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Trial registered on ANZCTR


Registration number
ACTRN12612000576820
Ethics application status
Approved
Date submitted
25/05/2012
Date registered
29/05/2012
Date last updated
30/09/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
Study to find out if the drug “Vessel Dilator” is absorbed from an infusion under the skin and is safe and tolerated and improves heart function in people diagnosed with stable congestive heart failure and a moderate degree of kidney function loss.
Scientific title
The pharmacokinetics, tolerability and safety of vessel dilator (VSDL) peptide following subcutaneous infusion to steady state in patients with stable congestive heart failure and moderate renal impairment.
Secondary ID [1] 280556 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stable Congestive Heart Failure 286554 0
Renal Impairment 286555 0
Condition category
Condition code
Cardiovascular 286822 286822 0 0
Other cardiovascular diseases
Renal and Urogenital 286823 286823 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-in group of two participants will receive a subcutaneous (SC) infusion for six hours targeting a steady state plasma concentration of VSDL of 10 ng/mL. Following review of the results in the lead-in group, a cohort of eight participants will be infused at the same rate, or a lower or higher infusion rate as determined by the results from the lead-in group, to achieve the same target steady state plasma concentration. Following evaluation of results in the first cohort, a second cohort of eight participants will subsequently be infused subcutaneously with VSDL for six hours at an infusion rate that is targeting a steady state plasma concentration of 20 ng/mL.
Intervention code [1] 284939 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 287188 0
To evaluate the pharmacokinetic characteristics of VSDL during steady state conditions following a six hour subcutaneous infusion
Timepoint [1] 287188 0
Blood samples are taken for quantification of VSDL plasma concentrations at -5 min pre-infusion and at 20, 40, 60, 80, 100 and 120 minutes, and 2.5, 3, 3.5, 4, 4.5, 5, and 6 hours after start of infusion. Following the end of the infusion, pharmacokinetic samples will be taken at 20, 40, 60, 80, 100 and 120 minutes, and 2.5, 3, 3.5, 4, 4.5, 5, 6 and 12 hours after end of infusion.
A spot urine pre-infusion, and continuous urine collections at 0-6, 6-12 and 12-24 hours will be collected for measurements of VSDL.
Secondary outcome [1] 297579 0
To evaluate the tolerability and safety of VSDL.
Timepoint [1] 297579 0
Biochemistry (MBA20) and FBE will be obtained at 6 and 24 hours post dose commencement.
CK-MB and Troponin-T will be measured at 6 and 24 hours post dose commencement.
Plasma NT-proBNP will be measured at 6 and 24 hours post dose commencement.
Serum Cystatin-C at baseline, 6, 12 and 24 hours post dose commencement.
Continuous urine collection will be carried out throughout three collection intervals, 0-6, 6-12 and 12-24 hours. An aliquot of urine will be taken from the total urine volume at the end of each collection interval for the assessment of renal safety biomarkers (KIM1 and NGAL), Na+, K+, creatinine.
Urine volume will be recorded continuously to observe for urine volume reduction.
Urine samples for routine analysis will be taken at 24 hours post dose commencement.
Vital sign assessments (NIBP, HR, respiratory rate, temperature, pulse and pulse oximetry) will be carried out every 10 minutes during the first hour, 15 minutely to 4 hours, 30 minutely to 8 hours, hourly to 12 hours and at 24 hours.
Non invasive cardiac output monitoring using the Cheetah NICOM (Non-Invasive Cardiac Output Monitoring) device will be performed every 10 minutes during the first hour, 15 minutely to 4 hours, 30 minutely to 8 hours, then hourly to 12 hours and at hour 24.
ECGs will be collected at 24 hours.
Non invasive cardiac imaging with transthoracic echocardiography (TTE, either 2D or 3D) at hours 2, 4, 6 and 24 hours post dose commencement.
Renal blood flow will be measured by the clearance of 99Tc-MAG3, which will be administered as an IV injection at 3 hours after start of VSDL infusion. Blood samples will be taken at 5, 10 and 15 minutes, and 1, 2 and 3 hours after administration of 99Tc-MAG3.
Monitoring for Adverse Events, for example hypotension, through self-report and questioning by site staff, at all time-points throughout the study.
Secondary outcome [2] 297580 0
To assess the non-invasive haemodynamics of VSDL
Timepoint [2] 297580 0
Vital sign assessments (NIBP, HR, respiratory rate, temperature, pulse and pulse oximetry) will be carried out every 10 minutes during the first hour, 15 minutely to 4 hours, 30 minutely to 8 hours, hourly to 12 hours and at 24 hours.
Non invasive cardiac output monitoring using the Cheetah NICOM (Non-Invasive Cardiac Output Monitoring) device will be performed every 10 minutes during the first hour, 15 minutely to 4 hours, 30 minutely to 8 hours, then hourly to 12 hours and at hour 24.
Secondary outcome [3] 297581 0
To evaluate whether VSDL has effects on renal function
Timepoint [3] 297581 0
Renal blood flow will be measured by the clearance of 99Tc-MAG3, which will be administered as an IV injection at 3 hours after start of VSDL infusion. Blood samples will be taken at 5, 10 and 15 minutes, and 1, 2 and 3 hours after administration of 99Tc-MAG3.
Continuous urine collection will be carried out throughout three collection intervals, 0-6, 6-12 and 12-24 hours. An aliquot of urine will be taken from the total urine volume at the end of each collection interval for the assessment of renal safety biomarkers (KIM1 and NGAL), Na+, K+, creatinine.
Urine volume will be recorded continuously to observe for urine volume reduction.
Urine samples for routine analysis will be taken at 24 hours post dose commencement.
Secondary outcome [4] 297582 0
To compare plasma concentrations of VSDL quantified with two different assays
Timepoint [4] 297582 0
Plasma concentrations of VSDL shall be compared when quantified via liquid chromatography/tandem mass spectrometry and radioimmunoassay methods. Blood samples are taken for quantification of VSDL plasma concentrations at -5 min pre-infusion and at 20, 40, 60, 80, 100 and 120 minutes, and 2.5, 3, 3.5, 4, 4.5, 5, and 6 hours after start of infusion. Following the end of the infusion, pharmacokinetic samples will be taken at 20, 40, 60, 80, 100 and 120 minutes, and 2.5, 3, 3.5, 4, 4.5, 5, 6 and 12 hours after end of infusion.

Eligibility
Key inclusion criteria
1. A history of stable, symptomatic CHF, with a left ventricular ejection fraction (LVEF) of less than or equal to 45% measured with transthoracic echocardiogram (TTE) or gated blood pool scan, performed 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. Brain Natriuretic Peptide (BNP) greater than or equal to 100 pg/mL
6. GFR greater than or equal to 25 mL/min and less than 70 mL/min as calculated by Cockroft Gault formula
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 evidenced by ST elevation by a 12-lead ECG or by creatine phosphokinase 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 >0.1
2. Evidence of Acute MI (ST elevation and/or elevation of Troponin-T), as determined by a 12-lead ECG and plasma troponin levels
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. Congenital heart defects
6. Cardiac surgery within past 4 weeks
7. Severe valvular heart disease: aortic stenosis (AS), hypertrophic obstructive cardiomyopathy (HOCM), aortic incompetence (AI) or mitral regurgitation (MR)
8. Alteration to dose/type/frequency of background therapeutic doses of a beta-blocker, ACE-I or ARB within the previous six weeks.
9. Alteration to dose/type/frequency of background therapeutic doses of a diuretic and/or aldosterone receptor inhibitor (e.g. spironolactone) within the previous six weeks.
10. History of cerebrovascular accident within past 4 weeks
11. Acute or chronic active infection, including pneumonia and urinary tract infection
12. Significant renal impairment as determined by a GFR of <25 ml/min as calculated with Cockroft Gault formula. All participants will be required to demonstrate a stable GFR pre-dose on Day 1 to ensure that GFR has not fallen below the protocol specified criteria for ongoing enrolment into the study.
13. Presence of hepatic impairment (defined as ALP, ALT, AST, GGT, Bilirubin >2x ULN) and/or the presence of ascites
14. 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)
15. Diagnosis of syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), Addison’s disease or renal salt wasting disease
16. Receipt of Investigational Drug within 30 days of screening or current enrollment in a clinical trial
17. History of clinically significant drug or alcohol abuse within the past 12 months – as judged by the Investigator
18. History of renal or cardiac transplantation
19. Insufficient venous access
20. History of current malignancy or malignancy requiring chemotherapy/radiotherapy within 2 years of enrolment (including any current or past history of prostatic malignancy)
21. History of nephrotic syndrome or clinically significant proteinuria (>1g/24hr)
22. Known history of infection with Hepatitis C, B or Human Immunodeficiency Virus
23. Use of NSAIDS within 24 hours, or five half-lives, whichever is longer, of start of infusion
24. History of chronic migraine (defined as >15 episodes per month)
25. Inability to conform to the conditions of the protocol.

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 congestive heart failure and moderate renal impairment will be recruited from outpatients 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
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] 285319 0
Commercial sector/Industry
Name [1] 285319 0
Madeleine Pharmaceuticals Pty Ltd
Address [1] 285319 0
PO Box 1474
Mount Barker
SA 5251
Country [1] 285319 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] 284176 0
None
Name [1] 284176 0
Address [1] 284176 0
Country [1] 284176 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287339 0
Royal Adelaide Hospital Research Ethics Committee
Ethics committee address [1] 287339 0
Level 3, Hanson Institute
Royal Adelaide Hospital
North Terrace
Adelaide
SA 5000
Ethics committee country [1] 287339 0
Australia
Date submitted for ethics approval [1] 287339 0
Approval date [1] 287339 0
06/03/2012
Ethics approval number [1] 287339 0
111133

Summary
Brief summary
The purpose of the study is to find out if the drug "Vessel Dilator" (VSDL) is absorbed from an infusion under the skin and whether it improves heart function and has an effect on kidney function in people diagnosed with stable congestive heart failure and a moderate degree of kidney function loss
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34225 0
Prof Stephen Worthley
Address 34225 0
Cardiovascular Investigation Unit Level 6, Theatre Block Royal Adelaide Hospital North Terrace Adelaide SA 5000
Country 34225 0
Australia
Phone 34225 0
+61 8 8222 5608
Fax 34225 0
Email 34225 0
stephen.worthley@adelaide.edu.au
Contact person for public queries
Name 17472 0
Ms Christine Edwards
Address 17472 0
Flinders Clinical Research
Box 15
Mark Oliphant Building
Laffer Drive
Science Park
Bedford Park
SA 5042
Country 17472 0
Australia
Phone 17472 0
+61 8 8201 7700
Fax 17472 0
+61 8 8201 7701
Email 17472 0
christine.edwards@sahmri.com
Contact person for scientific queries
Name 8400 0
Prof Professor Stephen Worthley
Address 8400 0
Cardiovascular Investigation Unit
Level 6, Theatre Block
Royal Adelaide Hospital
North Terrace
Adelaide
SA 5000
Country 8400 0
Australia
Phone 8400 0
+61 8 8222 5608
Fax 8400 0
+61 8 8222 2454
Email 8400 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