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

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.

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.

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)