Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000619448
Ethics application status
Approved
Date submitted
2/05/2016
Date registered
12/05/2016
Date last updated
17/11/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and Efficacy study of CRD-102 in patients with Heart Failure with Preserved Ejection Fraction
Scientific title
Safety and Efficacy study of CRD-102 in patients with Heart Failure with Preserved Ejection Fraction
Secondary ID [1] 289111 0
Nil
Universal Trial Number (UTN)
Trial acronym
CRD-102 HFPEF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure with Preserved Ejection Fraction 298579 0
Condition category
Condition code
Cardiovascular 298657 298657 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Administration of CRD-102 vs placebo, with a two week placebo run in period.

Day one - all participants will commence oral administration of one placebo capsule, identical in appearance to CRD-102, twice daily for 14 day duration, at which point 1:1 randomisation will occur, 50% of participants will continue to take the placebo capsule twice daily while the other 50% will take one 14mg oral capsule of CRD-102 twice daily (12 hourly) days 15 - 42. The study will run for 43 days (+/-3 days). All empty medication containers will be collected and returned to pharmacy for accountability and to monitor adherence, as well as a participant diary, which will be given to participants to record any missed dosed etc.
Intervention code [1] 294615 0
Treatment: Drugs
Comparator / control treatment
Placebo drug administered - polymer/methylcellulose encapsulated mintabs
Control group
Placebo

Outcomes
Primary outcome [1] 298151 0
-Safety and tolerability of CRD-102, Adverse event monitoring e.g arrhythmia, assessed using 12-lead ECG, Holter monitoring or Internal Cardiac Defibrillator (ICD) checks. Renal function, assessed using serum bloods.
Timepoint [1] 298151 0
Adverse event monitoring Days 1, 15, 29, 43, 12-lead ECG at Baseline, day 15, 29 and 43. Holter monitor (for patients without ICD) at Baseline, Day 29 and 43. ICD check at Baseline and Day 43. laboratory bloods at Screening, Day 1, 15, 29 and 43.
Primary outcome [2] 298176 0
-Change in E/e’ from baseline of patients receiving CRD-102 vs placebo, assessed by Echocardiography.
Timepoint [2] 298176 0
Echocardiography at Screening and Day 43
Secondary outcome [1] 323285 0
Change in symptoms of living with heart failure assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to day 43 in CRD-102 treated patients compared to placebo
Timepoint [1] 323285 0
KCCQ performed at Days 1, 15 and 43.
Secondary outcome [2] 323387 0
Change in functional ability assessed by 6MWT from baseline to day 43 in CRD-102 treated patients compared to placebo
Timepoint [2] 323387 0
6MWT performed at Baseline, Day 1, 29 and 43.
Secondary outcome [3] 323388 0
Change in N terminal BNP levels from baseline to day 43 in CRD-102 treated patients compared to placebo
Timepoint [3] 323388 0
assessed by serum blood sample on Screening Days 1, 29 and 43.
Secondary outcome [4] 323389 0
Change in renal function (eGFR) from baseline to day 43 in CRD-102 treated patients compared to placebo
Timepoint [4] 323389 0
Renal function assessed by serum blood sample on Screening Days 1, 29 and 43.
Secondary outcome [5] 323390 0
Change in ambulatory activity (assessed by actigraphy) from baseline to day 43 in CRD-102 treated patients compared to placebo
Timepoint [5] 323390 0
Actigraphy measured using the 'Active Pal' inclinometer device, for two 14 day periods from day 1 - 14 and again from day 29 - 43 to compare.
Secondary outcome [6] 323391 0
Composite secondary outcome - Change in echocardiographic parameters including lateral E/e’, average E/e’, RVSP, left atrial volume index, left atrial contractility from baseline to day 43 in CRD-102 treated patients compared to placebo
Timepoint [6] 323391 0
Echocardiography at Screening/Baseline and Day 43

Eligibility
Key inclusion criteria
1. Subject is willing and able to provide informed consent
2. Subject is willing and able to comply to all protocol requirements and procedures, including visits
3. Males and Females 18 years of age or older
4. Patients with symptoms of heart failure (NYHA III)
5. LVEF>40% at screening
6. HF Hospitalisation within 12 months or NT-BNP>400pg/mL (in SR) or NT-BNP>600pg/mL (in AF)
7. Septal E/e’>12 and <20
8. Left atrial volume index >28ml/m2
9. Stable medical therapy including diuretics for 2 weeks
If subject is female of childbearing potential, the subject agrees to use an accepted form of contraception throughout the study, including follow-up. (Women who are post-menopausal for at least 2 years or are surgically sterile are not considered to be of childbearing potential.)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subject has had a myocardial infarct (MI) within 90 days before Screening
2. Subject is listed for heart transplant or a LVAD
3. Subject has a systolic blood pressure less than 90 mm Hg at time of screening
4. Subject has undergone cardiac surgery within the 60 days before screening
5. Subject is suspected of having symptoms primarily related to pericardial disease as suggested by relevant imaging or hemodynamic features
6. Subject has a moderate or greater degree of cardiac valvular stenosis or regurgitation
7. Subject has, at screening, clinically significant hepatic disease (serum total bilirubin equal to 3.0 mg/dL [= 51.3 micromol/L]), renal disease (eGFR less than 30 mL/min), or hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease
8. Subject is symptomatically too unwell to be considered for trial, as evidenced by 6MWT less than 150m
9. Symptomatic ventricular arrhythmia or ICD firing within 90 days before screening
10. Poorly controlled atrial fibrillation (resting heart rate greater than 100 bpm)
11. Subjects who are receiving flecainide, encainide, propafenone, dofetilide, or disopyramide up to 2 weeks prior to screening
12. Subjects who have received within 7 days before the Screening or dosing visits:
a. An IV positive inotropic agent
b. A human B-type natriuretic peptide, including nesiritide
c. An oral or IV phosphodiesterase III inhibitor (PDEI III), including levosimendan and cilostazol
13. Subjects who have the following laboratory results at screening
a. Serum potassium concentration less than 4.0 or greater than 5.5 mEq/L
b. Serum magnesium concentration less than 1.0 mEq/L
c. Serum digoxin concentration less than 1.2 ng/mL
14. Female subjects who are pregnant and/or lactating

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Double blinded, randomized controlled trial. Following a single blind placebo run in for 14 days, patients will be randomized on a 1:1 ratio to receive either 14mg bd of CRD-102, or matching placebo capsules. 24 patients will be required to complete the trial, and patients who do not complete the trial will be replaced.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2016
Actual
6/12/2016
Date of last participant enrolment
Anticipated
30/06/2018
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
24
Accrual to date
10
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5705 0
The Alfred - Prahran

Funding & Sponsors
Funding source category [1] 293483 0
Commercial sector/Industry
Name [1] 293483 0
Cardiora pty Ltd
Country [1] 293483 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Cardiora pty Ltd
Address
Level 9, 278 Collins Street
Melbourne, Vic 3000
Australia
Country
Australia
Secondary sponsor category [1] 292304 0
None
Name [1] 292304 0
None
Address [1] 292304 0
None
Country [1] 292304 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294924 0
The Alfred Human Research Ethics Committee
Ethics committee address [1] 294924 0
55 Commercial Rd
Melbourne 3004
Victoria
Ethics committee country [1] 294924 0
Australia
Date submitted for ethics approval [1] 294924 0
18/04/2016
Approval date [1] 294924 0
24/06/2016
Ethics approval number [1] 294924 0
HREC/16/Alfred/45

Summary
Brief summary
Heart failure is a condition where the heart’s pumping cycle does not function as it should. There are two types of heart failure, with about half of patients with the condition falling into each group. One where the pump/contraction function of the heart is reduced. That is called systolic heart failure. In the other type, the heart does not fully relax, so it does not fill properly with blood. This is called diastolic heart failure or “heart failure with normal pump function”. The official medical term is “heart failure with preserved ejection fraction”, and is abbreviated as HFPEF. At the moment, there are no established medical therapies for HFPEF.
Our research has shown that people with HFPEF develop breathlessness very quickly during physical activity because the heart muscle cannot relax normally. In this study we want to test the effect of a medicine, CRD-102, on the pressure in the heart during exercise in HFPEF patients.
The use of CRD-102 tablets in this study is considered experimental. CRD-102 tablets have not been approved for marketing by the Therapeutics Goods Administration (TGA) in Australia. Because of its actions on the heart we hope that it may be helpful in patients with diastolic heart failure.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65506 0
Dr Shane Nanayakkara
Address 65506 0
3rd Floor Philip Block Alfred Hospital
55 Commercial Rd
Melbourne 3004
Victoria
Country 65506 0
Australia
Phone 65506 0
+61 411 355 414
Fax 65506 0
Email 65506 0
nanayakkara@me.com
Contact person for public queries
Name 65507 0
Prof David Kaye
Address 65507 0
3rd Floor Philip Block Alfred Hospital
55 Commercial Rd
Melbourne 3004
Victoria
Country 65507 0
Australia
Phone 65507 0
+61 3 9076 3265
Fax 65507 0
Email 65507 0
David.Kaye@bakeridi.edu.au
Contact person for scientific queries
Name 65508 0
Prof David Kaye
Address 65508 0
3rd Floor Philip Block Alfred Hospital
55 Commercial Rd
Melbourne 3004
Victoria
Country 65508 0
Australia
Phone 65508 0
+61 3 9076 3265
Fax 65508 0
Email 65508 0
David.Kaye@bakeridi.edu.au

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Results publications and other study-related documents

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