Trial Outcomes & Findings for 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 (NCT NCT02649556)

NCT ID: NCT02649556

Last Updated: 2020-12-04

Results Overview

Concentrations (mg/dL) measured in serum. Mean values are provided as descriptive statistics.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 672 participants
• Primary outcome timeframe: 52 weeks
• Results posted on: 2020-12-04

Participant Flow

Of the 984 subjects (488 in the THS arm and 496 in the CC arm) who were enrolled and randomized into the original study, NCT02396381, 672 subjects were enrolled into the extension study (309 in the THS arm and 363 in the CC arm).

672 subjects enrolled in the extension study; the 857 subjects in the Full Analysis Set - As Exposed (FAS-EX) included subjects for combined analyses from the original six month study who did not enter the extension study. The analysis was performed according to subjects' exposure over the 12 month period as detailed in "Arm/Group" (Reporting Groups) table.

Participant milestones

Measure	THS 2.2 Use This reporting group comprised 230 subjects. The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use This reporting group comprised 424 subjects. The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use This reporting group comprised 152 subjects. The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use This reporting group comprised 51 subjects. "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Overall Study STARTED	230	424	152	51
Overall Study COMPLETED	167	312	102	28
Overall Study NOT COMPLETED	63	112	50	23

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	THS 2.2 Use n=230 Participants The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=424 Participants The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=152 Participants The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use n=51 Participants "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)	Total n=857 Participants Total of all reporting groups
Age, Continuous	43.8 years STANDARD_DEVIATION 9.68 • n=5 Participants	45.2 years STANDARD_DEVIATION 9.54 • n=7 Participants	44.2 years STANDARD_DEVIATION 9.76 • n=5 Participants	44.5 years STANDARD_DEVIATION 8.21 • n=4 Participants	44.6 years STANDARD_DEVIATION 9.55 • n=21 Participants
Sex: Female, Male Female	87 Participants n=5 Participants	180 Participants n=7 Participants	67 Participants n=5 Participants	19 Participants n=4 Participants	353 Participants n=21 Participants
Sex: Female, Male Male	143 Participants n=5 Participants	244 Participants n=7 Participants	85 Participants n=5 Participants	32 Participants n=4 Participants	504 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	17 Participants n=5 Participants	28 Participants n=7 Participants	6 Participants n=5 Participants	2 Participants n=4 Participants	53 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	213 Participants n=5 Participants	396 Participants n=7 Participants	146 Participants n=5 Participants	49 Participants n=4 Participants	804 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	6 Participants n=21 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	5 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	8 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	3 Participants n=21 Participants
Race (NIH/OMB) Black or African American	41 Participants n=5 Participants	73 Participants n=7 Participants	25 Participants n=5 Participants	12 Participants n=4 Participants	151 Participants n=21 Participants
Race (NIH/OMB) White	182 Participants n=5 Participants	338 Participants n=7 Participants	123 Participants n=5 Participants	36 Participants n=4 Participants	679 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	10 Participants n=21 Participants
BMI	27.0 kg/m^2 STANDARD_DEVIATION 4.06 • n=5 Participants	27.1 kg/m^2 STANDARD_DEVIATION 4.13 • n=7 Participants	26.9 kg/m^2 STANDARD_DEVIATION 4.25 • n=5 Participants	26.6 kg/m^2 STANDARD_DEVIATION 4.91 • n=4 Participants	27.0 kg/m^2 STANDARD_DEVIATION 4.18 • n=21 Participants

PRIMARY outcome

Timeframe: 52 weeks

Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Concentrations (mg/dL) measured in serum. Mean values are provided as descriptive statistics.

Outcome measures

Measure	THS 2.2 Use n=168 Participants The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=315 Participants The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=103 Participants The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use n=28 Participants "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Levels of High Density Lipoprotein C (HDL-C).	52.2 mg/dL Interval 49.5 to 54.8	50.6 mg/dL Interval 48.9 to 52.3	54.0 mg/dL Interval 49.7 to 58.4	54.7 mg/dL Interval 49.2 to 60.3

PRIMARY outcome

Timeframe: 52 weeks

Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Total count in blood (GI/L). Mean values are provided as descriptive statistics.

Outcome measures

Measure	THS 2.2 Use n=167 Participants The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=312 Participants The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=102 Participants The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use n=28 Participants "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Levels of White Blood Cells (WBC).	6.73 GI/L Interval 6.47 to 6.99	7.31 GI/L Interval 7.07 to 7.54	7.28 GI/L Interval 6.85 to 7.71	7.57 GI/L Interval 6.85 to 8.29

PRIMARY outcome

Timeframe: 52 weeks

Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Mean values are provided as descriptive statistics.

Outcome measures

Measure	THS 2.2 Use n=153 Participants The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=288 Participants The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=95 Participants The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use n=27 Participants "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1).	93.2 Percent of predicted FEV1 Interval 91.1 to 95.2	92.3 Percent of predicted FEV1 Interval 90.7 to 94.0	91.1 Percent of predicted FEV1 Interval 88.2 to 94.1	95.2 Percent of predicted FEV1 Interval 90.1 to 100.0

PRIMARY outcome

Timeframe: 52 weeks

Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Concentrations (ng/mL) measured in serum. Geometric Mean values are provided as descriptive statistics.

Outcome measures

Measure	THS 2.2 Use n=168 Participants The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=315 Participants The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=103 Participants The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use n=28 Participants "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1).	246 ng/mL Interval 230.0 to 263.0	258 ng/mL Interval 244.0 to 272.0	269 ng/mL Interval 252.0 to 286.0	255 ng/mL Interval 222.0 to 292.0

PRIMARY outcome

Timeframe: 52 weeks

Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.

Outcome measures

Measure	THS 2.2 Use n=166 Participants The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=312 Participants The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=102 Participants The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use n=27 Participants "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Concentrations of 11-dehydrothromboxane B2 (11-DTXB2).	582 pg/mg creat Interval 518.0 to 654.0	586 pg/mg creat Interval 538.0 to 638.0	595 pg/mg creat Interval 510.0 to 693.0	536 pg/mg creat Interval 396.0 to 727.0

PRIMARY outcome

Timeframe: 52 weeks

Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.

Outcome measures

Measure	THS 2.2 Use n=167 Participants The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=312 Participants The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=102 Participants The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use n=27 Participants "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α).	307 pg/mg creat Interval 279.0 to 338.0	327 pg/mg creat Interval 307.0 to 348.0	326 pg/mg creat Interval 293.0 to 362.0	364 pg/mg creat Interval 289.0 to 458.0

PRIMARY outcome

Timeframe: 52 weeks

Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.

Outcome measures

Measure	THS 2.2 Use n=167 Participants The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=312 Participants The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=102 Participants The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use n=27 Participants "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL).	133 pg/mg creat Interval 105.0 to 168.0	269 pg/mg creat Interval 238.0 to 305.0	253 pg/mg creat Interval 207.0 to 309.0	304 pg/mg creat Interval 214.0 to 431.0

PRIMARY outcome

Timeframe: 52 weeks

Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Carboxyhemoglobin (COHb) is assayed from whole blood. Expressed as % of saturation of hemoglobin. Geometric Mean values are provided as descriptive statistics.

Outcome measures

Measure	THS 2.2 Use n=141 Participants The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=257 Participants The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=86 Participants The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.)	Other Use n=26 Participants "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Levels of Carboxyhemoglobin (COHb).	2.59 percent change Interval 2.24 to 3.01	4.06 percent change Interval 3.77 to 4.38	3.92 percent change Interval 3.44 to 4.46	5.22 percent change Interval 4.47 to 6.11

Adverse Events

THS 2.2 Use

Serious events: 12 serious events

Other events: 40 other events

Deaths: 1 deaths

CC Use

Serious events: 15 serious events

Other events: 87 other events

Deaths: 1 deaths

Dual Use

Serious events: 1 serious events

Other events: 26 other events

Deaths: 0 deaths

Other Use

Serious events: 1 serious events

Other events: 13 other events

Deaths: 1 deaths

Serious adverse events

Measure	THS 2.2 Use n=241 participants at risk The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=434 participants at risk The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=159 participants at risk The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.) .	Other Use n=106 participants at risk "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Infections and infestations Appendicitis with Peritonitis	0.41% 1/241 • Number of events 2 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Infections and infestations Cellulitis	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Infections and infestations Cellulitis staphylococcal	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Infections and infestations Epiglottitis	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Infections and infestations Influenza	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Infections and infestations Pneumonia mycoplasmal	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Infections and infestations Tooth infection	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Infections and infestations Urosepsis with Nephrolithiasis	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 2 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Injury, poisoning and procedural complications Head injury with Seizure	0.41% 1/241 • Number of events 2 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Injury, poisoning and procedural complications Hip fracture	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Injury, poisoning and procedural complications Laceration	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Injury, poisoning and procedural complications Multiple fractures	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.63% 1/159 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Injury, poisoning and procedural complications Rib fracture, Clavicle fracture, Pulmonary contusion, Pleural effusion, and Traumatic Hemothorax	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 5 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Psychiatric disorders Alchohol abuse	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.94% 1/106 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Psychiatric disorders Completed suicide	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Psychiatric disorders Suicidal ideation	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 2 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to small intestine with Anaemia	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.94% 1/106 • Number of events 2 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Papillary thyroid cancer	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Nervous system disorders Transient ischaemic attack	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Musculoskeletal and connective tissue disorders Costochondritis	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Musculoskeletal and connective tissue disorders Vertebral osteophyte with Cervical Myelopathy	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 2 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Cardiac disorders Acute myocardial infarction	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Gastrointestinal disorders Pancreatitis chronic	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
General disorders Death	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Reproductive system and breast disorders Menorrhagia	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Social circumstances Bereavement and Adjustment Disorder with Depressed Mood	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.94% 1/106 • Number of events 2 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Vascular disorders Peripheral ischaemia	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Injury, poisoning and procedural complications Foot Fracture	0.41% 1/241 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/434 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/159 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Infections and infestations Pyelonephritis Acute	0.00% 0/241 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.23% 1/434 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.63% 1/159 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.00% 0/106 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.

Other adverse events

Measure	THS 2.2 Use n=241 participants at risk The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on \>50% of days in the analysis period.)	CC Use n=434 participants at risk The "CC use" product use category was defined as THS use of less than 1% over the entire analysis period. (≥1 THS 2.2 or CC use, and \<1% THS 2.2 use over the entire analysis period and \<1% THS 2.2 use on ≥ 50% of days in the analysis period.)	Dual Use n=159 participants at risk The "Dual use" product use category was defined as THS use of less than 70% over the entire analysis period. (≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 \<70% over the analysis period, or THS 2.2-use and CC use categories do not apply to 50% of these days.) .	Other Use n=106 participants at risk "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Infections and infestations Upper respiratory tract infection	8.7% 21/241 • Number of events 25 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	9.2% 40/434 • Number of events 45 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	6.9% 11/159 • Number of events 14 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	7.5% 8/106 • Number of events 9 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Vascular disorders Hypertension	3.7% 9/241 • Number of events 13 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	6.0% 26/434 • Number of events 40 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	5.7% 9/159 • Number of events 11 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	3.8% 4/106 • Number of events 5 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Investigations Blood triglycerides increased	4.1% 10/241 • Number of events 10 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	6.0% 26/434 • Number of events 28 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	3.8% 6/159 • Number of events 6 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.	0.94% 1/106 • Number of events 1 • 18 months (from March 2015 to September 2016) Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.

Additional Information

Christelle Haziza

Philip Morris Products S.A.

Phone: +41 58 242 11 11

Email: christelle.haziza@pmi.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER