Study to Evaluate Changes in Smokers Using on!® Nicotine Pouches

Study Overview
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Brief Summary
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The purpose of this study is to generate evidence regarding the extent of reduction in exposure to selected HPHCs in adult smokers switching to on!® NPs. The study intends to determine changes in exposure to selected HPHCs by measuring biomarkers in adult smokers who completely switch from smoking to use of on!® NP compared to those who continue smoking cigarettes or stop using all tobacco products.

Detailed Description
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This is an open-label, randomized, 5 parallel-group clinical study evaluating changes in exposure to selected harmful and potentially harmful constituents (HPHCs) and product use behavior in adult smokers who are randomly assigned to 1 of the 5 groups; continue smoking, partially or completely switch to oral tobacco-derived nicotine products, or stop using any tobacco products for 7 days.

Official Title
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A Randomized, Controlled, Open-label Short-term Study to Evaluate Changes in Exposure to Harmful and Potentially Harmful Constituents in Adult Smokers Who Completely Switch to on!® Nicotine Pouches in a Clinical Setting

Conditions
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Tobacco Use

Intervention / Treatment
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* Other: OTDN Product 1
* Other: OTDN Product 2
* Other: OTDN Product 3
* Other: No Tobacco


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary consent to participate in this study documented on the signed ICF Smoking history (self-reported at screening) of an average of at least 10 but no more than 30 factory-manufactured combustible cigarettes (either menthol or non-menthol) daily for at least 12 months prior to screening. Brief periods (ie, up to 7 consecutive days) of non-smoking during the 3 months prior to screening (eg, due to illness or participation in a study where smoking was prohibited) will be permitted Positive urine cotinine (≥ 500 ng/mL) at screening Female subjects who are heterosexually active and of childbearing potential (eg, neither surgically sterile at least 6 months prior to check-in nor postmenopausal with amenorrhea for at least 12 months prior to check-in with follicle-stimulating hormone [FSH] levels consistent with postmenopausal status) must have been using one of the following forms of contraception for the time period indicated and agree to continue using it through completion of the study: Hormonal (eg, oral, vaginal ring, transdermal patch, implant, injection) consistently for at least 3 months prior to check-in, double barrier (ie, condom with spermicide or diaphragm with spermicide) consistently for at least 4 weeks prior to check-in, an intrauterine device for at least 4 months prior to check-in Exclusive partner who has been vasectomized for at least 6 months (inclusive) prior to check-in Female subjects of childbearing potential who are not currently engaging in heterosexual intercourse must agree to use one of the above methods of birth control through completion of study, in the event that they have heterosexual intercourse during the course of the study. Female subjects who are of nonchildbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to check-in: Hysteroscopic sterilization (including Essure® or similar nonsurgical sterilization procedures); bilateral tubal ligation or bilateral salpingectomy; hysterectomy; bilateral oophorectomy Or be postmenopausal with amenorrhea for at least 12 months prior to check-in and have FSH levels consistent with postmenopausal status Willing to comply with the requirements of the study Willing to use all 3 on!® NP after the Product Trial at check-in Willing and able to abstain from cigarettes from Day 1 through the end of the study (EOS) Healthy adult males and females, 21 to 65 years of age, inclusive at screening, with subjects aged 46 to 65 years being fully vaccinated for COVID-19 (SARS-CoV-2) at least 14 days before the screening visit. Exclusion Criteria: Use of any type of tobacco- or nicotine-containing products other than manufactured cigarettes (eg, e-vapor products, roll-your-own cigarettes, bidis, snuff, nicotine inhaler, pipe, cigar, chewing tobacco, nicotine patch, nicotine spray, nicotine lozenge, or nicotine gum) in the 7 days prior to check-in Self-reported puffers (ie, adult smokers who draw smoke from the cigarette into the mouth and throat but do not inhale) Planning to quit smoking in the next 30 days (from screening visit) History or presence of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, urologic, existing respiratory diseases, immunologic, psychiatric, lymphatic, 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 Clinically significant abnormal findings on the vital signs, physical examination, medical history, electrocardiogram (ECG), or clinical laboratory results, in the opinion of the investigator Positive test for human immunodeficiency virus, hepatitis B surface antigen, or hepatitis C virus at screening History or presence of any type of malignant tumors Current evidence or any history of congestive heart failure Diabetes mellitus (fasting glucose ≥126 mg/L [7 mmol/L]) that is not controlled by diet/exercise alone, in the opinion of the investigator An acute illness (eg, upper respiratory infection, viral infection) requiring treatment with prescribed medicines within 2 weeks prior to check-in Dentition that prevents subjects from using on!® NP products Allergic to or cannot tolerate mint flavoring agents or phenylalanine Any planned surgery from the time of screening through EOS History of drug or alcohol abuse within 24 months prior to check-in Fever (ie, body temperature >100.5°F) at screening or check-in. One recheck may be performed at the investigator's discretion Body mass index greater than 40.0 kg/m2 or less than 18.0 kg/m2 at screening Systolic blood pressure >150 mmHg and/or diastolic blood pressure > 90 mmHg at screening or check-in, measured after being seated for at least 5 minutes. One recheck may be performed at the investigator's discretion Estimated creatinine clearance (by Cockcroft-Gault equation) < 80 mL/minute at screening Serum alanine aminotransferase ≥1.5 times the upper limit of normal and/or aspartate aminotransferase ≥1.5 times the upper limit of normal at screening Positive screen for alcohol (breath) or any of the following drugs of abuse (urine), regardless of the reason of use: amphetamines, methamphetamines, opiates, cannabinoids, or cocaine at screening or check-in Female subjects who are pregnant (positive serum pregnancy test at screening or urine pregnancy test at check-in), lactating, or intend to become pregnant from screening through EOS Use of prescription or over-the-counter bronchodilator medication (eg, inhaled or oral ß-agonists) within 12 months prior to check-in Use of medications or foods known or are suspected to interact with cytochrome P450 2A6 (including, but not limited to, amiodarone, amlodipine, amobarbital, buprenorphine, clofibrate, clotrimazole, desipramine, disulfiram, entacapone, fenofibrate, isoniazid, grapefruit, ketoconazole, letrozole, methimazole, methoxsalen, metyrapone, miconazole, modafinil, orphenadrine, pentobarbital, phenobarbital, pilocarpine, primidone, propoxyphene, quinidine, rifampicin, rifampin, secobarbital, selegiline, sulconazole, tioconazole, tranylcypromine) within 14 days or 5 half-lives of the drug, whichever is longer, prior to check-in or during the study Use of antibiotic treatment within 2 weeks prior to check-in Plasma donation within 7 days prior to check-in Donation of blood or blood products (with the exception of plasma as noted above), had significant blood loss, or received whole blood or a blood product transfusion within 56 days prior to check-in Participation in a previous clinical study for an investigational drug, device, biologic, or a tobacco product within 30 days prior to check-in Participation in 2 or more Altria Client Services (ALCS) studies within the past 12-month period prior to check-in Subject or a first-degree relative (ie, parent, sibling, child, spouse/partner) is a current or former employee of the tobacco industry or a named party or class representative in litigation with any tobacco company Subject or a first-degree relative (ie, parent, sibling, child, spouse/partner) is a current employee of the study site Positive result for coronavirus disease (COVID)-19 (SARS-CoV-2) test at screening or check-in One or more yes answers to any of the questions on the COVID-19 (SARS-CoV-2) screening questionnaire (provided by the study site) at screening or check-in. Have been diagnosed with major depressive disorder or have a history of suicide attempt.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Group 1<br>Subjects will be asked to continue smoking their UBCs ad libitum for 7 days. | |
| Experimental: Group 2<br>Subjects will exclusively use 2 mg NP, using at least 3 pouches per day for 7 days. | Other: OTDN Product 1<br>* Mint on!® 2 mg nicotine pouches<br>|
| Experimental: Group 3<br>Subjects will exclusively use 4 mg NP, using at least 3 pouches per day for 7 days. | Other: OTDN Product 2<br>* Mint on!® 4 mg nicotine pouches<br>|
| Experimental: Group 4<br>Subjects will exclusively use 8 mg NP, using at least 3 pouches per day for 7 days. | Other: OTDN Product 3<br>* Mint on!® 8 mg nicotine pouches<br>|
| Experimental: Group 5<br>Subjects will completely stop all tobacco product usage for 7 days. | Other: No Tobacco<br>* subjects completely stop all tobacco product usage for 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NNAL Exposure and Change from Baseline | To compare 24-hour urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in subjects using nicotine pouches (NP) for 7 days versus subjects who continue to smoke cigarettes for 7 days | Samples collected on Day -1 (baseline) and Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers of Exposure (Except NNAL) and Change from Baseline | To compare biomarkers of exposure (BOEs) (except total NNAL) in subjects using NP for 7 days versus subjects who continue to smoke cigarettes for 7 days and subjects who stopped using any tobacco products for 7 days. BOE: NE, 2-AN, 4-ABP, HEMA, CEMA, SPMA, HMPMA, 3-HPMA, 2-HPMA, AAMA, GAMA, 2-MHBMA, 2-OH-Flu, 2-OH-Nap, 1-OH-Phe, 3-OH-B[a]P, 1-OH-Pyr, COHb | Samples collected on Day -1 (baseline) and Day 7 | 
| Product Use Behavior | To characterize product use behaviors (such as number of cigarettes smoked per day and number of nicotine pouches used per day). | Data collected on Days 1, 2, 3, 4, 5, 6 and 7 |