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

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

Study Overview

• Status: Completed
• Conditions: Heart Failure; Healthy
• Intervention / Treatment: Drug: milrinone 10mg ER; Drug: milrinone 14mg; Drug: Milrinone 6mg

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Alfred Hospital
    • Melbourne, Victoria, Australia, 3004
      • Nucleus Network

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 41 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Part A: Healthy volunteers; Part B: Heart failure patients Inclusion Criteria - Part A Healthy Volunteers

Participants must:

1. Provide written informed consent prior to any study procedure and agree to adhere to all protocol requirements
2. Be aged between 18 to 45 years old inclusive at the time of consent
3. Be in good general health without clinically significant medical history
4. Have a body mass index (BMI) between 19- 30 kg/m2 inclusive
5. Documented 12-lead ECG with no clinically significant abnormalities, as determined by the Investigator
6. No clinically significant abnormalities in screening or Day 0 laboratory tests, as determined by the Investigator;
7. 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
8. Negative Human Immunodeficiency Virus (HIV), Hepatitis B and Hepatitis C Screening test results

Inclusion Criteria - Part B Heart Failure Patients

Participants must:

1. Provide written informed consent prior to any study procedure and agree to adhere to all protocol requirements
2. Heart Failure patients with LVEF less than45%
3. NYHA II-III
4. Stable medications (for greater than 48hrs)
5. 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:

1. If female, pregnant or lactating
2. 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
3. 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
4. No clinically relevant findings in the medical history, laboratory examination and physical examination, especially with regards to cardiovascular system and renal function
5. A positive urine test for drugs of abuse or alcohol at Screening or on the day of admittance to the Study Unit
6. Normal dietary habits
7. Any major surgical procedure within one month of entry into the study
8. Have difficulties communicating reliably with the Investigator or unlikely to co-operate with the requirements of the study.
9. 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

1. Unstable heart failure including NYHA IV symptoms
2. Treatment with intravenous inotropes or mechanical circulatory support.
3. Unstable rhythm including frequent non-sustained ventricular tachycardia or poorly controlled atrial fibrillation (ventricular rate >100).
4. Severe renal impairment Cr>200umol/L or dialysis.
5. Life-threatening haematological, hepatic or pulmonary disease.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Milrinone 6mg; 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; Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements; Other Names: Milirone; Drug: milrinone 14mg; Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements; Other Names: Milirone
Active Comparator: Milrinone 10mg ER; single oral dose of 10 mg ER milrinone tablet (Part A) single oral dose of 10 mg ER milrinone tablet (Part B)	Drug: milrinone 14mg; Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements; Other Names: Milirone; Drug: Milrinone 6mg; Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements
Active Comparator: Milrinone 14mg; 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 14mg; Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements; Other Names: Milirone; Drug: Milrinone 6mg; Administration of study medications, PK sampling If Part B - add on 6 hour haemodynamic invasive measurements

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The Alfred

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: April 30, 2013
• First Submitted That Met QC Criteria: May 7, 2013
• First Posted (Estimate): May 8, 2013

Study Record Updates

• Last Update Posted (Estimate): January 14, 2015
• Last Update Submitted That Met QC Criteria: January 12, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Milrinone
• Other Study ID Numbers: DK-MIL-1