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Selective PDE9 Inhibition With IMR-687 in Adults With Heart Failure With Preserved Ejection Fraction (SP9In-HFpEF)

Primary Purpose

Heart Failure With Preserved Ejection Fraction

Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
IMR-687
IMR-687 Placebo
Sponsored by
Imara, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure With Preserved Ejection Fraction focused on measuring heart failure, HFpEF, preserved ejection fraction, IMR-687, PDE9

Eligibility Criteria

45 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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%

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    IMR-687

    Placebo

    Arm Description

    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.

    Participants randomly assigned to this arm will take placebo orally with food BID for 16 weeks.

    Outcomes

    Primary Outcome Measures

    Change in NT-proBNP
    Calculated as the percent change from Baseline to Week 16 in NT-proBNP

    Secondary Outcome Measures

    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.
    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.
    NYHA Classification
    Change from Baseline to Week 16 in NYHA classification
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    Exercise Capacity
    Change from Baseline to Week 16 in 6MWT
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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

    Full Information

    First Posted
    March 8, 2022
    Last Updated
    March 6, 2023
    Sponsor
    Imara, Inc.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05312021
    Brief Title
    Selective PDE9 Inhibition With IMR-687 in Adults With Heart Failure With Preserved Ejection Fraction
    Acronym
    SP9In-HFpEF
    Official Title
    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)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Study Termination
    Study Start Date
    April 2022 (Anticipated)
    Primary Completion Date
    September 2023 (Anticipated)
    Study Completion Date
    November 2023 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Imara, Inc.

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Heart Failure With Preserved Ejection Fraction
    Keywords
    heart failure, HFpEF, preserved ejection fraction, IMR-687, PDE9

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    IMR-687
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Participants randomly assigned to this arm will take placebo orally with food BID for 16 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    IMR-687
    Intervention Description
    150 mg and 200 mg tablets
    Intervention Type
    Other
    Intervention Name(s)
    IMR-687 Placebo
    Intervention Description
    Matching placebo to IMR-687
    Primary Outcome Measure Information:
    Title
    Change in NT-proBNP
    Description
    Calculated as the percent change from Baseline to Week 16 in NT-proBNP
    Time Frame
    Baseline to Week 16
    Secondary Outcome Measure Information:
    Title
    To evaluate the safety and tolerability in IMR-687 versus placebo (TEAEs: Treatment-emergent adverse events
    Description
    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.
    Time Frame
    Baseline to Week 16
    Title
    Change in Baseline to Week 16 in the Kansas City Cardiomyopathy Questionnaire overall summary score
    Description
    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.
    Time Frame
    Baseline to Week 16
    Title
    NYHA Classification
    Description
    Change from Baseline to Week 16 in NYHA classification
    Time Frame
    Baseline to Week 16
    Title
    Change in Baseline to Week 16 in Clinical Composite Score
    Description
    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.
    Time Frame
    Baseline to Week 16
    Title
    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
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change From Baseline in Echocardiography Parameters: Left Ventricular Mass
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A ratio < 1 indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change in Echocardiography Parameters: Isovolumic Relaxation Time
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity
    Description
    A limited two-dimensional and Doppler ECHO examination will be done to assess ECHO parameters. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Exercise Capacity
    Description
    Change from Baseline to Week 16 in 6MWT
    Time Frame
    Baseline to Week 16
    Title
    Body Composition and Biomarker Measures
    Description
    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.
    Time Frame
    Baseline to Week 16
    Title
    Body Composition and Biomarker Measures
    Description
    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.
    Time Frame
    Baseline to Week 16
    Title
    Body Composition and Biomarker Measures
    Description
    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.
    Time Frame
    Baseline to Week 16
    Title
    Body Composition and Biomarker Measures
    Description
    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.
    Time Frame
    Baseline to Week 16
    Title
    Body Composition and Biomarker Measures
    Description
    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.
    Time Frame
    Baseline to Week 16
    Title
    Change from Baseline to Week 16 for Estimated Glomerular Filtration Rate (eGFR)
    Description
    eGFR will be calculated from the serum creatinine concentration determined by central laboratory assessment. A positive change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change from Baseline to Week 16 for Interferon-gamma (Ifn-gamma)
    Description
    Evaluation of serum Ifn-gamma will be performed by central laboratory. A negative change from baseline indicates improvement.
    Time Frame
    Baseline to Week 16
    Title
    Change from Baseline to Week 16 in body composition quantification by dual-energy X-ray absorptiometry scan (at selected sites)
    Description
    A dual-energy X-ray absorptiometry scan will be done to assess body composition parameters. A negative change indicates improvement
    Time Frame
    Baseline to Week 16

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    45 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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%
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Steve Luperchio
    Organizational Affiliation
    Cardurion Pharmaceuticals
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Learn more about this trial

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

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