Relative Bioavailability Study of Marketed and Lower Dose Ambrisentan in Healthy Adult Participants

NCT04095286 | Completed Phase 1 Results

• 1 other identifier: 205019
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single center, open-label, randomized, single-dose, three-period cross-over study in healthy participants. The aim of this study is to provide clinically relevant information on the pharmacokinetic (PK) and safety profile of a new lower dose formulation ambrisentan (AMB) tablet, which is intended for pediatric use. The study will compare the relative bioavailability of the lower dose tablet, dispersed in water and administered orally, with the reference marketed AMB tablet in healthy adults. The total study duration for each participant is expected to be approximately 9 weeks.

Conditions

Hypertension, Pulmonary

Keywords

Ambrisentan; Oral dosage forms; Pulmonary arterial hypertension; Bioavailability

Outcome Measures

Primary Outcomes (6)

• Maximum Observed Plasma Concentration (Cmax) After Administration of AMB Under Fasted Condition

  Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis. PK Parameter Population included all participants who provided PK parameter data.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

• Time to Cmax (Tmax) After Administration of AMB Under Fasted Condition

  Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

• Time of Last Quantifiable Concentration (Tlast) After Administration of AMB Under Fasted Condition

  Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

• Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [(AUC(0-inf)] After Administration of AMB Under Fasted Condition

  Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

• Area Under the Plasma Concentration-time Curve From Time Zero to Last Time of Quantifiable Concentration [AUC(0-t)] After Administration of AMB Under Fasted Condition

  Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

• Apparent Terminal Phase Half-life (t1/2) After Administration of AMB Under Fasted Condition

  Blood samples were collected at indicated time-points for PK analysis of AMB. PK parameters were calculated by standard non-compartmental analysis.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose

Secondary Outcomes (6)

• Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (Non-SAEs >=2%)

  Up to 40 days

• Number of Participants With Worst Case Vital Sign Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

  Baseline (Day 1) and up to 40 days

• Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings

  Baseline (Day 1) and up to 40 days

• Number of Participants With Worst Case Hematology Results Relative to PCI Criteria Post-Baseline Relative to Baseline

  Baseline (Day -1) and up to 40 days

• Number of Participants With Worst Case Clinical Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline

  Baseline (Day -1) and up to 40 days

Study Arms (6)

AMB dispersed in water/AMB oral tablet/reference AMB

EXPERIMENTAL

Eligible participants will receive a single oral dose of 5 milligram (mg) AMB tablet dispersed in water during treatment period 1 followed by a single dose of 5 mg AMB oral tablet in treatment period 2. In treatment period 3, participants will receive a single oral dose of reference 5 mg AMB tablet. There will be a washout period of 7 days between doses in each treatment period.

Drug: AMB new formulation (1 mg); Drug: Reference AMB (5 mg)

AMB oral tablet/reference AMB/AMB dispersed in water

EXPERIMENTAL

Eligible participants will receive single dose of 5 mg AMB oral tablet during treatment period 1 followed by single dose of reference 5 mg AMB oral tablet in treatment period 2. In treatment period 3, participants will receive single dose of 5 mg AMB tablet dispersed in water. There will be a washout period of 7 days between doses in each treatment period.

Drug: AMB new formulation (1 mg); Drug: Reference AMB (5 mg)

Reference AMB/AMB dispersed in water/AMB oral tablet

EXPERIMENTAL

Eligible participants will receive single dose of reference 5 mg AMB oral tablet during treatment period 1 followed by single dose of 5 mg AMB tablet dispersed in water in treatment period 2. In treatment period 3 participants will receive single dose of 5 mg AMB oral tablet. There will be a washout period of 7 days between doses in each treatment period.

Drug: AMB new formulation (1 mg); Drug: Reference AMB (5 mg)

AMB dispersed in water/reference AMB/AMB oral tablet

EXPERIMENTAL

Eligible participants will receive single dose of 5 mg AMB tablet dispersed in water during treatment period 1 followed by single dose of reference 5 mg AMB oral tablet in treatment period 2. In treatment period 3 participants will receive single dose of 5 mg AMB oral tablet. There will be a washout period of 7 days between doses in each treatment period.

Drug: AMB new formulation (1 mg); Drug: Reference AMB (5 mg)

AMB oral tablet/AMB dispersed in water/reference AMB

EXPERIMENTAL

Eligible participants will receive single dose of 5 mg AMB oral tablet during treatment period 1 followed by single dose of 5 mg AMB tablet dispersed in water in treatment period 2. In treatment period 3 participants will receive single dose of reference 5 mg AMB oral tablet. There will be a washout period of 7 days between doses in each treatment period.

Drug: AMB new formulation (1 mg); Drug: Reference AMB (5 mg)

Reference AMB/AMB oral/AMB dispersed in water

EXPERIMENTAL

Eligible participants in this arm will receive single dose of reference 5 mg AMB oral tablet during treatment period 1 followed by single dose of 5 mg AMB oral tablet in treatment period 2. In treatment period 3 participants will receive single dose of 5 mg AMB tablet dispersed in water There will be a washout period of 7 days between doses in each treatment period.

Drug: AMB new formulation (1 mg); Drug: Reference AMB (5 mg)

Interventions

AMB new formulation (1 mg) DRUG

AMB tablets will be available at a unit dose strength of 1 mg. Participants will orally administer 5 tablets of 1 mg unit dose.

AMB dispersed in water/AMB oral tablet/reference AMB; AMB dispersed in water/reference AMB/AMB oral tablet; AMB oral tablet/AMB dispersed in water/reference AMB; AMB oral tablet/reference AMB/AMB dispersed in water; Reference AMB/AMB dispersed in water/AMB oral tablet; Reference AMB/AMB oral/AMB dispersed in water

Reference AMB (5 mg) DRUG

AMB reference tablet will be available as film-coated tablet at unit dose strength of 5 mg. Participants will orally administer 1 tablet of 5 mg unit dose

AMB dispersed in water/AMB oral tablet/reference AMB; AMB dispersed in water/reference AMB/AMB oral tablet; AMB oral tablet/AMB dispersed in water/reference AMB; AMB oral tablet/reference AMB/AMB dispersed in water; Reference AMB/AMB dispersed in water/AMB oral tablet; Reference AMB/AMB oral/AMB dispersed in water

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
• Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, vital signs and cardiac monitoring.
• Average systolic blood pressure between 100-160 millimeter of mercury (mmHg) and diastolic between 55-90 mmHg (inclusive) over 3 readings at Screening.
• Body weight \>=50 kilogram (kg) for men and \>= 45kg for women, and body mass index (BMI) within the range 18-30 kilogram per meter square (kg/m\^2) (inclusive).
• Male participants are eligible to participate if they agree to the following during the study and for at least 13 weeks afterwards corresponding to time needed to eliminate study intervention (5 terminal half-lives) plus an additional 90 days (a spermatogenesis cycle): 1. Refrain from donating sperm plus either 2. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR
• Must agree to use contraception/barrier, as follows: Agree to use a male condom; and Female partner to use an additional highly effective contraceptive method with a failure rate of \<1% per year as described.
• A female participant is eligible to participate if she is not a woman of childbearing potential (WOCBP).
• Capable of giving signed informed consent.

You may not qualify if:

• History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal,endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data.
• History or presence of palpitations or tachyarrhythmia.
• Hemoglobin (Hb) below the normal range (Hb \<133 grams per liter \[g/L\] for male participants ; and Hb \<114 g/L for female participants).
• Alanine transaminase (ALT) \>1.5 times upper limit of normal (ULN)
• Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Corrected QT interval (QTc) \>450 millisecond (msec).
• Past or intended use of over-the-counter or prescription medication (including vitamins and dietary or herbal supplements but excluding paracetamol \<=2 grams/day) within 7 days (or 14 days if the drug is a potential enzyme inhibitor) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless approved by the Investigator in conjunction with GlaxoSmithKline Medical Monitor.
• Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within a 56-day period.
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
• Current enrolment or past participation within 30 days before Screening in any other clinical study involving an investigational study intervention or any other type of medical research.
• Presence of Hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to first dose of study intervention.
• Positive Hepatitis C antibody test result at Screening or within 3 months prior to first dose of study intervention.
• Positive Hepatitis C Ribonucleic acid (RNA) test result at Screening or within 3 months prior to first dose of study intervention.
• Positive human immunodeficiency virus (HIV) antibody test.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, Cambridgeshire, CB2 2GG, United Kingdom

Location

MeSH Terms

Conditions

Hypertension, Pulmonary; Pulmonary Arterial Hypertension

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 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a three-period crossover study

Study Record Dates

• First Submitted: September 18, 2019
• First Posted: September 19, 2019
• Study Start: September 30, 2019
• Primary Completion: December 17, 2019
• Study Completion: December 17, 2019
• Last Updated: August 6, 2020
• Results First Posted: August 6, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

GB (1)