Efficacy and Safety of Ambrisentan in Children 8-18yrs

NCT01332331 | Terminated Phase 2 Results DMC

• 2 other identifiers: 1125292010-019547-19
• Study Type: interventional
• Target: 41
• Locations: 9 countries
• Sites: 24

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.

Conditions

Hypertension, Pulmonary

Keywords

pulmonary arterial hypertension; pediatric

Outcome Measures

Primary Outcomes (17)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  Baseline, Week 12 and 24

Secondary Outcomes (5)

• Change From Baseline in the 6 Minutes Walking Distance (6MWD) Test

  Baseline, Weeks 4, 8, 12, 16, 20 and 24

• Time to the First Clinical Worsening of Pulmonary Arterial Hypertension (PAH)

  Up to Week 24

• Change From Baseline in Subject Global Assessment to Week 24 Using the SF-10 Health Survey for Children

  Baseline and Week 24

• Change From Baseline in World Health Organization (WHO) Functional Class to Week 24

  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

  Baseline, Week 12 and 24

Study Arms (2)

Low Dose Ambrisentan

EXPERIMENTAL

body weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg

Drug: Ambrisentan - low dose

High Dose Ambrisentan

EXPERIMENTAL

body weight 20 to 35 kg - 5.0 mg; body weight 35 to 50 kg - 7.5 mg; body weight 50 kg and over - 10.0 mg

Drug: Ambrisentan - high dose

Interventions

Ambrisentan - low dose DRUG

body weight 20 to 35 kg - 2.5 mg; body weight 35 kg and over - 5.0 mg

Low Dose Ambrisentan

Ambrisentan - high dose DRUG

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

High Dose Ambrisentan

Eligibility Criteria

• Age: 8 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (24)

GSK Investigational Site

Aurora, Colorado, 80045, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02115, United States

Location

GSK Investigational Site

Ann Arbor, Michigan, 48109-4204, United States

Location

GSK Investigational Site

New York, New York, 10032, United States

Location

GSK Investigational Site

Guymallen, Mendoza Province, 5521, Argentina

Location

GSK Investigational Site

Ciudad de Buenos Aires, 1118, Argentina

Location

GSK Investigational Site

Córdoba, 5000, Argentina

Location

GSK Investigational Site

Paris, 75743, France

Location

GSK Investigational Site

Pessac, 33604, France

Location

GSK Investigational Site

Toulouse, 31059, France

Location

GSK Investigational Site

Erlangen, Bavaria, 91054, Germany

Location

GSK Investigational Site

Giessen, Hesse, 35385, Germany

Location

GSK Investigational Site

Berlin, 13353, Germany

Location

GSK Investigational Site

Budapest, 1096, Hungary

Location

GSK Investigational Site

Rome, Lazio, 00165, Italy

Location

GSK Investigational Site

San Donato Milanese (MI), Lombardy, 20097, Italy

Location

GSK Investigational Site

Kanagawa, 232-8555, Japan

Location

GSK Investigational Site

Osaka, 565-0871, Japan

Location

GSK Investigational Site

Tokyo, 104-8560, Japan

Location

GSK Investigational Site

Tokyo, 143-8541, Japan

Location

GSK Investigational Site

Kemerovo, 650002, Russia

Location

GSK Investigational Site

Moscow, 125412, Russia

Location

GSK Investigational Site

Novosibirsk, 630055, Russia

Location

GSK Investigational Site

Madrid, 28046, Spain

Location

Related Publications (2)

• Ivy D, Beghetti M, Juaneda-Simian E, Miller D, Lukas MA, Ioannou C, Okour M, Narita J, Berger RMF. A Randomized Study of Safety and Efficacy of Two Doses of Ambrisentan to Treat Pulmonary Arterial Hypertension in Pediatric Patients Aged 8 Years up to 18 Years. J Pediatr X. 2020 Sep 22;5:100055. doi: 10.1016/j.ympdx.2020.100055. eCollection 2020 Spring.

  PMID: 37332660 DERIVED

• Okour M, Thapar MM, Farrell C, Lukas MA, Beghetti M, Beerahee M. Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data. J Clin Pharmacol. 2023 May;63(5):593-603. doi: 10.1002/jcph.2199. Epub 2023 Jan 29.

  PMID: 36579617 DERIVED

MeSH Terms

Conditions

Hypertension, Pulmonary; Pulmonary Arterial Hypertension

Interventions

ambrisentan

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2011
• First Posted: April 11, 2011
• Study Start: January 4, 2011
• Primary Completion: November 12, 2013
• Study Completion: November 12, 2013
• Last Updated: October 8, 2019
• Results First Posted: October 8, 2019

Record last verified: 2019-09

Locations

DE (3); RU (3); US (4); AR (3); FR (3); JP (4); ES (1); IT (2); HU (1)