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Trial registered on ANZCTR


Registration number
ACTRN12611000806965
Ethics application status
Approved
Date submitted
1/08/2011
Date registered
1/08/2011
Date last updated
21/07/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Study to find out if the drug “Vessel Dilator” is absorbed from an injection under the skin and, whether it improves heart function in people diagnosed with chronic heart failure and a moderate degree of kidney function loss.
Scientific title
The pharmacokinetics and pharmacodynamics of subcutaneously administered vessel dilator peptide in stable patients with chronic heart failure and moderate renal impairment.
Secondary ID [1] 262739 0
Made02
The Sponsor - Madeleine Pharmaceuticals Pty Ltd.
Universal Trial Number (UTN)
U1111-1123-2828
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Heart Failure 270447 0
Renal Impairment 270467 0
Condition category
Condition code
Cardiovascular 270594 270594 0 0
Other cardiovascular diseases
Renal and Urogenital 270617 270617 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will receive the Study Drug, Vessel Dilator peptide ('VSDL' or Atrial Natriuretic Peptide (ANP)[31-67]).
A lead group of 2 patients will receive a single dose of 250 microgram on day 1 and 500 microgram on Day 2 by subcutaneous bolus. Following review of pharmacokinetic and safety data, a further 6 patients will receive the same doses or up to 2 fold higher if plasma concentrations from the lead group were insufficient to characterise the concentration-time profile.
Intervention code [1] 267086 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 269338 0
Pharmacokinetics of vessel dilator peptide following subcutaneous administration in stable patients with chronic heart failure.
Pharmacokinetic parameters Cmax, Tmax, AUC, CL/F, Vz/F and t1/2 will be determined by standard non-compartmental methods. Cmax and Tmax will be taken directly from the observed data.
Timepoint [1] 269338 0
On each of the two dosing days (Day 1 & Day 2):
Blood samples are taken for VSDL assay at -5 minutes pre dose and post dose at 10, 20, 30, 45, 60 min and at hours 2, 3, 4, 6, 8, 10, 12, 18, 24.
Continuous urine collections for measurements of VSDL assay at 0-6, 6-12 and12-24h are collected.
Primary outcome [2] 269339 0
To assess the tolerability and non-invasive haemodynamics of vessel dilator peptide following subcutaneous administration in stable patients with chronic heart failure.
Timepoint [2] 269339 0
On each of the two dosing days (Day 1 & Day 2):
Non invasive BP, HR, respiratory rate, temperature and pulse oximetry will be assessed (using a Philips Intellivue MP5 Bedside Monitor) pre dose and then every 10 mins for first hour post dose, 15 minutely until 4 hours, 30 minutely to 8 hours, then 2 hourly to 14 hours post dose and again at hour 24 and, approximately 1 week post-dosing.
ECGs will be collected pre dose (within 30 minutes of dose administration) and at hour 24 post dose and, approximately 1 week post-dosing.
Transthoracic echocardiography (using a Philips IE33 machine) will be performed to measure estimated EF% (3D and 2D Simpson's), systolic and diastolic strain estimation (speckle tracking, E/E' and tissue doppler) and estimates of PA pressure (PA acceleration time, TR jet peak velocity) at predose (within 1 hour of dose administration) and at hours 2,4 and 6 post dose on each study day.
NT pro-BNP and Troponin will be assessed at baseline, 24 and 48 hours and, approximately 1 week post-dosing.
Biochemistry and a Full Blood Count will be assessed at hour 6 and hour 24 (including CK-MB) post dose on Day 1 and Day 2 and, approximately 1 week post dosing.
Physical examination will be performed one week after dosing.
Monitoring for Adverse Events, for example, hypotension, at all time-points throughout the study.
Secondary outcome [1] 279408 0
To compare the pharmacokinetic results when the plasma samples are assessed by radio immunoassay compared to LC/MS/MS assay.
Timepoint [1] 279408 0
On each of the two dosing days (Day 1 & Day 2):
Blood samples are taken for VSDL assay at -5 minutes pre dose and post dose at 10, 20, 30, 45, 60 min and at hours 2, 3, 4, 6, 8, 10, 12, 18, 24.
Continuous urine collections for measurements of VSDL assay at 0-6, 6-12 and12-24h are collected.
Secondary outcome [2] 279409 0
To determine whether vessel dilator peptide has effects on renal function as assessed by changes in plasma creatinine and a panel of renal safety biomarkers.
Timepoint [2] 279409 0
On each of the two dosing days (Day 1 & Day 2):
Biochemistry and a Full Blood Count will be assessed at hour 6 and hour 24 (including CK-MB) post dose on Day 1 and Day 2 and, approximately 1 week post dosing.
Continuous urine collections for measurements of urine creatinine, Na+, K+ and renal safety biomarkers (Kidney Injury Molecule -1; Neutrophil Gelatinase Lipocalin) at 0-6, 6-12 and12-24h will be collected. Urine volume will also be recorded to observe for urine volume reduction. Urinalysis and Biomarkers will be assessed at Baseline, 24 hours and, approximately 1 week post dosing.

Eligibility
Key inclusion criteria
1. Patients with a history of stable, symptomatic chronic heart failure, with a left ventricular ejection fraction of less than or equal to 45% measured by echocardiogram or nuclear imaging (measurement within 90 days prior to screening).
2. Signed Informed Consent.
3. Aged 18 years or older.
4. Non-pregnant females, as evidenced by serum pregnancy test at screening and negative urine pregnancy test pre dose at Day 1 (for women of child bearing potential only). Women of child bearing potential must agree to use a medically acceptable method of contraception (as determined by the Investigator) for the entire study duration. Females of non child bearing potential are defined as having amenorrhea for at least 2 years prior to study entry or have been surgically sterilized.
5. GFR greater than or equal to 25 ml/min/1.73m2 and less than 70 ml/min/1.73 m2(MDRD method).
6. Patients on a stable (defined as no alteration to dose/type/frequency within the previous 6 weeks), background therapeutic doses of a beta-blocker, ACE-I or ARB, unless contraindicated and documented as such.
7. Patients on a stable (defined as no alteration to dose/type/frequency within the previous 6 weeks) background therapeutic dose of a diuretic and/or aldosterone receptor inhibitor (e.g. spironolactone) unless contraindicated and documented as such.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Evidence of myocardial infarction (MI) or high risk acute coronary syndrome within past 6 weeks, as determined by creatinine kinase (CK)/creatinine kinase a muscle-brain isoenzyme (CK-MB) greater than or equal to 3 times upper limit of normal (as defined by Institute of Medical and Veterinary Science (IMVS) or elevation of troponin T at baseline >0.1.
2. Evidence of Acute MI (ST elevation and/or elevation of Troponin T), as determined by a 12-lead ECG.
3. Hypotension (Systolic Blood Pressure (SBP)<90 mmHg), cardiogenic shock, volume depletion or any other clinical condition that would contraindicate administration of an agent with potent vasodilatory effects.
4. Persistent, uncontrolled hypertension (SBP>180 mm Hg).
5. Presence of any Cardiac Magnetic Resonance (CMR) contra-indication (includes Permanent Pacemaker (PPM), cerebral aneurysm clips).
6. Congenital heart defects.
7. Cardiac surgery within past 4 weeks
8. Severe valvular heart disease: aortic stenosis (AS), idiopathic hypertrophic subaortic stenosis (IHSS), hypertrophic obstructive cardiomyopathy (HOCM), acute aortic Incompetence (AI) or mitral regurgitation (MR).
9. History of cerebrovascular accident within past 4 weeks.
10. Acute or chronic active infection, including pneumonia and urinary tract infection.
11. Significant renal impairment as determined by a creatinine clearance of <25 ml/min/1.73 m2 (MDRD).
12. Presence of hepatic impairment (defined as ALP, ALT, AST, GGT, Bilirubin >2x ULN) and/or the presence of ascites.
13. Other clinically significant findings on any of the screening laboratory tests, as determined by the Investigator, including but not limited to: hyponatremia, hyperkalaemia, acidosis, anaemia (defined as Hb <9g/dL).
14. Diagnosis of SIADH, Addison’s disease or renal salt wasting disease.
15. Receipt of Investigational Drug within 30 days of screening or current enrolment in a clinical trial.
16. History of clinically significant drug or alcohol abuse within the past 12 months – as judged by the Investigator.
17. History of renal or cardiac transplantation.
18. Insufficient venous access.
19. History of current malignancy or malignancy requiring chemotherapy/radiotherapy within 2 years of enrolment.
20. History of nephrotic syndrome or clinically significant proteinuria.
21. Known history of infection with Hepatitis C, B or HIV.
22. Use of NSAIDS.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients with stable chronic heart failure will be recruited from outpatient cardiology sources, as coordinated by the Principal Investigator.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
The study is a within-patient dose escalation, adaptive design.
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 267575 0
Commercial sector/Industry
Name [1] 267575 0
Madeleine Pharmaceuticals Pty Ltd
Address [1] 267575 0
PO Box 1474
Mount Barker
SA 5251
Country [1] 267575 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Madeleine Pharmaceuticals Pty Ltd
Address
PO Box 1474
Mount Barker
SA 5251
Country
Australia
Secondary sponsor category [1] 266609 0
None
Name [1] 266609 0
Address [1] 266609 0
Country [1] 266609 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 269531 0
Royal Adelaide Hospital Research Ethics Committee
Ethics committee address [1] 269531 0
Level 3, Hanson Institute
Royal Adelaide Hospital
North Terrace
Adelaide
SA 5000
Ethics committee country [1] 269531 0
Australia
Date submitted for ethics approval [1] 269531 0
27/07/2011
Approval date [1] 269531 0
30/09/2011
Ethics approval number [1] 269531 0
110828

Summary
Brief summary
The purpose of this study is to find out if the drug “Vessel Dilator” (VSDL) is absorbed from an injection under the skin and whether it improves heart function in people diagnosed
with stable chronic heart failure and a moderate degree of kidney function loss. additionally, the study will find out if Vessel Dilator has effects on kidney function.
Trial website
Trial related presentations / publications
No trial related citations for this study, not published as yet.
Public notes

Contacts
Principal investigator
Name 32953 0
Prof Stephen Worthley
Address 32953 0
Cardiovascular Investigation Unit Level 6, Theatre Block Royal Adelaide Hospital North Terrace Adelaide SA 5000
Country 32953 0
Australia
Phone 32953 0
+61 8 8222 5608
Fax 32953 0
Email 32953 0
stephen.worthley@adelaide.edu.au
Contact person for public queries
Name 16200 0
Ms Christine Edwards
Address 16200 0
SAHMRI
North Terrace
Adelaide SA 5001
Country 16200 0
Australia
Phone 16200 0
+61 8 8168 4511
Fax 16200 0
+61 8 8128 4004
Email 16200 0
christine.edwards@sahmri.com
Contact person for scientific queries
Name 7128 0
Prof Professor Stephen Worthley
Address 7128 0
Cardiovascular Investigation Unit
Level 6, Theatre Block
Royal Adelaide Hospital
North Terrace
Adelaide
SA 5000
Country 7128 0
Australia
Phone 7128 0
+61 8 8222 5608
Fax 7128 0
+61 8 8222 2454
Email 7128 0
stephen.worthley@adelaide.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary