FUTURE 3 Study Extension

Pulmonary Arterial Hypertension Clinical Trial

— FUTURE 3 Ext  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01338415
• Other study ID #: AC-052-374
• Secondary ID: 2010-021793-12
• Status: Completed
• Phase: Phase 3
• Start date: March 8, 2011
• Est. completion date: May 29, 2020

Study information

• Verified date: May 2021
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 58
• Est. completion date: May 29, 2020
• Est. primary completion date: August 13, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 12 Years

Eligibility

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.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Bosentan
Oral dispersible tablet administered as 2mg/kg two (b.i.d.) or three (t.i.d.) times per day

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	Cardiovascular Institute and Fuwai Hospital	Beijing
China	Shanghai Children's Medical Center - Site 5102	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
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
Poland	Uniwersyteckie Centrum Kliniczne Klinika Kardiologii Dzieciecej i Wad Wrodzonych Serca - Site 3604	Gdansk
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	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	Columbia University Medical Center Children's Hospital of New York Presbyterian - Site 9101	New York	New York
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,  Poland,  Russian Federation,  Serbia,  South Africa,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline up to 12 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC)	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.	At Month 12
Other	Change From Baseline up to 18 Months of Study Treatment in the World Health Organization Functional Classification (WHO FC)	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.	At Month 18
Other	Change From Baseline up to 12 Months of Study Treatment in the Global Clinical Impression Scale (GCIS)	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.	At Month 12
Other	Change From Baseline up to 18 Months of Study Treatment in the Global Clinical Impression Scale (GCIS)	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.	At Month 18
Other	Number of Patients With Pulmonary Arterial Hypertension (PAH) Worsening Components up to the Last Day of Treatment + 7 Days	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.	Up to 62 weeks in average
Other	Pulmonary Arterial Hypertension (PAH) Progression up to End of Treatment + 7 Days	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.	From baseline to Month 18
Other	Overall Survival	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.	From baseline to month 18
Other	Exceptional Use Treatment Period (EUTP): Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) up to 7 Days After Permanent Discontinuation of Study Drug	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.	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Other	EUTP: Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) up to 7 Days After Permanent Discontinuation of Study Drug	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.	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Other	EUTP: Percentage of Participants With AEs Leading to Premature Discontinuation of Study Drug	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.	Up to 3 years and 4 months
Other	EUTP: Percentage of Participants With SAEs From 7 up to 60 Days After Permanent Discontinuation of Study Drug	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.	From 7 up to 60 days after permanent discontinuation of study drug (up to 3 years and 4 months)
Other	EUTP: Percentage of Participants With Deaths	Percentage of participants with deaths were reported.	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Other	EUTP: Percentage of Participants With Adverse Events of Special Interest (AESI)	Percentage of participants with AESI including liver abnormalities and anemia were reported.	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Other	EUTP: Percentage of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 7 Days After Permanent Discontinuation of Study Drug	Percentage of participants with treatment-emergent marked laboratory abnormalities were reported.	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Other	EUTP: Percentage of Participants With Liver Function Abnormalities	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.	Up to 7 days after discontinuation of study drug (up to 3 years and 4 months)
Other	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)	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.	Baseline, up to 7 days after end of treatment (up to 3 years and 4 months)
Primary	Treatment Emergent Adverse Events (AEs) up to 7 Days After Permanent Study Drug Discontinuation	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.	Up to 62 weeks in average