Hypertension, PulmonaryPhase 2NCT01332331
Efficacy and Safety of Ambrisentan in Children 8-18yrs
A Phase 2 study testing Ambrisentan - low dose and Ambrisentan - high dose in people with Hypertension, Pulmonary, run by GlaxoSmithKline at 24 sites in 9 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 8 to 18 years
- Conditions the study is for
- Hypertension, Pulmonary
- What is being tested?
- Ambrisentan - low dose and Ambrisentan - high dose
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 41 participants
- Where
- 24 sitesin 9 countries
- Study dates
- 4 Jan 2011to 12 Nov 2013
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 8 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 13Show fewer
- 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.
Trial locations and contacts
24 sites in 9 countries.
24 sites in 9 countries
United States4 sites
GSK Investigational Site
Ann Arbor, Michigan, 48109-4204
GSK Investigational Site
Aurora, Colorado, 80045
GSK Investigational Site
Boston, Massachusetts, 02115
GSK Investigational Site
New York, New York, 10032
Japan4 sites
GSK Investigational Site
Kanagawa, 232-8555
GSK Investigational Site
Osaka, 565-0871
GSK Investigational Site
Tokyo, 104-8560
GSK Investigational Site
Tokyo, 143-8541
Argentina3 sites
GSK Investigational Site
Ciudad de Buenos Aires, 1118
GSK Investigational Site
Córdoba, 5000
GSK Investigational Site
Guymallen, Mendoza Province, 5521
France3 sites
GSK Investigational Site
Paris, 75743
GSK Investigational Site
Pessac, 33604
GSK Investigational Site
Toulouse, 31059
Germany3 sites
GSK Investigational Site
Berlin, 13353
GSK Investigational Site
Erlangen, Bavaria, 91054
GSK Investigational Site
Giessen, Hesse, 35385
Russia3 sites
GSK Investigational Site
Kemerovo, 650002
GSK Investigational Site
Moscow, 125412
GSK Investigational Site
Novosibirsk, 630055
Italy2 sites
GSK Investigational Site
Rome, Lazio, 00165
GSK Investigational Site
San Donato Milanese (MI), Lombardy, 20097
About this study
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
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.
Read the 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).
- Conditions
- Hypertension, Pulmonary
- Being tested
- Ambrisentan - low dose, Ambrisentan - high dose
- Keywords
- pulmonary arterial hypertension, pediatric
- Medical subject headings
- Hypertension, Pulmonary, Pulmonary Arterial Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ambrisentan - low doseDrug
body weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg
Ambrisentan - high doseDrug
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
| Study group | Role | What they receive |
|---|---|---|
| Low Dose Ambrisentan | Experimental | body weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg Receives: Drug: Ambrisentan - low dose |
| High Dose Ambrisentan | Experimental | 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 Receives: Drug: Ambrisentan - high dose |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Treatment-emergent Adverse Events (SAEs)
AEs defined as any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAEs defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect, medical events that may not immediately life threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention as per medical or scientific judgement and events of drug-induced liver injury with hyperbilirubinaemia. Safety population comprised of all randomized participants who received at least 1 dose of study drug.
Measured: Up to 24 Weeks
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
Blood samples were collected from participants for analysis of following clinical chemistry parameters: ALT, AST, GGT, total bilirubin and creatinine. PCI ranges were <3 times the upper limit of normal (ULN), <34.2 Micromoles per liter (UMOL/L) for total bilirubin and <176.8 (UMOL/L) for creatinine. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Measured: Up to 24 Weeks
Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hemoglobin
Blood samples were collected from participants for analysis of following hematology parameters: hemoglobin. PCI ranges were Males: 98 to180 grams per liter (G/L), Females: 91 to 161 (G/L) for hemoglobin. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Measured: Up to 24 Weeks
Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hematocrit
Blood samples were collected from participants for analysis of following hematology parameter: hematocrit. PCI ranges were males: <0.32 to >0.54, females: <0.29 to >0.506 proportion of red blood cells in blood for hematocrit. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Measured: Up to 24 Weeks
Number of Participants With Post Baseline PCI Value for Hematology Parameter: Platelet Count
Blood samples were collected from participants for analysis of following hematology parameter: platelet count. PCI ranges were 100 to 400 for Giga cells per liter platelet count. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Measured: Up to 24 Weeks
Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size
Physical examination included measurement of liver size. Any abnormal enlargement or reduction in the size of the liver is reported.
Measured: Week 12 and 24
Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure
Physical examination of participants jugular venous pressure is measured.
Measured: Week 12 and 24
Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema
Physical examination of paricipants peripheral edema is measured. Day 1 was considered as Baseline.
Measured: Week 12 and 24
Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites
Physcial examination of paricipants ascites was measured. Day 1 was considered as Baseline.
Measured: Week 12 and 24
Percentage of Physical Examination Parameter: Saturated Oxygen Level
Physical examination of participants saturated oxygen level was measured. Day 1 was considered as Baseline.
Measured: Week 12 and 24
Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
SBP and DBP were measured in semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges were <80 to >160 millimeters of mercury (mmHg) for SDP and <40 to >110 mmHg for DBP. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Measured: Up to 24 Weeks
Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Heart Rate
Heart rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges were <50 to >120 beats per minute (beats/min). Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Measured: Up to 24 Weeks
Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Weight
Weight of the participants was measured. PCI ranges were <20 kilogram (kg) for weight. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Measured: Up to 24 Weeks
Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24
Testicular volume was assessed by Prader's orchiodometer and the assessment was performed by a pediatric endocrinologist using the Tanner's criteria. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Measured: Baseline, Week 12 and 24
Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24
FSH and LH level of participants were measured. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Measured: Baseline, Week 12 and 24
Change From Baseline in Plasma Endocrine Parameter - Female : Inhibin B at Weeks 12 and 24
Inhibin B level of participants were measured. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Measured: Baseline, Week 12 and 24
Change From Baseline in Plasma Endocrine Parameter - Female : Sex Hormone Binding Globulin at Weeks 12 and 24
Sex hormone binding globulin level of participants were measured. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Measured: Baseline, Week 12 and 24
Secondary outcomes (5)
Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test
Participant's 6MWD data has been presented into three categories as overall, with oxygen use and without oxygen use. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. NA indicates that standard deviation could not be calculated for single participant. Intent-to-Treat (ITT) population consist of all randomized participants who received at least one dose of study drug.
Measured: Baseline, Weeks 4, 8, 12, 16, 20 and 24
Time to the First Clinical Worsening of Pulmonary Arterial Hypertension (PAH)
Time to clinical worsening of PAH is defined as the time from randomization to the first occurrence of death or placed for lung transplant, hospitalization due to PAH deterioration, addition or increased dose of other targeted PAH therapeutic agents like prostanoids and PDE-5 inhibitors) and/or atrial septostomy, other PAH related deterioration identified by increase in WHO functional class, deterioration in exercise testing and clinical signs or symptoms of right sided heart failure.
Measured: Up to Week 24
Change From Baseline in Subject Global Assessment to Week 24 Using the SF-10 Health Survey for Children
Short-form 10 (SF-10) Health Survey for Children is a 10-item parent-completed health assessment that measures physical and psychosocial functioning for children ages five and over. Each item has either 4, 5 or 6 response choices with associated point systems. Two summary scores were calculated: a Physical Summary Score (PHS) and a Psychosocial Summary Score (PSS) with a range of 5 to 30 points for each 5-item score. This aggregated point score was then standardized and transformed to a norm-based scoring metric in accordance with the developer's algorithms using associated mean and standard deviation derived from 2006 sample data. This generated the final standardized norm-based scores for PHS (range -10.90 to 57.21) and for PSS (range 8.81 to 62.28), respectively. A higher value on each summary score indicates better functioning. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Measured: Baseline and Week 24
Change From Baseline in World Health Organization (WHO) Functional Class to Week 24
PAH was classified by WHO functional class (FC) at specific time points. There were four WHO FC grades based on severity of PAH symptoms (Class I=none, Class IV=most severe). Grades were then mapped to numeric scale, for which scores ranged from 1 to 4 (Class I=1 and Class IV=4). Score at Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Measured: Baseline, Week 4, 8, 12, 16, 20 and 24
Ratio to Baseline in Plasma N-terminal Pro-B Type Natriuretic Peptide (NT-Pro BNP) Concentration at Week 24
NT-Pro BNP plasma concentrations were determined at specific time points. Geometric mean and SD logs has been presented. Day 1 was considered as Baseline. Ratio to Baseline is expressed as percentage change from Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Measured: Baseline, Week 12 and 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Apr 2011 (estimated)
- Study start4 Jan 2011
- Primary completion12 Nov 2013
- Study completion12 Nov 2013
Why it stopped: Ongoing juvenile rat toxicology studies.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Hypertension, PulmonaryStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 41 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01332331
- Sponsor's protocol ID
- 112529
- Other IDs
- 2010-019547-19
- Status last verified
- Sep 2019
- First submitted
- 24 Mar 2011
- Last updated
- 8 Oct 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Ivy D, Beghetti M, Juaneda-Simian E, Miller D, Lukas MA, Ioannou C, Okour M, Narita J, Berger RMF. A Randomized Study of Safety and Efficacy of Two Doses of Ambrisentan to Treat Pulmonary Arterial Hypertension in Pediatric Patients Aged 8 Years up to 18 Years. J Pediatr X. 2020 Sep 22;5:100055. doi: 10.1016/j.ympdx.2020.100055. eCollection 2020 Spring.
PubMed 37332660Okour M, Thapar MM, Farrell C, Lukas MA, Beghetti M, Beerahee M. Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data. J Clin Pharmacol. 2023 May;63(5):593-603. doi: 10.1002/jcph.2199. Epub 2023 Jan 29.
PubMed 36579617
Study at a glance
From the registry record, last updated by the sponsor on 8 Oct 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01332331
- Acronym / sponsor ID
- 112529
- Conditions
- Hypertension, Pulmonary
- Keywords
- pulmonary arterial hypertension, pediatric
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Ongoing juvenile rat toxicology studies.
- Enrolment
- 41 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- 4 Jan 2011 (actual)
- Primary completion
- 12 Nov 2013 (actual)
- Study completion
- 12 Nov 2013 (actual)
- First posted
- 11 Apr 2011 (estimated)
- Results
- Posted 8 Oct 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Low Dose Ambrisentan | Experimental | Drug: Ambrisentan - low dosebody weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg |
| High Dose Ambrisentan | Experimental | Drug: Ambrisentan - high dosebody 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 |
Who may qualify
- Ages
- 8 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (13 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ambrisentan - low dosebody weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg | Drug | Low Dose Ambrisentan |
| Ambrisentan - high dosebody 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 | Drug | High Dose Ambrisentan |
Primary outcome
Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Treatment-emergent Adverse Events (SAEs)
Time frame: Up to 24 Weeks
AEs defined as any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAEs defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect, medical events that may not immediately life threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention as per medical or scientific judgement and events of drug-induced liver injury with hyperbilirubinaemia. Safety population comprised of all randomized participants who received at least 1 dose of study drug.
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
Time frame: Up to 24 Weeks
Blood samples were collected from participants for analysis of following clinical chemistry parameters: ALT, AST, GGT, total bilirubin and creatinine. PCI ranges were <3 times the upper limit of normal (ULN), <34.2 Micromoles per liter (UMOL/L) for total bilirubin and <176.8 (UMOL/L) for creatinine. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hemoglobin
Time frame: Up to 24 Weeks
Blood samples were collected from participants for analysis of following hematology parameters: hemoglobin. PCI ranges were Males: 98 to180 grams per liter (G/L), Females: 91 to 161 (G/L) for hemoglobin. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hematocrit
Time frame: Up to 24 Weeks
Blood samples were collected from participants for analysis of following hematology parameter: hematocrit. PCI ranges were males: <0.32 to >0.54, females: <0.29 to >0.506 proportion of red blood cells in blood for hematocrit. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Number of Participants With Post Baseline PCI Value for Hematology Parameter: Platelet Count
Time frame: Up to 24 Weeks
Blood samples were collected from participants for analysis of following hematology parameter: platelet count. PCI ranges were 100 to 400 for Giga cells per liter platelet count. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size
Time frame: Week 12 and 24
Physical examination included measurement of liver size. Any abnormal enlargement or reduction in the size of the liver is reported.
Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure
Time frame: Week 12 and 24
Physical examination of participants jugular venous pressure is measured.
Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema
Time frame: Week 12 and 24
Physical examination of paricipants peripheral edema is measured. Day 1 was considered as Baseline.
Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites
Time frame: Week 12 and 24
Physcial examination of paricipants ascites was measured. Day 1 was considered as Baseline.
Percentage of Physical Examination Parameter: Saturated Oxygen Level
Time frame: Week 12 and 24
Physical examination of participants saturated oxygen level was measured. Day 1 was considered as Baseline.
Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Time frame: Up to 24 Weeks
SBP and DBP were measured in semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges were <80 to >160 millimeters of mercury (mmHg) for SDP and <40 to >110 mmHg for DBP. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Heart Rate
Time frame: Up to 24 Weeks
Heart rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges were <50 to >120 beats per minute (beats/min). Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Weight
Time frame: Up to 24 Weeks
Weight of the participants was measured. PCI ranges were <20 kilogram (kg) for weight. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24
Time frame: Baseline, Week 12 and 24
Testicular volume was assessed by Prader's orchiodometer and the assessment was performed by a pediatric endocrinologist using the Tanner's criteria. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24
Time frame: Baseline, Week 12 and 24
FSH and LH level of participants were measured. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Change From Baseline in Plasma Endocrine Parameter - Female : Inhibin B at Weeks 12 and 24
Time frame: Baseline, Week 12 and 24
Inhibin B level of participants were measured. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Change From Baseline in Plasma Endocrine Parameter - Female : Sex Hormone Binding Globulin at Weeks 12 and 24
Time frame: Baseline, Week 12 and 24
Sex hormone binding globulin level of participants were measured. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
5 secondary outcomes
Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test
Time frame: Baseline, Weeks 4, 8, 12, 16, 20 and 24
Time to the First Clinical Worsening of Pulmonary Arterial Hypertension (PAH)
Time frame: Up to Week 24
Change From Baseline in Subject Global Assessment to Week 24 Using the SF-10 Health Survey for Children
Time frame: Baseline and Week 24
Change From Baseline in World Health Organization (WHO) Functional Class to Week 24
Time frame: Baseline, Week 4, 8, 12, 16, 20 and 24
Ratio to Baseline in Plasma N-terminal Pro-B Type Natriuretic Peptide (NT-Pro BNP) Concentration at Week 24
Time frame: Baseline, Week 12 and 24
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Oct 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37332660Ivy D, Beghetti M, Juaneda-Simian E, Miller D, Lukas MA, Ioannou C, Okour M, Narita J, Berger RMF. A Randomized Study of Safety and Efficacy of Two Doses of Ambrisentan to Treat Pulmonary Arterial Hypertension in Pediatric Patients Aged 8 Years up to 18 Years. J Pediatr X. 2020 Sep 22;5:100055. doi: 10.1016/j.ympdx.2020.100055. eCollection 2020 Spring.
- Derived from this study: PubMed 36579617Okour M, Thapar MM, Farrell C, Lukas MA, Beghetti M, Beerahee M. Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data. J Clin Pharmacol. 2023 May;63(5):593-603. doi: 10.1002/jcph.2199. Epub 2023 Jan 29.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
24 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ambrisentan - low dose and Ambrisentan - high dose in people with Hypertension, Pulmonary, run by GlaxoSmithKline at 24 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 8 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 24 sites in United States, Japan, Argentina, France, Germany and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Oct 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Treatment-emergent Adverse Events (SAEs) (time frame: Up to 24 Weeks). The study lists 17 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01332331, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Oct 2019.