Clinical trial NCT01342952: Long-term Ambrisentan Extension Study for Pediatric Patients Who Participated in AMB112529
Official title: An Open-label, Long Term Extension Study for Treatment of Pulmonary Arterial Hypertension in Paediatric Patients Aged 8 Years up to 18 Years Who Have Participated in AMB112529 and in Whom Continued Treatment With Ambrisentan is Desired
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertension, Pulmonary
Keywords: pulmonary arterial hypertension
pediatrics
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-04-27
Enrollment: 38
Sex: ALL
Minimum age (years): 8
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: An open label, long term extension to Study AMB112529. All subjects may remain in the extension study for a minimum of six months. Beyond the six month period, subjects may continue in the extension study until one of the following conditions is met:

the subject turns 18 years of age (when the subject can receive marketed product) the product is approved and available for use in the subject's age group, development for use in the paediatric population is discontinued. the subject decides he/she no longer wants to participate in the study, the investigator considers it is in the best interest of the subject to discontinue ambrisentan (e.g. for safety reasons).

The primary objective is the long-term safety and tolerability of ambrisentan in the paediatric PAH population. Secondary objectives are all cause mortality and change from baseline in Study AMB112529 on efficacy parameters.

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 paediatric 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 long term paediatric study is to provide clinically relevant information on the long term safety of ambrisentan in children with the most common causes of PAH in this age group. This study is only open to patients who have participated in Study AMB112529, 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, and in whom continued treatment with ambrisentan is warranted.

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:

* Have participated in and complied, to the best of their ability, with the protocol for AMB112529 and have met one of the following:

  1. Completed the Week 24 visit in AMB112529;
  2. Required additional targeted treatment for PAH due to inadequate response to the current treatment or worsening of their clinical condition prior to week 24 in AMB112529;
  3. Required reduction in dose of baseline targeted treatment for PAH after ambrisentan was added to the treatment regimen;
  4. In the opinion of the investigator, continued treatment with ambrisentan is warranted.
* A female is eligible to participate in this study, as assessed by the investigator, if she is of:

  1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant); or,
  2. Child-bearing potential - has a negative pregnancy test and is not lactating and, if sexually active, agrees to continue to use 2 reliable methods of contraception until study completion and for at least 30 days following the last dose of study drug (reliable methods of contraception are listed in Appendix 2).
* 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:

* Subjects who were withdrawn from ambrisentan in Study AMB112529;
* Subjects who did not comply with the protocol in Study AMB112529;
* Female subjects who are pregnant or breastfeeding;
* Subjects with severe renal impairment (estimated creatinine clearance \<30 mL/min assessed within the previous 45 days) at the point of transition from Study AMB112529 into this study;
* Subject with clinically significant fluid retention in the opinion of the investigator;
* Subject with clinically significant anaemia in the opinion of the investigator;
* Subjects who are to enter another clinical trial or be treated with another investigational product after exiting Study AMB112529.

Primary outcomes:
measure: Number of Participants With Non-serious Treatment-emergent Adverse Events (Non-STEAEs) and Serious Treatment-emergent Adverse Events (STEAEs)
timeFrame: Up to 10 years and 11 months
measure: Change From Baseline in Liver Function Parameters: Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Gamma Glutamyl Transferase (GGT), Total Bilirubin
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Chemistry Parameters: Calcium, Chloride, Carbon Dioxide (CO2) Content, Glucose, Potassium, Magnesium, Sodium, Phosphorus Inorganic, Blood Urea Nitrogen (BUN)
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Chemistry Parameters: Alkaline Phosphatase (ALP), Creatine Kinase (CK), Lactate Dehydrogenase (LDH)
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Chemistry Parameters: Creatinine, Uric Acid
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Chemistry Parameters: Albumin, Total Protein
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Hematology Parameters: Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC)
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Hematology Parameters: Hematocrit
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, White Blood Cells (WBC), Platelet Count
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Hematology Parameter: Mean Corpuscle Volume
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Hematology Parameters: Red Blood Cell Count, Reticulocytes
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Number of Participants With Abnormal Values for Physical Examination Parameter: Liver Size
timeFrame: Up to 10 years and 11 months
measure: Number of Participants With Abnormal Values for Physical Examination Parameter: Jugular Venous Pressure
timeFrame: Up to 10 years and 11 months
measure: Number of Participants With Abnormal Values for Physical Examination Parameters: Ascites
timeFrame: Up to 10 years and 11 months
measure: Number of Participants With Abnormal Values for Physical Examination Parameter: Peripheral Edema
timeFrame: Up to 10 years and 11 months
measure: Percentage of Saturated Oxygen Level (Physical Examination Parameter)
timeFrame: Up to 10 years and 11 months
measure: Change From Baseline in Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Vital Signs Parameter: Heart Rate
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Vital Signs Parameter: Weight
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Vital Sign Parameter: Height
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Vital Sign Parameter: Body Mass Index
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Vital Sign Parameter: Body Surface Area
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Inhibin B at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Inhibin B at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Sex Hormone Binding Globulin at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Sex Hormone Binding Globulin at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Estrone at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Estrone at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Estriol at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Estriol at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Estradiol at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Female: Estradiol at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline in Plasma Endocrine Parameters - Male: FSH and LH at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Male: FSH and LH at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline in Plasma Endocrine Parameters - Male: Inhibin B at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Male: Inhibin B at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline in Plasma Endocrine Parameters - Male: Sex Hormone Binding Globulin at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Male: Sex Hormone Binding Globulin at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline in Plasma Endocrine Parameters - Male: Total Testosterone at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline in Plasma Endocrine Parameters - Male: Total Testosterone at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Change From Baseline of Pubertal Development in Male: Testicular Volume at End of Study
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Change From Baseline of Pubertal Development in Male: Testicular Volume at 20 Years of Age of Participants
timeFrame: Baseline (Day 1) and at 20 years of age of participants
measure: Time to Change in Dose of Ambrisentan or Other Targeted PAH Therapeutic Agents (Prostanoids, Phosphodiesterase Type 5 [PDE-5] Inhibitors) Due to Tolerability Issues
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
Secondary outcomes:
measure: Number of Participants With All-cause Death
timeFrame: Up to 10 years and 11 months
measure: Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Time to the First Clinical Worsening of PAH
timeFrame: Up to 10 years and 11 months
measure: Time to the Addition of Another Targeted PAH Therapeutic Agent Due to Deterioration of Clinical Condition
timeFrame: Up to 10 years and 11 months
measure: Time to the Addition of Another Targeted PAH Therapeutic Agent Due to Lack of Beneficial Effect With Previous Therapy
timeFrame: Up to 10 years and 11 months
measure: Time to Change in Dose of Ambrisentan or Other Targeted PAH Therapeutic Agents (Prostanoids, PDE-5 Inhibitors) Due to Deterioration of Clinical Condition
timeFrame: Up to 10 years and 11 months
measure: Change From Baseline in Subject Global Assessment (SF-10) Health Survey for Children
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class of PAH
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
measure: Percentage Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-Pro BNP) Concentration
timeFrame: Baseline (Day 1) and up to 10 years and 11 months
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
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: 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: 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: