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

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT01342952

Collaborator

(none)

Enrollment

Locations

Arm

132

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hypertension, Pulmonary	Drug: Ambrisentan	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

66 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 21, 2011

Anticipated Primary Completion Date :

Jun 20, 2022

Anticipated Study Completion Date :

Jun 20, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ambrisentan Open label, flexible dosing from 2.5 mg to 10 mg (not to exceed 0.25 mg/kg) per day	Drug: Ambrisentan open label, flexible dosing from 2.5 to 10 mg (not to exceed 10 mg/kg) per day

Arm

Intervention/Treatment

Experimental: Ambrisentan

Open label, flexible dosing from 2.5 mg to 10 mg (not to exceed 0.25 mg/kg) per day

Drug: Ambrisentan

open label, flexible dosing from 2.5 to 10 mg (not to exceed 10 mg/kg) per day

Outcome Measures

Primary Outcome Measures

Serious Adverse Events [up to 18 years of age]
Number of patients with a serious adverse event
Adverse Events [up to 18 years of age]
Number of patients with adverse events
Liver Function Tests [up to 18 years of age]
AST, ALT, GGT, and total bilirubin
Clinical Chemistries [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 [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 [up to 18 years of age]
Change from baseline from Study AMB112529 in physical parameters
Vital signs [up to 18 years of age]
Change from baseline from Study AMB112529 in blood pressure, respiratory rate, and heart rate
12-lead ECG [up to 18 years of age]
Change from baseline from Study AMB112529
Endocrinology assessments [up to 20 years of age]
FSH, LH, sex hormone binding globulin, inhibin B, testosterone (males only) and estrogen (females only)
Pubertal Development [up to 20 years of age]
Assessed using Tanner criteria. Testicular volume will be estimated in males using Prader's orchidometer

Secondary Outcome Measures

6 minute walk distance [up to 18 years of age]
Change from baseline from study AMB112529 in the distance walked in six minutes
WHO functional class [up to 18 years of age]
Change from baseline from study AMB112529 i nWHO functional class
Health outcomes assessments [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 [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 [up to 18 years of age]
Change from baseline from study AMB112529 in plasma NT-Pro BNP
Time to clinical worsening [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

8 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Aurora	Colorado	United States	80045
2	GSK Investigational Site	Boston	Massachusetts	United States	02115
3	GSK Investigational Site	Ann Arbor	Michigan	United States	48109-4204
4	GSK Investigational Site	New York	New York	United States	10032
5	GSK Investigational Site	Guymallen	Mendoza	Argentina	5521
6	GSK Investigational Site	Ciudad de Buenos Aires		Argentina	1118
7	GSK Investigational Site	Córdoba		Argentina	5000
8	GSK Investigational Site	Paris cedex 15		France	75743
9	GSK Investigational Site	Pessac cedex		France	33604
10	GSK Investigational Site	Toulouse cedex 9		France	31059
11	GSK Investigational Site	Giessen	Hessen	Germany	35385
12	GSK Investigational Site	Berlin		Germany	13353
13	GSK Investigational Site	Budapest		Hungary	1096
14	GSK Investigational Site	Roma	Lazio	Italy	00165
15	GSK Investigational Site	San Donato Milanese (MI)	Lombardia	Italy	20097
16	GSK Investigational Site	Osaka		Japan	565-0871
17	GSK Investigational Site	Tokyo		Japan	104-8560
18	GSK Investigational Site	Tokyo		Japan	143-8541
19	GSK Investigational Site	Kemerovo		Russian Federation	650002
20	GSK Investigational Site	Moscow		Russian Federation	125412
21	GSK Investigational Site	Novosibirsk		Russian Federation	630055
22	GSK Investigational Site	Madrid		Spain	28046