Clinical trial NCT01332331: Efficacy and Safety of Ambrisentan in Children 8-18yrs
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hypertension, Pulmonary
Keywords: pulmonary arterial hypertension
pediatric
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-04-11
Enrollment: 41
Sex: ALL
Minimum age (years): 8
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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.

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Treatment-emergent Adverse Events (SAEs)
timeFrame: Up to 24 Weeks
measure: Number of Participants With Post Baseline Potential Clinical Importance (PCI) Value for Clinical Chemistry Parameters: Alanine Amino Transferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT), Total Bilirubin and Creatinine
timeFrame: Up to 24 Weeks
measure: Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hemoglobin
timeFrame: Up to 24 Weeks
measure: Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hematocrit
timeFrame: Up to 24 Weeks
measure: Number of Participants With Post Baseline PCI Value for Hematology Parameter: Platelet Count
timeFrame: Up to 24 Weeks
measure: Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size
timeFrame: Week 12 and 24
measure: Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure
timeFrame: Week 12 and 24
measure: Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema
timeFrame: Week 12 and 24
measure: Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites
timeFrame: Week 12 and 24
measure: Percentage of Physical Examination Parameter: Saturated Oxygen Level
timeFrame: Week 12 and 24
measure: Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Up to 24 Weeks
measure: Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Heart Rate
timeFrame: Up to 24 Weeks
measure: Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Weight
timeFrame: Up to 24 Weeks
measure: Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24
timeFrame: Baseline, Week 12 and 24
measure: Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24
timeFrame: Baseline, Week 12 and 24
measure: Change From Baseline in Plasma Endocrine Parameter - Female : Inhibin B at Weeks 12 and 24
timeFrame: Baseline, Week 12 and 24
measure: Change From Baseline in Plasma Endocrine Parameter - Female : Sex Hormone Binding Globulin at Weeks 12 and 24
timeFrame: Baseline, Week 12 and 24
Secondary outcomes:
measure: Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20 and 24
measure: Time to the First Clinical Worsening of Pulmonary Arterial Hypertension (PAH)
timeFrame: Up to Week 24
measure: Change From Baseline in Subject Global Assessment to Week 24 Using the SF-10 Health Survey for Children
timeFrame: Baseline and Week 24
measure: Change From Baseline in World Health Organization (WHO) Functional Class to Week 24
timeFrame: Baseline, Week 4, 8, 12, 16, 20 and 24
measure: Ratio to Baseline in Plasma N-terminal Pro-B Type Natriuretic Peptide (NT-Pro BNP) Concentration at Week 24
timeFrame: Baseline, Week 12 and 24
Other outcomes:
Locations:
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Guymallen
country: Argentina
facility: GSK Investigational Site
state: Mendoza
city: Ciudad de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Córdoba
country: Argentina
facility: GSK Investigational Site
city: Paris cedex 15
country: France
facility: GSK Investigational Site
city: Pessac cedex
country: France
facility: GSK Investigational Site
city: Toulouse cedex 9
country: France
facility: GSK Investigational Site
city: Erlangen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Giessen
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: San Donato Milanese (MI)
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Novosibirsk
country: Russian Federation
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: