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Trial registered on ANZCTR


Registration number
ACTRN12623000120673
Ethics application status
Approved
Date submitted
27/01/2023
Date registered
3/02/2023
Date last updated
26/05/2024
Date data sharing statement initially provided
3/02/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The Anti-Anginal effect of Zinc in Angina with Non-Obstructive Coronary Arteries (ANOCA) Patients
Scientific title
The Anti-Anginal effect of Zinc in Angina with Non-Obstructive Coronary Arteries (ANOCA) Patients
Secondary ID [1] 308693 0
None
Universal Trial Number (UTN)
Trial acronym
ZIANOCA Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Angina with Non Obstructive Coronary Arteries (ANOCA) 328624 0
Condition category
Condition code
Cardiovascular 325627 325627 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Zinc Tablets - Nature's Own Australia
- Dose - 30mg 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.

Participants will report the angina frequency through an angina diary.
The drug compliance will be assessed through drug tablet return.
Intervention code [1] 325158 0
Treatment: Drugs
Comparator / control treatment
The placebo capsules are identical green Size 000, hard gelatin capsules filled with microcrystalline cellulose. The capsules are packed in HDPE bottles with child-resistant caps and induction sealed for tamper evidence.

Compliance for taking test products will be assessed by asking each patient to return their
product containers and a tablet count performed at each visit.
Control group
Placebo

Outcomes
Primary outcome [1] 333475 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] 333475 0
-End of medication Phase 1 (frequency at the end of 4 weeks)
-End of medication Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [1] 417195 0
Frequency of prolonged angina episodes (episodes > 20 minutes) as recorded in participant angina diary.
Timepoint [1] 417195 0
-End of medication Phase 1 (frequency at the end of 4 weeks)
-End of medication Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [2] 417196 0
Sublingual nitrate consumption as recorded in participant diary.
Timepoint [2] 417196 0
-End of medication Phase 1 (frequency at the end of 4 weeks)
-End of medication Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [3] 417197 0
Angina frequency as assessed by Seattle Angina Questionnaire (SAQ)
Timepoint [3] 417197 0
-End of medication Phase 1 (frequency at the end of 4 weeks)
-End of medication Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [4] 417198 0
Quality of life as assessed by Seattle Angina Questionnaire (SAQ)
Timepoint [4] 417198 0
-End of medication Phase 1 (frequency at the end of 4 weeks)
-End of medication Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [5] 417199 0
Physical limitation as assessed by Seattle Angina Questionnaire (SAQ)
Timepoint [5] 417199 0
-End of medication Phase 1 (frequency at the end of 4 weeks)
-End of medication Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [6] 417200 0
Treatment satisfaction as assessed by Seattle Angina Questionnaire (SAQ)
Timepoint [6] 417200 0
-End of medication Phase 1 (frequency at the end of 4 weeks)
-End of medication Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [7] 417201 0
Quality of life as assessed by EQ 5D
Timepoint [7] 417201 0
-End of medication Phase 1 (frequency at the end of 4 weeks)
-End of medication Phase 2 (frequency at the end of 4 weeks)
Secondary outcome [8] 417202 0
Dietary Zinc intake as measured by DHQ 3
Timepoint [8] 417202 0
At baseline ( expressed as mg/day 12 months prior to administration of the drug)
Secondary outcome [9] 417203 0
Plasma Zinc levels
Timepoint [9] 417203 0
-Start of medication Phase 1 (at the start of the first 4 weeks)
-End of medication Phase 1 (at the end of the first 4 weeks)
-Start of medication Phase 2 (at the start of the second 4 weeks)
-End of medication Phase 2 (at the end of the second 4 weeks)

Eligibility
Key inclusion criteria
For inclusion in the study subjects should fulfill the following criteria:
a) Provision of informed consent prior to any study-specific procedures
b) Female and/or male patients aged 18 years or older
c) Documented angiographic features of the ANOCA as defined by TIMI-2 flow (i.e. requiring equal or more than 3 beats to opacify a major epicardial vessel) in the absence of obstructive CAD (i.e. no epicardial lesion equal or greater than 50%).
d) Chest pain occurring more than or equal to 3 times/week in the preceding two weeks.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a) 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.

b) Secondary causes of angina including:
i. clinically significant anaemia (haemoglobin less than 100g/dL),
ii. uncontrolled atrial fibrillation (i.e. ventricular response rate more than 108 bpm),
iii. haemodynamically significant aortic stenosis (mean valve gradient more than or equal to 40mmHg).

c) Patients with known concomitant disease with life expectance of less than 1 year.
d) Abnormalities in liver function tests (ALT and/or AST more than equal to the upper limit of normal (ULN) or ALP more than or equal to ULN or Bilirubin more than or equal to 1.5 x ULN)
e) Contraindication to any of the study treatments or known or suspected hypersensitivity to Zn.
f) Patients with moderate to severe hepatic impairment
g) Patients with moderate and severe renal failure (defined as a CLCR of less than 50 mL/minute determined using the Cockcroft-Gaul equation or by 24-hour CLCR), including patients undergoing renal dialysis
h) Unwilling, or unable, to give informed consent.
i) Concomitant participation in another clinical trial or research study (except where in the opinion of the Primary Investigator, the participant could benefit from enrolling in another 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)
Statistician from the University of Adelaide will manage the randomization 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)
Simple randomisation using a randomisation table created by computer software (i.e. computerised 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
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Efficacy
Zn’s anti-anginal efficacy will be undertaken by blinded analysis of the angina diary endpoints and other endpoints. The comparison between patients with respect to treatment order will be analyzed utilizing a linear mixed-effects model.

Safety
Frequency and severity of adverse events.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/04/2023
Actual
24/10/2023
Date of last participant enrolment
Anticipated
30/04/2026
Actual
Date of last data collection
Anticipated
1/12/2026
Actual
Sample size
Target
50
Accrual to date
14
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 23769 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 39214 0
5011 - Woodville

Funding & Sponsors
Funding source category [1] 312922 0
Charities/Societies/Foundations
Name [1] 312922 0
The Hospital Research Foundation Group
Country [1] 312922 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] 314757 0
None
Name [1] 314757 0
Address [1] 314757 0
Country [1] 314757 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312194 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 312194 0
The Queen Elizabeth Hospital
Ground Floor, Basil Hetzel Institute
28 Woodville Road
WOODVILLE SOUTH SA 5011
Ethics committee country [1] 312194 0
Australia
Date submitted for ethics approval [1] 312194 0
31/01/2023
Approval date [1] 312194 0
16/05/2023
Ethics approval number [1] 312194 0

Summary
Brief summary
In 30% of patients with angina, angiography does not reveal obstructive coronary artery disease and the myocardial ischaemia may arise from large vessel coronary artery spasm (vasospastic angina) or coronary microvascular dysfunction (microvascular angina). Collectively, these patients are labelled as ANOCA (Angina with Non Obstructive Coronary Arteries) with 1,800 patients/year being afflicted within South Australia. These patients are significantly disabled with an impaired quality of life and have limited available effective therapies, except for calcium channel blockers in vasospastic angina. There is a need to develop novel therapies that effectively target coronary vasomotor dysfunction.

Zinc (Zn), an essential micronutrient, is critical to the functioning of many metalloenzymes and transcription factors. Deficiency of Zn can exacerbate or complicate disease in multiple organ systems. We have demonstrated the importance of Zn homeostasis for the vasculature, including potentiating vasodilator responses via the nitric oxide production and inhibiting endothelin-1-induced constriction. We have recently conducted the first systematic study in Australian cardiac patients, showing a high prevalence of Zn deficiency (29%, n = 400), associated with worse disease.

This study is a randomised, double-blind, placebo-controlled crossover study assessing the anti-anginal benefits and impact on health status of Zn 30mg once daily in ANOCA patients experiencing angina at least 3 times/week.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123806 0
Prof John Beltrame
Address 123806 0
The Queen Elizabeth Hospital
Level 5B
Discipline of Medicine
28 Woodville Road
Woodville South, SA, 5011
Country 123806 0
Australia
Phone 123806 0
+61 8 8222 6740
Fax 123806 0
Email 123806 0
[email protected]
Contact person for public queries
Name 123807 0
Sivabaskari Pasupathy
Address 123807 0
Basil Hetzel Institute
Level 2
37a Woodville Road
Woodville South, South Australia 5011
Country 123807 0
Australia
Phone 123807 0
+61 8 8222 8685
Fax 123807 0
Email 123807 0
[email protected]
Contact person for scientific queries
Name 123808 0
John Beltrame
Address 123808 0
The Queen Elizabeth Hospital
Level 5B
Discipline of Medicine
28 Woodville Road
Woodville South, SA, 5011
Country 123808 0
Australia
Phone 123808 0
+61 8 8222 6740
Fax 123808 0
Email 123808 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17956Study protocol  [email protected]
17957Informed consent form  [email protected]
17958Ethical approval  [email protected]



Results publications and other study-related documents

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