Clinical trial NCT06890507: The Anti-Anginal Effects of N-Acetylcysteine (NAC) in Patients with Angina and Non-Obstructive Coronary Arteries (ANOCA)
Official title: The Anti-Anginal Effects of N-Acetylcysteine (NAC) in Patients with Angina and Non-Obstructive Coronary Arteries (ANOCA)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Angina Attacks
Non Obstructive Coronary Artery Disease
Keywords: ANOCA
Angina with Non Obstructive Coronary Arteries
N-acetylcysteine
Lead sponsor: University of Adelaide
Sponsor class: OTHER
First posted: 2025-03-24
Enrollment: 25
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomised, double-blind, placebo-controlled crossover study assessing the anti-anginal effect and impact on health status of NAC 600mg twice daily in patients with ANOCA experiencing angina at least 3 times/week32
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Frequency of angina episodes recorded in angina diary.
timeFrame: 8 weeks (4 weeks of NAC treatment and 4 weeks of placebo treatment)
Secondary outcomes:
measure: Frequency of Short-acting nitrate consumption (i.e., Glyceryl trinitrate (GTN) spray use)
timeFrame: 8 weeks (4 weeks treatment compared to 4 weeks placebo)
measure: Frequency of prolonged angina episodes (ie episodes persisting > 20 minutes)
timeFrame: 8 weeks (4 weeks of NAC treatment and 4 weeks of placebo treatment)
measure: Angina frequency score as assessed by Seattle Angina Questionnaire (SAQ)
timeFrame: End of Phase 1 (Score at the end of 4 weeks) & End of Phase 2 ( Score at the end of 4 weeks)
measure: Angina-related physical limitations score as assessed on Seattle Angina Questionnaire
timeFrame: End of Phase 1 (Score at the end of 4 weeks) & End of Phase 2 ( Score at the end of 4 weeks)
measure: Angina-related quality of life score as assessed on Seattle Angina Questionnaire
timeFrame: End of Phase 1 (Score at the end of 4 weeks) & End of Phase 2 ( Score at the end of 4 weeks)
measure: Patient satisfaction with angina therapy score as assessed on Seattle Angina Questionnaire
timeFrame: End of Phase 1 (Score at the end of 4 weeks) & End of Phase 2 ( Score at the end of 4 weeks)
measure: Overall physical health as assessed by EQ-5D Questionnaire
timeFrame: End of Phase 1 (Score at the end of 4 weeks) & End of Phase 2 ( Score at the end of 4 weeks)
measure: Severity score of angina episodes as assessed on angina diary
timeFrame: 8 weeks (4 weeks of NAC treatment and 4 weeks of placebo treatment)
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
Study officials:
affiliation: University of Adelaide
name: John Beltrame, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Adelaide
name: Sivabaskari Pasupathy, PhD
role: PRINCIPAL_INVESTIGATOR
References: