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Efficacy and Safety of Ambrisentan in Children 8-18yrs

Information source: GlaxoSmithKline
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Hypertension, Pulmonary

Intervention: Ambrisentan - low dose (Drug); Ambrisentan - high dose (Drug)

Phase: Phase 2

Status: Suspended

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline

Summary

A 6-month (24-week), randomized, open label evaluation of the safety, tolerability, and efficacy of a high and low dose ambrisentan (adjusted for body weight) treatment group in subjects aged 8 years up to 18 years with pulmonary arterial hypertension (PAH). An additional objective is to determine the ambrisentan population pharmacokinetics in the paediatric population. The study will include a screening/baseline period and a treatment period. The treatment period will be 24 weeks or until the subject's clinical condition deteriorates to the point that alternative/additional treatment is necessary. Patients who participate in the study and in whom continued treatment with ambrisentan is desired will be eligible to enrol into a long term follow-up study. The primary comparison will be the safety and tolerability of the two ambrisentan dose groups (Low vs. High) in the paediatric PAH population The secondary comparison will be the change from baseline for the efficacy parameters between the two treatment groups.

Clinical Details

Official title: 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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Serious Adverse Events

Adverse Events

Clinical Laboratory Parameters

Physical Examination

Vital Signs

Endocrinology assessments

Hematology

12 lead ECG

Secondary outcome:

Population pharmacokinetic assessment

Pharmacokinetic/pharmacodynamic modelling

6 minute walking distance

Subject Global Assessment

WHO functional class

Plasma N-Terminal pro-B-type Natriuretic Peptide (NT-Pro BNP) concentration

Echocardiogram parameters

Time to Clinical Worsening

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 pediatric 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 paediatric study is to provide clinically relevant information on the safety and pharmacokinetic profile of ambrisentan in children with the most common causes of PAH in this age group. The design of the study is also intended to provide information to guide dose selection and supportive efficacy data in this age group. Despite the fact that none of the currently available adult treatments are licensed for use in children <12 yrs, (with the exception of bosentan which was recently approved for use in paediatric population from 2 years of age) they are widely used off label. This study will provide useful prescribing information to the medical community for treating this orphan disease in children in this environment of rapidly changing medical practice. This study is part of a Paediatric Investigational Plan (PIP; EMEA-000434-PIP01-08) agreed with the European Medicines Agency's Paediatric Committee (PDCO).

Eligibility

Minimum age: 8 Years. Maximum age: 18 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Current diagnosis of PAH (WHO Group 1) with WHO class II or III symptoms in one of

the following categories: Idiopathic, Heritable [familial], Secondary to connective tissue disease (e. g., limited scleroderma, diffuse scleroderma, mixed connective tissue disease (CTD), systemic lupus erythematosus, or overlap syndrome), or Persistent PAH despite surgical repair (at least 6 months prior to the screening visit) of atrial septal defects, ventricular septal defects, atrio-ventricular septal defects, and persistent patent ductus.

- Have met the following hemodynamic criteria for subjects with right heart

catheterization (RHC) when performed as part of the diagnosis or routine care: mean pulmonary arterial pressure (mPAP) of >/=25 mmHg, pulmonary vascular resistance (PVR) of >/=240 dyne sec/cm5, left ventricular end diastolic pressure (LEVDP) or pulmonary capillary wedge pressure (PCWP) of ≤15 mmHg.

- be treatment naïve, have discontinued treatment with another ERA (e. g., bosentan) at

least 1 month previously because of elevated liver function tests (LFTs), or have been on a stable dose of drug therapy for PAH (e. g., sildenafil or prostacyclin) for at least one month prior to the Screening Visit.

- Subjects who discontinued ERA treatment due to elevated LFTs, must have LFTs of <3 x

Upper Limit of Normal (ULN).

- A female is eligible to participate in this study, as assessed by the investigator,

if she is of: a. non-childbearing potential (i. e., physiologically incapable of

becoming pregnant); or, b. Child-bearing potential - has a negative pregnancy test

and is not lactating at the Screening and Baseline/Randomisation Visits and, if sexually active, agrees to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of study drug.

- 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:

- currently taking an ERA.

- currently taking cyclosporine A.

- body weight is less than 20 Kg.

- have not tolerated PAH therapy due to adverse effects which may be related to their

mechanism of action (e. g., prostanoids, ERA, PDE-5 inhibitors) with the exception of liver abnormalities for those subjects who were receiving another ERA.

- pregnant or breastfeeding.

- diagnosis of active hepatitis (hepatitis B surface antigen and hepatitis C antibody),

or clinically significant hepatic enzyme elevation (i. e., ALT, AST or AP >3xULN) at Screening.

- severe renal impairment (creatinine clearance <30 mL/min) at Screening.

- clinically significant fluid retention in the opinion of the investigator.

- clinically significant anaemia in the opinion of the investigator.

- a known hypersensitivity to the study drug, the metabolites, or formulation

excipients.

- have participated in another trial or have taken another investigational product

during the previous 30 days.

- alcohol abuse, illicit drug use within 1 year.

- any concurrent condition or concurrent use of medication that would affect subject

safety in the opinion of the investigator.

Locations and Contacts

GSK Investigational Site, Ciudad de Buenos Aires 1118, Argentina

GSK Investigational Site, Corrientes W3400AMZ, Argentina

GSK Investigational Site, Córdoba 5000, Argentina

GSK Investigational Site, Paris cedex 15 75743, France

GSK Investigational Site, Pessac cedex 33604, France

GSK Investigational Site, Toulouse cedex 9 31059, France

GSK Investigational Site, Berlin 13353, Germany

GSK Investigational Site, Budapest 1096, Hungary

GSK Investigational Site, Kanagawa 232-8555, Japan

GSK Investigational Site, Osaka 565-0871, Japan

GSK Investigational Site, Tokyo 104-8560, Japan

GSK Investigational Site, Tokyo 143-8541, Japan

GSK Investigational Site, Groningen 9713 GZ, Netherlands

GSK Investigational Site, Kemerovo 650002, Russian Federation

GSK Investigational Site, Moscow 125412, Russian Federation

GSK Investigational Site, Novosibirsk 630055, Russian Federation

GSK Investigational Site, Samara 443070, Russian Federation

GSK Investigational Site, Barcelona 08035, Spain

GSK Investigational Site, Madrid 28034, Spain

GSK Investigational Site, Madrid 28046, Spain

GSK Investigational Site, Erlangen, Bayern 91054, Germany

GSK Investigational Site, Palo Alto, California 94304-1601, United States

GSK Investigational Site, Napoli, Campania 80131, Italy

GSK Investigational Site, Aurora, Colorado 80045, United States

GSK Investigational Site, Bologna, Emilia-Romagna 40138, Italy

GSK Investigational Site, Giessen, Hessen 35385, Germany

GSK Investigational Site, Roma, Lazio 00165, Italy

GSK Investigational Site, Genova, Liguria 16147, Italy

GSK Investigational Site, San Donato Milanese (MI), Lombardia 20097, Italy

GSK Investigational Site, Boston, Massachusetts 02115, United States

GSK Investigational Site, Guymallen, Mendoza 5521, Argentina

GSK Investigational Site, Ann Arbor, Michigan 48109, United States

GSK Investigational Site, New York, New York 10032, United States

GSK Investigational Site, Toronto, Ontario M5G 1X8, Canada

Additional Information

Starting date: January 2011
Last updated: March 19, 2015

Page last updated: August 23, 2015

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