Evaluating the Safety, Pharmacokinetics and Haemodynamic Effect of a Slow Release Oral Formulation of Milrinone

Study Overview
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Brief Summary
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To determine the pharmacokinetic profile of a new (extended release) formulation of milrinone and to demonstrate evidence of hemodynamic effect Primary: Pharmacokinetic profile - to demonstrate stable plasma levels Secondary (HF cohort) - to demonstrate evidence of haemodynamic benefit Study Design: Open label

Conditions
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Healthy, Heart Failure

Intervention / Treatment
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* Drug: Milrinone 6mg
* Drug: milrinone 10mg ER
* Drug: milrinone 14mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A: Healthy volunteers; Part B: Heart failure patients Inclusion Criteria - Part A Healthy Volunteers Participants must: Provide written informed consent prior to any study procedure and agree to adhere to all protocol requirements Be aged between 18 to 45 years old inclusive at the time of consent Be in good general health without clinically significant medical history Have a body mass index (BMI) between 19- 30 kg/m2 inclusive Documented 12-lead ECG with no clinically significant abnormalities, as determined by the Investigator No clinically significant abnormalities in screening or Day 0 laboratory tests, as determined by the Investigator; Female subjects of reproductive potential must have a negative serum pregnancy (β-HCG) test at screening and a negative urine pregnancy test at Day 0 prior to dosing. Female subjects must also be non-lactating Negative Human Immunodeficiency Virus (HIV), Hepatitis B and Hepatitis C Screening test results Inclusion Criteria - Part B Heart Failure Patients Participants must: Provide written informed consent prior to any study procedure and agree to adhere to all protocol requirements Heart Failure patients with LVEF less than45% NYHA II-III Stable medications (for greater than 48hrs) Systolic BP greater than 90 Exclusion Criteria: Exclusion Criteria - Part A Healthy Volunteers Participants will not be enrolled if they meet any of the following criteria: If female, pregnant or lactating Receipt of any investigational agent or drug within 30 days or 5 half-lives (whichever is longer) prior to the first dose of Investigational product Use of prescription drugs within 4 weeks prior to first dosing. Subjects who have used over the counter medication excluding paracetamol, topical over the counter medications and routine vitamins but including megadose (intake of 20 to 600 times the recommended daily dose) vitamin therapy within 7 days of first dosing, unless agreed as non-clinically relevant by the Principal Investigator No clinically relevant findings in the medical history, laboratory examination and physical examination, especially with regards to cardiovascular system and renal function A positive urine test for drugs of abuse or alcohol at Screening or on the day of admittance to the Study Unit Normal dietary habits Any major surgical procedure within one month of entry into the study Have difficulties communicating reliably with the Investigator or unlikely to co-operate with the requirements of the study. Any other condition which in the view of the Investigator is likely to interfere with study or put the subject at risk. Exclusion Criteria - Part B Heart Failure Patients Unstable heart failure including NYHA IV symptoms Treatment with intravenous inotropes or mechanical circulatory support. Unstable rhythm including frequent non-sustained ventricular tachycardia or poorly controlled atrial fibrillation (ventricular rate >100). Severe renal impairment Cr>200umol/L or dialysis. Life-threatening haematological, hepatic or pulmonary disease.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Milrinone 6mg<br>single oral dose of 6mg ER milrinone tablet (Part A). 1. single intravenous infusion of milrinone (per Alfred Hospital protocol. 50ug/kg loading dose over 15 mins followed by infusion at 0.375 ug/kg/min for 6 hrs) - Part B. | Drug: milrinone 10mg ER<br>* Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements<br>* Other names: Milirone;Drug: milrinone 14mg<br>* Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements<br>* Other names: Milirone;|
| Active Comparator: Milrinone 10mg ER<br>single oral dose of 10 mg ER milrinone tablet (Part A) single oral dose of 10 mg ER milrinone tablet (Part B) | Drug: Milrinone 6mg<br>* Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements<br>Drug: milrinone 14mg<br>* Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements<br>* Other names: Milirone;|
| Active Comparator: Milrinone 14mg<br>single oral dose of 14 mg ER milrinone tablet (Part A) single dose of 14 mg ER milrinone tablet 4. single oral dose of 18 mg ER milrinone tablet (if the group average plasma milrinone levels is less than 150 ug/L with 15 mg dose) - (Part B) | Drug: Milrinone 6mg<br>* Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements<br>Drug: milrinone 14mg<br>* Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements<br>* Other names: Milirone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile - to demonstrate stable plasma levels | Laboratory Analysis: Plasma milrinone concentration | 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Heart Failure cohort) - to demonstrate evidence of haemodynamic benefit | ECG and Blood pressure and HR Monitoring Swan Ganz insertion for haemodynamic measurements (RA volume , RVSP, CO, PA, PAWP) | 6 hours |