Effect of Switching From Cigarette Smoking to the Use of IQOS on Periodontitis Treatment Outcome

• Sponsor: Philip Morris Products S.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03364751
• Collaborator: (none)
• Enrollment: 179
• Locations: 26
• Arms: 2
• Actual Duration (Months): 19.1
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study was to demonstrate in patients with generalized chronic periodontitis that switching from cigarette smoking to using IQOS improves the response to periodontal therapy and the overall oral health status compared to continuing cigarette smoking.

Note: "IQOS" is the Tobacco Heating System (THS) with Marlboro Heatsticks, marketed in Japan under the brand name IQOS

Condition or Disease	Intervention/Treatment	Phase
Periodontal Diseases; Chronic Periodontitis; Periodontal Pocket; Tooth Mobility; Gingival Diseases; Smoking, Cigarette	Other: IQOS; Other: Cigarette	N/A

Detailed Description

This was 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 (10-19 cigarettes/day vs. > 19 cigarettes/day) and disease severity recorded at Visit 1 (< 5 mm Pocket Depth [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 cigarette smoking to IQOS use or continuing cigarette smoking.

Study Design

• Study Type: Interventional
• Actual Enrollment: 179 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Single (Investigator)
• Masking Description: The Dentist (Investigator) or Dental Hygienist performing the periodontal assessments will be blinded to the arm allocation.
• Primary Purpose: Other
• Official 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.
• Actual Study Start Date: Nov 7, 2017
• Actual Primary Completion Date: Dec 21, 2018
• Actual Study Completion Date: Jun 12, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: IQOS arm ~86 patients, switching from cigarette smoking to IQOS use.	Other: IQOS; Patients will switch from cigarette smoking to ad libitum IQOS use.
Active Comparator: Cigarette arm ~86 patients, continuing cigarette smoking.	Other: Cigarette; Patients will continue to smoke cigarettes ad libitum.

Outcome Measures

Primary Outcome Measures

1. Periodontal Pocket Depth (PD) Change From Baseline at 6 Months [At 6 months]

   Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Mean Periodontal PD change from baseline will be measured in all sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.

Secondary Outcome Measures

1. Periodontal Pocket Depth (PD) Change Over Time. (Mean PD in All Subjects With Initial PD ≥ 4 mm) [At 3 months]

   Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Mean Periodontal PD change from baseline will be measured in all sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.

2. Clinical Attachment Level (CAL) Change Over Time (Mean CAL in All Subjects With Initial PD ≥ 4 mm) [At 3 months and 6 months]

   Clinical attachment level (CAL) is the measured distance from cementoenamel junction (CEJ) to the bottom of pocket using a periodontal probe. Mean CAL change from baseline will be measured in sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.

3. Periodontal Pocket Depth (PD) Change Over Time. (Mean PD in All Subjects With Initial PD ≥ 4 mm) - Descriptive Statistics [From baseline to 3 months and 6 months]

   Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Mean Periodontal PD change from baseline will be measured in all sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.

4. Clinical Attachment Level (CAL) Change Over Time (Mean CAL in All Subjects With Initial PD ≥ 4 mm) - Descriptive Statistics [From baseline to 3 months and 6 months]

   Clinical attachment level (CAL) is the measured distance from cementoenamel junction (CEJ) to the bottom of pocket using a periodontal probe. Mean CAL change from baseline will be measured in sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.

5. Full-mouth Periodontal PD Change Over Time. [From baseline to 3 months and 6 months]

   Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Change in mean full-mouth PD will be measured, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.

6. Full-mouth Clinical Attachment Level (CAL) Over Time. [From baseline to 3 months and 6 months]

   Clinical attachment level (CAL) is the measured distance from cementoenamel junction (CEJ) to the bottom of pocket using a periodontal probe. Change in mean full-mouth CAL will be measured, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.

7. Peridontal PD Reduction. [From baseline to 3 months and 6 months]

   Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Mean PD change will be measured 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.

8. Clinical Attachment Level Improvement [From baseline to 3 months and 6 months]

   Clinical attachment level (CAL) is the measured distance from cementoenamel junction (CEJ) to the bottom of pocket using a periodontal probe. Mean CAL change will be measured 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.

9. Number of Periodontally Diseased Sites. [From baseline to 3 months and 6 months]

   Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Any change will be recorded in the number of periodontally diseased sites with Pocket Depth (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. PD is the distance from the gingival margin to which a probe penetrates into the pocket.

10. Gingival Inflammation [From baseline to 3 months and 6 months]

    Gingival inflammation will be measured by calculating the gingival index (GI) score for each target tooth. The gingival index (GI) scores each site on a 0 to 3 scale, with 0 being normal and 3 being severe inflammation characterized by edema, redness, swelling, and spontaneous bleeding.

11. Tooth Mobility [From baseline to 3 months and 6 months]

    Tooth mobility will be graded according to Miller's mobility index (MMI), which is the most widely accepted method for routine clinical examinations of tooth mobility. The tooth is held between the metallic handles of two instruments and moved in the buccolingual or buccopalatal direction, and the moved distance is visually estimated by the person conducting the examination. 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.

12. Presence of Plaque on Tooth Surfaces in Full Mouth [From baseline to 3 months and 6 months]

    Plaque will be measured using the plaque control record (PCR) percentage.

13. Inflammatory Status in Periodontal Pockets [From baseline to 3 months and 6 months]

    Gum inflammation was measured using percentage of teeth bleeding on probing (BOP). BOP in full mouth was measured to assess inflammatory status in the pocket and was assessed as YES or NO of bleeding at 6 sites per tooth. Gently probing (approximately 20 g pressure), the bleeding site within 30 seconds was assessed as YES.

14. Concentrations of Urinary Nicotine Equivalents (NEQ) [From baseline to 3 months and 6 months]

    This biomarker of exposure to a tobacco smoke constituent will be measured in patients who switch to IQOS use and patients who continue cigarette smoking. Concentrations measured in urine and expressed as concentration adjusted for creatinine (mg/g creat).

15. Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) [From baseline to 3 months and 6 months]

    This biomarker of exposure to a tobacco smoke constituent will be measured in patients who switch to IQOS use and patients who continue cigarette smoking. Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat).

16. Concentrations of 2-cyanoethylmercapturic Acid (CEMA) [From baseline to 3 months and 6 months]

    This biomarker of exposure to a tobacco smoke constituent will be measured in patients who switch to IQOS use and patients who continue cigarette smoking. Concentrations measured in urine and expressed as concentration adjusted for creatinine (ng/mg creat).

17. Use of Tobacco or Nicotine-containing Products in Patients Switching to IQOS Use and Patients Who Continue Cigarette Smoking. [From baseline to 6 months]

    Self-reported use of tobacco or nicotine containing products will be measured over the study in patients switching to IQOS use and patients who continue cigarette smoking.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Main Inclusion Criteria:

1. Patient is aged ≥ 30 years old.

2. Patient has smoked on average at least 10 commercially available cigarettes per day for at least 5 years

3. Patient has generalized chronic periodontitis (i.e., more than 30% of diseased teeth with a PD ≥ 4 mm).

Main Exclusion Criteria:

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).

2. Patient received root planing therapy within the 6 months prior to Visit 1.

3. Patient received surgical periodontal therapy within 3 years prior to Visit

4. Patient was treated within the 3 months prior to Visit 1 with systemic antibiotics or was treated with topical antibiotics applied in the mouth.

5. 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).

6. Female patients who are pregnant, breast-feeding, or planning a pregnancy within the course of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mase Dental Clinic	Futtsu	Chiba	Japan	293-0001
2	Tsudanuma Olive Dental Clinic	Narashino	Chiba	Japan	275-0016
3	Matsunobu Dental Office	Miyako	Fukuoka	Japan	800-0323
4	Taniguchi Dental Clinic	Sapporo	Hokkaido	Japan	003-0023
5	Takano Dental Clinic	Chikusei	Ibaraki	Japan	308- 0031
6	Tsukuba Healthcare Dental Clinic	Tsukuba	Ibaraki	Japan	305-0834
7	AOI Universal Hospital	Kawasaki	Kanagawa	Japan	210-0822
8	Yoshinaga Dental Office	Uki	Kumamoto	Japan	869-0521
9	Yoshino Dental Clinic	Kawaguchi	Saitama	Japan	332-0016
10	Saida Dental Clinic	Tokorozawa	Saitama	Japan	359-1146
11	Sakai Dental Clinic	Bunkyō	Tokyo	Japan	113-0033
12	Kudan Dental Clinic	Chiyoda	Tokyo	Japan	102-0074
13	Yano Dental Clinic	Chōfu	Tokyo	Japan	182-0024
14	Nikaido Dental Clinic	Chūō	Tokyo	Japan	103-0027
15	Mune Dental Clinic	Setagaya	Tokyo	Japan	157-0072
16	Kikuchi Dental Clinic	Shinjuku	Tokyo	Japan	160-0023
17	Miyata Dental Clinic	Toshima	Tokyo	Japan	171-0043
18	Kato Dental Clinic	Himi	Toyama	Japan	935-0015
19	Kimura Dental Clinic	Fukuoka		Japan	810-0001
20	Yamashita Dental Office	Fukuoka		Japan	810-0001
21	Yasumasu Dental Office	Fukuoka		Japan	810-0001
22	Tsukiyama Dental Clinic	Fukuoka		Japan	811-1302
23	Yoshida Shigeru Dental Office	Fukuoka		Japan	812-0011
24	Yamashita Dental Clinic	Kagoshima		Japan	890-0053
25	Heart Dental Clinic	Kagoshima		Japan	892-0844
26	Higashi Dental Office	Kumamoto		Japan	860-0855

Sponsors and Collaborators

• Philip Morris Products S.A.

Investigators

• Study Chair: Christelle Haziza, PhD, Philip Morris Products S.A.

Study Documents (Full-Text)

• Study Protocol - Jan 9, 2019
• Statistical Analysis Plan - Jun 7, 2019

More Information

Publications

None provided.

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT03364751
• Other Study ID Numbers: P1-OHS-01-JP
• First Posted: Dec 7, 2017
• Last Update Posted: Feb 18, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Philip Morris Products S.A.: Oral Health; Smoking; Cigarette; Reduced risk product; Tobacco heating system; THS; Modified risk tobacco product; Clinical attachment level
• Additional relevant MeSH terms: Periodontitis; Periodontal Diseases; Chronic Periodontitis; Periodontal Pocket; Gingival Diseases; Tooth Mobility

Study Results

Participant Flow

Pre-assignment Detail	179 subjects were enrolled in the study. 172 subjects were randomized to the IQOS arm (n=87) or to the cigarette arm (n=85). The analysis was performed according to subjects' exposure (Product Use Category, i.e., IQOS; Cigarette; Dual use; or Other) over the study period as detailed in the "Arm/Group" (Reporting Groups) table.

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category: Subjects using over 30 HeatSticks, but less than 30 cigarettes monthly were classified as "IQOS" users (based on self-report).	Cigarette Product Use Category: Monthly users of less than 30 HeatSticks, but over 30 cigarettes were classified as "Cigarette" users (based on self-report).	Dual User Product Use Category: Users of over 30 HeatSticks and over 30 cigarettes per month were classified as "Dual User" (based on self-report).	Other Product Use Category: All other use patterns were classified as "Other" (based on self-report).
Period Title: Overall Study
STARTED	70	84	17	1
COMPLETED	69	83	17	1
NOT COMPLETED	1	1	0	0

Baseline Characteristics

Arm/Group Title	IQOS	Cigarette	Dual User	Other	Total
Arm/Group Description	IQOS Product Use Category	Cigarette Product Use Category	Dual User Product Use Category	Other Product Use Category	Total of all reporting groups
Overall Participants	70	84	17	1	172
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	48.1	46.5	54.4	54.0	48.0
Sex: Female, Male (Count of Participants)
Female	13 18.6%	17 20.2%	3 17.6%	0 0%	33 19.2%
Male	57 81.4%	67 79.8%	14 82.4%	1 100%	139 80.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	70 100%	84 100%	17 100%	1 100%	172 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Japan	70 100%	84 100%	17 100%	1 100%	172 100%
Nationality (Count of Participants)
Japanese	70 100%	84 100%	17 100%	1 100%	172 100%
Non-Japanese	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Periodontal Pocket Depth (PD) Change From Baseline at 6 Months
Description	Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Mean Periodontal PD change from baseline will be measured in all sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.
Time Frame	At 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements). The "Other" reporting group, which included one subject, was not included in this analysis.

Arm/Group Title	IQOS	Cigarette	Dual User
Arm/Group Description	IQOS Product Use Category	Cigarette Product Use Category	Dual User Product Use Category
Measure Participants	70	84	17
Mean (95% Confidence Interval) [millimeters]	-1.046	-1.114	-1.177

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IQOS, Cigarette
	Comments	Month 6: Difference between Cigarette and IQOS
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.297
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.068
	Confidence Interval	(2-Sided) 95%; -0.060 to 0.196
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cigarette, Dual User
	Comments	Month 6: Difference between Cigarette and Dual Use
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.550
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.064
	Confidence Interval	(2-Sided) 95%; -0.273 to 0.146
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Periodontal Pocket Depth (PD) Change Over Time. (Mean PD in All Subjects With Initial PD ≥ 4 mm)
Description	Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Mean Periodontal PD change from baseline will be measured in all sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.
Time Frame	At 3 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements). The "Other" reporting group, which included one subject, was not included in this analysis.

Arm/Group Title	IQOS	Cigarette	Dual User
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set
Measure Participants	70	84	17
Least Squares Mean (95% Confidence Interval) [millimeters]	-0.972	-1.016	-1.035

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IQOS, Cigarette
	Comments	Month 3: Difference between Cigarette and IQOS
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.502
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.043
	Confidence Interval	(2-Sided) 95%; -0.084 to 0.171
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cigarette, Dual User
	Comments	Month 3: Difference between Cigarette and Dual Use
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.851
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.020
	Confidence Interval	(2-Sided) 95%; -0.229 to 0.189
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Clinical Attachment Level (CAL) Change Over Time (Mean CAL in All Subjects With Initial PD ≥ 4 mm)
Description	Clinical attachment level (CAL) is the measured distance from cementoenamel junction (CEJ) to the bottom of pocket using a periodontal probe. Mean CAL change from baseline will be measured in sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.
Time Frame	At 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements). The "Other" reporting group, which included one subject, was not included in this analysis.

Arm/Group Title	IQOS	Cigarette	Dual User
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set
Measure Participants	70	83	17
Month 3: Change from Baseline	-0.820	-0.889	-0.865
Month 6: Change from Baseline	-0.903	-0.995	-1.100

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IQOS, Cigarette
	Comments	Month 3: Difference between Cigarette and IQOS
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.376
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.070
	Confidence Interval	(2-Sided) 95%; -0.085 to 0.224
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cigarette, Dual User
	Comments	Month 3: Difference between Cigarette and DualUse
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.848
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.025
	Confidence Interval	(2-Sided) 95%; -0.229 to 0.279
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	IQOS, Cigarette
	Comments	Month 6: Difference between Cigarette and IQOS
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.246
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.092
	Confidence Interval	(2-Sided) 95%; -0.064 to 0.247
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cigarette, Dual User
	Comments	Month 6: Difference between Cigarette and Dual Use
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.417
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.105
	Confidence Interval	(2-Sided) 95%; -0.359 to 0.150
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Periodontal Pocket Depth (PD) Change Over Time. (Mean PD in All Subjects With Initial PD ≥ 4 mm) - Descriptive Statistics
Description	Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Mean Periodontal PD change from baseline will be measured in all sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category
Measure Participants	70	84	17	1
Baseline	4.45	4.43	4.34	4.07
Month 3	3.44	3.47	4.34	3.04
Month 6	3.36	3.37	3.29	3.09

5. Secondary Outcome

Title	Clinical Attachment Level (CAL) Change Over Time (Mean CAL in All Subjects With Initial PD ≥ 4 mm) - Descriptive Statistics
Description	Clinical attachment level (CAL) is the measured distance from cementoenamel junction (CEJ) to the bottom of pocket using a periodontal probe. Mean CAL change from baseline will be measured in sites with initial PD ≥ 4 mm, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	4.65	4.64	4.60	4.13
Month 3	3.82	3.79	3.87	3.20
Month 6	3.74	3.69	3.64	3.21

6. Secondary Outcome

Title	Full-mouth Periodontal PD Change Over Time.
Description	Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Change in mean full-mouth PD will be measured, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	3.15	3.20	2.99	2.92
Month 3	2.70	2.78	2.69	2.57
Month 6	2.70	2.72	2.62	2.55

7. Secondary Outcome

Title	Full-mouth Clinical Attachment Level (CAL) Over Time.
Description	Clinical attachment level (CAL) is the measured distance from cementoenamel junction (CEJ) to the bottom of pocket using a periodontal probe. Change in mean full-mouth CAL will be measured, following mechanical periodontal therapy, in patients who switch to IQOS use compared to those who continue cigarette smoking.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	3.48	3.52	3.34	2.99
Month 3	3.10	3.13	3.15	2.70
Month 6	3.10	3.09	2.97	2.70

8. Secondary Outcome

Title	Peridontal PD Reduction.
Description	Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Mean PD change will be measured 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.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
<4mm (Baseline)	2.5	2.6	2.5	2.6
<4mm (Month 3: Change from Baseline)	-0.2	-0.2	-0.1	-0.1
<4mm (Month 6: Change from Baseline)	-0.2	-0.2	-0.1	-0.1
4mm-5mm (Baseline)	4.0	4.0	4.0	4.0
4mm-5mm (Month 3: Change from Baseline)	-0.8	-0.8	-0.8	-1.0
4mm-5mm (Month 6: Change from Baseline)	-0.9	-0.9	-0.8	-0.9
5mm-6mm (Baseline)	5.0	5.0	5.0	5.0
5mm-6mm (Month 3: Change from Baseline)	-1.2	-1.1	-1.0	-1.8
5mm-6mm (Month 6: Change from Baseline)	-1.2	-1.2	-1.2	-2.0
6mm-7mm (Baseline)	6.0	6.0	6.0	NA
6mm-7mm (Month 3: Change from Baseline)	-1.3	-1.2	-1.4	NA
6mm-7mm (Month 6: Change from Baseline)	-1.5	-1.4	-1.8	NA
≥7mm (Baseline)	7.6	7.5	8.4	NA
≥7mm (Month 3: Change from Baseline)	-2.1	-1.6	-2.5	NA
≥7mm (Month 6: Change from Baseline)	-2.3	-1.7	-2.3	NA

9. Secondary Outcome

Title	Clinical Attachment Level Improvement
Description	Clinical attachment level (CAL) is the measured distance from cementoenamel junction (CEJ) to the bottom of pocket using a periodontal probe. Mean CAL change will be measured 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.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
<4mm (Baseline)	3.0	3.0	2.9	2.6
<4mm (Month 3: Change from Baseline)	-0.2	-0.2	0.0	-0.1
<4mm (Month 6: Change from Baseline)	-0.2	-0.2	-0.2	-0.1
4mm-5mm (Baseline)	4.2	4.2	4.3	4.1
4mm-5mm (Month 3: Change from Baseline)	-0.7	-0.7	-0.6	-0.9
4mm-5mm (Month 6: Change from Baseline)	-0.8	-0.8	-0.8	-0.9
5mm-6mm (Baseline)	5.2	5.2	5.2	5.0
5mm-6mm (Month 3: Change from Baseline)	-0.9	-1.0	-0.8	-1.2
5mm-6mm (Month 6: Change from Baseline)	-1.0	-1.1	-1.2	-1.8
6mm-7mm (Baseline)	6.2	6.3	6.3	NA
6mm-7mm (Month 3: Change from Baseline)	-1.0	-1.0	-1.2	NA
6mm-7mm (Month 6: Change from Baseline)	-1.3	-1.3	-1.7	NA
≥7mm (Baseline)	7.5	7.9	8.8	NA
≥7mm (Month 3: Change from Baseline)	-1.3	-1.7	-1.6	NA
≥7mm (Month 6: Change from Baseline)	-1.6	-1.9	-2.0	NA

10. Secondary Outcome

Title	Number of Periodontally Diseased Sites.
Description	Pocket depth (PD) is the distance from the gingival margin to which a probe penetrates into the pocket. Any change will be recorded in the number of periodontally diseased sites with Pocket Depth (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. PD is the distance from the gingival margin to which a probe penetrates into the pocket.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
<4mm: Baseline	7688	9194	1911	127
<4mm: Month 3	9332	11146	2181	154
<4mm: Month 6	9241	11199	2227	159
4mm - 5mm: Baseline	2067	2571	469	37
4mm - 5mm: Month 3	1037	1393	261	14
4mm - 5mm: Month 6	934	1241	259	8
5mm - 6mm: Baseline	724	1042	136	4
5mm - 6mm: Month 3	366	483	102	0
5mm - 6mm: Month 6	333	426	76	1
6mm - 7mm: Baseline	291	333	55	0
6mm - 7mm: Month 3	151	238	31	0
6mm - 7mm: Month 6	189	219	23	0
≥7mm: Baseline	220	222	15	0
≥7mm: Month 3	124	113	10	0
≥7mm: Month 6	126	120	7	0
Missing/Not done: Baseline	26	12	0	0
Missing/Not done: Month 3	6	1	1	0
Missing/Not done: Month 6	7	1	0	0

11. Secondary Outcome

Title	Gingival Inflammation
Description	Gingival inflammation will be measured by calculating the gingival index (GI) score for each target tooth. The gingival index (GI) scores each site on a 0 to 3 scale, with 0 being normal and 3 being severe inflammation characterized by edema, redness, swelling, and spontaneous bleeding.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	1.46	1.48	1.46	1.38
Month 3	1.06	1.08	1.22	0.5
Month 3: Change from Baseline	-0.40	-0.40	-0.24	-0.88
Month 6	1.03	1.04	1.05	1.38
Month 6: Change from Baseline	-0.43	-0.44	-0.41	0.00

12. Secondary Outcome

Title	Tooth Mobility
Description	Tooth mobility will be graded according to Miller's mobility index (MMI), which is the most widely accepted method for routine clinical examinations of tooth mobility. The tooth is held between the metallic handles of two instruments and moved in the buccolingual or buccopalatal direction, and the moved distance is visually estimated by the person conducting the examination. 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.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	0.18	0.19	0.23	0
Month 3	0.17	0.16	0.19	0
Month 3: Change from Baseline	-0.01	-0.03	-0.04	0.00
Month 6	0.18	0.17	0.16	0
Month 6: Change from Baseline	0.00	-0.02	-0.07	0.00

13. Secondary Outcome

Title	Presence of Plaque on Tooth Surfaces in Full Mouth
Description	Plaque will be measured using the plaque control record (PCR) percentage.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	62.07	62.48	55.81	77.68
Month 3	48.03	50.14	44.56	60.71
Month 3: Change from Baseline	-14.27	-12.34	-11.25	-16.96
Month 6	49.60	51.55	47.92	58.04
Month 6: Change from Baseline	-13.27	-11.22	-7.89	-19.64

14. Secondary Outcome

Title	Inflammatory Status in Periodontal Pockets
Description	Gum inflammation was measured using percentage of teeth bleeding on probing (BOP). BOP in full mouth was measured to assess inflammatory status in the pocket and was assessed as YES or NO of bleeding at 6 sites per tooth. Gently probing (approximately 20 g pressure), the bleeding site within 30 seconds was assessed as YES.
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	41.25	42.93	30.80	48.81
Month 3	26.68	24.21	19.03	53.57
Month 3: Change from Baseline	-14.57	-18.72	-11.78	4.76
Month 6	26.90	23.80	19.80	38.10
Month 6: Change from Baseline	-14.85	-18.71	-11.00	-10.71

15. Secondary Outcome

Title	Concentrations of Urinary Nicotine Equivalents (NEQ)
Description	This biomarker of exposure to a tobacco smoke constituent will be measured in patients who switch to IQOS use and patients who continue cigarette smoking. Concentrations measured in urine and expressed as concentration adjusted for creatinine (mg/g creat).
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	6.777	7.649	6.452	8.527
Month 3	6.766	6.699	5.911	7.681
Month 6	6.471	6.563	5.467	5.213

16. Secondary Outcome

Title	Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL)
Description	This biomarker of exposure to a tobacco smoke constituent will be measured in patients who switch to IQOS use and patients who continue cigarette smoking. Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat).
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	83.30	112.52	93.01	159.05
Mionth 3	25.77	100.67	68.62	124.39
Month 6	22.55	96.70	77.17	48.74

17. Secondary Outcome

Title	Concentrations of 2-cyanoethylmercapturic Acid (CEMA)
Description	This biomarker of exposure to a tobacco smoke constituent will be measured in patients who switch to IQOS use and patients who continue cigarette smoking. Concentrations measured in urine and expressed as concentration adjusted for creatinine (ng/mg creat).
Time Frame	From baseline to 3 months and 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment. Subjects were analyzed based on their actual self-reported product use. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Baseline	67.29	90.44	92.10	140.95
Month 3	9.94	80.30	50.36	5.19
Month 6	7.56	76.65	69.02	1.97

18. Secondary Outcome

Title	Use of Tobacco or Nicotine-containing Products in Patients Switching to IQOS Use and Patients Who Continue Cigarette Smoking.
Description	Self-reported use of tobacco or nicotine containing products will be measured over the study in patients switching to IQOS use and patients who continue cigarette smoking.
Time Frame	From baseline to 6 months

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized subjects with at least one product use experience and at least one valid non-safety assessment analyzed by actual product use. Results were reported only for subjects with exposure to a specific tobacco or nicotine-containing product.

Arm/Group Title	IQOS	Cigarette	Dual User	Other
Arm/Group Description	IQOS Product Use Category - As Exposed Set	Cigarette Product Use Category - As Exposed Set	Dual User Product Use Category - As Exposed Set	Other Product Use Category - As Exposed Set
Measure Participants	70	84	17	1
Cigarettes/day over the last five years (Baseline)	18.2	17.7	18.1	20.0
Cigarettes/day	0.22	17.06	8.16
IQOS Heatsticks/day	16.60	0.30	9.06
Other Heat-Not-Burn/day	1.67	3.72	0.01	30.00
E-cigarettes/day	2.67
Nicotine Replacement Therapy/day	0.81	0.50

Adverse Events

Time Frame	Adverse events were collected from the signature of the ICF by each subject until the end of the safety follow-up period, for a total study duration of up to 31 weeks for each subject.
Adverse Event Reporting Description	The safety population comprised the 179 subjects enrolled in the study, of which 172 subjects were randomized to the IQOS or Cigarette arms. Adverse events are reported according to subjects' product exposure over the study period (Product Use Category, i.e., IQOS use; Cigarette use; Dual use; or Other use) as detailed in the "Arm/Group" (Reporting Groups) table. The seven subjects who were enrolled but not randomized are included in the Cigarette group for adverse event reporting.
Arm/Group Title	IQOS		Cigarette		Dual		Other
Arm/Group Description	IQOS users (safety population)		Cigarette users (safety population; includes 7 subjects who were enrolled but not randomized and were considered to be in the cigarette users group)		Dual users (safety population)		Other users (safety population)
All Cause Mortality
	IQOS		Cigarette		Dual		Other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/91 (0%)		0/17 (0%)		0/1 (0%)
Serious Adverse Events
	IQOS		Cigarette		Dual		Other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		2/91 (2.2%)		0/17 (0%)		0/1 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/70 (0%)	0	1/91 (1.1%)	1	0/17 (0%)	0	0/1 (0%)	0
Jaw cyst	0/70 (0%)	0	1/91 (1.1%)	1	0/17 (0%)	0	0/1 (0%)	0
Other (Not Including Serious) Adverse Events
	IQOS		Cigarette		Dual		Other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/70 (35.7%)		29/91 (31.9%)		13/17 (76.5%)		1/1 (100%)
Gastrointestinal disorders
Dental caries	6/70 (8.6%)	6	12/91 (13.2%)	12	3/17 (17.6%)	3	0/1 (0%)	0
Toothache	4/70 (5.7%)	4	1/91 (1.1%)	1	0/17 (0%)	0	0/1 (0%)	0
Gingival Pain	2/70 (2.9%)	2	3/91 (3.3%)	3	1/17 (5.9%)	1	0/1 (0%)	0
Infections and infestations
Cellulitis	0/70 (0%)	0	0/91 (0%)	0	1/17 (5.9%)	1	0/1 (0%)	0
Oral herpes	0/70 (0%)	0	0/91 (0%)	0	1/17 (5.9%)	1	0/1 (0%)	0
Viral upper respiratory tract infection	8/70 (11.4%)	8	5/91 (5.5%)	5	2/17 (11.8%)	2	0/1 (0%)	0
Gastroenteritis	0/70 (0%)	0	0/91 (0%)	0	1/17 (5.9%)	1	0/1 (0%)	0
Gingivitis	1/70 (1.4%)	1	0/91 (0%)	0	1/17 (5.9%)	1	0/1 (0%)	0
Injury, poisoning and procedural complications
Tooth fracture	2/70 (2.9%)	2	1/91 (1.1%)	1	1/17 (5.9%)	1	1/1 (100%)	1
Procedural Pain	1/70 (1.4%)	1	4/91 (4.4%)	4	1/17 (5.9%)	1	0/1 (0%)	0
Metabolism and nutrition disorders
Gout	0/70 (0%)	0	0/91 (0%)	0	1/17 (5.9%)	1	0/1 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/70 (0%)	0	0/91 (0%)	0	1/17 (5.9%)	1	0/1 (0%)	0
Pain in extremity	0/70 (0%)	0	0/91 (0%)	0	1/17 (5.9%)	1	0/1 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oral papilloma	0/70 (0%)	0	0/91 (0%)	0	1/17 (5.9%)	1	0/1 (0%)	0
Nervous system disorders
Hyperaesthesia	0/70 (0%)	0	2/91 (2.2%)	2	2/17 (11.8%)	2	0/1 (0%)	0
Product Issues
Device breakage	0/70 (0%)	0	0/91 (0%)	0	1/17 (5.9%)	1	0/1 (0%)	0
Device failure	1/70 (1.4%)	1	1/91 (1.1%)	1	1/17 (5.9%)	1	0/1 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/70 (0%)	0	0/91 (0%)	0	2/17 (11.8%)	2	0/1 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

We confirm we have the contractual provisions in place which specify that in no event will the study site be allowed to disclose to any third party (or publicly release) any information obtained through the study without the CRO's prior written consent which in turn cannot provide such consent without Sponsor's approval unless such publication is made to satisfy regulatory requirements. The Intellectual Property rights and research results from the present study belong to the Sponsor.