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Trial registered on ANZCTR


Registration number
ACTRN12619001171101
Ethics application status
Approved
Date submitted
20/05/2019
Date registered
20/08/2019
Date last updated
20/08/2019
Date data sharing statement initially provided
20/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigator Led Study of Intravenous Milrinone in Heart Failure with Preserved Ejection Fraction (HFpEF).
Scientific title
Investigator Led Study to evaluate the effect of IV milrinone on exercise hemodynamics in patients with heart failure.
Secondary ID [1] 298286 0
MilHFpEF-IV-02
Universal Trial Number (UTN)
U1111-1233-7570
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure 312912 0
Condition category
Condition code
Cardiovascular 311405 311405 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 314525 0
Treatment: Drugs
Comparator / control treatment
8 patients will be included in the trial. This will comprise of 6 patients receiving active (IV milrinone), and 2 patients being assigned to receiving placebo. Up to a maximum of 8 patients may be studied. Placebo will be a saline infusion.
Control group
Placebo

Outcomes
Primary outcome [1] 320123 0
Changes compared to baseline (at rest, 20 W and peak supine exercise) in pulmonary capillary wedge pressure (PCWP). This analysis will be conducted utilising a swann ganz catheter during an exercise Right Heart Catheterisation in order to obtain a PCWP and snapshot the PCWP waveform.
Timepoint [1] 320123 0
during exercise RHC (Procedure D1)
Primary outcome [2] 320124 0
Changes compared to baseline (at rest, 20 W and peak supine exercise) in pulmonary artery pressures (mean, systolic, diastolic and pulse pressure) and derived parameters including pulmonary arterial compliance and elastance. These changes in pressures are measured in an exercise right heart cath on procedure day,

This is a composite outcome - the elements of this outcome outlined/broken down here will aid in providing one outcome on pulmonary artery pressures.
Timepoint [2] 320124 0
during exercise RHC (Procedure D1)
Primary outcome [3] 320125 0
Changes compared to baseline (at rest, 20 W and peak supine exercise) in Cardiac Output (thermodilution)
Timepoint [3] 320125 0
during exercise RHC (Procedure D1)
Secondary outcome [1] 370614 0
Safety Endpoint:
• All adverse event (AE) recording and assessments.


Safety will be assessed by recording of AEs, vital signs, laboratory parameters, and physical/cardiovascular examinations.
• Each subject will undergo a complete medical history (including weight measurement) and physical exam prior to randomization to assess their clinical status and to confirm eligibility for study participation. Physical examinations during the study will include height (at Screening only) and weight, and assessment of skin, head, neck, lymphatic, eyes, ears, nose and throat, abdomen, and respiratory, cardiovascular/peripheral vascular, endocrine, central nervous, genitourinary and musculoskeletal systems as appropriate to determine general condition. New or worsening clinically significant abnormalities will be reported as an AE. Post Screening, a symptom-directed PE will be conducted if required, based on prior findings and symptoms.
• A focused cardiovascular exam will be conducted at the study visit by the PI or a designated specialist heart failure cardiologist.
• Subjects will undergo a 12-lead ecg at the study visit.
• Subjects will be questioned and monitored throughout the study with regard to any AEs they may have experienced.


An example of a possible adverse event: while administering or post the IV Mil/Placebo, the patient experiences an arrhythmia or a drop in blood pressure. (no evidence as to this occurring with this drug and no known instances prior).

Another example: post screening for this study but prior to prcoedure day (while patient is enrolled) the patient experiences an exacerbation in their heart failure (shortness of breath, oedema, feelings unwell) and presents to ED for review. The patient stays there for less than 24hrs and is discharged with follow up medical care.
Timepoint [1] 370614 0
Periodic review of adverse events by PI and medical monitor over course of study.
On a monthly/2 monthly basis dependent on patients recruited. This information can be reviewed retrospectively (the patient does not still need to be actively participating in the study to review data queries). This follow up will continue until all patients are recruited.

The screening and procedure day can be on the same day. However, the subject has 28 days from screening to participate in the exercise right heart catheterisation.
Secondary outcome [2] 370615 0
Changes compared to baseline (at rest, 20 W and peak supine exercise) in hemodynamics, including::
• Systemic blood pressure (measured non-invasively using digital BP cuff)
• Peripheral vascular resistance (measured using a swann-ganz catheter during an Ex RHC)
• Heart rate (measured non-invasively usig cardiac monitoring)

This is a composite outcome.
Timepoint [2] 370615 0
during exercise RHC (Procedure D1)

Eligibility
Key inclusion criteria
Inclusion Criteria:
1. Males and females aged 18-85.
2. Symptoms of heart failure (NYHA class III or ambulatory class IV).
3. Left Ventricular Ejection Fraction (LVEF) greater than or equal to 50%.
4. Heart Failure hospitalization within 12 months or NT-proBNP greater than 125 pg/mL.
5. Evidence of prior diagnosis of HFpEF, confirmed via:
• Echocardiographic parameters (one or more of the following) observed//recorded in previous 6 months:
o septal E/e’ greater than or equal to 13 (a measure of LV filling pressure) or
o left atrial volume index greater than 34ml/m2 or
o LV mass index greater than or equal to 115 g/m2 (male) or greater than or equal to 95 g/m2 (female).
or
• Hemodynamic exercise test within 12 months.
6. Stable medical heart failure therapy including diuretics for 2 weeks.
7. Able to give written informed consent and agree to adhere to all protocol requirements.
8. Potassium between 4 – 5.5mmol/L
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria:
1. Myocardial infarction or acute coronary syndromes within 90 days.
2. Hypotension (systolic BP <90 mmHg) at Screening or Baseline
3. Severe Hypertension (systolic BP >180 mmHg) at Screening or Baseline
4. Poorly controlled atrial fibrillation (ventricular rate>120bpm).
5. History of significant ventricular arrhythmia in the past year
6. Significant renal impairment (eGFR <30 ml/min/1.73 m2)
7. Severe physical limitation defined by inability to complete a minimum exercise tolerance time of 120 seconds on two treadmill tests within 2 weeks of enrollment
8. Restrictive or infiltrative cardiomyopathy.
9. Pregnancy
10. History of allergic reaction to milrinone or any excipients in the study drug.
11. Participation in another clinical trial

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation - pharmacy randomisation table utilising envelopes. 6 patients active 2 placebo.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
After Screening, eligible subjects will return for the study day during which they will undergo a right heart catheterization study while receiving a specified dose of iv milrinone or placebo.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
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).
The primary objective is 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.

Changes in variables will be compared using a paired t-test.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
26/08/2019
Actual
Date of last participant enrolment
Anticipated
16/03/2020
Actual
Date of last data collection
Anticipated
29/06/2020
Actual
Sample size
Target
8
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 13805 0
The Alfred - Prahran
Recruitment postcode(s) [1] 26555 0
3004 - Melbourne
Recruitment postcode(s) [2] 26556 0
3004 - Prahran

Funding & Sponsors
Funding source category [1] 302830 0
Hospital
Name [1] 302830 0
Alfred Hospital
Country [1] 302830 0
Australia
Primary sponsor type
Hospital
Name
Alfred Hospital
Address
Level 3 Philip Block, 55 Commercial Road, Prahran, VIC 3004
Country
Australia
Secondary sponsor category [1] 302778 0
None
Name [1] 302778 0
Address [1] 302778 0
Country [1] 302778 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303410 0
Alfred Health HREC
Ethics committee address [1] 303410 0
Ethics committee country [1] 303410 0
Australia
Date submitted for ethics approval [1] 303410 0
15/05/2019
Approval date [1] 303410 0
26/06/2019
Ethics approval number [1] 303410 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 48958 0
A/Prof Justin Mariani
Address 48958 0
Cardiology, Heart Centre,
Level 3 Philip Block, Alfred Hospital, 55 Commercial Road, VIC, 3004
Country 48958 0
Australia
Phone 48958 0
+61 390763263
Fax 48958 0
Email 48958 0
justin.mariani@me.com
Contact person for public queries
Name 48959 0
Eliza Dean
Address 48959 0
Cardiology HF Research, Heart Centre, Level 3, Philip Block, 55 Commercial Road, Alfred Hospital, VIC 3004.
Country 48959 0
Australia
Phone 48959 0
+61 390763040
Fax 48959 0
+61 390762461
Email 48959 0
eliza.dean@alfred.org.au
Contact person for scientific queries
Name 48960 0
Eliza Dean
Address 48960 0
Cardiology HF Research, Heart Centre, Level 3, Philip Block, 55 Commercial Road, Alfred Hospital, VIC 3004.
Country 48960 0
Australia
Phone 48960 0
+61 390763040
Fax 48960 0
+61 390762461
Email 48960 0
eliza.dean@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
In order to protect patient privacy, individualised data will not be available.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
2140Study protocol  hfresearch@alfred.org.au These documents can also be obtained from the loca... [More Details] 366475-(Uploaded-20-05-2019-14-54-26)-Study-related document.docx
4060Informed consent form  hfresearch@alfred.org.au 366475-(Uploaded-15-08-2019-09-56-30)-Study-related document.docx
4061Clinical study report  hfresearch@alfred.org.au This will be available upon conclusion and publica... [More Details]
4062Ethical approval  hfresearch@alfred.org.au 366475-(Uploaded-15-08-2019-09-57-21)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.