Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction
- Conditions
- Heart Failure With Preserved Ejection Fraction
- Interventions
- Diagnostic Test: Iohexol measurementDiagnostic Test: EchocardiographyDiagnostic Test: 6-minute walking distance testDiagnostic Test: EndoPATDiagnostic Test: Para-amino Hippuric Acid testDiagnostic Test: Electrocardiogram
- Registration Number
- NCT05672134
- Lead Sponsor
- Amsterdam UMC, location VUmc
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 43
-
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.
- 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
- Not able to undergo the complete study protocol
- Doubt about compliance
- Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control
- Chronic absorption problems
- Proven allergy for lactose products or cow-milk.
- Proven allergy for Iodide-containing contrast, Iohexol or PAH.
- 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
- Currently enrolled in another investigational device or drug trial
- Estimated life expectancy <1 year
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Experimental arm Geranylgeranylacetone (GGA) 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. Experimental arm EndoPAT 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. Experimental arm Electrocardiogram 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. Experimental arm Iohexol measurement 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. Experimental arm 6-minute walking distance test 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. Experimental arm Para-amino Hippuric Acid test 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. Placebo arm EndoPAT 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. Placebo arm Para-amino Hippuric Acid test 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. Experimental arm Echocardiography 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. Placebo arm Iohexol measurement 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. Placebo arm 6-minute walking distance test 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. Placebo arm Electrocardiogram 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. Placebo arm Geranylgeranylacetone (GGA) 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. Placebo arm Echocardiography 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.
- Primary Outcome Measures
Name Time Method Filling pressures after 13 weeks of treatment Changes in echocardiography determined filling pressures (E/e')?
Endothelial function after 13 weeks of treatment Changes in EndoPAT®-derived reactive hyperemia index (RHI)
- Secondary Outcome Measures
Name Time Method Pulmonary Artery Pressure After 13 weeks of treatment Change in echocardiographically determined PAP
Left atrial global strain After 13 weeks of treatment Changes in echogardiographic measured LA global strain (LAGS)
Nitrate (microvascular marker) After 13 weeks of treatment Changes in nitrate concentration in serum
Left Ventricular global longitudinal strain Ater 13 weeks of treatment Changes in echocardiographically determinded LV global longitudinal strain (LGS)
Measured Glomerular Filtration Rate (mGFR) After 13 weeks of treatment Changes in mGFR using Iohexol measurements in urine
Patient reported symptoms After 13 weeks of treatment Evaluation of symptoms using New York Heart Association class (NYHA)
Left atrial volumes After 13 weeks of treatment Changes in echogardiographic measured left atrial volume index (LAVI)
Left atrial emptying fractions After 13 weeks of treatment. Changes in echogardiographic LA emptying fractions. Formula: (LA maximum volume-LA minimum volume)/LA maximum volume × 100%
CRP (inflammatory biomarker) After 13 weeks of treatment Changes in CRP concentration in serum
H2S (microvascular marker) After 13 weeks of treatment Changes in H2S concentration in serum
Urine Albumine Creatinin Ratio After 13 weeks of treatment Changes in UACR concentration measured in urine.
Right Ventricular systolic function After 13 weeks of treatment Change in echocardiographically determined RV TAPSE
Left Ventricular Myocardial relaxation Ater 13 weeks of treatment Change in echocardiographically determined myocardial relaxation (e')
Left Ventricular distensibility After 13 weeks of treatment Change in echocardiographically determined LV distensibility, measured by E.
Quality of life assessment After 13 weeks of treatment. Evaluation of quality of life using the Kansas City Cariomyopathy Questionnaire
Functional capacity After 13 weeks of treatment. Evaluation of Functional Capacity using 6-minute walking distance test (6MWD)
Nitrosated hemoglobin (microvascular marker) After 13 weeks of treatment Changes in Nitrosated hemoglobin (Hb(NO)4) concentration in serum
Endothelin-1 (microvascular marker) After 13 weeks of treatment Changes in Endothelin-1 concentration in serum
Neutrophil gelatinase associated lipocalin (NGAL) After 13 weeks of treatment Changes in NGAL concentration measured in urine and serum
Effective Renal Plasma Flow (ERPF) After 13 weeks of treatment Changes in ERPF using PAH-measurements in urine
Renal vascular resistance (RVR) After 13 weeks of treatment Changes in intrakidney hemodynamic function (Systemic Blood pressure / Renal Blood Flow)
Kidney Injury marker 1 (KIM-1) After 13 weeks of treatment Changes in KIM-1 concentration measured in urine and serum
Trial Locations
- Locations (1)
Amsterdam UMC, loc VUmc
🇳🇱Amsterdam, Noord-Holland, Netherlands