A Phase 2 Study of the Effects of Ponsegromab on Health-Related Quality of Life and Safety in Patients With Heart Failure (GARDEN-TIMI 74)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

18 May 2023 → 5 Mar 2025

Decision date (initial)

2024-04-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2023-509747-27-00

EudraCT number

2022-001809-50

ClinicalTrials.gov

NCT05492500

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacogenetic, Pharmacodynamic, Therapy, Pharmacokinetic, Safety

To compare the effect of ponsegromab versus placebo, on HF diseasespecific health status in participants with HF

Secondary objectives 6

1. Main Cohort: • To compare the effect of ponsegromab versus placebo on HF disease-specific overall health status in participants with HF.
2. Main Cohort: • To compare the effect of ponsegromab versus placebo on HF disease-specific health status in participants with HF.
3. Main Cohort: • To compare the effect of ponsegromab versus placebo on the physical function of participants with HF.
4. Main Cohort: • To compare the effect of ponsegromab versus placebo on fatigue reported by participants with HF.
5. Main Cohort: • To describe the safety and tolerability of ponsegromab in participants with HF.
6. Open-Label, PK Cohort • To evaluate the safety and tolerability of ponsegromab in participants with HF and elevated circulating GDF-15 concentrations.

Conditions and MedDRA coding

Heart failure

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. 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.
2. 2. 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.
3. 3. Serum GDF-15 concentration ≥2000 pg/mL at screening.
4. 4. Main cohort only: KCCQ-23 CSS <75 at screening.
5. 5. 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.
6. 6. 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 14

1. 1. Acute decompensated HF within 1 month prior to SV1 or during the screening period.
2. 2. 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.
3. 3. History of heart transplantation, currently listed for heart transplant, current/planned mechanical circulatory support, or current/planned use of intravenous inotropes (eg, dobutamine, milrinone).
4. 4. Acute coronary syndrome within 1 month prior to randomization.
5. 5. 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.
6. 6. Untreated indication for an implantable cardiac defibrillator or pacemaker to treat a cardiac rhythm abnormality (ie, tachyarrhythmia or bradyarrhythmia).
7. 7. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody (IgG protein) or molecules made of components of monoclonal antibody.
8. 8. 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.
9. 9. Current use of any prohibited concomitant medication(s). Refer to Section 6.9 Prior and Concomitant Therapy.
10. 10. 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.
11. 11. Previous exposure to ponsegromab in a prior clinical study.
12. 12. Renal disease requiring ongoing dialysis.
13. 13. 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).
14. 14. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline in KCCQ-23 CSS at Week 22.

Secondary endpoints 6

1. Main Cohort: • Change from baseline in KCCQ-23 OSS, TSS, and physical limitation at Week 22.
2. Main Cohort: • Responses as defined by a ≥5-point increase from baseline in KCCQ-23 CSS, OSS, TSS, and physical limitation at Week 22.
3. Main Cohort: • Change from baseline in 6MWD at Week 22.
4. Main Cohort: • Change from baseline in PROMIS Fatigue 7a at Week 22.
5. Main Cohort: • Incidence of TEAEs, TESAEs, abnormal laboratory results, and vital signs.
6. Open-Label, PK Cohort: • Incidence of TEAEs, TESAEs, abnormal laboratory results, and vital signs.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Michelle Rossulek

Public contact point

Organisation

Pfizer Inc.

Contact name

Michelle Rossulek

Third parties 4

Locations

5 EU/EEA countries · 48 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications