Clinical trial NCT05672134: Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction
Official title: Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure With Preserved Ejection Fraction
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
First posted: 2023-01-05
Enrollment: 43
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: crossover multi-centre, double-blind, randomized control trial.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Filling pressures
timeFrame: after 13 weeks of treatment
measure: Endothelial function
timeFrame: after 13 weeks of treatment
Secondary outcomes:
measure: Left atrial volumes
timeFrame: After 13 weeks of treatment
measure: Left atrial global strain
timeFrame: After 13 weeks of treatment
measure: Left atrial emptying fractions
timeFrame: After 13 weeks of treatment.
measure: Left Ventricular global longitudinal strain
timeFrame: Ater 13 weeks of treatment
measure: Left Ventricular Myocardial relaxation
timeFrame: Ater 13 weeks of treatment
measure: Left Ventricular distensibility
timeFrame: After 13 weeks of treatment
measure: Right Ventricular systolic function
timeFrame: After 13 weeks of treatment
measure: Pulmonary Artery Pressure
timeFrame: After 13 weeks of treatment
measure: Patient reported symptoms
timeFrame: After 13 weeks of treatment
measure: Quality of life assessment
timeFrame: After 13 weeks of treatment.
measure: Functional capacity
timeFrame: After 13 weeks of treatment.
measure: CRP (inflammatory biomarker)
timeFrame: After 13 weeks of treatment
measure: Nitrosated hemoglobin (microvascular marker)
timeFrame: After 13 weeks of treatment
measure: Nitrate (microvascular marker)
timeFrame: After 13 weeks of treatment
measure: Endothelin-1 (microvascular marker)
timeFrame: After 13 weeks of treatment
measure: H2S (microvascular marker)
timeFrame: After 13 weeks of treatment
measure: Measured Glomerular Filtration Rate (mGFR)
timeFrame: After 13 weeks of treatment
measure: Effective Renal Plasma Flow (ERPF)
timeFrame: After 13 weeks of treatment
measure: Renal vascular resistance (RVR)
timeFrame: After 13 weeks of treatment
measure: Urine Albumine Creatinin Ratio
timeFrame: After 13 weeks of treatment
measure: Neutrophil gelatinase associated lipocalin (NGAL)
timeFrame: After 13 weeks of treatment
measure: Kidney Injury marker 1 (KIM-1)
timeFrame: After 13 weeks of treatment
Other outcomes:
measure: N-terminal pro Brain Natriuretic Peptide (NT-proBNP)
timeFrame: After 13 weeks of treatment
measure: Troponin T
timeFrame: After 13 weeks of treatment
measure: Clinical events
timeFrame: After 13 weeks of treatment
measure: Serious Adverse Events (SAE's)
timeFrame: After 13 weeks of treatment.
measure: Treatment Emergent Adverse Events (TEAE's)
timeFrame: After 13 weeks of treatment.
measure: Adverse events of specific interest (AESI's)
timeFrame: After 13 weeks of treatment
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, loc VUmc
state: Noord-Holland
Study officials:
affiliation: Amsterdam University Medical Center
name: Louis Handoko, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Groningen
name: Adriaan Voors, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Onze Lieve Vrouwe Gasthuis, Amsterdam
name: Loek van Heerebeek, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: