A 6-month Randomized, Controlled, Open-label, 2-arm Parallel Group, Multicenter Study to Evaluate the Effect of Switching From Cigarette Smoking to the Use of IQOS in Smokers With Generalized Chronic Periodontitis on the Response to Mechanical Periodontal Treatment and Oral Health Status.
Phase: NA
Conditions: Periodontal Diseases, Chronic Periodontitis, Periodontal Pocket, Tooth Mobility, Gingival Diseases, Smoking, Cigarette
Sponsor: Philip Morris Products S.A.

 
 
 
 
 
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Clinical Study Protocol  
P1-OHS-01-JP  
Study title: 
A 6-month randomized, controlled, open-label, 2-arm parallel 
group, multicenter study to evaluate the effect of switching from 
cigarette smoking to the use of IQOS in smokers with 
generalized chronic periodontitis on the response to mechanical 
periodontal treatment and oral health status.  
Short name: 
Effect of switching from cigarette smoking to the use of IQOS 
on periodontitis treatment outcome 
Product name: 
IQOS (Tobacco Heating System (THS) with Marlboro 
Heatsticks) 
Registration number 
Not assigned 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Version number: 
Final version 4.0 
Date : 
09 January 2019 
Author: 
, PhD, Clinical Scientist 
 MD, Medical Safety Officer 
 PhD, Statistician 

 
 
 
 
 
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SUMMARY OF CHANGES 
Clinical Study Protocol 
P1-OHS-01-JP 
 
Version 
Date 
Amendment 
Second updated 
protocol 
4.0 
09 January 2019 
Non-substantial 
changes 
First updated 
protocol 
3.0 
06 April 2018 
Non-substantial 
changes 
Original protocol 
2.0 
05 September 2017 
 
 
The main purpose of this above table is to summarize the updates between original clinical 
study protocol P1-OHS-01-JP (Final Version 2.0) dated 05 September 2017, its first updated 
version (Final Version 3.0) dated 06 April 2018, and its second updated version (Final version 
4.0 dated 09 January 2019.  
More precise details on the protocol sections changed are provided in the Appendix 5, with the 
list of changes, including the previous and the amended texts, as well as the reasons to change. 
The new text has been highlighted in bold (e.g. new text) and deleted text has been crossed 
out (e.g. deleted text). 

 
 
 
 
 
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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Name of Product: 
IQOS (Tobacco Heating System (THS) with Marlboro Heatsticks) 
Study Title: 
A 6-month randomized, controlled, open-label, 2-arm parallel group, multicenter study to 
evaluate the effect of switching from cigarette smoking to the use of IQOS in smokers with 
generalized chronic periodontitis on the response to mechanical periodontal treatment and 
oral health status. 
Study Number: 
P1-OHS-01-JP 
Objectives and Endpoints 
Primary Objective and Endpoint: 
The primary objective of this study is: 
To demonstrate the effect of switching to IQOS use compared to continued cigarette 
smoking on the response of pocket depth (PD) to mechanical periodontal therapy. 
Endpoint (6 months):  
Mean PD reduction in all sites with initial PD ≥ 4 mm after mechanical periodontal 
therapy. 
Secondary Objectives and Endpoints: 
The secondary objectives of this study are: 
1. To evaluate the effect of switching to IQOS use compared to continued cigarette smoking 
on the response of PD and CAL to mechanical periodontal therapy over time. 
Endpoint: 
 Mean PD change in sites with initial PD ≥ 4 mm after mechanical periodontal therapy 
(3 months only). 
 Mean CAL change in sites with initial PD ≥ 4 mm after mechanical periodontal 
therapy (3 and 6 months). 

 
 
 
 
 
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2. To evaluate the differences of periodontal parameters in the response to periodontal 
therapy in patients who switch to IQOS use compared to those who continue to smoke 
cigarettes. 
Endpoints (3 and 6 months): 
 Change in mean full-mouth CAL 
 Change in mean full-mouth PD 
 Mean PD change in sites with initial PD < 4 mm, and with initial PD of 4 mm to < 
5mm, 5 mm to < 6 mm, 6 mm to < 7 mm and ≥ 7 mm 
 Mean CAL change in sites with initial PD < 4 mm, and with initial PD of 4 mm to < 
5mm, 5 mm to < 6 mm, 6 mm to < 7 mm and ≥ 7 mm 
 Change in the number of sites with PD < 4 mm, with PD 4 mm to < 5mm, with PD 
5 mm to < 6 mm , with PD 6 mm to < 7 mm and with PD ≥ 7 mm 
 Change in gingival index (GI) score 
 Change in tooth mobility (grade) 
 Change in plaque control record (PCR) 
 Change in bleeding on probing (BOP) scores 
3. To evaluate the levels of biomarkers of exposure (BoExp) over the exposure period in 
patients who switch to IQOS use and patients who continue to smoke cigarettes. 
Endpoint (3 and 6 months): 
 Urinary nicotine equivalents (NEQ), total 4-[methylnitrosamino]-1-[3-pyridyl]-1-
butanol (NNAL) and 2-cyanoethylmercapturic acid (CEMA). 
4. To describe self-reported tobacco or nicotine containing product use over the duration of 
the study in patients switching to IQOS use and patients who continue to smoke 
cigarettes. 
Endpoint:  
 Number of self-reported tobacco or nicotine containing product use.  
5. To monitor safety. 
Endpoint:  
 Incidence of adverse events (AEs)/serious adverse events (SAEs), including AEs 
related to device events, and device events, including device malfunction/misuse, 
over the duration of the study. 

 
 
 
 
 
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Exploratory objectives and Endpoints: 
1. To determine quantitative changes in the inflammatory response by measuring pro-
inflammatory and immuno-regulatory mediators in the gingival crevicular fluid (GCF) 
in patients switching to IQOS use compared to those continuing to smoke cigarettes. 
Endpoints (3 months): 
 Measurement of pro-inflammatory and immuno-regulatory mediators in the GCF 1  
2. To evaluate the microbiological status in patients switching to IQOS use compared to 
those continuing to smoke cigarettes. 2 
Endpoint (6 months) : 
 Microbiological status from subgingival plaque (SP) samples. 
3. To evaluate the transcriptomics profile of buccal swabs in patients switching to IQOS 
use compared to those continuing to smoke cigarettes. 2 
Endpoint (3 and 6 months) : 
 Full transcriptomics profile assessment of buccal swabs derived from the right and 
left buccal mucosa. 
Study Hypotheses: 
The primary study hypothesis is that there will be a favorable difference in the mean PD at 
6 months in IQOS users as compared to smokers who continue to smoke cigarettes in patients 
with generalized chronic periodontitis.  
Evaluation criteria: 
The study will substantiate that IQOS improves periodontitis if there is a statistically 
significant improvement in primary endpoint for smokers who switch to IQOS use as 
compared to smoker who continue to smoke cigarettes. 
The secondary study hypotheses that will be tested in IQOS users and smokers are: 
                                                 
1 sCD40L, CRP, EGF, Eotaxin/CCL11, Flt3 ligand, GM-CSF, GRO, IFNα2, IL-1α, IL-1β, IL-1Ra, IL-2, IL-3, 
IL-4, IL-5, IL-6, IL-7, IL-8/CXCL8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A/CTLA8, IP-
10/CXCL10, MCP-1/CCL2, MCP-3/CCL7, MDC/CCL22, MIP-1α/CCL3, MIP-1β/CCL4, MMP-1, MMP-8, 
MMP-9, MMP-10, MMP-12, MMP-13, osteoprotegerin, PDGF-AA, PDGF-AB/BB, RANKL, RANTES/CCL5, 
TGFα, TIMP-1, TNFα, TNFβ / LT-α, (please refer to the Abbreviations for full spelling). 
2 Results of these exploratory objectives will be reported in separate reports, and will not be part of the main 
clinical study report (CSR). 

 
 
 
 
 
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 That there will be favorable changes of PD at 3 months in IQOS users as compared 
to smokers who continue to smoke cigarettes in patients with generalized chronic 
periodontitis. 
 That there will be favorable changes of CAL at 3 and 6 months in IQOS users as 
compared to smokers who continue to smoke cigarettes in patients with generalized 
chronic periodontitis. 
 That there will be favorable changes at 3 and 6 months in total NNAL and CEMA 
levels in IQOS users as compared to smokers who continue to smoke cigarettes  
Study Design: 
This is a randomized, controlled, open-label, 2-arm, parallel group ambulatory study with 
the randomization stratified by daily cigarette consumption over the month (30 days) prior 
to Visit 1 (V1) (10-19 cigarettes/day vs. > 19 cigarettes/day) and disease severity recorded 
at Visit 1 (< 5 mm PD vs. ≥ 5 mm PD) based on the most severely diseased tooth, in smokers 
with generalized chronic periodontitis who are randomized to either switch from smoking 
cigarettes to IQOS use or continuing smoking cigarettes. 

 
 
 
 
 
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enrolled but not randomized may be discontinued. 
 
IQOS arm: ~86 patients, switching from cigarette smoking to IQOS use 
 
Cigarette arm: ~86 patients, continuing cigarette smoking 
For each patient, standard of care procedures as defined by the Japanese guidelines on 
periodontal disease will be applied, and supplemented by additional assessments as per this 
study protocol. Patients will be encouraged to follow the recommended standard of care 
treatment as advised by the Investigator.  
Study Population and Main Criteria for Inclusion: 
Criteria for Inclusion: 
A sufficient number of patients will be enrolled in order to randomize at least 172 patients 
meeting the following main inclusion criteria. 
1. Patient is Japanese. 
2. Informed consent form (ICF) has been signed. 
3. Patient is aged ≥ 30 years old. 
4. Patient has smoked on average at least 10 commercially available cigarettes per day 
(no brand restriction) for at least 5 years prior to Visit 1, based on self-reporting. 
Smoking status will be verified based on a urinary cotinine test (i.e., cotinine ≥ 200 
ng/mL). 
5. Patient has at least 15 natural teeth (refer to Definition of Terms), excluding the teeth 
which need to be extracted or whose mobility grade is ≥ 3. 
6. Patient has generalized chronic periodontitis (i.e., more than 30% of diseased teeth 
with a PD ≥ 4 mm), considering only teeth that do not need to be extracted or whose 
mobility grade is < 3. 
7. Patient does not intend to quit smoking during the study. 
8. Patient is ready to comply with study procedures and to use the product he/she is 
allocated to for the duration of the study. 
Criteria for Exclusion: 
1. Patient has self-reported history of diagnosed systemic diseases (e.g., stroke or acute 
cardiovascular event within the last 5 years, diabetes, active cancer), or any other 
conditions that in the opinion of the Investigator would jeopardize the safety of the 
participant or affect the validity of the study results. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
2. Patient is legally incompetent, physically or mentally incapable of giving consent 
(e.g., emergency situation, under guardianship, in a social or psychiatric institution, 
prisoner or involuntarily incarcerated). 
3. As per the Investigator’s judgment, patient cannot participate in the study for any 
reason (e.g., medical, psychiatric and/or social reason). 
4. As per the Investigator’s or designee’s judgment, patient has medical conditions 
which require or will require in the course of the study, a medical intervention (e.g., 
start of treatment, surgery, hospitalization) which may interfere with the study 
participation and/or study results.  
5. Patient has orthodontic appliances. 
6. Patient received root planing therapy within the 6 months prior to V1. 
7. Patient received surgical periodontal therapy within 3 years prior to V1. 
8. Patient has identifiable premalignant changes of the oral mucosa at V1. 
9. Patient was treated within the 3 months prior to V1 with systemic antibiotics or was 
treated with topical antibiotics applied in the mouth. 
10. Continuous systemic use of steroidal or non-steroidal anti-inflammatory drugs for 
more than 20 days during the past 30-day period (except for low dose aspirin, i.e., ≤ 
300 mg, e.g., for prevention of thrombus/embolus in angina pectoris, myocardial 
infarction, transient ischemic cerebrovascular accidents, bypass operations). 
11. Patient has been previously screened or enrolled in this study 
12. Female patients who are pregnant, breast-feeding, or planning a pregnancy within 
the course of the study. 
13. Patient is a current or former employee of the tobacco industry or their first-degree 
relatives (parent and child). 
14. Patient is an employee of the investigational site or any other parties involved in the 
study or their first-degree relatives (parent and child). 
15. Patient has participated in a clinical study within 3 months prior V1. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
Investigational Products; Dose and Mode of Use:  
Test product: IQOS with HeatSticks. An IQOS starter kit (IQOS device and a selection of 
HeatStick flavor variants available on the Japanese market) will be supplied to the patient 
randomized to IQOS arm at the end of V2. Patient allocated to IQOS arm will be asked to 
buy his/her HeatSticks for his/her own use during the entire investigational period as 
HeatSticks will not be provided by the Sponsor. Patients will use IQOS ad libitum with no 
flavor restrictions. 
Reference product: The patient’s own preferred brand of commercially available cigarettes 
will not be provided by the Sponsor but purchased by the patients for their own use for the 
duration of the study. Patients will use ad libitum their preferred brand of commercially 
available cigarettes with no brand restrictions. 
Study Duration:  
The study duration per patient will be of maximum of up to 31 weeks, including a 1-day visit 
(V1), up to 2 weeks interval between V1 and V2, followed by a 6-month investigational 
exposure period, with 1-day visits after 3 and 6 months (V3, ± 7 days, V4, ± 14 days at each 
visit), and a 1-week safety follow-up period. The end of the study for an individual patient 
will be defined as V4 or the date of early termination plus the 7 days for the safety follow-
up period. The end of the entire study is the latest date that an individual patient reaches the 
end of the study. 
Statistical Methods:  
The Full Analysis Set (FAS) will consist of all randomized patients (who have signed the 
ICF) who have at least post-randomization product use experience, and who have at least 
one valid non-safety assessment after randomization/enrollment. 
The Per Protocol Set (PP) is the subset of the FAS who fulfill key compliance criteria of the 
protocol, and have no major protocol deviation that influences the evaluability of the study 
data.  
As Exposed Set is the FAS analyzed by actual exposure. 
The Safety Set will consist of all enrolled patients with at least one valid value for safety 
assessment analyzed by actual exposure. 
Descriptive statistics for continuous variables will include the number of patients, number 
and percent of patients with missing data, the mean and standard deviation, median, first and 
third quartiles, minimum and maximum, and 95% confidence interval (CI) for each product 
exposure, and summary across all patients. In addition, the results may be presented as a 
stratified summary as defined in the Statistical Analysis Plan (SAP). 

 
 
 
 
 
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The primary analysis will be performed on the As Exposed Set using a mixed model for 
repeated measures. The treatment by visit interaction term will be included in the model 
from which the p-values at each time point will be taken. 
Sample Size:  
The sample size needed to attain 80% power to show at least a 0.25 mm gain of PD in IQOS 
compared to the cigarette arm, using a one-sided test with 2.5% type I error probability, 
assuming a dropout rate of 15% and a 10% rate of patients not-adherent to product allocation. 
A total of 172 patients (86 in each arm) are required to be randomized. 
Safety Assessments: 
AEs (including SAEs) and device events will be captured. Any AEs (including SAEs) will 
be assessed by the Investigator(s) or designee(s) in order to establish relationship to 
Investigational Products (IPs) and study procedures. AEs and device events will be collected 
from the time the patients have signed their ICFs until the end of the study. 
The Investigator must notify the Sponsor of all SAEs and pregnancies within 24 hours of the 
first awareness. 

 
 
 
 
 
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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................................ 3 
TABLE OF CONTENTS ........................................................................................................ 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 20 
1 
ETHICS AND REGULATIONS .................................................................................... 26 
1.1 
Institutional Review Board (IRB) Approval ......................................................... 26 
1.2 
Ethical Conduct of the Study ................................................................................ 27 
1.3 
Patient Information and Consent .......................................................................... 27 
1.3.1 
Informed Study Consent Form/Patient Information Sheet for 
Participation to the Study ............................................................................ 27 
1.3.2 
Amendment Informed Consent Forms/ Patient Information Sheet for 
Participation to the Study ............................................................................ 27 
1.4 
Good Clinical Practice and Regulatory Requirements ......................................... 28 
2 
INTRODUCTION .......................................................................................................... 29 
2.1 
Background ........................................................................................................... 29 
2.2 
Purpose of the Study ............................................................................................. 33 
2.3 
Anticipated Benefits and Risks ............................................................................. 33 
2.3.1 
Anticipated Benefits .................................................................................... 33 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures ............................ 34 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Products ................. 34 
2.3.4 
Unforeseeable Risks .................................................................................... 34 
3 
STUDY OBJECTIVES ................................................................................................... 35 
3.1 
Primary Objective and Endpoint ........................................................................... 35 
3.2 
Secondary Objectives and Endpoints .................................................................... 35 
3.3 
Exploratory Objectives and Endpoints ................................................................. 36 
4 
OVERALL STUDY DESIGN AND PLAN ................................................................... 38 
4.1 
Rationale for Study Design and Control Group(s) ............................................... 42 
4.2 
Appropriateness of Measurements ........................................................................ 44 
4.3 
Study Duration ...................................................................................................... 45 
5 
STUDY POPULATION ................................................................................................. 46 
5.1 
Selection of Study Population ............................................................................... 46 
5.1.1 
Inclusion Criteria ........................................................................................ 46 
5.1.2 
Exclusion Criteria ....................................................................................... 46 

 
 
 
 
 
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5.2 
Discontinuation of Patients from the Study .......................................................... 47 
5.2.1 
Violation of Selection Criteria .................................................................... 49 
5.2.2 
Other Reasons for Discontinuation of Patients from the Study .................. 49 
5.3 
Lost to Follow-up .................................................................................................. 49 
6 
INVESTIGATIONAL PRODUCT(S) ............................................................................ 50 
6.1 
Description of Investigational Product(s) ............................................................. 50 
6.1.1 
Test Product(s) ............................................................................................ 50 
6.1.2 
Reference and Baseline Product(s) ............................................................. 51 
6.1.3 
Packaging and Labeling .............................................................................. 51 
6.2 
Administration of Investigational Product(s) ........................................................ 51 
6.2.1 
From Enrollment to Randomization ........................................................... 51 
6.2.2 
Investigational Period ................................................................................. 52 
6.2.3 
Safety Follow-up Period ............................................................................. 52 
6.3 
Method for Assigning Patients to Study Arms ..................................................... 52 
6.4 
Blinding ................................................................................................................. 53 
6.4.1 
Blinding of the Examiner ............................................................................ 53 
6.4.2 
Blinding of Data .......................................................................................... 53 
6.5 
Investigational Product Accountability and Adherence........................................ 54 
6.5.1 
Dispensing Investigational Product ............................................................ 54 
6.5.2 
Storage and Accountability ......................................................................... 54 
6.5.3 
Investigational Product Retention ............................................................... 55 
6.5.4 
Adherence to Investigational Product(s) ..................................................... 55 
6.5.5 
Product Use Restrictions ............................................................................. 55 
6.5.6 
Dietary Restrictions .................................................................................... 55 
6.6 
Concomitant Medication ....................................................................................... 55 
6.7 
Concomitant Therapeutic Procedures ................................................................... 56 
7 
STUDY PROCEDURES ................................................................................................ 57 
7.1 
Informed Consent and Guidance .......................................................................... 57 
7.2 
Advice on the Risks of Smoking/Smoking Cessation Advice and Debriefing 
on IQOS ................................................................................................................ 57 
7.3 
Dental/Clinical Assessments ................................................................................. 58 
7.3.1 
Demographic Data ...................................................................................... 58 
7.3.2 
Questions on Smoking History/Habits and Intention to Quit Smoking ...... 58 

 
 
 
 
 
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7.3.3 
Presentation of IQOS .................................................................................. 58 
7.3.4 
Dental/Medical History and Previous and Ongoing Medications .............. 58 
7.3.5 
Dental Assessments .................................................................................... 59 
7.4 
Biomarker Assessments ........................................................................................ 62 
7.4.1 
Assessments in Urine .................................................................................. 62 
7.5 
Other Clinical Assessments and Sampling ........................................................... 63 
7.5.1 
Urine Pregnancy Testing ............................................................................. 63 
7.5.2 
Cotinine Test ............................................................................................... 63 
7.5.3 
Assessments in GCF ................................................................................... 63 
7.5.4 
Assessments in Subgingival Plaque ............................................................ 64 
7.5.5 
Assessments in Buccal Swabs .................................................................... 64 
7.5.6 
Sample Handling, Storage, and Shipment .................................................. 64 
7.5.7 
Self-reported Tobacco- or Nicotine-Containing Product Use .................... 64 
7.6 
Periodontal Treatment/Maintenance ..................................................................... 65 
7.6.1 
Scaling ......................................................................................................... 65 
7.6.2 
Scaling and Root Planing (SRP) ................................................................. 65 
8 
ADVERSE EVENTS ...................................................................................................... 66 
8.1 
Definitions ............................................................................................................. 66 
8.1.1 
Adverse Events ........................................................................................... 66 
8.1.2 
Serious Adverse Event ................................................................................ 66 
8.2 
Assessment of Adverse Events ............................................................................. 67 
8.2.1 
Assessment of Adverse Events ................................................................... 67 
8.2.2 
Period of Collection .................................................................................... 67 
8.2.3 
Intensity of Adverse Event .......................................................................... 68 
8.2.5 
Expectedness ............................................................................................... 69 
8.2.6 
Medical Monitor ......................................................................................... 69 
8.3 
Reporting and Follow-Up of Serious Adverse Events .......................................... 69 
8.4 
Reporting of other events critical to safety evaluations ........................................ 70 
8.5 
Reporting and Follow-Up of Pregnancies ............................................................. 71 
8.6 
Adverse Events Leading to Discontinuation ......................................................... 71 
8.7 
Device Events / Investigational Product Malfunction and Misuse ....................... 72 
9 
STUDY ACTIVITIES .................................................................................................... 73 
9.1 
Screening, Enrollment and Baseline Visit: V1 ..................................................... 73 

 
 
 
 
 
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9.2 
1st SRP and Randomization Visit: V2 ................................................................... 75 
9.3 
Investigational Period Visit: V3 ............................................................................ 77 
9.4 
End of Study Assessments Visit: V4 .................................................................... 78 
9.5 
Safety Follow-up Period ....................................................................................... 79 
9.6 
Early Termination Procedures .............................................................................. 80 
10 QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 81 
10.1 
Monitoring ............................................................................................................ 81 
10.2 
Training of Staff .................................................................................................... 81 
10.2.1 
Calibration of Examiners ............................................................................ 82 
10.3 
Audits and Inspections .......................................................................................... 82 
11 DATA MANAGEMENT ACTIVITIES ......................................................................... 83 
11.1 
Data Capture ......................................................................................................... 83 
11.1.1 
Case Report Forms and Study Records ...................................................... 83 
11.1.2 
Protocol Deviations ..................................................................................... 83 
11.2 
Data Handling ....................................................................................................... 84 
11.2.1 
Data Validation ........................................................................................... 84 
11.2.2 
Coding ......................................................................................................... 84 
11.2.3 
Database Lock ............................................................................................. 85 
12 PLANNED STATISTICAL METHODS ....................................................................... 86 
12.1 
General Considerations ......................................................................................... 86 
12.1.1 
Stratification Criteria .................................................................................. 86 
12.1.2 
Definitions for Statistical Data Analysis ..................................................... 86 
12.1.3 
Descriptive Statistics ................................................................................... 86 
12.1.4 
Handling of Missing Values and of Values Outside the Detection Limits . 86 
12.1.5 
Significance Level for Inferential Analysis ................................................ 87 
12.2 
Determination of Sample Size and Power Consideration ..................................... 88 
12.3 
Product use ............................................................................................................ 89 
12.4 
Analysis Populations ............................................................................................. 90 
12.4.1 
As Exposed Set ........................................................................................... 90 
12.4.2 
Full Analysis Set (FAS) .............................................................................. 90 
12.4.4 
Adherent Use Set ........................................................................................ 91 
12.4.5 
Safety Set .................................................................................................... 91 
12.5 
Demographics and Baseline Characteristics ......................................................... 91 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
12.6 
Primary Analysis ................................................................................................... 91 
12.7 
Secondary Analysis ............................................................................................... 92 
12.8 
Safety Analysis ..................................................................................................... 93 
12.8.1 
Vital Signs ................................................................................................... 94 
12.8.2 
Laboratory Safety Parameters ..................................................................... 94 
12.8.3 
Other Safety Endpoints ............................................................................... 94 
12.9 
Exploratory Analysis ............................................................................................ 94 
12.9.1 
Exploratory Endpoint Analysis ................................................................... 94 
12.9.2 
Descriptive Analysis ................................................................................... 94 
12.10 Interim Analysis .................................................................................................... 95 
13 ADMINISTRATIVE CONSIDERATIONS ................................................................... 96 
13.1 
Sites, Principal Investigators and Study Administrative Structure ....................... 96 
13.1.1 
Sites and Principal Investigators ................................................................. 96 
13.1.2 
Sponsor ....................................................................................................... 96 
13.1.3 
Other Responsibilities ................................................................................. 96 
13.2 
Patient Confidentiality .......................................................................................... 97 
13.3 
Access to Source Documentation ......................................................................... 97 
13.4 
Record Retention .................................................................................................. 98 
13.5 
Assessment Study Report ..................................................................................... 99 
13.6 
Financial Disclosure ............................................................................................ 100 
13.7 
Publication and Disclosure Policy ...................................................................... 100 
13.8 
Insurance ............................................................................................................. 100 
14 REFERENCE LIST ...................................................................................................... 101 
Appendix 1 
Schedule of Events .......................................................................... 111 
Appendix 2 
Participating Laboratories ............................................................... 115 
Appendix 3 
Investigational Product and Instructions for Use ............................ 116 
Appendix 4 
List of Sites and Principal Investigators ......................................... 116 
Appendix 5 
Changes in Protocol Amendments .................................................. 117 
 
 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
LIST OF IN-TEXT TABLES 
Table 1 
Test Product (IQOS) ............................................................................................... 50 
Table 2 
Blinding Scheme .................................................................................................... 53 
Table 3 
Schedule - Screening, Enrollment and Baseline Visit: V1 ..................................... 73 
Table 4 
Time Schedule – 1st SRP Visit and Randomization: V2 ....................................... 75 
Table 5 
Time Schedule – 3 Months Visit: V3 ..................................................................... 77 
Table 6 
Time Schedule – 6 Months Visit: V4 ..................................................................... 78 
Table 7 
Sample sizes for PD differences between smokers and non-smokers and standard 
deviations based on the literature ........................................................................... 89 
 
 
 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
LIST OF IN-TEXT FIGURES 
Figure 1 Study Flow Chart ...................................................................................................... 7 
Figure 2 Study Flow Chart .................................................................................................... 39 
Figure 3  Product Use Categorization ................................................................................... 90 
 
 
 
 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .................................................................................... 111 
Appendix 2 
Participating Laboratories ......................................................................... 115 
Appendix 3 
Investigational Product and Instructions for Use ...................................... 116 
Appendix 4 
List of Sites and Principal Investigators ................................................... 116 
Appendix 5 
Changes in Protocol Amendments ............................................................ 117 
 

 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
AE 
Adverse event 
BoExp 
Biomarkers of exposure 
BOP 
Bleeding on probing  
CAL 
Clinical attachment level 
CCL11 
Chemokine (C-C motif) ligand 11 
CEJ 
Cementoenamel junction  
CEMA 
2-Cyanoethylmercapturic acid  
CI 
Confidence interval 
CPI 
Community Periodontal Index 
CRF 
Case report from 
CRP 
C-reactive protein 
CV 
Coefficient of variation 
CRO 
Contract research organization 
CSF 
Colony stimulating factor 
CSF-2 
Colony stimulating factor-2 
CSR 
Clinical study report 
CTMS 
Clinical Trial Management System 
CXCL8 
Chemokine (C-X-C motif) ligand 8 
CXCL10 
Chemokine (C-X-C motif) ligand 10 
DMP 
Data Management Plan 
EGF 
Epidermal growth factor 
EOS 
End of study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
Flt3 ligand 
Fms-related tyrosine kinase 3 ligand 
GCF 
Gingival crevicular fluid 
GCP 
Good clinical practice 
GI 
Gingival index 

 
 
 
 
 
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GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GR 
Gingival recession 
GRO 
Growth-regulated oncogene  
HPHC 
Harmful and potentially harmful constituents  
ICF 
Informed consent form  
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IFNα2 
Interferon alpha-2 
IL-1α 
Interleukin-1 alpha 
IL-1β 
Interleukin-1 beta 
IL-1Ra 
Interleukin-1 receptor antagonist 
IL-2 
Interleukin-2  
IL-3 
Interleukin-3 
IL-4 
Interleukin-4 
IL-5 
Interleukin-5 
IL-6 
Interleukin-6 
IL-7 
Interleukin-7 
IL-8/CXCL8 
Interleukin-8/Chemokine (C-X-C motif) ligand 8 
IL-9 
Interleukin-9 
IL-10 
Interleukin-10 
IL-12 (p40) 
Interleukin-12 subunit p40 
IL-12 (p70) 
Interleukin-12 subunit p70 
IL-13 
Interleukin-13 
IL-15 
Interleukin-15 
IL-17A/CTLA8 
Interleukin-17A/Cytotoxic T lymphocyte associated antigen 8 
IP 
Investigational Product (i.e., IQOS or cigarette) 
IP-10/CXCL10 
Interferon gamma-induced protein 10/Chemokine (C-X-C motif) ligand 
10  
IRB 
Institutional review board  
IXRS 
Interactive Web and Voice Response System 
LLOQ 
Lower limit of quantification 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
LT-α 
Lymphotoxin alpha 
MAD 
Median absolute deviation 
MAP 
Multiplex assay 
MCP-1/CCL2 
Monocyte chemoattractant protein 1/Chemokine (C-C motif) ligand 2 
MCP-3/CCL7 
Monocyte chemotactic protein 3/Chemokine (C-C motif) ligand 7 
MDC/CCL22 
Macrophage-derived chemokine/Chemokine (C-C motif) ligand 22 
MIP-1α/CCL3 
Macrophage inflammatory protein-1 alpha/Chemokine (C-C motif) 
ligand 3 
MIP-1β/CCL4 
Macrophage inflammatory protein-1 beta/Chemokine (C-C motif) 
ligand 4 
MedDRA 
Medical dictionary for regulatory activities 
MMP-1 
Matrix metalloproteinase-1 
MMP-8 
Matrix metalloproteinase-8 
MMP-9 
Matrix metalloproteinase-9 
MMP-10 
Matrix metalloproteinase-10 
MMP-12 
Matrix metalloproteinase-12 
MMP-13 
Matrix metalloproteinase-13 
MMRM 
Mixed model for repeated measurements 
MRTP 
Modified risk tobacco product 
NEQ 
Nicotine equivalents 
NNAL 
4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol 
NNK 
Nicotine-derived nitrosamine ketone 
NRT 
Nicotine replacement therapy 
PCR 
Plaque control record 
PD 
Pocket depth 
PDGF-AA 
Platelet-derived growth factor-AA 
PDGF-AB/BB 
Platelet-derived growth factor-AB/BB 
PK 
Pharmacokinetics 
PMI 
Philip Morris International 
PP 
Per protocol set 
PRM 
Parallel reaction monitoring 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
RANKL 
Receptor activator for nuclear factor kappa B ligand 
RANTES/CCL5 
Regulated upon activation, normal T-cell expressed and secreted/C-C 
motif chemokine ligand 5 
sCD40L 
Soluble CD40 ligand 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SHM 
Sample handling manual 
SMP 
Safety management plan 
SOC 
System organ class 
SP 
Subgingival plaque 
SPI 
Summary of product information 
SRP 
Scaling and root planing 
TBI 
Tooth brush instructions 
TGFα 
Transforming growth factor alpha  
THS 
Tobacco Heating System 
TNFα 
Tumor necrosis factor alpha 
TIMP-1 
Tissue inhibitor of metalloproteinases 1 
TNFβ/LT-α 
Tumor necrosis factor beta/Lymphotoxin-alpha 
ULOQ 
Upper limit of quantification 
VEGF-A 
Vascular endothelial growth factor-A 
WHO 
World Health Organization 
 
 
 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
Explanation of terms 
The following special terms are used in this protocol: 
Cigarette  
The term ‘cigarette’ refers to commercially available cigarettes 
(manufactured) and excludes IQOS with HeatSticks, cigars, cigarillos, e-
cigarettes, hand-rolled cigarettes pipes, hookah, bidis, and other tobacco- or 
nicotine-containing products. 
Dental medical 
monitors 
Co-primary contacts (dentists) for dental medical questions 
End of study 
 
The end of the study for an individual patient will be defined as Visit 4, or 
the date of early termination of the patient, plus the 7 days for the safety 
follow-up period. 
The end of the entire study is defined as the last individual patients’ end of 
the study. 
Enrollment 
 
At V1 for eligible patients after all applicable entry criteria have been 
satisfactorily met. 
HeatSticks 
The HeatStick is designed to be used with IQOS only. The HeatStick is made 
up of: tobacco plug, hollow acetate tube, polymer-film filter, mouth piece 
filter, outer and mouth-end papers. 
IQOS 
Unless otherwise specified, IQOS in this document refers to PMI’s Tobacco 
Heating System (THS) with HeatSticks of Marlboro brands. No other 
tobacco sticks should be used with the IQOS device. 
Investigator 
Principal Investigator or sub-Investigator (dentist). 
Maintenance 
treatment  
Scaling, plaque control and occlusal adjustment as needed. 
Medical expert Dentist who is the primary contact for dental medical questions 
Medical 
monitor 
Medical doctor who answers any medical and safety questions from the 
Investigators.  
Natural tooth 
In this study, a natural tooth is defined as a tooth with its natural root, 
including a tooth with a crown. In the case of a dental bridge, the two teeth 
with the crowns holding the pontic are considered as natural teeth, while the 
pontic is not. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
Periodontal 
assessment 
Full mouth assessment of PD, CAL, BOP, tooth mobility, PCR, and 
assessment of gingival inflammation of the target teeth. 
Randomization 
 
After all assessments of V1 have been completed, patients will be 
randomized to IQOS or cigarette arm. Patients will be informed of their 
randomized study arm by the study site during V2. All patients will be 
instructed to continue to solely use their assigned product until they 
complete the study. 
Safety follow-
up 
After the day of Discharge at V4, patients will enter into a 7-day safety 
follow-up for the recording of spontaneously reported new AEs/SAEs and 
the follow-up of ongoing AEs/SAEs by the study site.  
Screen failure  
Patient who signs ICF but was not enrolled. Re-screening of patients who did 
not meet any entry criteria will not be permitted. 
Target site 
The site of a target tooth, preferably the deepest of the tooth, from which the 
GCF will be collected.  
Target tooth 
At V1, for all eligible patients, the Investigator or designee will designate 4 
target teeth, i.e., preferably one per quadrant. Teeth with PD ≥ 5 mm but < 7 
mm will be preferably selected. If their location does not correspond to one per 
quadrant, the Investigator or designee will designate the target teeth preferably 
as single-rooted, and distributed as evenly as possible. Target teeth 
identification will be reported in the CRF.  

 
 
 
 
 
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1 
ETHICS AND REGULATIONS 
1.1 
Institutional Review Board (IRB) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated documents 
(informed consent forms [ICFs] including both patient information sheet and consent form, 
patient recruitment procedures [e.g., advertisements], written information to be provided to the 
patients, Summary of Product Information [SPI] [1], available safety information, the Principal 
Investigator’s curriculum vitae and/or other evidence of qualifications, the list of sub-
Investigators and any other documents requested by the Institutional Review Board [IRB]), 
will be submitted for review and approval to the relevant IRB. The IRB shall be appropriately 
constituted and perform its functions in accordance with the International Council for 
Harmonization of Technical Requirements for pharmaceuticals for Human Use (ICH) 
Guidance for Good Clinical Practice (GCP), and Ministerial Ordinance on Good Clinical 
Practice for Drugs and local requirements, as applicable. 
In accordance with GCP, a written confirmation of the IRB approval should be provided to the 
Sponsor and the Investigator. This should identify the study (Principal Investigator’s name, 
study number and title) and the documents that have been approved by the IRB, with dates and 
version numbers, as well as the date of approval. The composition of the IRB, including the 
name and occupation of the chairperson, should be supplied to the Sponsor together with a 
GCP compliance statement. 
The written approval from the IRB will be filed in the Investigator Site File and in the Study 
Master File at the Sponsor or designated organization. The study must not start before the 
Sponsor has obtained written confirmation of favorable opinion/approval from the concerned 
IRB. 
Any change to this protocol will require a written protocol amendment that must be approved 
by the Sponsor and the Principal Investigators. All amendments will be submitted to the IRB, 
and substantial amendments will only be implemented after approval by the IRB. 
These requirements for approval should in no way prevent any action from being taken by the 
Principal Investigator or sub-Investigator (Investigator) or by the Sponsor in order to eliminate 
immediate hazards to the patients. If such a change to the protocol is considered necessary by 
the Investigator, and is implemented for safety reasons, the Sponsor and the IRB should be 
informed immediately. 
Relevant safety information will be submitted to the IRB during the course of the study in 
accordance with national regulations and requirements. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
1.2 
Ethical Conduct of the Study 
The study will follow the principles as defined in the ICH GCP [2], in the Ministerial 
Ordinance on Good Clinical Practice for Drugs (Ministry of Health and Welfare, 1997 (as last 
amended by the Ordinance of Ministry of Health, Labor and Welfare No. 9 of January 22, 
2016) [3], in the Declaration of Helsinki [4] and other applicable regulation. Prior to the 
initiation of any study procedures, the protocol will be approved by an IRB and the patient will 
have received information on the study, as well as signed the study ICF. 
1.3 
Patient Information and Consent 
1.3.1 Informed Study Consent Form/Patient Information Sheet for Participation to 
the Study 
Before or at the screening visit, the Investigator will ensure each patient is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits of 
the study, and the Investigator will answer all questions the patient might have to his/her full 
satisfaction. The patient will have sufficient time for consideration of his/her participation in 
the study and will be notified that he/she is free to discontinue his/her participation at any time. 
Once the patient has received all necessary information, and if he/she agrees to participate, this 
will be documented in the ICF by the date, time and signature of both the patient and the person 
who conducted the inform consent discussion. No study-specific procedures will be performed 
before the ICF has been signed. 
The original, dated and signed ICF must be kept in the Investigator file at the site, and a copy 
must be given to the patient. 
The patient will be informed that if he/she withdraws from the study, the data collected until 
the point of withdrawal will be maintained as part of the study data and the samples collected 
prior to withdrawal will be analyzed, unless he/she refuses in writing. The patient will be 
informed that additional data analyses not mentioned in the protocol or the statistical analysis 
plan might be performed with the collected data at a later time. If any additional analyses will 
be performed, they will fully be covered by data confidentiality, as for the main analyses 
described in this protocol. 
1.3.2 Amendment Informed Consent Forms/ Patient Information Sheet for 
Participation to the Study 
If a protocol amendment is required, an amendment may be required to the ICF. If revision of 
the ICF is necessary, the Principal Investigator or designee will, with the support of the Sponsor 
or authorized representative, ensure that the documents have been reviewed and approved by 
the IRB before study participants are required to re-sign and time and date the ICF. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Principal Investigator abide by the principles of the current version of the 
ICH guidelines on GCP and will carry out the clinical study in accordance with these 
principles. Although these guidelines were written specifically to set a standard for 
pharmaceutical development, they nevertheless provide a robust and ethical framework for 
conducting clinical studies of tobacco products.  

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
2 
INTRODUCTION 
2.1 
Background 
Based on the most recent classification system developed by the American Academy of 
Periodontology, there are at least eight categories of periodontal diseases and conditions [5]. 
Of these, the two most common are gingivitis and chronic periodontitis. Periodontal disease is 
characterized by a non-resolving inflammatory response of the human host to a lasting bacterial 
infection of the gingiva leading first to gingivitis, followed by connective tissue damage, 
destruction of the periodontal ligament and alveolar bone loss surrounding the teeth, ultimately 
leading to tooth loss [6, 7]. The involvement of dental plaque in the development of gingivitis 
and periodontal diseases is well-recognized as evidenced by several epidemiological studies 
[8, 9]. Furthermore, periodontal disease is associated with an increased risk in systemic 
diseases such as cardiovascular disease, diabetes, respiratory disease as well as various types 
of cancer (neck and head, breast, pancreas, colorectal and lung cancer) and cancer risk overall 
[8, 10-16]. The prevalence of severe periodontal disease (i.e., when a patient had at least one 
site with a pocket depth (PD) ≥ 6 mm) was up to 10% in Japan, China, Brazil, Denmark, 
Poland, Norway and more than 20% in the populations of Bangladesh, Canada, Germany, 
India, Belarus and Chile as reported by the World Health Organization (WHO) [17]. 
Gingivitis is the first, reversible stage of periodontal diseases, and is characterized by 
symptoms such as red, swollen and painful gums, gums that bleed easily while brushing and 
flossing and a receding gum line. The modified gingival index (GI) developed by Lobene et 
al. [18], is a good indicator of gingival health, and reducing it would eventually lead to reduced 
risk of developing periodontal disease. This index is robust, and can change upon short period 
of times. When the gingival inflammation process is not stopped, gingivitis usually progresses 
to periodontitis. The assessment of periodontitis is determined through a complete clinical 
examination, and the measurement of clinical attachment level (CAL). CAL is calculated by 
adding the periodontal PD and the gingival recession (GR) from the cementoenamel junction 
(CEJ) as a fixed reference point. During full periodontal assessment, CAL and PD are recorded 
at 6 sites per tooth, using graduated periodontal probes. Bleeding after probing is noted after 
recording the PD for each site. Tooth mobility is graded from 0 to III following the method 
described by Miller [19] and plaque control record (PCR) is often assessed following the 
method described by O’Leary et al. [20]. 
The oral cavity is the first part of the human anatomy to be exposed to mainstream smoke in 
active smokers and consequently smoking has been shown to be a significant risk factor for 
periodontal disease and tooth loss [21-24]. The association is robust across a wide range of 
case definitions, populations, and study designs [8]. There is also evidence of a dose-response 
relationship between smoking intensity and the risk for periodontitis [24, 25]. Both, the number 
of cigarettes smoked and the duration of smoking are positively associated with disease risk. 
The magnitude of the relative risk estimates for periodontal disease associated with smoking 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
varies from 1.4 to 5.0 in different studies [24]. In Japan, based on data from the Survey of 
Dental Diseases and the National Nutrition Survey in 1999, the prevalence of periodontal 
disease was shown to vary significantly by smoking status with 39.3%, 49.5% and 47.3% with 
a Community Periodontal Index (CPI) > 3 (moderate periodontal disease) and 7.9%, 11.7% 
and 12.4% with a CPI > 4 (severe periodontal disease), for non-smokers, former smokers and 
current smokers, respectively [22]. The lack of difference between former and current smokers 
in this study can likely be explained by the lack of data on time since cessation. A study in 
Korea has indeed shown that the prevalence in former smokers becomes similar to never 
smokers only if cessation occurred since more than 10 years [26]. In a Japanese study, the odds 
ratio of having periodontitis, among current smokers compared with those whom had never 
smoked was 1.74 [27]. A cross-sectional study in Brazil showed a significant dose-response 
relationship between pack-years of smoking and periodontitis prevalence, as well as a 
significant decrease in the risk of periodontitis as years of smoking cessation increased [28]. 
Periodontal disease affects not only the gums, but also the connective tissues and bone that 
surround and support the teeth, thus chronic periodontitis affects tooth mobility, and eventually 
tooth loss. Tooth mobility, as assessed by the method of Miller [19] is a good predictor of tooth 
loss. Tooth loss has been shown to be associated in a dose-dependent manner with smoking 
[24]. It may take up to 20 years of smoking cessation to decrease the excess risk of tooth loss 
to the levels of never smokers. Plaque has been shown to be more present in smokers than non-
smokers, however, after mechanical treatment, plaque control record, as assessed by the 
method of O'Leary et al. [20], is often sufficient to decrease the plaque of smokers to levels of 
non-smokers or quitters. 
The likely mechanism for the increase in periodontal disease prevalence in active smokers is 
that smoking alters the inflammatory host response, with increasing cytokine and inflammatory 
mediator release and therefore negatively impacts the reparative and regenerative potential of 
the periodontium and the cell lining of the oral cavity in general [21, 29]. Pro-inflammatory 
cytokines can be assessed from the gingival crevicular fluid (GCF) of diseased teeth, as 
described by Tymkiw et al. [29], and serve as markers for inflammation [29]. In periodontitis, 
clinical parameters, including PD and CAL, were found to be increased in smokers compared 
to non-smokers (reviewed in [30]). On the other hand, it has been shown that bleeding on 
probing (BOP) and inflammatory response associated with plaque accumulation are reduced 
or delayed in smokers compared to never smokers [31-33] . The volumes of gingival cervicular 
fluid [34] are also less in smokers, like the gingival blood flow [35]. Furthermore, in smokers, 
signs and symptoms of gingivitis, such as bleeding, erythema and edema, are often less 
pronounced than in non-smokers [34, 35]. Gingival inflammation, as evaluated by the GI of 
Löe and Silness [36], is also lower in smokers than non-smokers [37].  
Additionally, smokers are more likely to incur dose-dependent quantitative and qualitative 
differences in the subgingival microflora (i.e., infection with Porphyromonas gingivalis and 
Tannerella forsythia, formerly called Bacteroides forsythus) compared to former and non-

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
smokers [38]. The presence of the three “red complex species” (i.e., Porphyromonas 
gingivalis, Tannerella forsythia and Treponema denticola), which are recognized as the most 
important pathogens in adult periodontal disease [39], was shown to be a predictor of higher 
attachment loss [40]. A study on subgingival microbiome showed that smokers have a highly 
diverse, pathogen-rich and commensal-poor, anaerobic microbiome, and that the smoking 
status supersedes the influence of genotypic factors such as ethnicity on the microbiome [41]. 
Only a few longitudinal studies have assessed the outcome of periodontal disease after smoking 
cessation, but they indicate that the recovery in PD, and to a lesser extent in CAL, after non-
surgical treatment is more successful in those who quit smoking [42-46]. Studies in smokers, 
non-smokers and former smokers indicate that smoking cessation has a beneficial effect on the 
outcome of periodontal treatment and thus that the negative impact of tobacco use on 
periodontal disease is reversible, within a time frame of a few weeks to a few years, depending 
on the clinical endpoint assessed [32, 33, 42, 47-49]. Volumes of GCF and gingival blood flow 
are increased within two months of smoking cessation [35]. Such findings can likely be 
explained by the effect of nicotine or its metabolites, that acts as a peripheral constrictive action 
on gingival vessels, but also potentially because of an increase of oral mucosa epithelium 
thickness in smokers [50, 51]. 
The first line of treatment in periodontal diseases is to restore a healthy periodontium, by 
instructing the patients on how to increase their oral hygiene, and by mechanically removing 
supra and subgingival plaque (SP) and calculus deposits (also called scaling and root planing, 
SRP), with or without antibiotic treatment [52]. In more severe cases, or cases that do not 
resolve after non-surgical intervention, surgery will be performed. In addition, dental and 
healthcare associations, such as the World Health Organization [53] and Japanese Society of 
Periodontology , all support professional education related to the importance of primary 
prevention of tobacco use and recommend cessation as an intervention for oral health diseases 
[54, 55]. Nicotine replacement therapy (NRT) is proposed to patients who are willing to quit 
smoking to reduce the withdrawal effects [56-59].  
Philip Morris International (PMI) develops, assesses and commercializes a portfolio of 
innovative products intended to (1) significantly reduce the risk of smoking-related disease 
compared to continued smoking of cigarettes and (2) are accepted by smokers as substitutes 
for cigarettes. 
More than 6000 smoke constituents have been identified when the tobacco is burned or 
combusted [60], and more than 100 of them have been categorized as harmful and potentially 
harmful constituents (HPHCs) [61]. Lowering the temperature and heating the tobacco instead 
of burning it can substantially reduce levels of HPHCs. PMI’s Tobacco Heating System (THS, 
marketed under the brand name of IQOS) is a novel tobacco heating system that heats a 
specifically designed tobacco stick (HeatSticks of Marlboro brand) within a precisely 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
controlled temperature range (far lower temperatures than cigarette) rather than burning it. 
IQOS replicates the ritual of smoking but without combustion. [60, 61]. 
IQOS is composed of the Holder and of dedicated HeatSticks. In this document, unless 
otherwise specified, IQOS refers to the device with HeatSticks. No other tobacco sticks should 
be used with the device. A Charger allows to recharge the Holder after each use. Unlike 
cigarettes, the HeatSticks do not burn down during their consumption and their lengths remain 
constant after use. IQOS has been commercialized in Japan since November 2014. With this 
product, the heating of the tobacco is maintained below 350°C, a temperature much lower than 
what is observed for cigarette, which can reach 900°C.  
PMI has undertaken a comprehensive assessment program on IQOS, including pre-clinical and 
clinical studies, aiming to demonstrate that IQOS is a reduced risk product 3. The non-clinical 
assessment of IQOS, consisting of the aerosol chemistry analysis, in vitro and in vivo studies, 
supported the initiation of clinical studies, as no new or increased toxicological hazard in the 
product’s aerosol was detected when compared with cigarette smoke. Results from pre-clinical 
in vivo studies comparing cigarette smoke with IQOS aerosol in continuous inhalation show 
that exposure to IQOS aerosol, at multiple concentrations, results in a dramatically lower 
systemic toxicity, extensively reduced lung inflammation and reduced histopathological 
changes in the nasal epithelium as well as lung tissue compared to cigarette smoking [62, 63]. 
Furthermore, exposure to IQOS aerosol in mice does not enhance cardiovascular disease or 
emphysema, as cigarette smoke does, and switching from cigarette smoke to IQOS aerosol 
exposure halts of e.g., aortic plaque growth in a similar manner as smoking cessation [64, 65]. 
Recent non-clinical data on human organotypic buccal epithelial cultures demonstrated that 
acute exposure to IQOS aerosols, when compared to cigarette smoke, had overall a 
significantly lower impact on buccal epithelial physiology [66]. Unlike cultures exposed to 
cigarette smoke, IQOS aerosol-exposed cultures showed no cytotoxicity, regardless of 
exposure, concentration, or time, and tissue damage was minimal, with no apical 
keratinization, intracellular granular structure, or loss of structural integrity. Furthermore, 
levels of pro-inflammatory mediators were significantly modulated in cigarette smoke-exposed 
cultures (e.g., increased VEGF-A, TGFα, MMP-1, IL1β and decreased Chemokine [C-X-C 
motif] ligand 10 [CXCL10], Chemokine [C-X-C motif] ligand 8 [CXCL8], CSF-2, and IL-6) 
and to a much lesser extent in IQOS. 
Several clinical studies have been conducted with IQOS, in Europe, Asia and the United States, 
in order to evaluate the nicotine pharmacokinetics (PK) profile [67-70], to demonstrate reduced 
exposure [71-74], and to determine functional and biological changes when adult smokers 
                                                 
3 Reduced risk products (“RRPs”) is the term used by PMI to refer to products that present, are likely to present, 
or have the potential to present less risk of harm to smokers who switch to these products versus continued 
smoking 

 
 
 
 
 
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hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
switch from cigarettes to IQOS use compared to smokers continuing smoking cigarettes [73, 
74]. The PK studies demonstrated similar nicotine absorption in subjects using IQOS and 
subjects smoking cigarettes. The Reduced Exposure studies showed reductions in the levels of 
biomarkers of exposure (BoExp) to selected HPHCs, in subjects using IQOS compared to 
subjects continuing smoking cigarettes close to levels observed when subjects stopped 
smoking for the duration of the study, both in controlled and ambulatory settings, for a duration 
of up to 3 months. These studies also indicated favorable biological and functional changes in 
clinical risk endpoints linked to smoking-related diseases.  
A 6-month exposure study [75], followed by a 6-month extension study [76], with the specific 
aim to demonstrate favorable changes in clinical risk endpoints in smokers switching from 
cigarettes to IQOS compared to smokers continuing smoking cigarettes is ongoing. Post-
marketing studies are ongoing, in order to have a better understanding of the product use 
behaviors and first insights in health outcomes [77]. Safety data available to date show a similar 
short-term safety profile for IQOS than for cigarettes. PMI is now launching a series of new 
clinical studies to better understand whether switching to IQOS can have beneficial effects on 
health outcomes. Because of the effects of smoking on oral diseases (such as periodontitis), 
this study is part of this program.  
Further product information can be found in the SPI [1]. 
2.2 
Purpose of the Study 
The purpose of this study is to demonstrate in patients with generalized chronic periodontitis 
that switching from smoking cigarette to using IQOS improves the response to periodontal 
therapy and the overall oral health status compared to continuing cigarette smoking. 
2.3 
Anticipated Benefits and Risks 
2.3.1 Anticipated Benefits 
Advice on health risk associated with tobacco smoking and smoking cessation advice will be 
provided at V1 and then at each visit from V2 to V4 as per Japanese guideline for treatment of 
periodontal disease [78]. The advice will follow the recommendations of the Japanese 
Circulation Society [79] and of the Ministry of Health, Labour and Welfare [80]. Patients who 
are motivated to quit using tobacco-containing products (e.g., IQOS and cigarette) are to be 
referred for additional smoking cessation counselling by their General Practitioner. Patients 
who participate in this study will also benefit from repeated, detailed oral check-ups, which may 
help to increase efficacy of periodontal therapy. 
 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
2.3.2 Anticipated Foreseeable Risks due to Study Procedures 
The risk of procedures (e.g., periodontal examination, standard of care, GCF, buccal swabs 
and SP collection) are deemed to be on par with procedures routinely performed during normal 
or extended buccal examinations by the patient’s dentist. 
2.3.3 Anticipated Foreseeable Risks due to Investigational Products 
A substantial body of evidence already exists on IQOS and its development product, Tobacco 
Heating System (THS) (please refer to SPI [81]). Adverse events (AEs) reported so far seem 
to be mostly in line with the side effects that can be observed while using NRT. 
2.3.4 Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained at V1. Non-expected 
malfunction of IQOS may lead to unforeseeable risks. Patients will be informed that IQOS is 
not demonstrated yet to be less harmful than cigarettes. Mitigation will include close 
monitoring and medical supervision to detect any unforeseeable risks or safety signals at the 
earliest time possible. 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective and Endpoint 
The primary objective of this study is: 
To demonstrate the effect of switching to IQOS use compared to continued cigarette 
smoking on the response of PD to mechanical periodontal therapy. 
Endpoint (6 months): 
 Mean PD reduction in all sites with initial PD ≥ 4 mm after mechanical periodontal 
therapy. 
3.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are: 
1. To evaluate the effect of switching to IQOS use compared to continued cigarette smoking 
on the response of PD and CAL to mechanical periodontal therapy over time. 
Endpoint (3 and 6 months): 
 Mean PD change in sites with initial PD ≥ 4 mm after mechanical periodontal therapy 
(3 months only). 
 Mean CAL change in sites with initial PD ≥ 4 mm after mechanical periodontal therapy 
(3 and 6 months). 
2. To evaluate the differences of periodontal parameters in the response to periodontal therapy 
in patients who switch to IQOS use compared to those who continue to smoke cigarette. 
Endpoints (3 and 6 months): 
 Change in mean full-mouth CAL 
 Change in mean full-mouth PD 
 Mean PD change in sites with initial PD < 4 mm, and with initial PD of 4 mm to < 5 
mm, 5 mm to < 6 mm, 6 mm to < 7 mm and ≥ 7 mm 
 Mean CAL change in sites with initial PD < 4 mm, and with initial PD of 4 mm to < 5 
mm, 5 mm to < 6 mm, 6 mm to < 7 mm and ≥ 7 mm 
 Change in the number of sites with PD < 4 mm, with PD 4 mm to < 5 mm, with PD 5 
mm to < 6 mm , with PD 6 mm to < 7 mm and with PD ≥ 7 mm 
 Change in GI score 
 Change in tooth mobility (grade) 
 Change in PCR 
 Change in BOP scores  

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
3. To evaluate the levels of BoExp over the exposure period in patients who switch to IQOS 
use and patients who continue to smoke cigarettes.  
Endpoint (3 and 6 months): 
 Urinary nicotine equivalents (NEQ), total 4-[methylnitrosamino]-1-[3-pyridyl]-1-
butanol (NNAL), and 2-cyanoethylmercapturic acid (CEMA). 
4. To describe self-reported tobacco or nicotine containing product use over the duration of 
the study in patients switching to IQOS use and patients who continue to smoke cigarettes.  
Endpoint:  
 Number of self-reported tobacco or nicotine containing product used. 
5. To monitor safety 
Endpoint:  
 Incidence of AEs/serious adverse events (SAEs), including AEs related to device 
events, and device events, including device malfunction/misuse, over the duration of 
the study. 
3.3 
Exploratory Objectives and Endpoints 
1. To determine quantitative changes in the inflammatory response by measuring pro-
inflammatory and immuno-regulatory mediators in the GCF in patients switching to IQOS 
use compared to those continuing to smoke cigarettes. 
Endpoints (3 months): 
 Measurement of pro-inflammatory and immuno-regulatory mediators in the GCF 4.  
2. To evaluate the microbiological status in patients switching to IQOS use compared to those 
continuing to smoke cigarettes. 5 
Endpoint (6 months):  
 Microbiological status from SP samples. 
                                                 
4 sCD40L, CRP, EGF, Eotaxin/CCL11, Flt3 ligand,  GM-CSF, GRO, IFNα2, IL-1α, IL-1β, IL-1Ra, IL-2, IL-3, 
IL-4, IL-5, IL-6, IL-7, IL-8/CXCL8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A/CTLA8, IP-
10/CXCL10, MCP-1/CCL2, MCP-3/CCL7, MDC/CCL22, MIP-1α/CCL3, MIP-1β/CCL4, MMP-1, MMP-8, 
MMP-9, MMP-10, MMP-12, MMP-13, osteoprotegerin, PDGF-AA, PDGF-AB/BB, RANKL, RANTES/CCL5, 
TGFα, TIMP-1, TNFα, TNFβ / LT-α, (please refer to the Abbreviations for full spelling). 
5 Results of these exploratory objectives will be reported in separate reports, and will not be part of the main 
clinical study report. 

 
 
 
 
 
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3. To evaluate the transcriptomics profile of buccal swabs in patients switching to IQOS use 
compared to those continuing to smoke cigarettes. 6 
Endpoint (3 and 6 months):  
 Full transcriptomics profile assessment of buccal swabs derived from the right and left 
buccal mucosa. 
                                                 
6 Results of these exploratory objectives will be reported in separate reports, and will not be part of the main 
clinical study report. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
4 
OVERALL STUDY DESIGN AND PLAN 
This is a randomized, controlled, open-label, 2-arm, parallel group ambulatory study with the 
randomization stratified by daily cigarette consumption over the month (30 days) prior to V1 
(10-19 cigarettes/day vs. > 19 cigarettes/day) and disease severity record at V1 (< 5 mm PD 
vs. ≥ 5 mm PD) based on the most severely diseased tooth, in smokers with generalized chronic 
periodontitis who are randomized to either switch from smoking cigarettes to IQOS use or 
continuing smoking cigarettes (Figure 2). Disease severity classification is based on the site 
having the most severe condition. Patients with a mild disease as per the inclusion criteria will 
not be eligible for this study.  
All patients included in the study will be first advised that the best way of preventing further 
periodontal disease progression is to stop smoking as defined in the Japanese guidelines for 
periodontitis. Only patients who are not willing to quit smoking cigarettes will be eligible for 
the study. The patients who quit smoking or using IQOS or those who quit smoking and start 
using IQOS will not be discontinued from the study, will receive their financial compensation 
and will come at all scheduled visits for assessments. 
A sufficient number of patients with generalized chronic periodontitis will be screened and 
enrolled in order to randomize at least 172 patients. Enrollment occurs after checking that all 
eligibility criteria have been met.  
Patients will be randomized using a stratified randomization with a 1:1 ratio into the IQOS or 
cigarette arms and will be instructed to use their allocated product for 6 month study period. 
In each arm, a quota should be applied to ensure that patients with PD ≥ 5 mm (based on the 
most severely diseased tooth) represent at least 50% of the randomized patients (section 6.3). 
When 172 randomized patients are reached, further enrollment will be stopped. Patients 
already enrolled in the study may still be randomized. Arm assignment for patients with PD < 
5 mm will be capped at n = 80, after which patients with PD < 5 mm will be considered as 
screen failure, while enrollment for PD ≥ 5 mm will continue until 172 patients are randomized 
and PD ≥ 5 mm represent at least 50% of the randomized patients. At this stage, patients’ 
enrollment will be stopped and patients already enrolled but not randomized may be 
discontinued. 
 IQOS arm: ~86 patients, switching from cigarette smoking to IQOS use 
 Cigarette arm: ~86 patients, continuing cigarette smoking 
From V2 onwards, information on the risks of the use of tobacco containing products and 
advice to quit smoking will be given to the patients at every visit. 
Any patient, who is willing to attempt quitting during the study will be encouraged to do so 
and will be referred to appropriate medical services. The patient will not be discontinued from 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
AEs/SAEs, including AEs related to device events, device events, pregnancies and 
concomitant medications will be part of the examination and recorded throughout the study. In 
addition standard of care procedures and procedures related to the assessments throughout the 
whole study duration, starting from ICF signature until end of study (EOS) will also be 
recorded. Patients identified by the site as potentially eligible will be provided with the 
information about the study and if interested, and they will be invited to the screening Visit 
(V1) by the site. The ICF can be distributed to these potential patients before V1. 
Screening, enrollment & baseline, periodontal assessment, and SP collection (V1) 
Patients will sign the ICF before the start of any study procedure, and will enter screening. All 
eligibility criteria will be checked, including periodontal assessment, which will be also used 
as baseline assessment for enrolled patients (Appendix 1). Patients who meet the eligibility 
criteria will be enrolled. Patients who do not meet the eligibility criteria will be considered as 
screen failures, and their urine samples will be discarded at the end of the visit. 
After enrollment, the remaining baseline assessments will be conducted (Appendix 1). Target 
teeth (see Definition of terms) will be designated by the Investigator or designee and will be 
identified in the source documents and in the case report form (CRF). Sampling of SP for 
microbiological status on 4 target teeth will be performed (Appendix 1). 
At this visit, a first supragingival scaling treatment will be performed, and occlusal adjustment 
will be implemented as needed. Patient will be provided with toothbrush instructions (TBI) 
and will be instructed to continue this method throughout the whole study. 
After all assessments of V1 have been completed, patients will be randomized to 1 of the 2 
study arms; continued cigarette smoking or IQOS use. Patients will be informed about their 
study arm allocation at V2. 
1st SRP visit, GCF and buccal swabs collection (V2/Day 1) 
This visit will be scheduled 7 to 14 days after V1. GCF and buccal swabs collection will be 
conducted before any periodontal assessment. PD, tooth mobility and BOP will be assessed 
before the SRP treatment as per standard of care, but will not be recorded in the CRF.  
The first SRP treatment will be performed on teeth with PD ≥ 4 mm and with the most severely 
diseased tooth. The following SRP treatments will be performed in subsequent visits as agreed 
and scheduled between the site and the patient. As the number and timing of the visits is 
flexible, the data will be captured in the CRF as “unscheduled” SRP visits. All SRP treatments 
must be completed within 8 weeks after V2. 
Patients will be informed of their randomized study arm during this visit and can start using 
their allocated product after the randomization. All patients will be instructed to use their 
assigned product until they complete the study. Patients randomized to the IQOS arm will 

 
 
 
 
 
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receive an IQOS starter kit which includes an IQOS device and a selection of HeatStick flavor 
variants available on the Japanese market. All patients will purchase their own product during 
the course of the study (no brand or flavor restrictions). During the study, switching to different 
cigarette brands or different IQOS devices or HeatStick flavor variants will be allowed. 
The Investigational period (from V3 to V4) 
V3 will be scheduled with a flexibility of ± 7 days, and V4 with a flexibility of ± 14 days. The 
3 and 6 months visits (i.e., V3 to V4) will be scheduled according to the randomization visit 
(V2).  
3 months, periodontal assessment & maintenance visit, GCF and buccal swabs collection  
Patients will come to the site for periodontal assessment (Appendix 1), including GCF 
collection from the same 4 target sites than at V1, and collection of buccal swabs. Maintenance 
treatment will be provided as needed. 
6 months, periodontal assessment & maintenance visit, SP and buccal swabs  
Patients will come to the site for periodontal assessment (Appendix 1). Sampling of SP for 
microbiological status from the same 4 target teeth than at V1 will be performed. Buccal 
samples will also be collected. Maintenance will be provided as needed. 
At the end of V4, patients will be discharged from the study. Procedure of discharge will 
include urine pregnancy test for all females (irrespective of age), as well as recording of 
AEs/SAEs or device events. For patients who terminate the study earlier, the same procedure 
of discharge will apply. 
Safety Follow-up Period 
After the procedures of discharge, patients will enter a 7-day Safety Follow-up Period. Any 
non-serious AE that is ongoing during the Safety Follow-up Period will be passively followed-
up by the Investigator during that period until it has been resolved, stabilized (i.e., no 
worsening of the condition), or an acceptable explanation has been found (e.g., a chronic 
condition). At the end of the Safety Follow-up Period, all ongoing non-serious AEs will be 
documented as “ongoing” and no follow-up information will be sought for on them anymore 
by the Investigator or designee. At that point, the Investigator will assess whether the patient 
should be referred to his/her General Practitioner to have their ongoing AEs for further follow 
up. All SAEs will be actively followed up by the Investigator, despite their continuation after 
the end of the Safety Follow-up Period, until their resolution, stabilization (i.e., no worsening 
of the condition), or until an acceptable explanation has been found (e.g., a chronic condition). 

 
 
 
 
 
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Unscheduled visits 
As a general rule, procedures requested in the protocol should be performed according to the 
visit schedule. However, as this study is focused on treating patients, there may be a number 
of reasons that the patient may visit the investigational site outside of the visit schedule during 
the course of the study. The site should record any site visit even if unscheduled and document 
the reason for the visit. For the SRP treatments, there is one required visit within the study 
procedures, and all additional visits that are required to complete the SRP treatment must be 
recorded as “unscheduled” SRP visits.  
4.1 
Rationale for Study Design and Control Group(s) 
PMI is now launching a series of new clinical studies to better understand whether IQOS can 
have beneficial effects on health outcomes. Because of the well-known adverse effects of 
smoking on oral diseases (such as periodontitis), this study is part of this program. The overall 
objective of the IQOS design is to provide an acceptable alternative to current, adult smokers, 
with substantial reduction of exposure to HPHCs by its aerosol compared to cigarette smoke. 
The purpose of this study is to demonstrate in patients with generalized chronic periodontitis 
that switching from smoking cigarette to using IQOS improves the response to periodontal 
therapy and the overall oral health status compared to continuing cigarette smoking. IQOS 
could then become an alternative to cigarettes for smokers with periodontitis who cannot stop 
smoking. 
Further product information on IQOS can be found in the SPI [81]. 
The minimum age of 30 years old in the inclusion criteria was selected based on:  
 The likelihood to develop chronic periodontal disease, which increases with age and 
smoking history. 
The rationale for having a minimum of 5 years of smoking history is to not discard long-term 
smokers who might have stopped smoking for some time in their life. 
This study will:  
 Provide a perspective of the use of IQOS on the healing of periodontal disease after 
mechanical treatment compared to the use of cigarettes. 
The healing of periodontal disease, as measured by the amelioration of different periodontal 
assessments, such as reduction in PD, has been shown to be influenced by smoking (reviewed 
in [30]). Other parameters measured, such as GI, tooth mobility, PCR and BOP will further 
illustrate potential benefits of switching to IQOS on the overall oral health, even though 
parameters such as CAL or tooth mobility may need more than 6 months to change favorably. 
Smokers have often reduced gingival inflammation, BOP and decreased volume of GCF [35], 

 
 
 
 
 
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probably due to the vasoconstrictive action of nicotine on gingival vessels. Because IQOS 
delivers nicotine, but much reduced levels of other HPHCs, this study may help to differentiate 
the effects of nicotine vs the effects of HPHCs. To investigate this, it is planned to collect 1) 
GCF samples, to measure inflammatory components of this oral fluid when switching to IQOS 
compared to continuing using cigarettes, 2) buccal swabs, to perform an RNA profiling of 
those cells which are directly exposed to cigarette smoke or IQOS aerosol; and 3) SP samples, 
to assess the change of the oral microbiome when switching to IQOS compared to patients 
continuing using cigarettes. The analyses of GCF and buccal swabs will help to better 
understand the underlying mechanism of the diseases related to cigarette smoke. 
The study will follow a two parallel arm randomization design with the following strata: 1) 
daily cigarette consumption over the month prior to V1 and 2) PD in smokers with generalized 
chronic periodontitis [78]. This selection is based on the fact that: 1) the degree of smoking 
exposure is related to the severity of periodontal destruction [25, 82] 2) pre-treatment depth of 
PD and CAL have been shown to affect response of therapy [83, 84]. 
The choice of the primary and secondary objectives are based as a selection of 1) the most 
published assessment, i.e., reduction of PD, which has been shown to occur rather rapidly after 
mechanical therapy (i.e., within 3 to 6 months) and is more representative of the overall 
inflammation, 2) the most clinically relevant endpoint, i.e., CAL change, which is more 
representative of tissue destruction, and is thus determinant in the increased risk of tooth loss. 
Data on CAL change in smokers vs non-smokers or quitters, are, however, sparser than data 
on PD. The assessment of both parameters as primary and secondary endpoint will thus provide 
evidence on both the effect of IQOS on inflammation status and on tissue repair and will 
provide information about the modification of the healing profile related to switching to IQOS. 
The limitation of use of antibiotics before and during the study is largely driven by the 
differential effect that those may have on healing after mechanical periodontal therapy [85], 
but also, to a slighter extent, because they will affect the microbial oral environment of the 
patients. Similarly, use of steroidal or non-steroidal anti-inflammatory drugs may affect 
healing [86, 87], bisphosphonates, which have been shown to be effective in periodontitis 
management through inhibition of the alveolar bone resorption, should be considered with care 
during the study because of a potential risk of osteonecrosis of the jaw [88]. Anti-coagulants 
should also be considered with care because of the risk of bleeding [89].  
BoExp to NEQ, nicotine-derived nitrosamine ketone (NNK) (total NNAL) and acrylonitrile 
(CEMA) will serve as indicators of overall exposure of the patients throughout the study. These 
markers have relatively long half-lives, and should provide a good estimate of the exposure, 
even if the patient comes early in the morning for his/her visit. Because nicotine is expected to 
be delivered with IQOS at levels comparable to cigarettes, levels of NEQ are not expected to 
be lower in IQOS users than cigarette users, but it will serve as an overall estimate of exposure 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
to nicotine exposure. Spot-urine collection will be performed, and the BoExp levels will be 
adjusted to creatinine to adjust urinary excretion rates.  
This study is designed as an ad libitum study without product use restriction in order to mimic 
as closely as possible “real life” condition.  
All patients will be asked to buy their own cigarettes or HeatSticks, according to their needs 
for the study, in order to minimize any changes in their smoking behavior, and to not promote 
one product over the other. 
4.2 
Appropriateness of Measurements 
All dental variables to be measured in this study were selected based on the following criteria: 1) 
commonly assessed by dentists; 2) acceptability by patients; 3) robustness of the method (i.e., 
index or evaluation criteria are available to assess improvement of periodontal disease); 4) clinical 
relevance to support the objectives of the study.  
Blinding of the examiners is planned to reduce the potential bias of the periodontal assessments 
that could be introduced by the smell of tobacco on patients using cigarettes, which is not present 
on patients using IQOS. Blinding was applied in studies by Preber and Bergstrom [90], Liu and 
Hwan [46], Rosa et al. [44] and Nair et al. [33]. If the examiner gets unblinded, this will be reported 
by the Investigator, but the patient will not be discontinued. Because mouth wash may influence 
the collection of samples, the patients will be instructed not to use mouth wash during the study. 
Blinding will be ensured by asking the patients to wash their hands before the examination, and 
the examiners will all wear the same mask, that will mask odors. The patients will also be asked 
not to drink, eat, chew gum, use mouth rinse or brush their teeth for at least 30 minutes before 
collection of oral samples, because of the influence it may have on the analytes. 
The measurement of PD or CAL can be quite variable, as it depends on 1) the extent to which a 
probe penetrates into a given pocket (can vary because + line, can vary by more than 0.5 mm 2) 
the diameter of the probe tip (e.g., WHO probe, Florida probe, Williams SE manual probe) 3) the 
tine (part of the probe with markings) 4) the probing force used, which is a further major factor 
influencing probe penetration 5) the angulation of the probe tine to the pocket wall 6) the accuracy 
or otherwise of markings on the tine, which even in the same batch from a production line can vary 
by more than 0.5 mm 7) the experience of the examiner 8) the presence of (overhanging) 
restorations [91]. Intra-examiner reproducibility has nevertheless been shown to be high, with 
calibration and operator training, rather than operator experience being fundamental for 
reproducibility [92]. In the oral health component of the National Health and Nutrition 
Examination Survey (NHANES), cycle 1999–2004, intraclass correlation coefficients for mean 
loss of periodontal attachment varied from 0.72 to 0.93 and for mean PD from 0.55 to 0.87 [93]. 
Another study where 3 periodontists were trained and calibrated showed inter-examiner variance 
from the “reference examiner” for the other 2 of 0.32 and 0.50 mm for PD measurement and 0.56 
and 0.52 mm for CAL measurement [32]. In a study involving 18 clinical centers, clinicians were 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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disclosed without the written consent of Philip Morris Products S.A. 
trained and calibrated to measure PD: interexaminer reliability was high, with intraclass 
coefficients and percent agreement (within 1 mm) values ranging from 0.81 to 0.98 and 87.5% to 
98.5%, respectively [94]. To decrease variability in the present study, the same dental probe 
will be used by all examiners, and a calibration session of all examiners will be organized.  
The BoExp measured in this study were selected based on the following criteria: 1) the 
availability of a validated analytical method; 2) the measure is known to be directly or 
indirectly affected by the use of tobacco product; 3) the measure is readily reversible after 
smoking cessation/abstinence; 4) the timeframe of reversibility of measure in the perspective 
of the study duration; 5) the practicality/acceptability by patients; 6) the robustness of the 
method (rapid, simple, accurate).  
4.3 
Study Duration 
The study duration per patient will be of maximum of up to 31 weeks, including a 1-day visit 
(V1), up to 2 weeks interval between V1 and V2, followed by a 6-month (the month means 30 
days) investigational exposure period, with 1-day visits after 3 and 6 months (V3, ± 7 days, 
V4, ± 14 days at each visit), and a 1-week safety follow-up period. The end of the study for an 
individual patient will be defined as V4 or the date of early termination plus the 7 days for the 
safety follow-up period. The end of the entire study is the latest date that an individual patient 
reaches the end of the study. 

 
 
 
 
 
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hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
5 
STUDY POPULATION  
5.1 
Selection of Study Population 
5.1.1 Inclusion Criteria 
At the screening visit (V1), each patient to be enrolled must meet the following criteria: 
Study Population and Main Criteria for Inclusion: 
A sufficient number of patients will be enrolled in order to randomize at least 172 patients 
meeting the following main inclusion criteria: 
1. Patient is Japanese. 
2. ICF has been signed. 
3. Patient is aged ≥ 30 years old. 
4. Patient has smoked on average at least 10 commercially available cigarettes per day 
(no brand restriction) for at least 5 years prior to V1, based on self-reporting. Smoking 
status will be verified based on a urinary cotinine test (i.e., cotinine ≥ 200 ng/mL). 
5. Patient has at least 15 natural teeth (refer to Definition of Terms), excluding the teeth 
which need to be extracted or whose mobility grade is ≥ 3. 
6. Patient has generalized chronic periodontitis (i.e., more than 30% of diseased teeth with 
a PD ≥ 4 mm), considering only teeth that do not need to be extracted or whose mobility 
grade is < 3. 
7. Patient does not intend to quit smoking during the study. 
8. Patient is ready to comply with study procedures and to use the product he/she is 
allocated to for the duration of the study. 
5.1.2 Exclusion Criteria 
Patients who meet any of the following exclusion criteria must not be enrolled into the study. 
Criteria for Exclusion: 
1. Patient has self-reported history of diagnosed systemic diseases (e.g., stroke or acute 
cardiovascular event within the last 5 years, diabetes, active cancer), or any other 
conditions that in the opinion of the Investigator would jeopardize the safety of the 
participant or affect the validity of the study results. 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
2. Patient is legally incompetent, physically or mentally incapable of giving consent (e.g., 
emergency situation, under guardianship, in a social or psychiatric institution, prisoner 
or involuntarily incarcerated). 
3. As per the Investigator’s judgment, patient cannot participate in the study for any 
reason (e.g., medical, psychiatric and/or social reason). 
4. As per the Investigator’s or designee’s judgment, patient has medical conditions which 
require or will require in the course of the study, a medical intervention (e.g., start of 
treatment, surgery, hospitalization) which may interfere with the study participation 
and/or study results. 
5. Patient has orthodontic appliances. 
6. Patient received root planing therapy within the 6 months prior to V1. 
7. Patient received surgical periodontal therapy within 3 years prior to V1. 
8. Patient has identifiable premalignant changes of the oral mucosa at V1. 
9. Patient was treated within the 3 months prior to V1 with systemic antibiotics or was 
treated with topical antibiotics applied in the mouth. 
10. Continuous systemic use of steroidal or non-steroidal anti-inflammatory drugs for more 
than 20 days during the past 30-day period (except for low dose aspirin, i.e., ≤ 300 mg 
e.g., for prevention of thrombus/embolus in angina pectoris, myocardial infarction, 
transient ischemic cerebrovascular accidents, bypass operations). 
11. Patient has been previously screened or enrolled in this study. 
12. Female patients who are pregnant, breast-feeding, or planning a pregnancy within the 
course of the study. 
13. Patient is a current or former employee of the tobacco industry or their first-degree 
relatives (parent and child). 
14. Patient is an employee of the investigational site or any other parties involved in the 
study or their first-degree relatives (parent and child). 
15. Patient has participated in a clinical study within 3 months prior V1. 
5.2 
Discontinuation of Patients from the Study 
Discontinued patients will include both, patients who withdraw from the study (patient’s 
decision) and patients who are discontinued from the study by the decision of the Investigator. 
A patient can only be discontinued from the study after enrollment. 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
Patients will be informed that they are free to withdraw from the study at any time. Patients 
should be questioned for the reason of withdrawal from the study, although they are not obliged 
to disclose it. 
If the patient withdraws from the study, he/she will be asked to perform the early termination 
procedures (section 9.6) as soon as possible after the time of withdrawal unless the patient 
refuses to do it in writing.  
If a patient expressed his/her wish to quit the study during a visit planned for clinical 
assessment, he/she will be asked whether he/she would agree to still do the dental/clinical 
assessments planned for this visit, but with no obligation. 
After the time of withdrawal, the patient will enter into the 7-day period of safety follow-up.  
Discontinuation from the study 
Patients must be discontinued from the study for any of the following reasons: 
1. Withdrawal of informed consent. 
2. Discontinuation is considered to be in the interest of the patient from a safety 
perspective as judged by the Investigator 
3. Positive or unclear pregnancy test. 
4. The Sponsor or Investigator terminates the study or the study terminates at a particular 
investigational site. If the Sponsor or the Investigator decides to prematurely terminate 
the study, the patient will be promptly informed. The head of the medical institution 
should report the fact and the reason in writing to the IRB. 
5. Patient has to undergo periodontal surgery (as per dentist’s decision).  
6. Patient becomes an employee of the investigational site or any other parties involved 
in the study. 
7. Lost to follow-up. 
Patients may be discontinued from the study for the following reasons: 
1. Non-compliance to the study procedures based on the judgment of the Investigator. 
2. Patient needs to take systemic antibiotic treatment for any medical condition other than 
periodontitis, for more than 2 consecutive weeks, during the course of the study.  
3. Patient needs to take systemic or topical (in the mouth) antibiotic for more than 5 
consecutive days for acute inflammation of periodontitis. 

 
 
 
 
 
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Confidentiality Statement 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
4. Patient needs to take systemic steroidal or non-steroidal anti-inflammatory drugs for 
more than 6 consecutive days 
5. Patient needs to take bisphosphonates or anti-coagulants. 
6. The number of patients in each randomization stratum has been reached before patient 
reached V2. 
5.2.1 Violation of Selection Criteria 
Patients who violate the entry criteria prior to enrollment will be considered as screen failures. 
Re-screening of patients will not be permitted. If a violation of selection criteria is detected 
after enrollment, patients might be discontinued from the study based on a case-by-case 
decision of the Investigator. 
5.2.2 Other Reasons for Discontinuation of Patients from the Study 
<NA>  
5.3 
Lost to Follow-up 
The date of the last contact with the patient (e.g., last visit, last phone call) should be recorded 
in the source document.  
After the last contact, reasonable number of attempts to contact the patient (including written 
correspondence and phone calls) should be done and documented in the source documents by 
the site.  
Following the contact attempts, if the Investigator(s) or designee(s) decides to discontinue the 
patient with the reason of lost to follow-up, the discontinuation date will be recorded. The 
discontinuation date for the patient will be the date the patient was determined to be lost to 
follow-up and will correspond to the date of the EOS of the patient.  
If the site has lost track of the patient, the discontinuation date cannot exceed the maximum 
number of study weeks (i.e., 31 weeks), then the Investigator(s) or designee(s) will discontinue 
the patient with reason as lost to follow-up. 
 
 

 
 
 
 
 
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hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
6 
INVESTIGATIONAL PRODUCT(S) 
6.1 
Description of Investigational Product(s) 
6.1.1 Test Product(s) 
The product tested in this study is the Tobacco Heating System with Marlboro Heatsticks, marketed 
in Japan under the brand name IQOS and referred to as IQOS in this protocol. All versions of IQOS 
and Marlboro Heatsticks available for sale in Japan at the time of study start or becoming available 
during the course of the study are allowed to be used in the context of this study. The IQOS is 
composed of the following components: a tobacco HeatStick, a Holder and a Charger (Table 1), 
as well as a cleaning tool, a power supply, and a USB cable (see information on the user guide in 
Appendix 3): 
Table 1 
Test Product (IQOS) 
HeatStick: 
The HeatStick is designed to function with the Holder. The 
HeatStick is made up of: tobacco plug, hollow acetate tube, polymer-
film filter, mouth piece filter, outer and mouth-end papers. 
All materials have been evaluated with regards to their toxicological 
potential and have been approved for use. 
The tobacco plug is made from tobacco, glycerin, water, guar gum, 
cellulose, propylene glycol, natural and artificial flavorings. 
The average amount of nicotine in the tobacco plug is 5-6 mg/stick 
per HeatStick. 
Holder: 
The Holder is a slim electrical heating unit that heats the HeatStick 
in a controlled manner by using a heater blade. 
The Holder stores enough energy for a single experience, delivering 
puffs over a period of about 6 minutes or 14 puffs (whichever comes 
first). A Light Emitting Diode indicates the end of the experience. 
Once this cycle is complete, the Holder must be recharged before a 
new HeatStick can be used. 
Charger: 
The power supply for the Holder is the Charger. 
The Charger holds enough energy for approximately 20 uses of the 
Holder and can be recharged from household power. 
The Charger stores the Holder when not in use, and provides a secure 
environment for the cleaning process of the heater blade. 
The overall objective of the product design is to provide an acceptable experience in which the 
HPHCs levels in the aerosol are substantially reduced in comparison with the smoke of a 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
cigarette [95, 96]. A summary of description of the product, pre-clinical and clinical data 
available on IQOS is provided in the SPI [81]. 
6.1.2 Reference and Baseline Product(s) 
Cigarette arm (reference product): patient’s own preferred brand of commercially available 
cigarettes will not be provided by the Sponsor but purchased by the patients for their own use 
for the duration of the study.  
6.1.3 Packaging and Labeling 
An IQOS starter kit (i.e., IQOS device and a selection of HeatSticks flavor variants available 
on the Japanese market) will be supplied to the site by the Sponsor or authorized representative 
in packages that protect against deterioration during transport and storage.  
The Sponsor or authorized representative will label in local language the IQOS starter kit 
ensuring adherence to local regulatory and requirements. This will include at least the 
following information: 
 
Statement ‘For investigational use only’ 
 
Name and address of the Sponsor (if the sponsor resides outside Japan, name of the 
sponsor and name of the country where the sponsor is located, and name and address 
of the clinical trial in-country representative) 
 
IQOS device serial number 
6.2 
Administration of Investigational Product(s) 
The study is designed as an ad libitum use study. The patients will be allowed to use their 
allocated products (cigarette or IQOS) according to their need. Patients should be advised that 
when smoking cigarette or using IQOS, they should temporarily stop using the products in the 
event of any signs suggesting nicotine overexposure, (e.g., gastrointestinal disturbance [nausea, 
vomiting, diarrhea, stomach or abdominal pain], cold sweats, headache, dizziness, breathing 
problems) or any reasons at the discretion of the Investigator. 
Any patient who wish to stop smoking during the study will be encouraged to do so and 
referred to their General Practitioner for a smoking cessation program. This will not lead to 
discontinuation. 
6.2.1 From Enrollment to Randomization 
From screening visit (V1) to randomization (V2), all patients will be allowed to continue 
smoking ad libitum their preferred usual brand of cigarettes. After randomization all patients 
will purchase their product, as it will not be provided by the Sponsor. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
At randomization, patients allocated to the IQOS arm will be supplied with an IQOS starter kit 
(i.e., IQOS device and a selection of HeatStick flavor variants available on the Japanese 
market) but thereafter they will have purchase their own HeatSticks for use during the study.  
6.2.2 Investigational Period 
6.2.2.1 
IQOS Arm 
IQOS arm: patients randomized to the IQOS arm will be instructed to use exclusively IQOS 
ad libitum. The switch to different flavors of HeatSticks as well as the use of other tobacco- or 
nicotine-containing products will not lead to discontinuation. 
6.2.2.2 
Cigarette Arm  
Cigarette arm: patients randomized to the cigarettes arm will be instructed to continue smoking 
their cigarettes ad libitum. The switch to different cigarette brands and the use of other tobacco- 
or nicotine-containing products will not lead to discontinuation. 
6.2.3 Safety Follow-up Period 
During the safety follow-up period (i.e., after the time of V4 or prematurely discontinued), all 
patients will be free to smoke their own cigarettes, or any other product of their choice. 
6.3 
Method for Assigning Patients to Study Arms 
After all assessments of V1 have been completed, patients will be randomized to 1 of the 2 
study arms; continued cigarette smoking or IQOS use. Patients will be informed about their 
study arm allocation at V2. Randomization will be done through the Interactive Web and Voice 
Response System (IXRS) at any time during the visit. Patients will be randomized in one of 
the two study arms, IQOS arm:cigarette arm in a 1:1 ratio using a stratified randomization 
(based on daily cigarette consumption over the month (30 days) prior to V1 (10-19 
cigarettes/day vs. >19 cigarettes/day), and disease severity (< 5 mm PD vs. ≥ 5 mm PD) in 
smokers with generalized chronic periodontitis. Disease severity is based on the tooth site 
having the most severe condition of PD [78]. In each arm, a quota will be applied to ensure 
that patients with PD ≥ 5 mm represent at least 50% of the randomized patients. Arm 
assignment for patients with PD < 5 mm will be capped at n = 80, after which enrollment of 
patients with PD < 5 mm will be stopped. Patients with PD < 5 mm already enrolled but not 
randomized may be discontinued in order to ensure that randomization quota are met. 
Enrollment of patients with PD ≥ 5 mm will continue until 172 patients are randomized. At 
this stage, patients’ enrollment will be stopped and patients already enrolled but not 
randomized may be discontinued. In case patients are discontinued after V1, they will be 
referred to their dentist/general practitioner and will receive financial compensation for the 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
visit. Patients will be informed of their randomized study arm by the study site during V2. All 
patients will be instructed to use their assigned product until they complete the study. 
6.4 
Blinding  
6.4.1 Blinding of the Examiner 
This is an open-label study, however, in order to avoid potential involuntary bias of the 
examiner by the smoking status, he/she will be kept blinded to the patient arm after 
randomization. In order to enforce the blinding, the examiner will wear a prescribed mask to 
avoid noticing the odor, during the full periodontal examination at 3 and 6 months. The blinded 
examiner should avoid contact with the patient outside of the required full periodontal 
examinations. In addition, the patients will be asked to wash their hands. If the examiner should 
become unblinded for any reason, including accidental disclosure, the unblinding event will be 
documented by the Investigator in a specific log kept in the Site Investigator File. A patient-
specific unblinding event will not lead to discontinuation of the patient and will not prevent 
the use of the patient’s data, including those recorded after disclosure.  
If a designee needs to perform the periodontal assessments, he/she needs to have been trained 
on the PD and CAL probing before doing it, i.e., by an examiner who attended the calibration 
session (section 10.2.1). This needs to be described in the back-up plan that will be provided 
by the sites (section 10.2.1). The blinding status of the designee will be described in the specific 
log for blinding. 
6.4.2 Blinding of Data 
There will be additional, even though limited, degree of blinding during the conduct of the 
study, including the data review and data analysis process. In particular, PMI and contract 
research organization (CRO) personnel will be as summarized in Table 2: 
Table 2 
Blinding Scheme 
Blinded Study 
Personnel 
Blinded Data 
End of Blinding Period  
PMI and CRO study 
statisticians  
Patient randomization arm and 
actual values of CAL and PD 
values after randomization 
After the SAP finalization or 
database lock, whichever comes 
last.  
PMI clinical scientist  
Patient randomization arm and 
actual values of CAL and PD 
values after randomization 
After the finalization of PMI blind 
database review. Can be 
actively un-blinded when 
appropriate.  

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
Any PMI and CRO personnel who are not listed in the above Table 2 will be unblinded by 
default.  
Unblinded information will not be shared with the blinded study team, until the end of the 
blinding period (Table 2). PMI will receive blinded and unblinded data for the pre-analysis 
data review as planned in the data review plan. Blinded data will be accessible by the blinded 
study personnel in a masked format or presented independent of the patient identifier so to 
ensure that data cannot be associated within or to a patient. Unblinded data will only be 
reviewed by the unblinded study team. 
6.5 
Investigational Product Accountability and Adherence 
6.5.1 Dispensing Investigational Product 
Patients allocated to IQOS arm will be supplied with an IQOS starter kit (IQOS device and a 
selection of HeatStick flavor variants available on the Japanese market) at the randomization 
visit (V2), but will be asked to buy his/her flavor of choice of HeatSticks for his/her own use 
for the entire duration of the study. In case the device needs replacement due to a device 
malfunction or in case of loss/theft of the device, the patient will need to contact his/her site. 
In case a patient decides to purchase their own device, these will not be replaced by the site. 
Patients allocated to cigarette arm will buy cigarettes for their own use for the entire duration 
of the study. 
6.5.2 Storage and Accountability 
The study collaborator (the investigational product (IP) storage manager) designated by the 
head of the investigational site will be responsible for the storage and accountability of the 
IQOS devices and HeatSticks to be distributed only once at V2, together with the device. The 
IQOS devices (charger and holder) as well as HeatSticks (to be distributed only once at V2, 
together with the device) will be stored in a secured storage site with access limited to 
authorized personnel only. Because cigarettes will be bought by the patients, cigarettes will 
not be stored at site. As for HeatSticks, a sufficient number of packs will be stored at site, to 
be delivered with the initial hand out of the IQOS device to patients allocated to the IQOS arm 
only. A few additional devices will be stored in case a patient needs to have his/her IQOS 
device replaced. Full accountability of the distributed IQOS starter kit and replacement devices, 
if any, will be ensured by the designated IP storage manager and recorded in IP accountability 
logs. This includes but is not limited to the record of the device serial number, HeatSticks batch 
number, the quantity of devices and HeatStick packs delivered per patient, date of delivery, 
total quantity available at site, the quantity of devices returned to the site at the end of the study. 

 
 
 
 
 
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Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
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disclosed without the written consent of Philip Morris Products S.A. 
Except for the initial packs of HeatSticks delivered together with the IQOS device at V2, 
neither HeatSticks nor cigarettes will be stored at site during the study as they will be bought 
by the patients throughout the study.  
6.5.3 Investigational Product Retention 
The patients will return the IQOS device, including replacement devices to the study site upon 
early discontinuation or at V4. The study site will return to the Sponsor or authorized 
representative the IQOS product components upon study completion. This does not apply to 
devices purchased by the patients. 
6.5.4 Adherence to Investigational Product(s) 
Adherence to the allocated product will be monitored using a questionnaire on self-reported 
current tobacco and nicotine containing tobacco product consumption (including frequency 
and quantity of product use) over the past month (section 7.5.7).  
6.5.5 Product Use Restrictions 
There will be no restriction on allocated product use. 
6.5.6 Dietary Restrictions 
From V2 to V4, patients will be asked not to drink, eat, chew gum, use mouth rinse or brush 
their teeth for at least 30 minutes before collection of oral samples (i.e., SP, GCF or buccal 
swabs).  
6.6 
Concomitant Medication 
Medications will be allowed and carefully monitored during the study by the Investigator or 
designee. The Investigator or designee is responsible for the medical care including medication 
of the patients during their participation in the study. Any use of concomitant medication must 
be fully documented in the source document and transcribed into the CRF. 
Records of medication taken include the drug name (preferably both generic and trade name), 
route of administration (e.g., oral, intravenous), total daily dose/unit (e.g., expressed in mg, 
mL or IU), indication, the start and if applicable, the stop date (day, month and year). Any 
therapy changes (including changes of regimen) during the study have to be documented. Any 
concomitant medication that is still being taken by the patient at the EOS will be recorded in 
the CRF. 
Treatment of periodontitis with antibiotics or bisphosphonates should be avoided as much as 
possible during the study. If required for the periodontal treatment, systemic or topical (in the 
mouth) antibiotics should not be given for more than 5 consecutive days and will be recorded 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
as concomitant medication, but this will not necessarily be a reason to discontinue the patient 
from the study (section 5.2). If required, systemic antibiotics for other medical conditions 
should ideally not be taken for more than 2 consecutive weeks. Systemic steroidal or non-
steroidal anti-inflammatory drugs should not be given for more than 6 consecutive days. Anti-
coagulants for any medical condition should also be avoided as much as possible. However all 
treatment needed must be in the best interest of the patient and would not lead to 
discontinuation. 
 
6.7 
Concomitant Therapeutic Procedures 
Any concomitant therapeutic procedure (e.g. tooth extraction due to cavity or due to worsening 
of periodontitis, appendicectomy), which is not part of study procedures (as described in 
Section 7), will be fully documented in the source document and transcribed into the CRF. All 
medications used during these concomitant procedures will also be captured in the source 
document and reported as concomitant medication in the CRF.  
 
 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 57 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
7 
STUDY PROCEDURES 
Personnel performing or recording study measurements must have appropriate and fully 
documented training. Quality control (QC) measures must be defined, implemented and 
documented. All study procedures are provided as an overview in the schedule of events 
(Appendix 1 – Schedule of Events).  
In this section, only the expected/planned time points for the various measurements are given. 
Considering that not all study participants can have a procedure at the same time point, 
adequate time windows are given for each study procedure and each time point in section 9. 
Site personnel will adhere to the site’s standard operating procedures (SOPs) for all activities 
relevant to the quality of the study. Appropriate dental/medical advice will be provided to the 
patients in case of any dental/medical findings requiring health care. 
7.1 
Informed Consent and Guidance 
Prior to any study assessment being performed, the patient will be asked to provide his/her 
written consent to participate to the study (ICF) section 1.3. All the assessments must start after 
the time of ICF signature by the patient before study participation. During the consent process, 
the Investigator or designee obtaining consent must inform each patient of the nature, risks and 
benefits of, and alternatives to study participation. In addition, each patient must review the 
ICF and must have sufficient time to understand and have adequate opportunity to ask 
questions. The ICF must be signed and dated (date and time) prior to undertaking any study-
specific procedures. A copy of the signed ICF must be given to the patient. 
7.2 
Advice on the Risks of Smoking/Smoking Cessation Advice and 
Debriefing on IQOS 
All patients included in the study will be first advised that the best ways of preventing further 
periodontal disease progression is to stop smoking as defined in the Japanese guidelines for 
periodontitis [78]. Only patients who are not willing to quit smoking cigarettes will be eligible 
for the study. 
From V1 onwards, information on the risks of smoking and advice to quit smoking will be 
given to all patients at every Visit. This will take the form of a brief interview according to 
WHO recommendations [97]. 
In addition to the information of the risk of use of tobacco-containing products on smoking 
products/smoking cessation advice, a debriefing of patients will be done at each visit to address 
any intended or unintended beliefs participants have about IQOS. The goal of the debriefing is 
to ensure that patients have an accurate understanding of product risks including an 
understanding that IQOS has not been demonstrated to be less harmful than cigarettes. 

 
 
 
 
 
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Clinical Study Protocol 
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Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
Any enrolled patient, who is willing to attempt quitting during the study will be encouraged to 
do so and will be referred to appropriate medical services. The patients who quit smoking or 
using IQOS or those who quit smoking and start using IQOS will not be discontinued from the 
study, will receive their financial compensation and will come at all scheduled visits for 
assessments. 
7.3 
Dental/Clinical Assessments 
As per medical responsibility plan, a medical expert (dentist) will be the primary contact for 
dental medical questions that Investigators might have. Dental medical monitors will be the 
co-primary contacts for dental medical questions. Other roles for medical expert and dental 
medical monitors are defined in the medical responsibility plan. 
7.3.1 Demographic Data 
Demographic data (sex, date of birth, ethnicity) will be recorded at V1. 
7.3.2 Questions on Smoking History/Habits and Intention to Quit Smoking 
Patients will be questioned for their smoking history and self-reported current tobacco and 
nicotine containing tobacco product use over the past month at V1. The patient will also be 
asked if he/she is planning to quit smoking during the study. This information will be used to 
assess their eligibility for the study. 
7.3.3 Presentation of IQOS 
IQOS including HeatSticks will be presented to all male patients by the Investigator or study 
collaborator at V1. With respect to female patients, it will be presented to the patients whose 
pregnancy test was negative.  
7.3.4 Dental/Medical History and Previous and Ongoing Medications 
Relevant dental/medical history and any concomitant disease will be documented at V1. 
Dental/medical history is defined as any condition that started and ended prior to ICF signature. 
A concomitant disease is defined as any condition that started prior to ICF signature and is still 
ongoing at the end of V1.  
Prior medication taken within 3 months prior to screening and any ongoing medication at 
screening needs to be documented. Any medication which is started prior to screening and is 
still being taken by the patient at screening or thereafter will be considered as concomitant 
medication. This applies to both prescription and over-the-counter products.  

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
If the use of a concomitant medication cannot be avoided for the patient’s safety, it must be 
fully documented in the Source Document and CRF. Therapy changes (including changes of 
regimen) during the study have to be documented.  
7.3.5 Dental Assessments 
In the investigational sites with two or more dentists, a dentist will measure each periodontal 
disease parameter. In the investigational sites with one dentist only, a dentist will preferably 
measure these parameters, however, a trained hygienist could also do it.  
From the moment the examiner meets the patient, blinding of the smoking status should be 
ensured, as described in section 6.4.1. 
A single examiner at each site will perform all measurements throughout the whole study 
duration, if possible. A calibration session between examiners from different sites must be 
organized before V1.  
Each site will need to develop a plan on how to ensure that they have properly qualified 
personnel, including back-up personnel necessary to conduct the required dental assessments. 
This will be documented in the delegation of authority log. 
Unified periodontal probes will be used to ensure that all examiners will apply the same 
pressure when probing. The probe in this study will be PCPUNC15 (#30) by Hu-Friedy. 
Measurements will be rounded to the nearest millimeter (mm), based on visual judgement.  
The dental assessments listed in the sections 7.3.5.1 to 7.3.5.8 below will be recorded on the 
prescribed periodontal charts. 
7.3.5.1 
Target Tooth 
At V1, for all eligible patients, the Investigator or designee will designate 4 target teeth, i.e., 
preferably one per quadrant. Teeth with PD ≥ 5 mm but < 7 mm will be preferably selected. If 
their location does not correspond to one per quadrant, the Investigator or designee will 
designate the target teeth preferably as single-rooted, and distributed as evenly as possible. 
Target teeth identification will be reported in the CRF. 
7.3.5.2 
Target site 
The Investigator or designee will designate one site on each target tooth (section 7.3.5.1), 
which will be the target sites for GCF collection (section 7.5.3). These four target sites should 
preferably be the deepest of the target teeth. Target site identification will be reported in the 
CRF. 

 
 
 
 
 
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Clinical Study Protocol 
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Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
7.3.5.3 
Pocket Depth (PD) 
PD is the distance from the gingival margin to which a probe penetrates into the pocket. Full 
mouth PD is measured based on 6 sites per tooth (6-site measurement method) at a pressure of 
approximately 20g using the intended probe at V1, V3 and V4. PD is recorded in 1 mm 
increments. If PD is not measurable on more than 2 sites, the whole tooth should be skipped 
and any periodontal parameters will not be measured for the tooth.  
The site must differentiate within their documentation when PD is not measured from when 
PD cannot be measured as there is no longer a pocket to measure.  
For each subject, full mouth PD is calculated by the following formula: 
Full Mouth PD (mm) = 1
𝑡∑∑𝑃𝐷𝑖𝑗
𝑠𝑖
𝑠𝑖
𝑗=1
𝑡
𝑖=1
 
where  𝑃𝐷𝑖𝑗 is the PD measurement of tooth 𝑖 , 𝑖= 1, … , 𝑡 at the site 𝑗 where 𝑗= 1, … , 𝑠𝑖. Note 
that 𝑠𝑖 is the number of measurable sites per tooth and 𝑠𝑖≥4. 
7.3.5.4 
Clinical Attachment Level (CAL) 
CAL is the measured distance from an invariable reference point such as CEJ to the bottom of 
pocket using the intended probe based on 6 sites per tooth (6-site measurement method) in full 
mouth at V1, V3 and V4. CAL is recorded in 1 mm increments. If CAL is not measurable on 
1 or 2 of 6 sites on V1, the site(s) should be skipped but the tooth can be included in the 
assessment. If CAL is not measurable on more than 2 sites, the whole tooth should be skipped. 
If the CEJ is unclear on site(s), the fixed point (e.g. margin of the crown) will be chosen if 
possible and distance from the chosen fixed point to the bottom of pocket will be measured, 
and the same position will be measured throughout the study period. The site must differentiate 
within their documentation when CAL is not measured from when CAL cannot be measured 
as there is no longer attachment loss to be measured.  
For each subject, the mean Full mouth CAL is calculated by the following formula: 
Full Mouth CAL (mm) = 1
𝑡∑∑𝐶𝐴𝐿𝑖𝑗
𝑠𝑖
𝑠𝑖
𝑗=1
𝑡
𝑖=1
 
Where  𝐶𝐴𝐿𝑖𝑗 is the 𝐶𝐴𝐿 measurement of tooth 𝑖 , 𝑖= 1, … , 𝑡 at the site 𝑗 where 𝑗= 1, … , 𝑠𝑖. 
Note that 𝑠𝑖 is the number of measurable sites per tooth and 𝑠𝑖≥4. 

 
 
 
 
 
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Clinical Study Protocol 
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Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
7.3.5.5 
Bleeding on Probing (BOP) 
BOP in full mouth is determined to assess inflammatory status in the pocket and is assessed as 
YES or NO of bleeding at 6 sites per tooth at V1, V3 and V4. Gently probing (approximately 
20g pressure), the bleeding site within 30 seconds is assessed as YES. For each subject, BOP 
is calculated by the following formula: 
Full Mouth BOP (%) = 100 ∗1
𝑡∑∑𝐵𝑂𝑃𝑖𝑗
𝑠𝑖
𝑠𝑖
𝑗=1
𝑡
𝑖=1
 
Where  𝐵𝑂𝑃𝑖𝑗 is a binary response (Yes = 1, No = 0) of bleeding of tooth 𝑖 , 𝑖= 1, … , 𝑡 at the 
site 𝑗 where 𝑗= 1, … , 𝑠𝑖.  
7.3.5.6 
Tooth Mobility 
Tooth mobility will be assessed by Miller’s classification [19] below to observe periodontal 
severity in full mouth at V1, V3 and V4: 
Grade 0: Physiologic movement within 0.2 mm 
Grade 1: Slight mobility, tooth can be moved 0.2 – 1 mm labiolingually 
Grade 2: Moderate mobility, tooth can be moved 1 – 2 mm labiolingually or mesiodistally 
Grade 3: Severe mobility, tooth can be moved more than 2 mm labiolingually or mesiodistally, 
or ability to depress the tooth in a vertical direction 
7.3.5.7 
Gingival Index (GI) 
The degree of gingival inflammation of the target teeth is assessed by calculating the GI of 
each target tooth. Six surfaces of each tooth of the target teeth are rated according to the score 
by Löe and Silness [36]. The surfaces are rated according to the following criteria:  
Score Criteria: 
0: Normal gingiva. 
1: Mild inflammation – slight change in color, slight edema, no bleeding on probing. 
2: Moderate inflammation – redness, edema and glazing, bleeding on probing. 
3: Severe inflammation – marked redness and edema, ulceration, tendency to spontaneous 
bleeding. 
For each subject, GI of target teeth is calculated by the following formula: 

 
 
 
 
 
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GI = 1
𝑡∑∑𝐺𝐼𝑖𝑗
𝑠𝑖
𝑠𝑖
𝑗=1
𝑡
𝑖=1
 
where  𝐺𝐼𝑖𝑗 is the GI of target tooth 𝑖 , 𝑖= 1, … , 𝑡 at surface 𝑗 where 𝑗= 1, … , 𝑠𝑖.  
7.3.5.8 
Plaque Control Record (PCR) 
Presence of the plaque on individual tooth surfaces in full mouth is assessed and PCR (%) is 
calculated.  
According to the PCR of O'Leary et al. [20], plaque retention in the dentogingival areas of 
mesial, distal, facial and lingual tooth surfaces is determined to be YES or NO and recorded at 
V1, V3 and V4. 
Usual plaque disclosing agent is used in each site and the product name of the plaque disclosing 
agent will be recorded. 
For each subject, PCR (%) is calculated by the following formula: 
𝐹𝑢𝑙𝑙 𝑀𝑜𝑢𝑡ℎ 𝑃𝐶𝑅 (%) = 100 ∗1
𝑡∑∑𝑃𝐶𝑅𝑖𝑗
𝑠𝑖
𝑠𝑖
𝑗=1
𝑡
𝑖=1
 
Where  𝑃𝐶𝑅𝑖𝑗 is a binary response (Yes = 1, No = 0) of PCR at tooth 𝑖 , 𝑖= 1, … , 𝑡 at the 
surface 𝑗 where 𝑗= 1, … , 𝑠𝑖.  
7.4 
Biomarker Assessments 
7.4.1 Assessments in Urine 
All bioanalytical assays will be carried out using validated methods (section 7.5.6). The 
bioanalytical methods used will be documented in the Bioanalytical Plans/Reports. A list of 
laboratories is provided in Appendix 2. 
7.4.1.1 
NEQ, total NNAL, CEMA, Creatinine Analysis 
Spot urine will be collected at V1, V3 and V4 for analysis of NEQ, total NNAL, a biomarker 
for NNK (i.e., nicotine-derived nitrosamine ketone, also known as 4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanone), CEMA, a biomarker for acrylonitrile, and creatinine. Creatinine will 
be measured for normalization of urinary BoExp, i.e., NEQ, total NNAL and CEMA. 

 
 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
7.5 
Other Clinical Assessments and Sampling 
Sample collection of GCF, SP and buccal swabs will be performed prior to periodontal 
assessment, scaling/maintenance or scaling and root planing (SRP). 
From V2 to V4, patients will be asked not to drink, eat, chew gum, use mouth rinse or brush 
their teeth for at least 30 minutes before collection of oral samples (i.e., SP, GCF or buccal 
swabs).  
7.5.1 Urine Pregnancy Testing 
All female patients will undergo urine pregnancy testing at all Visits. 
Female patients with a urine positive pregnancy test at the V1 cannot be enrolled and will be 
considered a screening failure. In any case of a positive urine pregnancy test, the Investigator 
will inform the patient about the risks associated with smoking during pregnancy.  
All pregnancies detected during the study must be reported and handled as described in Section 
8.5. 
7.5.2 Cotinine Test 
A urine cotinine test will be performed at V1 in order to confirm the patient’s smoking status. 
The test must detect cotinine with a cotinine of ≥ 200 ng/mL (e.g., One-Step Cotinine Test 
008A086, Ultimed, Belgium). 
7.5.3 Assessments in GCF 
GCF will be collected from 4 target sites at V2 and V3. The sampling should be performed 
before periodontal assessments. The selection of the target sites is described in section 7.3.5.2).  
At the time of the analysis, in order to characterize the inflammatory response, immuno-
regulatory mediators in GCF 7 will be measured with two types of technologies, i.e., bead-
based multiplex assays (MAP) using the Luminex technology or targeted mass spectrometry. 
Targeted mass spectrometry analysis will be performed using the quantitative parallel reaction 
monitoring (PRM) where the unique peptides of the selected protein targets will be analyzed 
for absolute quantitation in reference to a synthetic unique peptide of the selected protein 
                                                 
7 sCD40L, CRP, EGF, Eotaxin/CCL11, Flt3 ligand, GM-CSF, GRO, IFNα2IL-1α, IL-1β, IL-1Ra, IL-2, IL-3, IL-
4, IL-5, IL-6, IL-7, IL-8/CXCL8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A/CTLA8, IP-
10/CXCL10, MCP-1/CCL2, MCP-3/CCL7, MDC/CCL22, MIP-1α/CCL3, MIP-1β/CCL4, MMP-1, MMP-8, 
MMP-9, MMP-10, MMP-12, MMP-13, osteoprotegerin, PDGF-AA, PDGF-AB/BB, RANKL, RANTES/CCL5, 
TGFα, TIMP-1, TNFα, TNFβ / LT-α (please refer to the Abbreviations for full spelling)  
 

 
 
 
 
 
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targets using mass spectrometry. Absolute quantitation will be performed using a heavy labeled 
synthetic peptide of the selected unique peptide of the target. The targets that will be analyzed 
by mass spectrometry are: MMP-8, MMP-12, MMP-13, CRP, RANKL, TIMP-1 and 
osteoprotegerin (please refer to the Abbreviations for full spelling). 
7.5.4 Assessments in Subgingival Plaque 
SP will be collected from 4 target teeth, at V1 and V4 in order to evaluate the microbiological 
status. The sampling should be performed before periodontal assessments, except at V1, when 
it will be performed after periodontal assessments and designation of target teeth. If plaque 
sample is too small, additional collection can be performed on mesiobuccal SP of second 
molars, which needs to be recorded by the examiner. These teeth are the same than those 
selected for GCF collection (section 7.5.3). DNA isolation from these samples will enable the 
evaluation of the bacterial diversity and the detection of the abundance of bacteria in these 
samples. Some human host DNA (i.e., of the patient) will also be isolated, however, the host 
DNA sequences obtained during the DNA sequencing will be filtered out of the raw sequencing 
data before analysis, and no formal analysis of the patient DNA will be performed. 
7.5.5 Assessments in Buccal Swabs 
Buccal swabs will be derived from the right and left cheeks (intraoral) to conduct 
transcriptomics analysis at V2, V3 and V4. These samples will be analyzed for whole human 
genome expression profiles, also known as transcriptome. No analysis of the patient DNA will 
be performed. 
7.5.6 Sample Handling, Storage, and Shipment 
The urine dip-stick for the urine pregnancy tests, and urine cotinine tests will be done by 
personnel at the study sites. Participating laboratories for the analyses of clinical samples are 
listed in Appendix 2. Detailed procedures for handling of samples are described in a separate 
Laboratory Manual / Sample Handling Manual (SHM). All samples that were planned for 
analysis will be destroyed post database lock or post finalization of the bioanalytical reports 
depending on which one is coming the latest.  
7.5.7 Self-reported Tobacco- or Nicotine-Containing Product Use 
Patients will be questioned for their smoking history at V1. At V1, patients will also answer a 
questionnaire on self-reported current tobacco- and nicotine-containing product, with 
instructions from study staff so that they can then answer the questionnaire on their own on a 
monthly basis. After randomization, patients will be asked to complete a monthly diary, to 
record their self-reported tobacco- and nicotine- containing product consumption (including 
frequency and quantity of product use) over the past month. In this case, a “month” is to be 

 
 
 
 
 
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Clinical Study Protocol 
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Study P1-OHS-01-JP  
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disclosed without the written consent of Philip Morris Products S.A. 
considered as 30 days, however a “calendar month” window is acceptable. A flexibility of ± 2 
day is allowed, whichever definition of the month is used. The sites will call the patients to 
remind them to fill the questionnaire. The Investigator or study collaborator will collect the 
completed diaries at V3 for Month 1 and Month 2 and for Month 3 only if the questionnaire 
completion date was before or on the day of the Visit. If the completion date of Month 3 
questionnaire is after the V3 date, the Month 3 questionnaire will be brought to the next visit. 
All remaining questionnaires will be collected at V4, even if the 30-day period for completion 
of Month 6 questionnaire is after the date of V4. The diary data will be transcribed into the 
CRF by study staff. 
7.6 
Periodontal Treatment/Maintenance 
For each patient, standard of care procedures as defined by the Japanese guideline on 
periodontal disease will be applied [78]. All medications/treatments provided to patients must 
be documented in source documentation. However, medication commonly used during SRP 
and maintenance treatment procedure will not be recorded as concomitant medication in the 
CRF, except if it is identified as causally related to an AE.  
This section describes more specifically the mechanical treatment which is targeted for this 
study. 
7.6.1 Scaling 
Supragingival scaling will be performed at V1, and at further visits if required, including at 
unscheduled visits, based on PI’s judgement. Maintenance treatment will be provided in the 
order of supragingival scaling and plaque control at all other visits. Ultrasonic scaler usually 
used at each site will be used for scaling. 
7.6.2 Scaling and Root Planing (SRP) 
First SRP will be performed on teeth with PD ≥ 4 mm by using Gracey Hand Curettes at V2. 
The following SRP treatments will be performed and recorded as “unscheduled” SRP visits. 
SRP treatments of teeth with PD < 4 mm will be performed based on PI’s judgment, at the time 
he/she finds it necessary. All SRP treatments must be completed within 8 weeks after V2. If 
additional SRP visits need to be performed because of periodontitis worsening, based on 
Investigator’s judgement, they will be recorded as unscheduled visits, including the reason for 
this unplanned SRP. 
PD, mobility and BOP before SRP will be measured as per the standard of care treatments at 
V2. These data will, however, not be reported in the CRF.  
The order of SRP should be determined for individual patients. The identification of each tooth 
treated and the respective time of treatment should be recorded. 

 
 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
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hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
8 
ADVERSE EVENTS 
A medically qualified monitor(s) (i.e., medical monitor) will be available during the study to 
address any safety question an Investigator may have. 
8.1 
Definitions 
8.1.1 Adverse Events 
According to ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting [98], an AE is defined as any untoward medical occurrence in a patient 
administered an IP or reference product, which does not necessarily have a causal relationship 
with the IP or reference product. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an IP or reference product, whether or not it is considered 
related to the IP or reference product. 
Any dental condition identified after signature of the ICF, caused by factors other than 
periodontitis (e.g. cavity, broken tooth) and requiring future treatment/s, will be identified as 
an AE. Treatment of this condition (e.g. cavity filling, tooth extraction) will be captured in the 
CRF. 
Worsening of the periodontitis parameters after baseline assessments will not be considered as 
an AE, as dental assessments will capture any worsening of the periodontal condition. Patients 
experiencing unexpected worsening of the disease, will be treated based on Investigator’s 
judgement, which will be recorded. 
8.1.2 Serious Adverse Event 
An SAE is defined as, but not limited to, any untoward medical occurrence that: 
 
Results in death. 
 
Is life-threatening. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
 
Results in persistent or significant disability/incapacity, or, 
 
Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, they 
may jeopardize the patient or the patient may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definitions. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
Any pre-planned hospitalizations that are known at the time of signing the study participation 
ICF will not be recorded as SAEs (they will be recorded only as AEs). However, any AE that 
occurs during this pre-planned hospitalization will be considered according to the above 
definitions. 
8.2 
Assessment of Adverse Events 
The Investigator is responsible for obtaining, assessing and documenting all AEs during the 
study. 
8.2.1 Assessment of Adverse Events 
Adverse event information will be collected from the time of signature of the study 
participation ICF onwards until the end of the safety follow-up period either by the Investigator 
via spontaneous reporting or by the use of consistent, open, non-directive questions from study 
site collaborators (e.g., “Have you had any health problems since the previous visit/How have 
you been feeling since you were last asked?”). The main source for AE collection will be face-
to-face interview(s) with the patient.  
Information recorded will include: verbatim description of the AE, start and stop dates and 
times, seriousness, severity (intensity), action taken (e.g., whether or not the AE led to the 
patient’s withdrawal from the study), and outcome (e.g., resolved, withdrawal due to AE). 
For each AE, the intensity (severity) will be graded on a 3-point intensity scale (mild, moderate, 
severe) using the definitions provided in section 8.2.3.  
Any exacerbation/worsening of an AE or pre-existing condition shall be evaluated and 
recorded.  
Correct medical terminology/concepts are preferred when recording AE terms, and 
abbreviations must be avoided. Wherever possible, a diagnosis is to be used to describe an AE 
rather than individual signs and symptoms (e.g., record ‘pneumonia’ rather than ‘fever,’ 
‘cough,’ ‘pulmonary infiltrate,’ or ‘septicemia,’ rather than ‘fever’ and ‘hypotension’ 
following blood sample). 
Any AE that meets the serious criteria must be recorded both on the AE report form of the 
CRF and on a separate SAE report form (section 8.3). 
8.2.2 Period of Collection 
Any AEs (including SAEs) will be captured by the study site collaborators and assessed by the 
Investigator(s) or designee(s) in order to establish relationship to Investigational Products and 
study procedures. AEs will be collected from the time the patients have signed their ICFs until 
the end of the safety follow-up period. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
All collected AEs will be reported in the clinical study report (CSR) and in accordance with 
the respective local regulatory guidelines. 
8.2.2.1 
Screening Visit (V1) 
All existing health conditions identified during the screening visit and judged by the 
Investigator as preexisting condition will be recorded as concomitant disease and the patient’s 
eligibility for admission to the study will be reviewed.  
8.2.2.2 
From End of V1 until the End of Study 
From V1 onwards until the EOS, all AEs will be documented.  
Any new, clinically relevant, abnormal finding or worsening of a pre-existing 
condition/concomitant disease detected during the study will be documented as an AE and/or 
SAE and assessed by the Investigator or designee. During the safety follow-up period AEs 
and/or SAEs will be recorded only if reported spontaneously by the patient.  
SAEs will be reported by the Investigator as described in this document and the safety 
management plan (SMP).  
At the end of the safety follow-up period, all ongoing non-serious AEs will be documented as 
“ongoing” and no follow-up information will be sought for on them anymore by the 
Investigator or designee. At that point, the Investigator will assess whether the patient should 
be referred to his/her General Practitioner to have their ongoing AEs addressed accordingly.  
All SAEs will be actively followed up by the Investigator, despite their continuation after the 
end of the safety follow-up period, until their resolution, stabilization (i.e., no worsening of the 
condition), or until an acceptable explanation has been found (e.g., a chronic condition). 
8.2.3 Intensity of Adverse Event 
For each AE, the intensity will be graded by the Investigator on a 3-point intensity scale (mild, 
moderate, severe) using the following definitions: 
Mild: The AE is easily tolerated and does not interfere with daily activity.  
Moderate: The AE interferes with daily activity, but the patient is still able to function.  
Severe: The AE is incapacitating and requires medical intervention. 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
In general, all AEs and/or SAEs will be assessed by the Investigator as either ‘related’ or ‘not 
related’ to IP (i.e., IQOS or cigarette) as described below. In addition to the assessment of the 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
relationship of the clinical event to the IP, the Investigator shall document a potential 
relationship of the clinical event to any particular study procedure. 
Not related: The temporal relationship of the dental or clinical event to IP administration or 
to a study procedure makes a causal relationship unlikely, or, concomitant 
medication, therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event. 
Related: 
The temporal relationship of the dental or clinical event to study IP 
administration or to a certain study procedure makes a causal relationship 
possible, and concomitant medication, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the observed event. 
8.2.5 Expectedness 
Any AE assessed as related to the IP will be assessed for its expectedness. An AE will be 
regarded as ‘unexpected’ if its nature or severity is not consistent with information already 
known about the IP, and is not listed in the current SPI [81].  
8.2.6 Medical Monitor 
All Investigator of this study are dentists. A medical monitor will be designated by Sponsor or 
authorized representative to answer any medical question that a dentist may have on any 
medical condition besides dental conditions, as well as on any question related to the safety of 
the patient (i.e., AE/SAE).  
8.3 
Reporting and Follow-Up of Serious Adverse Events 
Any SAEs reported or observed during the study whether or not attributable to the IP, or to 
any study procedures, or any SAE related to the product and spontaneously reported after the 
safety follow-up period must be reported by the Investigator within 24 hours after first 
awareness by any party involved in the study to 
 and to the Sponsor.  
An SAE report form must be e-mailed or faxed as an attachment to: 
: 
Phone number: 
 
E-mail: 
Fax: 
 
  
 
Address: 
 
 
 
 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
Sponsor: 
 
Phone number: 
 
 
E-mail: 
 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
5 Quai Jeanrenaud 
2000 Neuchâtel 
Switzerland 
The Investigator/head of the investigational site is responsible for local reporting (i.e., to the 
IRB) of SAEs that occur during the study, according to local regulations.  
Any additional/follow-up information that becomes available after the initial SAE report form 
has been completed will be forwarded to 
 and the Sponsor within 24 hours after 
first awareness by any person at the site using a new SAE report form and indicating that this 
is a follow-up report. 
The follow-up SAE report form must include the minimum information required for form 
completion and only changed/new information needs to be specified. Information provided in 
the follow-up SAE report form supersedes any information that was initially reported.  
All SAEs will be actively followed up by the Investigator until their resolution or until the 
Investigator considers the event to be stabilized (i.e., no worsening of condition), or until an 
acceptable explanation has been found (e.g., a chronic condition). The details of the SAE 
management will be provided in a separate document, namely the safety management plan 
(SMP) for this study. 
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will be recorded on the relevant CRF page, in addition to the SAE report form. 
8.4 
Reporting of other events critical to safety evaluations 
An ongoing medical condition, clinically relevant finding detected during the screening visit 
(V1), will be considered a concomitant disease and the patient’s eligibility for participating to 
the study will be reviewed. 
Any new, clinically relevant, abnormal finding or worsening of a pre-existing condition 
detected during the study after the screening visit until the end of the study will be documented 
as an AE. 
Any new onset of symptoms or worsening of pre-existing symptoms identified through the 
study questionnaires may be documented as AEs at the discretion of the Investigator. 

 
 
 
 
 
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hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
In order to avoid duplicate reports, the patients will be instructed to report AEs, SAEs and 
occurrences of malfunction of the IQOS device only to a member of the study staff and not to 
the IQOS hotline. 
8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected between the time of signature of the study participation ICF and the 
enrollment of the patient, the patient will be considered as a screen failure. In that situation, 
the pregnancy will not be reported to the Sponsor, however, the identified pregnancy(ies) must 
be captured in the screen failure CRF. No pregnancy form will be filled. 
For pregnancies detected between enrollment and V2 prior to randomization, patients will be 
discontinued, and reported as “enrolled but not randomized” patients. Early termination 
procedures shall apply. No pregnancy form will be filled. 
Any pregnancy detected after randomization, must be reported by the Investigator to the 
Sponsor within 24 hours of the first awareness and must be followed-up up to 8 weeks after 
the pregnancy outcome is reached. This also includes pregnancies spontaneously reported to 
the Investigator after the end of the study for a patient. 
The Investigator will complete a pregnancy form (provided as a separate document) for all 
pregnancies diagnosed (including positive urine pregnancy tests) after randomization.  
The procedure to report a pregnancy and provide any additional/follow-up information to 
 
 and the Sponsor must be followed in the same manner and within the same timelines as 
described for an SAE (section 8.3). No invasive procedures must be done in such patients after 
the discovery of pregnancy. 
 will follow up pregnancies only if they were detected 
after first product use (i.e., IQOS or cigarettes after V2). If pregnancies are to be followed-up, 
they will be followed-up until an outcome is reached (e.g., normal delivery, spontaneous 
abortion, or voluntary termination) and also until 8 weeks after delivery.  
Any pregnancy complication, adverse pregnancy outcome, or maternal complications will be 
recorded as an AE (or SAE).  
The Principal Investigator/head of the investigational site is responsible for informing the IRB 
of any pregnancy that occurs during the study and its outcome, according to local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Patients who are discontinued from the study because of an AE will undergo the early 
termination procedures, as described in section 9.6, as soon as possible and will enter the safety 
follow-up period. The Investigator will follow up these AEs as described in section 8.2.2.  

 
 
 
 
 
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hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
8.7 
Device Events / Investigational Product Malfunction and Misuse 
Any occurrences of device events, including IQOS malfunction (e.g., holder does not charge 
when inserted into the charger) or misuse (use not in accordance with its label and instruction) 
by a patient, will be documented by a site collaborator in a device issue log developed by the 
site.  
Investigational product misuse may result in use-related hazards (section 2.3.4).  
Furthermore, any misuse or malfunction of the IQOS that leads to an AE/SAE will follow the 
same processes as described above for the reporting of the AE/SAE. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
9 
STUDY ACTIVITIES 
A detailed schedule of assessment can be found in Appendix 1. 
If no start time for the procedures is provided, then the procedure can be performed at any time 
during the visit. Assessments will be conducted only by qualified and trained site personnel. 
Toothbrush instructions will be provided throughout the study as per standard of care. 
From V2 to V4, patients will be asked not to drink, eat, chew gum, use mouth rinse or brush 
their teeth for at least 30 minutes before collection of oral samples (i.e., SP, GCF or buccal 
swabs).  
9.1 
Screening, Enrollment and Baseline Visit: V1 
The screening, enrollment and baseline visit (V1) will be scheduled within 2 weeks (Day -14 
to -7) prior to randomization visit (V2).  
Patient will sign the study participation ICF before the start of any procedure, and will enter 
Screening. All eligibility criteria will be checked, including periodontal assessment, which will 
be also used as baseline assessment for enrolled patients.  
Table 3 shows the assessments that will be performed at the screening, enrollment and baseline 
visit: 
Table 3 
Schedule - Screening, Enrollment and Baseline Visit: V1 
Time 
Sample 
collection 
Procedures 
Additional information 
Start of 
procedure 
 
Screening, Enrollment and Baseline 
 
Start of the visit 1 
 
ICF signature 
 
During the visit 
Before enrollment 
 
Advice on the risks of smoking/smoking 
cessation advice and debriefing on IQOS 
 
 
 
Demographics data 
Sex, date of birth, ethnicity 
 
 
Dental/medical history, including history of 
alcohol or drug abuse, concomitant diseases, 
 
 
 
Prior medication and/or concomitant 
medication / Procedures 
 
 
U 
Spot urine collection for pregnancy (all 
females) and cotinine tests, and collection 
Pregnancy test (all females): 
at the study site 
                                                 
1 The informed consent process can be started as soon as the patient is invited to participate in the study, but the 
ICF must be signed no later than before the first assessment at V1.  

 
 
 
 
 
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Time 
Sample 
collection 
Procedures 
Additional information 
Start of 
procedure 
 
Screening, Enrollment and Baseline 
 
for NEQ, total NNAL, CEMA and 
creatinine samples. 
 
Cotinine test: at the study 
site. Cotinine ≥ 200 ng/mL 
Process samples for NEQ, 
total NNAL, CEMA, 
creatinine analysis according 
to laboratory manual/SHM. 
 
 
IQOS presentation 
To all males. For females, 
only those who presented 
negative pregnancy test. 
 
 
Smoking history 
Patients will be questioned 
on their smoking history.  
 
 
Tobacco or nicotine containing product use 
self-reporting 
Patients will answer this 
questionnaire on site, with 
instructions from study staff 
so that they can then fill it 
alone on a monthly basis 1. 
Distribution of the diaries for 
the next Visit. 
 
 
Readiness to comply to study procedures, 
and to use the product he/she has been 
allocated to for the duration of the study 
 
 
 
Patient is not planning to quit smoking 
during the study 
 
 
 
Periodontal assessment: 
Last assessment performed as 
part of the eligibility criteria, 
to avoid unnecessary 
examination for those 
patients who are in any case 
not eligible. 
 
 
 
Full mouth PD 
 
 
Full mouth CAL  
 
 
Full mouth BOP 
 
 
Full mouth tooth mobility 
 
 
Full mouth PCR 2 
 
 
Judgment on eligibility 
All eligibility criteria must be 
checked. 
                                                 
1 For the questionnaire, “monthly” can be considered as 30 days, or as a calendar month. A flexibility of ± 2 day 
is allowed to fill it. 
2 PCR can be performed after enrollment based on PI’s decision. 

 
 
 
 
 
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Time 
Sample 
collection 
Procedures 
Additional information 
Start of 
procedure 
 
Screening, Enrollment and Baseline 
 
 
 
Enrollment 
If all eligibility criteria are 
met. 
 
 
Designation of 4 target teeth and 4 target 
sites 
Target teeth: preferably 4 
teeth with ≥ 5 mm initial PD, 
from which SP and GCF will 
be collected at their 
respective visits indicated in 
the Appendix 1. Target sites: 
preferably the deepest sites of 
the target teeth. 
 
After enrollment 
 
Gingival inflammation of target teeth 
Part of periodontal 
assessment, to be performed 
after designation of 4 target 
teeth 
 
SP 
Collect from 4 target teeth 
For microbiological status. 
Store the sample according to 
laboratory manual/SHM. 
 
 
Supragingival scaling 
 
 
 
AE/SAE recording 
 
For screen failures 
 
Discard any urine samples that might have 
been collected for patients who are not 
enrolled. 
 
End of the visit 
 
 
 
Abbreviations: AE = Adverse event; BOP = Bleeding on probing; CAL = Clinical attachment level; CEMA = 2-
cyanoethylmercapturic acid; GCF = Gingival crevicular fluid; NEQ = nicotine equivalents, consisting of the molar 
sum of free nicotine, nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine and 
trans-3’-hydroxycotinineglucuronide; NNAL = 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol; PCR = Plaque 
control record; PD = Pocket depth; SAE = Serious adverse event; SHM = Sample handling manual; SP = 
Subgingival plaque; U = Urine 
9.2 
1st SRP and Randomization Visit: V2  
The first SRP visit (V2) will be scheduled 7 to 14 days after V1.  
Table 4 shows the assessments that will be performed at V2: 
Table 4 
Time Schedule – 1st SRP Visit and Randomization: V2 

 
 
 
 
 
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Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of 
procedure 
 
1st SRP and Randomization 
 
Start of the visit 
 
Advice on the risks of smoking/smoking 
cessation advice and debriefing on IQOS 
 
During the visit 
 
Concomitant medication / Procedures 
 
 
U 
Spot urine collection for pregnancy (all 
females). 
Pregnancy test (all females): 
at the study site 
 
 
BS 
Derived from the right and left cheek 
Store the sample according 
to SHM for transcriptomics 
evaluation. 
 
GCF 
Collect from 4 target sites. 
 
Same teeth as SP collection 
at V1. 
Store the sample according 
to SHM. 
 
 
PD 
BOP 
Tooth mobility 
As per standard of care 
(optional, as per PI’s 
judgment). Will not be 
recorded in the CRF. 
 
 
SRP treatment 
Start treatment on teeth with 
PD ≥ 4 mm. 
 
 
AE/SAE recording 
 
 
 
Randomization 
 
 
 
Patients are informed of their randomized 
study arm. 
 
 
 
Distribution of IQOS starter kit to the 
patient allocated to the IQOS arm 
A selection of HeatStick 
flavor variants available on 
the Japanese market is 
included. 
Patients are instructed to 
report AEs, SAEs and for 
IQOS arms, occurrences of 
malfunction of the IQOS 
device only to a member of 
the study staff and not to the 
IQOS hotline. 
End of the visit 
 
Patients start using their allocated product 
 
Abbreviations: AE = Adverse event; BOP = Bleeding on probing; BS = Buccal swabs; CEMA = 2-
cyanoethylmercapturic acid; CRF = Case Report Form; GCF = Gingival crevicular fluid; NEQ = nicotine 
equivalents, consisting of the molar sum of free nicotine, nicotine-glucuronide, free cotinine, cotinine-glucuronide, 

 
 
 
 
 
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free trans-3’-hydroxycotinine and trans-3’-hydroxycotinineglucuronide; NNAL = 4-[methylnitrosamino]-1-[3-
pyridyl]-1-butanol; PD = Pocket depth; SAE = Serious adverse event; SHM = Sample handling manual; SP= 
Subgingival plaque; SRP=Scaling and root planing; U = Urine 
9.3 
Investigational Period Visit: V3 
V3 will be scheduled 3 months after V2 with a flexibility of ± 7 days. 
Table 5 shows the assessments that will be performed at V3: 
Table 5 
Time Schedule – 3 Months Visit: V3 
Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of 
procedure 
 
 
 
Start of the visit 
 
Advice on the risks of smoking/smoking 
cessation advice and debriefing on IQOS. 
 
During the visit 
 
Tobacco or nicotine containing product use 
self-reporting 
Collection of the diaries 
from the previous Visit, and 
distribution of the diaries for 
the next Visit 
 
 
Concomitant medication / Procedures 
 
 
U 
Spot urine collection for pregnancy (all 
females), and collection for NEQ, total 
NNAL, CEMA and creatinine samples. 
Test at the study site. 
Store the sample according 
to SHM 
 
BS 
Derived from the right and left cheek 
Store the sample according 
to SHM for transcriptomics 
evaluation. 
 
GCF 
Collect from 4 target sites 
Same teeth as SP collection 
at V1. 
Store the sample according 
to SHM 
 
 
Periodontal assessment 
Same examiner as V1 
 
 
Full mouth PD 
Full mouth CAL 
Examiner wears mask. 
Patients wash hands. 
 
 
Full mouth BOP 
 
 
 
Full mouth tooth mobility 
 
 
 
Gingival inflammation of the target 
teeth 
Full mouth PCR 
 
 
 
Maintenance treatment  
 

 
 
 
 
 
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Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of 
procedure 
 
 
 
 
 
AE/SAE/device event recording 
 
End of the visit 
 
 
 
Abbreviations: AE = Adverse event; BOP = Bleeding on probing; CAL = Clinical attachment level; CEMA = 2-
cyanoethylmercapturic acid; GCF = Gingival crevicular fluid ; NEQ = nicotine equivalents, consisting of the 
molar sum of free nicotine, nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-
hydroxycotinine and trans-3’-hydroxycotinineglucuronide; NNAL = 4-[methylnitrosamino]-1-[3-pyridyl]-1-
butanol; PCR = Plaque control record; PD = Pocket depth; SAE = Serious adverse event; SHM = Sample handling 
manual; SP = Subgingival plaque ; U = Urine 
9.4 
End of Study Assessments Visit: V4 
V4 will be scheduled 6 months after V2 with a flexibility of ± 14 days. 
At the end of V4, patients will be discharged from the study. 
Table 6 shows the assessments that will be performed at V4. The procedure of discharge in 
case of early termination, i.e., before V4, is described in section 9.6.  
Table 6 
Time Schedule – 6 Months Visit: V4 
Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of  
procedure 
 
 
 
Start of the visit 
 
Advice on the risks of smoking/smoking 
cessation advice and debriefing on IQOS 
 
During the visit 
 
Tobacco or nicotine containing product use 
self-reporting 
Collection of the diaries 
from the previous Visit, 
including questionnaire of 
Month 6. 
 
 
Concomitant medication / Procedures 
 
 
U 
Spot urine collection for pregnancy (all 
females), and collection for NEQ, total 
NNAL, CEMA and creatinine 
Test at the study site. 
Store the sample according 
to SHM. 
The pregnancy test is part of 
the procedures of discharge. 
 
SP 
Collect from 4 target teeth. 
For microbiological status: 
Same teeth than for SP 
collection at V1. 
Store the sample according 

 
 
 
 
 
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Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of  
procedure 
 
 
 
to SHM. 
 
BS 
Derived from the right and left cheeks. 
Store the sample according 
to SHM for transcriptomics 
evaluation: 
 
 
Periodontal assessment: 
Full mouth PD 
Full mouth CAL 
Full mouth BOP 
Full mouth tooth mobility 
Gingival inflammation of the target 
teeth 
Full mouth PCR 
Same examiner as V1 
Examiner wears mask. 
Patients wash hands. 
 
 
Maintenance treatment 
 
 
 
AE/SAE/device event recording  
The AE/SAE/device event 
recording is part of the 
procedures of discharge. 
End of the visit 
 
Discharge 
 
Abbreviations: AE = Adverse event; BOP = Bleeding on probing; BS = Buccal swab; CAL = Clinical attachment 
level; CEMA = 2-cyanoethylmercapturic acid; GCF = Gingival crevicular fluid ; NEQ = nicotine equivalents, 
consisting of the molar sum of free nicotine, nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-
3’-hydroxycotinine and trans-3’-hydroxycotinineglucuronide; NNAL = 4-[methylnitrosamino]-1-[3-pyridyl]-1-
butanol; PCR = Plaque control record; PD = Pocket depth; SAE = Serious adverse event; SHM = Sample handling 
manual; SP = Subgingival plaque; U = Urine 
9.5 
Safety Follow-up Period 
After the procedures of discharge, patients will enter a 7-day Safety Follow-up Period. Any 
non-serious AE that is ongoing during the Safety Follow-up Period will be followed-up by the 
Investigator during that period until it has been resolved, stabilized (i.e., no worsening of the 
condition), or an acceptable explanation has been found (e.g., a chronic condition). At the end 
of the follow-up, all ongoing non-serious AEs will be documented as “ongoing” and no follow-
up information will be sought for on them anymore by the Investigator or designee. At that 
point, the Investigator will assess whether the patient should be referred to his/her General 
Practitioner to have their ongoing AEs addressed accordingly. All SAEs will be actively 
followed up by the Investigator, despite their continuation after the end of the safety follow-
up period, until their resolution, stabilization (i.e., no worsening of the condition), or until an 
acceptable explanation has been found (e.g., a chronic condition). 

 
 
 
 
 
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9.6 
Early Termination Procedures 
For patients who terminate the study earlier, i.e., before V4, the procedure of discharge planned 
for V4 will be performed as early termination procedures (see Section 9.4). AE recording will 
be done for each patient. 
If the patient withdraws from the study or is discontinued based on PI judgment, he/she will 
be asked to perform the early termination procedures as soon as possible after the time of 
withdrawal unless the patient has withdrawn their informed consent to do so (section 5.2). 
He/she will be asked whether he/she would agree to still do the dental/clinical assessments 
planned for this visit, but with no obligation. 
These early termination procedures consist in: 
 AE/SAE/device event recording 
 Pregnancy test (for all females). 
Safety follow-up period will be applicable for these patients. 

 
 
 
 
 
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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
The Clinical Research Associate (“Monitor”) will be responsible for the monitoring of the 
study. Monitoring will be performed according to CRO’s Standard Operating Procedures 
(SOPs) and as per the agreed monitoring plan with the Sponsor. 
The Principal Investigator/head of the investigational site shall permit the Monitor to review 
study data as frequently as considered necessary to ensure that data are being recorded in an 
adequate manner and that protocol adherence is satisfactory. 
The Investigator shall access medical records for the Monitor in order that entries in the CRFs 
may be verified. The Investigator, as part of their responsibilities, is expected to ensure that 
the study adheres to GCP requirements. 
An Investigator’s meeting will be held prior to the site initiation visit. During this meeting, the 
general training of the study procedures and specific training on selected procedures will be 
done and documented. 
Subsequent to the Investigator’s meeting, and before the first patient is screened into the study, 
site initiation visit will be conducted by the Monitor and, if necessary, with the Sponsor or its 
authorized representative. The purpose of the site initiation visit will be detailed in the 
monitoring plan. 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Investigator and study personnel will cooperate with the Monitor, provide all 
appropriate documentation, and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other study collaborator at the sites need information and advice. 
Site visits will be made at regular intervals during the study. The frequency of the monitoring 
visits will be defined in the monitoring plan agreed with the Sponsor. 
The Investigator, or a designated member of the Investigator’s study collaborator, must be 
available during the monitoring visit to review the data and resolve any queries, and to allow 
direct access to the patient’s records for source data verification. 
10.2 Training of Staff 
A formal meeting (Investigator meeting) will be conducted prior to site initiation. During this 
meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training in the relevant 
systems and other study-specific procedures. The activities of the Investigator meeting will be 
described in the monitoring plan.  

 
 
 
 
 
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In addition to the Investigator meeting, the Investigator will ensure that appropriate training 
relevant to the study is provided to all study collaborators involved in the study, and that any 
new information relevant to the performance of this study is forwarded to the study collaborator 
involved in a timely manner. The record of all individuals involved in the study will be 
maintained in the Site Investigator File. 
10.2.1 Calibration of Examiners 
Sites will provide a plan on how to ensure that they have properly qualified personnel, 
including back-up personnel necessary to conduct the required dental assessments (section 
7.3.5). 
10.3  Audits and Inspections 
Good Clinical Practice regulations require that there are independent inspections of clinical 
program activities. Such inspections may be performed at any time before, during and/or after 
the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or the IRB may perform 
audits or inspections, including source data verification. The purpose of an audit or inspection 
is to systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, ICH/GCP guidelines, and any applicable 
regulatory requirements. The Principal Investigator/head of investigational site will contact the 
Sponsor or the authorized representative immediately, if contacted by a regulatory agency 
about an inspection at their site. 
The Investigator and study collaborator are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection at 
any time by the Sponsor, its authorized representative, and/or regulatory agencies. In signing 
this protocol, the Investigator understands and agrees to provide access to the necessary 
documentation and files. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
11 DATA MANAGEMENT ACTIVITIES 
All Data Management activities will be described in detail in the Data Management Plan 
(DMP) and documents specified therein. 
11.1 Data Capture 
11.1.1 Case Report Forms and Study Records 
Data Collection Procedures: 
The results from the clinical assessments will be recorded in the source data file by the 
Investigator or their authorized designee and then captured in the CRFs. 
Trained study personnel will be responsible for capturing the data from the observations, tests, 
and assessments specified in the protocol and in the source documents, and transferring the 
data to the CRF according to the CRF Completion Guidelines. 
The Investigator has ultimate responsibility for the collection and reporting of all data related 
to the clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring, and available when required. The CRF must be signed by the 
Investigator to attest that the data contained on the CRF are true and accurate. Any corrections 
made to source documents must be clearly recorded, without obscuring the original values and 
be accompanied by the date of change, reason for change, and identification of the person 
making the change. The CRF data will be verified against the source documents at the study 
site by the clinical research associate. Instances of missing or unclear data will be discussed 
with the Investigator for resolution. 
11.1.2 Protocol Deviations 
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) or 
other approved format. 
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be considered 
and handled as important communication, and documented and tracked as protocol deviations, 
as necessary. 
Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following site monitoring and other manual reviews will be reviewed against the 
individual data points in the CRF database but will not be formally reconciled with the CRF 
database (e.g., their description or occurrence date). The overall procedures for managing 

 
 
 
 
 
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protocol deviations are described in the SOPs of the CRO Data Management Team. All 
deviations will be reviewed periodically, as determined at study start, to identify trends to 
improve monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the Data Management Team at the CRO. The overall 
procedures for quality assurance of clinical study data are described in the SOPs of the CRO 
Data Management Team. The Data Management Team at CRO will prepare a DMP, to be 
reviewed and approved by the Sponsor, prior to the start of the study. This document will 
describe, in detail, the Data Management related procedures and processes. 
All data of all patients enrolled and screening failures who experience an AE during the study 
(from time of informed consent) will be captured. 
All data collected during the study is property of the Sponsor irrespective of the location of the 
database and the Data Management CRO. 
11.2.1 Data Validation 
The data will be validated as defined in the DMP and Data Validation Specifications. 
Discrepancies will be reported as defined in DMP and Data Validation Specifications. 
Data queries will be raised for discrepant or missing data. All changes to data will be captured 
in the database with a comprehensive audit trail. 
11.2.2 Coding 
AEs, medical/surgical history, and prior/concomitant medication will be classified according 
to the terminology of the latest version of the following Dictionaries, at time of coding the first 
entry: 
Medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Adverse events / 
Procedures: 
MedDRA® 
Medications: 
WHODrug Global 
IQOS device issues 
and/or malfunctions: 
C54451/Medical_Device_Problem_Codes_FDA_CDRH 
 

 
 
 
 
 
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hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
11.2.3 Database Lock 
When all outstanding Data Management issues have been resolved and all validation, quality 
review, and cleaning activities are complete, the database or selected data is/are declared soft 
locked. Access to change data in the soft-locked database or to change selected data at this 
time is limited. 
After the data is reviewed by the Sponsor, resolution of all raised queries and QC of the 
changed data, database, or selected data upon Sponsor approval as applicable, is declared 
locked. 
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the Data Management and Statistical Teams at the CRO. Any of those changes 
must be documented in the database log file. 
After study completion, the study database will be transferred to the Sponsor in the format 
specified in the DMP and compliant with CDISC Study Data Tabulation Model (SDTM). 

 
 
 
 
 
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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
Full details of the statistical analysis will be given in the Statistical Analysis Plan (SAP). Any 
changes to the planned statistical methods will be documented in the CSR. The statistical 
evaluation will be performed using SAS®, version 9.2 or later. 
12.1.1 Stratification Criteria 
For the primary analysis of PD, the following stratification criteria will be used:  
1. Daily cigarette consumption over the month (30 days) prior to V1 (10-19 
cigarettes/day vs. >19 cigarettes/day) 
2. Disease severity in smokers with generalized chronic periodontitis (< 5 mm vs. ≥ 5 
mm PD). 
In each arm, a quota should be applied to ensure that patients with PD ≥ 5 mm represent at 
least 50% of the randomized patients (section 6.3). 
12.1.2 Definitions for Statistical Data Analysis 
In general, baseline value for any given variable will be the last assessment prior to 
randomization. 
12.1.3 Descriptive Statistics 
Data will be presented in listings, sorted by product exposure, patient, and study visit, unless 
otherwise specified. 
For continuous data, summary statistics will include the number of patients [n], number and 
percent of patients with missing data, the mean and standard deviation (SD), median, first and 
third quartiles, minimum and maximum, and 95% confidence interval (CI). Log-normally 
distributed data (e.g., BoExp data) will also include the geometric mean, and coefficient of 
variation (CV) will be presented in addition to the mean and SD. For categorical data, 
frequency counts and percentages will be presented. 
Descriptive statistics will be presented by product exposure and overall (across the entire study 
population) at each time point, where applicable.  
12.1.4 Handling of Missing Values and of Values Outside the Detection Limits 
For periodontal parameters:  
 Six sites per tooth are to be evaluated. At least 4 of the 6 sites per tooth must be 
evaluated and have the measurements recorded for the tooth to be included in the 

 
 
 
 
 
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assessment. If the site is evaluated and there is no PD to measure, the site must be 
recorded as 0 to indicate that there was no PD at the site (and to distinguish it from a 
site that was not evaluated). When less than 4 sites are recorded, the assessment of the 
tooth will be considered as missing, and the values will be excluded from the 
calculation of the means. 
For BoExp parameters: 
 Values below the lower limit of quantification (LLOQ) will be imputed using LLOQ/2. 
For values above the upper limit of quantification (ULOQ), the ULOQ will be imputed. 
 The number of values below LLOQ or above ULOQ will be presented in each summary 
table. If more than 50% of the data are below LLOQ, only the number and percentage 
of values below LLOQ will be reported in the summary together with the minimum 
and maximum values. 
For self-reported tobacco or nicotine containing tobacco product use over the duration of the 
study data:  
 Only available data will be included in the product use summaries. 
 Overall product exposure groups will be defined based on the data collected from 
randomization until EOS. 
Further details will be provided in the SAP. 
12.1.5 Significance Level for Inferential Analysis 
The primary analysis, of PD at 6 months will be tested using a one-sided alpha level of 2.5%.  
1. PD at 6 months will be tested.  
The secondary analysis of PD at 3 months and CAL at 6 and 3 months will be tested in a 
hierarchical manner, using a one-sided alpha level of 2.5%, depending on the outcome of the 
test at previously specified endpoint in hierarchical testing order. 
1. PD at 3 months will be tested only if the test for PD at 6 months is significant. 
2. CAL at 6 months will be tested only if the test for PD at 3 months is significant 
3. CAL at 3 months will be tested only if the test for CAL at 6 months is significant.  
Additional analysis of the secondary endpoint, the BoExp will be tested, in a hierarchical 
manner within each BoExp (independent of the other statistical tests being performed), using 
a one-sided alpha level of 2.5%. The hierarchical order will be: 
1. BoExp at 6 months will be tested. 

 
 
 
 
 
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2. BoExp at 3 months will be tested only if the test for BoExp at 6 months is significant. 
Total NNAL and CEMA levels (concentration data adjusted for creatinine), analyzed on a 
logarithmic scale, will be tested at 6 and then 3 months, in that order, so that the testing of each 
BoExp will stop if the test is not significant. 
Unless stated otherwise, all statistical tests will be one-sided and conducted at the 2.5% level, 
and all CIs will be two-sided 95%. 
12.2 Determination of Sample Size and Power Consideration 
The patients will be randomized into 1 of 2 study groups: IQOS or cigarettes. Patients will be 
analyzed by their actual exposure throughout the course of the study. Therefore, there will be 
patients who predominantly use IQOS or patients who predominantly use cigarettes, however, 
there will also be patients who predominantly use other tobacco and nicotine containing 
tobacco products, or have a pattern of mixed tobacco product use. All patients will continue in 
the study but will be analyzed based on their exposure pattern during the study. Depending on 
the patterns of product use observed in the study, sensitivity analyses and descriptive 
summaries will be implemented. 
The statistical hypothesis that will be tested for PD at 6 months is: 
 H0: XIQOS – Xcigarette ≤ 0. 
 HA: XIQOS – Xcigarette > 0. 
Where XIQOS and Xcigarette are the adjusted mean changes from baseline values (baseline minus 
endline) of PD for IQOS and cigarettes, respectively. The H0 is rejected with a one-sided alpha 
level of 2.5%. 
In the literature reviewed, the papers of Rosa [44] and Preshaw [43] are similar to the study 
described in this protocol, in that they include: 
 Some requirements on minimum PD for inclusion 
 Comparison of smokers with former smokers 
 Means and SDs (or standard errors of the mean and sample size) 
Therefore it is assumed that the cigarette arm will have similar results to what is described in 
the literature for current smokers and that the results in the IQOS arm will be similar to what 
is observed in former smokers. 
Based on the published data and recommendations from the American clinical practice 
guidelines [85], the following estimates with PD differences and standard deviations between 
smokers and non-smokers Table 7) are based on data assessed at 3, 9 and 12 months: 

 
 
 
 
 
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Table 7 
Sample sizes for PD differences between smokers and non-smokers 
and standard deviations based on the literature 
                  difference (mm) 
SD 
0.2 
0.25 
0.3 
0.35 
0.4 
64 
42 
29 
22 
0.45 
81 
52 
37 
27 
0.5 
100 
64 
45 
33 
Abbreviation: SD = Standard deviation 
Thus, the sample size selected above gives sufficient power for testing PD. 
With alpha of 2.5%, power of 80%, SD of 0.5, and effect difference of 0.25 mm, then sample 
size needed in each arm is 64 patients. By considering 25% of drop out and product switching, 
86 patients per arm, i.e., 172 patients in total, are needed. 
12.3 Product use 
Although patients are being requested to use solely the product allocated to their respective 
study arm, it is considered that not all patients randomized to the IQOS arm or to continue 
smoking cigarettes will exclusively use the randomized product at all times during the study. 
Patients may concomitantly use IQOS and cigarettes (dual-use). To assess dual use of IOQS 
and cigarettes, PMI has defined categories of pattern of product use.  
Product use pattern categories will be specified based on the average number of product used 
per month of each category (i.e., Marlboro HeatSticks or smoked cigarettes) as self-reported 
in the product use questionnaire over the study duration. Further determinants, such as 
percentages of the respective products, or numbers of other nicotine-containing products may 
be used, and will be provided in the SAP. 
Actual product use pattern categorization is described in Figure 3. Primary analysis will 
consider only those patients who used only HeatSticks and/or cigarettes. Those who used other 
nicotine-containing products (e.g., e-cigarettes) will be considered in a separate category, 
“Other” (not represented in Figure 3). More granular product exposure categories may be used 
for the detailed description of the product use patterns observed in the study. Full details of the 
product use categories will be reported in the SAP. 

 
 
 
 
 
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12.4.3 Per Protocol Set (PP)  
The Per Protocol Set (PP) is the subset of the FAS who fulfill key compliance criteria of the 
protocol and have no major protocol deviation that influences the evaluability of the study data 
(to be further described in the SAP).  
12.4.4 Adherent Use Set 
The Adherent Use Set is the subset of the FAS who are adherent to their randomized study 
product. 
12.4.5 Safety Set 
The Safety Set consists of all patients enrolled with signed ICF who have at least one valid 
safety assessment during the course of the study. The Safety Set will be analyzed by actual 
exposure (product use pattern). 
12.5 Demographics and Baseline Characteristics 
The demographic variables will be summarized by product use pattern categories and by the 
randomization strata (daily cigarette consumption and disease severity) for the As Exposed 
Set. In addition, they will be summarized by randomization arm for the FAS and PP Sets. Data 
will be listed by randomization arm. No inferential analyses will be presented for the 
demographics and baseline characteristics. 
12.6 Primary Analysis 
The primary analysis evaluates the change from baseline in PD, which will be calculated for 
each patient across all sites with a baseline PD > 4 mm, resulting in one value per patient per 
endpoint for each visit (baseline, Month 3 and 6). 
The primary analysis will be performed on the As Exposed Set using a mixed model for 
repeated measurements (MMRM) for only subjects who have used cigarettes and/or Heatsticks. 
The model will include the PD change from baseline as the dependent variable, adjusting for 
daily cigarette consumption and disease severity at V1, full mouth PD at V1, exposure group 
and its interaction with visit. Site will be included as a random effect. The modeling 
assumptions will be evaluated and the model fit will be assessed by the analysis of the residual 
(diagnostics) and by comparing the values predicted vs. the observed values (calibration). 
Additionally, the analysis will be performed on the FAS, PP and Adherent Use populations as 
a supportive sensitivity analysis. Additional sub group analyses such as for “Other” product 
use groups may be analyzed and will be defined in the SAP. 

 
 
 
 
 
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Descriptive statistics for PD will be summarized at each visit by exposure group, and overall 
(across all patients). The primary endpoint will also be summarized by strata (daily cigarette 
consumption and disease severity). 
Study Hypothesis: 
The primary study hypothesis is that there will be a favorable difference in the mean PD at 6 
months in IQOS users as compared to smokers who continue to smoke cigarettes in patients 
with generalized chronic periodontitis.  
Evaluation Criteria: 
The study will substantiate that IQOS improves periodontitis if there is a statistically 
significant improvement in primary endpoint for smokers who switch to IQOS use (as defined 
in Figure 3) as compared to smoker who continue to smoke cigarettes. 
12.7 Secondary Analysis 
The analysis of PD at 3 months, CAL at 3 and 6 months will be also performed, as a secondary 
endpoint.  
There will be an adjustment for multiplicity for the secondary testing of CAL and PD within 
the As Exposed Set as defined in section 12.1.5.  
Urinary NEQ, total NNAL and CEMA levels (concentration data adjusted for creatinine will 
be analyzed on a logarithmic scale) using an MMRM with the BoExp geometric mean value 
as the dependent variable, adjusting for daily cigarette consumption at baseline and sex, visit, 
baseline BoExp level, exposure group and its interaction with visit. Site will be included as a 
random effect. The modeling assumptions will be evaluated similar to that in the primary 
analysis. 
Descriptive statistics for the BoExp will be summarized at each visit by exposure group and 
overall (across all patients). The primary endpoint will also be summarized by strata (daily 
cigarette consumption and sex). 
The other secondary endpoints will be summarized descriptively at each visit by exposure 
group and overall (across all patients) in the As Exposed Set (unless otherwise defined): 
 Change in mean full-mouth PD. 
 Change in mean full-mouth CAL. 
 Mean PD change in sites with initial PD < 4 mm, and with initial PD of 4 mm to < 
5mm, 5 mm to < 6 mm, 6 mm to < 7 mm and ≥ 7 mm. 

 
 
 
 
 
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 Mean CAL change in sites with initial PD < 4 mm, and with initial PD of 4 mm to < 
5mm, 5 mm to < 6 mm, 6 mm to < 7 mm and ≥ 7 mm. 
 Change in the number of sites with PD < 4 mm, with PD 4 mm to < 5mm, with PD 5 
mm to < 6 mm , with PD 6 mm to < 7 mm and with PD ≥ 7 mm. The number of sites 
will be treated as a continuous variable. 
 Change in BOP scores, GI score, tooth mobility (grade) and PCR. 
 Number of tobacco or nicotine containing products used, (including cigarettes and 
HeatSticks) based on self-reporting. 
 Incidence of AEs/SAEs and device events will be presented as frequencies and 
percentages of the number of patients per group in the Safety Set. 
Additionally, the analyses will be performed on the FAS; PP and Adherent Use populations as 
a supportive sensitivity analysis. Any sub group analyses will be defined in the SAP.  
Study Hypotheses: 
The secondary study hypotheses that will be tested in IQOS users and smokers (as defined in 
Figure 3) are: 
 That there will be favorable changes of PD at 3 months in IQOS users as compared to 
smokers who continue to smoke cigarettes in patients with generalized chronic 
periodontitis. 
 That there will be favorable changes of CAL at 3 and 6 months in IQOS users as 
compared to smokers who continue to smoke cigarettes in patients with generalized 
chronic periodontitis. 
 That there will be favorable changes at 3 and 6 months in total NNAL and CEMA 
levels in IQOS users as compared to smokers who continue to smoke cigarettes. 
12.8 Safety Analysis 
In general, safety data will be provided in listings by exposure group, site, and patient. The 
data will be tabulated on the Safety Set by exposure group, using the approach described in 
section 12.1.3.  
Adverse events data will serve as the primary assessment of safety. 
The number and percentage of patients with AEs and SAEs will be tabulated by using the 
MedDRA® system organ class (SOC) and preferred term (PT), summarized for the Safety Set. 
Summaries will also be presented for AEs leading to discontinuation, AEs leading to death, 
AEs by relatedness to product exposure, and AEs by severity. Tabulations will be performed 

 
 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
for both the number of patients experiencing an event and the number of events experienced 
during the study period. 
The number and percentage of patients with clinical findings will be summarized for the Safety 
Set.  
Incidence and frequency of concomitant medications and device events will be tabulated by 
exposure group. 
12.8.1 Vital Signs 
Not Applicable. 
12.8.2 Laboratory Safety Parameters 
Not Applicable. 
12.8.3 Other Safety Endpoints 
Not Applicable. 
12.9 Exploratory Analysis  
12.9.1 Exploratory Endpoint Analysis 
See section 3.3. 
12.9.2 Descriptive Analysis 
The analysis for the exploratory endpoints of cytokine/chemokine (MAP) and targeted unique 
peptides (PRM) will follow the statistical approach described for the secondary endpoints and 
include descriptive and inferential statistics. Descriptive statistics will be reported by treatment 
group and strata, and will include basic descriptive statistics such as the sample size, the sample 
mean, standard deviation, standard error of the mean, and CV. Robust measures for the center 
(median) and the dispersion (median absolute deviation, MAD) of the data will be also 
included. Inferential statistics will focus on treatment group differences and will take into 
account stratification criteria as well as repeated measurements. The general statistical linear 
mixed model developed for the primary endpoint may be used if necessary for the exploratory 
endpoints in order to test treatment differences and to adjust for stratification factors and 
repeated measurements. For the exploratory endpoints, a two-sided alternative for the 
differences between groups will be tested on the 5% type I error rate, while no adjustment for 
multiplicity will take place. The null hypothesis tested will be that all means of groups tested 
for a given variable are equal. The alternative hypothesis is that at least one of the means is 
different from the others. Further details will be specified in the SAP. 

 
 
 
 
 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
After DNA extraction for the iSWAB-Microbiome Collection Kit, Illumina HiSeq sequencing 
libraries will be prepared and sequenced. The resulting raw data will be filtered to remove 
patient sequences based on the human reference genome. Filtered data from each sample will 
be mapped individually to a reference database consisting of all available bacterial genomes. 
These mapped reads constitute the analysis set and will be free from human sequences to the 
best of our ability. 
The composition of the microbiome in the SP will be determined by counting high quality 
mapped sequencing reads at the highest possible taxonomic resolution. The reported 
microbiome compositions will consist of these counts aggregated at the genus and phylum 
level percentages. 
To assess whether or not the microbiome compositions in the SP differ between continued 
smoking and switching to IQOS, the relative abundance of each detected genus or phylum will 
be analyzed as a function of time.  
Descriptive analysis of buccal swabs RNA profiles will be performed to compare patients 
switching to IQOS to patients continuing to smoke cigarettes. 
12.10 Interim Analysis 
Not Applicable 

 
 
 
 
 
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Confidentiality Statement 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Sites, Principal Investigators and Study Administrative Structure 
13.1.1 Sites and Principal Investigators  
See the Protocol Appendix 4. 
13.1.2 Sponsor 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Phone: +41 (58) 242 2111 
Fax: +41 (58) 242 2811 
Clinical Scientist 
, Clinical Scientist 
Phone: +41 
 
Fax: +41 
 
Mobile: +41 
 
E-mail: 
 
Statistician 
, PhD, Statistician 
Phone: +41 
 
Fax: +41 
 
E-mail: 
 
Medical Safety Officer 
, MD, Medical Safety Officer  
Phone: +41 
 
Mobile: +41 
  
E-mail: 
 
13.1.3 Other Responsibilities 
 

 
 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
 is the local CRO designated by PMI to manage and monitor the study; all duties and 
responsibilities transferred to 
 by PMI will be defined in the agreement signed between 
the two parties.  
 
 
 
 
Responsible person (
): 
 
 
 
13.2 Patient Confidentiality 
All information obtained during the conduct of the study with respect to the patients, state of 
health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the patient. An agreement to disclose any such information will be 
obtained from the patient in writing and signed by the patient, in compliance with all local and 
national da ta protection and privacy legislation. 
The anonymity of patients participating in this study will be maintained. Patients will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their patient (or randomization) number/code, sex and date of birth, but not by 
name, initial, or any other details relating to identifiable person (e.g., address, health insurance 
ID card, medical chart number, etc.). The assignment of a patient number/code for patient 
identification will be based on the appropriate data protection rules. 
Any documents that allow full identification of the patient (e.g., the patient’s signed study 
participation ICF) must be maintained in confidence by the Investigator. If any document 
relating to this study shows a patient’s name or any other details relating to an identifiable 
person (e.g., address, health insurance ID card, medical chart number, etc.), the name or other 
identifiable details must be obscured before a copy of that document is supplied to the Sponsor 
or the Sponsor’s authorized representative. 
13.3 Access to Source Documentation 
Patients will be informed that, during the course of the clinical study, the Sponsor, any 
authorized representatives of the Sponsor, IRB, or regulatory authorities may inspect their 
medical records to verify the information collected, and ensure that all personal information 

 
 
 
 
 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
made available for inspection is handled in the strictest confidence and in accordance with 
national and local data protection and privacy legislation. 
The Investigator/head of the investigational site and all study site trial collaborators involved 
with the study must permit direct access to source data/documents for study related monitoring, 
audits, IRB review, and regulatory inspection(s). 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), in 
any form (including, but not limited to, written, electronic, magnetic, optical records and scans) 
that describe or record the methods, conduct, and/or results of the study, the factors affecting 
the study, and the actions taken will be maintained by the Principal Investigator/head of 
investigational site for the study, as required by ICH GCP and any other applicable local or 
national regulations.  
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in Article 41 of 
Ministerial Ordinance on GCP (Ordinance of the Ministry of Health and Welfare No. 28 of 
March 27, 1997 (as last amended by the Ordinance of Ministry of Health, Labour and Welfare 
No. 161 of December 28, 2012). Essential documents must be retained by the Principal 
Investigator/head of investigational site for a minimum of: 
 
At least 15 years after completion or discontinuation of the study, or 
 
At least 2 years depending on, for example, the circumstances, or 
 
After formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
 
Signed informed consent documents for all patients and study participation ICF. 
 
Patient identification code list, Screening Log and Enrollment Log (if applicable). 
 
Record of all communications between the Principal Investigator and the IRB, 
composition of the IRB. 
 
Record of all communications/contact between the Investigator, Sponsor, and its 
authorized representatives. 

 
 
 
 
 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
 
List of sub-Investigators and other appropriately qualified persons to whom the head 
of the investigational site has delegated significant study-related duties, together with 
their roles in the study. 
 
Investigator Logs. 
 
CRFs, study specific questionnaires (and associated data/scoring), patient diaries. 
 
AE reports and details of follow-up investigations, details of concomitant medication. 
 
All other source documents or any electronically captured study source data. 
 
Original medical/hospital records, if applicable (the medical files of study patients 
must be retained in accordance with local legislation and in accordance with the 
maximum period of time permitted by the hospital or study site). 
 
Record of any body fluids or tissue samples collected and retained. 
 
Device Issue Log, IP Accountability Logs, dispensing records. 
 
Information regarding patients’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Principal Investigator/head of 
investigational site as to when these documents no longer need to be retained. 
The Principal Investigator/head of investigational site must take measures to prevent accidental 
or premature destruction of these documents. 
If the head of the investigational site wishes to assign the study records to another party or 
move them to another location, the Sponsor must be notified in advance. 
The head of the investigational site must obtain written approval from the Sponsor before 
destruction of any records. Normally, these records will be held in the Investigator’s archives. 
If the head of the investigational site is unable to meet this obligation, they must ask the 
Sponsor for permission to make alternative arrangements. Details of these arrangements must 
be documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study as long as the IP is on the market, and/or for 15 years after the CSR has been finalized. 
13.5 Assessment Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the study 
is completed or prematurely terminated. 
The CSR will be written based on standards of the ICH Guideline for the Structure and Content 
of Clinical Study Reports. In certain circumstances, an abbreviated CSR may be acceptable. 
Submission of the CSR to the IRB will be complied with as requested by local requirements. 

 
 
 
 
 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
The results of the additional variables for analysis will be presented in reports separate from 
the CSR. 
13.6 Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor. In 
addition, the Investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 1 year 
following the completion of the study. 
13.7 Publication and Disclosure Policy 
This document contains data, information and trades secretes that are confidential and 
proprietary to the Sponsor. This document is being provided solely for the purpose of 
evaluation and/or conducting this clinical study for the Sponsor. Disclosure of the content of 
this document is allowed only to study personnel, IRB, or duly authorized representatives of 
regulatory agencies for this purpose under the condition that confidentiality is maintained. The 
contents of this document may not be used in any other clinical study or disclosed to any other 
person or entity without the prior written permission of the Sponsor. The foregoing shall not 
apply to disclosure required by any regulations; however, prompt notice will be given to the 
Sponsor prior to any such disclosure. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly available, 
clinical trial register database (e.g., ClinicalTrials.gov). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage of the patients who are associated with 
the IQOS product which are used during the study, except for AEs and health damage of the 
patients caused by a negligent or an intentional misconduct and/or significant deviation to 
the protocol of the Investigator or the clinical study site or the patients. The Sponsor has taken 
out insurance to cover any bodily injury and property damage caused by the operations cried 
out by the insured. 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
14 REFERENCE LIST 
[1] 
Philip Morris Products S.A. Unpublished on file data: Summary of product 
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[2] 
ICH E6 (R2). Integrated addendum to ICH E6 (R1): guideline for good clinical 
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[3] 
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[6] 
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Wactawski-Wende J, Scannapieco FA. Chronic periodontitis and the risk of tongue 
cancer. Arch Otolaryngol Head Neck Surg. 2007; 133(5):450-4. 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
[12] 
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C, Wennstrom JL, Bergstrom J. Oral health risks of tobacco use and effects of 
cessation. Int Dent J. 2010; 60(1):7-30. 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
[25] 
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and response to periodontal therapy. J Periodontol. 1996; 67(7):675-81. 
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of smoking and smoking cessation with oral health status in Japanese men. J 
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KA, Guthmiller JM. Influence of smoking on gingival crevicular fluid cytokines in 
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fluid secretion. J Indian Soc Periodontol. 2012; 16(1):101-3. 
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smoking increases the risk for subgingival infection with periodontal pathogens. J 
Periodontol. 1996; 67(10 Suppl):1050-4. 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
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Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
[39] 
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periodontitis. Int J Dent. 2013; 2013:587279. 
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subgingival microbiome of clinically healthy current and never smokers. ISME J. 
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[49] 
Hughes FJ, Syed M, Koshy B, Bostanci N, McKay IJ, Curtis MA, Marcenes W, 
Croucher RE. Prognostic factors in the treatment of generalized aggressive 
periodontitis: II. Effects of smoking on initial outcome. J Clin Periodontol. 2006; 
33(9):671-6. 
[50] 
Villar CC, de Lima AF. Smoking influences on the thickness of marginal gingival 
epithelium. Pesqui Odontol Bras. 2003; 17:41-5. 
[51] 
Bergstrom J, Persson L, Preber H. Influence of cigarette smoking on vascular reaction 
during experimental gingivitis. Scand J Dent Res. 1988; 96(1):34-9. 
[52] 
Plessas A. Nonsurgical periodontal treatment: review of the evidence. Oral Health 
Dent Manag. 2014; 13(1):71-80. 

 
 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
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Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
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Philip Morris Products S.A. Nicotine pharmacokinetic profile and safety of the 
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Clinical Study Protocol 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
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http://clinicaltrials.gov/show/NCT01967706 NLM Identifier: NCT01967706. 
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to investigate the nicotine pharmacokinetic profile and safety of THS 2.2 Menthol 
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from: http://clinicaltrials.gov/show/NCT01967719 NLM Identifier: NCT01967719. 
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Philip Morris Products S.A. A randomized, controlled, open-label, 3-arm parallel 
group, single center study to demonstrate reductions in exposure to selected smoke 
constituents in smoking, healthy subjects switching to the THS 2.2 or smoking 
abstinence, compared to continuing to use conventional cigarettes, for 5 days in 
confinement (ZRHR-REXC-03-EU). In: ClinicalTrials.gov [Internet]. Bethesda 
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reductions in exposure to smoke constituents in smoking subjects switching to THS 
2.2 or to smoking abstinence, compared to smoking conventional cigarettes for 5 days 
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REXA-08-US]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of 
Medicine (US). 2013-2015 [cited 2015 Jun 16]. Available from: 
http://clinicaltrials.gov/show/NCT01989156 NLM Identifier: NCT01989156. 
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Philip Morris Products S.A. A randomized, controlled, multi-center study to 
demonstrate reductions in exposure to selected smoke constituents in smokers 
switching to THS 2.2 Menthol or smoking abstinence compared to smoking menthol 
conventional cigarettes, for 90 days [ZRHM-REXA-07-JP]. In: ClinicalTrials.gov 
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2015 Jun 16]. Available from: http://clinicaltrials.gov/show/NCT01970995 NLM 
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Philip Morris Products S.A. Evaluation of biological and functional changes in 
healthy Smokers after switching to THS 2.2 for 26 weeks [ZRHR-ERS-09-US]. In: 
ClinicalTrialsgov [Internet] Bethesda (MD): National Library of Medicine (US) 
2015- [cited 2015 Aug 26] Available from: 

 
 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
https://clinicaltrialsgov/ct2/show/NCT02396381?term=NCT02396381&rank=1 NLM 
Identifier: NCT02396381. 
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Philip Morris S.A. A 26-week extension of the ZRHR-ERS-09-US study evaluating 
biological and functional changes in healthy smokers after switching to THS 2.2 
[ZRHR-ERS-09-EXT-US]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): 
National Library of Medicine (US). 2015- [cited 2016 Jun 01]. Available from: 
http://clinicaltrials.gov/show/NCT02649556 NLM Identifier: NCT02649556. 
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2016- [cited 2017 Jan 16]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT03020667 NLM Identifier: NCT03020667. 
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information (SPI) - iQOS with HeatSticks. Version 2.0. 2017. 
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Rossmann J, Harrel SK, Forrest JL, Hujoel PP, Noraian KW, Greenwell H, Frantsve-
Hawley J, Estrich C, Hanson N. Evidence-based clinical practice guideline on the 

 
 
 
 
 
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Study P1-OHS-01-JP  
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
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harmful and potentially harmful constituents of the Tobacco Heating System 2.2 
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Tricker AR, Gautier L, Yerly M, Reis Pires R, Le Bouhellec S, Hofer I, Garcia E, 
Vanscheeuwijck P. Evaluation of the Tobacco Heating System 2.2. Part 2: Chemical 
composition, genotoxicity, cytotoxicity, and physical properties of the aerosol. Regul 
Toxicol Pharmacol. 2016; Suppl 2. Available from: 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
http://www.sciencedirect.com/science/article/pii/S0273230016302902 (Accessed on 
03 May 2017):S27-47. 
[97] 
Raw M, Anderson P, Batra A, Dubois G, Harrington P, Hirsch A, Le Houezec J, 
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[98] 
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reporting - Guideline. 1994; Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
2A/Step4/E2A_Guideline.pdf (Accessed on 17 July 2014). 
 

 
 
 
 
 
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provided to such trade secrets and confidential information are hereby claimed under the applicable provisions of applicable law. No part of this document may be 
publicly disclosed without the written consent of Philip Morris Products S.A. 
Appendix 1 
Schedule of Events 
Visit 
V1 
Screening, Enrollment & 
Baseline 
V2 
1st SRP and randomization 
V3 
 
V4 
Last visit 
Follow-up 
7 days 
Study Day or Month 
Day -14 to -7 
From Day 1 
Day 1 
Month 3 
(± 7 days) 
From Day 1 
Month 6 
(± 14 days) 
From Day 1 
Visit 4 + 7 days 
ICF signature a 
● 
 
 
 
 
Advice on the risks of 
smoking/smoking cessation 
advice and debriefing on 
IQOS 
● 
● 
● 
● 
 
IQOS presentation 
● 
 
 
 
 
Inclusion/exclusion criteria 
● 
 
 
 
 
Distribution of IQOS and 
HeatSticks 
 
● b 
 
 
 
Enrollment 
● 
 
 
 
 
Randomization 
 
● 
 
 
 
Smoking history 
● 
 
 
 
 
Tobacco- or nicotine-
containing product use self-
reporting 
● 
 
● c 
● c 
 
Readiness to comply to 
study procedures, including 
● 
 
 
 
 

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections 
provided to such trade secrets and confidential information are hereby claimed under the applicable provisions of applicable law. No part of this document may be 
publicly disclosed without the written consent of Philip Morris Products S.A. 
Visit 
V1 
Screening, Enrollment & 
Baseline 
V2 
1st SRP and randomization 
V3 
 
V4 
Last visit 
Follow-up 
7 days 
Study Day or Month 
Day -14 to -7 
From Day 1 
Day 1 
Month 3 
(± 7 days) 
From Day 1 
Month 6 
(± 14 days) 
From Day 1 
Visit 4 + 7 days 
switching to IQOS if 
randomized in the IQOS arm 
Patient is not planning to 
quit smoking during the 
study 
● 
 
 
 
 
Demographics d, 
dental/medical history, 
including history of alcohol 
or drug abuse, concomitant 
diseases 
● 
 
 
 
 
Prior medication and/or 
concomitant medication / 
procedure  
● e 
● 
● 
● 
 
U: spot urine collection for 
pregnancy test (all females)  
● f 
● 
● 
● 
 
U: spot urine collection for 
NEQ, total NNAL, CEMA, 
creatinine analysis  
● f, g 
 
● 
● 
 
U: cotinine test 
● f 
 
 
 
 
Full periodontal examination 
h 
●  
 
● 
● 
 

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 113 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections 
provided to such trade secrets and confidential information are hereby claimed under the applicable provisions of applicable law. No part of this document may be 
publicly disclosed without the written consent of Philip Morris Products S.A. 
Visit 
V1 
Screening, Enrollment & 
Baseline 
V2 
1st SRP and randomization 
V3 
 
V4 
Last visit 
Follow-up 
7 days 
Study Day or Month 
Day -14 to -7 
From Day 1 
Day 1 
Month 3 
(± 7 days) 
From Day 1 
Month 6 
(± 14 days) 
From Day 1 
Visit 4 + 7 days 
Supragingival Scaling (or 
maintenance) 
●  
 
● 
● 
 
PD, BOP and tooth mobility 
as per standard of care for 
SRP (optional, as per PI’s 
judgment) 
 
● i 
 
 
 
1st SRP treatment 
 
● j 
 
 
 
SP collection for 
microbiological status k, l 
● 
 
 
● 
 
Collection of GCF for 
cytokine analysis k, m 
 
● 
● 
 
 
Buccal swabs k, n 
 
● 
● 
● 
 
AE/SAE/device event 
recording o 
●  
● 
● 
● 
● 
Discharge  
 
 
 
● 
 
The month means 30 days. 
Abbreviations: AE = adverse event; BOP = bleeding on probing; CEMA = 2-cyanoethylmercapturic acid; GCF = gingival crevicular fluid; ICF = informed 
consent form; NEQ = nicotine equivalents, consisting of the molar sum of free nicotine, nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-
hydroxycotinine and trans-3’-hydroxycotinineglucuronide; NNAL = 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol; SAE = serious adverse event; SP = 
subgingival plaque; SRP = scaling and root planing; U = urine sample required.  

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections 
provided to such trade secrets and confidential information are hereby claimed under the applicable provisions of applicable law. No part of this document may be 
publicly disclosed without the written consent of Philip Morris Products S.A. 
a. 
The informed consent process can be started as soon as the patient is invited to participate in the study, but the ICF must be signed no later than before the first assessment at 
V1.  
b. 
IQOS starter kit (i.e., device and a selection of HeatStick flavor variants available on the Japanese market) will be delivered to all patients randomized to the IQOS arm. They 
will start using it as soon as possible. 
c. 
The Investigator or study collaborator will collect the completed diaries at V3 and V4, and the diary data will be transcribed into the CRF. The questionnaire can be filled before 
or after V3, but because V4 is the last Visit, the questionnaire for Month 6 must be filled before or at V4, regardless of the time when the previous questionnaire was filled. 
d. 
Sex, date of birth, ethnicity. 
e. 
Prior medication taken within 3 months prior to V1. 
f. 
The same spot urine collection will be used for pregnancy (all females) and cotinine tests, and for NEQ, CEMA, total NNAL and creatinine measurements (BoExp). Sampling 
for BoExp should be performed as soon as possible, and samples frozen immediately. 
g. 
These tubes will be discarded at the end of the visit if the patient is not enrolled. 
h. 
Full periodontal examination consists in the measurement of PD, CAL and BOP on 6 sites per tooth, tooth mobility, plaque control record and gingival inflammation of the 
target teeth. At V1, full periodontal examination should be the last assessment performed as part of the eligibility criteria, to avoid unnecessary examination for those patients 
who are in any case not eligible.  
i. 
Will not be recorded in the case report form. 
j. 
Additional SRP treatments will be performed during “unscheduled” visits and will be completed within 8 weeks after initial treatment. 
k. 
From V2 to V4, patients will be asked not to drink, eat, chew gum, use mouth rinse or brush their teeth for at least 30 minutes before collection of oral samples (i.e., SP, GCF 
or buccal swabs). 
l. 
SP collection will be collected from 4 target teeth (the largest PD will be selected). These teeth are the same than those selected for GCF collection m.  
m. GCF will be collected from 4 target sites. These sites are located on the same teeth than those selected for SP collection l.  
n. 
Two buccal samples will be taken (left and right) for transcriptomics evaluation.  
o. 
Spontaneous reporting of new AEs/SAEs & AEs related to device events by the patient, and active follow-up of ongoing SAEs by the site. 
 
 
 
 

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 115 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
Appendix 2 
Participating Laboratories 
The following laboratories will be used in the study: 
Lab logistics, storage, shipment: 
 
 
 
 
Lab for analyses of GCF, buccal swabs 
and SP: 
Philip Morris Products S.A. 
c/o 
 
Quai Jeanrenaud 3 
R&D Innovation Cube T1532 
2000 Neuchatel 
Switzerland 
Lab for analysis of urine samples 
(NEQ, CEMA, total NNAL and 
creatinine): 
 
 
 
 
and/or 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 116 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
Appendix 3 
Investigational Product and Instructions for Use 
The product user guide will be provided as part of the IQOS starter kit. 
 
 
 
Appendix 4 
List of Sites and Principal Investigators 
The list of investigators and sites will be provided as a separate document. 
 
 

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 117 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
Appendix 5 
Changes in Protocol Amendments  
The changes made in the different protocol versions are listed in the below table, including 
previous and amended texts, as well as the reasons to change. The new text has been 
highlighted in bold (e.g. new text) and deleted text has been crossed out (e.g. old text). 
Changes from Version 3.0 to Version 4.0 
Section 
Number 
Section 
Name 
Changes 
 
General 
The version number and the revision date were updated 
accordingly to the most current version and date. 
- 
- 
Section 
3.3 
Section 
7.5.3 
Synopsis 
List of 
abbreviations 
Exploratory 
objectives and 
endpoints 
Assessments in 
GCF 
Amended text 
sCD40L, CRP, EGF, Eotaxin/CCL11, FGF-2/FGF-basic, Flt3 ligand, 
Fractalkine /CX3CL1, G-CSF, GM-CSF, GRO, IFNα2, IFNγ, IL-1α, IL-
1β, IL-1Ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8/CXCL8, IL-9, IL-10, 
IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A/CTLA8, IP-10/CXCL10, 
MCP-1/CCL2, MCP-3/CCL7, MDC/CCL22, MIP-1α/CCL3, MIP-
1β/CCL4, MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-10, MMP-
12, MMP-13, osteoprotegerin, PDGF-AA, PDGF-AB/BB, RANKL, 
RANTES/CCL5, TGFα, TIMP-1, TNFα, TNFβ / LT-α, VEGF-A (please 
refer to the Abbreviations for full spelling). 
Reason to change: The number of analytes to be analyzed in 
the GCF was decreased, as method development showed that 
some analytes had low sensitivity, thus their results would not 
be accurate. Another analyte, TIMP-1, was added, because the 
method development showed that it can be detected. List of 
abbreviations was updated accordingly. 
- 
 
List of 
Abbreviations 
and Definitions 
of Terms 
 
Amended text 
Dental medical monitors: co-primary contacts (dentists) 
for dental medical questions 
Medical expert: dentist who is the primary contact for 
dental medical questions 
Medical monitor Advisor: medical doctor who answers any 
medical and safety questions from the Investigators.  
Reason to change: The role of Medical Advisor was not well 
defined, and did not correspond to the definitions of the 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
medical responsibility plan. The above definitions were added, 
as per medical responsibility plan. 
 
 
 
Section 
7.3 
Dental/Clinical 
Assessments 
Amended text 
As per medical responsibility plan, a medical expert 
(dentist) will be the primary contact for dental medical 
questions that Investigators might have. Dental medical 
monitors will be the co-primary contacts for dental 
medical questions. Other roles for medical expert and 
dental medical monitors are defined in the medical 
responsibility plan. 
Reason to change: The roles of medical expert and dental 
medical monitors as defined in the medical responsibility plan 
were not defined in the protocol, thus the definitions were 
added at the beginning of the section on dental assessments. 
Section 8 Adverse 
Events 
Amended text 
A medically qualified advisormonitor(s) (i.e., medical 
advisormonitor) will be available during the study to address 
any safety question an Investigator may have. 
Reason to change: “advisor” in the medical responsibility plan 
is called “monitor” 
Section 
6.1.1 
Test Product(s) Amended text 
The average amount of nicotine in the tobacco plug is 4.3-5.4 
5-6 mg/stick per HeatStick. 
Reason to change: Aligned with current version of Summary 
of Product Information. 
Section 
6.4.2 
Blinding of 
data 
Amended text 
Patient randomization arm and actual values of CAL and 
PD values after randomization 
Reason to change: In Table 2, for all blinded personnel, the 
“patient randomization arm” was added. It was implied, but 
not clearly stated. 

 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
Section 
7.3.5 
Dental 
assessments 
Amended text 
The following dental assessments listed in the sections 
7.3.5.1 to 7.3.5.8 below will be recorded on the prescribed 
periodontal charts. 
Reason to change: The sentence about dental assessments was 
moved to the end of the paragraph, and the sections referring 
to these assessments were added. 
Section 
7.3.5.3 
Dental 
Assessments – 
Pocket Depth 
(PD) 
Amended text 
For each subject, full mouth PD is calculated by the following 
formula: 
Full mouth PD = 
Sum of all PD measurements (in mm)
Total number of examined sites
 
 
𝐅𝐮𝐥𝐥 𝐌𝐨𝐮𝐭𝐡 𝐏𝐃 (𝐦𝐦) = 𝟏
𝒕∑∑
𝑷𝑫𝒊𝒋
𝒔𝒊
𝒔𝒊
𝒋=𝟏
𝒕
𝒊=𝟏
 
where  𝑷𝑫𝒊𝒋 is the PD measurement of tooth 𝒊 , 𝒊= 𝟏, … , 𝒕 
at the site 𝒋 where 𝒋= 𝟏, … , 𝒔𝒊. Note that 𝒔𝒊 is the number 
of measurable sites per tooth and 𝒔𝒊≥𝟒. 
Reason to change: while developing the statistical analysis 
plan, the way of calculating mean values was modified. 
Section 
7.3.5.4 
Dental 
Assessments – 
Clinical 
Attachment 
Level (CAL) 
Amended text 
Full mouth CAL is calculated by the following formula: 
Full mouth CAL = 
Sum of all CAL measurements (in mm)
Total number of examined sites
 
For each subject, the mean Full mouth CAL is calculated 
by the following formula: 
𝐅𝐮𝐥𝐥 𝐌𝐨𝐮𝐭𝐡 𝐂𝐀𝐋 (𝐦𝐦) = 𝟏
𝒕∑∑
𝑪𝑨𝑳𝒊𝒋
𝒔𝒊
𝒔𝒊
𝒋=𝟏
𝒕
𝒊=𝟏
 

 
 
 
 
 
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Where  𝑪𝑨𝑳𝒊𝒋 is the 𝑪𝑨𝑳 measurement of tooth 𝒊 , 𝒊=
𝟏, … , 𝒕 at the site 𝒋 where 𝒋= 𝟏, … , 𝒔𝒊. Note that 𝒔𝒊 is the 
number of measurable sites per tooth and 𝒔𝒊≥𝟒. 
Reason to change: while developing the statistical analysis 
plan, the way of calculating mean values was modified. 
Section 
7.3.5.5 
Dental 
Assessments – 
Bleeding on 
Probing (BOP) 
Amended text 
The BOP percentage is the percentage of the total number of 
YES sites to the total number of sites being examined. BOP is 
calculated by the following formula. 
BOP percentage (%) = 
Total number of YES sites
Total number of examined sites×100 
For each subject, BOP is calculated by the following 
formula: 
𝐅𝐮𝐥𝐥 𝐌𝐨𝐮𝐭𝐡 𝐁𝐎𝐏 (%) = 𝟏𝟎𝟎∗𝟏
𝒕∑∑
𝑩𝑶𝑷𝒊𝒋
𝒔𝒊
𝒔𝒊
𝒋=𝟏
𝒕
𝒊=𝟏
 
Where  𝑩𝑶𝑷𝒊𝒋 is a binary response (Yes = 1, No = 0) of 
bleeding of tooth 𝒊 , 𝒊= 𝟏, … , 𝒕 at the site 𝒋 where 𝒋=
𝟏, … , 𝒔𝒊.  
Reason to change: while developing the statistical analysis 
plan, the way of calculating mean values was modified 
Section 
7.3.5.7 
Dental 
Assessments – 
Gingival Index 
(GI) 
Amended text 
GI of target teeth is calculated by the following formula. 
GI = 
Total scores of 24 surfaces of target teeth 
24
  
For each subject, GI of target teeth is calculated by the 
following formula: 
𝐆𝐈= 𝟏
𝒕∑∑
𝑮𝑰𝒊𝒋
𝒔𝒊
𝒔𝒊
𝒋=𝟏
𝒕
𝒊=𝟏
 
where  𝑮𝑰𝒊𝒋 is the GI of target tooth 𝒊 , 𝒊= 𝟏, … , 𝒕 at 
surface 𝒋 where 𝒋= 𝟏, … , 𝒔𝒊.  

 
 
 
 
 
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Reason to change: while developing the statistical analysis 
plan, the way of calculating mean values was modified 
Section 
7.3.5.8 
Dental 
Assessments – 
Plaque Control 
Record 
Amended text 
PCR (%) is calculated by the following formula. 
PCR (%) = 
Total number of YES surfaces
Total number of examined surfaces × 100 
For each subject, PCR (%) is calculated by the following 
formula: 
𝑭𝒖𝒍𝒍 𝑴𝒐𝒖𝒕𝒉 𝑷𝑪𝑹 (%) = 𝟏𝟎𝟎∗𝟏
𝒕∑∑
𝑷𝑪𝑹𝒊𝒋
𝒔𝒊
𝒔𝒊
𝒋=𝟏
𝒕
𝒊=𝟏
 
Where  𝑷𝑪𝑹𝒊𝒋 is a binary response (Yes = 1, No = 0) of 
PCR at tooth 𝒊 , 𝒊= 𝟏, … , 𝒕 at the surface 𝒋 where 𝒋=
𝟏, … , 𝒔𝒊.  
Reason to change: while developing the statistical analysis 
plan, the way of calculating mean values was modified 
Section 
12.3 
Product Use 
Amended text 
Product use pattern categories within an analysis period will 
be categorized specified based on the average percentage of 
all product use that is the randomized productnumber of 
product used per month of each category (i.e., Marlboro 
HeatSticks or smoked cigarettes) as self-reported in the 
product use questionnaire over the study duration. Further 
determinants, such as percentages of the respective products, 
or numbers of other nicotine-containing products may be used, 
and will be provided in the SAP. 
Actual product use general pattern categories categorization 
are is describeddefined in Figure 3Table 8. Primary analysis 
will consider only those patients who used only HeatStick 
and/or cigarettes. Those who used other nicotine-containing 
products (e.g., e-cigarettes) will be considered in a separate 
category, “Other” (not represented in Figure 3). More granular 
product exposure categories will may be used for the detailed 
description of the product use patterns observed in the study. 

 
 
 
 
 
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Dual user 
 Used at least 100 
HeatSticks and cigarettes 
 Uses IQOS and cigarettes 
daily > 1/day 
 Broken into categories: 70 - 
95% IQOS, 30< - > 70% 
IQOS and 5 - 30% IQOS 
Other tobacco product 
user 
 Uses 1 or more other 
tobacco product daily 
 Not using IQOS or 
cigarettes 
 Broken into categories 
(combustible tobacco 
product vs. non-
combustible) 
Smoking cessation 
 No tobacco product use 
Details of the product use categories will be reported in the SAP. 
Reason to change: Product use categorization was revised to 
reflect not so much the percentage of each product used, but 
rather to reflect an actual number of products. 
Section 
12.6 
Primary 
Analysis 
Amended text 
The primary analysis will be performed on the As Exposed Set 
using a mixed model for repeated measurements (MMRM) for 
only subjects who have used cigarettes and/or Heatsticks. 
Reason to change: primary analysis will focus on patients who 
used only cigarettes and/or HeatSticks, not on those who used 
other nicotine-containing products. 
Section 
12.6 
Primary 
Analysis 
Amended text 
Additional sub group analyses such as for “Other” product 
use groups may be analyzed and will be defined in the SAP. 
Reason to change: categories for patients using products other 
than cigarettes and/or HeatSticks were not mentioned. 
Section 
13.1.2 
and 
Sponsor 
Amended text 
, PhD, Manager Clinical Science, Lead 
Clinical Scientist 

 
 
 
 
 
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Front 
page 
Reason to change: 
 role has changed, and 
is not applicable to this study anymore. 
Section 
13.1.3 
Other 
responsibilities 
Amended text 
Responsible person (
): 
 
 
 
 
Reason to change: change of responsiblity 
14 
References 
Amended text: [1] Philip Morris Products S.A. Unpublished 
on file data: Summary of product information (SPI) - iQOS 
with HeatSticks Tobacco Heating System (THS). Version 
42.0. 20182017. 
Reason to change: an updated version of the SPI has been 
made available. 
 
Changes from Version 2.0 to Version 3.0 
Section 
Number 
Section Name 
Changes 
 
General  
The version number and the revision date were 
updated accordingly to the most current version and 
date. 
The statistician has changed. 
 has thus 
replaced 
.  
A table containing the “Summary of changes” has 
been added, referring to this Appendix 5 for the 
detailed changes. 
4 
Overall Study Design 
Old text 
Patients will be invited to the screening Visit (V1) 
by the Investigator, based on his/her evaluation of 
the patients examined as part of a standard visit of 
the patient to the Investigators dentistry practice. 

 
 
 
 
 
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Information about the study will be provided and the 
ICF will be distributed to the patients. 
Amended text 
Patients identified by the site as potentially 
eligible will be provided with the information 
about the study and if interested, they will be 
invited to the screening Visit (V1) by the site. 
Investigator, based on his/her evaluation of the 
patients examined as part of a standard visit of the 
patient to the Investigators dentistry practice. 
Information about the study will be distributed and 
tThe ICF will can be distributed to these potential 
patients before V1. 
Reason to change: potential candidates can now be 
identified by phone or emails, thus the text needed to 
be updated to reflect this new possibility of patients’ 
identification. 
4 
Overall Study Design 
Old text 
Patients will sign the ICF before the start of any 
procedure, and will enter screening. 
Amended text 
Patients will sign the ICF before the start of any 
study procedure, and will enter screening. 
Reason to change: to clarify which procedure. 
4 
Overall Study Design 
Old text 
Target teeth (see Definition of terms) will be 
designated by the Investigator or designee and will 
be identified in the case report form (CRF). 
Amended text 
Target teeth (see Definition of terms) will be 
designated by the Investigator or designee and will 
be identified in the source documents and in the 
case report form (CRF). 
Reason to change: to clarify that this needs to be 
captured in source data. 
4 
Overall Study Design 
Old text 
As the number and timing of the visits is flexible, 
the data will be capture as “unscheduled” SRP visits. 

 
 
 
 
 
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All SRP treatments must be completed within 8 
weeks after V2. 
Amended text 
As the number and timing of the visits is flexible, 
the data will be captured in the CRF as 
“unscheduled” SRP visits. All SRP treatments must 
be completed within 8 weeks after V2. 
Reason to change: to correct typo and clarify that 
how these visits need to be captured in the CRF. 
4 
Overall Study Design 
Old text: 
3 months, periodontal assessment & maintenance 
visit, GCF and buccal swabs collection  
Patients will come to the site for periodontal 
assessment (Appendix 1), including GCF collection 
from the same 4 target teeth than at V1, and 
collection of buccal swabs. Maintenance treatment 
will be provided. 
6 months, periodontal assessment & maintenance 
visit, SP and buccal swabs  
Patients will come to the site for periodontal 
assessment (Appendix 1). Sampling of SP for 
microbiological status from the same 4 target teeth 
than at V1 will be performed. Buccal samples will 
also be collected. Maintenance will be provided. 
Amended text 
3 months, periodontal assessment & maintenance 
visit, GCF and buccal swabs collection  
Patients will come to the site for periodontal 
assessment (Appendix 1), including GCF collection 
from the same 4 target sitesteeth than at V1, and 
collection of buccal swabs. Maintenance treatment 
will be provided as needed. 
6 months, periodontal assessment & maintenance 
visit, SP and buccal swabs  
Patients will come to the site for periodontal 
assessment (Appendix 1). Sampling of SP for 
microbiological status from the same 4 target teeth 
than at V1 will be performed. Buccal samples will 

 
 
 
 
 
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also be collected. Maintenance will be provided as 
needed. 
Reason to change: as per PI’s suggestions. 
4 
Overall Study Design 
Old text 
The site should record any site visit and document 
the reason for the visit. 
Amended text 
The site should record any site visit even if 
unscheduled and document the reason for the visit. 
Reason to change: to clarify that all visits should be 
recorded. 
5.2 
Discontinuation of 
Patients from the Study 
 
Old text 
2. Patient needs to take antibiotic treatment for any 
medical condition other than periodontitis, for 
more than 2 consecutive weeks, during the 
course of the study.  
3. Patient needs to take antibiotic for more than 5 
consecutive days for acute inflammation of 
periodontitis. 
4. Patient needs to take steroidal or non-steroidal 
anti-inflammatory drugs for more than 6 
consecutive days 
Amended text 
2. Patient needs to take systemic antibiotic 
treatment for any medical condition other than 
periodontitis, for more than 2 consecutive weeks, 
during the course of the study.  
3. Patient needs to take systemic or topical (in the 
mouth) antibiotic for more than 5 consecutive 
days for acute inflammation of periodontitis. 
4. Patient needs to take systemic steroidal or non-
steroidal anti-inflammatory drugs for more than 6 
consecutive days 
Reason to change: to clarify systemic vs topical use 
of antibiotics anti-inflammatory drugs. 

 
 
 
 
 
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6.5.4 
Adherence to 
Investigational 
Product(s) 
Old text 
Adherence to the allocated product will be 
monitored using a questionnaire on self-reported 
current tobacco and nicotine containing tobacco 
product consumption (including frequency and 
quantity of product use) over the past month. 
Amended text 
Adherence to the allocated product will be 
monitored using a questionnaire on self-reported 
current tobacco and nicotine containing tobacco 
product consumption (including frequency and 
quantity of product use) over the past month 
(section 7.5.7). 
Reason to change: following a number of questions 
regarding on when the questionnaire needs to be 
filled, we provided a more exhaustive explanation in 
section 7.5.7. 
6.6 
Concomitant 
medication 
Old text 
If required for the periodontal treatment, antibiotics 
should not be given for more than 5 consecutive 
days and will be recorded as concomitant 
medication, but this will not necessarily be a reason 
to discontinue the patient from the study (section 
5.2). If required, antibiotics for other medical 
conditions should ideally not be taken for more than 
2 consecutive weeks. Steroidal or non-steroidal anti-
inflammatory drugs should not be given for more 
than 6 consecutive days. 
Amended text 
If required for the periodontal treatment, systemic 
or topical (in the mouth) antibiotics should not be 
given for more than 5 consecutive days and will be 
recorded as concomitant medication, but this will 
not necessarily be a reason to discontinue the patient 
from the study (section 5.2). If required, systemic 
antibiotics for other medical conditions should 
ideally not be taken for more than 2 consecutive 
weeks. Systemic sSteroidal or non-steroidal anti-

 
 
 
 
 
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inflammatory drugs should not be given for more 
than 6 consecutive days. 
Reason to change: The distinction between topical 
and systemic drug was not clearly made, thus has 
been clarified. 
6.7 
New 
section 
Concomitant 
Therapeutic 
Procedures 
Amended text 
Concomitant Therapeutic Procedures 
Any concomitant therapeutic procedure (e.g. 
tooth extraction due to cavity or due to worsening 
of periodontitis, appendicectomy), which is not 
part of study procedures (as described in Section 
7), will be fully documented in the source 
document and transcribed into the CRF. All 
medications used during these concomitant 
procedures will also be captured in the source 
document 
and 
reported 
as 
concomitant 
medication in the CRF.  
Reason to change: worsening of periodontitis is not 
considered as an AE, however, if a tooth is 
extracted, we need to understand why (e.g. broken 
tooth or worsening of the disease?). We have thus 
clarified the fact that the reason for extracting a 
tooth must be recorded in the CRF. 
7 
Study procedures 
Old text 
All study procedures are provided as an overview in 
the schedule of events (section 15.1, Appendix 1 – 
Schedule of Events) 
Amended text 
All study procedures are provided as an overview in 
the schedule of events (section 15.1, Appendix 1 – 
Schedule of Events) 
Reason to change: wrong reference 
7.2 
Advice on the Risks of 
Smoking/Smoking 
Cessation Advice and 
Debriefing on IQOS 
Old text 
will be given to all patients at every visit 
Amended text 
will be given to all patients at every vVisit 

 
 
 
 
 
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Reason to change: to be consistent throughout the 
text 
7.5.6 
Sample Handling, 
Storage, and Shipment 
Old text 
All samples will be destroyed post database lock or 
post finalization of the bioanalytical reports 
depending on which one is coming the latest. 
Amended text 
All samples that were planned for analysis will be 
destroyed post database lock or post finalization of 
the bioanalytical reports depending on which one is 
coming the latest. 
Reason to change: to distinguish those that should be 
discarded during the course of the study, for 
example, of a discontinued patient who refuses to 
have his/her samples analyzed. 
7.5.7 
Self-reported Tobacco- 
or Nicotine-Containing 
Product Use 
Old text: 
The sites will call the patients to remind them to fill 
the questionnaire. The Investigator or study 
collaborator will collect the completed diaries at 
every visit and the diary data will be transcribed into 
the CRF.  
Amended text: 
In this case, a “month” can is to be considered as 
30 days, however a “calendar month” window is 
acceptable. A flexibility of ± 2 day is allowed, 
whichever definition of the month is used. The 
sites will call the patients to remind them to fill the 
questionnaire. The Investigator or study collaborator 
will collect the completed diaries at every visit and 
the diary data will be transcribed into the CRF. The 
Investigator or study collaborator will collect the 
completed diaries at V3 for Month 1 and Month 2 
and for Month 3 only if the questionnaire 
completion date was before or on the day of the 
Visit. If the completion date of Month 3 
questionnaire is after the V3 date, the Month 3 
questionnaire will be brought to the next visit. All 
remaining questionnaires will be collected at V4, 
even if the 30-day period for completion of 
Month 6 questionnaire is after the date of V4. 

 
 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
The diary data will be transcribed into the CRF 
by study staff. 
Reason to change: It was not clear for the sites when 
the questionnaire had to be filled exactly, considering 
that the study is planned for 6 months, but with a 
flexibility of ± 7 days at V3 and ± 14 days et V4. Also, 
months don’t all have the same number of days. We 
have thus added flexibility in the definition of 
“monthly”, 
while 
explaining 
that 
the 
last 
questionnaire should be filled for V4, regardless of 
when the end of the month is. 
7.6 
Periodontal 
Treatment/Maintenance 
Amended text (new):  
All medications/treatments provided to patients 
must be documented in source documentation. 
However, medication commonly used during SRP 
and maintenance treatment procedure will not be 
recorded as concomitant medication in the CRF, 
except if it is identified as causally related to an 
AE. 
Reason to change: it was not clear for PIs what had 
to be recorded in the CRF or not, thus we clarified it 
with this added text. 
7.6.1 
Scaling 
Old text: 
Supragingival scaling will be performed at V1. 
Maintenance treatment will be provided in the order 
of supragingival scaling and plaque control at all 
other visits. Ultrasonic scaler usually used at each 
site will be used for scaling. 
Amended text: 
Supragingival scaling will be performed at V1, and 
at further visits if required, including at 
unscheduled visits, based on PI’s judgement. 
Maintenance treatment will be provided in the order 
of supragingival scaling and plaque control at all 
other visits. Ultrasonic scaler usually used at each 
site will be used for scaling. 
Reason to change: it was not clear for PIs that scaling 
could be performed as many times as needed. 

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 132 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
7.6.2 
Scaling and Root 
Planing (SRP)  
Amended text (new): SRP treatments of teeth with 
PD < 4 mm will be performed based on PI’s 
judgment, at the time he/she finds it necessary. 
Reason to change: it was not clear for a PI how to treat 
the teeth with PD < 4mm. 
8.1.1 
Adverse Events 
Amended text (new): Any dental condition 
identified after signature of the ICF, caused by 
factors other than periodontitis (e.g. cavity, 
broken tooth) and requiring future treatment/s, 
will be identified as an AE. Treatment of this 
condition (e.g. cavity filling, tooth extraction) will 
be captured in the CRF. 
Reason to change: it was not clear for PIs what had to 
be recorded in the CRF or not, thus we clarified it with 
this added text. 
8.1.1 
Adverse Events 
Old text 
Worsening of the periodontitis parameters will not 
be considered as an AE, as dental assessments will 
capture any worsening of the periodontal condition. 
Amended text 
Worsening of the periodontitis parameters after 
baseline assessments will not be considered as an 
AE, as dental assessments will capture any 
worsening of the periodontal condition. 
Reason to change: added to clarify from when 
“worsening” is meant. 
8.4 
Reporting of other 
events critical to safety 
evaluations 
Old text 
the IQOS device only to the a member of the 
Amended text 
the IQOS device only to the a member of the 
Reason to change: typo 
9.1 
Table 3 
Old text: 
Start of the visit 
Amended text (addition of a footnote) 
1 The informed consent process can be started as 
soon as the patient is invited to participate in the 
study, but the ICF must be signed no later than 
before the first assessment at V1.  

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 133 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
Reason to change: added to clarify that ICF can be 
signed before the beginning of assessments. 
9.1 
Table 3 
Old text: Prior medication and/or concomitant 
medication 
Amended text: Prior medication and/or concomitant 
medication / procedures 
Reason to change: “procedures” was added to 
distinguish from concomitant medication 
9.1 
Table 3 
Old text: 
Patients will answer this questionnaire on site, with 
instructions from study staff so that they can then fill 
it alone on a monthly  
Amended text (including addition of a footnote):  
Patients will answer this questionnaire on site, with 
instructions from study staff so that they can then fill 
it alone on a monthly basis 1. Distribution of the 
diaries for the next Visit. 
1 For the questionnaire, “monthly” can be 
considered as 30 days, or as a calendar month. A 
flexibility of ± 2 day is allowed to fill it. 
Reason to change: it was not clear for the sites when 
the questionnaire had to be filled exactly. 
9.1 
Table 3 
Old text: 
Full mouth PCR 
Amended text (including addition of a footnote): 
Full mouth PCR 2 
 PCR can be performed after enrollment based on 
PI’s decision. 
Reason to change: a PI commented that PCR can 
prevent proper evaluation of gingival inflammation. 
9.2 
Table 4 
Old text: Concomitant medication 
Amended text: Concomitant medication / 
procedures 
Reason to change: “procedures” was added to 
distinguish from concomitant medication 
9.2 
Table 4 
Old text (Next to PD, BOP, Tooth mobility): As per 
standard of care. 
Amended text: (optional, as per PI’s judgment). 

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 134 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
Reason to change: not all sites have the same 
practices, thus added clarification. 
9.3 
Table 5 
Amended text (added next to Tobacco or nicotine 
containing product use self-reporting): Collection of 
the diaries from the previous Visit, and 
distribution of the diaries for the next Visit. 
Reason to change: to clarify when questionnaires are 
distributed and collected. 
9.3 
Table 5 
Old text: Concomitant medication 
Amended text: Concomitant medication / 
procedures 
Reason to change: “procedures” was added to 
distinguish from concomitant medication 
9.3 
Table 5 
Moved text (After “gingival inflammation”): 
Full mouth PCR 
Reason to change: a PI commented that PCR can 
prevent proper evaluation of gingival inflammation. 
9.4 
Table 6 
Amended text (added next to Tobacco or nicotine 
containing product use self-reporting): Collection of 
the diaries from the previous Visit, including 
questionnaire of Month 6. 
Reason to change: to clarify when questionnaires are 
collected. 
9.4 
Table 6 
Old text: Concomitant medication 
Amended text: Concomitant medication / 
procedures 
Reason to change: “procedures” was added to 
distinguish from concomitant medication 
9.4 
Table 6 
Moved text (After “gingival inflammation”): 
Full mouth PCR 
Reason to change: a PI commented that PCR can 
prevent proper evaluation of gingival inflammation. 
11.2.2 
Coding 
Old text: 
WHO Drug Dictionary Enhanced and Anatomical 
Therapeutic and Chemical Classification System 

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 135 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
Amended text: WHO Drug Dictionary Enhanced 
and Anatomical Therapeutic and Chemical 
Classification SystemDrug Global 
11.2.2 
Coding 
Old text: adverse events 
Amended text: adverse events / Procedures 
Reason to change: procedures also need to be coded 
following MedDRA 
13.1.2 
Sponsor 
Old text: 
, PhD, Statistician 
Phone: +41 
 
Mobile: +41 
 
Email: 
 
Replaced with: 
 PhD, Statistician 
Phone: +41 
 
Fax: +41 
 
Email: 
 
Appendix 
1 
Schedule of events 
Two footnotes were added. The other footnotes were 
“renumbered” accordingly. 
Added: 
ICF signature a 
a The informed consent process can be started as 
soon as the patient is invited to participate in the 
study, but the ICF must be signed no later than 
before the first assessment at V1.  
Tobacco- or nicotine-containing product use self-
reporting c 
c The Investigator or study collaborator will 
collect the completed diaries at V3 and V4, and 
the diary data will be transcribed into the CRF. 
The questionnaire can be filled before or after 
V3, but because V4 is the last Visit, the 
questionnaire for Month 6 must be filled before 
or at V4, regardless of the time when the previous 
questionnaire was filled. 
Reason to change: to clarify, like in the text that ICF 
can be signed before V1, and to clarify when the 
questionnaires need to be filled/collected. 

 
 
 
 
 
Philip Morris Products S.A. 
Assessment Study Protocol 
Confidential 
Study P1-OHS-01-JP  
Final version 4.0 / 09 January 2019 
Page 136 of 136 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
Appendix 
1 
Schedule of events 
(footnote h) 
Old text: PD CAL on 6 sites per tooth, BOP, tooth 
mobility 
New text: PD, CAL and BOP on 6 sites per tooth, 
BOP, tooth mobility 
Reason to change: BOP is also measured on 6 sites 
per tooth