randomly assigned to this arm will take placebo orally with food BID for 16 weeks. | Other: IMR-687 Placebo<br>* Matching placebo to IMR-687<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in NT-proBNP | Calculated as the percent change from Baseline to Week 16 in NT-proBNP | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and tolerability in IMR-687 versus placebo (TEAEs: Treatment-emergent adverse events | 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. | Baseline to Week 16 | 
| Change in Baseline to Week 16 in the Kansas City Cardiomyopathy Questionnaire overall summary score | 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. | Baseline to Week 16 | 
| NYHA Classification | Change from Baseline to Week 16 in NYHA classification | Baseline to Week 16 | 
| Change in Baseline to Week 16 in Clinical Composite Score | 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. | Baseline to Week 16 | 
| 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 | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change From Baseline in Echocardiography Parameters: Left Ventricular Mass | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A ratio < 1 indicates improvement. | Baseline to Week 16 | 
| Change in Echocardiography Parameters: Isovolumic Relaxation Time | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity | A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Exercise Capacity | Change from Baseline to Week 16 in 6MWT | Baseline to Week 16 | 
| Body Composition and Biomarker Measures | 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. | Baseline to Week 16 | 
| Body Composition and Biomarker Measures | Change from Baseline to Week 16 for Procollagen III N-terminal Peptide (PIIINP) Evaluation of PIIINP will be performed by central laboratory assessment. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Body Composition and Biomarker Measures | Change from Baseline to Week 16 for Matrix Metalloproteinase-2 (MMP-2) Evaluation of serum MMP-2 will be performed by central laboratory assessment. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Body Composition and Biomarker Measures | Change from Baseline to Week 16 for C-peptide Evaluation of serum C-peptide will be performed by central laboratory assessment. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Body Composition and Biomarker Measures | Change from Baseline to Week 16 for Interleukin-6 (IL-6) Evaluation of serum IL-6 will be performed by central laboratory assessment. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change from Baseline to Week 16 for Estimated Glomerular Filtration Rate (eGFR) | eGFR will be calculated from the serum creatinine concentration determined by central laboratory assessment. A positive change from baseline indicates improvement. | Baseline to Week 16 | 
| Change from Baseline to Week 16 for Interferon-gamma (Ifn-gamma) | Evaluation of serum Ifn-gamma will be performed by central laboratory. A negative change from baseline indicates improvement. | Baseline to Week 16 | 
| Change from Baseline to Week 16 in body composition quantification by dual-energy X-ray absorptiometry scan (at selected sites) | A dual-energy X-ray absorptiometry scan will be done to assess body composition parameters. A negative change indicates improvement | Baseline to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, HFpEF, preserved ejection fraction, IMR-687, PDE9