Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction

NCT05672134 | Completed Phase 2

• 1 other identifier: NL 80684
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this double-blind randomized, placebo-controlled cross-over trial is to evaluate the effectiveness of GerenylGeranylAcetone (GGA) in patients with Heart Failure with a preserved ejection fraction. The main questions it aims to answer are:

• What is the effect of GGA on diastolic function?
• What is the effect of GGA on endothelial function? Main study tasks:
• Participants will be treated with either GGA or placebo for 13 weeks. After this they will have a break (wash-out) period for 6 weeks and then cross over to the other study arm.
• Cardiac function will be measured using echocardiogram in all participants
• Renal measurements and endothelial measurements will be performed on the participants.
• Participants will perform a 5 minute walking distance test for functional capacity.
• Participants will fill out questionnaires to score signs \& symptoms. Researchers will compare the patients to themselves to see if the drug improves diastolic- and endothelial function.

Conditions

Heart Failure With Preserved Ejection Fraction

Outcome Measures

Primary Outcomes (2)

• Filling pressures

  Changes in echocardiography determined filling pressures (E/e')?

  after 13 weeks of treatment

• Endothelial function

  Changes in EndoPAT®-derived reactive hyperemia index (RHI)

  after 13 weeks of treatment

Secondary Outcomes (22)

• Left atrial volumes

  After 13 weeks of treatment

• Left atrial global strain

  After 13 weeks of treatment

• Left atrial emptying fractions

  After 13 weeks of treatment.

• Left Ventricular global longitudinal strain

  Ater 13 weeks of treatment

• Left Ventricular Myocardial relaxation

  Ater 13 weeks of treatment

Other Outcomes (6)

• N-terminal pro Brain Natriuretic Peptide (NT-proBNP)

  After 13 weeks of treatment

• Troponin T

  After 13 weeks of treatment

• Clinical events

  After 13 weeks of treatment

Study Arms (2)

Experimental arm

EXPERIMENTAL

Patients will receive 13 weeks of experimental treatment, followed by a 7 week wash-out period, continuing with 13 weeks of placebo as per crossover design.

Diagnostic Test: Iohexol measurement; Drug: Geranylgeranylacetone (GGA); Diagnostic Test: Echocardiography; Diagnostic Test: 6-minute walking distance test; Diagnostic Test: EndoPAT; Diagnostic Test: Para-amino Hippuric Acid test; Diagnostic Test: Electrocardiogram

Placebo arm

PLACEBO COMPARATOR

Patients will receive 13 weeks of placebo treatment, followed by a 7 week wash-out period, continuing with 13 weeks of experimental treatment as per crossover design.

Diagnostic Test: Iohexol measurement; Drug: Geranylgeranylacetone (GGA); Diagnostic Test: Echocardiography; Diagnostic Test: 6-minute walking distance test; Diagnostic Test: EndoPAT; Diagnostic Test: Para-amino Hippuric Acid test; Diagnostic Test: Electrocardiogram

Interventions

Iohexol measurement DIAGNOSTIC_TEST

Invasive renal hemodynamic measurement of mGFR through the administration of Iohexol.

Experimental arm; Placebo arm

Geranylgeranylacetone (GGA) DRUG

13 weeks of treatment with GGA/placebo orally, followed by a wash-out period of 6 weeks, then reversal of the treatment arms.

Experimental arm; Placebo arm

Echocardiography DIAGNOSTIC_TEST

The investigators will perform echocardiography to find changes in cardiac function.

Experimental arm; Placebo arm

6-minute walking distance test DIAGNOSTIC_TEST

6 minute walking distance test to compare exercise tolerance in participants.

Experimental arm; Placebo arm

EndoPAT DIAGNOSTIC_TEST

Use of EndoPAT to measure endothelial function.

Experimental arm; Placebo arm

Para-amino Hippuric Acid test DIAGNOSTIC_TEST

PAH-measurement to measure ERPF.

Experimental arm; Placebo arm

Electrocardiogram DIAGNOSTIC_TEST

12-lead Electrocardiogram

Experimental arm; Placebo arm

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age≥ 50 years
• Patients with a diagnosis of symptomatic chronic heart failure (New York Heart Association class II or III) AND preserved systolic LV function (LV ejection fraction or LVEF ≥ 50%) documented within the last 6 months AND evidence of diastolic LV dysfunction with at least 1 out of the following 4 criteria:
• HFA-PEFF score ≥5
• H2FPEF score ≥6
• HFpEF according to the 2021 ESC HF Guidelines (NT-proBNP\>125 pg/ml AND either LV mass indexed or LVMI \>95 g/m2 for women and \>115 g/m2 for men OR left atrial volume indexed or LAVI \>34 ml/m2 OR mean e; septal/lateral \< 9 cm/s) OR E/e' \>13 OR TR velocity at rest \>2,8m/s.
• Pulmonary capillary wedge pressure (PCWP) \>15 mmHg and/or \>25 mmHg during exercise.

You may not qualify if:

• Current acute decompensated heart failure, requiring hospitalization or augmented therapy with intravenous diuretics, vasodilators, and/or inotropic drugs
• Acute coronary syndrome, transient ischemic attack/cerebrovascular accident, major surgery within the previous 3 months
• Hemoglobin \<9 g/dl at screening
• LVEF \<40% measured at any time point in the history of the patient
• History of mitral valve repair or replacement
• Presence of significant valvular disease defined as mitral valve regurgitation defined as grade ≥ 3+ MR; tricuspid valve regurgitation defined as grade ≥ 2+ TR; aortic valve disease defined as ≥ 2+ AR or \> moderate AS
• Acute myocarditis within 3 months prior to randomization
• Infiltrative cardiomyopathy
• Genetic cardiomyopathy
• Severe pulmonary disease requiring home oxygen or chronic oral steroid therapy
• Precapillary pulmonary hypertension
• BMI \>40 kg/m2
• Estimated glomerular filtration rate (GFR) \<20 ml/min or \>90 ml/min
• History of solid organ transplantation including kidney transplantation
• Atrial fibrillation or atrial flutter with resting ventricular rate \>110 bpm

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead

Study Sites (1)

Amsterdam UMC, loc VUmc

Amsterdam, North Holland, Netherlands

Location

MeSH Terms

Interventions

geranylgeranylacetone; Echocardiography; Electrocardiography

Intervention Hierarchy (Ancestors)

Cardiac Imaging Techniques; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Ultrasonography; Heart Function Tests; Diagnostic Techniques, Cardiovascular; Electrodiagnosis

Study Officials

• Louis Handoko, MD, PhD

  Amsterdam University Medical Center

  PRINCIPAL INVESTIGATOR

• Adriaan Voors, MD, PhD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

• Loek van Heerebeek, MD, PhD

  Onze Lieve Vrouwe Gasthuis, Amsterdam

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Principal investigator

Model Details: crossover multi-centre, double-blind, randomized control trial.

Study Record Dates

• First Submitted: June 8, 2022
• First Posted: January 5, 2023
• Study Start: April 26, 2023
• Primary Completion: August 30, 2024
• Study Completion: August 30, 2024
• Last Updated: April 1, 2025

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)