Biomarkers of Exposure and Biomarkers of Potential Harm in Adult Smokers Who Completely Switch to E-vapor Products

An Open-Label, Parallel-Group, Controlled Study to Evaluate Changes in Biomarkers of Cigarette Smoke Exposure and Biomarkers of Potential Harm in Adult Smokers Who Completely Switch to Using e-Vapor Products for 24 Weeks

The purpose of this study was to estimate changes in biomarkers of exposure (BoE) and biomarkers of potential harm (BoPH) in adult cigarette smokers (AS) who switched to using an e-vapor product (EVP) relative to adult smokers who continue smoking exclusively.

This study was conducted as a randomized, parallel-group, open-label, 24-week, controlled clinical study split into an initial 12-week study (Study 1), with a follow-up at 24 weeks (Study 2) in a sub-population of switchers. For Study 1 a total of 450 subjects were enrolled. Of those subjects who successfully completed Study 1, 150 were then enrolled into Study 2 with no interruption in study participation. The study compared changes in BoE and BoPH in AS who switched to ad libitum use of one of two test EVPs with those in the Control group who continued to smoke conventional cigarettes. The study enrolled AS who were considered to be in overall good health.

Inclusion Criteria:

Study 1

Subjects must satisfy the following criteria before being enrolled into the study. Subjects must:

1. sign an IRB-approved informed consent form (ICF) for the study;

2. be between the ages of 30 and 65 years, inclusive, at the time of Screening, Visit 1;

3. have > 500 ng/ml urine cotinine measurement at Screening, Visit 1;

4. have smoked for ≥ 10 years and smoked an average of ≥ 10 manufactured cigarettes per day during the 12 months prior to Screening, Visit 1;

   a) Brief periods [i.e., up to 7 consecutive days] of non smoking during the 12 months prior to Screening, Visit 1 due to illness, trying to quit, or participation in a study where smoking was prohibited are acceptable.

5. indicate that he/she is "definitely" or "probably" willing and able to replace their cigarettes for 12 weeks with the assigned test e-Vapor product;

6. have daily access to text messaging capable cellular phone for daily product use reporting;

7. have a negative ethanol breath test and amphetamines, opiates, cannabinoids, and cocaine urine drug screen results at Screening, Visit 1;

   a) Subjects with a prescription from a licensed physician will not be exempted from this criterion.

8. if female (all females), have a negative serum pregnancy test at Visit 1 and negative urine pregnancy test at Visit 2 through Visit 7, inclusive;

9. if female, heterosexually active, and of childbearing potential (i.e., not surgically sterile or 2 years naturally postmenopausal), must have used a medically accepted method of contraception (listed below in a) and b)) prior to Screening, Visit 1 and must agree to continue to use such method(s) through the End of Study;

   1. Surgically sterile includes bilateral tubal ligation, Essure, hysterectomy, or bilateral oophorectomy at least 6 months prior to Screening, Visit 1. Naturally postmenopausal is defined as women having 2 years without menses.
   2. Acceptable methods of contraception are: hormonal (i.e., oral, transdermal patch, implant, or injection) consistently for at least 3 months prior to Screening, Visit 1; double barrier (i.e., condom with spermicide or diaphragm with spermicide) consistently for at least 4 weeks prior to Screening, Visit 1; and intrauterine device for at least 3 months prior to Screening, Visit 1; or only have a partner who has been vasectomized for at least 6 months prior to Screening, Visit 1.

10. Be willing and able to comply with the requirements of the study.

Study 2

Subjects must satisfy the following criteria before being enrolled into the study. Subject must:

1. have participated in and completed the 12-week ALCS-RA-16-06-EV study and have Baseline biomarker samples collected;

2. demonstrate willingness to participate by signing an Institutional Review Board (IRB)-approved ICF for the study;

3. have demonstrated consistent daily reporting of product use in the 12-week ALCS-RA-16-06-EV (≥ 80% reporting compliance);

4. if randomized to a Test group, have reported an average of no more than 10% of Baseline cigarette smoking per day through Week 11 of the 12-week ALCS-RA-16-06-EV study;

5. if randomized to a Test group, have reported use of at least two Test product cartridges per week in the 12-week ALCS-RA-16-06-EV study;

6. if randomized to a Test group, have exhaled carbon monoxide (eCO) measurements of ≤ 8 ppm at each post-Baseline time point in the 12-week ALCS-RA-16-06-EV study;

7. have daily access to text messaging capable cellular phone for daily product use reporting;

8. if female (all females), have a negative urine pregnancy test at Week 12 (Visit 1) through Week 24 (Visit 5), inclusive;

9. if female, heterosexually active, and of childbearing potential (i.e., not surgically sterile or 2 years naturally postmenopausal), must have used a medically accepted method of contraception (listed below in a) and b)) prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study and must agree to continue to use such method(s) through Week 24 (EOS);

   1. Surgically sterile includes bilateral tubal ligation, Essure, hysterectomy, or bilateral oophorectomy at least 6 months prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study. Naturally postmenopausal is defined as women having 2 years without menses.
   2. Acceptable methods of contraception are: hormonal (i.e., oral, transdermal patch, implant, or injection) consistently for at least 3 months prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study; double barrier (i.e., condom with spermicide or diaphragm with spermicide) consistently for at least 4 weeks prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study; and intrauterine device for at least 3 months prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study; or only have a partner who has been vasectomized for at least 6 months prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study.

10. Be willing and able to comply with the requirements of the study.

Exclusion Criteria:

Study 1

Subjects may be excluded from the study if there is evidence of any of the following criteria. Exceptions may be permitted at the discretion of the Investigator and in consultation with the Sponsor or designee provided there would be no additional risk to the subject. Any exceptions will be documented.

1. History or presence of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, urologic, diabetes, existing respiratory diseases, immunologic, psychiatric, or cardiovascular disease, or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or impact the validity of the study results. (Note: chronic medical conditions controlled and on stable medications [over past 3 months] may not necessarily be exclusionary per Investigator discretion);
2. Currently taking medication for depression, asthma or diabetes;
3. Allergy to menthol;
4. Systolic blood pressure > 140 mmHg and / or diastolic blood pressure > 90 mmHg at Screening Visit 1.
5. Have clinically significant abnormal findings on the physical examination, vital signs, electrocardiogram (ECG), or medical history that would jeopardize the safety of the subject, in the opinion of the Investigator;
6. Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV) at Screening, Visit 1;
7. Current evidence or any history of congestive heart failure;
8. Any acute illness (e.g., upper respiratory infection, viral infection) requiring treatment within 2 weeks before Visit 3 (Day 1);
9. History of drug or alcohol abuse within 24 months of Visit 3 (Day 1) as defined by the Investigator;
10. BMI greater than 40.0 kg/m2 or less than 18.0 kg/m2 at Screening, Visit 1;
11. Post-bronchodilator Forced expiratory volume at one second (FEV1):Forced vital capacity (FVC) ratio < 0.7 and FEV1 < 50% of predicted at Screening, Visit 2;
12. Post-bronchodilator FEV1:FVC ratio < 0.75 and FEV1 increase ≥ 12% and > 200 mL from pre- to post-bronchodilator at Screening, Visit 2;
13. Estimated creatinine clearance (by Cockcroft-Gault equation) < 80 mL/min at Screening, Visit 1;
14. Serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 1.5 times the upper limit of the reference range at Screening, Visit 1;
15. Female candidates who are pregnant, lactating, or intend to become pregnant from Screening, Visit 1 through End of Study;
16. Use of HDL-C raising medication / supplements (e.g., niacin, gemfibrizole, fenofibrate, etc.) within the past 3 months prior to Screening, Visit 1 or any time during the study;
17. Use of nicotine-containing products other than manufactured cigarettes (e.g., roll-your-own cigarettes, e-cigarette or e-Vapor products, Bidis, snuff, nicotine inhaler, pipe, cigar, smokeless tobacco, nicotine patch, nicotine spray, nicotine lozenge, or nicotine gum) within 14 days prior to Screening, Visit 1 through Visit 3 (Day 1) except as required for the purpose of this study;
18. Donation of blood or blood products, including plasma, history of significant blood loss in the opinion of the investigator, or receipt of whole blood or a blood product transfusion within 60 days prior to Visit 3 (Day 1);
19. Participation in a clinical study of an investigational drug, medical device, biologic, or of a tobacco product, within 30 days before Visit 3 (Day 1);
20. Participation in more than two ALCS studies within 12 months before Visit 3 (Day 1);
21. Already enrolled or failed screening for the current study at a different study site;
22. Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current or former employee of the tobacco industry or a named party or class representative in litigation with any tobacco company.

Study 2

Subjects may be excluded from the study if there is evidence of any of the following. Exceptions may be permitted at the discretion of the Investigator and in consultation with the Sponsor or designee provided there would be no additional risk to the subject. Any exceptions will be documented.

1. Have clinically significant abnormal findings on the physical examination, vital signs, or ECG at the EOS visit (Visit 7) of the 12-week ALCS-RA-16-06-EV study that would jeopardize the safety of the subject, in the opinion of the Investigator;
2. Female subjects who are pregnant (as determined at the EOS visit [Visit 7] of the 12-week study), lactating, or intend to become pregnant from Visit 1 (Week 12) through Week 24 (EOS);
3. Use of any medication for depression, asthma, or diabetes at any time during the study;
4. Use of HDL-C raising medication / supplements (e.g., niacin, gemfibrozil, fenofibrate, etc.) at any time during the study;
5. Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current or former employee of the tobacco industry or a named party or class representative in litigation with any tobacco company;
6. Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current or former employee of Celerion or any of the clinical study sites.