Investigator Led Study of Intravenous Milrinone in Heart Failure with Preserved Ejection Fraction (HFpEF).

Study Overview: This is a phase 1b, exploratory study to evaluate the effect of IV milrinone on exercise hemodynamics. This is a double blinded, placebo-controlled investigator led trial. The study cohort will comprise of 8 patients (6 active, 2 placebo). Subjects who are successfully screened will be enrolled into trial. After baseline evaluation on day 1, subjects will be randomly allocated. After the baseline rest and exercise haemodynamic evaluation, subjects will be randomised to receive either active (milrinone) or placebo (saline) infusion. At the conclusion of the infusion, rest and exercise measures will be repeated. Exercise will be conducted at individual matched workloads and durations. The primary objective was to compare the between-group changes in exercise hemodynamics after administration of placebo versus milrinone. Parameters to be evaluated are described in the prior sections. Drug: The product investigated is the approved product, Intravenous Milrinone (Primacor®), the dose being 25 ug/kg. This drug will only be administered on the day of the Exercise Right Heart Cath. This study aims to examine the effects a low dose of intravenous milrinone to determine the concentration/dose vs hemodynamic profile. Exercise Right Heart Cath: Hemodynamic Evaluation: Subjects will undergo right heart catheterisation via the cubital vein or internal jugular vein according to local clinical practice at baseline visit. This procedure will be performed at The Alfred Hospital in a Catheterisation Lab. A senior interventionalist will perform this procedure with the help of a senior clinical research nurse. Right atrial, right ventricular and pulmonary artery and wedge pressures will be measured at gentle held expiration. Thermodilution cardiac output measurement will be performed in triplicate. o Following baseline measures, subjects will supine perform symptom-limited supine cycling at incremental levels of 20 Watts for 3 minutes (exercise will not be performed if the resting Right Heart Cath unexpectedly demonstrates severe pulmonary hypertension PA systolic>60mmHg). The test will be stopped when the patient experiences limiting dyspnoea or other limiting symptoms. Measures will be obtained at rest, 20Watts and peak exercise. o Following initial rest and exercise evaluation, patients will be randomly allocated to receive either a standard loading dose of milrinone (25 ug/kg) over 10 min or placebo. Neither the patient nor the investigator will know which group the subject has been allocated to. o Rest and exercise hemodynamic (as above) will be repeated after a further 10 minutes. • At the designated time point (after 20 minute infusion), blood will be drawn (2 samples) for the measurement of plasma milrinone levels. Blood samples will be collected and stored according to the Study Reference Manual. Milrinone levels (ng/mL) will be determined using liquid chromatography- tandem mass spectrometry (LC/MS/MS) by CPR Pharma Services Pty Ltd, Adelaide, Australia.