Trial Outcomes & Findings for Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome (NCT NCT00429364)

NCT ID: NCT00429364

Last Updated: 2025-03-07

Results Overview

The rate of aortic root enlargement, expressed as the annual change in the maximum aortic-root-diameter z score indexed to body-surface area over a 3-year period following randomization

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 608 participants
• Primary outcome timeframe: Up to 3 years following randomization.
• Results posted on: 2025-03-07

Participant Flow

From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants into the study.

For subjects on prophylactic therapy with atenolol or other BB, ARB, ACEi, or calcium-channel blocker, before the study, the drug will be weaned over a 14-day period. After that, a drug washout period of 14-21 days will take place before baseline assessment and randomization.

Participant milestones

Measure	Atenolol Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Overall Study STARTED	303	305
Overall Study COMPLETED	271	272
Overall Study NOT COMPLETED	32	33

Reasons for withdrawal

Measure	Atenolol Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Overall Study Withdrawal by Subject	11	5
Overall Study Physician Decision	4	2
Overall Study Lost to Follow-up	7	6
Overall Study Death	0	1
Overall Study Underwent aortic root surgery	10	18
Overall Study Pregnancy	0	1

Baseline Characteristics

Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome

Baseline characteristics by cohort

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).	Total n=608 Participants Total of all reporting groups
Age, Continuous	11.5 years STANDARD_DEVIATION 6.5 • n=5 Participants	11.0 years STANDARD_DEVIATION 6.2 • n=7 Participants	11.2 years STANDARD_DEVIATION 6.3 • n=5 Participants
Age, Customized Young adult	76 participants n=5 Participants	75 participants n=7 Participants	151 participants n=5 Participants
Age, Customized Child	227 participants n=5 Participants	230 participants n=7 Participants	457 participants n=5 Participants
Sex: Female, Male Female	123 Participants n=5 Participants	119 Participants n=7 Participants	242 Participants n=5 Participants
Sex: Female, Male Male	180 Participants n=5 Participants	186 Participants n=7 Participants	366 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	36 Participants n=5 Participants	46 Participants n=7 Participants	82 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	266 Participants n=5 Participants	259 Participants n=7 Participants	525 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White	266 participants n=5 Participants	260 participants n=7 Participants	526 participants n=5 Participants
Race/Ethnicity, Customized Black	21 participants n=5 Participants	25 participants n=7 Participants	46 participants n=5 Participants
Race/Ethnicity, Customized Asian	6 participants n=5 Participants	10 participants n=7 Participants	16 participants n=5 Participants
Race/Ethnicity, Customized Other	10 participants n=5 Participants	10 participants n=7 Participants	20 participants n=5 Participants
Presence of causal FBN1 mutation Yes	93 participants n=5 Participants	88 participants n=7 Participants	181 participants n=5 Participants
Presence of causal FBN1 mutation No	9 participants n=5 Participants	15 participants n=7 Participants	24 participants n=5 Participants
Presence of causal FBN1 mutation Unknown	201 participants n=5 Participants	202 participants n=7 Participants	403 participants n=5 Participants
Family history of Marfan Yes	180 participants n=5 Participants	181 participants n=7 Participants	361 participants n=5 Participants
Family history of Marfan No	115 participants n=5 Participants	109 participants n=7 Participants	224 participants n=5 Participants
Family history of Marfan Unknown	8 participants n=5 Participants	15 participants n=7 Participants	23 participants n=5 Participants
Maximum aortic-root diameter, cm	3.4 centimeter STANDARD_DEVIATION 0.7 • n=5 Participants	3.4 centimeter STANDARD_DEVIATION 0.7 • n=7 Participants	3.4 centimeter STANDARD_DEVIATION 0.7 • n=5 Participants
Maximum aortic-root diameter z-score	4.0 z-score n=5 Participants	4.0 z-score n=7 Participants	4.0 z-score n=5 Participants
Maximum aortic-root diameter z-score ≥z-score of 4.5	106 participants n=5 Participants	114 participants n=7 Participants	220 participants n=5 Participants
Maximum aortic-root diameter z-score <z-score of 4.5	197 participants n=5 Participants	191 participants n=7 Participants	388 participants n=5 Participants
Had medical history of cardiac surgery Yes	6 participants n=5 Participants	6 participants n=7 Participants	12 participants n=5 Participants
Had medical history of cardiac surgery No	297 participants n=5 Participants	299 participants n=7 Participants	596 participants n=5 Participants
Had medical history of cardiovascular disorder Yes	39 participants n=5 Participants	36 participants n=7 Participants	75 participants n=5 Participants
Had medical history of cardiovascular disorder No	264 participants n=5 Participants	269 participants n=7 Participants	533 participants n=5 Participants
Prior use of beta-blocker Yes	173 participants n=5 Participants	171 participants n=7 Participants	344 participants n=5 Participants
Prior use of beta-blocker No	130 participants n=5 Participants	134 participants n=7 Participants	264 participants n=5 Participants
Had medical history of endocrine disorder Yes	7 participants n=5 Participants	0 participants n=7 Participants	7 participants n=5 Participants
Had medical history of endocrine disorder No	296 participants n=5 Participants	305 participants n=7 Participants	601 participants n=5 Participants
Had medical history of neurodevelopmental disorder Yes	56 participants n=5 Participants	61 participants n=7 Participants	117 participants n=5 Participants
Had medical history of neurodevelopmental disorder No	247 participants n=5 Participants	244 participants n=7 Participants	491 participants n=5 Participants
Had medical history of psychiatric disorder Yes	23 participants n=5 Participants	16 participants n=7 Participants	39 participants n=5 Participants
Had medical history of psychiatric disorder No	280 participants n=5 Participants	289 participants n=7 Participants	569 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 3 years following randomization.

The rate of aortic root enlargement, expressed as the annual change in the maximum aortic-root-diameter z score indexed to body-surface area over a 3-year period following randomization

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Body-surface-area-adjusted Z-score	-0.139 z-score/year Standard Error 0.013	-0.107 z-score/year Standard Error 0.013

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

The rate of change in the absolute dimension of the aortic root over a 3-year period following randomization

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension	0.069 cm/year Standard Error 0.004	0.075 cm/year Standard Error 0.004

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants whose ascending-aorta-diameter z scores were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=296 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Ascending-aorta-diameter Z Score, Adjusted by Body-surface-area.	-0.140 z-score/year Standard Error 0.013	-0.114 z-score/year Standard Error 0.013

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants whose absolute dimensions of the ascending aorta were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=296 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in the Absolute Diameter of the Ascending Aorta	0.039 cm/year Standard Error 0.004	0.044 cm/year Standard Error 0.004

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants whose aortic-annulus-diameter z scores were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=302 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=304 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Aortic-annulus-diameter Z Score, Adjusted by Body-surface Area	-0.279 z-score/year Standard Error 0.018	-0.175 z-score/year Standard Error 0.018

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants whose absolute dimensions of the aortic annulus were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=302 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=304 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in the Absolute Diameter of the Aortic Annulus	0.015 cm/year Standard Error 0.003	0.030 cm/year Standard Error 0.003

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants whose total aortic proximal regurgitant jet area indexes were measured at baseline or at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=301 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Total Aortic Proximal Regurgitant Jet Area Indexed to Body-surface-area	0.005 (mm^2/m^2)/year Standard Error 0.003	0.001 (mm^2/m^2)/year Standard Error 0.003

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Weight	0.239 kg/year Standard Error 0.153	0.229 kg/year Standard Error 0.154

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who were between 0-20 years of age and whose weight-for-age z-scores were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=270 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=278 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Weight-for-age Z-score	0.011 z-score/year Standard Error 0.013	0.019 z-score/year Standard Error 0.013

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who were \<120 cm in heights and whose weight-for-height z-scores were measured at baseline or at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=58 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=61 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Weight-for-height Z-score	-0.001 z-score/year Standard Error 0.072	-0.157 z-score/year Standard Error 0.076

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants whose heights were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Height	0.822 cm/year Standard Error 0.204	0.935 cm/year Standard Error 0.202

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who were between 0-20 years of age and whose heights were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=269 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=272 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Height-for-age Z-score	0.046 z-score/year Standard Error 0.013	0.019 z-score/year Standard Error 0.013

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants whose body mass indexes were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=283 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=295 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Body Mass Index	0.063 kg/m^2 per year Standard Error 0.044	0.076 kg/m^2 per year Standard Error 0.044

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who were between 0-20 years of age and whose body mass index for age z-scores were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=250 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=263 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Body Mass Index for Age Z-score	0.007 z-score/year Standard Error 0.022	0.021 z-score/year Standard Error 0.022

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants whose arm span to height ratios were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=301 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Arm Span to Height Ratio	0.001 1/year Standard Error 0.001	0.001 1/year Standard Error 0.001

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants whose upper to lower segment ratios were measured at baseline and at any of the follow-up visits.

Outcome measures

Measure	Atenolol n=301 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=301 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Annual Rate of Change in Upper to Lower Segment Ratio	-0.014 1/year Standard Error 0.002	-0.015 1/year Standard Error 0.002

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who received the treatment

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Number of Participants With Aortic Dissection.	0 participants	2 participants

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who received the treatment

Percentage of participants who had aortic dissection over a 3-year period following randomization.

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Event Rate of Aortic Dissection.	0 Percentage of participants Interval 0.0 to 0.0	0.7 Percentage of participants Interval 0.2 to 2.7

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who received the treatment

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Number of Participants With Aortic-root Surgery.	10 participants	18 participants

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who received the treatment

Percentage of participants who had aortic-root surgery over a 3-year period following randomization.

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Event Rate of Aortic-Root Surgery	3.4 Percentage of participants Interval 1.9 to 6.3	6.0 Percentage of participants Interval 3.8 to 9.4

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who received the treatment

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Number of Death.	0 participants	1 participants

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who received the treatment

Percentage of participants who died over a 3-year period following randomization.

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Event Rate of Death	0 Percentage of participants Interval 0.0 to 0.0	0.3 Percentage of participants Interval 0.0 to 2.4

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who received the treatment

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Number of Participants With the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death.	10 participants	19 participants

SECONDARY outcome

Timeframe: Up to 3 years following randomization.

Population: All randomized participants who received the treatment

Percentage of participants who had aortic dissection, aortic-root surgery or death over a 3-year period following randomization

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Event Rate of the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death.	3.4 Percentage of participants Interval 1.9 to 6.3	6.4 Percentage of participants Interval 4.1 to 9.8

SECONDARY outcome

Timeframe: At baseline

Population: All randomized participants.

Outcome measures

Measure	Atenolol n=303 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Adverse Drug Reactions Reported at the Baseline Visit Headache, any severity	112 participants	114 participants
Adverse Drug Reactions Reported at the Baseline Visit Headache, bothersome	10 participants	10 participants
Adverse Drug Reactions Reported at the Baseline Visit Fatigue, any severity	84 participants	105 participants
Adverse Drug Reactions Reported at the Baseline Visit Fatigue, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Mood alterations, any severity	54 participants	49 participants
Adverse Drug Reactions Reported at the Baseline Visit Mood alterations, bothersome	7 participants	3 participants
Adverse Drug Reactions Reported at the Baseline Visit Behavior changes, any severity	21 participants	23 participants
Adverse Drug Reactions Reported at the Baseline Visit Behavior changes, bothersome	2 participants	1 participants
Adverse Drug Reactions Reported at the Baseline Visit Insomnia, any severity	60 participants	61 participants
Adverse Drug Reactions Reported at the Baseline Visit Insomnia, bothersome	2 participants	2 participants
Adverse Drug Reactions Reported at the Baseline Visit Nightmares, any severity	52 participants	53 participants
Adverse Drug Reactions Reported at the Baseline Visit Nightmares, bothersome	2 participants	3 participants
Adverse Drug Reactions Reported at the Baseline Visit Dizziness with standing, any severity	60 participants	58 participants
Adverse Drug Reactions Reported at the Baseline Visit Dizziness with standing, bothersome	0 participants	2 participants
Adverse Drug Reactions Reported at the Baseline Visit Dizziness - other, any severity	25 participants	27 participants
Adverse Drug Reactions Reported at the Baseline Visit Dizziness - other, bothersome	0 participants	1 participants
Adverse Drug Reactions Reported at the Baseline Visit Fainting with loss of consciousness, any severity	5 participants	9 participants
Adverse Drug Reactions Reported at the Baseline Visit Fainting with loss of consciousness, bothersome	5 participants	9 participants
Adverse Drug Reactions Reported at the Baseline Visit Palpitations, any severity	60 participants	53 participants
Adverse Drug Reactions Reported at the Baseline Visit Palpitations, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Chest pain, any severity	54 participants	58 participants
Adverse Drug Reactions Reported at the Baseline Visit Chest pain, bothersome	1 participants	5 participants
Adverse Drug Reactions Reported at the Baseline Visit Dyspnea, any severity	43 participants	38 participants
Adverse Drug Reactions Reported at the Baseline Visit Dyspnea, bothersome	3 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Wheezing, any severity	15 participants	14 participants
Adverse Drug Reactions Reported at the Baseline Visit Wheezing, bothersome	2 participants	1 participants
Adverse Drug Reactions Reported at the Baseline Visit Upper respiratory/Nasal congestion, any severity	106 participants	117 participants
Adverse Drug Reactions Reported at the Baseline Visit Upper respiratory/Nasal congestion, bothersome	0 participants	2 participants
Adverse Drug Reactions Reported at the Baseline Visit Cough, any severity	47 participants	59 participants
Adverse Drug Reactions Reported at the Baseline Visit Cough, bothersome	1 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Dysgeusia, any severity	10 participants	3 participants
Adverse Drug Reactions Reported at the Baseline Visit Dysgeusia, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Stomach pain/Indigestion, any severity	47 participants	61 participants
Adverse Drug Reactions Reported at the Baseline Visit Stomach pain/Indigestion, bothersome	0 participants	1 participants
Adverse Drug Reactions Reported at the Baseline Visit Nausea, any severity	30 participants	35 participants
Adverse Drug Reactions Reported at the Baseline Visit Nausea, bothersome	1 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Vomiting, any severity	23 participants	23 participants
Adverse Drug Reactions Reported at the Baseline Visit Vomiting, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Diarrhea, any severity	35 participants	43 participants
Adverse Drug Reactions Reported at the Baseline Visit Diarrhea, bothersome	1 participants	1 participants
Adverse Drug Reactions Reported at the Baseline Visit Constipation, any severity	44 participants	35 participants
Adverse Drug Reactions Reported at the Baseline Visit Constipation, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Vascular (hands, feet), any severity	35 participants	34 participants
Adverse Drug Reactions Reported at the Baseline Visit Vascular (hands, feet), bothersome	0 participants	1 participants
Adverse Drug Reactions Reported at the Baseline Visit Muscle pain or Cramps, any severity	59 participants	58 participants
Adverse Drug Reactions Reported at the Baseline Visit Muscle pain or Cramps, bothersome	2 participants	4 participants
Adverse Drug Reactions Reported at the Baseline Visit Back pain, any severity	60 participants	67 participants
Adverse Drug Reactions Reported at the Baseline Visit Back pain, bothersome	3 participants	2 participants
Adverse Drug Reactions Reported at the Baseline Visit Periorbital edema, any severity	13 participants	15 participants
Adverse Drug Reactions Reported at the Baseline Visit Periorbital edema, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Pedal edema, any severity	2 participants	3 participants
Adverse Drug Reactions Reported at the Baseline Visit Pedal edema, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported at the Baseline Visit Other, any severity	21 participants	16 participants
Adverse Drug Reactions Reported at the Baseline Visit Other, bothersome	3 participants	1 participants

SECONDARY outcome

Timeframe: From 6 months to 3 years following randomization.

Population: All subjects who had any of the follow-up visits after 6 months post-randomization.

Outcome measures

Measure	Atenolol n=291 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=297 Participants Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Other, any severity	105 participants	108 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Headache, any severity	202 participants	208 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Headache, bothersome	27 participants	20 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Fatigue, any severity	152 participants	153 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Fatigue, bothersome	7 participants	5 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Mood alterations, any severity	89 participants	86 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Mood alterations, bothersome	13 participants	13 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Behavior changes, any severity	51 participants	46 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Behavior changes, bothersome	5 participants	8 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Insomnia, any severity	108 participants	107 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Insomnia, bothersome	6 participants	4 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Nightmares, any severity	100 participants	94 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Nightmares, bothersome	7 participants	4 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Dizziness with standing, any severity	119 participants	105 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Dizziness with standing, bothersome	6 participants	0 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Dizziness - other, any severity	60 participants	61 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Dizziness - other, bothersome	2 participants	0 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Fainting with loss of consciousness, any severity	21 participants	16 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Fainting with loss of consciousness, bothersome	21 participants	16 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Palpitations, any severity	86 participants	101 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Palpitations, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Chest pain, any severity	114 participants	106 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Chest pain, bothersome	14 participants	1 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Dyspnea, any severity	75 participants	72 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Dyspnea, bothersome	1 participants	3 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Wheezing, any severity	36 participants	32 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Wheezing, bothersome	2 participants	5 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Upper respiratory/Nasal congestion, any severity	188 participants	186 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Upper respiratory/Nasal congestion, bothersome	3 participants	3 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Cough, any severity	117 participants	113 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Cough, bothersome	1 participants	1 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Dysgeusia, any severity	29 participants	16 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Dysgeusia, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Stomach pain/Indigestion, any severity	119 participants	121 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Stomach pain/Indigestion, bothersome	2 participants	8 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Nausea, any severity	99 participants	78 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Nausea, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Vomiting, any severity	81 participants	75 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Vomiting, bothersome	1 participants	2 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Diarrhea, any severity	94 participants	90 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Diarrhea, bothersome	1 participants	3 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Constipation, any severity	77 participants	66 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Constipation, bothersome	1 participants	0 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Vascular (hands, feet), any severity	73 participants	66 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Vascular (hands, feet), bothersome	0 participants	0 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Muscle pain or Cramps, any severity	148 participants	124 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Muscle pain or Cramps, bothersome	6 participants	7 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Back pain, any severity	137 participants	134 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Back pain, bothersome	5 participants	8 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Periorbital edema, any severity	22 participants	27 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Periorbital edema, bothersome	0 participants	1 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Pedal edema, any severity	6 participants	5 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Pedal edema, bothersome	0 participants	0 participants
Adverse Drug Reactions Reported During Routine Follow-up Surveillance Other, bothersome	10 participants	12 participants

Adverse Events

Atenolol

Serious events: 27 serious events

Other events: 135 other events

Deaths: 0 deaths

Losartan

Serious events: 33 serious events

Other events: 121 other events

Deaths: 0 deaths

Serious adverse events

Measure	Atenolol n=303 participants at risk Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 participants at risk Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Blood and lymphatic system disorders Blood/bone marrow(sickle cell crisis)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Atrial fibrillation	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 4 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Left ventricular failure	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Pericarditis NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Supraventricular tachycardia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Valvular heart disease NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.98% 3/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Ventricular tachycardia	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Retinal detachment	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Abdominal pain NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Diarrhoea NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Pancreatitis NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Chest pain	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Pyrexia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Immune system disorders Autoimmune disorder NOS	0.33% 1/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Immune system disorders Hypersensitivity NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Immune system disorders Serum sickness	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Cellulitis	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Pneumonia	1.3% 4/303 • Number of events 5 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Respiratory tract infection NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Soft tissue infection NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Urinary tract infection NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Viral infection	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Wound - snake bite	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Wound infection	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Injury, poisoning and procedural complications Haematoma	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Injury, poisoning and procedural complications Vascular: vessel injury-artery, other NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Investigations Weight decreased	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Metabolism and nutrition disorders Dehydration	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Scoliosis	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Cerebral abscess	0.33% 1/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Convulsions NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Dizziness	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Headache	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Pregnancy, puerperium and perinatal conditions Pregnancy	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Agitation	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Anxiety	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Depression	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Psychosis aggravated	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Renal and urinary disorders Urethral obstruction	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Reproductive system and breast disorders Uterine haemorrhage	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Pneumonitis NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Pneumothorax NOS	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.6% 5/305 • Number of events 7 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Pulmonary/upper respiratory-other	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Culture wound negative	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Surgical and medical procedures Aortic root enlargement	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Surgical and medical procedures Cardiac General-other: mitral valve replacement	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Vascular disorders Thrombosis	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.

Other adverse events

Measure	Atenolol n=303 participants at risk Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Losartan n=305 participants at risk Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).
Blood and lymphatic system disorders Anemia	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Blood and lymphatic system disorders Haemoglobin	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Blood and lymphatic system disorders Lymph node pain	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Cardiac General - Other - Murmur	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Cardiac General - other - nonresponsive and pale	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Palpitations	3.0% 9/303 • Number of events 9 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	3.3% 10/305 • Number of events 10 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Sinus tachycardia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Cardiac disorders Supraventricular tachycardia	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Ear and labyrinth disorders Auditory/ear-other	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Ear and labyrinth disorders Hypersensitivity to sound	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Endocrine disorders Hot flushes NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Conjunctivitis	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Eyelid function disorder NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Lacrimation increased	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Ocular-other (L eye burning/redness 4 mos. s/p lensectomy with lens insertion)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Ocular-other (right eye hemorrhage)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Ocular/Visual - Squinting of OS to see things more clearly.	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Ocular/visual-other (redness and itching of eyes)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Photopsia	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Eye disorders Vision blurred	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Abdominal pain NOS	2.3% 7/303 • Number of events 7 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	2.3% 7/305 • Number of events 7 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Constipation	1.3% 4/303 • Number of events 4 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Diarrhoea NOS	1.3% 4/303 • Number of events 6 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Dysgeusia	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Dyspepsia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Dysphagia	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Gastrointestinal - HERNIA	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Haemorrhoids	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Intestinal Hernia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Nausea	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Oesophageal pain	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Oral pain	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Oseophagitis NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Peridontal disorder NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Stomach discomfort	1.7% 5/303 • Number of events 5 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.98% 3/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Tooth disorder NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Gastrointestinal disorders Vomiting NOS	0.66% 2/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.6% 5/305 • Number of events 7 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Bilateral pedal edema	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Chest pain	5.3% 16/303 • Number of events 18 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	5.6% 17/305 • Number of events 18 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Constitutional symptoms -other(flu)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Constitutional symptoms-other (unusual dreams)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Constitutional-other (general body cold sensation)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Edema:head and neck	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Edema:limb	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Falling asleep	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Fatigue	5.9% 18/303 • Number of events 19 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	3.6% 11/305 • Number of events 12 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Hypothermia	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Influenza-like illness	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Nightmare	2.3% 7/303 • Number of events 8 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	4.3% 13/305 • Number of events 13 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Pain-other (right hip pain)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Pain-other:chest pain/costochondritis (diagnosed in ER as costochondritis)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
General disorders Pyrexia	1.3% 4/303 • Number of events 6 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Immune system disorders Allergy/Immunology - Other (rash)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Immune system disorders Hypersensitivity NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.98% 3/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Abcessed tooth	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Bronchitis NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Gum infection	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection - Eye NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection - Other - Parvovirus	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection Pharnyx	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection with unknown ANC-eye, NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection with unknown ANC-middle ear	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection with unknown ANC-pharynx	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection with unknown ANC-sinus	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection with unknown ANC-upper ariway NOS	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection-bladder(urinary)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection-other (sinus, bronchitis, pharyngeal)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection-other (skin on foot)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection-other-Lyme disease	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Infection: Dental - Tooth	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Middle ear infection	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Mononucleosis	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Pneumonia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.3% 4/305 • Number of events 4 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Shingles	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Sinus infection	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Sinusitis NOS	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Urinary tract infection NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Vaginitis	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Infections and infestations Viral infection coxsackievirus	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Injury, poisoning and procedural complications Haematoma	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Investigations Neutrophil count	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Investigations Weight decreased	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Metabolism and nutrition disorders Anorexia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.98% 3/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Metabolism and nutrition disorders Dehydration	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Arthralgia	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.98% 3/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Back pain	2.6% 8/303 • Number of events 8 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	2.6% 8/305 • Number of events 8 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Chest wall pain	2.0% 6/303 • Number of events 6 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.6% 5/305 • Number of events 5 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Joint disorder NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Joint effusion	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Msk/soft tissue, other (Nodule on back)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Muscle weakness, generalized or specific area	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Musculoskeletal (other) (loose joints-causing pain)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Musculoskeletal/soft tissue - other (patellar dislocation)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Musculoskeletal/soft tissue-other (Bursa on left shoulder blade due to back brace)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Musculoskeletal/soft tissue-other (nodule on back)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Musculoskeletal/soft tissue-other( left arm pain)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Myalgia	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	3.9% 12/305 • Number of events 12 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Neck pain	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Musculoskeletal and connective tissue disorders Pain in extremity	1.7% 5/303 • Number of events 5 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.3% 4/305 • Number of events 4 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Cognitive disorder	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Convulsions NOS	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Dizziness	9.6% 29/303 • Number of events 29 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	5.6% 17/305 • Number of events 18 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Dizziness upon standing	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Extrapyramidal disorder	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Headache	10.2% 31/303 • Number of events 36 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	5.9% 18/305 • Number of events 19 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Memory impairment	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Mental status changes	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Neuralgia NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Neurology - other	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Neurology-other (panic attacks)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Panick attack	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Syncope	4.3% 13/303 • Number of events 14 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	3.0% 9/305 • Number of events 9 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Syncope vasovagal	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Nervous system disorders Tremor	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Pregnancy, puerperium and perinatal conditions Sexual/reproductive function-other (4.5 cm cyst on right ovary)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Pregnancy, puerperium and perinatal conditions Sexual/reproductive function-other (abnormal pap smear)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Agitation	3.6% 11/303 • Number of events 12 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.98% 3/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Anxiety	1.7% 5/303 • Number of events 5 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Confusional state	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Depression	3.0% 9/303 • Number of events 11 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Insomnia	3.3% 10/303 • Number of events 10 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	3.9% 12/305 • Number of events 12 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Mood alteration	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Neurology-other (expression of anger and sadness)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Neurology-other (irritability)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Psychiatric disorders Personality change	2.0% 6/303 • Number of events 6 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.98% 3/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Renal and urinary disorders Chromaturia	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Renal and urinary disorders Pollakiuria	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Renal and urinary disorders Renal/genitourinary-increased urinary frequency, daytime only, associated w/ po water intake	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Renal and urinary disorders Urinary incontinence	0.33% 1/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Renal and urinary disorders Urogenital haemorrhage	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Reproductive system and breast disorders Gynaecomastia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Reproductive system and breast disorders Vaginal haemorrhage	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.3% 4/305 • Number of events 4 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Cough	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.3% 4/305 • Number of events 4 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.0% 6/303 • Number of events 6 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.6% 5/305 • Number of events 5 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Epistaxis	3.0% 9/303 • Number of events 9 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	2.3% 7/305 • Number of events 7 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Hemorrhage/Bleeding - other	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.98% 3/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Nasal conjestion/inf with unk ANC upper airway NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Obstructive sleep apnea	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Pulmonary/upper respiratory-other	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Respiratory, thoracic and mediastinal disorders Upper Respiratory - Other	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Acne NOS	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Alopecia	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.3% 4/305 • Number of events 4 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Burn on skin	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Decubitus ulcer	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Derm/skin-other (Poison Ivy)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Derm/skin-other (mild chin rash)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Derm/skin-other (possible aczema)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Derm/skin-other (worsening of underlying hand skin disorder)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Dermatitis exfoliative NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Dermatology - other - Erythema Nodosum	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Dermatology/skin-other (Poison Ivy)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Dermatology/skin-other (cervical dysplasia)	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Dermatology/skin-other (papules on legs)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Dermatology/skin-other (rash: nonspecific maculopapular rash)	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Ecchymosis	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Eczema	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Erythema multiforme	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Pruritus	0.99% 3/303 • Number of events 4 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Rash	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Rash on torso and neck	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Skin irritation	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.66% 2/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Sweating increased	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Skin and subcutaneous tissue disorders Urticaria NOS	0.99% 3/303 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	1.3% 4/305 • Number of events 4 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Surgical and medical procedures Cardiac general-chest tightness	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Vascular disorders Flushing	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Vascular disorders Hypertension NOS	0.33% 1/303 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.00% 0/305 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Vascular disorders Hypotension NOS	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.98% 3/305 • Number of events 3 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Vascular disorders Raynaud's Phenomena	0.66% 2/303 • Number of events 2 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.
Vascular disorders Thrombosis	0.00% 0/303 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.	0.33% 1/305 • Number of events 1 • The adverse event (AE) data were collected since randomization till the end of the study, for up to 3 years. Serious AEs and important medical events (including pregnancy) were reported within 24 hours of first knowledge of event; Non-Serious AEs were reported within 7 calendar days of first knowledge of event.

Additional Information

Paul Stark, PhD

New England Research Institutes, Inc.

Phone: 617-972-3362

Email: pstark@neriscience.com

Results disclosure agreements

• Principal investigator is a sponsor employee All publications and presentations resulting from studies from the PHN Network must be approved by the Publications and Presentations Committee before submission. The Sponsor (NERI) and funding agency (NHLBI) both are represented on the P\&P Committee along with Network Investigators. Members of the P\&P Committee can recommend changes to publications.
• Publication restrictions are in place

Restriction type: OTHER