Statins Against Bushfire Smoke (SABS)

Does Short-term or Long-term Statin Use Protect the Heart and Brain During Exposure to Bushfire Smoke? A Parallel-group Statin Trial With Cross-over, Order-randomised Smoke Exposure vs Filtered Air Among Healthy Australian Adults.

The goal of this clinical trial is to test whether statins can protect the heart and brain from the biological stress and inflammatory responses caused by breathing bushfire smoke in healthy adult volunteers aged 18-64 years. The main questions it aims to answer are:

1. Does short-term statin use (2 days) reduce bushfire smoke-induced changes in heart rate variability, blood pressure, arterial stiffness, inflammation and oxidative stress markers, and cognitive function?
2. Does long-term statin use (≥12 months) reduce bushfire smoke-induced changes in heart rate variability, blood pressure, arterial stiffness, inflammation and oxidative stress markers, and cognitive function?

The study includes two streams:

Stream 1:short-term statin use (2 days) where participants receive either statin tablets (80mg atorvastatin) or placebo; Stream 2: long-term statin use (≥12 months) where participants include those already taking statins (≥12 months) with statin-naïve individuals.

Participants will:

• Attend two 3½-hour visits to a Climate Hut, which are approximately 4 weeks apart, where they will spend 2 hours exposed to either filtered air or simulated dilute bushfire smoke (average particulate matter (PM2.5) concentration of 300μg/m^3) in randomised order;
• Have continuous heart monitoring with ECG leads and blood pressure checks every 15 minutes during each visit
• Provide urine, saliva, and nose swab samples before and after each exposure, plus follow-up samples the next morning
• Complete cognitive tests (reaction time, memory tasks) and postural balance measurements during exposure
• Complete questionnaires about anxiety levels, symptoms, diet, and health status
• Have blood samples collected and pulse wave velocity measurements (assessing arterial stiffness) immediately after each exposure session.

Potential risks include time commitment, muscle pain from statins, eye irritation or throat discomfort from smoke exposure, and minor discomfort from blood collection.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy Adults
• Intervention / Treatment: Drug: Atorvastatin; Drug: Placebo

Detailed Description

Background and Rationale:

Climate-driven increases in landscape fire activity are substantially increasing population exposure to air pollution, the most important environmental driver of cardiovascular disease (CVD). The 2019-20 Australian bushfires exposed approximately 80% of the population to increased air pollution for several months, resulting in an estimated 429 excess deaths, 3,230 extra hospitalizations for cardiorespiratory problems, and 1,323 emergency presentations for asthma. Despite strong evidence linking air pollution to adverse cardiovascular outcomes, no intervention has been proven effective against bushfire smoke exposure in individuals. Oxidative stress, inflammation, and autonomic dysregulation are key mechanisms underlying these effects. Statins, beyond their cholesterol-lowering properties, have autonomic stabilizing, anti-inflammatory and antioxidant activity that may protect against cardiovascular impacts of air pollution. However, no clinical trials have tested this hypothesis.

Exposure Methodology:

The study utilizes the Climate Hut, a purpose-built facility at the University of Tasmania that allows controlled manipulation of air quality, temperature and humidity. The facility contains a small internal room with one transparent wall enabling observation and communication. Bushfire smoke is generated from eucalyptus fuel burned in a controlled combustion chamber, then diluted and delivered to maintain an average PM2.5 concentration of 300 μg/m³ during 2-hour exposure sessions. This concentration simulates community exposure during planned burns or bushfires and is comparable to smoke experienced at outdoor events with open fire heating. Filtered air sessions use HEPA filtration to remove particulate matter. Real-time monitoring of PM2.5, temperature, and humidity ensures consistent exposure conditions. Each participant undergoes both exposure conditions in randomized order, separated by ≥3 weeks washout period.

Intervention Protocol:

Stream 1 participants are randomized 1:1 to receive atorvastatin 80mg (supplied as two 40mg tablets) or identical placebo. The investigational product is supplied by SYNTRO Health in individual HDPE bottles containing 8 tablets per participant. Participants take 2 tablets on the morning of the day before each exposure visit and 2 tablets 1-2 hours before each exposure session. Stream 2 intervention group consists of participants who have been taking statin medication (primarily atorvastatin 40mg daily, or alternatives if myalgia occurred) for ≥12 months as part of the CAUGHT-CAD clinical trial or usual clinical care. The comparison group comprises statin-naïve individuals matched for age, sex, and cardiovascular risk profile.

Technical Measurements:

Heart rate variability is assessed through continuous 3-lead ECG monitoring (AMBPPro Research, Machinery Forum Medical Systems) throughout each 2-hour exposure. Time-domain measures (SDNN, RMSSD) and frequency-domain measures are calculated. Blood pressure is measured at 15-minute intervals using oscillometric monitoring. Pulse wave velocity is measured non-invasively using applanation tonometry (SphygmoCor, Atcor Medical) to assess carotid-femoral arterial stiffness pre- and post-exposure. Serum biomarkers including oxidized LDL, C-reactive protein, soluble ICAM-1 and VCAM-1, and serum amyloid A are quantified using multiplex protein assays (Abcam). Exploratory analyses include respiratory tract microbiome composition via 16S rRNA gene sequencing from nasopharyngeal swabs and urinary metabolites of PAH exposure (hydroxynaphthalenes, pyrene carboxylic acid) measured by LC-MS/MS.

Safety Monitoring:

Continuous ECG and regular blood pressure monitoring throughout exposure sessions enable real-time detection of cardiovascular changes. A study cardiologist (Prof Tom Marwick) is on-call for any medical concerns during exposure visits. An independent Medical Monitor (a cardiologist from the local hospital in Hobart) provides oversight of all adverse events. Pre-defined stopping criteria include sustained symptomatic tachycardia, bradycardia, arrhythmias, or blood pressure elevation requiring intervention. Participants are actively monitored for adverse events before, during, and immediately after exposure sessions, with passive collection continuing for 4 weeks post-exposure.

Sample Size and Analysis:

Each stream enrolls 50 participants (25 per treatment arm), providing 80% power to detect moderate effect sizes in the primary outcome (HRV changes) with α=0.05. Linear mixed-effects models will account for the crossover design, with each participant serving as their own control across exposure conditions. The primary comparison tests whether statin treatment modifies the change in HRV between filtered air and smoke exposure.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Study coordinator; Phone Number: +61 8 6226 4875; Email: sabs@utas.edu.au
• Study Contact Backup: Name: Fay Johnston, MD PhD; Phone Number: +61 408 266 652; Email: fayj@utas.edu.au

Study Locations

• Australia
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Menzies Institute for Medical Research
      • Contact: Lieke Scheepers, PhD; Phone Number: +61 8 6226 4875; Email: lieke.scheepers@utas.edu.au
      • Contact: Madeline Carins Murphy, PhD; Email: Madeline.CarinsMurphy@utas.edu.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Good general health and, if aged 45 year or more, low to intermediate (<10%) atherosclerotic cardiovascular disease (ASCVD) risk category, based on clinical data measured within 12 months prior to enrolment.

Exclusion Criteria:

• History of severe chronic lung diseases such as chronic obstructive pulmonary disease or asthma as determined by participants' care providers.
• History of chest pain, irregular heartbeats, heart failure, heart attack, heart pacemaker or coronary bypass surgery.
• High cardiovascular risk (>10%) category on the ASCVD risk calculator or judged to be at high risk by study cardiologist, for those aged 45 years or older.
• History of stroke, dementia or other neurological condition
• Untreated high blood pressure (≥ 140 systolic, ≥ 90 diastolic)
• History of autoimmune or inflammatory rheumatic disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, spondyloarthritis). Osteoarthritis alone is not an exclusion.
• History of immunodeficiency
• Diabetes (any type)
• Current medications: Long term medications that interact with atorvastatin (such as verapamil, digoxin and warfarin); Medications that affect heart rate variability including beta-blockers (such as atenolol, metoprolol, propranolol, and acebutolol), tricyclic antidepressants and selective serotonin reuptake inhibitors (such as amitriptyline, sertraline, fluoxetine or citalopram), or medications with anti-cholinergic action (such as promethazine or prochlorperazine); stimulant medications, such as those prescribed for ADHD (such as methylphenidate, dexamphetamine, lisdexamfetamine); anti-inflammatory, immunosuppressive or immune modulating medications including systemic corticosteroids (such as prednisolone, dexamethasone) and non-steroidal anti-inflammatory drugs (NSAIDS) (such as ibuprofen, naproxen or diclofenac)
• Currently smoking, or have smoked: more than one pack of cigarettes in the past year, or have smoked more than 100 packs of cigarettes in their lifetime
• Currently vaping or have vaped: more than 200 puffs in the last year, more than 20,000 puffs in their lifetime
• Currently pregnant, attempting to become pregnant or breastfeeding
• History of skin allergy to tape or electrodes
• Inability to travel to the study site

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stream 1. Short term atorvastatin; Participants randomly assigned to receive statin (80mg atorvastatin) to be taken in the morning the day before and on the morning of the exposure, 1 to 2 hours before each visit.	Drug: Atorvastatin; Statin treatment is being investigated to see if it will modify subclinical adverse cardiovascular effects of bushfire smoke. Controlled dilute bushfire smoke is delivered on two occasions 4 weeks apart in a specialist facility. It is order randomised and masked.; Other Names: Another class of statin in those who do not tolerate atorvastatin
Placebo Comparator: Stream 1. Short term placebo; Participants randomly assigned to receive placebo tablets identical to the experimental arm, to be taken in the morning the day before and on the morning of the exposure, 1 to 2 hours before each visit.	Drug: Placebo; Identical placebo tablets to the atorvastatin tablets used in the intervention group
Active Comparator: Stream 2. Long term statin treatment; Long-term statin (stream 2): Participants in this study will have been taking a statin medication for at least one year.	Drug: Atorvastatin; Statin treatment is being investigated to see if it will modify subclinical adverse cardiovascular effects of bushfire smoke. Controlled dilute bushfire smoke is delivered on two occasions 4 weeks apart in a specialist facility. It is order randomised and masked.; Other Names: Another class of statin in those who do not tolerate atorvastatin
No Intervention: Stream 2. Statin naïve comparison group; Long-term statin (stream 2): The comparison group will be statin naïve with comparable age gender and cardiovascular risk groupings.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in heart rate variability (HRV) associated with smoke exposure in the groups treated with statins, compared with the groups not treated with statins.	Heart rate variability measured as (1) Standard Deviation of Normal-to-Normal intervals (SDNN) and Root Mean Square of Successive Differences (RMSSD).	HRV is measured on two occasions at least 4 weeks apart, one with 2 hours of smoke exposure and one with 2 hours of filtered air exposure. The measurement is continuous over three hours including the half hour before and after the environmental exposure.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in blood pressure (BP) associated with smoke exposure in the group treated with statins, compared with the group not treated with statins.	Non invasive, ambulant brachial BP is measured using the ABPM-Pro. The first baseline measure is taken a rest with the third of three measures recorded. Thereafter results from a single measurement are recorded every 15 minutes.	BP is measured 15 minutely for 3 hours on two occasions at least 4 weeks apart. Once incorporating 2 hours of smoke exposure and once incorporating 2 hours of filtered air exposure.
Change in aortic vascular stiffness associated with smoke exposure in the group treated with statins, compared with the group not treated with statins.	Aortic vascular stiffness is asses by measuring pulse wave velocity (PWV). PWV from the carotid to the femoral artery is measured with a Sphygmo-cor device using with a carotid tonometer and a femoral BP cuff.	PWV is measured on two occasions at least 4 weeks apart, one immediately following 2 hours of smoke exposure and the other following 2 hours of filtered air exposure.
Difference in Oxidised Low-Density Lipoprotein (oxLDL) Levels Following Clean Air vs. Simulated Bushfire Smoke Exposure in Participants Treated with Statins Compared to Those Not Treated with Statins	Oxidised low-density lipoprotein (oxLDL) is a biomarker of oxidative stress and inflammation. Blood samples will be collected following each 2-hour exposure session (clean air and simulated bushfire smoke) to measure oxLDL levels. Changes in oxLDL between the clean air and simulated bushfire smoke conditions will be compared between participants currently treated with statins and those not treated with statins, to assess whether statin use modifies the oxidative stress response to bushfire smoke exposure.	Following each 2-hour exposure session (clean air and simulated bushfire smoke), with sessions separated by at least 4 weeks.
Difference in High-Sensitivity C-Reactive Protein (hsCRP) Levels Following Clean Air vs. Simulated Bushfire Smoke Exposure in Participants Treated with Statins Compared to Those Not Treated with Statins	High-sensitivity C-reactive protein (hsCRP) is a biomarker of systemic inflammation and oxidative stress. Blood samples will be collected following each 2-hour exposure session (clean air and simulated bushfire smoke) to measure hsCRP levels. Changes in hsCRP between the clean air and simulated bushfire smoke conditions will be compared between participants currently treated with statins and those not treated with statins, to assess whether statin use modifies the inflammatory response to bushfire smoke exposure. The two exposure sessions are separated by a minimum washout period of at least 4 weeks.	Following each 2-hour exposure session (clean air and simulated bushfire smoke), with sessions separated by at least 4 weeks.
Difference in Soluble Intercellular and Vascular Cell Adhesion Molecule Levels (sICAM-1 and sVCAM-1) Following Clean Air vs. Simulated Bushfire Smoke Exposure in Participants Treated with Statins Compared to Those Not Treated with Statins	Soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) are biomarkers of vascular inflammation and endothelial activation. Blood samples will be collected following each 2-hour exposure session (clean air and simulated bushfire smoke) to measure sICAM-1 and sVCAM-1 levels. Changes in these markers between the clean air and simulated bushfire smoke conditions will be compared between participants currently treated with statins and those not treated with statins, to assess whether statin use modifies the vascular inflammatory response to bushfire smoke exposure. The two exposure sessions are separated by a minimum washout period of at least 4 weeks.	Following each 2-hour exposure session (clean air and simulated bushfire smoke), with sessions separated by at least 4 weeks.
Difference in Serum Amyloid A (SAA) Levels Following Clean Air vs. Simulated Bushfire Smoke Exposure in Participants Treated with Statins Compared to Those Not Treated with Statins.	Serum amyloid A (SAA) is a major acute-phase protein and highly sensitive biomarker of inflammation. Blood samples will be collected following each 2-hour exposure session (clean air and simulated bushfire smoke) to measure SAA levels. Changes in SAA between the clean air and simulated bushfire smoke conditions will be compared between participants currently treated with statins and those not treated with statins, to assess whether statin use modifies the acute-phase inflammatory response to bushfire smoke exposure. The two exposure sessions are separated by a minimum washout period of at least 4 weeks.	Following each 2-hour exposure session (clean air and simulated bushfire smoke), with sessions separated by at least 4 weeks
Spatial Working Memory Score as Assessed by the CANTAB Spatial Working Memory Test During Clean Air vs. Simulated Bushfire Smoke Exposure	Spatial working memory will be assessed using the CANTAB Spatial Working Memory (SWM) test, administered on a tablet during the second hour of each 2-hour exposure session. The test requires participants to search through boxes to find hidden tokens, measuring the ability to retain and manipulate spatial information. Outcome metrics include between-errors, strategy scores, and latency. Scores will be compared between the clean air and simulated bushfire smoke exposure sessions	During the second hour of each 2-hour exposure session (clean air and simulated bushfire smoke)
Cognitive Inhibition and Processing Speed Score as Assessed by the Modified Stroop Test During Clean Air vs. Simulated Bushfire Smoke Exposure	Cognitive inhibition and processing speed will be assessed using the modified Stroop test, administered on a laptop during the second hour of each 2-hour exposure session. Participants are required to identify ink colours while suppressing the reading of incongruent colour words. Outcome metrics include response accuracy and reaction time. Scores will be compared between the clean air and simulated bushfire smoke exposure sessions.	During the second hour of each 2-hour exposure session (clean air and simulated bushfire smoke)
Self-Reported Anxiety Score as Assessed by the State-Trait Anxiety Inventory (STAI) During Clean Air vs. Simulated Bushfire Smoke Exposure	Anxiety will be assessed using the State-Trait Anxiety Inventory (STAI), a validated self-report questionnaire completed during the second hour of each 2-hour exposure session. The STAI consists of two 20-item subscales measuring state anxiety (current feelings) and trait anxiety (general tendency). Each item is rated on a 4-point scale, with total scores ranging from 20 to 80 per subscale; higher scores indicate greater anxiety. Scores will be compared between the clean air and simulated bushfire smoke exposure sessions.	During the second hour of each 2-hour exposure session (clean air and simulated bushfire smoke)
Postural Stability as Assessed by a Standing Balance Test (Floor and Foam Surfaces, Eyes Open and Closed) During Clean Air vs. Simulated Bushfire Smoke Exposure	Postural stability will be assessed using a short standing balance test administered during the second hour of each 2-hour exposure session. Participants stand quietly at a comfortable foot width under four conditions: floor with eyes open, floor with eyes closed, foam with eyes open, and foam with eyes closed. Outcome metrics include sway and balance performance scores. Results will be compared between the clean air and simulated bushfire smoke exposure sessions	During the second hour of each 2-hour exposure session (clean air and simulated bushfire smoke)
Symptoms	Short survey (10 minutes) collecting information about muscular, respiratory and general health symptoms.	Collected immediately before and after environmental exposure sessions
Salivary cortisol	1 to 1.8 mls of saliva will be collected using the passive drool method for cortisol assay	Collected before and after each environmental exposure session
Urinary markers of oxidative stress	50ml of urine for measurement of 1-OH-NAP, 2-OH-NAP, and pyrene carboxylic acid	A total of three samples will be collected. Before and after each environmental exposure session and the first void urine the following morning.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nasopharyngeal Microbiome Composition and Diversity as Assessed by 16S rRNA Sequencing of Nasopharyngeal Swabs Before and After Simulated Bushfire Smoke Exposure	Nasopharyngeal swabs will be collected using a COPAN swab placed into eNAT medium and frozen for later sequencing analysis at both exposure visits (clean air and simulated bushfire smoke); however, microbiome analysis will only be performed for the simulated bushfire smoke condition.	Pre-exposure (baseline) and the day following the 2-hour simulated bushfire smoke exposure session.
Previous-Day Dietary Intake as Assessed 24-Hour Dietary Recall (assessed by Food frequency Questionnaire Intake24) During Each Environmental Exposure Visit"	During each 2-hour environmental exposure session (clean air and simulated bushfire smoke), participants will be asked to recall all food and drink consumed in the 24 hours prior to the visit. Dietary data will be collected using Intake24, a validated, self-administered multiple-pass 24-hour dietary recall tool completed on a laptop. The multiple-pass method uses structured prompts to improve accuracy of recall. Intake24 captures food and drink items, portion sizes, and eating occasions, from which nutrient and food group intakes are derived. Dietary data will be used as an exploratory variable to assess whether previous-day dietary intake influences the study outcomes	During each 2-hour environmental exposure session (i.e., clean air and simulated bushfire smoke)"

Collaborators and Investigators

• Sponsor: Menzies Institute for Medical Research
• Investigators: Principal Investigator: Fay Johnston, MD, PhD, Menzies Institute for Medical Research, University of Tasmania; Study Director: Lieke Scheepers, PhD, Menzies Institute for Medical Research; Study Director: Quan Huynh, MD, PhD, Menzies Institute for Medical Research

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: February 27, 2026
• First Submitted That Met QC Criteria: March 5, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 5, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: cognitive function; cardiovascular function; statin; air pollution; inflamation; bushfire smoke; wildfire
• Additional Relevant MeSH Terms: Pemphigus and fogo selvagem; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fatty Acids; Lipids; Azoles; Pyrroles; Heptanoic Acids; Atorvastatin
• Other Study ID Numbers: H40420; 2039822 (Other Grant/Funding Number: Australian National Health and Medical Research Council (NHMRC))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD), including the analyzable dataset, will be made available to other researchers on a case-by-case basis following study completion and publication of primary results. Participant consent to share de-identified data with other investigators is obtained at the time of enrolment.
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years after the publication of results.
• IPD Sharing Access Criteria: Requests for access to de-identified IPD will be considered on a case-by-case basis. Researchers wishing to access the data should contact the principal investigator with a brief description of the proposed analysis. Data sharing will be subject to ethical approval and a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No