Comparison of Abdominal Aortic Aneurysm Growth in Adult Smoking Patients Who Either Switch to IQOS, Continue Smoking, or Quit Smoking.

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the reduction of the Abdominal Aortic Aneurysm (AAA) annual growth rate in patients who switch from smoking cigarettes to using IQOS as compared to patients who continue to smoke cigarettes. The study also aims to provide context to the scale of reduction in the growth rate, by comparing the AAA annual growth rates for continuing to smoke and switching to IQOS with the AAA annual growth rate in smokers who had stopped smoking. The study will further evaluate the effects of switching to IQOS on co-morbidities observed in AAA patients that are related to smoking as well as to assess the effects on relevant clinical risk endpoints linked to smoking related diseases.

Detailed Description
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This is a controlled, open-label, 3-arm parallel group, multi-center study in patients diagnosed with Abdominal Aortic Aneurysm (AAA) to evaluate the AAA annual growth rate in adult smokers randomized to either continue smoking combustible cigarettes (CC) or to switch to IQOS and in adults who had stopped smoking, as a non-randomized control arm. This is a descriptive study, designed to gain an understanding of how changes in smoking behaviors impact AAA growth rate and disease progression. Therefore, there are no formal statistical hypotheses to be tested. Smoking patients with AAA who did not quit smoking after their AAA diagnosis, and who are not intending to quit within the next 6 months will be screened for enrollment and randomization in the CC and IQOS arms if all other eligibility criteria are met. Smoking patients with AAA who had completely stopped smoking and using of any other tobacco or nicotine-containing products within 2 months of their AAA diagnosis, and are still abstinent at the time of the Screening Visit and of the Baseline Visit will be screened to be enrolled in the smoking cessation (SC) arm without randomization.

Official Title
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A Controlled, Open-label, 3-arm Parallel Group, Multi-center Study to Evaluate the Abdominal Aortic Aneurysm (AAA) Growth Rate in Adult Smoking Patients Randomized to Either Cigarette Smoking or IQOS Use and to Compare With the AAA Growth Rate in Patients Who Had Stopped Smoking

Conditions
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Smoking, Abdominal Aortic Aneurysm, IQOS Use

Intervention / Treatment
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* Other: IQOS
* Other: Cigarette
* Other: Smoking Cessation


Participation Criteria
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Eligibility Criteria
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General Inclusion Criteria: Patient diagnosed with AAA (infrarenal, fusiform type) with a current aortic maximum minor-axis diameter of 30 to ≤ 49 mm (in male patient) and 30 to ≤ 44 mm (in female patient). Patient has smoked on average at least 10 commercially available CC per day (no brand restrictions) for at least 5 years prior to AAA diagnosis, based on self-reporting Patient is ready to comply with the study protocol (e.g., to use their assigned product/regimen during the course of the study) Inclusion criteria specific to patients screened for enrollment and randomization to the CC or IQOS arm: Patient has smoked on average at least 10 commercially available CC per day (no brand restriction) for the last 12 months, based on self-reporting. Intermittent attempts to quit smoking not exceeding 2 months or short-term interruption of smoking up to 10 days within the last 12 months will be allowed. Smoking status will be verified based on a urinary cotinine test (i.e., cotinine ≥ 200 ng/mL). Not intending to quit smoking within the next 6 months. Inclusion Criteria specific to patients screened for enrollment into the SC arm: Patient had completely quit smoking and stopped the use of any other tobacco or nicotine-containing products within 2 months after AAA diagnosis, and is still abstinent at Screening and at Baseline. Smoking status will be verified based on a urinary cotinine test (i.e., cotinine < 100 ng/mL). Exclusion Criteria: Patient is legally incompetent, physically or mentally incapable of giving consent. Patient is a current or former employee of the tobacco industry or their first-degree relatives (parent and child); patient is an employee of the investigational site or any other parties involved in the study or their first-degree relatives (parent and child). Patient has been previously screened or enrolled in this study or was enrolled in any clinical study within 3 months prior to the Screening Visit. Female patient who is pregnant or breast-feeding. Patient is ineligible as judged by the Investigator to participate in the study for any reason. Patient with acute severe cardiovascular events or respiratory diseases, within the last 3 months; with currently active cancer or history of cancer within the last 5 years; with dissecting aneurysm(s) of the aorta; with infrarenal pseudo-AAA (false AAA); with a diagnosis of COPD Stage 3 and 4 in the medical history; with a recent (within 1 year) or current history of alcohol or other substance abuse based on self-reporting. Patient with a diagnosis of concomitant genetic diseases such as but not limited to Marfan syndrome, Loeys-Dietz syndrome, Vascular Ehlers-Danlos syndrome, Turner syndrome, Polycystic kidney disease, Noonan syndrome, Alagile syndrome, Arterial tortuosity syndrome and Cutis laxa.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IQOS Arm<br>Patients diagnosed with AAA, switching from cigarette smoking to IQOS use | Other: IQOS<br>* AAA patients will switch from cigarette smoking to ad libitum IQOS use, with no flavor variant restrictions.<br>|
| Active Comparator: CC Arm<br>Patients diagnosed with AAA, continuing to smoke cigarettes | Other: Cigarette<br>* AAA patients will continue to smoke their cigarettes ad libitum, with no brand restrictions.<br>|
| Active Comparator: Smoking Cessation Arm<br>Patients diagnosed with AAA, who have completely stopped smoking and are not using any other tobacco or nicotine-containing product(s) | Other: Smoking Cessation<br>* AAA patients who have completely quit smoking will continue to remain abstinent from smoking cigarettes or using any tobacco or nicotine-containing product(s)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AAA annual growth rate over time | AAA annual growth rate will be measured in AAA patients who switch from smoking cigarettes to using IQOS, and AAA patients who continue to smoke CC, as compared to AAA patients who had stopped smoking. Maximum minor-axis AAA diameter in mm will be measured. Annual growth rate will be calculated by annualizing the slope of the linear regression over the available diameter measurements. | At 6-month intervals from baseline to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Period of time from diagnosis of the AAA until open surgical AAA treatment or AAA endovascular repair or AAA rupture | The time from diagnosis of the AAA until open surgical AAA treatment or AAA endovascular repair or AAA rupture will be measured in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue smoking CC and AAA patients who had stopped smoking. | From diagnosis of AAA to 5 years | 
| Incidence of open surgical AAA treatment or AAA endovascular repair and AAA rupture | The incidence of open surgical AAA treatment or AAA endovascular repair and AAA rupture will be measured in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue to smoke CC and AAA patients who had stopped smoking. Incidence rate will be calculated annually. | From baseline to 5 years | 
| Incidence of AAA growth above 5 mm within 6 months | Incidence of AAA growth above 5 mm within 6 months will be measured in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue smoking CC and AAA patients who had stopped smoking. Incidence rate will be calculated annually by counting the number of patients with an increase in maximum minor-axis AAA diameter of more than 5 mm within 6 months. | At 6-month intervals from baseline to 5 years | 
| AAA patients with an overall maximum minor-axis AAA diameter of >55mm in male patients and >50mm in female patients | The number of AAA patients with an overall maximum minor-axis AAA diameter >55mm in male AAA patients and >50mm in female AAA patients will be counted in AAA patients who switch from smoking CC to using IQOS, as compared to AAA patients who continue smoking CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Incidence of ischemic heart disease (IHD) in AAA patients | Number of AAA patients with a diagnosis of IHD, IHD progression (by number of new myocardial infarction, stroke or death) or IHD related event annually. | From baseline to 5 years | 
| Incidence of chronic obstructive pulmonary disease (COPD) in AAA patients | Number of AAA patients with a diagnosis of COPD, COPD progression (by disease stage) or a COPD related event annually. | From baseline to 5 years | 
| Incidence of hypertension in AAA patients | Number of AAA patients with a diagnosis of hypertension, progression of their hypertension (by disease stage), or a hypertension related event annually. | From baseline to 5 years | 
| Incidence of peripheral arterial disease (PAD) in AAA patients | Number of AAA patients with a diagnosis of PAD, PAD progression (by disease stage) or PAD related event annually. | From baseline to 5 years | 
| Incidence rate of other smoking-related diseases, and their related events, in AAA patients | Number of AAA patients with adverse events related to the diagnosis of other co-morbidities, events related to the other co-morbidities. | From baseline to 5 years | 
| Urinary nicotine equivalents (NEQ) | To measure nicotine exposure over time in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC, and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Systolic blood pressure | This cardiovascular clinical risk endpoint (systolic blood pressure) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Diastolic blood pressure | This cardiovascular clinical risk endpoint (diastolic blood pressure) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Body weight | This cardiovascular clinical risk endpoint (body weight) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Waist circumference | This cardiovascular clinical risk endpoint (waist circumference) will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| High sensitive C-reactive protein (hs-CRP) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Low density lipoprotein (LDL) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| High density lipoprotein (HDL) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Total Cholesterol (TC) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Triglyceride (TG) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Fasting blood glucose | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Hemoglobin A1c (HbA1c) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| White blood cell (WBC) and platelet counts | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| D-dimer | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Fibrinogen | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Total Antioxidant Capacity (TAC) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| 11-dehydro-thromboxane B2 (11-DTX-B2) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| 8-Epi Prostaglandin F2 Alpha (8-epi-PGF2α) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Metalloproteinase 2 (MMP- 2) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, patients who continue to smoke CC and patients who had stopped smoking. | From baseline to 5 years | 
| Metalloproteinase 9 (MMP-9) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, patients who continue to smoke CC and patients who had stopped smoking. | From baseline to 5 years | 
| Soluble inter-cellular adhesion molecule-1 (sICAM-1) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Apolipoprotein A1 (Apo A1) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Apolipoprotein B (Apo B) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Homocysteine (Hcy) | This cardiovascular clinical risk endpoint will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) | This biomarker of exposure to a tobacco smoke constituent will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Total N-nitrosonornicotine (Total NNN) | This biomarker of exposure to a tobacco smoke constituent will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| 2-cyanoethylmercapturic acid (CEMA) | This biomarker of exposure to a tobacco smoke constituent will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Ankle-brachial index (ABI) | The ABI will be measured in AAA patients who switch from smoking CC to using IQOS, AAA patients who continue to smoke CC, and AAA patients who had stopped smoking. | From baseline to 5 years | 
| Transcriptomic profile assessment in blood samples | To evaluate differential changes in gene expressions, transcriptomics analyses will be performed on collected blood samples. Isolated RNAs will be applied to a gene chip that contains 54,000 transcripts. The gene chip will then be scanned using Affymetrix. The outcome measurements that will be reported are relative changes and relative fold changes in gene expressions in AAA patients who continue smoking cigarettes and those switching to IQOS. | From baseline to 5 years | 
| Proteomic profile assessment in plasma derived from blood samples | To evaluate changes in selected protein concentrations, targeted proteomics analyses will be performed on plasma derived from collected blood samples. Proteins will be isolated from plasma and targeted proteomics analyses will be performed using liquid chromatography mass spectrometry (LC MS/MS) and antibody-based Luminex. The outcome measurements that will be reported are the concentrations of the selected proteins measured in AAA patients who continue smoking cigarettes and those switching to IQOS. | From baseline to 5 years | 
| Lipidomic profile assessment in plasma derived from blood samples | To evaluate changes in selected ceramide concentrations, targeted lipidomics analyses will be performed on plasma derived from collected blood samples. Ceramides will be isolated from plasma and targeted lipidomics analyses will be performed using liquid chromatography mass spectrometry (LC MS/MS). The outcome measurements that will be reported are the concentrations of the selected ceramides measured in AAA patients who continue smoking cigarettes and those switching to IQOS. | From baseline to 5 years | 
| Lipidomic profile assessment in urine | To evaluate changes in selected eicosanoid concentrations, targeted lipidomics analyses will be performed in urine. Eicosanoids will be isolated from urine and targeted lipidomics analyses will be performed using liquid chromatography mass spectrometry (LC MS/MS). The outcome measurements that will be reported are the concentrations of selected eicosanoids measured in AAA patients who continue smoking cigarettes and those switching to IQOS. | From baseline to 5 years |