In-Bedroom Renewed Air as Anti-inflammatory Adjuvant Therapy in Cancer Survivors (BREATHS)
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About
The BREATHS trial aims to investigate whether overnight in-bedroom air filtration reduces inflammation and cardiac biomarkers in adult survivors of cancer who are at high risk for cardiovascular complications.
The study consists of individualized experiments (N-of-1 trials) conducted in the home settings of adults residing in densely populated urban areas with the most severe air quality levels in Valencia, Spain, where fine particulate matter (PM2.5) and nitrogen dioxide levels exceed the limits set by the World Health Organization (WHO) and EU Directive.
Participants will be exposed to 3 treatment sets (blinded phase), each consisting of a 14-day period of filtered air using a portable air filtration unit ("true-HyperHepa) and a 14-day period of unfiltered air (using the same portable unit with "sham filters"). The intervention will be administered nightly for a minimum of 7 consecutive hours and will last between 4 and 12 weeks for each participant, contingent upon the demonstration of clinical benefit, defined by a reduction in the levels of the blood biomarker C-reactive protein. An unblinded phase will be implemented for participants who do not experience a clinically meaningful change in CRP. During this phase, they will undergo a 14-day period without treatment, followed by 14-day period of both nightly and daily filtered air therapy.
The primary endpoint of this study is defined as the change in blood concentrations of CRP. The secondary endpoints include the changes in levels of three other noninvasive blood biomarkers associated with inflammation and cardiovascular health, and blood pressure.
Both indoor and outdoor fine particulate matter (PM2.5) exposure concentrations will be continuously monitored in the study.
Full description
Background. Inflammation, a common result of anticancer therapies, correlates with poor survival and cardiovascular issues in cancer survivors. High levels of C-reactive protein (CRP), D-dimer, and serum amyloid A (SAA) indicate cancer recurrence, mortality, and cardiotoxicity. CRP-lowering clinical trials have proven that the magnitude of the reduction in cardiac events in patients with residual inflammatory risk is directly proportional to the achieved reduction in CRP, with the greatest benefit in those achieving a threshold below than 2 milligrams per litre (mg/L).
Cancer survivors may benefit from non-pharmacological anti-inflammatory treatments that do not exacerbate cardiotoxicity burden. Evidence suggests the air purifiers lower inflammatory biomarkers in high-risk cardiovascular groups. Air filtration presents a promising alternative to inflammation-inhibiting drugs, but its anti-inflammatory and cardioprotective effects in cancer survivors and interactions with medications remain unclear.
Design, setting and participants. A series of N-of-1 randomised, adaptive, blinded, placebo-controlled trials will be conducted at the home sitting of community-dwelling cancer survivors who are registered in primary care practices of the city of Valencia, Spain. Participants eligible are aged 18 years or older, have a history of breast, colorectal, prostate, lung and haematologic cancer, completed curative cancer treatment with evidence of remission and screened blood CRP level of at least 3 mg/L (within individual SD CRP of ~0.20 mg/L at baseline is accepted).
Screening for CRP levels. Up to two home visits could be carried out to collect a 5 microlitres (µl) blood microsample and analyse the CRP levels in real-time of the potentially eligible participants. These screening visits will be done no more than 28 and 7 days prior to blinded N-of-1 phase, respectively.
Recruitment. Participants will be identified via 3 strategies: advertisements on social media, snowball sampling and in-primary care clinics referrals. Staff from local primary care setting participating in the study will identify eligible potentially participant. The selection criteria for primary care settings were based on neighborhood air quality, specifically urban areas with the highest index impact of pollutant on population > 125 and NO2 levels exceeding WHO and EU Directive 2008/50/EC limits: Malilla, Russafa, and Arrancapins.
Intervention. Each participant will be randomly allocated (1:1 ratio per cycle) to 3 treatment sets, each comprising a 14-day period of active therapy (portable air filtration unit [PAFU] at 275 m3/h) and a 14-day period of placebo (unit with sham filters - standard of care) in the bedroom. Active therapy and placebo will be nightly administered during at least 7-hours consecutive within a time window between 10:00 p.m. and 10:00 a.m. The blinded N-of-1 trial enrolment will be between 4 and 12 weeks per participant, depending on the treatment set(s) received to produce evidence of clinical benefit (CRP < 2 mg/L or CRP reductions ≥ 35%) .
After 2-weeks wash-out period of the last blinded treatment set, participants who do not achieve a clinically meaningful change will be given an open-label phase to take 14-days of no treatment and 14-days of nightly and daily active therapy - the PAFU will be continuously operated (filtered air at 275 m3/h) in bedrooms with the door and windows closed. The nightly active therapy keeps the same as the blinded treatment sets and participants will be asked to remain in the bedrooms for as long as possible (e.g., nap time). Time exposed to the in-bedroom air quality will be recorded.
Outcomes measures. The primary outcome is the level change in CRP after air filtration treatment compared with placebo. The secondary outcomes are changes in D-dimer, SAA and HbA1c concentrations, and systolic and diastolic BP. Primary and secondary outcomes will be collected at baseline and in the day 7 and 14 of each period using at-home minimally invasive medical devices.
Self-reported questionnaires. Four short versions of self-reported questionnaires will be weekly completed as potential inflammation modifying confounding factors: Godin Leisure-Time Exercise Questionnaire (GLTEQ), Food Frequency Questionnaire (FFQ), Pittsburg Sleep Quality Index (PSQI) and in-home Patterns & Time-Activity Questionnaire (PTAQ).
In-bedroom and outdoor air quality measurement. The changes in airborne pollutants will be continuously measured in real-time throughout the trial period using two monitors that integrates a combination of sensors, including particulate matter.
Statistical plan. Following treatment set 1 and 2, interim analysis will be conducted to establish whether the active treatment, as compared with placebo, is clinically effective: achievement of CRP levels < 2 mg/L or CRP reductions ≥ 35%. While participants who achieve this clinically meaningful change will be discontinued of the N-of-1 trial, those who do not achieve it in the treatment set 3 will be given the open-label phase.
Changes from baseline data for treatment and placebo per cycle will be determined. The means and 95% confidence intervals (CIs) for the differences will be calculated within treatment pairs for each outcome. The N-of-1 trials will be combined using a hierarchical Bayesian effects model to estimate the average effect that incorporate variance within- and between-individuals.
Sample size. A sample size of 8 participants will provide a power of 80% to detect a minimal clinically important difference (MCID) of change in CRP (≥ 35% reductions in this trial). A maximum of 10 participants will be enrolled (dropout rate of 20%). The estimation was based on the Yang et al. equations and implemented into an R Shiny app [https://jiabeiyang.shinyapps.io/SampleSizeNof1/].
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
- Adult-onset cancer survivors with a diagnosis of breast, colon, colorectum, rectum, prostate, non-small lung, Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphoid leukaemia and chronic myeloid leukaemia cancer.
- Aged ≥ 18 years at cancer diagnosis -upper age limit to study entry = 75 years.
- People of both genders, all racial and ethnic backgrounds.
- Non-smokers (i.e., not smoking during previous 12 months).
- A history of local, regional or distant recurrence, primary second cancers or multiple primary tumours will be not reasons to exclude.
- No previous evidence for metastatic disease.
- Evidence of complete remission defined as a decrease in or disappearance of signs and symptoms of cancer after treatment.
- Having completed definitive treatment (surgery, neoadjuvant/adjuvant cytotoxic chemotherapy, radiotherapy, immunotherapy) at least 12 months.
- Continuous, maintenance therapy is considered if initiated ≥3 months prior to study treatment and prescribed for long-term, chronic use without interruption during the trial, or completed for at least ≥3 months before starting the trial.
- Having a high inflammatory cardiac risk profile at the initial screening defined as a CRP measurement ≥ 3 to < 10 mg/L, or ≥ 10 mg/L if acute inflammation is ruled out.
- Having stable hypertension (if applicable): no medication changes in prior 30 days, systolic BP <160 mm Hg and either ≥ 130 mm Hg without antihypertensive medications, or diagnosis of hypertension in medical records.
- Clinical evidence of cardiovascular, respiratory and/or musculoskeletal disease, and/or other controlled and stable chronic medical conditions will not be reason of exclusion.
- Any medical prescription(s) if routinely administered and continued through the trial period.
- Living at one of the urban areas of the city of Valencia with the highest index impact of pollutant on population values (IIPP > 125): Russafa, Malilla and Arrancapins neighbourhoods.
- Permanent residence in their usual home at least 3 months prior to the first collected blood sample in the first cycle and without plans to move out toward another dwelling during the trial study.
- Living in a non-smoking household.
- Internet connection (Wi-Fi) in the house.
- Signed informed consent prior to commencement of specific protocol procedures.
Exclusion criteria
- Recently diagnosed with cancer or plans for additional cancer therapy and/or surgery during the trial period.
- Metastatic disease.
- Planned medication prescription to start during the trial.
- Current chronic anti-inflammatory drug prescriptions or other chronic drugs (e.g., antihypertensive drugs) will be no reason for exclusion if its use is continued for the duration of the trial period.
- Having uncontrolled hypertension: participants with average systolic BP >160 mmHg over any 10-day period prior and during the study.
- History of uncontrolled, unstable chronic disease as defined by clinical practice guidelines and documented in medical records - within past 6 months to screening visit(s) and during the study (i.e., uncontrolled diabetes mellitus). Psychiatric illness that would limit compliance with trial requirements and/or prevent the patient from giving informed consent.
- History of ongoing, chronic or recurrent infectious disease, and having suspected or proven immunocompromised state (i.e., Human Immunodeficiency Virus infection).
- Self-report of alcohol or substance abuse within the past 12 months, including at-risk drinking (current consumption of more than 14 alcoholic drinks per week).
- Shift workers or subjects who have the work schedule falling outside the hours of 07:00 a.m. and 10:00 p.m.
- Plans to move out of usual home during the trial period.
- Unwilling to spend at least 7-h/overnight in the bedroom.
- Pre-existing an air filtration system that improve household air quality. If so, the device will be disconnected during all the trial cycles.
- Unwilling to give consent.
Additional inclusion criteria (non-exclusive; when CRP test is unavailable in medical records) associated with high or very high cardiovascular (CV) toxicity risk factors (according to the European Society of Cardiology guidelines on Cardio-Oncology):
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High or very high baseline CV toxicity risk pre-treatment (HFA-ICOS risk stratification score); risk factors including:
- Prior history of CV disease (e.g., coronary artery disease).
- Presence of multiple CV-risk factors (e.g., hypertension, dyslipidemia).
- Current or concomitant cancer treatment.
- Prior cardiotoxic cancer therapy (e.g., anthracycline, radiotherapy to left chest).
- Lifestyle risk factors (history of smoking, body mass index >30).
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Specific cardiotoxic cancer therapies with a high risk of long-term CV complications (any of these):
- Total lifetime cumulative dose anthracycline ≥ 250 mg/m2 doxorubicin equivalent.
- High-dose anthracycline ≥ 250 mg/m2 doxorubicin equivalent.
- High-dose RT > 15 Gray (Gy) Mean Heart Dose (MHD).
- Anthracycline ≥ 100 mg/m2 doxorubicin equivalent in combination with radiotherapy 5-15 Gy MHD.
- Multitargeted tyrosine kinase inhibitors (TKI) targeting BCR-ABL and concomitant high-dose dexamethasone therapy >160 mg/month.
- Combination of RAF and MEK inhibition.
- Single-agent immune checkpoints inhibitors (ICI) therapy followed by previous cardiotoxic cancer therapies: RT, anthracyclines, 5-fluorouracil, and TKI.
- Combination of two types of ICI (anti-PD1, e.g., nivolumab and anti-CTLA-4, e.g., ipilimumab).
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Moderate or severe cancer therapy-related CV toxicity detected during cancer treatment or new CV symptomatic/asymptomatic abnormalities at the end of cancer treatment (3 or 12 months after therapy).
Trial design
Primary purpose
Allocation
Interventional model
Masking
10 participants in 4 patient groups
Trial contacts and locations
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Central trial contact
Eva Hernandez-Garcia
Data sourced from clinicaltrials.gov
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