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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Actelion
ClinicalTrials.gov Identifier:
NCT01223352
First received: October 12, 2010
Last updated: June 2, 2016
Last verified: June 2016
  Purpose
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 Intervention Phase
Pulmonary Arterial Hypertension
Drug: bosentan
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Actelion:

Primary Outcome Measures:
  • Daily exposure [AUC(0-24c)] to bosentan [ Time Frame: At Week 4, after at least 2 weeks of stable study drug treatment ] [ Designated as safety issue: No ]

    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 12 hours or up to 8 hours post-dose for the b.i.d and t.i.d. dosing regimen, respectively. AUC(0-24) was calculated as a multiple of AUCtau (i.e., 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:
  • Maximum plasma concentration [Cmaxc] of bosentan [ Time Frame: At Week 4, after at least 2 weeks of stable study drug treatment ] [ Designated as safety issue: No ]

    Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.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 to reach Cmax [tmax] of bosentan [ Time Frame: At Week 4, after at least 2 weeks of stable study drug treatment ] [ Designated as safety issue: No ]

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

    tmax was obtained directly from the measured plasma concentrations.


  • Daily exposure [AUC(0-24c)] to bosentan metabolites (Ro 478634, Ro 485033, Ro 641056) [ Time Frame: At Week 4, after at least 2 weeks of stable study drug treatment. ] [ Designated as safety issue: No ]
    Concentrations of the metabolites were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.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)].

  • Change from baseline in WHO functional class at end of study [ Time Frame: Baseline and end of study ] [ Designated as safety issue: No ]
    Number of patients with improvement, worsening or no change in WHO functional class at end of study compared to baseline.

  • Change from baseline in Global clincial impression scale (GCIS) at end of study [ Time Frame: Baseline and end of study ] [ Designated as safety issue: No ]

    The GCIS is an assessment tool to rate 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. Number of patients with clinical condition (as measured by the GCIS) considered as worsened, improved or unchanged are reported here


  • Number of patients with treatment-emergent liver function abnormalities [ Time Frame: From baseline up to 7 days after end of treatment ] [ Designated as safety issue: Yes ]
    Number of patients with increase in alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) above 3 x ULN (upper limit of normal). The worst post-baseline value was considered.

  • Number of patients with treatment-emergent hemoglobin abnormalities [ Time Frame: From baseline up to 7 days after end of treatment ] [ Designated as safety issue: Yes ]
    Number of patients with marked hemoglobin decreases. The worst post-baseline value was considered.


Enrollment: 64
Study Start Date: March 2011
Study Completion Date: August 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   3 Months to 12 Years   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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-CHD associated with systemic-to-pulmonary shunts (after global amendment dated 09 May 2012)
  2. WHO functional Class 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, PDE-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. AST and/or ALT 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01223352

  Hide Study Locations
Locations
United States, Colorado
The Children's Hospital - Site 9102
Aurora, Colorado, United States, 80045
United States, District of Columbia
Children's National Medical Center - Site 9104
Washington, District of Columbia, United States, 20010
United States, New York
Columbia University Medical Center Children's Hospital of New York Presbyterian - Site 9101
New York, New York, United States, 10032
United States, Texas
Texas Children's Hospital - Department of Cardiology - Site 9107
Houston, Texas, United States, 77030
United States, Washington
Seattle Children's Hospital - Site 9106
Seattle, Washington, United States, 98105
Australia
Royal Children's Hospital Melbourne, Cardiology - Site 5001
Parkville, Australia, 3052
Belarus
The Republican Scientific-Practical Center "Cardiology" - Site 3001
Minsk, Belarus, 220036
China
Beijing Anzhen Hospital, Capital Medical University- Department of Pediatric Cardiology - Site 5103
Beijing, China, 100029
Cardiovascular Institute and Fuwai Hospital
Beijing, China, 100037
West China 2nd university Hospital-Center of interventional diagnosis and therapy for Children's cardiovascular disease - Site 5104
Chengdu, China, 610041
Guangdong General Hospital - Site 5105
Guangdong, China, 510080
Shanghai Children's Medical Center - Site 5102
Shanghai, China, 200127
Shanghai Pulmonary Hospital, Department of Pulmonary Circulation - Site 5101
Shanghai, China, 200433
Czech Republic
Fakultní nemocnice v Motole, dětské kardiocentrum - Site 3301
Prague, Czech Republic, 150 06
France
Hopital Necker-Enfants Malades, Service de Cardiologie Pédiatrique - Site 2201
Paris, France, 75743
CHU de Toulouse - Hôpital des Enfants, Service de Cardiologie Pédiatrique - Site 2202
Toulouse, France, 31059
Germany
Deutsches Herzzentrum Kinderkardiologie - Site 1401
Berlin, Germany, 13353
Universitätsklinikum Bonn Abteilung für Kinderkardiologie - Site 1404
Bonn, Germany, 53113
Justus-Liebig-Universität Giessen, Kinderherzzentrum - Site 1403
Giessen, Germany, 35392
Hungary
Gottsegen György Országos Kardiológiai Intézet, Gyermekszív Központ, Gyermek Kardiológiai osztály - Site 3401
Budapest, Hungary, 1096
Szegedi Tudományegyetem ÁOK Szent-Györgyi Albert Klinikai Központ, Gyermekgyógyászati Klinika és Gyermekegészségügyi Központ - Site 3402
Szeged, Hungary, 6720
India
CARE Hospitals, Cardiology Dep. Hyderabad - Site 5302
Hyderabad, India, 500001
Indraprashta Apollo Hospitals, Pediatric Cardiology - Site 5303
New Dehli, India, 110076
Israel
Schneider Children's Medical Center- Institute of pediatric cardiology - Site 7101
Petach Tikvah, Israel, 49202
Italy
Università Degli Studi di Padova - Dipartimento di Pediatria - Servizio di Cardiologia Pediatrica - Site 1501
Padova, Italy, 35128
Ospedale Pediatrico "Bambino Gesù" - Dipartimento Medico Chirurgico di Cardiologia Pediatrica - Site 1502
Rome, Italy, 00193
Mexico
Instituto Nacional de Cardiologia (INC) Ignacio Chavez - Site 8401
Mexico City, Mexico, 14080
Unidad de Investigacion Clinica en Medicina, SC (UDICEM) - Site 8402
Monterrey, Mexico, 64710
Netherlands
Universitair Medish Centrum Groningen, Kindercardiologie - Site 1601
Groningen, Netherlands, 9713 GZ
Poland
Uniwersyteckie Centrum Kliniczne Klinika Kardiologii Dziecięcej i Wad Wrodzonych Serca - Site 3604
Gdansk, Poland, 80-952
Instytut Centrum Zdrowia Matki Polki Klinika Kardiologii ICMP w Lodz - Site 3602
Lodz, Poland, 93-336
Instytut Pomnik - Centrum Zdrowia Dziecka Klinika Kardiologii Dziecięcej - Site 3601
Warszawa, Poland, 04-730
Wojewódzki Szpital Specjalistyczny we Wrocławiu Oddział Kardiologii Dziecięcej z pododdziałem Intensywnego Nadzoru Kardiologicznego - Site 3605
Wroclaw, Poland, 51-124
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, 650002
Scientific Center of Cardiovascular Surgery named after A.N.Bakulev of the RAMS - Site 3803
Moscow, Russian Federation, 121552
Moscow Scientific Research Institute for Pediatrics and Childrens Surgery of Rosmedtechnologies - Site 3804
Moscow, Russian Federation, 125412
Federal State Institution "Federal center of Heart, Blood and Endocrinology named after V.A.Almazov Rosmedtekhnologies" - Site 3802
St. Petersberg, Russian Federation, 197341
State Educational Institution of Higher Professional Education "Saint Petersburg State Pediatric Medical Academy of Roszdrav" - Site 3801
St. Petersburg, Russian Federation, 194100
Serbia
Univerzitetska dečja klinika, Služba za kardiologiju - Site 3901
Belgrade, Serbia, 11000
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
South Africa
Department of Paediatric Cardiology University of the Free State - Site 6001
Bloemfontein, South Africa, 9300
Paediatric Cardiology Albert Luthuli Central Hospital - Site 6003
Durban, South Africa, 4001
Division of Paediatric Cardiology, Steve Biko Academic Hospital - Site 6002
Pretoria, South Africa, 0001
Spain
Hospital Universitatario Vall d'Hebron, Neumologia - Site 1907
Barcelona, Spain, 08035
Hospital Universitario La Paz - Paediatric Cardiology Department - Site 1906
Madrid, Spain, 28046
Ukraine
Clinical Diagnostic Center - Pediatric Cardiovascular and ANES and Intensive Care Department - Site 4103
Dnepropetrovsk, Ukraine, 49060
Gusak Ins Urgent and Recovery SUR AMS - Cardiovascular Rehabilitation Pediatric Department - Site 4101
Donetsk, Ukraine, 83045
Gover INS - Scientific Practical Cardiovascular Pediatric Center - MOH Ukraine - Site 4102
Kiev, Ukraine, 01135
Sponsors and Collaborators
Actelion
Investigators
OverallOfficial: Andjela Kusic-Pajic, MD Actelion
  More Information

Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT01223352     History of Changes
Other Study ID Numbers: AC-052-373 
Study First Received: October 12, 2010
Last Updated: June 2, 2016
Health Authority: China: Food and Drug Administration
United States: Food and Drug Administration
Russia: Pharmacological Committee, Ministry of Health
Czech Republic: State Institute for Drug Control
Serbia: Medicines and Medical Devices Agency of Serbia
Netherlands: Medicines Evaluation Board
Russia: Ministry of Health of the Russian Federation
Germany: Federal Institute for Drugs and Medical Devices
South Africa: Medicines Control Council
Hungary: National Institute of Pharmacy
Ukraine: State Pharmacological Center - Ministry of Health
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Australia: Department of Health and Ageing Therapeutic Goods Administration
Mexico: Federal Commission for Protection Against Health Risks
Israel: Ministry of Health
Italy: The Italian Medicines Agency
Russia: FSI Scientific Center of Expertise of Medical Application
Belarus: Ministry of Health
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
India: Drugs Controller General of India

Keywords provided by Actelion:
pulmonary arterial hypertension
children
pediatric
bosentan

Additional relevant MeSH terms:
Hypertension
Familial Primary Pulmonary Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Bosentan
Antihypertensive Agents
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 22, 2016