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

The Alfred

Status and phase: Completed; Phase 2; Phase 1

Conditions: Healthy; Heart Failure

Treatments: Drug: Milrinone 6mg; Drug: milrinone 14mg; Drug: milrinone 10mg ER

Study type: Interventional

Funder types: Other

Identifiers

NCT01849094

DK-MIL-1

Details and patient eligibility

About

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

Enrollment: 9 patients

Sex: Male

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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9 participants in 3 patient groups

Milrinone 6mg

Experimental group

Description:

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.

Treatment:

Drug: milrinone 10mg ER

Drug: milrinone 14mg

Milrinone 10mg ER

Active Comparator group

Description:

single oral dose of 10 mg ER milrinone tablet (Part A) single oral dose of 10 mg ER milrinone tablet (Part B)

Treatment:

Drug: Milrinone 6mg

Drug: milrinone 14mg

Milrinone 14mg

Active Comparator group

Description:

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)

Treatment:

Drug: Milrinone 6mg

Drug: milrinone 14mg