Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction (GLADIATOR)

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands
      • Amsterdam UMC, loc VUmc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age≥ 50 years

2. 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.

Exclusion Criteria:

1. Current acute decompensated heart failure, requiring hospitalization or augmented therapy with intravenous diuretics, vasodilators, and/or inotropic drugs
2. Acute coronary syndrome, transient ischemic attack/cerebrovascular accident, major surgery within the previous 3 months
3. Hemoglobin <9 g/dl at screening
4. LVEF <40% measured at any time point in the history of the patient
5. History of mitral valve repair or replacement
6. 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
7. Acute myocarditis within 3 months prior to randomization
8. Infiltrative cardiomyopathy
9. Genetic cardiomyopathy
10. Severe pulmonary disease requiring home oxygen or chronic oral steroid therapy
11. Precapillary pulmonary hypertension
12. BMI >40 kg/m2
13. Estimated glomerular filtration rate (GFR) <20 ml/min or >90 ml/min
14. History of solid organ transplantation including kidney transplantation
15. Atrial fibrillation or atrial flutter with resting ventricular rate >110 bpm
16. Not able to undergo the complete study protocol
17. Doubt about compliance
18. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control
19. Chronic absorption problems
20. Proven allergy for lactose products or cow-milk.
21. Proven allergy for Iodide-containing contrast, Iohexol or PAH.
22. Any documented or suspected malignancy or history of malignancy within 1 year prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix
23. Currently enrolled in another investigational device or drug trial
24. Estimated life expectancy <1 year

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental arm; 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; Invasive renal hemodynamic measurement of mGFR through the administration of Iohexol.; Drug: Geranylgeranylacetone (GGA); 13 weeks of treatment with GGA/placebo orally, followed by a wash-out period of 6 weeks, then reversal of the treatment arms.; Diagnostic test: Echocardiography; The investigators will perform echocardiography to find changes in cardiac function.; Diagnostic test: 6-minute walking distance test; 6 minute walking distance test to compare exercise tolerance in participants.; Diagnostic test: EndoPAT; Use of EndoPAT to measure endothelial function.; Diagnostic test: Para-amino Hippuric Acid test; PAH-measurement to measure ERPF.; Diagnostic test: Electrocardiogram; 12-lead Electrocardiogram
Placebo Comparator: Placebo arm; 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; Invasive renal hemodynamic measurement of mGFR through the administration of Iohexol.; Drug: Geranylgeranylacetone (GGA); 13 weeks of treatment with GGA/placebo orally, followed by a wash-out period of 6 weeks, then reversal of the treatment arms.; Diagnostic test: Echocardiography; The investigators will perform echocardiography to find changes in cardiac function.; Diagnostic test: 6-minute walking distance test; 6 minute walking distance test to compare exercise tolerance in participants.; Diagnostic test: EndoPAT; Use of EndoPAT to measure endothelial function.; Diagnostic test: Para-amino Hippuric Acid test; PAH-measurement to measure ERPF.; Diagnostic test: Electrocardiogram; 12-lead Electrocardiogram

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left atrial volumes	Changes in echogardiographic measured left atrial volume index (LAVI)	After 13 weeks of treatment
Left atrial global strain	Changes in echogardiographic measured LA global strain (LAGS)	After 13 weeks of treatment
Left atrial emptying fractions	Changes in echogardiographic LA emptying fractions. Formula: (LA maximum volume-LA minimum volume)/LA maximum volume × 100%	After 13 weeks of treatment.
Left Ventricular global longitudinal strain	Changes in echocardiographically determinded LV global longitudinal strain (LGS)	Ater 13 weeks of treatment
Left Ventricular Myocardial relaxation	Change in echocardiographically determined myocardial relaxation (e')	Ater 13 weeks of treatment
Left Ventricular distensibility	Change in echocardiographically determined LV distensibility, measured by E.	After 13 weeks of treatment
Right Ventricular systolic function	Change in echocardiographically determined RV TAPSE	After 13 weeks of treatment
Pulmonary Artery Pressure	Change in echocardiographically determined PAP	After 13 weeks of treatment
Patient reported symptoms	Evaluation of symptoms using New York Heart Association class (NYHA)	After 13 weeks of treatment
Quality of life assessment	Evaluation of quality of life using the Kansas City Cariomyopathy Questionnaire	After 13 weeks of treatment.
Functional capacity	Evaluation of Functional Capacity using 6-minute walking distance test (6MWD)	After 13 weeks of treatment.
CRP (inflammatory biomarker)	Changes in CRP concentration in serum	After 13 weeks of treatment
Nitrosated hemoglobin (microvascular marker)	Changes in Nitrosated hemoglobin (Hb(NO)4) concentration in serum	After 13 weeks of treatment
Nitrate (microvascular marker)	Changes in nitrate concentration in serum	After 13 weeks of treatment
Endothelin-1 (microvascular marker)	Changes in Endothelin-1 concentration in serum	After 13 weeks of treatment
H2S (microvascular marker)	Changes in H2S concentration in serum	After 13 weeks of treatment
Measured Glomerular Filtration Rate (mGFR)	Changes in mGFR using Iohexol measurements in urine	After 13 weeks of treatment
Effective Renal Plasma Flow (ERPF)	Changes in ERPF using PAH-measurements in urine	After 13 weeks of treatment
Renal vascular resistance (RVR)	Changes in intrakidney hemodynamic function (Systemic Blood pressure / Renal Blood Flow)	After 13 weeks of treatment
Urine Albumine Creatinin Ratio	Changes in UACR concentration measured in urine.	After 13 weeks of treatment
Neutrophil gelatinase associated lipocalin (NGAL)	Changes in NGAL concentration measured in urine and serum	After 13 weeks of treatment
Kidney Injury marker 1 (KIM-1)	Changes in KIM-1 concentration measured in urine and serum	After 13 weeks of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
N-terminal pro Brain Natriuretic Peptide (NT-proBNP)	Changes in NT-proBNP measured in serum	After 13 weeks of treatment
Troponin T	Changes in Troponin T measured in serum	After 13 weeks of treatment
Clinical events	Comparison of the frequency of a combined safety endpoint of death, myocardial infarction and heart failure hospitalization	After 13 weeks of treatment
Serious Adverse Events (SAE's)	Comparison of the frequency of Serious Adverse Events between both groups.	After 13 weeks of treatment.
Treatment Emergent Adverse Events (TEAE's)	Comparison of the frequency of Treatment Emergent Adverse Events between both groups.	After 13 weeks of treatment.
Adverse events of specific interest (AESI's)	Comparison of the frequency of Adverse events of specific interest between both groups.	After 13 weeks of treatment

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: Adriaan Voors, MD, PhD, University Medical Center Groningen; Principal Investigator: Loek van Heerebeek, MD, PhD, Onze Lieve Vrouwe Gasthuis, Amsterdam; Principal Investigator: Louis Handoko, MD, PhD, Amsterdam University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2023
• Primary Completion (Actual): August 30, 2024
• Study Completion (Actual): August 30, 2024

Study Registration Dates

• First Submitted: June 8, 2022
• First Submitted That Met QC Criteria: January 2, 2023
• First Posted (Actual): January 5, 2023

Study Record Updates

• Last Update Posted (Actual): April 1, 2025
• Last Update Submitted That Met QC Criteria: March 26, 2025
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Antineoplastic Agents; Gastrointestinal Agents; Anti-Ulcer Agents; Geranylgeranylacetone
• Other Study ID Numbers: NL 80684

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No