Selexipag (ACT-293987) in Pulmonary Arterial Hypertension (GRIPHON)

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ClinicalTrials.gov Identifier: NCT01106014

Recruitment Status : Completed

First Posted : April 19, 2010

Results First Posted : March 1, 2016

Last Update Posted : January 11, 2018

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Actelion

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Pulmonary Arterial Hypertension
Interventions	Drug: Selexipag Drug: Placebo
Enrollment	1156

Participant Flow

Recruitment Details	A total of 1351 patients were screened from 181 sites in 39 countries worldwide. Of these, 1156 were randomized
Pre-assignment Details	Screening assessments were performed up to a maximum of 28 days before baseline


Arm/Group Title	SELEXIPAG	PLACEBO
Arm/Group Description	During the 12-week titration phase,...	Matching placebo was administered o...
Arm/Group Description	During the 12-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated weekly in 200 μg b.i.d. increments to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d. At Week 12, patients continued the treatment at their individual MTD up to Week 26. Thereafter the dose could be up-titrated at scheduled visits if needed for patients receiving a dose < 1600 μg b.i.d. The dose could be decreased at any time in case of tolerability issues.	Matching placebo was administered orally following the same administration schedule as described for selexipag
Period Title: Overall Study
Started	574	582
Completed	289	252
Not Completed	285	330
Reason Not Completed
Morbidity or Mortality primary endpoint	155	242
Adverse Event	78	42
Withdrawal by Subject	43	37
Administrative reason	7	6
Lost to Follow-up	2	3

Baseline Characteristics

Arm/Group Title		Selexipag	Placebo	Total
Arm/Group Description		During the 12-week titration phase,...	Matching placebo was administered o...	Total of all reporting groups
Arm/Group Description		During the 12-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated weekly in 200 μg b.i.d. increments to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d. At Week 12, patients continued the treatment at their individual MTD up to Week 26. Thereafter the dose could be up-titrated at scheduled visits if needed for patients receiving a dose < 1600 μg b.i.d. The dose could be decreased at any time in case of tolerability issues.	Matching placebo was administered orally following the same administration schedule as described for selexipag	Total of all reporting groups
Overall Number of Baseline Participants		574	582	1156
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	574 participants	582 participants	1156 participants
		48.2 (15.19)	47.9 (15.55)	48.1 (15.37)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	574 participants	582 participants	1156 participants
	Female	457 79.6%	466 80.1%	923 79.8%
	Male	117 20.4%	116 19.9%	233 20.2%
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	574 participants	582 participants	1156 participants
Caucasion / White		376	375	751
Asian		125	120	245
Hispanic		51	63	114
Black		13	14	27
Other		9	10	19
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	574 participants	582 participants	1156 participants
Western Europe & Australia		161	160	321
Eastern Europe		149	155	304
Asia		115	113	228
North America		95	98	193
Latin America		54	56	110
PAH etiology ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	574 participants	582 participants	1156 participants
Idiopathic		312	337	649
Heritable		13	13	26
Associated with connective tissue disease		167	167	334
Assoc. with corrected (>=12Mo) congenital shunts		60	50	110
Associated with drug or toxin exposure		17	10	27
Associated with HIV infection		5	5	10
		[1] Measure Description: Number of patients in each PAH etiology category
Modified NYHA/WHO Functional class (FC) ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	574 participants	582 participants	1156 participants
FC I		4	5	9
FC II		274	255	529
FC III		293	314	607
FC IV		3	8	11
		[1] Measure Description: Number of patients in each NYHA/WHO Functional class (FC) at screening. The WHO FC ranges from I to IV, with higher ranges indicating more severe functional restrictions
PAH medications at baseline ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	574 participants	582 participants	1156 participants
None		112	124	236
Endothelin Receptor Agonists (ERA)		94	76	170
Phosphodiesterase type 5 inhibitors (PDE5-I)		189	185	374
ERA and PDE5I in combination		179	197	376
		[1] Measure Description: Number of patients receiving PAH background medication at the time of study drug start
Time since PAH diagnosis Median (Full Range) Unit of measure: Years
	Number Analyzed	574 participants	582 participants	1156 participants
		0.9 (0.0 to 37.3)	1.1 (0.0 to 38.9)	1.0 (0.0 to 38.9)
6-minute walk distance (6MWD) at baseline Median (Full Range) Unit of measure: Meters
	Number Analyzed	574 participants	582 participants	1156 participants
		376 (90 to 482)	369 (50 to 515)	372 (50 to 515)

Outcome Measures

1.Primary Outcome


Title	Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake
Description	Time from randomization to the first occurrence of a morbidity event o...
Description	Time from randomization to the first occurrence of a morbidity event or death (all causes) was analyzed with the Kaplan-Meier method (event-free KM estimates at different time points). Morbidity event was defined as any of the following events confirmed by the Critical Event committee: Hospitalization for worsening of pulmonary arterial hypertension (PAH), Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy, Initiation of parenteral prostanoid therapy or chronic oxygen therapy due to worsening of PAH, Disease progression which was defined by a decrease in 6-minute walk distance from baseline (>=15%, confirmed by a 2nd test on a different day) combined with worsening of WHO FC for patients belonging to WHO FC II/III at baseline, or combined with the need for additional PAH-specific therapy for patients belonging to WHO FC III/IV at baseline. Note: The number of patients at risk decreased over time but this cannot be captured below
Time Frame	Up to 7 days after end of double-blind treatment (maximum: 4.3 years)

Outcome Measure Data

Analysis Population Description

The primary endpoint was analyzed using the full analysis set, which includes all randomized patients evaluated according to the study drug to which they have been randomized (intention-to treat analysis set).


Arm/Group Title	Selexipag	Placebo
Arm/Group Description:	During the 12-week titration phase,...	Matching placebo was administered o...
Arm/Group Description:	During the 12-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated weekly in 200 μg b.i.d. increments to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d. At Week 12, patients continued the treatment at their individual MTD up to Week 26. Thereafter the dose could be up-titrated at scheduled visits if needed for patients receiving a dose < 1600 μg b.i.d. The dose could be decreased at any time in case of tolerability issues	Matching placebo was administered orally following the same administration schedule as described for selexipag
Overall Number of Participants Analyzed	574	582
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of patients free of events
KM estimate at Month 6	91.2 (88.5 to 93.4)	81.7 (78.2 to 84.7)
KM estimate at Month 12	83.1 (79.5 to 86.1)	70.6 (66.6 to 74.3)
KM estimate at Month 18	75.5 (71.2 to 79.2)	61.3 (56.8 to 65.5)
KM estimate at Month 24	67.9 (63.0 to 72.4)	53.9 (49.0 to 58.5)
KM estimate at Month 30	61.9 (56.3 to 66.9)	49.3 (44.2 to 54.3)
KM estimate at Month 36	58.2 (51.7 to 64.1)	41.7 (35.2 to 48.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Selexipag, Placebo
	Comments	The primary analysis was performed on the Full Analysis Set by a one-sided unstratified log-rank test
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	one-sided p-value
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 99% 0.46 to 0.78
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough
Description	The 6-minute walk distance test (6MWD) is a non-encouraged test perfor...
Description	The 6-minute walk distance test (6MWD) is a non-encouraged test performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. If the patient was used to taking bronchodilators before a walk, he/she was given them 5 to 30 min before the test. Also if the patient was on chronic oxygen therapy, oxygen was given at their standard rate during the test. Absolute change from baseline to Week 26 in 6MWD was measured at trough, i.e., either on the next day after the last study drug administration or at least 12 hours after study drug administration if on the same day.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Selexipag	Placebo
Arm/Group Description:	During the 12-week titration phase,...	Matching placebo was administered o...
Arm/Group Description:	During the 12-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated weekly in 200 μg b.i.d. increments to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d. At Week 12, patients continued the treatment at their individual MTD up to Week 26. Thereafter the dose could be up-titrated at scheduled visits if needed for patients receiving a dose < 1600 μg b.i.d. The dose could be decreased at any time in case of tolerability issues	Matching placebo was administered orally following the same administration schedule as described for selexipag
Overall Number of Participants Analyzed	574	582
Median (Full Range) Unit of Measure: Meters
6MWD at baseline - Overall	376 (90 to 482)	369 (50 to 515)
6MWD at Week 26- Overall	370 (0 to 617)	346 (0 to 650)
6MWD Change from baseline at Week 26	4 (-448 to 260)	-9 (-438 to 262)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Selexipag, Placebo
	Comments	Non-parametric ANCOVA with 6MWD as covariate at baseline. Missing values were imputed based on the following imputation rules: 1) if patient was unable to walk at week 26, 0 meter was imputed, 2) if rule 1 did not apply, the second lowest observed 6MWD value (10 meters) at Week 26 was imputed. Missing values were imputed for 21.6% of the subjects.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0027
	Comments	One-sided p-value of the nonparametric ANCOVA, adjusted for 6-minute walk distance at baseline
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	12
	Confidence Interval	(2-Sided) 99% 1 to 24
	Estimation Comments	Point estimate and 2-sided 99% CI for location shift using the HodgesLehmann method

3.Secondary Outcome


Title	Absence of Worsening From Baseline to Week 26 in Modified NYHA/WHO Functional Class (WHO FC)
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set. Patients with WHO FC IV at baseline were excluded from this analysis as they could not shift to a worse category


Arm/Group Title	Selexipag	Placebo
Arm/Group Description:	During the 12-week titration phase,...	Matching placebo was administered o...
Arm/Group Description:	During the 12-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated weekly in 200 μg b.i.d. increments to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d. At Week 12, patients continued the treatment at their individual MTD up to Week 26. Thereafter the dose could be up-titrated at scheduled visits if needed for patients receiving a dose < 1600 μg b.i.d. The dose could be decreased at any time in case of tolerability issues	Matching placebo was administered orally following the same administration schedule as described for selexipag
Overall Number of Participants Analyzed	571	574
Measure Type: Number Unit of Measure: Percentage of patients
	77.8	74.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Selexipag, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	It was assumed that the probabilities for absence of worsening in WHO FC at Week 26 were the same for both treatment groups

Statistical Test of Hypothesis	P-Value	0.2843
	Comments	Cochran-Mantel-Haenszel test stratified by WHO FC at baseline. For patients with missing NYHA/WHO FC at Week 26, the NYHA/WHO FC is considered as having worsened from baseline at Week 26. Missing values were imputed for 18.3% of subjects .
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	1.161
	Confidence Interval	(2-Sided) 99% 0.811 to 1.664
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	From baseline up to up to 7 days after end of treatment (EOT)
Adverse Event Reporting Description	Median duration of exposure to study drug was 70.7 weeks (range: 0.3-216.7 weeks) in the selexipag group and 63.7 weeks (range: 0.7-192.0 weeks) in the placebo group

Arm/Group Title	Selexipag		Placebo
Arm/Group Description	This group includes patients who re...		This group includes patients who re...
Arm/Group Description	This group includes patients who received at least one dose of selexipag. One subject who was randomized to placebo received a single dose of 8 tablets of selexipag due to an error in the dispensation of the medication bottle. Therefore, this patient was assigned to the selexipag group in the safety analysis set.		This group includes patients who received at least one dose of placebo. Four patients who were randomized to placebo never received the drugs and another patient received selexipag by mistake (see Selexipag group for more details). Therefore, these patients were excluded from the placebo group in the safety analysis set.
All-Cause Mortality
	Selexipag		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events Serious Adverse Events
	Selexipag		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	252/575 (43.83%)		272/577 (47.14%)
Blood and lymphatic system disorders
ANAEMIA ^† 1	5/575 (0.87%)	7	3/577 (0.52%)	5
HAEMORRHAGIC ANAEMIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
IDIOPATHIC THROMBOCYTOPENIC PURPURA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
LEUKOPENIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
NEUTROPENIA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
THROMBOCYTOPENIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Cardiac disorders
ACUTE CORONARY SYNDROME ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ACUTE MYOCARDIAL INFARCTION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ACUTE RIGHT VENTRICULAR FAILURE ^† 1	2/575 (0.35%)	2	5/577 (0.87%)	5
ANGINA PECTORIS ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	2
ARRHYTHMIA ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
ATRIAL FIBRILLATION ^† 1	7/575 (1.22%)	9	4/577 (0.69%)	5
ATRIAL FLUTTER ^† 1	3/575 (0.52%)	3	5/577 (0.87%)	5
ATRIAL TACHYCARDIA ^† 1	1/575 (0.17%)	1	2/577 (0.35%)	4
ATRIAL THROMBOSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ATRIOVENTRICULAR BLOCK SECOND DEGREE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
BRADYARRHYTHMIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
BRADYCARDIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CARDIAC ARREST ^† 1	2/575 (0.35%)	2	4/577 (0.69%)	4
CARDIAC FAILURE ^† 1	1/575 (0.17%)	1	2/577 (0.35%)	2
CARDIAC FAILURE CONGESTIVE ^† 1	2/575 (0.35%)	2	1/577 (0.17%)	1
CARDIO-RESPIRATORY ARREST ^† 1	2/575 (0.35%)	2	2/577 (0.35%)	2
CARDIOGENIC SHOCK ^† 1	1/575 (0.17%)	1	2/577 (0.35%)	2
CARDIOPULMONARY FAILURE ^† 1	3/575 (0.52%)	3	1/577 (0.17%)	1
CHRONIC RIGHT VENTRICULAR FAILURE ^† 1	2/575 (0.35%)	3	2/577 (0.35%)	2
COR PULMONALE ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
COR PULMONALE ACUTE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
COR PULMONALE CHRONIC ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CORONARY ARTERY INSUFFICIENCY ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CORONARY ARTERY OCCLUSION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CORONARY ARTERY STENOSIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
CYANOSIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
MYOCARDIAL INFARCTION ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
PALPITATIONS ^† 1	2/575 (0.35%)	2	1/577 (0.17%)	1
RIGHT VENTRICULAR DYSFUNCTION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	2
RIGHT VENTRICULAR FAILURE ^† 1	34/575 (5.91%)	42	41/577 (7.11%)	49
SUPRAVENTRICULAR TACHYCARDIA ^† 1	1/575 (0.17%)	1	4/577 (0.69%)	6
TACHYCARDIA ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
VENTRICULAR FIBRILLATION ^† 1	3/575 (0.52%)	3	0/577 (0.00%)	0
VENTRICULAR TACHYCARDIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Ear and labyrinth disorders
VERTIGO ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Endocrine disorders
AUTOIMMUNE THYROIDITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
BASEDOW'S DISEASE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HYPERTHYROIDISM ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HYPOTHYROIDISM ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Eye disorders
CATARACT ^† 1	2/575 (0.35%)	3	0/577 (0.00%)	0
CHOROIDITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
MACULOPATHY ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
VISION BLURRED ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Gastrointestinal disorders
ABDOMINAL DISCOMFORT ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ABDOMINAL DISTENSION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ABDOMINAL HERNIA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ABDOMINAL PAIN ^† 1	5/575 (0.87%)	6	4/577 (0.69%)	4
ANAL HAEMORRHAGE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	2
ASCITES ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
COLITIS ISCHAEMIC ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
DIARRHOEA ^† 1	3/575 (0.52%)	3	3/577 (0.52%)	3
DUODENAL ULCER ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
DYSPEPSIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ENTERITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ENTEROCELE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
GASTRITIS ^† 1	3/575 (0.52%)	3	1/577 (0.17%)	1
GASTROINTESTINAL ANGIODYSPLASIA HAEMORRHAGIC ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
GASTROINTESTINAL HAEMORRHAGE ^† 1	3/575 (0.52%)	3	3/577 (0.52%)	4
GASTROOESOPHAGEAL REFLUX DISEASE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
HAEMATEMESIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HAEMATOCHEZIA ^† 1	0/575 (0.00%)	0	2/577 (0.35%)	2
ILEUS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
INTESTINAL OBSTRUCTION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	2
LARGE INTESTINE POLYP ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
MELAENA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
NAUSEA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
NECROTISING COLITIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
OESOPHAGEAL OBSTRUCTION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
OESOPHAGEAL VARICES HAEMORRHAGE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PANCREATITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PANCREATITIS ACUTE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
SIGMOIDITIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	2
UPPER GASTROINTESTINAL HAEMORRHAGE ^† 1	2/575 (0.35%)	3	1/577 (0.17%)	1
VOMITING ^† 1	2/575 (0.35%)	2	2/577 (0.35%)	2
General disorders
ASTHENIA ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
CHEST DISCOMFORT ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CHEST PAIN ^† 1	6/575 (1.04%)	7	6/577 (1.04%)	8
DEATH ^† 1	1/575 (0.17%)	1	2/577 (0.35%)	2
EXERCISE TOLERANCE DECREASED ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
FATIGUE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
GENERAL PHYSICAL HEALTH DETERIORATION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	2
IMPAIRED HEALING ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
INFLUENZA LIKE ILLNESS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
MULTI-ORGAN FAILURE ^† 1	1/575 (0.17%)	1	2/577 (0.35%)	2
NON-CARDIAC CHEST PAIN ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
OEDEMA PERIPHERAL ^† 1	3/575 (0.52%)	4	4/577 (0.69%)	5
PYREXIA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
SUDDEN CARDIAC DEATH ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
SUDDEN DEATH ^† 1	5/575 (0.87%)	5	4/577 (0.69%)	4
Hepatobiliary disorders
ACUTE HEPATIC FAILURE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
CHOLANGITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CHOLECYSTITIS ACUTE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CHOLELITHIASIS ^† 1	1/575 (0.17%)	1	2/577 (0.35%)	2
HEPATIC CIRRHOSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HEPATIC CYST ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HEPATIC MASS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HEPATORENAL SYNDROME ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
NODULAR REGENERATIVE HYPERPLASIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Immune system disorders
HYPERSENSITIVITY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
LUNG TRANSPLANT REJECTION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
SARCOIDOSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
SECONDARY IMMUNODEFICIENCY ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Infections and infestations
ABDOMINAL INFECTION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ABSCESS INTESTINAL ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ABSCESS LIMB ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ABSCESS ORAL ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
APPENDICITIS PERFORATED ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ATYPICAL PNEUMONIA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	2
BRONCHITIS ^† 1	6/575 (1.04%)	7	4/577 (0.69%)	4
BRONCHOPNEUMONIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CATHETER SITE INFECTION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
CELLULITIS ^† 1	3/575 (0.52%)	4	3/577 (0.52%)	3
CLOSTRIDIUM DIFFICILE COLITIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
CYSTITIS ESCHERICHIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
DIABETIC GANGRENE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
DIVERTICULITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ENTEROCOLITIS VIRAL ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ERYSIPELAS ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
GASTROENTERITIS ^† 1	1/575 (0.17%)	1	3/577 (0.52%)	3
HEPATITIS C ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
HERPES ZOSTER ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
INFECTION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
INFLUENZA ^† 1	2/575 (0.35%)	3	0/577 (0.00%)	0
LOBAR PNEUMONIA ^† 1	0/575 (0.00%)	0	2/577 (0.35%)	2
LOCALISED INFECTION ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
LOWER RESPIRATORY TRACT INFECTION ^† 1	4/575 (0.70%)	4	4/577 (0.69%)	4
LUNG ABSCESS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
LUNG INFECTION ^† 1	4/575 (0.70%)	4	2/577 (0.35%)	2
LYMPHANGITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
NASOPHARYNGITIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
OSTEOMYELITIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
PARAINFLUENZAE VIRUS INFECTION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PAROTITIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	3
PERITONITIS ^† 1	0/575 (0.00%)	0	2/577 (0.35%)	2
PILONIDAL CYST ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PNEUMONIA ^† 1	17/575 (2.96%)	18	25/577 (4.33%)	30
PNEUMONIA BACTERIAL ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
POST PROCEDURAL INFECTION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
POST PROCEDURAL SEPSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PYELONEPHRITIS ^† 1	2/575 (0.35%)	2	1/577 (0.17%)	1
PYELONEPHRITIS ACUTE ^† 1	3/575 (0.52%)	3	0/577 (0.00%)	0
PYELONEPHRITIS CHRONIC ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
RESPIRATORY TRACT INFECTION ^† 1	4/575 (0.70%)	5	3/577 (0.52%)	3
SEPSIS ^† 1	3/575 (0.52%)	3	1/577 (0.17%)	1
SEPTIC SHOCK ^† 1	3/575 (0.52%)	3	1/577 (0.17%)	1
STAPHYLOCOCCAL SEPSIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
TOOTH ABSCESS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
TOOTH INFECTION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
TRACHEOBRONCHITIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
UPPER RESPIRATORY TRACT INFECTION ^† 1	4/575 (0.70%)	4	3/577 (0.52%)	3
URINARY TRACT INFECTION ^† 1	2/575 (0.35%)	2	1/577 (0.17%)	1
VIRAL INFECTION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Injury, poisoning and procedural complications
ACCIDENT ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
ACETABULUM FRACTURE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
BRAIN HERNIATION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CRANIOCEREBRAL INJURY ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
FALL ^† 1	3/575 (0.52%)	3	6/577 (1.04%)	8
FEMORAL NECK FRACTURE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
FEMUR FRACTURE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
FOOT FRACTURE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
GINGIVAL INJURY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
HEAD INJURY ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
INJURY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
JAW FRACTURE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
JOINT DISLOCATION ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
LIGAMENT SPRAIN ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
LIP INJURY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
LOWER LIMB FRACTURE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
LUMBAR VERTEBRAL FRACTURE ^† 1	1/575 (0.17%)	1	2/577 (0.35%)	2
MULTIPLE INJURIES ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PELVIC FRACTURE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
POST PROCEDURAL COMPLICATION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
POST PROCEDURAL HAEMATOMA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
POST PROCEDURAL HAEMORRHAGE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PROCEDURAL HAEMORRHAGE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
PUBIS FRACTURE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
RESPIRATORY FUME INHALATION DISORDER ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ROAD TRAFFIC ACCIDENT ^† 1	4/575 (0.70%)	5	2/577 (0.35%)	2
SUBDURAL HAEMATOMA ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
TOXICITY TO VARIOUS AGENTS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
TRAUMATIC FRACTURE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
VACCINATION COMPLICATION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
VASCULAR PROCEDURE COMPLICATION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
VASCULAR PSEUDOANEURYSM ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Investigations
ALANINE AMINOTRANSFERASE INCREASED ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
ASPARTATE AMINOTRANSFERASE INCREASED ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
BRAIN NATRIURETIC PEPTIDE INCREASED ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
CARDIAC INDEX DECREASED ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
CATHETERISATION CARDIAC ^† 1	3/575 (0.52%)	3	1/577 (0.17%)	1
INTERNATIONAL NORMALISED RATIO INCREASED ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
INVESTIGATION ^† 1	2/575 (0.35%)	3	1/577 (0.17%)	1
LIVER FUNCTION TEST ABNORMAL ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
OXYGEN SATURATION DECREASED ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PULMONARY ARTERIAL PRESSURE INCREASED ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
PULMONARY ARTERIAL WEDGE PRESSURE INCREASED ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
RED BLOOD CELL COUNT INCREASED ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
TRANSPLANT EVALUATION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
WALKING DISTANCE TEST ABNORMAL ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
WEIGHT DECREASED ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
WEIGHT INCREASED ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
Metabolism and nutrition disorders
DEHYDRATION ^† 1	2/575 (0.35%)	2	2/577 (0.35%)	2
DIABETES MELLITUS INADEQUATE CONTROL ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
DYSLIPIDAEMIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ELECTROLYTE IMBALANCE ^† 1	2/575 (0.35%)	2	1/577 (0.17%)	1
FLUID OVERLOAD ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
FLUID RETENTION ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
GOUT ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
HYPOGLYCAEMIA ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	2
HYPONATRAEMIC SYNDROME ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Musculoskeletal and connective tissue disorders
BACK PAIN ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
CHONDROCALCINOSIS PYROPHOSPHATE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
CREST SYNDROME ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	2
CRYSTAL ARTHROPATHY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
INTERVERTEBRAL DISC PROTRUSION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
MIXED CONNECTIVE TISSUE DISEASE ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
MYALGIA ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
OSTEOPOROSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
OSTEOPOROTIC FRACTURE ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
PAIN IN EXTREMITY ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
POLYMYOSITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
RHEUMATOID ARTHRITIS ^† 1	0/575 (0.00%)	0	2/577 (0.35%)	4
STILL'S DISEASE ADULT ONSET ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
SYSTEMIC LUPUS ERYTHEMATOSUS ^† 1	5/575 (0.87%)	5	1/577 (0.17%)	1
SYSTEMIC SCLEROSIS ^† 1	1/575 (0.17%)	1	2/577 (0.35%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
BREAST CANCER ^† 1	1/575 (0.17%)	1	3/577 (0.52%)	5
BREAST CANCER RECURRENT ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CEREBRAL HAEMANGIOMA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
COLORECTAL CANCER METASTATIC ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
DIFFUSE LARGE B-CELL LYMPHOMA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HEPATIC NEOPLASM ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
LUNG ADENOCARCINOMA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
LYMPHANGIOSIS CARCINOMATOSA ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
MALIGNANT MELANOMA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
Nervous system disorders
AGEUSIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
APHASIA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ATAXIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
AUTONOMIC NERVOUS SYSTEM IMBALANCE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
CEREBELLAR SYNDROME ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
CEREBRAL INFARCTION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CEREBROVASCULAR ACCIDENT ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
DEMYELINATION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
DIZZINESS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HAEMORRHAGE INTRACRANIAL ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HEADACHE ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
HYPOGLYCAEMIC UNCONSCIOUSNESS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ISCHAEMIC STROKE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
LOSS OF CONSCIOUSNESS ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
MENTAL IMPAIRMENT ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
MIGRAINE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
PARKINSON'S DISEASE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
POST HERPETIC NEURALGIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PRESYNCOPE ^† 1	2/575 (0.35%)	2	1/577 (0.17%)	1
SUBARACHNOID HAEMORRHAGE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
SYNCOPE ^† 1	10/575 (1.74%)	13	20/577 (3.47%)	23
THALAMIC INFARCTION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
TRANSIENT ISCHAEMIC ATTACK ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
VOCAL CORD PARALYSIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
Pregnancy, puerperium and perinatal conditions
PREGNANCY ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
RUPTURED ECTOPIC PREGNANCY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
Psychiatric disorders
ALCOHOLISM ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	3
MENTAL STATUS CHANGES ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
SCHIZOAFFECTIVE DISORDER ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
SOMNAMBULISM ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
STRESS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
SUICIDE ATTEMPT ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
Renal and urinary disorders
ACUTE PRERENAL FAILURE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ANURIA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
LUPUS NEPHRITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
OLIGURIA ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
RENAL FAILURE ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
RENAL FAILURE ACUTE ^† 1	6/575 (1.04%)	6	6/577 (1.04%)	6
URETHRAL STENOSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Reproductive system and breast disorders
CERVICAL DYSPLASIA ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
CYSTOCELE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ENDOMETRIOSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
MENORRHAGIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
OVARIAN CYST ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
OVARIAN CYST RUPTURED ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
Respiratory, thoracic and mediastinal disorders
ACUTE LUNG INJURY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ACUTE RESPIRATORY FAILURE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ASTHMA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
DYSPNOEA ^† 1	17/575 (2.96%)	21	13/577 (2.25%)	17
DYSPNOEA EXERTIONAL ^† 1	1/575 (0.17%)	2	2/577 (0.35%)	2
EPISTAXIS ^† 1	4/575 (0.70%)	4	4/577 (0.69%)	4
HAEMOPTYSIS ^† 1	5/575 (0.87%)	5	5/577 (0.87%)	7
HYPOXIA ^† 1	1/575 (0.17%)	1	3/577 (0.52%)	4
INTERSTITIAL LUNG DISEASE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ORGANISING PNEUMONIA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
ORTHOPNOEA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PULMONARY ARTERIAL HYPERTENSION ^† 1	83/575 (14.43%)	106	127/577 (22.01%)	183
PULMONARY ARTERY DILATATION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
PULMONARY EMBOLISM ^† 1	4/575 (0.70%)	4	3/577 (0.52%)	3
PULMONARY HAEMORRHAGE ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
PULMONARY HYPERTENSION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PULMONARY INFARCTION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
PULMONARY OEDEMA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PULMONARY VENO-OCCLUSIVE DISEASE ^† 1	2/575 (0.35%)	2	1/577 (0.17%)	2
RESPIRATORY FAILURE ^† 1	0/575 (0.00%)	0	3/577 (0.52%)	3
RESPIRATORY GAS EXCHANGE DISORDER ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
SLEEP APNOEA SYNDROME ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
TACHYPNOEA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
Skin and subcutaneous tissue disorders
DERMATITIS CONTACT ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
DERMATOMYOSITIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
PAIN OF SKIN ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
RASH ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
SCLERODERMA ASSOCIATED DIGITAL ULCER ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
SKIN ULCER ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
TELANGIECTASIA ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
Surgical and medical procedures
BARIATRIC GASTRIC BALLOON INSERTION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
BLADDER NECK SUSPENSION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
CARDIAC PACEMAKER INSERTION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CARDIOVERSION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CERVICAL CONISATION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
CHOLECYSTECTOMY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	2
DRUG THERAPY CHANGED ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
GLAUCOMA SURGERY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
HAEMODIALYSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
LUNG TRANSPLANT ^† 1	2/575 (0.35%)	2	1/577 (0.17%)	1
MASTECTOMY ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
NASAL SEPTAL OPERATION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
SALPINGECTOMY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
SKIN NEOPLASM EXCISION ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
STEM CELL TRANSPLANT ^† 1	1/575 (0.17%)	2	0/577 (0.00%)	0
TURBINECTOMY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
URETHRAL OPERATION ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
Vascular disorders
CIRCULATORY COLLAPSE ^† 1	2/575 (0.35%)	2	1/577 (0.17%)	1
DEEP VEIN THROMBOSIS ^† 1	2/575 (0.35%)	3	1/577 (0.17%)	1
EXTREMITY NECROSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
FLUSHING ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HAEMATOMA ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
HAEMODYNAMIC INSTABILITY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
HYPERTENSION ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
HYPOTENSION ^† 1	3/575 (0.52%)	3	3/577 (0.52%)	3
HYPOVOLAEMIC SHOCK ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
ORTHOSTATIC HYPOTENSION ^† 1	1/575 (0.17%)	1	1/577 (0.17%)	1
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
PERIPHERAL ARTERY THROMBOSIS ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
PERIPHLEBITIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
THROMBOPHLEBITIS SUPERFICIAL ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
VASCULITIS ^† 1	2/575 (0.35%)	2	0/577 (0.00%)	0
VENA CAVA THROMBOSIS ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
VENOUS INSUFFICIENCY ^† 1	0/575 (0.00%)	0	1/577 (0.17%)	1
VENOUS THROMBOSIS LIMB ^† 1	1/575 (0.17%)	1	0/577 (0.00%)	0
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 16.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Selexipag		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	544/575 (94.61%)		486/577 (84.23%)
Blood and lymphatic system disorders
ANAEMIA ^† 1	43/575 (7.48%)	53	28/577 (4.85%)	37
Cardiac disorders
PALPITATIONS ^† 1	32/575 (5.57%)	40	31/577 (5.37%)	41
Gastrointestinal disorders
ABDOMINAL PAIN ^† 1	44/575 (7.65%)	54	29/577 (5.03%)	37
ABDOMINAL PAIN UPPER ^† 1	34/575 (5.91%)	39	32/577 (5.55%)	38
DIARRHOEA ^† 1	242/575 (42.09%)	375	109/577 (18.89%)	137
NAUSEA ^† 1	192/575 (33.39%)	265	107/577 (18.54%)	136
VOMITING ^† 1	103/575 (17.91%)	143	48/577 (8.32%)	53
General disorders
ASTHENIA ^† 1	29/575 (5.04%)	33	24/577 (4.16%)	27
CHEST PAIN ^† 1	34/575 (5.91%)	37	39/577 (6.76%)	54
FATIGUE ^† 1	46/575 (8.00%)	54	58/577 (10.05%)	72
OEDEMA PERIPHERAL ^† 1	77/575 (13.39%)	90	100/577 (17.33%)	138
Infections and infestations
BRONCHITIS ^† 1	42/575 (7.30%)	46	41/577 (7.11%)	49
NASOPHARYNGITIS ^† 1	75/575 (13.04%)	105	63/577 (10.92%)	95
UPPER RESPIRATORY TRACT INFECTION ^† 1	72/575 (12.52%)	100	79/577 (13.69%)	119
URINARY TRACT INFECTION ^† 1	24/575 (4.17%)	30	30/577 (5.20%)	34
Metabolism and nutrition disorders
DECREASED APPETITE ^† 1	34/575 (5.91%)	38	19/577 (3.29%)	23
Musculoskeletal and connective tissue disorders
ARTHRALGIA ^† 1	62/575 (10.78%)	82	44/577 (7.63%)	57
BACK PAIN ^† 1	34/575 (5.91%)	36	35/577 (6.07%)	38
MYALGIA ^† 1	90/575 (15.65%)	120	34/577 (5.89%)	37
PAIN IN EXTREMITY ^† 1	95/575 (16.52%)	142	46/577 (7.97%)	62
PAIN IN JAW ^† 1	148/575 (25.74%)	188	36/577 (6.24%)	38
Nervous system disorders
DIZZINESS ^† 1	85/575 (14.78%)	111	85/577 (14.73%)	106
HEADACHE ^† 1	374/575 (65.04%)	649	189/577 (32.76%)	261
SYNCOPE ^† 1	30/575 (5.22%)	35	34/577 (5.89%)	42
Respiratory, thoracic and mediastinal disorders
COUGH ^† 1	56/575 (9.74%)	67	67/577 (11.61%)	87
DYSPNOEA ^† 1	79/575 (13.74%)	100	110/577 (19.06%)	143
PULMONARY ARTERIAL HYPERTENSION ^† 1	46/575 (8.00%)	64	84/577 (14.56%)	141
Vascular disorders
FLUSHING ^† 1	69/575 (12.00%)	80	29/577 (5.03%)	31
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 16.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

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Name/Title:	Clinical trial disclosure desk
Organization:	Actelion Pharmaceuticals Ltd
EMail:	clinical-trials-disclosure@actelion.com

Publications of Results:

Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, Ghofrani HA, Hoeper MM, Lang IM, Preiss R, Rubin LJ, Di Scala L, Tapson V, Adzerikho I, Liu J, Moiseeva O, Zeng X, Simonneau G, McLaughlin VV; GRIPHON Investigators. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015 Dec 24;373(26):2522-33. doi: 10.1056/NEJMoa1503184.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Galie N, Gaine S, Channick R, Coghlan JG, Hoeper MM, Lang IM, McLaughlin VV, Lassen C, Rubin LJ, Hsu Schmitz SF, Sitbon O, Tapson VF, Chin KM. Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension. Adv Ther. 2022 Jan;39(1):796-810. doi: 10.1007/s12325-021-01898-1. Epub 2021 Oct 30.

Gaine S, Sitbon O, Channick RN, Chin KM, Sauter R, Galie N, Hoeper MM, McLaughlin VV, Preiss R, Rubin LJ, Simonneau G, Tapson V, Ghofrani HA, Lang I. Relationship Between Time From Diagnosis and Morbidity/Mortality in Pulmonary Arterial Hypertension: Results From the Phase III GRIPHON Study. Chest. 2021 Jul;160(1):277-286. doi: 10.1016/j.chest.2021.01.066. Epub 2021 Feb 3.

Chin KM, Rubin LJ, Channick R, Di Scala L, Gaine S, Galie N, Ghofrani HA, Hoeper MM, Lang IM, McLaughlin VV, Preiss R, Simonneau G, Sitbon O, Tapson VF. Association of N-Terminal Pro Brain Natriuretic Peptide and Long-Term Outcome in Patients With Pulmonary Arterial Hypertension. Circulation. 2019 May 21;139(21):2440-2450. doi: 10.1161/CIRCULATIONAHA.118.039360.

McLaughlin VV, Hoeper MM, Channick RN, Chin KM, Delcroix M, Gaine S, Ghofrani HA, Jansa P, Lang IM, Mehta S, Pulido T, Sastry BKS, Simonneau G, Sitbon O, Souza R, Torbicki A, Tapson VF, Perchenet L, Preiss R, Verweij P, Rubin LJ, Galie N. Pulmonary Arterial Hypertension-Related Morbidity Is Prognostic for Mortality. J Am Coll Cardiol. 2018 Feb 20;71(7):752-763. doi: 10.1016/j.jacc.2017.12.010.

Coghlan JG, Channick R, Chin K, Di Scala L, Galie N, Ghofrani HA, Hoeper MM, Lang IM, McLaughlin V, Preiss R, Rubin LJ, Simonneau G, Sitbon O, Tapson VF, Gaine S. Targeting the Prostacyclin Pathway with Selexipag in Patients with Pulmonary Arterial Hypertension Receiving Double Combination Therapy: Insights from the Randomized Controlled GRIPHON Study. Am J Cardiovasc Drugs. 2018 Feb;18(1):37-47. doi: 10.1007/s40256-017-0262-z.

Gaine S, Chin K, Coghlan G, Channick R, Di Scala L, Galie N, Ghofrani HA, Lang IM, McLaughlin V, Preiss R, Rubin LJ, Simonneau G, Sitbon O, Tapson VF, Hoeper MM. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. Eur Respir J. 2017 Aug 17;50(2):1602493. doi: 10.1183/13993003.02493-2016. Print 2017 Aug.

Krause A, Machacek M, Lott D, Hurst N, Bruderer S, Dingemanse J. Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension. CPT Pharmacometrics Syst Pharmacol. 2017 Jul;6(7):477-485. doi: 10.1002/psp4.12202. Epub 2017 May 27.

Skoro-Sajer N, Lang IM. Selexipag for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2014 Feb;15(3):429-36. doi: 10.1517/14656566.2014.876007. Epub 2014 Jan 7.

Layout table for additonal information

Responsible Party:	Actelion
ClinicalTrials.gov Identifier:	NCT01106014
Other Study ID Numbers:	AC-065A302
First Submitted:	April 2, 2010
First Posted:	April 19, 2010
Results First Submitted:	February 2, 2016
Results First Posted:	March 1, 2016
Last Update Posted:	January 11, 2018

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