A Study of Ponsegromab in People With Heart Failure

Study Overview
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Brief Summary
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The primary purpose of this clinical trial is to compare the effects of study medicine (Ponsegromab/PF-06946860) with a placebo (an injection that looks like the study medicine but does not contain the active medicine) to find out if the study medicine is better than the placebo (an injection that looks like the study medicine but does not contain the active medicine) for treatment of symptoms related to heart failure. Participants will not know which treatment group they are assigned to. Most participants in this study will receive the study medicine or placebo by shots under the skin every four weeks. People may be able to participate in this study if they have heart failure. Participants will take part in this study for about 9 months. During this time participants will visit the study clinic once a month. A separate PK cohort within this clinical trial will receive open-label study medicine (Ponsegromab/PF-06946860) only. Participants in this open-label, PK cohort will not receive placebo. These participants will receive the study medicine by shots under the skin every four weeks. People may be able to participate in this study cohort if they also have heart failure. Participants will take part in the open-label, PK cohort for about 7 months.

Detailed Description
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The primary purpose of this study is to assess the effect of repeated subcutaneous administration of ponsegromab (PF-06946860) compared to placebo on frequency, severity, and burden of symptoms as well as physical limitations in participants with heart failure and elevated circulating GDF-15 concentrations. The study will also assess the safety, tolerability, PK, PD, and immunogenicity of ponsegromab. A separate, open-label, PK cohort, with more frequent PK and GDF-15 collection after single and multiple subcutaneous administration of ponsegromab (PF-06946860), will be enrolled at certain sites in the United States and Canada to facilitate a more comprehensive assessment of PK characteristics and PK/PD relationship for GDF-15 in participants with heart failure.

Official Title
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A PHASE 2, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 4-ARM STUDY TO INVESTIGATE SYMPTOMS, FUNCTION, HEALTH-RELATED QUALITY OF LIFE AND SAFETY WITH REPEATED SUBCUTANEOUS ADMINISTRATION OF PONSEGROMAB VERSUS PLACEBO IN ADULT PARTICIPANTS WITH HEART FAILURE

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Main cohort: Ponsegromab low dose
* Drug: Main cohort: Ponsegromab medium dose
* Drug: Main cohort: ponsegromab high dose
* Other: Main cohort: Matched placebo
* Drug: Open-label, PK Cohort: ponsegromab low dose
* Drug: Open-label, PK Cohort: ponsegromab medium dose
* Drug: Open-label, PK Cohort: ponsegromab high dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants aged 18 years or older -. Clinical evidence of HF with each of the following criteria: LVEF <50% on most recent measurement, within 12 months of screening. Note: An assessment of LVEF in the prior 12 months is not required in situations where LVEF has been persistently <50% on prior assessments obtained at least 3 months apart (including the most recent measurement). NYHA class II-IV at screening. Main cohort only: NT-proBNP ≥400 pg/mL at screening. Serum GDF-15 concentration ≥2000 pg/mL at screening. Main cohort only: KCCQ-23 CSS <75 at screening. Main cohort only: Evidence of cachexia or fatigue or functional impairment, as demonstrated by at least one of the following at screening: Non-edematous unintentional weight loss ≥5% in the last 6 months or current BMI <20 kg/m2, associated with subjective fatigue or anorexia; or Fatigue at least 3 times per week AND at least moderately bothersome fatigue in the past 2 weeks based on the KCCQ-23 administered at screening; or A score of <60 on the Physical Limitations Domain of the KCCQ 23 administered at screening. Exclusion Criteria: Acute decompensated HF within 1 month prior to Screening Visit 1 or during the screening period. Implantation of a cardiac resynchronization therapy device or valve repair or replacement within 3 months prior to randomization or intent to do so during the trial. For the open-label, PK cohort only: implantation of a cardiac resynchronization therapy device more than 1 month prior to randomization is permitted. History of heart transplantation, currently listed for heart transplant, current/planned mechanical circulatory support, or current/planned use of intravenous inotropes (eg, dobutamine, milrinone). Acute coronary syndrome within 1 month prior to randomization. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) within 3 months prior to randomization or intent to undergo coronary revascularization during the trial. For the open-label, PK cohort only: coronary revascularization more than 1 month prior to randomization is permitted. Untreated indication for an implantable cardiac defibrillator or pacemaker to treat a cardiac rhythm abnormality (ie, tachyarrhythmia or bradyarrhythmia). Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half lives (whichever is longer) preceding the first dose of study intervention used in this study. Treatment with an investigational biologic agent within 6 months or 5 half-lives (whichever is longer) of Day 1. Previous exposure to ponsegromab in a prior clinical study. Renal disease requiring ongoing dialysis. Cirrhosis with evidence of portal hypertension not due to HF, or the following LFT abnormalities at the time of screening, confirmed by a repeat test if deemed necessary: AST or ALT level ≥ 3 x ULN, or total bilirubin level ≥ 2 x ULN (unless history of Gilbert's syndrome).

Ages Eligible for Study
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Minimum Age: 18 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In the main cohort, ponsegromab will be administered at low, medium and high doses every 4 weeks by subcutaneous injections for a total of 6 doses. Participants will be randomized to 1 of the 3 doses of ponsegromab or placebo. In a separate open-label, PK cohort, ponsegromab will be administered at low, medium and high doses every 4 weeks by subcutaneous injections for a total of 4 doses. Participants will be randomized to 1 of the 3 doses of ponsegromab. There is no placebo in the open-label, PK cohort.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Main cohort: ponsegromab low dose<br>Participants will receive a low dose Q4W SC | Drug: Main cohort: Ponsegromab low dose<br>* Ponsegromab low dose subcutaneous injection<br>* Other names: PF-06946860 low dose;|
| Experimental: Main cohort: ponsegromab medium dose<br>Participants will receive a medium dose Q4W SC | Drug: Main cohort: Ponsegromab medium dose<br>* Ponsegromab medium dose subcutaneous injection<br>* Other names: PF-06946860 medium dose;|
| Experimental: Main cohort: ponsegromab high dose<br>Participants will receive a high dose Q4W SC | Drug: Main cohort: ponsegromab high dose<br>* Ponsegromab high dose subcutaneous injection<br>* Other names: PF-06946860 high dose;|
| Placebo Comparator: Main cohort: placebo<br>matched placebo | Other: Main cohort: Matched placebo<br>* Matched placebo subcutaneous injection<br>* Other names: Placebo;|
| Experimental: Open-label, PK Cohort: ponsegromab low dose<br>Participants will receive a low dose Q4W SC | Drug: Open-label, PK Cohort: ponsegromab low dose<br>* ponsegromab low dose subcutaneous injection<br>* Other names: PF-06946860 low dose;|
| Experimental: Open-label, PK Cohort: ponsegromab medium dose<br>Participants will receive a medium dose Q4W SC | Drug: Open-label, PK Cohort: ponsegromab medium dose<br>* Ponsegromab medium dose subcutaneous injection<br>* Other names: PF-06946860 medium dose;|
| Experimental: Open-label, PK Cohort: ponsegromab high dose<br>Participants will receive a high dose Q4W SC | Drug: Open-label, PK Cohort: ponsegromab high dose<br>* Ponsegromab high dose subcutaneous injection<br>* Other names: PF-06946860 high dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main cohort: Change from baseline in Kansas City Cardiomyopathy Questionnaire 23 Clinical Summary Score | To compare the effect of ponsegromab versus placebo, on heart failure disease-specific health status in participants with heart failure | baseline, 22 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main cohort: Change from baseline in Kansas City Cardiomyopathy Questionnaire 23 Overall Summary Score | To compare the effect of ponsegromab versus placebo on HF disease-specific overall health status in participants with HF | baseline, 22 weeks | 
| Main cohort: Change from baseline in Kansas City Cardiomyopathy Questionnaire 23 Total Symptom Score | To compare the effect of ponsegromab versus placebo on HF disease-specific overall health status in participants with HF | baseline, 22 weeks | 
| Main cohort: Change from baseline in Kansas City Cardiomyopathy Questionnaire 23 physical limitations domain | To compare the effect of ponsegromab versus placebo on HF disease-specific overall health status in participants with HF | baseline, 22 weeks | 
| Main cohort: Responses as defined by a ≥5 point increase from baseline in Kansas City Cardiomyopathy Questionnaire 23 Clinical Summary Score | To compare the effect of ponsegromab versus placebo on HF disease-specific health status in participants with HF | baseline, 22 weeks | 
| Main cohort: Responses as defined by a ≥5 point increase from baseline in Overall Summary Score | To compare the effect of ponsegromab versus placebo on HF disease-specific health status in participants with HF | baseline, 22 weeks | 
| Main cohort: Responses as defined by a ≥5 point increase from baseline in Total Symptom Score | To compare the effect of ponsegromab versus placebo on HF disease-specific health status in participants with HF | baseline, 22 weeks | 
| Main cohort: Responses as defined by a ≥5 point increase from baseline in physical limitation | To compare the effect of ponsegromab versus placebo on HF disease-specific health status in participants with HF | baseline, 22 weeks | 
| Main cohort: Change from baseline in 6-Minute Walk Distance | To compare the effect of ponsegromab versus placebo on the physical function of participants with HF | baseline, 22 weeks | 
| Main cohort: Change from baseline in PROMIS-Fatigue 7a which will be completed by study participants on an electronic device, so as to compare the effect of ponsegromab versus placebo on fatigue as reported by participants with HF | To compare the effect of ponsegromab versus placebo on fatigue reported by participants with HF | baseline, 22 weeks | 
| Main cohort: Incidence of treatment-emergent adverse events | To describe the safety and tolerability of ponsegromab in participants with HF | 32 weeks | 
| Main cohort: Incidence of treatment-emergent serious adverse events | To describe the safety and tolerability of ponsegromab in participants with HF | 32 weeks | 
| Main cohort: Incidence of abnormal laboratory results | To describe the safety and tolerability of ponsegromab in participants with HF | 32 weeks | 
| Main cohort: Incidence of abnormal vital signs | To describe the safety and tolerability of ponsegromab in participants with HF | 32 weeks | 
| Open-Label, PK Cohort: Incidence of treatment-emergent adverse events | To describe the safety and tolerability of ponsegromab in participants with HF | 22 weeks | 
| Open-Label, PK Cohort: Incidence of treatment-emergent serious adverse events | To describe the safety and tolerability of ponsegromab in participants with HF | 22 weeks | 
| Open-Label, PK Cohort: Incidence of abnormal laboratory results | To describe the safety and tolerability of ponsegromab in participants with HF | 22 weeks | 
| Open-Label, PK Cohort: Incidence of abnormal vital signs | To describe the safety and tolerability of ponsegromab in participants with HF | 22 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, N-terminal pro-B type natriuretic peptide, Kansas City Cardiomyopathy Questionnaire, Patient's Global Impression of Severity, Patient's Global Impression of Change, Patient Reported Outcome Measurement Information System, Growth differentiation factor 15, New York Heart Association