Efficacy and Safety of Ambrisentan in Children 8-18yrs

• Serious Adverse Events [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  Number of patients with a serious adverse event
• Adverse Events [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  Number of patients with adverse events
• Clinical Laboratory Parameters [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  sodium, magnesium, potassium, calcium, glucose, chloride, bicarbonate (CO2,) phosphorus-inorganic, creatinine, total protein, albumin, ALT (SGPT), AST (SGOT), GGT, LDH, total bilirubin, creatine phosphokinase (CPK), blood urea nitrogen (BUN), uric acid, and alkaline phosphatase
• Physical Examination [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  Change from baseline in physical parameters
• Vital Signs [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  Change from baseline in blood pressure, rispiratory rate, and heart rate
• Endocrinology assessments [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  FSH, LH, sex hormone binding globulin, inhibin B, testosterone (males only) and estrogen (females only)
• Hematology [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  RBC count, reticulocyte count, hematocrit, hemoglobin, RBC indices (mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], and mean corpuscular haemoglobin concentration [MCHC]), WBC count, automated WBC differential (neutrophils-total, lymphocytes, monocytes, eosinophils, basophils)
• 12 lead ECG [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  Change from baseline

• Population pharmacokinetic assessment [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  A single plasma sample will be collected at each visit in each subject for the determination of plasma ambrisentan concentrations. The time that the plasma sample is obtained and the time that the two doses of ambrisentan immediately prior to the plasma sample were injested will be recorded. All dose, ambrisentan concentration and time data will be pooled and a population pharmacokinetic model will be fit to the data. Expected parameters will be clearance, volume of distribution, absorption rate constant, and elimination rate constant.
• Pharmacokinetic/pharmacodynamic modelling [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Relationship between plasma drug concentration and change from baseline in six minute walk distance
• 6 minute walking distance [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Change from baseline in the distance walked in six minutes
• Subject Global Assessment [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Change from baseline in SF 10 and the proportion of days missed from school due to symptoms of the disease
• WHO functional class [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Change from baseline in WHO functional classe
• Plasma N-Terminal pro-B-type Natriuretic Peptide (NT-Pro BNP) concentration [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Change from baseline plasma NT-Pro BNP
• Echocardiogram parameters [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Pericardial effusion, right atrial pressure, tricuspid annular plane systolic excursion, eccentricity index (systolic and diastolic), and right ventricular pressure by tricuspid regurgitant jet velocity
• Time to Clinical Worsening [ Designated as safety issue: No ]
  The time from randomization to the first occurrence 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) and/or atrial septostomy; or PAH related deterioration (increase in WHO functional class; deterioration in exercise testing; clinical signs or symptoms of right sided heart).

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).

• Drug: Ambrisentan - low dose
  body weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg
• Drug: Ambrisentan - high dose
  body weight 20 to 35 kg - 5.0 mg; body weight 35 to 50 kg - 7.5 mg; body weight 50 kg and over - 10.0 mg

• Experimental: Low Dose Ambrisentan
  body weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg
  Intervention: Drug: Ambrisentan - low dose
• Experimental: High Dose Ambrisentan
  body weight 20 to 35 kg - 5.0 mg; body weight 35 to 50 kg - 7.5 mg; body weight 50 kg and over - 10.0 mg
  Intervention: Drug: Ambrisentan - high dose

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.