Clinical trial NCT03654105: Screening and Multiple Intervention on Lung Epidemics
Official title: Multifactorial Intervention of Primary Prevention in High Risk Subjects: a Randomized Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Inflammation
Smoking Cessation
Diet Modification
Physical Activity
Lung Cancer
Keywords: Inflammation
Primary Prevention
Multiple Prevention
Lung Cancer Screening
Smoking Cessation
Diet
Physical Activity
CRP
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
Collaborators: name: Istituto Di Ricerche Farmacologiche Mario Negri
First posted: 2018-08-31
Enrollment: 2000
Sex: ALL
Minimum age (years): 55
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief summary: This prospective randomized pilot trial will evaluate a multiple intervention program of prevention in lifelong smokers aiming at reduction of chronic inflammation status through treatment with low-dose acetylsalicylic acid (ASA), smoking cessation with cytisine, targeted modification of diet and physical activity, in addition to early diagnosis with annual ultra low-dose spiral computed tomography (LDCT).

Detailed description: The most recent population-based studies carried out in Europe and the US on hundreds of thousands of individuals have unequivocally identified three principal causes of mortality, morbidity and chronic disability: tobacco smoke, inadequate diet, and reduced physical activity. These risk factors are in large part reversible, because in heavy smokers, even after 60 years of age, cessation is associated with a clear reduction in all-cause mortality. The finding that lifestyle and eating habits are associated with the development of cancer has been confirmed in many studies: smoking, a sedentary lifestyle, excess red meat, processed foods and sugars are associated with increased risk, while an active lifestyle, non-exposure to smoke (both active and passive), consumption of whole grains, legumes and vegetables are associated with protection or a reduced incidence in at-risk subjects.

What is clear, and confirmed by many studies, is that cancer occurs more often in overweight individuals, and that cancer patients who are overweight have more difficulty treating their disease. Elevated plasma levels of C-reactive protein (CRP), even when still within normal limits, are the reflection of a chronic state of inflammation and are associated with poor prognosis in several tobacco-related diseases. CRP measurement is besides a simple test to predict the risk of heart attack and stroke as well as mortality from all causes and from cardiovascular disease. In a systematic review on adult solid tumors, elevated CRP levels were associated with higher mortality and recurrence rates, and this observation was confirmed in early-stage lung cancer by a recent meta-analysis. In patients with chronic obstructive pulmonary disease (COPD), high CRP is a strong and independent predictor of future morbidity and mortality, and an increase in CRP concurrent with a reduction of the forced expiratory volume in 1 second (FEV1) shows an even stronger effect on patient's outcome.

High levels of CRP are associated with poor prognosis in cancers of the upper aerodigestive tract, rhinopharynx, lung and urinary tract. From a dietary point of view, consumption of saturated fats has been directly associated with an increase in inflammatory status as measured by high levels of CRP, just like consumption of meat, while an inverse correlation with consumption of vegetables has been observed. For example, low levels of inflammatory factors have been found in individuals adhering to a Mediterranean diet. Another recurrent finding, at least for cancer, is the importance of daily physical activity, such as brisk walking for 30 minutes. Moreover, regular physical activity is associated with better prognosis and increased survival in patients with a cancer diagnosis.

The number of heavy smokers that will participate in early-diagnosis programs using spiral CT will undoubtedly increase in the future as a result of awareness campaigns, and the participating volunteers represent an excellent opportunity to evaluate the efficacy of targeted primary prevention programs.

The present program will combine several interventions according to the randomization arm, proposed in combination or in single treatment, including treatment with cytisine, reduction of chronic inflammation by treatment with low-dose aspirin (ASA), targeted modification of diet and physical activity, in addition to early diagnosis with annual ultra low-dose spiral computed tomography (LDCT).

At baseline each volunteer will undergo:

* questionnaires on population evaluation (e.g. socio-demographic, smoking habits, physical activity, etc)
* blood sampling for the assessment of the inflammatory and metabolic profile
* evaluation of respiratory function and measurement of carbon monoxide (CO)
* thorax ultra low-dose computed tomography (LDCT) without contrast
* anthropometric evaluation (e.g. weight, height, BMI, etc)

To reduce levels of chronic inflammation will be used:

* treatment with low-dose acetylsalicylic acid (ASA)
* dietary / nutritional intervention in order to promote an optimal diet, based on characteristic of the Mediterranean Diet, for weight maintenance, visceral fat control and an adequate nutritional status
* physical activity intervention, through the reduction of sedentary behaviour and the implementation of a moderate intensity activity of about 30 min a day

In the Smoking cessation will be used Cytisine. It is a molecule known since the early 60s for the treatment of smoking. In recent clinical trials it revealed efficacy in smoking cessation. In 2014, the NHS (National Health Service) produced a document evaluating the cost-effectiveness of drug treatment of smoking, concluding that cytisine has the most favorable profile among the drugs taken into consideration

The imaging will be performed by volumetric acquisition with a computed tomography scanner equipped with advanced technology hardware and software, including: high performance X-ray tube with low potential, high sensitivity detectors combined with dedicated reconstruction algorithms for optimisation of the signal to noise ratio within an ultra low radiation dose. The protocol for ultra-low dose computed tomography will be specifically set for lung cancer screening with semiautomated image analysis and nodule quantification, according to the international standard for image quality (Quantitative Imaging Biomarker Alliance). In particular, the ultra-low dose computed tomography protocol will be developed for the lowest radiation exposure and tested by dedicated phantom for quantitative analysis of imaging metrics.

In the control group subjects will receive an information booklet containing advice on an optimal lifestyle with particular reference to smoking, diet and physical activity according to the best international guidelines.

Eligibility criteria: Inclusion Criteria:

* Age between 55 and 75 years
* High consumption of cigarettes (≥ 30 packs/year)
* Elegibility to annual LDCT screening
* Confidence in Internet use
* Absence of tumors for at least 5 years
* Signed informed consent form

Exclusion Criteria:

* Hypersensitivity to acetylsalicylic acid, salicylates or any of the excipients (excipients: cellulose powder, corn starch, coating: copolymers of methacrylic acid, sodium lauryl sulfate, polysorbate 80, talc, triethyl citrate)
* Chronic treatment with acetylsalicylic acid, or other anti-clotting or anti-coagulant drugs (for example: heparin, dicumarol)
* Treatment with methotrexate
* Existing Mastocytosis
* History of asthma induced by the administration of salicylates or substances to similar activity, particularly non-steroidal anti-inflammatory drugs
* Gastroduodenal ulcer
* Hemorrhagic diathesis
* Severe chronic pathology (eg: severe respiratory and / or renal and / or hepatic and / or cardiac insufficiency)
* Serious psychiatric problems
* Previous treatment with Cytisine
* Abuse of alcohol or other substances (even previous)

Primary outcomes:
measure: Change in chronic inflammatory status
timeFrame: 1 year
Secondary outcomes:
measure: Change in smoking status
timeFrame: 1 year
measure: Change in dietary habits
timeFrame: 1 year
measure: Change in the physical activity
timeFrame: 1 year
measure: Change in body mass index (BMI)
timeFrame: 1 year
measure: Change in waist circumference
timeFrame: 1 year
measure: Change in metabolic profile
timeFrame: 1 year
measure: Change in lung cancer incidence
timeFrame: 3 years
measure: Change in lung cancer specific and overall mortality
timeFrame: 3 years
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
Study officials:
affiliation: IRCCS IstitutoNazionale dei Tumori di Milano
name: Ugo Pastorino, MD
role: PRINCIPAL_INVESTIGATOR
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