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Trial registered on ANZCTR


Registration number
ACTRN12618000021279
Ethics application status
Approved
Date submitted
4/12/2017
Date registered
11/01/2018
Date last updated
23/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The anti-anginal effect of Zibotentan in the Coronary Slow Flow Phenomenon (CSFP)
Scientific title
The anti-anginal effects of Zibotentan in patients with the Coronary Slow Flow Phenomenon (CSFP)
Secondary ID [1] 292081 0
None
Universal Trial Number (UTN)
N/A
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Coronary Slow Flow Phenomenon 305719 0
Condition category
Condition code
Cardiovascular 304935 304935 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Zibotentan (ZD4054) (Manufacturer: AstraZeneca)
- Dose - 10mg once daily
- Duration - 8 weeks (4 weeks drug intervention and 4 weeks placebo)
- The mode of administration - oral tablet

Each subject will undergo treatment with Zibotentan and matched placebo for 4 weeks in a computer-generated random order (double-blind, crossover design) giving a total dosing period of 8 weeks. There will be a 2-week washout interval between the two treatment periods.

Patient will report the angina frequency through and angina diary.
The drug compliance will be assessed through drug tablet return.


Intervention code [1] 299764 0
Treatment: Drugs
Comparator / control treatment
The placebo product consists of a beige, plain, round, biconvex, film-coated tablet containing mannitol, microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate and in the film coat hypromellose, titanium dioxide, macrogol 400, iron oxide yellow, iron oxide red and iron oxide black. The placebo tablets contain the same ingredients except the active ingredient.

The drug adherence will be assessed through tablet returns.
Control group
Placebo

Outcomes
Primary outcome [1] 304128 0
Primary endpoint of this study is to assess the angina (chest pain) frequency between the active treatment and placebo.
This will be assessed as a comparison between the Phase 1 and Phase 2 angina diary reported frequency.
Timepoint [1] 304128 0
The chest pain frequency will be calculated using the angina diary. Patient will report the angina in the diary only when it occurs during both phases (Phase 1-4 weeks and Phase 2-4 weeks). Eg: If there is no chest pain during a phase, patient will return an empty diary for that phase. If patient experiences 3 or more chest pain in a day, patient will report each incident in the diary. The chest pain frequency will be compared between 2 phases once completed.

Medication phase 1 : For 4 weeks using the angina diary
Medication phase 2 (cross over) : For 4 weeks using the angina diary
Secondary outcome [1] 341042 0
Sublingual nitrate consumption assessed by angina diary
Timepoint [1] 341042 0
-At baseline (frequency in the 4 week prior to administration of the drug)
-End of Phase 1 (frequency at the end of 4 weeks)
-End of Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [2] 341043 0
Frequency of prolonged angina episodes (ie episodes persisting > 20 minutes) - assessed from patient's self reported angina diary
Timepoint [2] 341043 0
Angina diary is completed every week and frequency compared as below.
-At baseline (frequency in the 4 week prior to administration of the drug)
-End of Phase 1 (frequency at the end of 4 weeks)
-End of Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [3] 341044 0
Angina frequency as assessed by Seattle Angina Questionnaire (SAQ)
Timepoint [3] 341044 0
-At baseline ( frequency in the 4 week prior to administration of the drug)
-End of Phase 1 (frequency at the end of 4 weeks)
-End of Phase 2 ( frequency at the end of 4 weeks)
Secondary outcome [4] 341045 0
Physical health summary scores assessed by Short form 36
Timepoint [4] 341045 0
-At baseline ( frequency in the 4 week prior to administration of the drug)
-End of Phase 1 (frequency at the end of 4 weeks)
-End of Phase 2 ( frequency at the end of 4 weeks)
Secondary outcome [5] 341046 0
Mental Health as scored by the SF-36 mental health summary score.
Timepoint [5] 341046 0
-At baseline ( frequency in the 4 week prior to administration of the drug)
-End of Phase 1 (frequency at the end of 4 weeks)
-End of Phase 2 ( frequency at the end of 4 weeks)
Secondary outcome [6] 341047 0
Plasma levels of ET-1 (blood test)
Timepoint [6] 341047 0
-At baseline (Before the administration of the drug)
-End of Phase 1
-End of Phase 2
Secondary outcome [7] 341048 0
Endothelin polymorphism - The +138 del/ins (-3A/-4A) polymorphism is a genetic variant located 138bp downstream from the transcription site in the 5’ un-translated region from the preproET-1 gene in exon 113. This mutated sequence involves the insertion of an extra adenine nucleotide in the DNA sequence, therefore changing the nucleotide sequence from =AAA’ to =AAAA’ resulting in increased expression of the active ET-1 through enhanced mRNA stability.

DNA samples from patients will be genotyped by real-time polymerase chain reaction (PCR) analysis.
Timepoint [7] 341048 0
At baseline (before the administration of the drug)
Secondary outcome [8] 341049 0
Endothelial nitric oxide synthase (eNOS) gene mutation - A polymorphism of endothelial NO synthase (eNOS) is located on chromosome 7q35-56 and influences NO production.
DNA samples from patients will be genotyped by real-time polymerase chain reaction (PCR) analysis.
Timepoint [8] 341049 0
At baseline (before the administration of the drug)
Secondary outcome [9] 341050 0
Patient medication compliance assessed by asking each patient to return their product containers and a tablet count performed at each visit.
Timepoint [9] 341050 0
-End of Phase 1
-End of Phase 2

Eligibility
Key inclusion criteria
For inclusion in the study subjects should fulfil the following criteria:
I. Provision of informed consent prior to any study specific procedures
II. Female or male patients aged greater than or equal to 18 years
III. Documented angiographic features of coronary slow flow. as de ned by TIMI-2 flow (i.e. requiring more than 3 beats to opacify a major epicardial vessel) in the absence of obstructive coronary artery disease (i.e. no epicardial lesion greater than 50%).
IV. Chest pain occurring more than or equal to 3 times/week in the preceding two weeks.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i. Acute coronary syndrome admission within the preceding month; i.e. hospital admission for prolonged angina pain at rest associated with new ischaemic ECG changes and/or a rise in cardiac troponin level.
ii. Secondary causes of the CSFP including - the no-reflow phenomenon and myocarditis.
iii. Secondary causes of angina including - clinically significant anaemia (haemoglobin lesser than 100g/dL), uncontrolled atrial fibrillation (i.e. ventricular response rate greater than 108 bpm), haemodynamically significant aortic stenosis (estimated mean aortic valve gradient greater than or equal to 40mmHg).
iv. Patients with known concomitant disease with life expectance of less than 1 year.
v. Previous use of endothelin receptor antagonist within 3 months of the study start
vi. Abnormalities in liver function tests (ALT and/or AST greater than or equal to 2 x upper limit of normal (ULN) or ALP greater than or equal to 2 x ULN or Bilirubin greater than or equal to 1.5 x ULN)
vii. Patients with body weight lesser than 40Kg
viii. Contraindication to any of the study treatments or known or suspected hypersensitivity to the investigational product, compounds of the same class, other study treatments or any excipients
ix. Previous history of epilepsy or the other CNS AEs, neurological symptoms or signs consistent with acute or evolving spinal cord compression or CNS metastases.
x. Patients with baseline EF lesser than 40% and/or New York Heart Association class III or IV heart failure
xi. Patients with moderate to severe hepatic impairment
xii. Patients with moderate and severe renal failure (defined as a CLCR of lesser than 50 mL/minute determined using the Cockcroft-Gaul equation or by 24-hour CLCR), including patients undergoing renal dialysis
xiii. QT interval corrected for heart rate (eg, by Bazett’s correction) greater than 450msec for men and greater than 470 msec for women.
xiv. Women of child-bearing potential
xv. Patients with known pregnancy or who are breast-feeding.
xvi. Male study participants who have a female partner of child-bearing potential and who are not willing to comply with requirements for use of contraception for the duration of the study and the specified period after the last dose of study drug.
xvii. Patients with pregnant partners
xviii. Patients with cancer or malignancy.
xix. Current evidence of drug abuse or significant history of drug abuse, as judged by the investigator.
xx. Current evidence of alcohol abuse or a significant history of alcohol abuse, as judged by the investigator.
xxi. Unwilling, or unable, to give informed consent.
xxii. Concomitant participation in another clinical trial or research study

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)
The Pharmacy Unit at the Queen Elizabeth Hospital will manage the randomisation so all Investigators and Participants are blinded throughout the study and analysis period.
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 assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Zibotentan’s anti-anginal efficacy will be undertaken by blinded analysis of the angina diary endpoints. This endpoint is count data and will be performed by comparison between patients with respect to treatment order utilizing Mann-Whitney U tests. Comparisions of the SAQ and SF-36 scores will be made with analysis of variance for repeated samples.
Zibotentan’s anti-anginal efficacy will be undertaken by blinded analysis of the angina diary endpoints. This endpoint is count data and will be performed by comparison between patients with respect to treatment order utilizing Mann-Whitney U tests. Comparisions of the SAQ and SF-36 scores will be made with analysis of variance for repeated samples.

Based upon previous experience, the mean total angina episodes expected in this study population is 28±31 episodes/month. This study showed a 56% reduction in total angina frequency with active study drug. Thus using a crossover study design to detect a 50% change in frequency with Zibotentan, 39 patients would be required for 80% power at alpha =0.05. Accounting for approximately 30% dropouts, 50 will be patients recruited.

Recruitment
Recruitment status
Recruiting
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)
SA
Recruitment hospital [1] 9485 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 18224 0
5011 - Woodville

Funding & Sponsors
Funding source category [1] 296613 0
Commercial sector/Industry
Name [1] 296613 0
AstraZeneca Pty Ltd
Address [1] 296613 0
5 Alma Road
North Ryde NSW 2113
Country [1] 296613 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
University of Adelaide- The Queen Elizabeth Hospital campus Level 5B- Dept of Medicine,
28, Woodville Road
Woodville South
SA 5011
Country
Australia
Secondary sponsor category [1] 295573 0
None
Name [1] 295573 0
Address [1] 295573 0
Country [1] 295573 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297841 0
Human Research Ethics Committee (The Queen Elizabeth Hospital/Lyell McEwin Hospital/Modbury Hospital)
Ethics committee address [1] 297841 0
The Queen Elizabeth Hospital
Basil Hetzel Institute
DX465101
28 Woodville Road
Woodville South SA 5011
Ethics committee country [1] 297841 0
Australia
Date submitted for ethics approval [1] 297841 0
17/03/2017
Approval date [1] 297841 0
24/10/2017
Ethics approval number [1] 297841 0
HREC/17/TQEH/57

Summary
Brief summary
The coronary slow flow phenomenon (CSFP) is a coronary microvascular disorder that was first clinically characterised by University of Adelaide researchers. It is defined using a coronary angiography, a x- ray like procedure where a dye is injected into the heart arteries to investigate the patency of arteries, by delayed dye opacification of the large heart arteries, reflecting the underlying increased microvascular (small arteries) resistance. Studies conducted both at the University and at other sites, have implicated Endothelin-1 (a potent microvascular vasoconstrictor) could explain the CSFP. Basing on the existing evidence, present study investigates, Zibotentan, a potent endothelin-1 receptor blocker, benefits the CSFP patients by reducing angina frequency using a randomized, double-blind, placebo-controlled, cross-over trial design.
Trial website
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 75242 0
Prof John F Beltrame
Address 75242 0
The Queen Elizabeth Hospital
Level 5B
Discipline of Medicine
28 Woodville Road
Woodville South, SA, 5011
Country 75242 0
Australia
Phone 75242 0
+61 8 8222 6740
Fax 75242 0
Email 75242 0
john.beltrame@adelaide.edu.au
Contact person for public queries
Name 75243 0
Dr Sivabaskari Pasupathy
Address 75243 0
The Queen Elizabeth Hospital
Level 5B
Discipline of Medicine
28 Woodville Road
Woodville South, SA, 5011
Country 75243 0
Australia
Phone 75243 0
+61 8 8222 7742
Fax 75243 0
Email 75243 0
sivabaskari.pasupathy@adelaide.edu.au
Contact person for scientific queries
Name 75244 0
Dr Sivabaskari Pasupathy
Address 75244 0
The Queen Elizabeth Hospital
Level 5B
Discipline of Medicine
28 Woodville Road
Woodville South, SA, 5011
Country 75244 0
Australia
Phone 75244 0
+61 8 8222 7742
Fax 75244 0
Email 75244 0
sivabaskari.pasupathy@adelaide.edu.au

No information has been provided regarding IPD availability
How or where can supporting documents be obtained?
Type [1] 2572 0
Ethical approval
Citation [1] 2572 0
Link [1] 2572 0
Email [1] 2572 0
sivabaskari.pasupathy@adelaide.edu.au
Other [1] 2572 0
Attachment [1] 2572 0
Type [2] 2573 0
Study protocol
Citation [2] 2573 0
Link [2] 2573 0
Email [2] 2573 0
sivabaskari.pasupathy@adelaide.edu.au
Other [2] 2573 0
Attachment [2] 2573 0
Summary results
No Results