Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of Ponsegromab in Adults with Heart Failure
- Trial ID
- 2023-509747-27-00
- Protocol
- C3651011
- Sponsor
- Pfizer Inc.
Trial statistics
Objectives
The primary objective of this study is to compare the effect of **ponsegromab** versus placebo on heart failure (HF) disease-specific health status in participants with HF. This is clinically relevant as it aims to assess the potential therapeutic benefits of ponsegromab in improving the health status of individuals suffering from HF, a condition characterized by the heart's inability to pump sufficient blood to meet the body's needs.
Secondary objectives include:
- Comparing the effect of ponsegromab versus placebo on HF disease-specific overall health status in participants with HF.
- Evaluating the effect of ponsegromab versus placebo on the physical function of participants with HF.
- Assessing the effect of ponsegromab versus placebo on fatigue reported by participants with HF.
- Describing the safety and tolerability of ponsegromab in participants with HF.
- In an open-label, pharmacokinetic cohort, evaluating the safety and tolerability of ponsegromab in participants with HF and elevated circulating GDF-15 concentrations.
Participants
The clinical trial involves a total of **322 participants** diagnosed with **heart failure**. The study population includes both male and female subjects aged 18 years or older, with no upper age limit specified. Participants are required to have a left ventricular ejection fraction (LVEF) of less than 50% and must fall within the New York Heart Association (NYHA) class II-IV at screening. The trial population was selected based on specific clinical evidence of heart failure, including serum GDF-15 concentration of 2000 pg/mL or higher and NT-proBNP levels of 400 pg/mL or more for the main cohort. Additionally, participants must demonstrate evidence of cachexia, fatigue, or functional impairment, as indicated by criteria such as unintentional weight loss, fatigue frequency, or physical limitations. The study includes individuals who are willing and able to comply with all scheduled visits and procedures. The trial does not exclude based on gender, and it includes a vulnerable population. Lifestyle considerations such as diet and physical activity are not explicitly detailed in the available data.
Plans and Procedures
The clinical trial is a **Phase 2**, double-blind, randomized, placebo-controlled study designed to evaluate the effects of **Ponsegromab** on health-related quality of life and safety in adult participants with **heart failure**. The trial involves a four-arm design, with participants receiving either Ponsegromab or a placebo, administered via subcutaneous injection. The study aims to compare the effect of Ponsegromab versus placebo on heart failure disease-specific health status, with the primary endpoint being the change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score (CSS) at Week 22. Secondary endpoints include changes in other KCCQ-23 scores, six-minute walk distance, and PROMIS Fatigue 7a, as well as the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs).
The trial is expected to last until June 2025, with participant recruitment having commenced in September 2022. Participants will be involved in the study for a maximum of 22 weeks, during which they will attend several study visits. The sequence of study visits includes an initial screening visit to assess eligibility based on criteria such as age, clinical evidence of heart failure, and serum GDF-15 concentration. Eligible participants will then be randomized to receive either Ponsegromab or placebo. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, with a final assessment of the primary and secondary endpoints.
Participants may be withdrawn from the study early if they experience significant adverse events, are unable to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is conducted in accordance with ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **Ponsegromab (PF-06946860)**, a humanised IgG1 monoclonal antibody targeting Growth/differentiation factor 15 (GDF15). This investigational medicinal product is provided as a **solution for injection** and is administered via **subcutaneous use**. The maximum daily dose is 300 mg, with a total maximum dose of 300 mg over the treatment period. The treatment duration is set for a maximum of 22 weeks. Ponsegromab is of biological/biotechnological origin and is not classified as an Advanced Therapy Investigational Medicinal Product (ATIMP). The administration schedule and participant compliance are monitored throughout the study to ensure adherence to the dosing regimen.
The study also includes a **placebo** comparator, which is designed to match the Ponsegromab solution for injection in appearance but does not contain the active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered following the same subcutaneous route and dosing schedule as the experimental medication. Compliance with the placebo administration is similarly monitored to maintain the integrity of the study results.
Efficacy
Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the change from baseline in the Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23) Clinical Summary Score (CSS) at Week 22. Secondary endpoints include changes from baseline in the KCCQ-23 Overall Summary Score (OSS), Total Symptom Score (TSS), and physical limitation at Week 22. Additionally, responses will be evaluated based on a ≥5-point increase from baseline in KCCQ-23 CSS, OSS, TSS, and physical limitation at Week 22. Other secondary endpoints include changes from baseline in the 6-Minute Walk Distance (6MWD) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue 7a at Week 22. The incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), abnormal laboratory results, and vital signs will also be monitored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening. a. A female participant is eligible to participate if she is not pregnant or breastfeeding. b. Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants.
- Clinical evidence of HF with each of the following criteria: a. 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). b. NYHA class II-IV at screening. c. 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: a. Non-edematous unintentional weight loss ≥5% in the last 6 months or current BMI <20 kg/m2, associated with subjective fatigue or anorexia; or b. 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 c. A score of <60 on the Physical Limitations Domain of the KCCQ-23 administered at screening.
- Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures (including but not limited to subcutaneous injection of study intervention).
Exclusion Criteria
- Acute decompensated HF within 1 month prior to SV1 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).
- History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody (IgG protein) or molecules made of components of monoclonal antibody.
- Other medical (eg, severe, uncorrected aortic stenosis; active malignancy) or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, may limit life expectancy to less than 1 year and/or make the participant inappropriate for the study.
- Current use of any prohibited concomitant medication(s). Refer to Section 6.9 Prior and Concomitant Therapy.
- 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).
- Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 26 Sept 2022 | 18 |
 Germany | Not Recruiting | 26 Sept 2022 | 14 |
 Hungary | Not Recruiting | 26 Sept 2022 | 36 |
 Poland | Not Recruiting | 26 Sept 2022 | 36 |
 Spain | Not Recruiting | 26 Sept 2022 | 51 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PonsegromabPF-06946860 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 300 | 22 | PRD10975327 |
Placebo for ponsegromab (pf-06946860) solution for injection | Placebo | N/A | — | — | — | N/A |