Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction

Heart Failure With Preserved Ejection Fraction Clinical Trial

— GLADIATOR  

Official title:

Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT05672134
• Other study ID #: NL 80684
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: April 26, 2023
• Est. completion date: April 26, 2025

Study information

• Verified date: April 2023
• Source: Amsterdam UMC, location VUmc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 40
• Est. completion date: April 26, 2025
• Est. primary completion date: April 26, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction

Intervention

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.
• 6-minute walking distance test
6 minute walking distance test to compare exercise tolerance in participants.
• EndoPAT
Use of EndoPAT to measure endothelial function.
• Para-amino Hippuric Acid test
PAH-measurement to measure ERPF.
• Electrocardiogram
12-lead Electrocardiogram

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC, loc VUmc	Amsterdam	Noord-Holland

Sponsors (1)

Lead Sponsor	Collaborator
Amsterdam UMC, location VUmc

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	N-terminal pro Brain Natriuretic Peptide (NT-proBNP)	Changes in NT-proBNP measured in serum	After 13 weeks of treatment
Other	Troponin T	Changes in Troponin T measured in serum	After 13 weeks of treatment
Other	Clinical events	Comparison of the frequency of a combined safety endpoint of death, myocardial infarction and heart failure hospitalization	After 13 weeks of treatment
Other	Serious Adverse Events (SAE's)	Comparison of the frequency of Serious Adverse Events between both groups.	After 13 weeks of treatment.
Other	Treatment Emergent Adverse Events (TEAE's)	Comparison of the frequency of Treatment Emergent Adverse Events between both groups.	After 13 weeks of treatment.
Other	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
Primary	Filling pressures	Changes in echocardiography determined filling pressures (E/e')?	after 13 weeks of treatment
Primary	Endothelial function	Changes in EndoPAT®-derived reactive hyperemia index (RHI)	after 13 weeks of treatment
Secondary	Left atrial volumes	Changes in echogardiographic measured left atrial volume index (LAVI)	After 13 weeks of treatment
Secondary	Left atrial global strain	Changes in echogardiographic measured LA global strain (LAGS)	After 13 weeks of treatment
Secondary	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.
Secondary	Left Ventricular global longitudinal strain	Changes in echocardiographically determinded LV global longitudinal strain (LGS)	Ater 13 weeks of treatment
Secondary	Left Ventricular Myocardial relaxation	Change in echocardiographically determined myocardial relaxation (e')	Ater 13 weeks of treatment
Secondary	Left Ventricular distensibility	Change in echocardiographically determined LV distensibility, measured by E.	After 13 weeks of treatment
Secondary	Right Ventricular systolic function	Change in echocardiographically determined RV TAPSE	After 13 weeks of treatment
Secondary	Pulmonary Artery Pressure	Change in echocardiographically determined PAP	After 13 weeks of treatment
Secondary	Patient reported symptoms	Evaluation of symptoms using New York Heart Association class (NYHA)	After 13 weeks of treatment
Secondary	Quality of life assessment	Evaluation of quality of life using the Kansas City Cariomyopathy Questionnaire	After 13 weeks of treatment.
Secondary	Functional capacity	Evaluation of Functional Capacity using 6-minute walking distance test (6MWD)	After 13 weeks of treatment.
Secondary	CRP (inflammatory biomarker)	Changes in CRP concentration in serum	After 13 weeks of treatment
Secondary	Nitrosated hemoglobin (microvascular marker)	Changes in Nitrosated hemoglobin (Hb(NO)4) concentration in serum	After 13 weeks of treatment
Secondary	Nitrate (microvascular marker)	Changes in nitrate concentration in serum	After 13 weeks of treatment
Secondary	Endothelin-1 (microvascular marker)	Changes in Endothelin-1 concentration in serum	After 13 weeks of treatment
Secondary	H2S (microvascular marker)	Changes in H2S concentration in serum	After 13 weeks of treatment
Secondary	Measured Glomerular Filtration Rate (mGFR)	Changes in mGFR using Iohexol measurements in urine	After 13 weeks of treatment
Secondary	Effective Renal Plasma Flow (ERPF)	Changes in ERPF using PAH-measurements in urine	After 13 weeks of treatment
Secondary	Renal vascular resistance (RVR)	Changes in intrakidney hemodynamic function (Systemic Blood pressure / Renal Blood Flow)	After 13 weeks of treatment
Secondary	Urine Albumine Creatinin Ratio	Changes in UACR concentration measured in urine.	After 13 weeks of treatment
Secondary	Neutrophil gelatinase associated lipocalin (NGAL)	Changes in NGAL concentration measured in urine and serum	After 13 weeks of treatment
Secondary	Kidney Injury marker 1 (KIM-1)	Changes in KIM-1 concentration measured in urine and serum	After 13 weeks of treatment