Long-term Ambrisentan Extension Study for Pediatric Patients Who Participated in AMB112529

Tracking Information
First Submitted Date ICMJE	April 26, 2011
First Posted Date ICMJE	April 27, 2011
Last Update Posted Date	March 30, 2018
Study Start Date ICMJE	June 1, 2011
Estimated Primary Completion Date	October 27, 2022 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: March 30, 2015)	Serious Adverse Events [ Time Frame: up to 18 years of age ]Number of patients with a serious adverse event; Adverse Events [ Time Frame: up to 18 years of age ]Number of patients with adverse events; Liver Function Tests [ Time Frame: up to 18 years of age ]AST, ALT, GGT, and total bilirubin; Clinical Chemistries [ Time Frame: up to 18 years of age ]sodium, magnesium, potassium, calcium, glucose, chloride, bicarbonate, phosphorus-inorganic, creatinine, total protein, albumin, LDH, creatine phosphokinase, blood urea nitrogen, uric acid, and alkaline phosphatase; Haematology [ Time Frame: up to 18 years of age ]platelet count, RBC count, reticulocyte count, hematocrit, hemoglobin, RBC indices (MVC, MCH, and MCHC), WBC count, and automated WBC differential; Physical examination [ Time Frame: up to 18 years of age ]Change from baseline from Study AMB112529 in physical parameters; Vital signs [ Time Frame: up to 18 years of age ]Change from baseline from Study AMB112529 in blood pressure, respiratory rate, and heart rate; 12-lead ECG [ Time Frame: up to 18 years of age ]Change from baseline from Study AMB112529; Endocrinology assessments [ Time Frame: up to 20 years of age ]FSH, LH, sex hormone binding globulin, inhibin B, testosterone (males only) and estrogen (females only); Pubertal Development [ Time Frame: up to 20 years of age ]Assessed using Tanner criteria. Testicular volume will be estimated in males using Prader's orchidometer
Original Primary Outcome Measures ICMJE; (submitted: April 26, 2011)	Seirous Adverse Events [ Time Frame: When patient reaches 18 years of age ]Number of patients with a serious adverse event; Adverse Events [ Time Frame: When patient reaches 18 years of age ]Number of patients with adverse events; Liver Function Tests [ Time Frame: When Patient reaches 18 years of age ]AST, ALT, GGT, and total bilirubin; Clinical Chemistries [ Time Frame: When patient reaches 18 years of age ]sodium, magnesium, potassium, calcium, glucose, chloride, bicarbonate, phosphorus-inorganic, creatinine, total protein, albumin, LDH, creatine phosphokinase, blood urea nitrogen, uric acid, and alkaline phosphatase; Haematology [ Time Frame: When patient reaches 18 years of age ]platelet count, RBC count, reticulocyte count, hematocrit, hemoglobin, RBC indices (MVC, MCH, and MCHC), WBC count, and automated WBC differential; Physical examination [ Time Frame: When patient reaches 18 years of age ]Change from baseline from Study AMB112529 in physical parameters; Vital signs [ Time Frame: Shen patient reaches 18 years of age ]Change from baseline from Study AMB112529 in blood pressure, respiratory rate, and heart rate; 12-lead ECG [ Time Frame: When patient reaches 18 years of age ]Change from baseline from Study AMB112529; Endocrinology assessments [ Time Frame: When patient reaches 20 years of age ]FSH, LH, sex hormone binding globulin, inhibin B, testosterone (males only) and estrogen (females only); Pubertal Development [ Time Frame: When patient reaches 20 years of age ]Assessed using Tanner criteria. Testicular volume will be estimated in males using Prader's orchidometer
Change History	Complete list of historical versions of study NCT01342952 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: March 30, 2015)	6 minute walk distance [ Time Frame: up to 18 years of age ]Change from baseline from study AMB112529 in the distance walked in six minutes; WHO functional class [ Time Frame: up to 18 years of age ]Change from baseline from study AMB112529 i nWHO functional class; Health outcomes assessments [ Time Frame: up to 18 years of age ]Change from baseline from study AMB112529 in SF 10 and the proportion of days missed from school due to symptoms of the disease; Echocardiogram [ Time Frame: up to 18 years of age ]Pericardial effusion, right atrial pressure, tricuspid annular plane systolic excursion, eccentricity index (systolic and diastolic), and right ventricular pressure by tricuspid regurgitant jet velocity; Plasma NT-Pro-BNP [ Time Frame: up to 18 years of age ]Change from baseline from study AMB112529 in plasma NT-Pro BNP; Time to clinical worsening [ Time Frame: up to 18 years of age ]The time from randomization in study AMB112529 until the first occurence of: death (all cause) or placed on active list for lung transplant; hospitalisation due to PAH deterioration; addition or increased dose of other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition; atrial septostomy; or PAH related deterioration (increase in WHO functional class, deterioration in exercise testing, clinical signs of symptoms of right sided heart failure)
Original Secondary Outcome Measures ICMJE; (submitted: April 26, 2011)	6 minute walk distance [ Time Frame: When patient reaches 18 years of age ]Change from baseline from study AMB112529 in the distance walked in six minutes; WHO functional class [ Time Frame: When patient reaches 18 years of age ]Change from baseline from study AMB112529 i nWHO functional class; Health outsomes assessments [ Time Frame: When patient reaches 18 years of age ]Change from baseline from study AMB112529 in SF 10 and the proportion of days missed from school due to symptoms of the disease; Echocardiogram [ Time Frame: When patient reaches 18 years of age ]Pericardial effusion, right atrial pressure, tricuspid annular plane systolic excursion, eccentricity index (systolic and diastolic), and right ventricular pressure by tricuspid regurgitant jet velocity; Plasma NT-Pro-BNP [ Time Frame: When patient reaches 18 years of age ]Change from baseline from study AMB112529 in plasma NT-Pro BNP; Time to clinical worsening [ Time Frame: When patient reaches 18 years of age ]The time from randomization in study AMB112529 until the first occurance of: death (all cause) or placed on active list for lung transplant; hospitalisation due to PAH deterioration; addition or increased dose of other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to derterioration of clinical condition; atrial septostomy; or PAH related deterioration (increase in WHO functional class, deterioration in exercise testing, clinical sighns of symptoms of right sided heart failure)
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Long-term Ambrisentan Extension Study for Pediatric Patients Who Participated in AMB112529
Official Title ICMJE	An Open-label, Long Term Extension Study for Treatment of Pulmonary Arterial Hypertension in Paediatric Patients Aged 8 Years up to 18 Years Who Have Participated in AMB112529 and in Whom Continued Treatment With Ambrisentan is Desired
Brief Summary	An open label, long term extension to Study AMB112529. All subjects may remain in the extension study for a minimum of six months. Beyond the six month period, subjects may continue in the extension study until one of the following conditions is met: the subject turns 18 years of age (when the subject can receive marketed product) the product is approved and available for use in the subject's age group, development for use in the paediatric population is discontinued. the subject decides he/she no longer wants to participate in the study, the investigator considers it is in the best interest of the subject to discontinue ambrisentan (e.g. for safety reasons). The primary objective is the long-term safety and tolerability of ambrisentan in the paediatric PAH population. Secondary objectives are all cause mortality and change from baseline in Study AMB112529 on efficacy parameters.
Detailed Description	Pulmonary arterial hypertension (PAH) is a rare, progressive, highly debilitating disease characterized by vascular obstruction and the variable presence of vasoconstriction, leading to increased pulmonary vascular resistance and right-sided heart failure. If left untreated, PAH ultimately leads to right ventricular failure and death; adult subjects have a median survival of 2.8 years without treatment. Epidemiological estimates vary but prevalence in Europe is thought to be of the order of 15 cases per million. Large scale epidemiology studies of PAH in children have not been conducted and there is no or limited outcome data in paediatric PAH patients. A register in France (1995-1996) estimates the prevalence in children is as low as 3.7 cases per million. In a national, comprehensive country wide survey of the epidemiology of idiopathic PAH (IPAH) management and survival in the United Kingdom (UK) the incidence was 0.48 cases per million children per year and the prevalence was 2.1 cases per million children. Ambrisentan (VOLIBRIS™ tablets) is an endothelin receptor antagonist (ERA) marketed in the European Union (EU) and some other countries by GlaxoSmithKline (GSK) and in the United States as LETAIRIS® by Gilead Sciences Inc. Ambrisentan is indicated for the treatment of adult patients with PAH to improve exercise capacity, decrease the symptoms of PAH, and delay clinical worsening. The primary purpose of this long term paediatric study is to provide clinically relevant information on the long term safety of ambrisentan in children with the most common causes of PAH in this age group. This study is only open to patients who have participated in Study AMB112529, A randomized, open label study comparing safety and efficacy parameters for a high and a low dose of ambrisentan (adjusted for body weight) for the treatment of pulmonary arterial hypertension in paediatric patients aged 8 years up to 18 years, and in whom continued treatment with ambrisentan is warranted. This study is part of a Paediatric Investigational Plan (PIP; EMEA-000434-PIP01-08) agreed with the European Medicines Agency's Paediatric Committee (PDCO).
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Hypertension, Pulmonary
Intervention ICMJE	Drug: Ambrisentan; open label, flexible dosing from 2.5 to 10 mg (not to exceed 10 mg/kg) per day
Study Arms	Experimental: Ambrisentan; Open label, flexible dosing from 2.5 mg to 10 mg (not to exceed 0.25 mg/kg) per day; Intervention: Drug: Ambrisentan
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Recruiting
Estimated Enrollment ICMJE; (submitted: May 10, 2012)	66
Original Estimated Enrollment ICMJE; (submitted: April 26, 2011)	60
Estimated Study Completion Date	October 24, 2024
Estimated Primary Completion Date	October 27, 2022 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Have participated in and complied, to the best of their ability, with the protocol for AMB112529 and have met one of the following: Completed the Week 24 visit in AMB112529; Required additional targeted treatment for PAH due to inadequate response to the current treatment or worsening of their clinical condition prior to week 24 in AMB112529; Required reduction in dose of baseline targeted treatment for PAH after ambrisentan was added to the treatment regimen; In the opinion of the investigator, continued treatment with ambrisentan is warranted.; A female is eligible to participate in this study, as assessed by the investigator, if she is of: Non-childbearing potential (i.e., physiologically incapable of becoming pregnant); or, Child-bearing potential - has a negative pregnancy test and is not lactating and, if sexually active, agrees to continue to use 2 reliable methods of contraception until study completion and for at least 30 days following the last dose of study drug (reliable methods of contraception are listed in Appendix 2).; Subject or subject's legal guardian is able and willing to give written informed consent. As part of the consent, female subjects of childbearing potential will be informed of the risk of teratogenicity and will need to be counselled in a developmentally appropriate manner on the importance of pregnancy prevention; and male subjects will need to be informed of potential risk of testicular tubular atrophy and aspermia. Exclusion Criteria: Subjects who were withdrawn from ambrisentan in Study AMB112529;; Subjects who did not comply with the protocol in Study AMB112529;; Female subjects who are pregnant or breastfeeding;; Subjects with severe renal impairment (estimated creatinine clearance <30 mL/min assessed within the previous 45 days) at the point of transition from Study AMB112529 into this study;; Subject with clinically significant fluid retention in the opinion of the investigator;; Subject with clinically significant anaemia in the opinion of the investigator;; Subjects who are to enter another clinical trial or be treated with another investigational product after exiting Study AMB112529.
Sex/Gender	Sexes Eligible for Study: All
Ages	8 Years to 18 Years (Child, Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact: US GSK Clinical Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Listed Location Countries ICMJE	Argentina, Canada, France, Germany, Hungary, Italy, Japan, Russian Federation, Spain, United States
Removed Location Countries	Brazil, Mexico, Netherlands
Administrative Information
NCT Number ICMJE	NCT01342952
Other Study ID Numbers ICMJE	114588
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	GlaxoSmithKline
Study Sponsor ICMJE	GlaxoSmithKline
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account	GlaxoSmithKline
Verification Date	March 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP