Bosentan in Children With Pulmonary Arterial Hypertension (FUTURE-1)

An Open Label, Multicenter Study to Assess the Pharmacokinetics, Tolerability, and Safety of a Pediatric Formulation of Bosentan in Children With Idiopathic or Familial Pulmonary Arterial Hypertension

The aim of the study is to demonstrate that the exposure to bosentan in children with idiopathic pulmonary arterial hypertension (PAH) or familial pulmonary arterial hypertension, using a pediatric formulation, is similar to that in adults with PAH and to evaluate the tolerability and safety of a pediatric formulation of bosentan in this patient population.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Bosentan

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Clamart, France, 92140
    • Hopital Antoine Beclere
  • Paris, France, 75743
    • Hopital Necker
  • Toulouse, France
    • CHE de Toulouse Hopital d'Enfants
• Germany
  • Augustenburger, Germany
    • Deutsches Herzzentrum
  • Giessen, Germany
    • Universitats Kinderklinik
• Italy
  • Bologna, Italy, 40138
    • Policlinico S. Orsola-Malpighi
• Netherlands
  • Groningen, Netherlands
    • Beatrix Children's Hospital
• Switzerland
  • Geneva, Switzerland
    • Hopital des Enfants
• United Kingdom
  • London, United Kingdom
    • The Institute of Child Health
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • The Children's Hospital Cardiac Care Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent by the parents or the legal representatives.
• Males or females >= 2 and < 12 years of age.
• Idiopathic PAH or familial PAH diagnosed by right heart catheterization (Clinical classification of pulmonary hypertension, Venice 2003).
• World Health Organization (WHO) functional class II or III.
• Oxygen saturation (SpO2) >= 88% (at rest, on room air).

• PAH treatment-naïve patients or patients already treated with either:

  • Bosentan monotherapy
  • Intravenous epoprostenol monotherapy
  • Intravenous or inhaled iloprost monotherapy
  • Combination of bosentan and intravenous epoprostenol
  • Combination of bosentan and intravenous or inhaled iloprost.
• All patients should start the study drug (bosentan pediatric formulation) at 2 mg/kg twice daily (b.i.d.), whether or not they were previously treated with bosentan.
• PAH therapy stable for at least 3 months prior to Screening.
• Stable treatment with calcium channel blockers, if any, for at least 3 months prior to Screening.
• Patient's PAH condition stable for at least 3 months prior to Screening.

Exclusion Criteria:

• PAH associated with conditions other than idiopathic or familial PAH.
• Non-stable patients, e.g., history (in the last 3 months prior to Screening) of recurrent syncope, or signs and symptoms of non-compensated right heart failure.
• Need or plan to wean patients from intravenous epoprostenol, or intravenous, or inhaled iloprost.
• Body weight < 4 kg.
• Systolic blood pressure < 80%, the lower limit of normal range, according to age and gender.
• AST and/or ALT values > 3 times the upper limit of normal ranges.
• Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
• Hemoglobin and/or hematocrit levels < 75% of the lower limit of normal ranges.
• Pregnancy.
• Known intolerance or hypersensitivity to bosentan or any of the excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bosentan; The initial dose of bosentan was 2 mg/kg b.i.d. for 4 weeks. After 4 weeks, the initial dose was up-titrated to the maintenance dose of 4 mg/kg b.i.d. up to the end of the study treatment at Week 12. If the maintenance dose was not well tolerated, the dose could be down-titrated to the initial dose.	Drug: Bosentan; Pediatric oral formulation of bosentan, i.e., 32 mg dispersible and breakable tablets; Other Names: ACT-050088; Ro 47-0203

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration-time curve during a dose interval (AUCt) for bosentan	AUCt was assessed at steady state (i.e., after at least 2 weeks of treatment with a same dose of the study drug) over 12 hours .	At pre-dose and 0.5h, 1h, 3h, 7.5h, and 12h post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax) of bosentan and its metabolites	Maximum observed plasma concentration for bosentan and its metabolites was directly derived from their respective plasma concentration-time curves.	At pre-dose and 0.5h, 1h, 3h, 7.5h, and 12h post-dose
Time to reach the maximum plasma concentration (tmax) of bosentan and its metabolites		At pre-dose and 0.5h, 1h, 3h, 7.5h, and 12h post-dose
Area under the plasma concentration-time curve during a dose interval (AUCt) for the metabolites of bosentan	AUCt was assessed at steady state (i.e., after at least 2 weeks of treatment with a same dose of the study drug) over 12 hours.	At pre-dose and 0.5h, 1h, 3h, 7.5h, and 12h post-dose

Collaborators and Investigators

• Sponsor: Actelion

Publications and helpful links

General Publications

• Beghetti M, Haworth SG, Bonnet D, Barst RJ, Acar P, Fraisse A, Ivy DD, Jais X, Schulze-Neick I, Galie N, Morganti A, Dingemanse J, Kusic-Pajic A, Berger RM. Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study. Br J Clin Pharmacol. 2009 Dec;68(6):948-55. doi: 10.1111/j.1365-2125.2009.03532.x.

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (Actual): December 1, 2006
• Study Completion (Actual): February 1, 2007

Study Registration Dates

• First Submitted: April 26, 2006
• First Submitted That Met QC Criteria: April 26, 2006
• First Posted (Estimate): April 27, 2006

Study Record Updates

• Last Update Posted (Estimate): May 24, 2016
• Last Update Submitted That Met QC Criteria: May 23, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: children; pharmacokinetics; pulmonary arterial hypertension; bosentan
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: AC-052-365; 2004-005157-63 (EudraCT Number)