Hypertension, Pulmonary
Conditions
Keywords
pulmonary arterial hypertension, pediatric
Brief summary
A 6-month (24-week), randomized, open label evaluation of the safety, tolerability, and efficacy of a high and low dose ambrisentan (adjusted for body weight) treatment group in subjects aged 8 years up to 18 years with pulmonary arterial hypertension (PAH). An additional objective is to determine the ambrisentan population pharmacokinetics in the paediatric population. The study will include a screening/baseline period and a treatment period. The treatment period will be 24 weeks or until the subject's clinical condition deteriorates to the point that alternative/additional treatment is necessary. Patients who participate in the study and in whom continued treatment with ambrisentan is desired will be eligible to enrol into a long term follow-up study. The primary comparison will be the safety and tolerability of the two ambrisentan dose groups (Low vs. High) in the paediatric PAH population The secondary comparison will be the change from baseline for the efficacy parameters between the two treatment groups.
Detailed description
Pulmonary arterial hypertension (PAH) is a rare, progressive, highly debilitating disease characterized by vascular obstruction and the variable presence of vasoconstriction, leading to increased pulmonary vascular resistance and right-sided heart failure. If left untreated, PAH ultimately leads to right ventricular failure and death; adult subjects have a median survival of 2.8 years without treatment. Epidemiological estimates vary but prevalence in Europe is thought to be of the order of 15 cases per million. Large scale epidemiology studies of PAH in children have not been conducted and there is no or limited outcome data in pediatric PAH patients. A register in France (1995-1996) estimates the prevalence in children is as low as 3.7 cases per million. In a national, comprehensive country wide survey of the epidemiology of idiopathic PAH (IPAH) management and survival in the United Kingdom (UK) the incidence was 0.48 cases per million children per year and the prevalence was 2.1 cases per million children. Ambrisentan (VOLIBRIS™ tablets) is an endothelin receptor antagonist (ERA) marketed in the European Union (EU) and some other countries by GlaxoSmithKline (GSK) and in the United States as LETAIRIS® by Gilead Sciences Inc. Ambrisentan is indicated for the treatment of adult patients with PAH to improve exercise capacity, decrease the symptoms of PAH, and delay clinical worsening. The primary purpose of this paediatric study is to provide clinically relevant information on the safety and pharmacokinetic profile of ambrisentan in children with the most common causes of PAH in this age group. The design of the study is also intended to provide information to guide dose selection and supportive efficacy data in this age group. Despite the fact that none of the currently available adult treatments are licensed for use in children \<12 yrs, (with the exception of bosentan which was recently approved for use in paediatric population from 2 years of age) they are widely used off label. This study will provide useful prescribing information to the medical community for treating this orphan disease in children in this environment of rapidly changing medical practice. This study is part of a Paediatric Investigational Plan (PIP; EMEA-000434-PIP01-08) agreed with the European Medicines Agency's Paediatric Committee (PDCO).
Interventions
DRUGAmbrisentan - low dose
body weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg
DRUGAmbrisentan - high 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
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Current diagnosis of PAH (WHO Group 1) with WHO class II or III symptoms in one of the following categories: Idiopathic, Heritable \[familial\], Secondary to connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed connective tissue disease (CTD), systemic lupus erythematosus, or overlap syndrome), or Persistent PAH despite surgical repair (at least 6 months prior to the screening visit) of atrial septal defects, ventricular septal defects, atrio-ventricular septal defects, and persistent patent ductus. * Have met the following hemodynamic criteria for subjects with right heart catheterization (RHC) when performed as part of the diagnosis or routine care: mean pulmonary arterial pressure (mPAP) of \>/=25 mmHg, pulmonary vascular resistance (PVR) of \>/=240 dyne sec/cm5, left ventricular end diastolic pressure (LEVDP) or pulmonary capillary wedge pressure (PCWP) of ≤15 mmHg. * be treatment naïve, have discontinued treatment with another ERA (e.g., bosentan) at least 1 month previously because of elevated liver function tests (LFTs), or have been on a stable dose of drug therapy for PAH (e.g., sildenafil or prostacyclin) for at least one month prior to the Screening Visit. * Subjects who discontinued ERA treatment due to elevated LFTs, must have LFTs of \<3 x Upper Limit of Normal (ULN). * A female is eligible to participate in this study, as assessed by the investigator, if she is of: a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant); or, b. Child-bearing potential - has a negative pregnancy test and is not lactating at the Screening and Baseline/Randomisation Visits and, if sexually active, agrees to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of study drug. * Subject or subject's legal guardian is able and willing to give written informed consent. As part of the consent, female subjects of childbearing potential will be informed of the risk of teratogenicity and will need to be counselled in a developmentally appropriate manner on the importance of pregnancy prevention; and male subjects will need to be informed of potential risk of testicular tubular atrophy and aspermia.
Exclusion criteria
* currently taking an ERA. * currently taking cyclosporine A. * body weight is less than 20 Kg. * have not tolerated PAH therapy due to adverse effects which may be related to their mechanism of action (e.g., prostanoids, ERA, PDE-5 inhibitors) with the exception of liver abnormalities for those subjects who were receiving another ERA. * pregnant or breastfeeding. * diagnosis of active hepatitis (hepatitis B surface antigen and hepatitis C antibody), or clinically significant hepatic enzyme elevation (i.e., ALT, AST or AP \>3xULN) at Screening. * severe renal impairment (creatinine clearance \<30 mL/min) at Screening. * clinically significant fluid retention in the opinion of the investigator. * clinically significant anaemia in the opinion of the investigator. * a known hypersensitivity to the study drug, the metabolites, or formulation excipients. * have participated in another trial or have taken another investigational product during the previous 30 days. * alcohol abuse, illicit drug use within 1 year. * any concurrent condition or concurrent use of medication that would affect subject safety in the opinion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Plasma Endocrine Parameter - Female : Sex Hormone Binding Globulin at Weeks 12 and 24 | 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. |
| Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Heart Rate | 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 | 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 | 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 | 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 | 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. |
| Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Treatment-emergent Adverse Events (SAEs) | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First Clinical Worsening of Pulmonary Arterial Hypertension (PAH) | Up to Week 24 | 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. |
| Change From Baseline in Subject Global Assessment to Week 24 Using the SF-10 Health Survey for Children | Baseline and Week 24 | 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. |
| Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Baseline, Week 4, 8, 12, 16, 20 and 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. |
| Ratio to Baseline in Plasma N-terminal Pro-B Type Natriuretic Peptide (NT-Pro BNP) Concentration at Week 24 | Baseline, Week 12 and 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. |
| Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Baseline, Weeks 4, 8, 12, 16, 20 and 24 | 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. |
Countries
Argentina, France, Germany, Hungary, Italy, Japan, Russia, Spain, United States
Participant flow
Recruitment details
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).
Pre-assignment details
A total of 41 participants were enrolled and randomized.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Ambrisentan Participants received ambrisentan low dose tablet either 2.5 mg or 5 mg orally once daily for 24 weeks. | 21 |
| High Dose Ambrisentan Participants received ambrisentan high dose tablet either 5 mg, 7.5 mg or 10 mg orally once daily for 24 weeks. | 20 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Low Dose Ambrisentan | High Dose Ambrisentan | Total |
|---|---|---|---|
| Age, Continuous | 11.8 Years STANDARD_DEVIATION 2.7 | 12.3 Years STANDARD_DEVIATION 2.85 | 12.0 Years STANDARD_DEVIATION 2.75 |
| Race/Ethnicity, Customized African American/African Heritage | 2 Count of participants | 0 Count of participants | 2 Count of participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 Count of participants | 0 Count of participants | 1 Count of participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 1 Count of participants | 0 Count of participants | 1 Count of participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 1 Count of participants | 0 Count of participants | 1 Count of participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 5 Count of participants | 0 Count of participants | 5 Count of participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 0 Count of participants | 1 Count of participants | 1 Count of participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 11 Count of participants | 19 Count of participants | 30 Count of participants |
| Sex: Female, Male Female | 12 Participants | 15 Participants | 27 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 21 | 0 / 20 |
| other Total, other adverse events | 16 / 21 | 16 / 20 |
| serious Total, serious adverse events | 6 / 21 | 2 / 20 |
Outcome results
Primary
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
Population: Safety population. Only those female participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24 | Week 12, FSH, n=11, 13 | 0.586 International unit per Liter | Standard Deviation 1.412 |
| Low Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24 | Week 24, FSH, n=10, 12 | 0.010 International unit per Liter | Standard Deviation 1.39 |
| Low Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24 | Week 12, LH, n=11, 13 | 0.39 International unit per Liter | Standard Deviation 3.117 |
| Low Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24 | Week 24, LH, n=11, 13 | -0.56 International unit per Liter | Standard Deviation 1.192 |
| High Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24 | Week 24, LH, n=11, 13 | 1.15 International unit per Liter | Standard Deviation 6.806 |
| High Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24 | Week 12, FSH, n=11, 13 | -0.023 International unit per Liter | Standard Deviation 2.104 |
| High Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24 | Week 12, LH, n=11, 13 | -0.28 International unit per Liter | Standard Deviation 6.881 |
| High Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at Weeks 12 and 24 | Week 24, FSH, n=10, 12 | 1.542 International unit per Liter | Standard Deviation 2.518 |
Primary
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
Population: Safety population. Only those female participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Inhibin B at Weeks 12 and 24 | Week 12, Right TV, n=9, 7 | 4.9 Nanogram per liter | Standard Deviation 10.03 |
| Low Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Inhibin B at Weeks 12 and 24 | Week 24, Left TV, n=9, 7 | -5.2 Nanogram per liter | Standard Deviation 36.44 |
| High Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Inhibin B at Weeks 12 and 24 | Week 12, Right TV, n=9, 7 | 1.7 Nanogram per liter | Standard Deviation 33.7 |
| High Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Inhibin B at Weeks 12 and 24 | Week 24, Left TV, n=9, 7 | 16.0 Nanogram per liter | Standard Deviation 37.96 |
Primary
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
Population: Safety population. Only those female participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Sex Hormone Binding Globulin at Weeks 12 and 24 | Week 12, Right TV, n=10, 9 | 1.3 Milliliter | Standard Deviation 9.55 |
| Low Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Sex Hormone Binding Globulin at Weeks 12 and 24 | Week 24, Left TV, n=10, 8 | -9.2 Milliliter | Standard Deviation 13.62 |
| High Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Sex Hormone Binding Globulin at Weeks 12 and 24 | Week 12, Right TV, n=10, 9 | 7.4 Milliliter | Standard Deviation 18.91 |
| High Dose Ambrisentan | Change From Baseline in Plasma Endocrine Parameter - Female : Sex Hormone Binding Globulin at Weeks 12 and 24 | Week 24, Left TV, n=10, 8 | 3.1 Milliliter | Standard Deviation 14.21 |
Primary
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
Population: Safety population. Only those male participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Ambrisentan | Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24 | Week 12, Right TV, n=7, 4 | 0.4 Milliliter | Standard Deviation 1.27 |
| Low Dose Ambrisentan | Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24 | Week 12, Left TV, n=8, 5 | 0.0 Milliliter | Standard Deviation 0.53 |
| Low Dose Ambrisentan | Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24 | Week 24, Right TV, n=6, 4 | 0.5 Milliliter | Standard Deviation 1.38 |
| Low Dose Ambrisentan | Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24 | Week 24, Left TV, n=7, 5 | 1.4 Milliliter | Standard Deviation 2.76 |
| High Dose Ambrisentan | Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24 | Week 24, Left TV, n=7, 5 | 0.5 Milliliter | Standard Deviation 1.5 |
| High Dose Ambrisentan | Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24 | Week 12, Right TV, n=7, 4 | 0.3 Milliliter | Standard Deviation 0.5 |
| High Dose Ambrisentan | Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24 | Week 24, Right TV, n=6, 4 | 0.1 Milliliter | Standard Deviation 0.25 |
| High Dose Ambrisentan | Change From Baseline of Pubertal Development: Men- Testicular Volume (TV) at Weeks 12 and 24 | Week 12, Left TV, n=8, 5 | 0.2 Milliliter | Standard Deviation 0.45 |
Primary
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
Population: Safety population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 12, Abnormal: Improved, n=20, 19 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 12, Abnormal: Worsened, n=20, 19 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 12, Abnormal: Unchanged, n=20, 19 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 24, Abnormal: Improved, n=19, 18 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 24, Abnormal: Worsened, n=19, 18 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 24, Abnormal: Unchanged, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 24, Abnormal: Worsened, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 12, Abnormal: Improved, n=20, 19 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 24, Abnormal: Improved, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 12, Abnormal: Worsened, n=20, 19 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 24, Abnormal: Unchanged, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Ascites | Week 12, Abnormal: Unchanged, n=20, 19 | 0 Participants |
Primary
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
Population: Safety population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 12, Abnormal: Improved, n=20, 19 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 12, Abnormal: Worsened, n=20, 19 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 12, Abnormal: Unchanged, n=20, 19 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 24, Abnormal: Improved, n=19, 18 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 24, Abnormal: Worsened, n=19, 18 | 1 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 24, Abnormal: Unchanged, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 24, Abnormal: Worsened, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 12, Abnormal: Improved, n=20, 19 | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 24, Abnormal: Improved, n=19, 18 | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 12, Abnormal: Worsened, n=20, 19 | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 24, Abnormal: Unchanged, n=19, 18 | 4 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Jugular Venous Pressure | Week 12, Abnormal: Unchanged, n=20, 19 | 3 Participants |
Primary
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
Population: Safety population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 12, Abnormal: Improved, n=20, 19 | 1 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 12, Abnormal: Worsened, n=20, 19 | 1 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 12, Abnormal: Unchanged, n=20, 19 | 1 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 24, Abnormal: Improved, n=19, 18 | 2 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 24, Abnormal: Worsened, n=19, 18 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 24, Abnormal: Unchanged, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 24, Abnormal: Worsened, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 12, Abnormal: Improved, n=20, 19 | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 24, Abnormal: Improved, n=19, 18 | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 12, Abnormal: Worsened, n=20, 19 | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 24, Abnormal: Unchanged, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Liver Size | Week 12, Abnormal: Unchanged, n=20, 19 | 0 Participants |
Primary
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
Population: Safety population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 12, Abnormal: Worsened, n=20, 19 | 1 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 24, Abnormal: Improved, n=19, 18 | 1 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 12, Abnormal: Improved, n=20, 19 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 24, Abnormal: Worsened, n=19, 18 | 1 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 12, Abnormal: Unchanged, n=20, 19 | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 24, Abnormal: Unchanged, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 24, Abnormal: Unchanged, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 12, Abnormal: Improved, n=20, 19 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 12, Abnormal: Worsened, n=20, 19 | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 12, Abnormal: Unchanged, n=20, 19 | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 24, Abnormal: Improved, n=19, 18 | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Abnormal Value for Physical Examination Parameter: Peripheral Edema | Week 24, Abnormal: Worsened, n=19, 18 | 0 Participants |
Primary
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
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hematocrit | Reference high range | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hematocrit | Reference low range | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hematocrit | Reference high range | 2 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hematocrit | Reference low range | 2 Participants |
Primary
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
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hemoglobin | Reference high range | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hemoglobin | Reference low range | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hemoglobin | Reference high range | 2 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Hemoglobin | Reference low range | 0 Participants |
Primary
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
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Platelet Count | Reference high range | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Platelet Count | Reference low range | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Platelet Count | Reference high range | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Hematology Parameter: Platelet Count | Reference low range | 1 Participants |
Primary
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
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Heart Rate | Reference range high | 2 Participants |
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Heart Rate | Reference range low | 1 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Heart Rate | Reference range high | 2 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Heart Rate | Reference range low | 0 Participants |
Primary
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
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Reference range high | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Reference range low | 1 Participants |
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Reference range high | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Reference range low | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Reference range low | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Reference range high | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Reference range high | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Reference range low | 2 Participants |
Primary
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
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Weight | Reference range high | 0 Participants |
| Low Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Weight | Reference range low | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Weight | Reference range high | 0 Participants |
| High Dose Ambrisentan | Number of Participants With Post Baseline PCI Value for Vital Signs Parameter: Weight | Reference range low | 0 Participants |
Primary
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
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | 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 | AST | 0 Participants |
| Low Dose Ambrisentan | 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 | Total bilirubin | 1 Participants |
| Low Dose Ambrisentan | 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 | GGT | 0 Participants |
| Low Dose Ambrisentan | 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 | Creatinine | 0 Participants |
| Low Dose Ambrisentan | 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 | ALT | 0 Participants |
| High Dose Ambrisentan | 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 | Creatinine | 0 Participants |
| High Dose Ambrisentan | 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 | ALT | 0 Participants |
| High Dose Ambrisentan | 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 | AST | 0 Participants |
| High Dose Ambrisentan | 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 | GGT | 0 Participants |
| High Dose Ambrisentan | 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 | Total bilirubin | 0 Participants |
Primary
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
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Ambrisentan | Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Treatment-emergent Adverse Events (SAEs) | Any AEs | 16 Participants |
| Low Dose Ambrisentan | Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Treatment-emergent Adverse Events (SAEs) | Any SAEs | 6 Participants |
| High Dose Ambrisentan | Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Treatment-emergent Adverse Events (SAEs) | Any AEs | 16 Participants |
| High Dose Ambrisentan | Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Treatment-emergent Adverse Events (SAEs) | Any SAEs | 2 Participants |
Primary
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
Population: Safety population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Ambrisentan | Percentage of Physical Examination Parameter: Saturated Oxygen Level | Week 12, n=20, 18 | 96.9 Percentage of oxygen saturation | Standard Deviation 2.59 |
| Low Dose Ambrisentan | Percentage of Physical Examination Parameter: Saturated Oxygen Level | Week 24, n=19, 18 | 97.3 Percentage of oxygen saturation | Standard Deviation 1.85 |
| High Dose Ambrisentan | Percentage of Physical Examination Parameter: Saturated Oxygen Level | Week 12, n=20, 18 | 96.9 Percentage of oxygen saturation | Standard Deviation 6.93 |
| High Dose Ambrisentan | Percentage of Physical Examination Parameter: Saturated Oxygen Level | Week 24, n=19, 18 | 97.4 Percentage of oxygen saturation | Standard Deviation 1.92 |
Secondary
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
Population: Intent-to-treat population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Ambrisentan | Change From Baseline in Subject Global Assessment to Week 24 Using the SF-10 Health Survey for Children | Physical health summary, n=16, 15 | 0.194 Scores on a scale | Standard Deviation 11.7733 |
| Low Dose Ambrisentan | Change From Baseline in Subject Global Assessment to Week 24 Using the SF-10 Health Survey for Children | Psychosocial summary, n=16, 15 | 0.725 Scores on a scale | Standard Deviation 8.6431 |
| High Dose Ambrisentan | Change From Baseline in Subject Global Assessment to Week 24 Using the SF-10 Health Survey for Children | Physical health summary, n=16, 15 | 2.811 Scores on a scale | Standard Deviation 13.1172 |
| High Dose Ambrisentan | Change From Baseline in Subject Global Assessment to Week 24 Using the SF-10 Health Survey for Children | Psychosocial summary, n=16, 15 | 0.412 Scores on a scale | Standard Deviation 10.1331 |
Secondary
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
Population: Intent-to-treat population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 4, Overall, n=21, 18 | 33.10 Meters | Standard Deviation 66.979 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 4, With oxygen use, n=2, 1 | -16.00 Meters | Standard Deviation 11.314 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 4, Without oxygen use, n=19, 17 | 38.27 Meters | Standard Deviation 68.421 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 8, Overall, n=20, 18 | 23.84 Meters | Standard Deviation 65.154 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 8, With oxygen use, n=2, 1 | -16.00 Meters | Standard Deviation 22.627 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 8, Without oxygen use, n=18, 17 | 28.26 Meters | Standard Deviation 67.133 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 12, Overall, n=19, 18 | 29.51 Meters | Standard Deviation 79.657 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 12, With oxygen use, n=2, 1 | -1.00 Meters | Standard Deviation 65.054 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 12, Without oxygen use, n=17, 17 | 33.09 Meters | Standard Deviation 82.121 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 16, Overall, n=19, 18 | 22.31 Meters | Standard Deviation 88.832 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 16, With oxygen use, n=2, 1 | -21.00 Meters | Standard Deviation 57.983 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 16, Without oxygen use, n=17, 17 | 27.41 Meters | Standard Deviation 91.681 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 20, Overall, n=19, 18 | 48.49 Meters | Standard Deviation 90.645 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 20, With oxygen use, n=3, 1 | -0.33 Meters | Standard Deviation 43.753 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 20, Without oxygen use, n=16, 17 | 57.64 Meters | Standard Deviation 95.07 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 24, Overall, n=18, 18 | 55.14 Meters | Standard Deviation 102.182 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 24, With oxygen use, n=3, 1 | 43.00 Meters | Standard Deviation 53.395 |
| Low Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 24, Without oxygen use, n=15, 17 | 57.57 Meters | Standard Deviation 110.605 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 20, With oxygen use, n=3, 1 | 73.20 Meters | — |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 4, Overall, n=21, 18 | 24.96 Meters | Standard Deviation 71.254 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 16, Overall, n=19, 18 | 36.43 Meters | Standard Deviation 78.22 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 4, With oxygen use, n=2, 1 | 85.20 Meters | — |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 24, Without oxygen use, n=15, 17 | 23.92 Meters | Standard Deviation 63.1 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 4, Without oxygen use, n=19, 17 | 21.41 Meters | Standard Deviation 71.793 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 16, With oxygen use, n=2, 1 | 65.40 Meters | — |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 8, Overall, n=20, 18 | 37.70 Meters | Standard Deviation 74.339 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 20, Without oxygen use, n=16, 17 | 28.72 Meters | Standard Deviation 72.6 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 8, With oxygen use, n=2, 1 | 81.10 Meters | — |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 16, Without oxygen use, n=17, 17 | 34.73 Meters | Standard Deviation 80.282 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 8, Without oxygen use, n=18, 17 | 35.15 Meters | Standard Deviation 75.809 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 24, With oxygen use, n=3, 1 | 65.90 Meters | — |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 12, Overall, n=19, 18 | 40.29 Meters | Standard Deviation 69.137 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 20, Overall, n=19, 18 | 31.19 Meters | Standard Deviation 71.209 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 12, With oxygen use, n=2, 1 | 75.40 Meters | — |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 24, Overall, n=18, 18 | 26.25 Meters | Standard Deviation 62.011 |
| High Dose Ambrisentan | Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test | Week 12, Without oxygen use, n=17, 17 | 38.22 Meters | Standard Deviation 70.69 |
Secondary
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
Population: Intent-to-treat population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 4, n=21, 19 | -0.1 Scores on a scale | Standard Deviation 0.36 |
| Low Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 8, n=20, 19 | -0.1 Scores on a scale | Standard Deviation 0.45 |
| Low Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 12, n=20, 19 | -0.1 Scores on a scale | Standard Deviation 0.45 |
| Low Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 16, n=20, 18 | -0.2 Scores on a scale | Standard Deviation 0.49 |
| Low Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 20, n=19, 18 | -0.2 Scores on a scale | Standard Deviation 0.5 |
| Low Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 24, n=19, 18 | -0.3 Scores on a scale | Standard Deviation 0.56 |
| High Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 20, n=19, 18 | -0.2 Scores on a scale | Standard Deviation 0.38 |
| High Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 4, n=21, 19 | -0.1 Scores on a scale | Standard Deviation 0.23 |
| High Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 16, n=20, 18 | -0.2 Scores on a scale | Standard Deviation 0.38 |
| High Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 8, n=20, 19 | -0.1 Scores on a scale | Standard Deviation 0.4 |
| High Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 24, n=19, 18 | -0.2 Scores on a scale | Standard Deviation 0.43 |
| High Dose Ambrisentan | Change From Baseline in World Health Organization (WHO) Functional Class to Week 24 | Week 12, n=20, 19 | 0.0 Scores on a scale | Standard Deviation 0.58 |
Secondary
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
Population: Intent-to-treat population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Ambrisentan | Ratio to Baseline in Plasma N-terminal Pro-B Type Natriuretic Peptide (NT-Pro BNP) Concentration at Week 24 | Week 12, n=19, 17 | -15.93 Percentage Change | Standard Deviation 0.895 |
| Low Dose Ambrisentan | Ratio to Baseline in Plasma N-terminal Pro-B Type Natriuretic Peptide (NT-Pro BNP) Concentration at Week 24 | Week 24, n=18, 17 | -30.91 Percentage Change | Standard Deviation 0.851 |
| High Dose Ambrisentan | Ratio to Baseline in Plasma N-terminal Pro-B Type Natriuretic Peptide (NT-Pro BNP) Concentration at Week 24 | Week 12, n=19, 17 | -12.43 Percentage Change | Standard Deviation 0.862 |
| High Dose Ambrisentan | Ratio to Baseline in Plasma N-terminal Pro-B Type Natriuretic Peptide (NT-Pro BNP) Concentration at Week 24 | Week 24, n=18, 17 | -28.25 Percentage Change | Standard Deviation 1.179 |
Secondary
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
Population: Intent-to-treat population. Only those participants with available data at the specified time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Ambrisentan | Time to the First Clinical Worsening of Pulmonary Arterial Hypertension (PAH) | 77.3 Days | Standard Deviation 62.56 |
| High Dose Ambrisentan | Time to the First Clinical Worsening of Pulmonary Arterial Hypertension (PAH) | 71.7 Days | Standard Deviation 29.26 |