PORtopulmonary Hypertension Treatment wIth maCitentan - a... | NCT02382016

Label	Type	Description	Intervention Names
Investigational treatment	Experimental	Macitentan film-coated tablet 10 mg once daily.	Drug: Macitentan
Placebo	Placebo Comparator	Matching placebo tablet once daily.	Other: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Macitentan	Drug	Macitentan film-coated tablet 10 mg once daily.	Investigational treatment

Measure	Description	Time Frame
Relative Change From Baseline to Week 12 in Pulmonary Vascular Resistance (PVR).	The relative change from baseline to Week 12 in PVR is expressed as a ratio of Week 12 to baseline PVR.	From enrollment/baseline to Week 12 in the Double Blind (DB) treatment period

Measure	Description	Time Frame
Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD)	The purpose of the six minute walk is to test exercise tolerance and capacity. 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.	From enrollment/baseline to Week 12 in the DB treatment period

Name	Affiliation	Role
Loïc Perchenet, PhD	Actelion	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Mayo Clinic -Clinical Studies Unit		Phoenix	Arizona	85054	United States
UCSD

PubMed Identifier	Type	Citation	Retractions
32031690	Derived	Raevens S, Fallon MB. PORTICO: First Randomized Controlled Trial of Vasomodulator Therapy in Portopulmonary Hypertension. Hepatology. 2020 May;71(5):1870-1872. doi: 10.1002/hep.31166. No abstract available.
31178422	Derived	Sitbon O, Bosch J, Cottreel E, Csonka D, de Groote P, Hoeper MM, Kim NH, Martin N, Savale L, Krowka M. Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial. Lancet Respir Med. 2019 Jul;7(7):594-604. doi: 10.1016/S2213-2600(19)30091-8. Epub 2019 Jun 6.

ID	Title	Description
FG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period . Participants (who were randomized at French sites) who completed the core phase of the study as scheduled and opted to continue receiving OL study treatment continued to receive macitentan 10 mg in OLE period.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Apr 21, 2016	Oct 25, 2018

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

Relative Change From Baseline to Week 12 in Pulmonary Vascular Resistance (PVR).

The relative change from baseline to Week 12 in PVR is expressed as a ratio of Week 12 to baseline PVR.

Posted

Geometric Mean

95% Confidence Interval

ratio

From enrollment/baseline to Week 12 in the Double Blind (DB) treatment period

ID	Title	Description
OG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
OG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

Units	Counts
Participants	OG00043 OG00142

Title

Denominators

Categories

Title	Measurements
	OG0000.63(0.58 to 0.67) OG0010.98(0.91 to 1.05)

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	The null hypothesis (change of PVR at Week 12 as a ratio of baseline PVR in subjects treated with placebo or macitentan is the same) is tested on the primary endpoint by means of an analysis of covariance (ANCOVA) model on the log(e) transformed ratio of PVR at Week 12 to baseline PVR.	ANCOVA	ANCOVA model adjusted by treatment, background PAH-specific therapy at baseline and region as factors & log-transformed PVR at baseline as a covariate	0.0001		ratio of geometric means	0.65			2-Sided	95	0.59	0.72					Superiority

Secondary

Change From Baseline to Week 12 in 6-minute Walk Distance (6MWD)

The purpose of the six minute walk is to test exercise tolerance and capacity. 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.

Posted

Mean

Standard Deviation

meter

From enrollment/baseline to Week 12 in the DB treatment period

ID	Title	Description
OG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
OG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

Units	Counts
Participants	OG000

Secondary

Change From Baseline to Week 12 in WHO Functional Class (FC)

Changes from baseline to Week 12 in WHO FC were dichotomized as worsening (i.e., change > 0) versus no change or improvement (i.e., change ≤ 0). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure.

Posted

Count of Participants

Participants

From enrollment/baseline to Week 12 in the DB treatment period

ID	Title	Description
OG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
OG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

Units	Counts

Secondary

Change From Baseline to Week 12 in the Biomarker N-terminal Pro B-type Natriuretic Peptide (NT-proBNP)

NT-proBNP functions as a strong indicator of prognosis in patients with pulmonary hypertension (PH). The relative change from baseline to Week 12 in NT-proBNP is expressed as a ratio of Week 12 to baseline NT-proBNP.

Full Analysis Set(FAS): All randomized participants who received at least one dose of study drug in DB treatment, have baseline value for PVR, evaluated As per assigned treatment. Here, 'N'(number of participants analyzed included population included participants with available baseline data.

Posted

Geometric Mean

95% Confidence Interval

ratio

From enrollment/baseline to Week 12 in the DB treatment period

ID	Title	Description
OG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
OG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

Units	Counts
Participants

Secondary

Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)

mRAP is the mean blood pressure in the right atrium of the heart.

Posted

Mean

Standard Deviation

mmHg

From enrollment/baseline to Week 12 in the DB treatment period

ID	Title	Description
OG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
OG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

Units	Counts
Participants	OG000

Secondary

Change From Baseline to Week 12 in Mean Pulmonary Artery Pressure (mPAP)

mPAP is the mean blood pressure inside the pulmonary artery which moves the blood from the heart to the lungs. Monitoring of mPAP can detect small changes in the function of the heart.

Posted

Mean

Standard Deviation

mmHg

From enrollment/baseline to Week 12 in the DB treatment period

ID	Title	Description
OG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
OG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

Units	Counts
Participants	OG000

Secondary

Change From Baseline to Week 12 in Cardiac Index

The cardiac index is an assessment of the function of the heart and relates the cardiac output to the patient's body size (the patient's body surface area).

Posted

Mean

Standard Deviation

L/min/m^2

From enrollment/baseline to Week 12 in the DB treatment period

ID	Title	Description
OG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
OG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

Units	Counts
Participants	OG000

Secondary

Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR)

TPR is the resistance the pulmonary circulation that must be overcome in order for the blood flow to occur. It takes into account the blood pressure in the pulmonary arteries and the cardiac output. It is an important measurement to monitor the function of the pulmonary circulation and detect disease progression or improvement.

Posted

Mean

Standard Deviation

dyn*sec/cm^5

From enrollment/baseline to Week 12 in the DB treatment period

ID	Title	Description
OG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
OG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

Units	Counts
Participants	OG000

Secondary

Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SVO2)

SVO2 help assess tissue oxygen delivery. It describes the percentage of oxygen bound to hemoglobin in the blood which returns to the heart. This reflects the amount of residual oxygen in the blood after oxygen extraction by the tissues throughout the body.

Posted

Mean

Standard Deviation

percent of oxygen bound to hemoglobin

From enrollment/baseline to Week 12 in the DB treatment period

ID	Title	Description
OG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
OG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.

Units	Counts
Participants

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0022 affected80 at risk EG0031 affected33 at risk
Iron Deficiency Anaemia	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Atrial Fibrillation	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Left Ventricular Failure	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Right Ventricular Failure	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0011 affected42 at risk EG0022 affected80 at risk EG003
Tinnitus	Ear and labyrinth disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Abdominal Pain	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Ascites	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Duodenal Vascular Ectasia	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Gastrointestinal Angiodysplasia	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Gastrointestinal Haemorrhage	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Ileus	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Intestinal Obstruction	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Melaena	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0022 affected80 at risk EG003
Portal Hypertensive Gastropathy	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Death	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Localised Oedema	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Oedema Peripheral	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Hepatic Failure	Hepatobiliary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Hypersensitivity	Immune system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Bronchitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Escherichia Pyelonephritis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Lung Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Pneumonia	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Staphylococcal Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Urosepsis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Humerus Fracture	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Subdural Haematoma	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Liver Function Test Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Troponin I Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Diabetes Mellitus	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Fluid Overload	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Intervertebral Disc Protrusion	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Osteitis	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Hepatocellular Carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0012 affected42 at risk EG0020 affected80 at risk EG003
Malignant Ascites	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Rectal Adenocarcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Testis Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Haemorrhagic Stroke	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Hepatic Encephalopathy	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0022 affected80 at risk EG003
Presyncope	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Syncope	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Acute Kidney Injury	Renal and urinary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Chronic Kidney Disease	Renal and urinary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Priapism	Reproductive system and breast disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Acute Pulmonary Oedema	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Alveolitis	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Pulmonary Arterial Hypertension	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Pulmonary Toxicity	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Localised Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Vascular Procedure Complication	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Aneurysm Repair	Surgical and medical procedures	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0010 affected42 at risk EG0029 affected80 at risk EG0035 affected33 at risk
Increased Tendency to Bruise	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Iron Deficiency Anaemia	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Leukopenia	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Arrhythmia	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Atrial Fibrillation	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Bradycardia	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Cyanosis	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Palpitations	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Pericarditis	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Right Ventricular Failure	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Tachycardia	Cardiac disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Ear Pain	Ear and labyrinth disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Tinnitus	Ear and labyrinth disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Vertigo	Ear and labyrinth disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Cataract	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Conjunctival Hyperaemia	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Diabetic Retinopathy	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Diplopia	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Dry Eye	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0022 affected80 at risk EG003
Eye Irritation	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Eye Oedema	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Eye Pruritus	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Eye Swelling	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Meibomian Gland Dysfunction	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Vision Blurred	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Abdominal Pain	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Abdominal Pain Upper	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Anal Polyp	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Ascites	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0022 affected80 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0014 affected42 at risk EG0021 affected80 at risk EG003
Dry Mouth	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0012 affected42 at risk EG0020 affected80 at risk EG003
Duodenal Polyp	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Gastritis	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Gastritis Erosive	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Gastrooesophageal Reflux Disease	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Gingival Bleeding	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0012 affected42 at risk EG0023 affected80 at risk EG003
Pancreatic Cyst	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Portal Hypertensive Gastropathy	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Rectal Haemorrhage	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Varices Oesophageal	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0022 affected80 at risk EG003
Asthenia	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0024 affected80 at risk EG003
Chest Pain	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Face Oedema	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Fatigue	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0022 affected80 at risk EG003
Generalised Oedema	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Influenza Like Illness	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0023 affected80 at risk EG003
Localised Oedema	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Malaise	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Non-Cardiac Chest Pain	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Oedema Peripheral	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG00010 affected43 at risk EG0015 affected42 at risk EG00213 affected80 at risk EG003
Pain	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Peripheral Swelling	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Swelling	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Temperature Intolerance	General disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Biliary Colic	Hepatobiliary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Cholelithiasis	Hepatobiliary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Hepatic Mass	Hepatobiliary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Jaundice	Hepatobiliary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Portal Vein Thrombosis	Hepatobiliary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Bacterial Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Bronchitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0004 affected43 at risk EG0010 affected42 at risk EG0023 affected80 at risk EG003
Candida Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Conjunctivitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Fungal Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Furuncle	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Gastrointestinal Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Herpes Virus Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Herpes Zoster	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Influenza	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Laryngitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Lower Respiratory Tract Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0012 affected42 at risk EG0023 affected80 at risk EG003
Periodontitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Rhinitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0010 affected42 at risk EG0024 affected80 at risk EG003
Sinusitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Sinusitis Fungal	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Tonsillitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Tooth Abscess	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Upper Respiratory Tract Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Urinary Tract Infection	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Anaemia Postoperative	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Contusion	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Eye Contusion	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Foot Fracture	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0012 affected42 at risk EG0020 affected80 at risk EG003
Head Injury	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Limb Injury	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Tooth Fracture	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Ammonia Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Aspartate Aminotransferase Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Blood Bilirubin Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Blood Creatinine Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Blood Glucose Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Blood Potassium Decreased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Blood Potassium Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Blood Sodium Decreased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Blood Uric Acid Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Blood Urine Present	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Brain Natriuretic Peptide Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Coronavirus Test Positive	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Haematocrit Decreased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Haemoglobin Decreased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0003 affected43 at risk EG0010 affected42 at risk EG0023 affected80 at risk EG003
Intestinal Transit Time Decreased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Liver Function Test Abnormal	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Oxygen Saturation Decreased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Platelet Count Decreased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Total Bile Acids Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Urine Output Decreased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Decreased Appetite	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Fluid Retention	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Folate Deficiency	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Gout	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0016 affected42 at risk EG0022 affected80 at risk EG003
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Iron Deficiency	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Magnesium Deficiency	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Vitamin D Deficiency	Metabolism and nutrition disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0011 affected42 at risk EG0022 affected80 at risk EG003
Back Pain	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Bone Pain	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Dupuytren's Contracture	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Joint Swelling	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Muscle Spasms	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0015 affected42 at risk EG0023 affected80 at risk EG003
Musculoskeletal Chest Pain	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0022 affected80 at risk EG003
Musculoskeletal Stiffness	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Neck Pain	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0022 affected80 at risk EG003
Pain in Extremity	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0013 affected42 at risk EG0026 affected80 at risk EG003
Pain in Jaw	Musculoskeletal and connective tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Sebaceous Adenoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Balance Disorder	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Dizziness	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0012 affected42 at risk EG0025 affected80 at risk EG003
Headache	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0007 affected43 at risk EG0017 affected42 at risk EG00210 affected80 at risk EG003
Hepatic Encephalopathy	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Hypoaesthesia	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Intracranial Aneurysm	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Lethargy	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Neuralgia	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Presyncope	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Restless Legs Syndrome	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Sciatica	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Syncope	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Tremor	Nervous system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Alcohol Abuse	Psychiatric disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Depression	Psychiatric disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Insomnia	Psychiatric disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Acute Kidney Injury	Renal and urinary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Oliguria	Renal and urinary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Renal Failure	Renal and urinary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Breast Mass	Reproductive system and breast disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Uterine Haemorrhage	Reproductive system and breast disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Bendopnoea	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Chronic Obstructive Pulmonary Disease	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0013 affected42 at risk EG0021 affected80 at risk EG003
Dry Throat	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0012 affected42 at risk EG0023 affected80 at risk EG003
Dyspnoea Exertional	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0023 affected80 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0022 affected80 at risk EG003
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Nasal Dryness	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Nasal Obstruction	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Oropharyngeal Pain	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Portopulmonary Hypertension	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Pulmonary Arterial Hypertension	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0011 affected42 at risk EG0021 affected80 at risk EG003
Sinus Congestion	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Sleep Apnoea Syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Sneezing	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Blister	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Dermal Cyst	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Erythema	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Hyperkeratosis	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0023 affected80 at risk EG003
Psoriasis	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0010 affected42 at risk EG0022 affected80 at risk EG003
Umbilical Haemorrhage	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0021 affected80 at risk EG003
Vitiligo	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Alcohol Use	Social circumstances	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Inguinal Hernia Repair	Surgical and medical procedures	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Oesophageal Variceal Ligation	Surgical and medical procedures	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Flushing	Vascular disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0001 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Haematoma	Vascular disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Hypotension	Vascular disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0002 affected43 at risk EG0010 affected42 at risk EG0023 affected80 at risk EG003
Peripheral Venous Disease	Vascular disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0010 affected42 at risk EG0020 affected80 at risk EG003
Leukocytosis	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Pancytopenia	Blood and lymphatic system disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Conjunctival Haemorrhage	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Lacrimation Decreased	Eye disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Abdominal Discomfort	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Abdominal Distension	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Glossodynia	Gastrointestinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Groin Abscess	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Onychomycosis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Pharyngitis	Infections and infestations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Joint Dislocation	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Procedural Pain	Injury, poisoning and procedural complications	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Intestinal Transit Time Abnormal	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Venous Pressure Jugular Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Weight Increased	Investigations	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Sleep Disorder	Psychiatric disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Chromaturia	Renal and urinary disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Gynaecomastia	Reproductive system and breast disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Nasal Congestion	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Throat Irritation	Respiratory, thoracic and mediastinal disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Injection	Surgical and medical procedures	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Skin Neoplasm Excision	Surgical and medical procedures	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003
Orthostatic Hypotension	Vascular disorders	MedDRA Version 21.0	Non-systematic Assessment	EG0000 affected43 at risk EG0011 affected42 at risk EG0020 affected80 at risk EG003

ID	Title	Description
BG000	Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
BG001	Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks in Double-blind treatment period.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Double-Blind (DB) Period: Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks during DB treatment period.	0	43	9	43	34	43
EG001	DB Period: Placebo	Participants received Macitentan matching placebo film-coated tablets orally once daily for 12 weeks during DB treatment period.	0	42	6	42	32	42
EG002	Open-Label (OL) Period: Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period.	4	80	18	80	62	80
EG003	OL Extension Period: Macitentan 10 mg	Participants received Macitentan 10 milligram (mg) film-coated tablets orally once daily for 12 weeks in Double-blind treatment period. Participants who completed DB treatment period continued to receive macitentan 10 mg for 12 weeks (up to Week 24) in OL treatment period . Participants (who were randomized at French sites) who completed the core phase of the study as scheduled and opted to continue receiving OL study treatment continued to receive macitentan 10 mg in OLE period.	2	33	11	33	30	33