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

Pulmonary Arterial Hypertension Clinical Trial

— FUTURE 3  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01223352
• Other study ID #: AC-052-373
• Status: Completed
• Phase: Phase 3
• First received: October 12, 2010
• Last updated: November 7, 2017
• Start date: March 8, 2011
• Est. completion date: August 19, 2013

Study information

• Verified date: November 2017
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 64
• Est. completion date: August 19, 2013
• Est. primary completion date: April 3, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 12 Years

Eligibility

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)

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

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

4. Body weight = 3.5 kg

5. Peripheral oxygen saturation (SpO2) = 88% (at rest, on room air)

6. 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

7. 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

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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

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.

Locations

Country	Name	City	State
Australia	Royal Children's Hospital Melbourne, Cardiology - Site 5001	Parkville
Belarus	The Republican Scientific-Practical Center "Cardiology" - Site 3001	Minsk
China	Beijing Anzhen Hospital, Capital Medical University- Department of Pediatric Cardiology - Site 5103	Beijing
China	Cardiovascular Institute and Fuwai Hospital	Beijing
China	West China 2nd university Hospital-Center of interventional diagnosis and therapy for Children's cardiovascular disease - Site 5104	Chengdu
China	Guangdong General Hospital - Site 5105	Guangdong
China	Shanghai Children's Medical Center - Site 5102	Shanghai
China	Shanghai Pulmonary Hospital, Department of Pulmonary Circulation - Site 5101	Shanghai
Czechia	Fakultní nemocnice v Motole, detské kardiocentrum - Site 3301	Prague
France	Hopital Necker-Enfants Malades, Service de Cardiologie Pédiatrique - Site 2201	Paris
France	CHU de Toulouse - Hôpital des Enfants, Service de Cardiologie Pédiatrique - Site 2202	Toulouse
Germany	Deutsches Herzzentrum Kinderkardiologie - Site 1401	Berlin
Germany	Universitätsklinikum Bonn Abteilung für Kinderkardiologie - Site 1404	Bonn
Germany	Justus-Liebig-Universität Giessen, Kinderherzzentrum - Site 1403	Giessen
Hungary	Gottsegen György Országos Kardiológiai Intézet, Gyermekszív Központ, Gyermek Kardiológiai osztály - Site 3401	Budapest
Hungary	Szegedi Tudományegyetem ÁOK Szent-Györgyi Albert Klinikai Központ, Gyermekgyógyászati Klinika és Gyermekegészségügyi Központ - Site 3402	Szeged
India	CARE Hospitals, Cardiology Dep. Hyderabad - Site 5302	Hyderabad
India	Indraprashta Apollo Hospitals, Pediatric Cardiology - Site 5303	New Delhi
Israel	Schneider Children's Medical Center- Institute of pediatric cardiology - Site 7101	Petach Tikvah
Italy	Università Degli Studi di Padova - Dipartimento di Pediatria - Servizio di Cardiologia Pediatrica - Site 1501	Padova
Italy	Ospedale Pediatrico "Bambino Gesù" - Dipartimento Medico Chirurgico di Cardiologia Pediatrica - Site 1502	Rome
Mexico	Instituto Nacional de Cardiologia (INC) Ignacio Chavez - Site 8401	Mexico City
Mexico	Unidad de Investigacion Clinica en Medicina, SC (UDICEM) - Site 8402	Monterrey
Netherlands	Universitair Medish Centrum Groningen, Kindercardiologie - Site 1601	Groningen
Poland	Uniwersyteckie Centrum Kliniczne Klinika Kardiologii Dzieciecej i Wad Wrodzonych Serca - Site 3604	Gdansk
Poland	Instytut Centrum Zdrowia Matki Polki Klinika Kardiologii ICMP w Lodz - Site 3602	Lodz
Poland	Instytut Pomnik - Centrum Zdrowia Dziecka Klinika Kardiologii Dzieciecej - Site 3601	Warszawa
Poland	Wojewódzki Szpital Specjalistyczny we Wroclawiu Oddzial Kardiologii Dzieciecej z pododdzialem Intensywnego Nadzoru Kardiologicznego - Site 3605	Wroclaw
Russian Federation	RAMS Institution, Research Institute for complex issues of cardiovascular diseases, Siberian branch of the Russian Academy of Medical Sciences - Site 3805	Kemerovo
Russian Federation	Moscow Scientific Research Institute for Pediatrics and Childrens Surgery of Rosmedtechnologies - Site 3804	Moscow
Russian Federation	Scientific Center of Cardiovascular Surgery named after A.N.Bakulev of the RAMS - Site 3803	Moscow
Russian Federation	Federal State Institution "Federal center of Heart, Blood and Endocrinology named after V.A.Almazov Rosmedtekhnologies" - Site 3802	St. Petersberg
Russian Federation	State Educational Institution of Higher Professional Education "Saint Petersburg State Pediatric Medical Academy of Roszdrav" - Site 3801	St. Petersburg
Serbia	Institut za zdravstvenu zaštitu majke i deteta Srbije "Dr Vukan Cupic", Služba za ispitivanje i lecenje bolesti srca i krvnih sudova - Site 3902	Belgrade
Serbia	Univerzitetska decja klinika, Služba za kardiologiju - Site 3901	Belgrade
South Africa	Department of Paediatric Cardiology University of the Free State - Site 6001	Bloemfontein
South Africa	Paediatric Cardiology Albert Luthuli Central Hospital - Site 6003	Durban
South Africa	Division of Paediatric Cardiology, Steve Biko Academic Hospital - Site 6002	Pretoria
Spain	Hospital Universitatario Vall d'Hebron, Neumologia - Site 1907	Barcelona
Spain	Hospital Universitario La Paz - Paediatric Cardiology Department - Site 1906	Madrid
Ukraine	Clinical Diagnostic Center - Pediatric Cardiovascular and ANES and Intensive Care Department - Site 4103	Dnepropetrovsk
Ukraine	Gusak Ins Urgent and Recovery SUR AMS - Cardiovascular Rehabilitation Pediatric Department - Site 4101	Donetsk
Ukraine	Gover INS - Scientific Practical Cardiovascular Pediatric Center - MOH Ukraine - Site 4102	Kiev
United States	The Children's Hospital - Site 9102	Aurora	Colorado
United States	Texas Children's Hospital - Department of Cardiology - Site 9107	Houston	Texas
United States	Columbia University Medical Center Children's Hospital of New York Presbyterian - Site 9101	New York	New York
United States	Seattle Children's Hospital - Site 9106	Seattle	Washington
United States	Children's National Medical Center - Site 9104	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Australia,  Belarus,  China,  Czechia,  France,  Germany,  Hungary,  India,  Israel,  Italy,  Mexico,  Netherlands,  Poland,  Russian Federation,  Serbia,  South Africa,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Dose-corrected Maximum Plasma Concentration [Cmaxc] of Bosentan	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).	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
Other	Time to Reach Cmax [Tmax] of Bosentan	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.	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
Other	Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan Metabolites (Ro 478634, Ro 485033, Ro 641056)	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)].	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
Other	Change From Baseline in WHO Functional Class at End of Study	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.	Baseline, up to Week 24 on average
Other	Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study	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.	Baseline, up to Week 24 on average
Other	Number of Patients With Treatment-emergent Liver Function Abnormalities	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.	Baseline, up to Week 24
Other	Number of Patients With Treatment-emergent Hemoglobin Abnormalities	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.	Baseline, up to Week 24
Primary	Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan	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)].	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