Evaluation of Canakinumab in High-Risk Former-Smokers

Eligibility Criteria

Age 40-73 (age criteria aligns with CANTOS trial) If female: evidence of post-menopausal status1 or negative urinary or serum pregnancy test (unknown impact on pregnancy) Former smoker with no use in ≥ 3 years prior to enrollment (targets former smoker population) CO ≤ 8ppm (targets/confirms former smoker population) Pack-years history of ≥ 20 (defined as high risk) No unstable or significant medical conditions as determined by medical history (see exclusion criteria below - to ensure safety of the subject, to minimize the effects of poor health on biomarker measures and to maximize compliance to study procedures) Negative COVID-19 test (if applicable)2 Able to read adequately to complete the survey and related study documents or give consent

Exclusion Criteria

Smoked tobacco or cannabis within 3 years of enrollment (target study population is former smokers) Used an electronic cigarette or vaped including THC within 3 years of enrollment (impacts biomarkers)3 CO \> 8ppm (target study population is former smokers) History of or recent exposure to tuberculosis (TB) as documented in the EMR and/or testing (impacts risk) BMI \> 45 (risk of unstable airway)

* Taking ASA or NSAIDs daily or most days per week (impacts biomarkers and risk)
* Concomitant diseases and life-threatening conditions (e.g., cancer or kidney, liver, immune system disorders)
* Prior diagnosis of chronic pulmonary disease that requires regular use of inhalers or medications that influence biomarkers (e.g., asthma, chronic bronchitis, and restrictive lung disease) (impacts biomarkers and risk)
* Acute bronchitis or pneumonia within 1 year (impacts biomarkers)
* COVID-19 diagnosis or related symptoms within the last 3 months (impacts biomarkers and risk)
* General anesthesia within 3 months (impacts biomarkers)
* Regular use of inhalant medications in the last 3 months (impacts biomarkers)
* Use of antibiotics in prior 30 days (impacts biomarkers)
* Use of steroids, including corticosteroids and inhaled corticosteroids, in prior 30 days (impacts biomarkers)
* Use of prohibited concomitant therapy including but not limited to immunosuppressants (impacts biomarkers and risk)4
* Live or attenuated vaccines within 90 days of study treatment and after initiation of study drug (impacts biomarkers and risk)5
* Allergies to study medications, such as, lidocaine, Versed, Fentanyl or Cetacaine (impacts risk)
* Bronchoscopy or any other lung procedure for any reason within the previous 6 months (impacts biomarkers)
* Current or recent (within three months) alcohol or drug abuse problems (impacts risk)
* Unable to read for comprehension or completion of study documents (impacts risk)

  1Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 6 weeks after stopping medication. Highly effective contraception methods include:
* Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
* Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
* Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant
* Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms). Women are considered not of a childbearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential.

Women will also be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:

Women ≥50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

2According to institutional standards, which may evolve throughout the study, if a subject self-reports testing positive for COVID-19, the condition should be resolved without ongoing symptoms for at least three months. If a subject tests positive before the first bronchoscopy, the subject would be placed on a wait list for at least three months and re-tested before his/her appointment; if a subject tests positive before a follow-up bronchoscopy, his/her participation will be withdrawn by the PI.

3Smoking or vaping any form of tobacco product or cannabis/THC is an exclusion; however, other use of THC administration (e.g., edible, topical, etc.) are permitted.

4Prohibited concomitant therapy:

Immunosuppressants Use of any treatments below is NOT allowed after the start of study treatment due to potential increase in immunosuppressant related concomitant conditions. They are prohibited for the duration of the study and for at least 130 days after discontinuation of study treatment. If a subject chooses to continue one of the medications below, they will be followed.

Anti-retro-viral and / or biologic drugs targeting the immune system (e.g., TNF blockers, anakinra, rituximab, abatacept, tocilizumab) Immune modulating agent in doses with systemic effects including but not limited to Prednisone \>20 mg (or equivalent) oral or intravenous daily for \>14 days; Prednisone \> 5 mg and ≤ 20 mg (or equivalent) daily for \> 30 days; Equivalent dose of methotrexate \>15 mg weekly. Cytochrome P450 Substrates - The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus, it is expected that for a molecule that binds to IL-1, such as canakinumab, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of canakinumab, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed and the individual dose of the medicinal product may need to be adjusted as needed. Ilaris USPI 2020 - 7.3 - https://www.novartis.com/us-en/sites/novartis\_us/files/ilaris.pdf

5Subjects must be discontinued from the trial if administered any live or attenuated vaccine during the course of the study.