The Anti-Anginal Effects of N-Acetylcysteine (NAC) in Patients with Angina and Non-Obstructive Coronary Arteries (ANOCA)

NCT ID: NCT06890507

Last Updated: 2025-03-24

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-06-01
• Study Completion Date: 2027-09-01

Brief Summary

The goal of this clinical trial is to determine if N-acetylcysteine (NAC) can reduce angina frequency in women with Angina with Non-Obstructive Coronary Arteries (ANOCA). It will also assess the impact of NAC on health status and quality of life. The main questions it aims to answer are:

(i) Does NAC reduce the number of angina episodes per week? (ii) How does NAC affect quality of life and symptom burden in ANOCA patients? (iii) Does NAC reduce the need for short-acting nitrate use?

Researchers will compare NAC to a placebo in a randomized, double-blind, placebo-controlled crossover study to determine its effectiveness.

Participants will receive treatment with NAC 600mg twice daily for 4 weeks (28 days) and matched placebo for 4 weeks (28 days) in a computer-generated random order giving a total dosing period of 8 weeks. There will be a 2-week washout between the two treatment periods.

The effectiveness of N-Acetylcysteine (NAC) will be assessed using the following measures:

Angina Diary: Participants will record the frequency and severity of their angina episodes.

Seattle Angina Questionnaire-7 (SAQ-7): Participants will complete this questionnaire to assess physical limitations, angina frequency, and quality of life.

EuroQol 5-Dimension (EQ-5D) Questionnaire: Participants will rate their overall health and quality of life.

Detailed Description

Background:

Angina with Non-Obstructive Coronary Arteries (ANOCA) refers to a condition where patients experience chronic angina despite having no significant coronary artery blockages. This condition affects 50-70% of women undergoing elective angiography, in stark contrast to just 7-17% of men. Many experience a prolonged delay in diagnosis, resulting in notable decreases in functional capacity.

NAC has been shown to reduce oxidative stress and potentiate the vasodilatory and antiaggregatory effects of nitrates, potentially reducing microvascular damage and improving myocardial perfusion, hence presenting a promising therapeutic option for ANOCA patients. Although there are no established clinical guidelines for ANOCA management, standard therapy typically includes both long-acting and short-acting nitrates to alleviate anginal symptoms. However, many ANOCA patients continue to experience symptoms despite standard therapy. As such, this trial will assess the beneficial effects of NAC therapy in ANOCA women.

Primary Objectives: To determine the effect of NAC 600mg twice daily on angina frequency in patients with ANOCA who experience angina at least 3 times/week as assessed by an angina diary.

Secondary Objective: The secondary objectives of this study are:

i. To assess the impact of NAC therapy (600mg twice daily) on quality of life/health status, utilising generic (EQ-5D) and disease-specific (SAQ-7) health status instruments to evaluate the following PROMs:

1. Overall physical health (EQ-5D)

2. Angina frequency (SAQ-7)

3. angina-related physical limitations (SAQ-7)

4. angina-related quality of life (SAQ-7)

5. patient satisfaction with angina therapy (SAQ-7) ii. To assess the impact of NAC therapy (600mg twice daily) on angina diary measures including:

a) Short-acting nitrate consumption (i.e., Glyceryl trinitrate (GTN) spray use) b) Duration of angina episodes c) Severity of angina episodes

Safety objectives i. Emergency Department (ED) presentations with Chest pain ii. Hospital admissions with chest pain iii. Major Adverse Coronary Events (MACE) Clinic Assessments: Visit 1: Screening: Screening assessments will be completed within 14 days prior to administration of NAC/Placebo.

• Consent to participate
• Baseline safety bloods (complete blood examination, electrolytes, liver & kidney functions tests, high sensitivity C-reactive protein, ionised calcium)
• Physical Examination
• Vital assessments
• Electrocardiogram (ECG) assessment Week 1 & 2
• Angina Diary Visit 2: Weeks 3-6: Phase 1 study medication period
• Angina Diary
• Health-related questionnaires (SAQ-7, EQ-5D) Visit 3: End of Phase 1 visit
• Angina Diary
• Health-related questionnaires (SAQ-7, EQ-5D) Weeks 7& 8 Wash out Period
• Angina Diary Visit 4: Weeks 9-12 Phase 2 study medication period
• Angina Diary
• Health-related questionnaires (SAQ-7, EQ-5D) Visit 5: End of Phase 2 visit
• Health-related questionnaires (SAQ-7, EQ-5D) Weeks 4,10 & 14 Follow up Phone Contact Duration of Therapy: Patients will receive treatment with NAC 600mg twice daily for 4 weeks (28 days) and matched placebo for 4 weeks (28 days) in a computer-generated random order (double-blind, crossover design) giving a total dosing period of 8 weeks. There will be a 2-week (14 day) washout between the two treatment periods.

Criteria for Evaluation: Angina diary: Results will be considered significant if participants have significantly (p<0.05) reduced features of angina extracted from angina diary during the NAC phase compared to placebo phase.

SAQ-7: Results will be considered significant if participants demonstrate reduced physical limitations & angina frequency and improved quality of life during NAC phase compared to placebo phase.

EQ-5D: Results will be considered significant if participants demonstrate improved quality of life scores during NAC Phase compared to placebo phase.

Statistical Methods: Efficacy Endpoint NAC'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 analysed utilising a linear mixed-effects model.

Safety Endpoint Frequency and severity of adverse events.

Conditions

Angina Attacks; Non Obstructive Coronary Artery Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Oral NAC 600mg (twice daily) Intervention Arm

This arm will assess the effects of oral N-Acetylcysteine (NAC) at a dose of 600mg twice daily in patients with ANOCA. Participants will receive the NAC treatment for a 4-week period.

Group Type: EXPERIMENTAL

N-Acetylcysteine (NAC)

Intervention Type: DRUG

The investigational product for this study is NAC 600 mg capsules. The NAC drug substance is sourced from a Good Manufacturing Practice (GMP)-certified supplier by Syntro Health Pty Ltd and tested on receipt

Placebo 600mg twice daily

This arm will serve as the placebo comparator in the crossover study design. Participants will receive a placebo treatment that is identical in appearance to the NAC medication but contains no active ingredient.The order of treatment (NAC vs placebo) is randomized and participants remain blinded throughout the study.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

To ensure appropriate blinding and to match the physical characteristics of the NAC capsules, the placebo capsules will be filled with dicalcium phosphate (DCP). DCP has been selected over microcrystalline cellulose due to the weight requirements of the NAC formulation.

Interventions

N-Acetylcysteine (NAC)

The investigational product for this study is NAC 600 mg capsules. The NAC drug substance is sourced from a Good Manufacturing Practice (GMP)-certified supplier by Syntro Health Pty Ltd and tested on receipt

Intervention Type: DRUG

Placebo

To ensure appropriate blinding and to match the physical characteristics of the NAC capsules, the placebo capsules will be filled with dicalcium phosphate (DCP). DCP has been selected over microcrystalline cellulose due to the weight requirements of the NAC formulation.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Provision of informed consent prior to any study specific procedures

2. Female patients aged ≥18 years

3. No obstructive CAD (defined as either absence of epicardial lesions with ≥50% luminal narrowing in any coronary artery segment on coronary angiography or normal findings on computed tomography (CT) angiogram, indicating the absence of significant stenosis) to account for chest pain symptoms.

4. Chest pain occurring ≥3 times/week in the preceding two weeks.

Exclusion Criteria

1. Known allergy to NAC or its components.

2. Acute myocardial infarction admission within the preceding month (hospital admission for prolonged angina paint associated with a cardiac troponin level above the 99th percentile, with a subsequent rise or fall).

3. Secondary causes of angina including:

i. clinically significant anaemia (haemoglobin <100g/dL) ii. uncontrolled atrial fibrillation (ventricular response rate >108bpm) iii. haemodynamically significant aortic stenosis (mean valve gradient ≥40mmHg) d) Known concomitant disease with life expectance of less than 1 year. e) Abnormalities in liver function tests suggesting hepatic impairment (ALT and/or AST 2 x upper limit of normal (ULN) or ALP 2 x ULN or Bilirubin 1.5 x ULN) f) Severe renal impairment (eGFR <30mL/min) or on dialysis. g) Pregnancy or lactation. h) Untreated hypertension i) Unwilling, or unable, to give informed consent, including due to severe psychiatric conditions affecting informed consent process or compliance.

j) History of substance abuse. k) Currently taking Chloroquine. l) Serious or unstable medical conditions that may interfere with the study, as determined by the PI.

m) Concomitant participation in another clinical trial or research study (except where in the opinion of the PI, the participant could benefit from enrolling in another trial)

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

University of Adelaide

OTHER

Sponsor Role: lead

Responsible Party

Sivabaskari Pasupathy

Post doctoral Research Fellow

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

John Beltrame, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Adelaide

Sivabaskari Pasupathy, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Adelaide

Locations

The Queen Elizabeth Hospital

Adelaide, South Australia, Australia

Countries

Australia

Central Contacts

Sivabaskari Pasupathy, PhD

Role: CONTACT

sivabaskari.pasupathy@adelaide.edu.au

+6182228685

John Beltrame, PhD

Role: CONTACT

john.beltrame@adelaide.edu.au

+6182226740

Other Identifiers

2025/HRE00080

Identifier Type: -

Identifier Source: org_study_id