A Phase 2 interventional study of Ambrisentan - low dose and Ambrisentan - high dose in Hypertension, Pulmonary, sponsored by GlaxoSmithKline. Terminated at 24 sites in 9 countries. Open to participants aged 8 Years to 18 Years. Per ClinicalTrials.gov, last updated 2019-10-08.
Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment
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).
761 studies on the registry are indexed under Pulmonary Arterial Hypertension; 142 are open to participants now.
This study's enrollment of 41 is close to the median of 38 across 509 interventional studies indexed under Pulmonary Arterial Hypertension.
Browse Pulmonary Arterial Hypertension studies →GlaxoSmithKline is the lead sponsor of 3,562 studies on the registry; 117 are open to participants now.
Of its 258 completed or terminated interventional studies of FDA-regulated products, 232 (90%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
body weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg
Drug: Ambrisentan - low 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
Drug: Ambrisentan - high dose
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
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline, Week 12 and 24
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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
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.
Time frame: Baseline, Week 12 and 24
This study investigated the safety and efficacy of a high and low dose ambrisentan (adjusted as per participants body weight) administered orally in participants aged 8 to 18 years with pulmonary arterial hypertension (PAH).
| Milestone | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Started | 21 | 20 |
| Completed | 19 | 18 |
| Not completed | 2 | 2 |
| Withdrew: Lost to follow-up | 0 | 1 |
| Withdrew: Adverse event | 1 | 1 |
| Withdrew: Physician decision | 1 | 0 |
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.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Any AEs | 16 | 16 |
| Any SAEs | 6 | 2 |
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.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| ALT | 0 | 0 |
| AST | 0 | 0 |
| GGT | 0 | 0 |
| Total bilirubin | 1 | 0 |
| Creatinine | 0 | 0 |
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.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Reference high range | 0 | 2 |
| Reference low range | 1 | 0 |
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.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Reference high range | 0 | 2 |
| Reference low range | 1 | 2 |
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.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Reference high range | 0 | 0 |
| Reference low range | 0 | 1 |
Physical examination included measurement of liver size. Any abnormal enlargement or reduction in the size of the liver is reported.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, Abnormal: Improved, n=20, 19 | 1 | 1 |
| Week 12, Abnormal: Worsened, n=20, 19 | 1 | 1 |
| Week 12, Abnormal: Unchanged, n=20, 19 | 1 | 0 |
| Week 24, Abnormal: Improved, n=19, 18 | 2 | 1 |
| Week 24, Abnormal: Worsened, n=19, 18 | 0 | 0 |
| Week 24, Abnormal: Unchanged, n=19, 18 | 0 | 0 |
Physical examination of participants jugular venous pressure is measured.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, Abnormal: Improved, n=20, 19 | 0 | 1 |
| Week 12, Abnormal: Worsened, n=20, 19 | 0 | 1 |
| Week 12, Abnormal: Unchanged, n=20, 19 | 0 | 3 |
| Week 24, Abnormal: Improved, n=19, 18 | 0 | 1 |
| Week 24, Abnormal: Worsened, n=19, 18 | 1 | 0 |
| Week 24, Abnormal: Unchanged, n=19, 18 | 0 | 4 |
Physical examination of paricipants peripheral edema is measured. Day 1 was considered as Baseline.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, Abnormal: Improved, n=20, 19 | 0 | 0 |
| Week 12, Abnormal: Worsened, n=20, 19 | 1 | 1 |
| Week 12, Abnormal: Unchanged, n=20, 19 | 0 | 1 |
| Week 24, Abnormal: Improved, n=19, 18 | 1 | 0 |
| Week 24, Abnormal: Worsened, n=19, 18 | 1 | 0 |
| Week 24, Abnormal: Unchanged, n=19, 18 | 0 | 0 |
Physcial examination of paricipants ascites was measured. Day 1 was considered as Baseline.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, Abnormal: Improved, n=20, 19 | 0 | 0 |
| Week 12, Abnormal: Worsened, n=20, 19 | 0 | 0 |
| Week 12, Abnormal: Unchanged, n=20, 19 | 0 | 0 |
| Week 24, Abnormal: Improved, n=19, 18 | 0 | 0 |
| Week 24, Abnormal: Worsened, n=19, 18 | 0 | 0 |
| Week 24, Abnormal: Unchanged, n=19, 18 | 0 | 0 |
Physical examination of participants saturated oxygen level was measured. Day 1 was considered as Baseline.
| Percentage of oxygen saturation | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, n=20, 18 | 96.9 ± 2.59 | 96.9 ± 6.93 |
| Week 24, n=19, 18 | 97.3 ± 1.85 | 97.4 ± 1.92 |
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.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| SBP, Reference range high | 0 | 0 |
| SBP, Reference range low | 1 | 2 |
| DBP, Reference range high | 0 | 0 |
| DBP, Reference range low | 0 | 0 |
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.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Reference range high | 2 | 2 |
| Reference range low | 1 | 0 |
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.
| Participants | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Reference range high | 0 | 0 |
| Reference range low | 0 | 0 |
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.
| Milliliter | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, Right TV, n=7, 4 | 0.4 ± 1.27 | 0.3 ± 0.50 |
| Week 12, Left TV, n=8, 5 | 0.0 ± 0.53 | 0.2 ± 0.45 |
| Week 24, Right TV, n=6, 4 | 0.5 ± 1.38 | 0.1 ± 0.25 |
| Week 24, Left TV, n=7, 5 | 1.4 ± 2.76 | 0.5 ± 1.50 |
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.
| International unit per Liter | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, FSH, n=11, 13 | 0.586 ± 1.412 | -0.023 ± 2.104 |
| Week 24, FSH, n=10, 12 | 0.010 ± 1.390 | 1.542 ± 2.518 |
| Week 12, LH, n=11, 13 | 0.39 ± 3.117 | -0.28 ± 6.881 |
| Week 24, LH, n=11, 13 | -0.56 ± 1.192 | 1.15 ± 6.806 |
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.
| Nanogram per liter | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, Right TV, n=9, 7 | 4.9 ± 10.03 | 1.7 ± 33.70 |
| Week 24, Left TV, n=9, 7 | -5.2 ± 36.44 | 16.0 ± 37.96 |
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.
| Milliliter | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, Right TV, n=10, 9 | 1.3 ± 9.55 | 7.4 ± 18.91 |
| Week 24, Left TV, n=10, 8 | -9.2 ± 13.62 | 3.1 ± 14.21 |
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.
| Meters | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 4, Overall, n=21, 18 | 33.10 ± 66.979 | 24.96 ± 71.254 |
| Week 4, With oxygen use, n=2, 1 | -16.00 ± 11.314 | 85.20 ± NA |
| Week 4, Without oxygen use, n=19, 17 | 38.27 ± 68.421 | 21.41 ± 71.793 |
| Week 8, Overall, n=20, 18 | 23.84 ± 65.154 | 37.70 ± 74.339 |
| Week 8, With oxygen use, n=2, 1 | -16.00 ± 22.627 | 81.10 ± NA |
| Week 8, Without oxygen use, n=18, 17 | 28.26 ± 67.133 | 35.15 ± 75.809 |
| Week 12, Overall, n=19, 18 | 29.51 ± 79.657 | 40.29 ± 69.137 |
| Week 12, With oxygen use, n=2, 1 | -1.00 ± 65.054 | 75.40 ± NA |
| Week 12, Without oxygen use, n=17, 17 | 33.09 ± 82.121 | 38.22 ± 70.690 |
| Week 16, Overall, n=19, 18 | 22.31 ± 88.832 | 36.43 ± 78.220 |
| Week 16, With oxygen use, n=2, 1 | -21.00 ± 57.983 | 65.40 ± NA |
| Week 16, Without oxygen use, n=17, 17 | 27.41 ± 91.681 | 34.73 ± 80.282 |
| Week 20, Overall, n=19, 18 | 48.49 ± 90.645 | 31.19 ± 71.209 |
| Week 20, With oxygen use, n=3, 1 | -0.33 ± 43.753 | 73.20 ± NA |
| Week 20, Without oxygen use, n=16, 17 | 57.64 ± 95.070 | 28.72 ± 72.600 |
| Week 24, Overall, n=18, 18 | 55.14 ± 102.182 | 26.25 ± 62.011 |
| Week 24, With oxygen use, n=3, 1 | 43.00 ± 53.395 | 65.90 ± NA |
| Week 24, Without oxygen use, n=15, 17 | 57.57 ± 110.605 | 23.92 ± 63.100 |
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.
| Days | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Time to the First Clinical Worsening of Pulmonary Arterial Hypertension (PAH) | 77.3 ± 62.56 | 71.7 ± 29.26 |
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.
| Scores on a scale | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Physical health summary, n=16, 15 | 0.194 ± 11.7733 | 2.811 ± 13.1172 |
| Psychosocial summary, n=16, 15 | 0.725 ± 8.6431 | 0.412 ± 10.1331 |
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.
| Scores on a scale | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 4, n=21, 19 | -0.1 ± 0.36 | -0.1 ± 0.23 |
| Week 8, n=20, 19 | -0.1 ± 0.45 | -0.1 ± 0.40 |
| Week 12, n=20, 19 | -0.1 ± 0.45 | 0.0 ± 0.58 |
| Week 16, n=20, 18 | -0.2 ± 0.49 | -0.2 ± 0.38 |
| Week 20, n=19, 18 | -0.2 ± 0.50 | -0.2 ± 0.38 |
| Week 24, n=19, 18 | -0.3 ± 0.56 | -0.2 ± 0.43 |
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.
| Percentage Change | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Week 12, n=19, 17 | -15.93 ± 0.895 | -12.43 ± 0.862 |
| Week 24, n=18, 17 | -30.91 ± 0.851 | -28.25 ± 1.179 |
Collected over On-treatment serious adverse events (SAEs) and non serious AEs were collected from the start of study treatment up to 24 weeks. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Low Dose Ambrisentan | 1/21 (4.8%) | 6/21 (28.6%) | 16/21 (76.2%) |
| High Dose Ambrisentan | 0/20 (0%) | 2/20 (10%) | 16/20 (80%) |
| Event | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| Cardiac failure acuteCardiac disorders | 0/21 | 1/20 |
| Right ventricular failureCardiac disorders | 0/21 | 1/20 |
| Device related infectionInfections and infestations | 0/21 | 1/20 |
| General physical health deteriorationGeneral disorders | 1/21 | 0/20 |
| PharyngitisInfections and infestations | 1/21 | 0/20 |
| PneumoniaInfections and infestations | 1/21 | 0/20 |
| SyncopeNervous system disorders | 1/21 | 0/20 |
| Device breakageProduct Issues | 1/21 | 0/20 |
| Pulmonary hypertensionRespiratory, thoracic and mediastinal disorders | 1/21 | 0/20 |
| Event | Low Dose Ambrisentan | High Dose Ambrisentan |
|---|---|---|
| HeadacheNervous system disorders | 4/21 | 6/20 |
| Abdominal painGastrointestinal disorders | 4/21 | 1/20 |
| NauseaGastrointestinal disorders | 4/21 | 3/20 |
| Abdominal pain upperGastrointestinal disorders | 3/21 | 2/20 |
| NasopharyngitisInfections and infestations | 3/21 | 2/20 |
| Upper respiratory tract infectionInfections and infestations | 3/21 | 1/20 |
| Face oedemaGeneral disorders | 1/21 | 2/20 |
| LaryngitisInfections and infestations | 0/21 | 2/20 |
| Back painMusculoskeletal and connective tissue disorders | 1/21 | 2/20 |
| Nasal congestionRespiratory, thoracic and mediastinal disorders | 2/21 | 2/20 |
| Age, Continuous(Years) | Low Dose Ambrisentan | High Dose Ambrisentan | Total |
|---|---|---|---|
| Mean | 11.8 ± 2.70 | 12.3 ± 2.85 | 12.0 ± 2.75 |
| Sex: Female, Male(Participants) | Low Dose Ambrisentan | High Dose Ambrisentan | Total |
|---|---|---|---|
| Female | 12 | 15 | 27 |
| Male | 9 | 5 | 14 |
| Race/Ethnicity, Customized(Count of participants) | Low Dose Ambrisentan | High Dose Ambrisentan | Total |
|---|---|---|---|
| African American/African Heritage | 2 | 0 | 2 |
| American Indian or Alaskan Native | 1 | 0 | 1 |
| Asian - Central/South Asian Heritage | 1 | 0 | 1 |
| Asian - East Asian Heritage | 1 | 0 | 1 |
| Asian - Japanese Heritage | 5 | 0 | 5 |
| Asian - South East Asian Heritage | 0 | 1 | 1 |
| White - White/Caucasian/European Heritage | 11 | 19 | 30 |
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Pulmonary Arterial Hypertension→
GlaxoSmithKline