The Efficacy and Safety of Initial Triple Versus Initial... | NCT02558231

Label	Type	Description	Intervention Names
Triple oral combination treatment	Experimental	Macitentan, tadalafil, and selexipag	Drug: Macitentan Drug: Tadalafil Drug: Selexipag
Dual oral combination treatment	Placebo Comparator	Macitentan, tadalafil, and placebo	Drug: Macitentan Drug: Tadalafil

Name	Type	Description	Arm Group Labels	Other Names
Macitentan	Drug	Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d.	Dual oral combination treatment Triple oral combination treatment

Measure	Description	Time Frame
Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR)	Change from baseline to Week 26 in PVR was expressed as the ratio of Week 26 to baseline PVR value (Week 26 divided by baseline) using re-calculated PVR. PVR was determined by right heart catheterization (RHC). A geometric least square mean ratio of Week 26 to baseline PVR less than (<) 1 corresponds to a reduction in PVR from baseline. Missing values were imputed using a last observation carried forward (LOCF) approach.	Baseline, Week 26

Measure	Description	Time Frame
Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD)	The change from baseline to Week 26 in 6MWD was calculated as Week 26 minus baseline. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. Missing values were imputed using a LOCF approach.	Baseline, Week 26

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Signed informed consent prior to any study-mandated procedure.
Male or female ≥ 18 and ≤ 75 years of age at screening.
Initial PAH diagnosis < 6 months prior to enrollment.
RHC performed between Day -28 and Day 1, meeting all the following criteria:
- Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg.
- Pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg.
- PVR ≥ 480 dyn•sec/cm5 (≥ 6 Wood Units).
- Negative vasoreactivity test mandatory in idiopathic, heritable, and drug/toxin induced PAH (at this or a previous RHC).
Symptomatic PAH belonging to one of the following subgroups:
- Idiopathic.
- Heritable.
- Drug or toxin induced.
- Associated with one of the following: connective tissue disease; HIV infection; congenital heart disease.
6-minute walk distance (6MWD) ≥ 50 m at screening.
Women of childbearing potential must not be pregnant, must perform regular pregnancy tests, and use reliable contraception.

Exclusion Criteria:

Any PAH-specific drug therapy at any time.
Cardio pulmonary rehabilitation program based on exercise (planned, or started ≤ 12 weeks prior to Day 1).
Body mass index (BMI) > 40 kg/m2 at screening.
Presence of three or more of the following risk factors for heart failure with preserved ejection fraction at screening:
- BMI > 30 kg/m2.
- Diabetes mellitus of any type.
- Essential hypertension.
- Coronary artery disease, i.e., any of the following:
  - History of stable angina or
  - More than 50% stenosis in a coronary artery (by coronary angiography) or
  - History of myocardial infarction or
  - History of or planned coronary artery bypass grafting and/or coronary artery stenting.
Acute myocardial infarction ≤ 12 weeks prior to screening.
Stroke ≤ 12 weeks prior to screening.
Known permanent atrial fibrillation.
SBP < 90 mmHg at screening or Day 1.
Ongoing or planned treatment with organic nitrates and/or doxazosin.
Presence of one or more of the following signs of relevant lung disease at any time up to screening:
- Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
- Forced vital capacity (FVC) < 60% of predicted.
- Forced expiratory volume in one second (FEV1) < 60% of predicted.
Known or suspected pulmonary veno-occlusive disease (PVOD).
Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × upper limit of the normal range (ULN) accompanied by aspartate aminotransferase (AST) > ULN (assessed by central laboratory at screening); and/or Child-Pugh Class C.
Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN (assessed by central laboratory at screening).
Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m2) assessed by central laboratory at screening.
Ongoing or planned dialysis.
Hemoglobin < 100 g/L assessed by central laboratory at screening.
Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
Loss of vision in one or both eyes because of non-arteritic ischemic optic neuropathy (NAION).
Treatment with strong inducers of cytochrome P450 3A4 (CYP3A4; e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John's wort) ≤ 28 days prior to Day 1.
Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) and/or strong inhibitors of CYP2C8 (e.g., gemfibrozil) ≤ 28 days prior to Day 1.
Treatment with another investigational drug (planned, or taken ≤ 12 weeks prior to Day 1).
Hypersensitivity to any of the 3 study treatments or any excipient of their formulations.
Pregnancy, breastfeeding, or intention to become pregnant during the study.
Concomitant life-threatening disease with a life expectancy < 12 months.
Alcohol abuse.
Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.

Facility	Status	City	State	ZIP	Country	Contacts
Arizona Pulmonary Specialists, LTD		Phoenix	Arizona	85012	United States
UCSD Health Sciences

PubMed Identifier	Type	Citation	Retractions
34593120	Derived	Chin KM, Sitbon O, Doelberg M, Feldman J, Gibbs JSR, Grunig E, Hoeper MM, Martin N, Mathai SC, McLaughlin VV, Perchenet L, Poch D, Saggar R, Simonneau G, Galie N. Three- Versus Two-Drug Therapy for Patients With Newly Diagnosed Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2021 Oct 5;78(14):1393-1403. doi: 10.1016/j.jacc.2021.07.057.

ID	Title	Description
FG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Dec 4, 2018	Aug 26, 2020

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR)

Change from baseline to Week 26 in PVR was expressed as the ratio of Week 26 to baseline PVR value (Week 26 divided by baseline) using re-calculated PVR. PVR was determined by right heart catheterization (RHC). A geometric least square mean ratio of Week 26 to baseline PVR less than (<) 1 corresponds to a reduction in PVR from baseline. Missing values were imputed using a last observation carried forward (LOCF) approach.

Full analysis set (FAS) included all randomized participants.

Posted

Geometric Least Squares Mean

95% Confidence Interval

ratio

Baseline, Week 26

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).

Units	Counts
Participants	OG000123 OG001124

Title

Denominators

Categories

Title	Measurements
	OG0000.46(0.422 to 0.503) OG0010.48(0.441 to 0.526)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		ANCOVA		0.4239		Ratio of geometric Least Square mean	0.96			2-Sided	95	0.86	1.07					Superiority

Secondary

Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD)

The change from baseline to Week 26 in 6MWD was calculated as Week 26 minus baseline. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. Missing values were imputed using a LOCF approach.

Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure.

Posted

Least Squares Mean

95% Confidence Interval

meter

Baseline, Week 26

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).

Secondary

Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels

The change from baseline to Week 26 in NT-proBNP was expressed as the ratio of Week 26 to baseline NT-proBNP (Week 26 divided by baseline). A geometric least square mean ratio of Week 26 to baseline NT-proBNP <1 corresponds to a reduction in NT-proBNP from baseline. Missing values were imputed using a LOCF approach.

Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure.

Posted

Geometric Least Squares Mean

95% Confidence Interval

ratio

Baseline, Week 26

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).

Secondary

Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC)

WHO FC is a classification graded from Class I to IV which reflects disease severity based on symptoms. Worsening was defined as death or hospitalization due to PAH. Class I: No limitation of activity; Class II: slight limitation with ordinary activities; Class III: may not have symptoms at rest but greatly limited activities; Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Missing values were imputed using a LOCF approach.

FAS included all randomized participants. Here, N (number of participants analyzed) signifies number of participants analyzed for this outcome measure. Participants with WHO FC IV at baseline were excluded from this analysis as they could not shift to a worse category.

Posted

Number

percentage of participants

Week 26

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)

Secondary

Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP)

Change from baseline to Week 26 in mean Pulmonary Arterial Pressure (mPAP) was measured. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Missing values were imputed using a LOCF approach.

Full analysis set included all randomized participants.

Posted

Least Squares Mean

95% Confidence Interval

millimeters of mercury (mmHg)

Baseline, Week 26

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).

Secondary

Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP)

Change from baseline to Week 26 in mean Right Atrial Pressure (mRAP) was measured. Missing values were imputed using a LOCF approach.

Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure.

Posted

Least Squares Mean

95% Confidence Interval

mmHg

Baseline, Week 26

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).

Secondary

Change From Baseline to Week 26 in Total Pulmonary Resistance

Change from baseline to Week 26 in total pulmonary resistance was measured. Total pulmonary resistance was calculated as mPAP/CO*80, where CO is cardiac output. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach.

Full analysis set included all randomized participants.

Posted

Least Squares Mean

95% Confidence Interval

dynes*second per centimeter^5

Baseline, Week 26

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).

Secondary

Change From Baseline to Week 26 in Cardiac Index

Change from baseline to Week 26 in cardiac index was measured. Cardiac index is the amount of blood pumped by the heart, per minute, per meter square of body surface area. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach.

Full analysis set included all randomized participants.

Posted

Least Squares Mean

95% Confidence Interval

liters per minute per meter square

Baseline, Week 26

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).

Secondary

Change From Baseline to Week 26 in Venous Oxygen Saturation (%)

Change from baseline to Week 26 in venous oxygen saturation was measured. Missing values were imputed using a LOCF approach.

Full analysis set included all randomized participants. Here, N (number of participants analyzed) signifies the number of participants analyzed for this outcome measure.

Posted

Least Squares Mean

95% Confidence Interval

percentage of oxygen saturation

Baseline, Week 26

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).

Secondary

Number of Participants With Disease Progression Event

Number of participants with disease progression event were reported. Disease progression event as adjudicated by the CEC, defined as any of the following: a. Death (all causes; adjudicated for PAH relationship); b. Hospitalization for worsening PAH; c. Initiation of prostacyclin, a prostacyclin analog, or a prostacyclin receptor agonist for worsening PAH; d. Clinical worsening defined as a post-baseline decrease in 6MWD by more than (>) 15 percent (%) from the highest 6MWD obtained at or after baseline, accompanied by WHO FC III or IV (both conditions confirmed at two consecutive post-baseline visits separated by 1-21 days).

Full analysis set included all randomized participants.

Posted

Count of Participants

Participants

Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months)

ID	Title	Description
OG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
OG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0003 affected119 at risk EG0012 affected127 at risk
Blood Loss Anaemia	Blood and lymphatic system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Febrile Neutropenia	Blood and lymphatic system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Iron Deficiency Anaemia	Blood and lymphatic system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0003 affected119 at risk EG0011 affected127 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Microcytic Anaemia	Blood and lymphatic system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Arrhythmia	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Atrial Fibrillation	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0012 affected127 at risk
Atrial Flutter	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0012 affected127 at risk
Cardiac Arrest	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0012 affected127 at risk
Cardiac Failure Chronic	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Ischaemic Cardiomyopathy	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Left Ventricular Failure	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0011 affected127 at risk
Palpitations	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Pericardial Effusion	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0013 affected127 at risk
Right Ventricular Failure	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0018 affected127 at risk
Supraventricular Tachycardia	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Ventricular Tachycardia	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Gastrointestinal Arteriovenous Malformation	Congenital, familial and genetic disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Deafness Neurosensory	Ear and labyrinth disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Blindness	Eye disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Abdominal Pain	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Anal Haemorrhage	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Constipation	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Gastrointestinal Amyloidosis	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Gastrointestinal Haemorrhage	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0003 affected119 at risk EG0012 affected127 at risk
Gastrointestinal Polyp Haemorrhage	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Incarcerated Umbilical Hernia	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Large Intestinal Haemorrhage	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Nausea	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0011 affected127 at risk
Pancreatitis	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Rectal Prolapse	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Small Intestinal Obstruction	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Upper Gastrointestinal Haemorrhage	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0010 affected127 at risk
Vomiting	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0012 affected127 at risk
Accidental Death	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Non-Cardiac Chest Pain	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0013 affected127 at risk
Oedema Peripheral	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0011 affected127 at risk
Pyrexia	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Sudden Cardiac Death	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Sudden Death	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Autoimmune Hepatitis	Hepatobiliary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Drug-Induced Liver Injury	Hepatobiliary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Hepatic Cirrhosis	Hepatobiliary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Hepatic Failure	Hepatobiliary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Liver Disorder	Hepatobiliary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Allergy to Arthropod Sting	Immune system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Bronchitis	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0012 affected127 at risk
Device Related Infection	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Escherichia Sepsis	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Gastroenteritis Viral	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Gastrointestinal Infection	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Hepatitis C	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Influenza	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0011 affected127 at risk
Lower Respiratory Tract Infection	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Osteomyelitis Chronic	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Pneumonia	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0008 affected119 at risk EG0014 affected127 at risk
Pneumonia Legionella	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Pneumonia Pseudomonal	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Pyelonephritis Acute	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Sepsis	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0004 affected119 at risk EG0013 affected127 at risk
Septic Shock	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0011 affected127 at risk
Staphylococcal Bacteraemia	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Upper Respiratory Tract Infection	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0012 affected127 at risk
Urinary Tract Infection	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0012 affected127 at risk
Urosepsis	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Vascular Device Infection	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Chest Injury	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Deep Vein Thrombosis Postoperative	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Fall	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0011 affected127 at risk
Intentional Overdose	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Overdose	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Procedural Haemorrhage	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Rib Fracture	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Road Traffic Accident	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Spinal Compression Fracture	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Thoracic Vertebral Fracture	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Toxicity to Various Agents	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Vascular Pseudoaneurysm	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Wrist Fracture	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Alanine Aminotransferase Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Aspartate Aminotransferase Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Blood Pressure Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Catheterisation Cardiac	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Haemoglobin Decreased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Hepatic Enzyme Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Influenza A Virus Test Positive	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Liver Function Test Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Rotavirus Test Positive	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Sleep Study	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Transaminases Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Waist Circumference Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0012 affected127 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0011 affected127 at risk
Back Pain	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Chest Wall Haematoma	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Costochondritis	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Muscular Weakness	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Musculoskeletal Chest Pain	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0010 affected127 at risk
Systemic Scleroderma	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Invasive Ductal Breast Carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Lung Neoplasm Malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Malignant Melanoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Plasma Cell Myeloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Squamous Cell Carcinoma of the Tongue	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Cerebral Infarction	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Dizziness	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Embolic Stroke	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Haemorrhagic Stroke	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Ischaemic Stroke	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Seizure	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Syncope	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0016 affected127 at risk
Device Dislocation	Product Issues	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0010 affected127 at risk
Confusional State	Psychiatric disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Psychotic Disorder	Psychiatric disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Schizophrenia	Psychiatric disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Acute Kidney Injury	Renal and urinary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0003 affected119 at risk EG0011 affected127 at risk
Nephropathy Toxic	Renal and urinary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Prerenal Failure	Renal and urinary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Renal Amyloidosis	Renal and urinary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Renal Failure	Renal and urinary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Renal Impairment	Renal and urinary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Scleroderma Renal Crisis	Renal and urinary disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Menorrhagia	Reproductive system and breast disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Priapism	Reproductive system and breast disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Acute Respiratory Failure	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0015 affected127 at risk
Choking	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0005 affected119 at risk EG0010 affected127 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0012 affected127 at risk
Interstitial Lung Disease	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0010 affected127 at risk
Pleural Effusion	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0011 affected127 at risk
Pleurisy	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Pneumonia Aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0012 affected127 at risk
Pulmonary Arterial Hypertension	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0008 affected119 at risk EG0018 affected127 at risk
Pulmonary Embolism	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0011 affected127 at risk
Pulmonary Mass	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Pulmonary Oedema	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Pulmonary Veno-Occlusive Disease	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0013 affected127 at risk
Respiratory Arrest	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Respiratory Distress	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0012 affected127 at risk
Respiratory Failure	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0011 affected127 at risk
Skin Ulcer	Skin and subcutaneous tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Drug Delivery Device Implantation	Surgical and medical procedures	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0011 affected127 at risk
Hip Arthroplasty	Surgical and medical procedures	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0012 affected127 at risk
Knee Arthroplasty	Surgical and medical procedures	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Lung Transplant	Surgical and medical procedures	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Open Reduction of Fracture	Surgical and medical procedures	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Penile Operation	Surgical and medical procedures	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Pericardial Drainage	Surgical and medical procedures	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Therapy Change	Surgical and medical procedures	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Deep Vein Thrombosis	Vascular disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0012 affected127 at risk
Hypertensive Crisis	Vascular disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Hypotension	Vascular disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0002 affected119 at risk EG0012 affected127 at risk
Paradoxical Embolism	Vascular disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Shock	Vascular disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Acute Left Ventricular Failure	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Acute Right Ventricular Failure	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Atrial Tachycardia	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Cardiac Failure	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0011 affected127 at risk
Cardiac Failure Acute	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Cardiac Failure Congestive	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0011 affected127 at risk
Cardiac Failure High Output	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Cardiogenic Shock	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Coronary Artery Disease	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0012 affected127 at risk
Sinus Tachycardia	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Intestinal Ischaemia	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Oesophageal Haemorrhage	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Retroperitoneal Haemorrhage	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Appendicitis	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Hip Fracture	Injury, poisoning and procedural complications	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0011 affected127 at risk
Cardiac Electrophysiologic Study	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Transplant Evaluation	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Failure to Thrive	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Fluid Overload	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Hypertriglyceridaemia	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Malnutrition	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Breast Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk
Lung Carcinoma Cell Type Unspecified Stage I	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Pulmonary Hypertension	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Toe Amputation	Surgical and medical procedures	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Hypertension	Vascular disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0000 affected119 at risk EG0011 affected127 at risk
Shock Haemorrhagic	Vascular disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0001 affected119 at risk EG0010 affected127 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00014 affected119 at risk EG00111 affected127 at risk
Iron Deficiency Anaemia	Blood and lymphatic system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0015 affected127 at risk
Palpitations	Cardiac disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00014 affected119 at risk EG00111 affected127 at risk
Abdominal Distension	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0014 affected127 at risk
Abdominal Pain	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0007 affected119 at risk EG0016 affected127 at risk
Abdominal Pain Upper	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0008 affected119 at risk EG0017 affected127 at risk
Constipation	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0007 affected119 at risk EG0019 affected127 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00066 affected119 at risk EG00141 affected127 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00027 affected119 at risk EG00117 affected127 at risk
Gastrooesophageal Reflux Disease	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00011 affected119 at risk EG00118 affected127 at risk
Nausea	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00056 affected119 at risk EG00133 affected127 at risk
Vomiting	Gastrointestinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00030 affected119 at risk EG00114 affected127 at risk
Chest Discomfort	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0007 affected119 at risk EG00110 affected127 at risk
Chest Pain	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0014 affected127 at risk
Chills	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0007 affected119 at risk EG0012 affected127 at risk
Fatigue	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00024 affected119 at risk EG00122 affected127 at risk
Non-Cardiac Chest Pain	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00010 affected119 at risk EG0016 affected127 at risk
Oedema Peripheral	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00045 affected119 at risk EG00146 affected127 at risk
Pain	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00011 affected119 at risk EG0019 affected127 at risk
Peripheral Swelling	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00011 affected119 at risk EG0014 affected127 at risk
Pyrexia	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00011 affected119 at risk EG00111 affected127 at risk
Bronchitis	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0016 affected127 at risk
Influenza	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0017 affected127 at risk
Nasopharyngitis	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG00020 affected119 at risk EG00123 affected127 at risk
Upper Respiratory Tract Infection	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG00014 affected119 at risk EG00121 affected127 at risk
Urinary Tract Infection	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0009 affected119 at risk EG00111 affected127 at risk
Alanine Aminotransferase Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0008 affected119 at risk EG0014 affected127 at risk
Aspartate Aminotransferase Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG00010 affected119 at risk EG0014 affected127 at risk
Haemoglobin Decreased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG00010 affected119 at risk EG0016 affected127 at risk
Weight Increased	Investigations	MedDRA Version 22.0	Non-systematic Assessment	EG0005 affected119 at risk EG0018 affected127 at risk
Decreased Appetite	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00014 affected119 at risk EG0014 affected127 at risk
Fluid Retention	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0018 affected127 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00017 affected119 at risk EG00115 affected127 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00019 affected119 at risk EG00119 affected127 at risk
Back Pain	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00013 affected119 at risk EG00119 affected127 at risk
Muscle Spasms	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0009 affected119 at risk EG0017 affected127 at risk
Musculoskeletal Pain	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0008 affected119 at risk EG0011 affected127 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00021 affected119 at risk EG00119 affected127 at risk
Pain in Extremity	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00037 affected119 at risk EG00124 affected127 at risk
Pain in Jaw	Musculoskeletal and connective tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00035 affected119 at risk EG00115 affected127 at risk
Dizziness	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00017 affected119 at risk EG00127 affected127 at risk
Headache	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00083 affected119 at risk EG00178 affected127 at risk
Hypoaesthesia	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0011 affected127 at risk
Paraesthesia	Nervous system disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0008 affected119 at risk EG0012 affected127 at risk
Anxiety	Psychiatric disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0009 affected119 at risk EG0015 affected127 at risk
Insomnia	Psychiatric disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0008 affected119 at risk EG0016 affected127 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00019 affected119 at risk EG00123 affected127 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00020 affected119 at risk EG00125 affected127 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00013 affected119 at risk EG00113 affected127 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0017 affected127 at risk
Nasal Congestion	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00022 affected119 at risk EG00123 affected127 at risk
Oropharyngeal Pain	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0009 affected119 at risk EG0012 affected127 at risk
Pulmonary Arterial Hypertension	Respiratory, thoracic and mediastinal disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0008 affected119 at risk EG0013 affected127 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0019 affected127 at risk
Swelling Face	Skin and subcutaneous tissue disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0008 affected119 at risk EG0012 affected127 at risk
Flushing	Vascular disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00021 affected119 at risk EG00122 affected127 at risk
Hypotension	Vascular disorders	MedDRA Version 22.0	Non-systematic Assessment	EG00010 affected119 at risk EG0018 affected127 at risk
Influenza Like Illness	General disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0006 affected119 at risk EG0017 affected127 at risk
Sinusitis	Infections and infestations	MedDRA Version 22.0	Non-systematic Assessment	EG0005 affected119 at risk EG0018 affected127 at risk
Iron Deficiency	Metabolism and nutrition disorders	MedDRA Version 22.0	Non-systematic Assessment	EG0003 affected119 at risk EG0017 affected127 at risk

ID	Term
D006976	Hypertension, Pulmonary
D008171	Lung Diseases
D012140	Respiratory Tract Diseases

ID	Term
D002243	Carbolines
D011725	Pyridines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D026121	Indole Alkaloids
D007211	Indoles
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006575	Heterocyclic Compounds, 3-Ring

ID	Title	Description
BG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
BG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG000123 BG001124 BG002247
Number	BG000123 BG001124 BG002247

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Triple Oral Therapy (Macitentan, Tadalafil, and Selexipag)	Participants received macitentan oral tablet, 10 milligrams (mg) once daily and tadalafil oral tablet, 20 mg, once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received selexipag oral tablet at a starting dose of 200 micrograms (mcg), twice daily from Day 15 up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	4	119	58	119	118	119
EG001	Double Oral Therapy (Macitentan, Tadalafil, and Placebo)	Participants received macitentan oral tablet, 10 mg once daily and tadalafil oral tablet, 20 once daily from Day 1 up to End of treatment (10 months after last participant was enrolled). Tadalafil was up-titrated from 20 mg to 40 mg on Day 8. In addition, participants received placebo matching to selexipag oral tablet, at a starting dose of 200 micrograms (mcg), twice daily from Day 15 and dose up-titrated to a maximum of 1600 mcg, up to End of treatment (10 months after last participant was enrolled).	12	127	48	127	119	127