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The overall goal of the study is to demonstrate reduction in the levels of biomarkers of exposure (BoExp) to selected harmful and potentially harmful constituents (HPHCs) identified in cigarettes and to obtain safety information in healthy adult smokers switching to the Carbon Heated Tobacco Product 1.2 (CHTP 1.2) as compared to subjects continuing smoking cigarettes (CC) in a confinement setting for 5 days (exclusive use) followed by an ambulatory setting of 85 days.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CHTP 1.2 | Experimental | Ad libitum use of the CHTP 1.2 |
|
| CC | Active Comparator | Ad libitum use of subject's own preferred non-menthol brand of CC |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CHTP 1.2 | Other | Ad libitum use of the CHTP 1.2 for 5 days in confinement followed by 85 days in an ambulatory setting. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Concentrations of Monohydroxybutenylmercapturic Acid (MHBMA) | Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 5 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. | 5 days |
| Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 5 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. | 5 days |
| Concentration of S-phenylmercapturic Acid (S-PMA) | Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 5 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. | 5 days |
| Levels of Carboxyhemoglobin (COHb) | % COHb blood measurements performed in the evening of Day 5, expressed as % of saturation of hemoglobin. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 5 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. | 5 days |
| Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) | Concentrations measured at Day 90 in urine, adjusted for creatinine. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 90 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christelle Haziza, PhD | Philip Morris Products S.A. | Study Chair |
| Monika Tomaszewska-Kiecana, MD | BioVirtus Research Site | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| BioVirtus Research Site Sp. z o.o. | Nadarzyn | 05-830 | Poland |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32380119 | Result | Bosilkovska M, Tran CT, de La Bourdonnaye G, Taranu B, Benzimra M, Haziza C. Exposure to harmful and potentially harmful constituents decreased in smokers switching to Carbon-Heated Tobacco Product. Toxicol Lett. 2020 Sep 15;330:30-40. doi: 10.1016/j.toxlet.2020.04.013. Epub 2020 May 5. |
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Following enrollment of 121 subjects, each subject received a product test of CHTP 1.2 prior to randomization.
One subject was not randomized due to the physician's decision. This subject is included in the "Exposed Not Randomized" reporting group of the Baseline Characteristics.
Consequently, 120 subjects were randomized.
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| ID | Title | Description |
|---|---|---|
| FG000 | CHTP 1.2 | Ad libitum use of the CHTP 1.2 CHTP 1.2: Ad libitum use of the CHTP 1.2 for 5 days in confinement followed by 85 days in an ambulatory setting. |
| FG001 | Cigarettes (CC) | Ad libitum use of subject's own preferred non-menthol brand of CC CC: Ad libitum use of subject's own preferred non-menthol brand of CC for 5 days in confinement followed by 85 days in an ambulatory setting. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Confinement Period |
|
| |||||||||||||||||||||
| Ambulatory Period |
|
Overall safety population refers to all subjects who were exposed and randomized or exposed and not randomized.
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| ID | Title | Description |
|---|---|---|
| BG000 | CHTP 1.2 | Ad libitum use of the CHTP 1.2 CHTP 1.2: Ad libitum use of the CHTP 1.2 for 5 days in confinement followed by 85 days in an ambulatory setting. |
| BG001 | Cigarettes (CC) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Concentrations of Monohydroxybutenylmercapturic Acid (MHBMA) | Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 5 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. | Per Protocol (PP) population | Posted | Geometric Least Squares Mean | 95% Confidence Interval | pg/mg creat | 5 days |
|
Adverse events were collected from the signature of the Informed Consent Form (ICF) until the end of the safety follow-up period, which covered a period of between 128 to 169 days for each subject.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Product Test | After all inclusion/exclusion criteria were checked, all eligible subjects were enrolled and performed a product test using up to five CHTP 1.2 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Appendicitis | Infections and infestations | MedDRA version 18.0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA version 18.0 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Christelle Haziza | Philip Morris Products S.A. | +41 58 242 11 11 | christelle.haziza@pmi.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 5, 2016 | Feb 24, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 27, 2017 | Mar 16, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D012907 | Smoking |
| ID | Term |
|---|---|
| D001519 | Behavior |
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| CC | Other | Ad libitum use of subject's own preferred non-menthol brand of CC for 5 days in confinement followed by 85 days in an ambulatory setting. |
|
| 90 days |
| NOT COMPLETED |
|
|
Ad libitum use of subject's own preferred non-menthol brand of CC
CC: Ad libitum use of subject's own preferred non-menthol brand of CC for 5 days in confinement followed by 85 days in an ambulatory setting.
| BG002 | Exposed Not Randomized | "Exposed not randomized" refers to all subjects exposed to CHTP 1.2 but not randomized. |
| BG003 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| BMI | Mean | Standard Deviation | kg/m2 |
|
Ad libitum use of subject's own preferred non-menthol brand of CC CC: Ad libitum use of subject's own preferred non-menthol brand of CC for 5 days in confinement followed by 85 days in an ambulatory setting. |
|
|
|
| Primary | Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 5 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. | Per Protocol (PP) population | Posted | Geometric Least Squares Mean | 95% Confidence Interval | ng/mg creat | 5 days |
|
|
|
|
| Primary | Concentration of S-phenylmercapturic Acid (S-PMA) | Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 5 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. | Per Protocol (PP) population | Posted | Geometric Least Squares Mean | 95% Confidence Interval | pg/mg creat | 5 days |
|
|
|
|
| Primary | Levels of Carboxyhemoglobin (COHb) | % COHb blood measurements performed in the evening of Day 5, expressed as % of saturation of hemoglobin. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 5 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. | Per Protocol (PP) population | Posted | Geometric Least Squares Mean | 95% Confidence Interval | % of saturation of hemoglobin | 5 days |
|
|
|
|
| Primary | Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) | Concentrations measured at Day 90 in urine, adjusted for creatinine. Geometric least squares (LS) means and confidence intervals (Cls) from a generalized linear model conducted on log-transformed Day 90 values with log-transformed baseline value, study arm, sex and CC consumption reported at admission as fixed effect factors. | Per Protocol (PP) population | Posted | Geometric Least Squares Mean | 95% Confidence Interval | pg/mg creat | 90 days |
|
|
|
|
| 0 |
| 121 |
| 0 |
| 121 |
| 62 |
| 121 |
| EG001 | CHTP 1.2 Confinement | Ad libitum use of the CHTP 1.2 for 5 days in confinement. | 0 | 80 | 1 | 80 | 37 | 80 |
| EG002 | CC Confinement | Ad libitum use of subject's own preferred non-menthol brand of CC for 5 days in confinement. | 0 | 40 | 0 | 40 | 12 | 40 |
| EG003 | CHTP 1.2 Ambulatory | Ad libitum use of the CHTP 1.2 for 85 days in an ambulatory setting. | 0 | 77 | 1 | 77 | 50 | 77 |
| EG004 | CC Ambulatory | Ad libitum use of subject's own preferred non-menthol brand of CC for 85 days in an ambulatory setting. | 0 | 39 | 1 | 39 | 26 | 39 |
| EG005 | CHTP 1.2 Safety FU | CHTP 1.2 Safety Follow-Up period of 28 days | 0 | 80 | 0 | 80 | 1 | 80 |
| EG006 | CC Safety FU | CC Safety Follow-Up period of 28 days | 0 | 40 | 0 | 40 | 1 | 40 |
| EG007 | CHTP 1.2 Post-Randomization | CHTP 1.2 Post-Randomization period | 0 | 80 | 2 | 80 | 64 | 80 |
| EG008 | CC Post-Randomization | CC Post-Randomization period | 0 | 40 | 1 | 40 | 31 | 40 |
| Peritonsillar Abscess | Infections and infestations | MedDRA version 18.0 |
|
| Joint Dislocation | Injury, poisoning and procedural complications | MedDRA version 18.0 |
|
| Nasopharyngitis | Infections and infestations | MedDRA version 18.0 |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA version 18.0 |
|
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA version 18.0 |
|
| Oropharyngeal Pain | Respiratory, thoracic and mediastinal disorders | MedDRA version 18.0 |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA version 18.0 |
|
| Alanine Aminotransferase Increased | Investigations | MedDRA version 18.0 |
|
| Blood Triglycerides Increased | Investigations | MedDRA version 18.0 |
|
| Gastrointestinal disorders | MedDRA version 18.0 |
|
| Vessel Puncture Site Bruise | General disorders | MedDRA version 18.0 |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA version 18.0 |
|
| Musculoskeletal and connective tissue disorders | MedDRA version 18.0 |
|
| Injury, poisoning and procedural complications | MedDRA version 18.0 |
|
| General disorders | General disorders | MedDRA version 18.0 | Systematic Assessment |
|
We confirm we have the contractual provisions in place which specify that in no event will the study site be allowed to disclose to any third party (or publicly release) any information obtained through the study without the CRO's prior written consent which in turn cannot provide such consent without Sponsor's approval unless such publication is made to satisfy regulatory requirements.
The Intellectual Property rights and research results from the present study belong to the Sponsor.
| Other |
The analysis will test if the geometric LS mean level of 3-HPMA for CHTP is lower than for CC. The following hypothesis will be evaluated: H0: XCHTP - XCC ≤ 0.0 HA: XCHTP - XCC > 0.0 where XCHTP and XCC are the geometric LS means of CHTP and CC, respectively. H0 is rejected with a type I error α = 2.5% (one-sided test). |
| Other |
The analysis will test if the geometric LS mean level of S-PMA for CHTP is lower than for CC. The following hypothesis will be evaluated: H0: XCHTP - XCC ≤ 0.0 HA: XCHTP - XCC > 0.0 where XCHTP and XCC are the geometric LS means of CHTP and CC, respectively. H0 is rejected with a type I error α = 2.5% (one-sided test). |
| Other |
The analysis will test if the geometric LS mean level of COHb for CHTP is lower than for CC. The following hypothesis will be evaluated: H0: XCHTP - XCC ≤ 0.0 HA: XCHTP - XCC > 0.0 where XCHTP and XCC are the geometric LS means of CHTP and CC, respectively. H0 is rejected with a type I error α = 2.5% (one-sided test). |
| Other |
The analysis will test if the geometric LS mean level of Total NNAL for CHTP is lower than for CC. The following hypothesis will be evaluated: H0: XCHTP - XCC ≤ 0.0 HA: XCHTP - XCC > 0.0 where XCHTP and XCC are the geometric LS means of CHTP and CC, respectively. H0 is rejected with a type I error α = 2.5% (one-sided test). |