Efficacy and Safety of Ambrisentan in Children 8-18yrs
Condition: Hypertension, Pulmonary
MeSH terms: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypertension
Intervention: Ambrisentan - low dose; Ambrisentan - high dose
Intervention description: body weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg; 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 MeSH terms: Ambrisentan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 41.0
Sex: All
Minimum age: 8 Years
Maximum age: 18 Years
Healthy volunteers: No
Keywords: pulmonary arterial hypertension; pediatric

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.
    

Eligibility 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.