Efficacy and Safety of Ambrisentan in Children 8-18yrs
Efficacy and Safety of Ambrisentan in Children 8-18yrs
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.
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).
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.