FUTURE 3: Effects of Two Dosing Regimens of Bosentan in Children With Pulmonary Arterial Hypertension

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01223352
• Collaborator: (none)
• Enrollment: 64
• Locations: 48
• Arms: 2
• Actual Duration (Months): 29.4
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The primary objective of AC-052-373 was to assess the pharmacokinetic (PK) profile of two dosing regimens of the pediatric formulation of bosentan in children with pulmonary arterial hypertension (PAH) <12 years of age.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Prospective Multicenter Study to Assess the Pharmacokinetics, Tolerability, Safety 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: Apr 3, 2013
• Actual Study Completion Date: Aug 19, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bosentan 2 mg/Kg t.i.d. 2 mg/kg bosentan administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks	Drug: bosentan; 32 mg quadrisected dispersible tablet. The dosage of bosentan (2 mg/Kg) was adjusted according to the patient's body weight at initiation of the study treatment. Dosage readjustment was permitted after 12 weeks of treatment.; Other Names: Tracleer ACT-050088
Experimental: Bosentan 2 mg/Kg b.i.d. 2 mg/kg bosentan administered twice daily (morning and evening) for a planned duration of 24 weeks	Drug: bosentan; 32 mg quadrisected dispersible tablet. The dosage of bosentan (2 mg/Kg) was adjusted according to the patient's body weight at initiation of the study treatment. Dosage readjustment was permitted after 12 weeks of treatment.; Other Names: Tracleer ACT-050088

Outcome Measures

Primary Outcome Measures

1. Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan [0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment]

   Daily exposure was measured by the area under the plasma concentration-time curve over a period of 24 hours [AUC(0-24)]. Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. AUC(0-24) was calculated as a multiple of AUCtau, which is the AUC over a dosing interval (AUCtau x 2 for the b.i.d. dosing regimen and AUCtau x 3 for the t.i.d. regimen). As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg. Therefore, AUC(0-24) was corrected to 2 mg/kg (target dose) [AUC(0-24c)].

Other Outcome Measures

1. Dose-corrected Maximum Plasma Concentration [Cmaxc] of Bosentan [0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment]

   Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. The peak plasma concentration (Cmax) of bosentan was directly obtained from the measured plasma concentrations and was dose-corrected to the target dose of 2 mg/kg (Cmaxc).

2. Time to Reach Cmax [Tmax] of Bosentan [0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment]

   Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. tmax was obtained directly from the measured plasma concentrations.

3. Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan Metabolites (Ro 478634, Ro 485033, Ro 641056) [0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment]

   Concentrations of the metabolites were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. Daily exposure to the metabolites corresponds to the area under the concentration-time curve [AUC(0-24)] of the corresponding metabolite over a period of 24 hours, and was calculated in the same manner as the primary endpoint. AUC(0-24c) was corrected to 2 mg/kg (target dose) [AUC(0-24c)].

4. Change From Baseline in WHO Functional Class at End of Study [Baseline, up to Week 24 on average]

   The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension (PH): Class I (FC I): No limitation of physical activity. Class II (FC II): Slight limitation of physical activity. Class IIII (FC III): Marked limitation of physical activity. Class IV (FC IV): Inability to carry out any physical activity without symptoms. Number of patients with improvement (shift from a higher to a lower class), worsening (shift from a lower to a higher class) or no change in WHO functional class at end of study compared to baseline are determined.

5. Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study [Baseline, up to Week 24 on average]

   The GCIS is an assessment tool providing a single global assessment of the patient's current overall clinical condition: Very Good, Good, Neither Good or Bad, Bad and Very Bad. The assessment was performed both by the physician and the parents / legal representatives independently. Global clinical impression (GCI) at end of study was compared to GCI at baseline and the number of patients with clinical condition considered as worsened, improved or unchanged are determined.

6. Number of Patients With Treatment-emergent Liver Function Abnormalities [Baseline, up to Week 24]

   Number of patients with increase in alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) above 3 times upper limit of normal (ULN). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date.

7. Number of Patients With Treatment-emergent Hemoglobin Abnormalities [Baseline, up to Week 24]

   Number of patients with marked hemoglobin decreases (absolute values below 10 g/dL). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. PAH diagnosis confirmed with right heart catheterization (RHC):

• Idiopathic or heritable PAH, or

• Associated PAH persisting after complete repair of a congenital heart defect (PAH has to be persistent for at least 6 months after surgery) or

• PAH-Congenital Heart Disease (PAH-CHD) associated with systemic-to-pulmonary shunts (after global amendment dated 09 May 2012)

1. World Health Organization functional Class (WHO FC) I, II or III

2. Male or female ≥ 3 months and < 12 years of age (maximum age at randomization is 11.5 years)

3. Body weight ≥ 3.5 kg

4. Peripheral oxygen saturation (SpO2) ≥ 88% (at rest, on room air)

5. Baseline PAH-therapy (Calcium channel blocker, bosentan, prostanoid, phosphodiesterase type-5 inhibitor) if present, has to be stable for at least 3 months prior to screening. During the study, all background treatments should remain stable

6. Signed informed consent by the parents or legal representatives

Exclusion Criteria:

1. PAH etiologies other than listed above

2. Non-stable disease status

3. Need or plan to wean patient from intravenous epoprostenol or intravenous or inhaled iloprost

4. Systolic blood pressure < 80% of the lower limit of normal range

5. Aspartate aminotransferase and/or alanine aminotransferase values > 1.5 times the upper limit of normal range.

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

7. Hemoglobin and/or hematocrit levels < 75% of the lower limit of normal range.

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

9. Treatment with forbidden medication within 2 weeks or at least 5 times the half-life prior to randomization, whichever is the longest:

• Glibenclamide (glyburide)

• Cyclosporin A

• Sirolimus

• Tacrolimus

• Fluconazole

• Rifampicin (rifampin)

• Ritonavir

• Co-administration of CYP2C9 inhibitors (e.g., amiodarone, voriconazole) and moderate/strong CYP3A4 inhibitors (e.g., amprenavir, erythromycin, ketoconazole, diltiazem, itraconazole)

• Endothelin receptor antagonists (ERAs) other than bosentan

1. Treatment with another investigational drug within 1 month prior to randomization or planned treatment

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	Texas Children's Hospital - Department of Cardiology - Site 9107	Houston	Texas	United States	77030
5	Seattle Children's Hospital - Site 9106	Seattle	Washington	United States	98105
6	Royal Children's Hospital Melbourne, Cardiology - Site 5001	Parkville		Australia	3052
7	The Republican Scientific-Practical Center "Cardiology" - Site 3001	Minsk		Belarus	220036
8	Beijing Anzhen Hospital, Capital Medical University- Department of Pediatric Cardiology - Site 5103	Beijing		China	100029
9	Cardiovascular Institute and Fuwai Hospital	Beijing		China	100037
10	West China 2nd university Hospital-Center of interventional diagnosis and therapy for Children's cardiovascular disease - Site 5104	Chengdu		China	610041
11	Guangdong General Hospital - Site 5105	Guangdong		China	510080
12	Shanghai Children's Medical Center - Site 5102	Shanghai		China	200127
13	Shanghai Pulmonary Hospital, Department of Pulmonary Circulation - Site 5101	Shanghai		China	200433
14	Fakultní nemocnice v Motole, dětské kardiocentrum - Site 3301	Prague		Czechia	150 06
15	Hopital Necker-Enfants Malades, Service de Cardiologie Pédiatrique - Site 2201	Paris		France	75743
16	CHU de Toulouse - Hôpital des Enfants, Service de Cardiologie Pédiatrique - Site 2202	Toulouse		France	31059
17	Deutsches Herzzentrum Kinderkardiologie - Site 1401	Berlin		Germany	13353
18	Universitätsklinikum Bonn Abteilung für Kinderkardiologie - Site 1404	Bonn		Germany	53113
19	Justus-Liebig-Universität Giessen, Kinderherzzentrum - Site 1403	Giessen		Germany	35392
20	Gottsegen György Országos Kardiológiai Intézet, Gyermekszív Központ, Gyermek Kardiológiai osztály - Site 3401	Budapest		Hungary	1096
21	Szegedi Tudományegyetem ÁOK Szent-Györgyi Albert Klinikai Központ, Gyermekgyógyászati Klinika és Gyermekegészségügyi Központ - Site 3402	Szeged		Hungary	6720
22	CARE Hospitals, Cardiology Dep. Hyderabad - Site 5302	Hyderabad		India	500001
23	Indraprashta Apollo Hospitals, Pediatric Cardiology - Site 5303	New Delhi		India	110076
24	Schneider Children's Medical Center- Institute of pediatric cardiology - Site 7101	Petach Tikvah		Israel	49202
25	Università Degli Studi di Padova - Dipartimento di Pediatria - Servizio di Cardiologia Pediatrica - Site 1501	Padova		Italy	35128
26	Ospedale Pediatrico "Bambino Gesù" - Dipartimento Medico Chirurgico di Cardiologia Pediatrica - Site 1502	Rome		Italy	00193
27	Instituto Nacional de Cardiologia (INC) Ignacio Chavez - Site 8401	Mexico City		Mexico	14080
28	Unidad de Investigacion Clinica en Medicina, SC (UDICEM) - Site 8402	Monterrey		Mexico	64710
29	Universitair Medish Centrum Groningen, Kindercardiologie - Site 1601	Groningen		Netherlands	9713 GZ
30	Uniwersyteckie Centrum Kliniczne Klinika Kardiologii Dziecięcej i Wad Wrodzonych Serca - Site 3604	Gdansk		Poland	80-952
31	Instytut Centrum Zdrowia Matki Polki Klinika Kardiologii ICMP w Lodz - Site 3602	Lodz		Poland	93-336
32	Instytut Pomnik - Centrum Zdrowia Dziecka Klinika Kardiologii Dziecięcej - Site 3601	Warszawa		Poland	04-730
33	Wojewódzki Szpital Specjalistyczny we Wrocławiu Oddział Kardiologii Dziecięcej z pododdziałem Intensywnego Nadzoru Kardiologicznego - Site 3605	Wroclaw		Poland	51-124
34	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
35	Scientific Center of Cardiovascular Surgery named after A.N.Bakulev of the RAMS - Site 3803	Moscow		Russian Federation	121552
36	Moscow Scientific Research Institute for Pediatrics and Childrens Surgery of Rosmedtechnologies - Site 3804	Moscow		Russian Federation	125412
37	Federal State Institution "Federal center of Heart, Blood and Endocrinology named after V.A.Almazov Rosmedtekhnologies" - Site 3802	St. Petersberg		Russian Federation	197341
38	State Educational Institution of Higher Professional Education "Saint Petersburg State Pediatric Medical Academy of Roszdrav" - Site 3801	St. Petersburg		Russian Federation	194100
39	Univerzitetska dečja klinika, Služba za kardiologiju - Site 3901	Belgrade		Serbia	11000
40	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
41	Department of Paediatric Cardiology University of the Free State - Site 6001	Bloemfontein		South Africa	9300
42	Paediatric Cardiology Albert Luthuli Central Hospital - Site 6003	Durban		South Africa	4001
43	Division of Paediatric Cardiology, Steve Biko Academic Hospital - Site 6002	Pretoria		South Africa	0001
44	Hospital Universitatario Vall d'Hebron, Neumologia - Site 1907	Barcelona		Spain	08035
45	Hospital Universitario La Paz - Paediatric Cardiology Department - Site 1906	Madrid		Spain	28046
46	Clinical Diagnostic Center - Pediatric Cardiovascular and ANES and Intensive Care Department - Site 4103	Dnepropetrovsk		Ukraine	49060
47	Gusak Ins Urgent and Recovery SUR AMS - Cardiovascular Rehabilitation Pediatric Department - Site 4101	Donetsk		Ukraine	83045
48	Gover INS - Scientific Practical Cardiovascular Pediatric Center - MOH Ukraine - Site 4102	Kiev		Ukraine	01135

Sponsors and Collaborators

• Actelion

Investigators

• Study Director: Andjela Kusic-Pajic, MD, Actelion

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT01223352
• Other Study ID Numbers: AC-052-373
• First Posted: Oct 19, 2010
• Last Update Posted: Dec 11, 2017
• Last Verified: Nov 1, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Actelion: pulmonary arterial hypertension; children; pediatric; bosentan
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Bosentan

Study Results

Participant Flow

Recruitment Details	Forty-five expert pediatric centers were initiated but only thirty of them enrolled children with pulmonary arterial hypertension (PAH)

Arm/Group Title	Bosentan 2 mg/kg t.i.d.	Bosentan 2 mg/kg b.i.d.
Arm/Group Description	2 mg/kg bosentan (dispersible tablets) was administered orally three times a day (t.i.d.) for a planned duration of 24 weeks	2 mg/kg bosentan (dispersible tablets) was administered orally twice daily (b.i.d.) for a planned duration of 24 weeks
Period Title: Overall Study
STARTED	31	33
COMPLETED	31	33
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Bosentan 2 mg/kg t.i.d.	Bosentan 2 mg/kg b.i.d.	Total
Arm/Group Description	2 mg/kg bosentan (dispersible tablets) was administered orally three times a day (t.i.d.) for a planned duration of 24 weeks	2 mg/kg bosentan (dispersible tablets) was administered orally twice daily (b.i.d.) for a planned duration of 24 weeks	Total of all reporting groups
Overall Participants	31	33	64
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	5.2 (3.81)	4.5 (3.35)	4.8 (3.57)
Sex: Female, Male (Count of Participants)
Female	10 32.3%	18 54.5%	28 43.8%
Male	21 67.7%	15 45.5%	36 56.3%
Region of Enrollment (Number) [Number]
Australia	2 6.5%	0 0%	2 3.1%
Belarus	1 3.2%	2 6.1%	3 4.7%
China	2 6.5%	4 12.1%	6 9.4%
Czech Republic	1 3.2%	1 3%	2 3.1%
France	1 3.2%	4 12.1%	5 7.8%
Germany	3 9.7%	1 3%	4 6.3%
Hungary	3 9.7%	0 0%	3 4.7%
India	1 3.2%	2 6.1%	3 4.7%
Israel	0 0%	2 6.1%	2 3.1%
Italy	1 3.2%	0 0%	1 1.6%
Mexico	1 3.2%	0 0%	1 1.6%
Poland	2 6.5%	3 9.1%	5 7.8%
Russia	4 12.9%	6 18.2%	10 15.6%
Serbia	2 6.5%	3 9.1%	5 7.8%
South Africa	4 12.9%	2 6.1%	6 9.4%
Spain	1 3.2%	2 6.1%	3 4.7%
USA	1 3.2%	1 3%	2 3.1%
Ukraine	1 3.2%	0 0%	1 1.6%
Etiology of pulmonary arterial hypertension (PAH) (Count of Participants)
Idiopathic	15 48.4%	14 42.4%	29 45.3%
Heritable	0 0%	2 6.1%	2 3.1%
PAH-Congenital heart disease	2 6.5%	6 18.2%	8 12.5%
Associated PAH	13 41.9%	11 33.3%	24 37.5%
Missing data	1 3.2%	0 0%	1 1.6%
World Health Organization functional class (WHO FC) (Number) [Number]
FC I	10 32.3%	9 27.3%	19 29.7%
FC II	15 48.4%	12 36.4%	27 42.2%
FC III	6 19.4%	12 36.4%	18 28.1%
PAH-specific therapy at baseline (Number) [Number]
Bosentan (adult tablet formulation)	4 12.9%	3 9.1%	7 10.9%
Prostanoid	1 3.2%	0 0%	1 1.6%
Phosphodiesterase type-5 (PDE-5) inhibitor	13 41.9%	10 30.3%	23 35.9%
Bosentan / PDE-5 inhibitor combination	2 6.5%	2 6.1%	4 6.3%
Bosentan /PDE-5 inhibitor /Prostanoid combination	2 6.5%	5 15.2%	7 10.9%
None	9 29%	13 39.4%	22 34.4%

Outcome Measures

1. Primary Outcome

Title	Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan
Description	Daily exposure was measured by the area under the plasma concentration-time curve over a period of 24 hours [AUC(0-24)]. Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. AUC(0-24) was calculated as a multiple of AUCtau, which is the AUC over a dosing interval (AUCtau x 2 for the b.i.d. dosing regimen and AUCtau x 3 for the t.i.d. regimen). As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg. Therefore, AUC(0-24) was corrected to 2 mg/kg (target dose) [AUC(0-24c)].
Time Frame	0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment

Outcome Measure Data

Analysis Population Description

Per-protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.

Arm/Group Title	Bosentan 2 mg/kg t.i.d. (PK Set)	Bosentan 2 mg/kg b.i.d. (PK Set)
Arm/Group Description	Patients randomized to the bosentan 2 mg/kg t.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.	Patients randomized to the bosentan 2 mg/kg b.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.
Measure Participants	27	31
Geometric Mean (95% Confidence Interval) [h*ng/mL]	7275.1	8535.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2 mg/kg t.i.d. (PK Set), Bosentan 2 mg/kg b.i.d. (PK Set)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	b.i.d. bosentan regimen was taken as reference

2. Other Pre-specified Outcome

Title	Dose-corrected Maximum Plasma Concentration [Cmaxc] of Bosentan
Description	Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. The peak plasma concentration (Cmax) of bosentan was directly obtained from the measured plasma concentrations and was dose-corrected to the target dose of 2 mg/kg (Cmaxc).
Time Frame	0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment

Outcome Measure Data

Analysis Population Description

Per-protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.

Arm/Group Title	Bosentan 2 mg/kg t.i.d. (PK Set)	Bosentan 2 mg/kg b.i.d. (PK Set)
Arm/Group Description	Patients randomized to the bosentan 2 mg/kg t.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.	Patients randomized to the bosentan 2 mg/kg b.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.
Measure Participants	27	31
Geometric Mean (95% Confidence Interval) [ng/mL]	527.9	742.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan 2 mg/kg t.i.d. (PK Set), Bosentan 2 mg/kg b.i.d. (PK Set)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.48 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	b.i.d. bosentan regimen was taken as reference

3. Other Pre-specified Outcome

Title	Time to Reach Cmax [Tmax] of Bosentan
Description	Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. tmax was obtained directly from the measured plasma concentrations.
Time Frame	0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment

Outcome Measure Data

Analysis Population Description

Per protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.

Arm/Group Title	Bosentan 2 mg/kg t.i.d. (PK Set)	Bosentan 2 mg/kg b.i.d. (PK Set)
Arm/Group Description	Patients randomized to the bosentan 2 mg/kg t.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.	Patients randomized to the bosentan 2 mg/kg b.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.
Measure Participants	27	31
Median (Full Range) [hours]	3	3

4. Other Pre-specified Outcome

Title	Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan Metabolites (Ro 478634, Ro 485033, Ro 641056)
Description	Concentrations of the metabolites were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. Daily exposure to the metabolites corresponds to the area under the concentration-time curve [AUC(0-24)] of the corresponding metabolite over a period of 24 hours, and was calculated in the same manner as the primary endpoint. AUC(0-24c) was corrected to 2 mg/kg (target dose) [AUC(0-24c)].
Time Frame	0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment

Outcome Measure Data

Analysis Population Description

Per protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.

Arm/Group Title	Bosentan 2 mg/kg t.i.d. (PK Set)	Bosentan 2 mg/kg b.i.d. (PK Set)
Arm/Group Description	Patients randomized to the bosentan 2 mg/kg t.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.	Patients randomized to the bosentan 2 mg/kg b.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.
Measure Participants	27	31
AUC(0-24C) for Ro 478634	173.2	200.4
AUC(0-24C) for Ro 485033	968.8	1352.5
AUC(0-24C) for Ro 641056	716.2	1014.1

5. Other Pre-specified Outcome

Title	Change From Baseline in WHO Functional Class at End of Study
Description	The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension (PH): Class I (FC I): No limitation of physical activity. Class II (FC II): Slight limitation of physical activity. Class IIII (FC III): Marked limitation of physical activity. Class IV (FC IV): Inability to carry out any physical activity without symptoms. Number of patients with improvement (shift from a higher to a lower class), worsening (shift from a lower to a higher class) or no change in WHO functional class at end of study compared to baseline are determined.
Time Frame	Baseline, up to Week 24 on average

Outcome Measure Data

Analysis Population Description

All-randomized set. Because all 64 randomized patients were treated with at least one dose of study drug, the All-randomized set was identical to the All-treated set.

Arm/Group Title	Bosentan 2 mg/kg t.i.d.	Bosentan 2 mg/kg b.i.d
Arm/Group Description	Patients randomized to the bosentan 2 mg/kg t.i.d. group.	Patients randomized to the bosentan 2 mg/kg b.i.d. group.
Measure Participants	31	33
Worsened WHO FC	1 3.2%	1 3%
Unchanged WHO FC	27 87.1%	25 75.8%
Improved WHO FC	3 9.7%	7 21.2%

6. Other Pre-specified Outcome

Title	Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study
Description	The GCIS is an assessment tool providing a single global assessment of the patient's current overall clinical condition: Very Good, Good, Neither Good or Bad, Bad and Very Bad. The assessment was performed both by the physician and the parents / legal representatives independently. Global clinical impression (GCI) at end of study was compared to GCI at baseline and the number of patients with clinical condition considered as worsened, improved or unchanged are determined.
Time Frame	Baseline, up to Week 24 on average

Outcome Measure Data

Analysis Population Description

All-randomized set. Because all 64 randomized patients were treated with at least one dose of study drug, the All-randomized set was identical to the All-treated set.

Arm/Group Title	Bosentan 2 mg/kg t.i.d.	Bosentan 2 mg/kg b.i.d.
Arm/Group Description	Patients randomized to the bosentan 2 mg/kg t.i.d. group	Patients randomized to the bosentan 2 mg/kg b.i.d. group
Measure Participants	31	33
Worsened as per physician evaluation	2 6.5%	2 6.1%
Worsened as per parents evaluation	4 12.9%	3 9.1%
Unchanged as per physician evaluation	24 77.4%	24 72.7%
Unchanged as per parents evaluation	19 61.3%	19 57.6%
Improved as per physician evaluation	5 16.1%	7 21.2%
Improved as per parents evaluation	8 25.8%	11 33.3%

7. Other Pre-specified Outcome

Title	Number of Patients With Treatment-emergent Liver Function Abnormalities
Description	Number of patients with increase in alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) above 3 times upper limit of normal (ULN). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date.
Time Frame	Baseline, up to Week 24

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study drug and with available data.

Arm/Group Title	Bosentan 2 mg/kg t.i.d. (ITT Set)	Bosentan 2 mg/kg b.i.d. (ITT Set)
Arm/Group Description	Patients randomized to the bosentan 2 mg/kg t.i.d. group who received at least one oral dose of bosentan.	Patients randomized to the bosentan 2 mg/kg b.i.d. group who received at least one oral dose of bosentan.
Measure Participants	30	33
ALT > 3 x ULN	1 3.2%	0 0%
AST > 3 x ULN	0 0%	0 0%

8. Other Pre-specified Outcome

Title	Number of Patients With Treatment-emergent Hemoglobin Abnormalities
Description	Number of patients with marked hemoglobin decreases (absolute values below 10 g/dL). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date.
Time Frame	Baseline, up to Week 24

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least one dose of study drug and with available data.

Arm/Group Title	Bosentan 2 mg/kg t.i.d. (ITT Set)	Bosentan 2 mg/kg b.i.d. (ITT Set)
Arm/Group Description	Patients randomized to the bosentan 2 mg/kg t.i.d. group who received at least one oral dose of bosentan.	Patients randomized to the bosentan 2 mg/kg b.i.d. group who received at least one oral dose of bosentan.
Measure Participants	30	33
Hemoglobin decrease with values < 10 g/dL	1 3.2%	3 9.1%
Hemoglobin decrease with values < 8 g/dL	0 0%	0 0%

Adverse Events

Time Frame	From the first dose of study treatment on Day 1 up to 7 days after treatment discontinuation, i.e. up to Week 25 on average
Adverse Event Reporting Description	One patient in group 2 mg/kg t.i.d. experienced a serious adverse event (SAE) (adenoviral gastroenteritis) that was reported to the investigator by the parents about 2 months after database closure. Therefore this SAE is not included in the safety summary of FUTURE 3 but is displayed in the cumulative safety data of the FUTURE 3 Extension (AC-052-374)
Arm/Group Title	Bosentan 2 mg/kg t.i.d		Bosentan 2 mg/kg b.i.d
Arm/Group Description	Patients received 2 mg/kg of bosentan 3 times a day (morning, afternoon, evening) for at least 0.4 week and up to 28.7 weeks		Patients received 2 mg/kg of bosentan twice daily (morning and evening) for at least 6 weeks and up to 26.4 weeks
All Cause Mortality
	Bosentan 2 mg/kg t.i.d		Bosentan 2 mg/kg b.i.d
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bosentan 2 mg/kg t.i.d		Bosentan 2 mg/kg b.i.d
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/31 (19.4%)		4/33 (12.1%)
Cardiac disorders
CARDIAC FAILURE	0/31 (0%)	0	1/33 (3%)	2
General disorders
MULTI-ORGAN FAILURE	0/31 (0%)	0	1/33 (3%)	1
PYREXIA	1/31 (3.2%)	2	0/33 (0%)	0
Immune system disorders
DRUG HYPERSENSITIVITY	0/31 (0%)	0	1/33 (3%)	1
Infections and infestations
BRONCHOPNEUMONIA	1/31 (3.2%)	1	0/33 (0%)	0
GASTROENTERITIS	1/31 (3.2%)	1	0/33 (0%)	0
INFECTION	0/31 (0%)	0	1/33 (3%)	1
RESPIRATORY TRACT INFECTION VIRAL	1/31 (3.2%)	1	0/33 (0%)	0
VIRAL INFECTION	1/31 (3.2%)	1	0/33 (0%)	0
Investigations
BODY TEMPERATURE INCREASED	1/31 (3.2%)	1	0/33 (0%)	0
OXYGEN SATURATION DECREASED	1/31 (3.2%)	1	0/33 (0%)	0
Metabolism and nutrition disorders
METABOLIC DISORDER	0/31 (0%)	0	1/33 (3%)	1
Nervous system disorders
LOSS OF CONSCIOUSNESS	0/31 (0%)	0	1/33 (3%)	1
Respiratory, thoracic and mediastinal disorders
PULMONARY ARTERIAL HYPERTENSION	1/31 (3.2%)	1	1/33 (3%)	1
RESPIRATORY DISTRESS	1/31 (3.2%)	1	0/33 (0%)	0
Surgical and medical procedures
ATRIAL SEPTAL DEFECT REPAIR	1/31 (3.2%)	1	0/33 (0%)	0
CARDIAC OPERATION	0/31 (0%)	0	1/33 (3%)	1
Other (Not Including Serious) Adverse Events
	Bosentan 2 mg/kg t.i.d		Bosentan 2 mg/kg b.i.d
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/31 (58.1%)		18/33 (54.5%)
Blood and lymphatic system disorders
THROMBOCYTOPENIA	0/31 (0%)	0	2/33 (6.1%)	2
Gastrointestinal disorders
CONSTIPATION	2/31 (6.5%)	2	1/33 (3%)	1
DIARRHOEA	4/31 (12.9%)	5	2/33 (6.1%)	2
VOMITING	4/31 (12.9%)	7	1/33 (3%)	1
General disorders
PYREXIA	6/31 (19.4%)	7	4/33 (12.1%)	7
Infections and infestations
BRONCHITIS	1/31 (3.2%)	1	2/33 (6.1%)	2
NASOPHARYNGITIS	3/31 (9.7%)	4	5/33 (15.2%)	8
OTITIS MEDIA	0/31 (0%)	0	2/33 (6.1%)	2
RESPIRATORY TRACT INFECTION	1/31 (3.2%)	2	2/33 (6.1%)	3
UPPER RESPIRATORY TRACT INFECTION	11/31 (35.5%)	13	6/33 (18.2%)	8
Respiratory, thoracic and mediastinal disorders
COUGH	3/31 (9.7%)	3	0/33 (0%)	0
EPISTAXIS	3/31 (9.7%)	3	0/33 (0%)	0
PULMONARY ARTERIAL HYPERTENSION	0/31 (0%)	0	2/33 (6.1%)	2
Skin and subcutaneous tissue disorders
RASH	2/31 (6.5%)	2	1/33 (3%)	1
Vascular disorders
FLUSHING	2/31 (6.5%)	2	0/33 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only agreement between the sponsor and the investigators is that any study-related article or abstract written independently by investigators must be submitted to the sponsor for review at least 60 days prior to submission for publication or presentation.