FUTURE 3 Ext: FUTURE 3 Study Extension

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01338415
• Collaborator: (none)
• Enrollment: 58
• Locations: 36
• Arms: 2
• Actual Duration (Months): 110.7
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The objectives of the FUTURE 3 Study Extension are to evaluate the long-term safety, tolerability and efficacy of the pediatric formulation of bosentan two versus three times a day in children with Pulmonary Arterial Hypertension (PAH).

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Bosentan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Multicenter, Open-label Extension of FUTURE 3 to Assess the Safety, Tolerability and Efficacy of the Pediatric Formulation of Bosentan Two Versus Three Times a Day in Children With Pulmonary Arterial Hypertension
• Actual Study Start Date: Mar 8, 2011
• Actual Primary Completion Date: Aug 13, 2014
• Actual Study Completion Date: May 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: bosentan 2mg/kg b.i.d. Patients who received 2 mg/kg bosentan twcie daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study	Drug: Bosentan; Oral dispersible tablet administered as 2mg/kg two (b.i.d.) or three (t.i.d.) times per day; Other Names: ACT-050088
Experimental: bosentan 2mg/kg t.i.d. Patients who received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study	Drug: Bosentan; Oral dispersible tablet administered as 2mg/kg two (b.i.d.) or three (t.i.d.) times per day; Other Names: ACT-050088

Outcome Measures

Primary Outcome Measures

1. Treatment Emergent Adverse Events (AEs) up to 7 Days After Permanent Study Drug Discontinuation [Up to 62 weeks in average]

   This is the total number of subjects with at least one adverse event (serious or not serious) whether or not causally related to the study drug and presented cumulatively in the FUTURE 3 and FUTURE 3 Extension study. NOTE: FUTURE 3 extension study was exploratory and no primary efficacy and safety endpoints were defined in the protocol. So, this safety outcome measure was selected and reported as primary endpoint here.

Other Outcome Measures

1. Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) [At Month 12]

   The WHO FC indicates the severity of Pulmonary Arterial Hypertension: class I (none) to class IV (most severe). Changes from baseline to month 12 and month 18 of treatment with bosentan included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or no change/stable (same FC at baseline and at the post-baseline time point). Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.

2. Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC) [At Month 18]

   The WHO FC indicates the severity of Pulmonary Arterial Hypertension: class I (none) to class IV (most severe). Changes from baseline to month 12 and month 18 of treatment with bosentan included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or no change/stable (same FC at baseline and at the post-baseline time point). Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.

3. Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) [At Month 12]

   The GCIS is a scale used to rate the patient's current overall clinical condition ("Very Good", "Good", "Neither Good or Bad", "Bad", and "Very Bad"). Rating was performed independently by the physician and parents or legal representatives. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.

4. Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS) [At Month 18]

   The GCIS is a scale used to rate the patient's current overall clinical condition ("Very Good", "Good", "Neither Good or Bad", "Bad", and "Very Bad"). Rating was performed independently by the physician and parents or legal representatives. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.

5. Number of Patients With Pulmonary Arterial Hypertension (PAH) Worsening Components up to the Last Day of Treatment + 7 Days [Up to 62 weeks in average]

   Number of patients with at least one PAH-worsening component (death, lung transplant, hospitalization due to PAH progression, initiation of new therapy for PAH, new/worsening right heart failure) reported cumulatively over FUTURE 3 core and extension study.

6. Pulmonary Arterial Hypertension (PAH) Progression up to End of Treatment + 7 Days [From baseline to Month 18]

   PAH progression was defined by time elapsed from the first study drug administration in the FUTURE core study to the day of the first occurrence of any of the following PAH worsening events: death, lung transplant, hospitalization due to PAH progression, initiation of new therapy for PAH or new / worsening right heart failure. Subjects without a PAH worsening event were censored at EOT + 7 days. PAH progression was estimated by Kaplan-Meier methodology and expressed by the percentage of participants free of events at different time points.

7. Overall Survival [From baseline to month 18]

   Overall survival was defined as the time elapsed between the first study drug administration and death (any cause) up to end of study (Month 18 survival follow-up), regardless of whether the patient was on study treatment. Patients who died, regardless of the cause of death, were considered to have had an event. Patients last known to have been alive were censored on their date of last contact. Percentage of participants without death at different time points was estimated using Kaplan-Meier methodology.

8. Exceptional Use Treatment Period (EUTP): Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) up to 7 Days After Permanent Discontinuation of Study Drug [Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)]

   An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline.

9. EUTP: Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) up to 7 Days After Permanent Discontinuation of Study Drug [Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)]

   An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

10. EUTP: Percentage of Participants With AEs Leading to Premature Discontinuation of Study Drug [Up to 3 years and 4 months]

    An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. Percentage of participants with AEs leading to premature discontinuation of study drug were reported.

11. EUTP: Percentage of Participants With SAEs From 7 up to 60 Days After Permanent Discontinuation of Study Drug [From 7 up to 60 days after permanent discontinuation of study drug (up to 3 years and 4 months)]

    A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

12. EUTP: Percentage of Participants With Deaths [Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)]

    Percentage of participants with deaths were reported.

13. EUTP: Percentage of Participants With Adverse Events of Special Interest (AESI) [Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)]

    Percentage of participants with AESI including liver abnormalities and anemia were reported.

14. EUTP: Percentage of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 7 Days After Permanent Discontinuation of Study Drug [Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)]

    Percentage of participants with treatment-emergent marked laboratory abnormalities were reported.

15. EUTP: Percentage of Participants With Liver Function Abnormalities [Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)]

    Percentage of participants with liver function abnormalities: Alanine aminotransferase (ALT) greater than (>)3*upper limit of normal (ULN), ALT/aspartate aminotransferase (AST) >3*ULN, ALT /AST >3*ULN and less than or equal to (<=) 5*ULN, ALT/AST >5*ULN and <=8*ULN, ALT/AST >8*ULN and ALT/AST >3*ULN, total bilirubin >2*ULN and alkaline phosphatase (ALP) <=2*ULN were reported.

16. EUTP: Percentage of Participants With Any Time Occurrence of Hemoglobin <=10 Gram Per Deciliter (g/dL) and <=8g/dL Between Baseline and up to 7 Days After End of Treatment (EOT) [Baseline, up to 7 days after end of treatment (up to 3 years and 4 months)]

    Percentage of participants with any time occurrence of hemoglobin (Hgb) less than or equal to (<=) 10 g/dL and 8 g/dL between baseline and up to the last day of treatment + 7 days during EUTP were reported. Here "N" (number of subjects analyzed) signifies subjects who were evaluable for this outcome measure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Months to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients who completed the FUTURE 3 core study (AC-052-373) or prematurely discontinued due to PAH-progression, if bosentan was not permanently discontinued

2. Patients who tolerated bosentan pediatric formulation and for whom bosentan is considered beneficial at the end of the FUTURE 3 core study (AC-052-373)

3. Signed informed consent by the parents or the legal representatives prior to any study-mandated procedure.

Exclusion Criteria:

1. Known intolerance or hypersensitivity to bosentan or any of the excipients of the dispersible bosentan tablet

2. Any clinically significant laboratory abnormality that precludes continuation of bosentan therapy

3. Pregnancy

4. AST and/or ALT values > 3 times the upper limit of normal range (ULN)

5. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C

6. Premature and permanent study drug discontinuation during the FUTURE 3 core study (AC-052-373)

7. Any major violation of the FUTURE 3 core study (AC-052-373) protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Children's Hospital - Site 9102	Aurora	Colorado	United States	80045
2	Children's National Medical Center - Site 9104	Washington	District of Columbia	United States	20010
3	Columbia University Medical Center Children's Hospital of New York Presbyterian - Site 9101	New York	New York	United States	10032
4	Royal Children's Hospital Melbourne, Cardiology - Site 5001	Parkville		Australia	3052
5	The Republican Scientific-Practical Center "Cardiology" - Site 3001	Minsk		Belarus	220036
6	Cardiovascular Institute and Fuwai Hospital	Beijing		China	100037
7	Shanghai Children's Medical Center - Site 5102	Shanghai		China	200127
8	Fakultní nemocnice v Motole, dětské kardiocentrum - Site 3301	Prague		Czechia	150 06
9	Hopital Necker-Enfants Malades, Service de Cardiologie Pédiatrique - Site 2201	Paris		France	75743
10	CHU de Toulouse - Hôpital des Enfants, Service de Cardiologie Pédiatrique - Site 2202	Toulouse		France	31059
11	Deutsches Herzzentrum Kinderkardiologie - Site 1401	Berlin		Germany	13353
12	Universitätsklinikum Bonn Abteilung für Kinderkardiologie - Site 1404	Bonn		Germany	53113
13	Justus-Liebig-Universität Giessen, Kinderherzzentrum - Site 1403	Giessen		Germany	35392
14	Gottsegen György Országos Kardiológiai Intézet, Gyermekszív Központ, Gyermek Kardiológiai osztály - Site 3401	Budapest		Hungary	1096
15	Szegedi Tudományegyetem ÁOK Szent-Györgyi Albert Klinikai Központ, Gyermekgyógyászati Klinika és Gyermekegészségügyi Központ - Site 3402	Szeged		Hungary	6720
16	CARE Hospitals, Cardiology Dep. Hyderabad - Site 5302	Hyderabad		India	500001
17	Schneider Children's Medical Center- Institute of pediatric cardiology - Site 7101	Petach Tikvah		Israel	49202
18	Università Degli Studi di Padova - Dipartimento di Pediatria - Servizio di Cardiologia Pediatrica - Site 1501	Padova		Italy	35128
19	Ospedale Pediatrico "Bambino Gesù" - Dipartimento Medico Chirurgico di Cardiologia Pediatrica - Site 1502	Rome		Italy	00193
20	Instituto Nacional de Cardiologia (INC) Ignacio Chavez - Site 8401	Mexico City		Mexico	14080
21	Uniwersyteckie Centrum Kliniczne Klinika Kardiologii Dziecięcej i Wad Wrodzonych Serca - Site 3604	Gdansk		Poland	80-952
22	Wojewódzki Szpital Specjalistyczny we Wrocławiu Oddział Kardiologii Dziecięcej z pododdziałem Intensywnego Nadzoru Kardiologicznego - Site 3605	Wroclaw		Poland	51-124
23	RAMS Institution, Research Institute for complex issues of cardiovascular diseases, Siberian branch of the Russian Academy of Medical Sciences - Site 3805	Kemerovo		Russian Federation	650002
24	Scientific Center of Cardiovascular Surgery named after A.N.Bakulev of the RAMS - Site 3803	Moscow		Russian Federation	121552
25	Moscow Scientific Research Institute for Pediatrics and Childrens Surgery of Rosmedtechnologies - Site 3804	Moscow		Russian Federation	125412
26	Federal State Institution "Federal center of Heart, Blood and Endocrinology named after V.A.Almazov Rosmedtekhnologies" - Site 3802	St. Petersberg		Russian Federation	197341
27	State Educational Institution of Higher Professional Education "Saint Petersburg State Pediatric Medical Academy of Roszdrav" - Site 3801	St. Petersburg		Russian Federation	194100
28	Univerzitetska dečja klinika, Služba za kardiologiju - Site 3901	Belgrade		Serbia	11000
29	Institut za zdravstvenu zaštitu majke i deteta Srbije "Dr Vukan Čupić", Služba za ispitivanje i lečenje bolesti srca i krvnih sudova - Site 3902	Belgrade		Serbia	11070
30	Department of Paediatric Cardiology University of the Free State - Site 6001	Bloemfontein		South Africa	9300
31	Division of Paediatric Cardiology, Steve Biko Academic Hospital - Site 6002	Pretoria		South Africa	0001
32	Hospital Universitatario Vall d'Hebron, Neumologia - Site 1907	Barcelona		Spain	08035
33	Hospital Universitario La Paz - Paediatric Cardiology Department - Site 1906	Madrid		Spain	28046
34	Clinical Diagnostic Center - Pediatric Cardiovascular and ANES and Intensive Care Department - Site 4103	Dnepropetrovsk		Ukraine	49060
35	Gusak Ins Urgent and Recovery SUR AMS - Cardiovascular Rehabilitation Pediatric Department - Site 4101	Donetsk		Ukraine	83045
36	Gover INS - Scientific Practical Cardiovascular Pediatric Center - MOH Ukraine - Site 4102	Kiev		Ukraine	01135

Sponsors and Collaborators

• Actelion

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT01338415
• Other Study ID Numbers: AC-052-374; 2010-021793-12
• First Posted: Apr 19, 2011
• Last Update Posted: Jun 16, 2021
• Last Verified: May 1, 2021

• Keywords provided by Actelion: pediatric; pulmonary arterial hypertension; bosentan; Tracleer
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Bosentan

Study Results

Participant Flow

Recruitment Details

Participants in this 1-year extension study were pediatric patients who completed the 6-month randomized open-label core study AC-052-373. In addition, patients were required to have tolerated study treatment during the FUTURE 3 core study and were considered by the investigator to benefit from continued bosentan treatment.

Pre-assignment Detail

64 patients were randomized in the FUTURE 3 core study, among whom 58 were enrolled in the FUTURE 3 extension study. Of the 58 participants in the FUTURE 3 extension study, a total of 10 participants entered the exceptional use treatment period (EUTP). Data for 3 participants in China after 19 Nov 2019 was not included in the report to meet the Human Genetic Resources Administration Office (HGRAO) requirements.

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Period Title: Core + Extension
STARTED	33	31	0
Enrolled in FUTURE 3 Extension	31	27	0
COMPLETED	23	22	0
NOT COMPLETED	10	9	0
Period Title: Core + Extension
STARTED	0	0	10
COMPLETED	0	0	4
NOT COMPLETED	0	0	6

Baseline Characteristics

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.	Total
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Total of all reporting groups
Overall Participants	33	31	64
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.5 (3.35)	5.2 (3.81)	4.8 (3.57)
Age, Customized (Count of Participants)
Infants and toddlers (28 days-23 months)	10 30.3%	11 35.5%	21 32.8%
Children (2-11 years)	23 69.7%	20 64.5%	43 67.2%
Sex: Female, Male (Count of Participants)
Female	18 54.5%	10 32.3%	28 43.8%
Male	15 45.5%	21 67.7%	36 56.3%
Race/Ethnicity, Customized (Count of Participants)
Caucasian/White	25 75.8%	23 74.2%	48 75%
Black	1 3%	2 6.5%	3 4.7%
Asian	6 18.2%	4 12.9%	10 15.6%
Hispanic	0 0%	1 3.2%	1 1.6%
Other	1 3%	1 3.2%	2 3.1%
Pulmonary Arterial Hypertension (PAH) etiology (Count of Participants)
Idiopathic	14 42.4%	15 48.4%	29 45.3%
Heritable	2 6.1%	0 0%	2 3.1%
Congenital heart disease	6 18.2%	2 6.5%	8 12.5%
Associated PAH (i.e.,PAH after surgery for CHD)	11 33.3%	13 41.9%	24 37.5%
Missing	0 0%	1 3.2%	1 1.6%
World Health Organization functional class (WHO FC) (Count of Participants)
FC I	9 27.3%	10 32.3%	19 29.7%
FC II	12 36.4%	15 48.4%	27 42.2%
FC III	12 36.4%	6 19.4%	18 28.1%

Outcome Measures

1. Primary Outcome

Title	Treatment Emergent Adverse Events (AEs) up to 7 Days After Permanent Study Drug Discontinuation
Description	This is the total number of subjects with at least one adverse event (serious or not serious) whether or not causally related to the study drug and presented cumulatively in the FUTURE 3 and FUTURE 3 Extension study. NOTE: FUTURE 3 extension study was exploratory and no primary efficacy and safety endpoints were defined in the protocol. So, this safety outcome measure was selected and reported as primary endpoint here.
Time Frame	Up to 62 weeks in average

Outcome Measure Data

Analysis Population Description

The analysis was performed on the Safety population analysis set, including all patients who received at least one dose of study treatment and evaluated according to the study treatment that they received.

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.
Measure Participants	33	31
Count of Participants [Participants]	29 87.9%	26 83.9%

2. Other Pre-specified Outcome

Title	Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC)
Description	The WHO FC indicates the severity of Pulmonary Arterial Hypertension: class I (none) to class IV (most severe). Changes from baseline to month 12 and month 18 of treatment with bosentan included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or no change/stable (same FC at baseline and at the post-baseline time point). Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.
Time Frame	At Month 12

Outcome Measure Data

Analysis Population Description

The intent to treat population was used. Where a missing visit score exists between two visits with scores, the missing score was imputed with the worse score of the non-missing scores; if the missing score was not between 2 visits with scores, it was replaced by the last non-missing score.

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.
Measure Participants	33	31
Stable WHO FC	22 66.7%	25 80.6%
Improved WHO FC	7 21.2%	3 9.7%
Worsened WHO FC	4 12.1%	3 9.7%

3. Other Pre-specified Outcome

Title	Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC)
Description	The WHO FC indicates the severity of Pulmonary Arterial Hypertension: class I (none) to class IV (most severe). Changes from baseline to month 12 and month 18 of treatment with bosentan included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or no change/stable (same FC at baseline and at the post-baseline time point). Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.
Time Frame	At Month 18

Outcome Measure Data

Analysis Population Description

The intent to treat population was used. Where a missing visit score exists between two visits with scores, the missing score was imputed with the worse score of the non-missing scores; if the missing score was not between 2 visits with scores, it was replaced by the last non-missing score.

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.
Measure Participants	33	31
Stable WHO FC	25 75.8%	25 80.6%
Improved WHO FC	3 9.1%	3 9.7%
Worsened WHO FC	5 15.2%	3 9.7%

4. Other Pre-specified Outcome

Title	Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS)
Description	The GCIS is a scale used to rate the patient's current overall clinical condition ("Very Good", "Good", "Neither Good or Bad", "Bad", and "Very Bad"). Rating was performed independently by the physician and parents or legal representatives. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.
Time Frame	At Month 12

Outcome Measure Data

Analysis Population Description

The intent to treat population was used for these analyses. No imputation method was used. Only patients with available results at the corresponding time point are included in the analysis.

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.
Measure Participants	28	23
Stable	16 48.5%	16 51.6%
Improved	10 30.3%	6 19.4%
Worsened	2 6.1%	1 3.2%
Stable	16 48.5%	12 38.7%
Improved	9 27.3%	11 35.5%
Worsened	3 9.1%	0 0%

5. Other Pre-specified Outcome

Title	Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS)
Description	The GCIS is a scale used to rate the patient's current overall clinical condition ("Very Good", "Good", "Neither Good or Bad", "Bad", and "Very Bad"). Rating was performed independently by the physician and parents or legal representatives. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study.
Time Frame	At Month 18

Outcome Measure Data

Analysis Population Description

The intent to treat population was used. No imputation method was used. Only patients with available results at the corresponding time point are including in the analysis.

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.
Measure Participants	19	18
Stable	9 27.3%	12 38.7%
Improved	6 18.2%	5 16.1%
Worsened	4 12.1%	1 3.2%
Stable	8 24.2%	7 22.6%
Improved	6 18.2%	10 32.3%
Worsened	5 15.2%	1 3.2%

6. Other Pre-specified Outcome

Title	Number of Patients With Pulmonary Arterial Hypertension (PAH) Worsening Components up to the Last Day of Treatment + 7 Days
Description	Number of patients with at least one PAH-worsening component (death, lung transplant, hospitalization due to PAH progression, initiation of new therapy for PAH, new/worsening right heart failure) reported cumulatively over FUTURE 3 core and extension study.
Time Frame	Up to 62 weeks in average

Outcome Measure Data

Analysis Population Description

The intent to treat population was used

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.
Measure Participants	33	31
At least one PAH-worsening event	10 30.3%	5 16.1%
No PAH-worsening event	23 69.7%	26 83.9%

7. Other Pre-specified Outcome

Title	Pulmonary Arterial Hypertension (PAH) Progression up to End of Treatment + 7 Days
Description	PAH progression was defined by time elapsed from the first study drug administration in the FUTURE core study to the day of the first occurrence of any of the following PAH worsening events: death, lung transplant, hospitalization due to PAH progression, initiation of new therapy for PAH or new / worsening right heart failure. Subjects without a PAH worsening event were censored at EOT + 7 days. PAH progression was estimated by Kaplan-Meier methodology and expressed by the percentage of participants free of events at different time points.
Time Frame	From baseline to Month 18

Outcome Measure Data

Analysis Population Description

These are the numbers of patients at risk at the time of study treatment initiation in the FUTURE 3 core study

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.
Measure Participants	33	31
Kaplan-Meier estimate at Month 12	74.9	88.9
Kaplan-Meier estimate at Month 18	68.2	81.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2mg/kg b.i.d., Bosentan 2mg/kg t.i.d.
	Comments	Post-hoc analysis: Cox proportional hazard regression univariate model with treatment as covariate (treatment-only univariate model)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.438
	Confidence Interval	(2-Sided) 95%; 0.470 to 4.399
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2mg/kg b.i.d., Bosentan 2mg/kg t.i.d.
	Comments	Post-hoc analysis: Cox proportional hazard regression univariate model with WHO FC at baseline (FC III vs FC I/II) as covariate
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0526
	Comments	p-value <= 10% indicates that the covariate WHO FC at baseline is related to the time to PAH worsening
	Method	Regression, Cox
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2mg/kg b.i.d., Bosentan 2mg/kg t.i.d.
	Comments	Post-hoc analysis: Treatment Hazard Ratio (HR) in the multivariate model with treatment and WHO FC at baseline as covariates
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.169
	Confidence Interval	() 95%; 0.371 to 3.681
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2mg/kg b.i.d., Bosentan 2mg/kg t.i.d.
	Comments	Test of improvement in model fit from the univariate to the multivariate model with WHO FC at baseline as covariate
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.076
	Comments	p-value <= 10% indicates an improvement in model fit
	Method	log(e) likelihood ratio
	Comments

8. Other Pre-specified Outcome

Title	Overall Survival
Description	Overall survival was defined as the time elapsed between the first study drug administration and death (any cause) up to end of study (Month 18 survival follow-up), regardless of whether the patient was on study treatment. Patients who died, regardless of the cause of death, were considered to have had an event. Patients last known to have been alive were censored on their date of last contact. Percentage of participants without death at different time points was estimated using Kaplan-Meier methodology.
Time Frame	From baseline to month 18

Outcome Measure Data

Analysis Population Description

These are the numbers of patients at risk at the time of study treatment initiation in the FUTURE 3 core study

Arm/Group Title	Bosentan 2mg/kg b.i.d.	Bosentan 2mg/kg t.i.d.
Arm/Group Description	Patients received 2 milligrams per kilogram (mg/kg) bosentan twice daily (b.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.	Patients received 2 mg/kg bosentan 3 times a day (t.i.d.) during the FUTURE 3 core study and continued with the same dose regimen during the extension study.
Measure Participants	33	31
Kaplan-Meier estimate at Month 12	81.8 247.9%	90.0 290.3%
Kaplan-Meier estimate at Month 18	75.8 229.7%	86.5 279%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2mg/kg b.i.d., Bosentan 2mg/kg t.i.d.
	Comments	Post-hoc analysis: Cox proportional hazard regression univariate model with treatment as covariate (treatment-only univariate model)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.935
	Confidence Interval	(2-Sided) 95%; 0.582 to 6.428
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2mg/kg b.i.d., Bosentan 2mg/kg t.i.d.
	Comments	Post-hoc analysis: Cox proportional hazard regression univariate model with WHO FC at baseline (FC III vs FC I/II) as covariate
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0085
	Comments
	Method	Regression, Cox
	Comments	p-value <= 10% indicates that the covariate is related to the time to the time to death up to end-of-study

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2mg/kg b.i.d., Bosentan 2mg/kg t.i.d.
	Comments	Post-hoc analysis: Treatment Hazard Ratio (HR) in the multivariate model with treatment and WHO FC at baseline as covariates
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.487
	Confidence Interval	(2-Sided) 95%; 0.437 to 5.052
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2mg/kg b.i.d., Bosentan 2mg/kg t.i.d.
	Comments	Test of the improvement in model fit from the univariate to the multivariate model with WHO FC at baseline as covariate
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	log(e) likelihood ratio
	Comments	p-value <= 10% indicates an improvement in model fit

9. Other Pre-specified Outcome

Title	Exceptional Use Treatment Period (EUTP): Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) up to 7 Days After Permanent Discontinuation of Study Drug
Description	An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline.
Time Frame	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)

Outcome Measure Data

Analysis Population Description

Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.

Arm/Group Title	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Measure Participants	10
Number [percentage of participants]	80 242.4%

10. Other Pre-specified Outcome

Title	EUTP: Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) up to 7 Days After Permanent Discontinuation of Study Drug
Description	An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time Frame	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)

Outcome Measure Data

Analysis Population Description

Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.

Arm/Group Title	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Measure Participants	10
Number [percentage of participants]	40 121.2%

11. Other Pre-specified Outcome

Title	EUTP: Percentage of Participants With AEs Leading to Premature Discontinuation of Study Drug
Description	An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. Percentage of participants with AEs leading to premature discontinuation of study drug were reported.
Time Frame	Up to 3 years and 4 months

Outcome Measure Data

Analysis Population Description

Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.

Arm/Group Title	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Measure Participants	10
Number [percentage of participants]	0 0%

12. Other Pre-specified Outcome

Title	EUTP: Percentage of Participants With SAEs From 7 up to 60 Days After Permanent Discontinuation of Study Drug
Description	A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time Frame	From 7 up to 60 days after permanent discontinuation of study drug (up to 3 years and 4 months)

Outcome Measure Data

Analysis Population Description

Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.

Arm/Group Title	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Measure Participants	10
Number [percentage of participants]	0 0%

13. Other Pre-specified Outcome

Title	EUTP: Percentage of Participants With Deaths
Description	Percentage of participants with deaths were reported.
Time Frame	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)

Outcome Measure Data

Analysis Population Description

Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.

Arm/Group Title	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Measure Participants	10
Number [percentage of participants]	10 30.3%

14. Other Pre-specified Outcome

Title	EUTP: Percentage of Participants With Adverse Events of Special Interest (AESI)
Description	Percentage of participants with AESI including liver abnormalities and anemia were reported.
Time Frame	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)

Outcome Measure Data

Analysis Population Description

Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.

Arm/Group Title	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Measure Participants	10
Number [percentage of participants]	20 60.6%

15. Other Pre-specified Outcome

Title	EUTP: Percentage of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 7 Days After Permanent Discontinuation of Study Drug
Description	Percentage of participants with treatment-emergent marked laboratory abnormalities were reported.
Time Frame	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)

Outcome Measure Data

Analysis Population Description

Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.

Arm/Group Title	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Measure Participants	10
Number [percentage of participants]	0 0%

16. Other Pre-specified Outcome

Title	EUTP: Percentage of Participants With Liver Function Abnormalities
Description	Percentage of participants with liver function abnormalities: Alanine aminotransferase (ALT) greater than (>)3*upper limit of normal (ULN), ALT/aspartate aminotransferase (AST) >3*ULN, ALT /AST >3*ULN and less than or equal to (<=) 5*ULN, ALT/AST >5*ULN and <=8*ULN, ALT/AST >8*ULN and ALT/AST >3*ULN, total bilirubin >2*ULN and alkaline phosphatase (ALP) <=2*ULN were reported.
Time Frame	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)

Outcome Measure Data

Analysis Population Description

Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.

Arm/Group Title	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Measure Participants	10
Number [percentage of participants]	0 0%

17. Other Pre-specified Outcome

Title	EUTP: Percentage of Participants With Any Time Occurrence of Hemoglobin <=10 Gram Per Deciliter (g/dL) and <=8g/dL Between Baseline and up to 7 Days After End of Treatment (EOT)
Description	Percentage of participants with any time occurrence of hemoglobin (Hgb) less than or equal to (<=) 10 g/dL and 8 g/dL between baseline and up to the last day of treatment + 7 days during EUTP were reported. Here "N" (number of subjects analyzed) signifies subjects who were evaluable for this outcome measure.
Time Frame	Baseline, up to 7 days after end of treatment (up to 3 years and 4 months)

Outcome Measure Data

Analysis Population Description

Exceptional-use set included all patients who entered the EUTP. Due to change in study conduct, patients treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17 March 2015 for Belarus and Ukraine, 1 April 2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the results were reported combined for bosentan b.i.d./t.i.d.

Arm/Group Title	Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d.
Measure Participants	9
Hgb <=10 g/dL	22.2 67.3%
Hgb <=8 g/dL	0 0%

Adverse Events

Time Frame	From baseline up to end of treatment (and up to additional 60 days for serious adverse events and deaths), i.e. an average of 62 weeks and for EUTP: up to 7 days after discontinuation of study drug (approximately 3 years and 4 months)
Adverse Event Reporting Description	Adverse events are reported cumulatively for the FUTURE 3 core and extension studies
Arm/Group Title	Bosentan 2mg/kg b.i.d.		Bosentan 2mg/kg t.i.d		Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
Arm/Group Description	2 mg/kg bosentan was administered twice daily for a cumulative mean (± SD) duration of 64.1 ± 3.38 weeks (FUTURE 3 core + extension studies)		2 mg/kg bosentan was administered 3 times a day for a cumulative mean (± SD) duration of 60.4 ± 4.20 weeks (FUTURE 3 core + extension studies)		Participants who entered the exceptional use treatment period (EUTP), continued receiving 2 mg/kg bosentan b.i.d or t.i.d up to Amendment B. After implementation of Amendment B, all participants received 2 mg/kg bosentan b.i.d. Due to change in study conduct, participants treated with bosentan t.i.d. switched to b.i.d. after local Amendment B to global protocol version 2 (17-03-2015 for Belarus and Ukraine, 1-04-2015 for China) and displaying summaries in the EUTP period by dose were not significant. Therefore, the data were combined for Bosentan b.i.d. and t.i.d.
All Cause Mortality
	Bosentan 2mg/kg b.i.d.		Bosentan 2mg/kg t.i.d		Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/33 (24.2%)		4/31 (12.9%)		1/10 (10%)
Serious Adverse Events
	Bosentan 2mg/kg b.i.d.		Bosentan 2mg/kg t.i.d		Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/33 (45.5%)		13/31 (41.9%)		4/10 (40%)
Cardiac disorders
CARDIAC ARREST	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
CARDIAC FAILURE	1/33 (3%)	2	0/31 (0%)	0	0/10 (0%)	0
CARDIAC FAILURE ACUTE	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
CARDIOPULMONARY FAILURE	1/33 (3%)	1	1/31 (3.2%)	1	0/10 (0%)	0
CYANOSIS	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
Congenital, familial and genetic disorders
MUCOPOLYSACCHARIDOSIS	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
Gastrointestinal disorders
GASTROOESOPHAGEAL REFLUX DISEASE	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
General disorders
DEATH	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
MULTI-ORGAN FAILURE	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
PYREXIA	0/33 (0%)	0	1/31 (3.2%)	2	0/10 (0%)	0
Immune system disorders
DRUG HYPERSENSITIVITY	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
Infections and infestations
BRONCHITIS	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
BRONCHOPNEUMONIA	0/33 (0%)	0	2/31 (6.5%)	2	0/10 (0%)	0
GASTROENTERITIS	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
GASTROENTERITIS ADENOVIRUS	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
GASTROENTERITIS ROTAVIRUS	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
INFECTION	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
LOWER RESPIRATORY TRACT INFECTION VIRAL	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
PNEUMONIA	1/33 (3%)	1	3/31 (9.7%)	3	1/10 (10%)	1
RESPIRATORY TRACT INFECTION VIRAL	0/33 (0%)	0	1/31 (3.2%)	1	1/10 (10%)	1
VIRAL INFECTION	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
VIRAL UPPER RESPIRATORY TRACT INFECTION	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
Injury, poisoning and procedural complications
FALL	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
HEAD INJURY	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
Investigations
BODY TEMPERATURE INCREASED	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
OXYGEN SATURATION DECREASED	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
Metabolism and nutrition disorders
METABOLIC DISORDER	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
Nervous system disorders
CONVULSION	0/33 (0%)	0	1/31 (3.2%)	4	0/10 (0%)	0
LOSS OF CONSCIOUSNESS	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
MIGRAINE WITH AURA	1/33 (3%)	1	0/31 (0%)	0	1/10 (10%)	1
SYNCOPE	2/33 (6.1%)	3	0/31 (0%)	0	0/10 (0%)	0
Respiratory, thoracic and mediastinal disorders
ADENOIDAL HYPERTROPHY	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
EPISTAXIS	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
PULMONARY ARTERIAL HYPERTENSION	4/33 (12.1%)	4	2/31 (6.5%)	2	0/10 (0%)	0
PULMONARY EMBOLISM	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
PULMONARY HYPERTENSIVE CRISIS	0/33 (0%)	0	1/31 (3.2%)	2	2/10 (20%)	2
RESPIRATORY DISTRESS	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
Haemoptysis	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Surgical and medical procedures
ATRIAL SEPTAL DEFECT REPAIR	0/33 (0%)	0	1/31 (3.2%)	1	0/10 (0%)	0
CARDIAC OPERATION	1/33 (3%)	1	0/31 (0%)	0	0/10 (0%)	0
Other (Not Including Serious) Adverse Events
	Bosentan 2mg/kg b.i.d.		Bosentan 2mg/kg t.i.d		Bosentan 2mg/kg b.i.d or t.i.d. During EUTP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/33 (72.7%)		23/31 (74.2%)		8/10 (80%)
Blood and lymphatic system disorders
THROMBOCYTOPENIA	2/33 (6.1%)	2	0/31 (0%)	0	1/10 (10%)	1
SPLENOMEGALY	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
ANAEMIA	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Cardiac disorders
CYANOSIS	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Gastrointestinal disorders
ABDOMINAL PAIN	1/33 (3%)	1	2/31 (6.5%)	2	0/10 (0%)	0
CONSTIPATION	1/33 (3%)	1	3/31 (9.7%)	4	0/10 (0%)	0
DIARRHOEA	2/33 (6.1%)	2	6/31 (19.4%)	9	0/10 (0%)	0
VOMITING	4/33 (12.1%)	5	6/31 (19.4%)	10	0/10 (0%)	0
ABDOMINAL DISCOMFORT	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
General disorders
OEDEMA PERIPHERAL	2/33 (6.1%)	2	0/31 (0%)	0	0/10 (0%)	0
PYREXIA	5/33 (15.2%)	15	7/31 (22.6%)	15	3/10 (30%)	3
CHEST PAIN	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
EXERCISE TOLERANCE DECREASED	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Hepatobiliary disorders
HEPATIC FUNCTION ABNORMAL	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Immune system disorders
SEASONAL ALLERGY	0/33 (0%)	0	2/31 (6.5%)	2	0/10 (0%)	0
HYPERSENSITIVITY	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Infections and infestations
BRONCHITIS	3/33 (9.1%)	4	2/31 (6.5%)	2	0/10 (0%)	0
EAR INFECTION	2/33 (6.1%)	2	0/31 (0%)	0	0/10 (0%)	0
GASTROENTERITIS	3/33 (9.1%)	3	3/31 (9.7%)	3	0/10 (0%)	0
INFLUENZA	0/33 (0%)	0	2/31 (6.5%)	2	0/10 (0%)	0
LARYNGITIS	2/33 (6.1%)	4	0/31 (0%)	0	0/10 (0%)	0
LOWER RESPIRATORY TRACT INFECTION	1/33 (3%)	1	2/31 (6.5%)	2	0/10 (0%)	0
NASOPHARYNGITIS	6/33 (18.2%)	16	5/31 (16.1%)	8	1/10 (10%)	1
OTITIS MEDIA	2/33 (6.1%)	5	1/31 (3.2%)	1	0/10 (0%)	0
OTITIS MEDIA CHRONIC	2/33 (6.1%)	2	0/31 (0%)	0	0/10 (0%)	0
PHARYNGITIS	2/33 (6.1%)	3	0/31 (0%)	0	0/10 (0%)	0
RESPIRATORY TRACT INFECTION	2/33 (6.1%)	3	1/31 (3.2%)	2	1/10 (10%)	2
RHINITIS	0/33 (0%)	0	2/31 (6.5%)	3	0/10 (0%)	0
TONSILLITIS	0/33 (0%)	0	2/31 (6.5%)	2	1/10 (10%)	1
UPPER RESPIRATORY TRACT INFECTION	9/33 (27.3%)	22	13/31 (41.9%)	26	2/10 (20%)	2
VIRAL INFECTION	2/33 (6.1%)	2	1/31 (3.2%)	1	0/10 (0%)	0
VIRAL UPPER RESPIRATORY TRACT INFECTION	4/33 (12.1%)	6	3/31 (9.7%)	3	2/10 (20%)	2
PNEUMONIA	0/33 (0%)	0	0/31 (0%)	0	2/10 (20%)	2
VARICELLA	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Injury, poisoning and procedural complications
ACCIDENTAL OVERDOSE	0/33 (0%)	0	2/31 (6.5%)	2	0/10 (0%)	0
Investigations
BLOOD BILIRUBIN INCREASED	2/33 (6.1%)	2	1/31 (3.2%)	1	1/10 (10%)	1
LIVER FUNCTION TEST ABNORMAL	0/33 (0%)	0	2/31 (6.5%)	2	0/10 (0%)	0
Metabolism and nutrition disorders
HYPOPROTEINAEMIA	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
METABOLIC ACIDOSIS	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
COUGH	4/33 (12.1%)	4	3/31 (9.7%)	3	1/10 (10%)	1
EPISTAXIS	0/33 (0%)	0	3/31 (9.7%)	4	1/10 (10%)	1
NASAL CONGESTION	0/33 (0%)	0	2/31 (6.5%)	2	0/10 (0%)	0
PULMONARY ARTERIAL HYPERTENSION	2/33 (6.1%)	2	0/31 (0%)	0	1/10 (10%)	2
RHINORRHOEA	3/33 (9.1%)	3	0/31 (0%)	0	1/10 (10%)	1
DYSPNOEA	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
OROPHARYNGEAL PAIN	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
RESPIRATORY FAILURE	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Haemoptysis	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
Skin and subcutaneous tissue disorders
DERMATITIS ALLERGIC	0/33 (0%)	0	2/31 (6.5%)	2	0/10 (0%)	0
RASH	1/33 (3%)	1	2/31 (6.5%)	2	0/10 (0%)	0
URTICARIA	0/33 (0%)	0	2/31 (6.5%)	2	0/10 (0%)	0
Vascular disorders
FLUSHING	0/33 (0%)	0	2/31 (6.5%)	2	0/10 (0%)	0
CIRCULATORY COLLAPSE	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1
HYPOTENSION	0/33 (0%)	0	0/31 (0%)	0	1/10 (10%)	1

Limitations/Caveats

The study was uncontrolled and exploratory. The main purpose of exceptional use treatment period of FUTURE 3 extension was to provide participants with bosentan beyond 12-month treatment period of FUTURE 3 extension. Providing bosentan as a study treatment required monitoring safety on an individual participant-level. No formal hypothesis was formulated, therefore results were exploratory.

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Certain Agreements

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

Any study-related article or abstract written independently by investigators must be submitted to Actelion for review at least 60 days prior to submission for publication or presentation.