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A Phase 1 Relative Bioavailability Study of Ambrisentan and Tadalfil Fixed Dose Combination Tablets in Healthy Subjects

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2016 by GlaxoSmithKline
Sponsor:
Collaborators:
Covance Harrogate
Hammersmith Medicines Research
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT02688387
First received: February 18, 2016
Last updated: July 21, 2016
Last verified: July 2016
  Purpose
This study is designed to understand the relative bioavailability (proportion of the administered dose that is absorbed into the bloodstream) of several fixed dose combinations (FDCs) tablets of ambrisentan and tadalafil for further development and to provide pharmacokinetic (PK - what the body does to the drug) data to enable a pivotal bioequivalence (BE - the relationship between two preparations of the same drug in the same dosage form that have a similar bioavailability) study. Depending on formulation work, the study will allow up to 8 new FDCs to be compared with the reference of ambrisentan and tadalafil monotherapies. The study will also evaluate up to 2 of the new formulations, that may be taken in to a BE study, to be tested for any effect on pharmacokinetics of the FDC in both fed and fasted state. This is a single centre, Phase 1, single dose, randomised, open label crossover study with 3 study parts; each study part will have up to a 5 way crossover in healthy subjects. Part 1 of the study will evaluate four formulations of the FDC (ambrisentan 10 milligram [mg] + tadalafil 40 mg) and the reference of the 2 monotherapy components taken concurrently (ambrisentan 10 mg and tadalafil 40 mg) in the fasted stated. If successful formulations are identified in this part of the study, then they will be re-formulated and tested in part 2. If no successful formulations are identified in part 1 of the study, then part 2 will be utilized to look at up to 4 new FDC formulations. However, if only two formulations, or less, are evaluated in part 2 then the FDC formulations may be tested both fed and fasted to assess food effect and part 3 will not be required. If successful formulations are identified in this study part, then up to 2 of these may be tested, for food effect, in Part 3 if not already assessed in this part. Therefore, part 3 is optional and utility is dependent on the results of the previous study parts.

Condition Intervention Phase
Hypertension, Pulmonary
Drug: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose
Drug: Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Study to Demonstrate the Relative Bioavailability of Fixed Dose Combinations of Ambrisentan and Tadalafil in Healthy Subjects

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Maximum plasma concentration (Cmax) of ambrisentan and tadalafil in FDCs and reference treatments after single dose under fasting conditions. [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48, 72 hour (h). ] [ Designated as safety issue: No ]
    Blood samples will be collected after each dose is administered under fasting condition in the each study part.

  • Area under the plasma concentration time curve (AUC) from predose to time 't' (AUC[0-t]) and predose to infinite time (AUC[0-infinity]) in FDCs and reference treatments after single dose under fasting conditions. [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48, 72 h. ] [ Designated as safety issue: No ]
    Blood samples will be collected after each dose is administered under fasting condition in the each study part.


Secondary Outcome Measures:
  • Time to maximum plasma concentration (tmax) of ambrisentan and tadalafil in FDCs and reference treatments after single dose under fasting conditions. [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48, 72 h. ] [ Designated as safety issue: No ]
    Blood samples will be collected after each dose administered under fasting condition in the each study part.

  • Plasma elimination half life (t1/2) of ambrisentan and tadalafil in FDCs and reference treatments after single dose under fasting conditions. [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48, 72 h. ] [ Designated as safety issue: No ]
    Blood samples will be collected after each dose administered under fasting condition in each study part.

  • Plasma Cmax of ambrisentan and tadalafil in FDCs after single dose under fed conditions. [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48, 72 h. ] [ Designated as safety issue: No ]
    Blood samples will be collected after each dose administered under fed condition in each study part.

  • AUC (0-t) and AUC (0-infinity) in FDCs after single dose under fed conditions. [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48, 72 h. ] [ Designated as safety issue: No ]
    Blood samples will be collected after each dose administered under fed condition in each study part.

  • Plasma tmax of ambrisentan and tadalafil in FDCs after single dose under fed conditions. [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48, 72 h. ] [ Designated as safety issue: No ]
    Blood samples will be collected after each dose administered under fasting condition in each study part.

  • Plasma t1/2 of ambrisentan and tadalafil in FDCs after single dose under fed conditions. [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48, 72 h. ] [ Designated as safety issue: No ]
    Blood samples will be collected after each dose administered under fed condition in each study part.

  • Body temperature assessment as a safety measure. [ Time Frame: Baseline to Day 14. ] [ Designated as safety issue: No ]
    Body temperature will be measured as a part of vital signs measurement in semi-supine position after 5 minutes rest at screening, pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72 h, and Day 7 to 14 after every single dose in Part 1, Part 2 and Part 3.

  • Blood pressure assessment as a safety measure. [ Time Frame: Baseline to Day 14. ] [ Designated as safety issue: No ]
    Systolic and diastolic blood pressure will be measured as a part of vital signs measurement in semi-supine position after 5 minutes rest at screening, pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 h, and Day 7 to 14 after every single dose in Part 1, Part 2 and Part 3.

  • Pulse rate as safety measure [ Time Frame: Baseline to Day 14. ] [ Designated as safety issue: No ]
    Pulse rate will be measured as a part of vital signs measurement in semi-supine position after 5 minutes rest at screening, pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72 h, and Day 7 to 14 after every single dose in Part 1, Part 2 and Part 3.

  • Electrocardiogram (ECG) assessment as a measure of safety. [ Time Frame: Baseline to Day 14. ] [ Designated as safety issue: No ]
    ECGs will be measured in semi-supine position after 5 minutes rest at screening, pre-dose, 1, 2, 4, 8, 12, 24, 72 h, and Day 14 after every single dose in Part 1, Part 2 and Part 3.

  • Number of subjects having abnormal haematology parameters as a measure of safety. [ Time Frame: Baseline to Day 14. ] [ Designated as safety issue: No ]
    Blood samples will be collected at screening, pre dose, and post dose on Day 3 and Day 14 after every single dose in Part 1, Part 2 and Part 3 to analyze platelet counts, red blood cells (RBC) count, haemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cells (WBC) count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils.

  • Number of subjects having clinical chemistry parameters as a measure of safety. [ Time Frame: Baseline to Day 14. ] [ Designated as safety issue: No ]
    Blood samples will be collected at screening, pre dose, and post dose on Day 3 and Day 14 after every single dose in Part 1, Part 2 and Part 3 to analyze blood urea nitrogen (BUN), creatinine, glucose level, composite electrolytes levels (potassium, sodium and calcium), aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase (ALP) levels, total and direct bilirubin, total protein and albumin levels.

  • Number of subjects having abnormal urine parameters using dipstick test as a measure of safety. [ Time Frame: Baseline to Day 14. ] [ Designated as safety issue: No ]
    Urine samples will be collected at screening, pre dose, and post dose on Day 3 and Day 14 after every single dose in Part 1, Part 2 and Part 3 to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, and microscopic examination (if blood or protein is abnormal).

  • Number of subjects with adverse event (AE) and serious adverse event (SAE). [ Time Frame: Up to Day 14 ] [ Designated as safety issue: No ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as SAE. It will be assessed after every single dose in Part 1, Part 2 and Part 3.


Estimated Enrollment: 60
Study Start Date: March 2016
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1
Enrolled subjects will receive single oral dose of 4 FDCs i.e., FDC1, FDC2, FDC3 and FDC4, and reference formulations of the 2 monotherapy components taken concurrently in the fasted state. The FDC and reference formulations contains 10 mg ambrisentan and 40 mg tadalafil. Each dosing period will be separated by 7 days wash out period.
Drug: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose
The four FDCs in part 1 will have the following formulation designation: FDC1, FDC2, FDC3 and FDC4. They are film-coated tablets. The dose will be administered orally. Study treatment for Part2 and Part 3 will be amended after Part 1 study
Drug: Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently)
Ambrisentan is a film-coated tablet. Each tablet of ambrisentan contains 10 mg of ambrisentan, approximately 95 mg of lactose (as monohydrate), 0.25 mg of lecithin and 0.11 mg of Allura red AC Aluminium Lake. Tadalafil is also a film-coated tablet. Each tablet of Tadalafil contains 20 mg tadalafil and 233 mg lactose. Both the tablets will be administered orally concurrently.
Experimental: Part 2
Enrolled subjects will receive single oral dose of 4 FDCs i.e., FDC5, FDC6, FDC7 and FDC8, and reference formulations of the 2 monotherapy components taken concurrently in the fasted state. The FDCs and reference formulations contains 10 mg ambrisentan and 40mg Tadalafil. OR Subjects will receive single dose of two FDCs from Part 1 in fed and fasted state. Each dosing period will be separated by 7 days wash out period.
Drug: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose
The four FDCs in part 1 will have the following formulation designation: FDC1, FDC2, FDC3 and FDC4. They are film-coated tablets. The dose will be administered orally. Study treatment for Part2 and Part 3 will be amended after Part 1 study
Drug: Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently)
Ambrisentan is a film-coated tablet. Each tablet of ambrisentan contains 10 mg of ambrisentan, approximately 95 mg of lactose (as monohydrate), 0.25 mg of lecithin and 0.11 mg of Allura red AC Aluminium Lake. Tadalafil is also a film-coated tablet. Each tablet of Tadalafil contains 20 mg tadalafil and 233 mg lactose. Both the tablets will be administered orally concurrently.
Experimental: Part 3
Enrolled subjects will receive single oral dose of 2 FDCs from Part 2 in fed and fasted state. The FDCs contains 10 mg ambrisentan and 40 mg Tadalafil. Each dosing period will be separated by 7 days wash out period.
Drug: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose
The four FDCs in part 1 will have the following formulation designation: FDC1, FDC2, FDC3 and FDC4. They are film-coated tablets. The dose will be administered orally. Study treatment for Part2 and Part 3 will be amended after Part 1 study

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Between 18 and 60 years of age inclusive, at the time of signing the informed consent.
  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests, vital signs and cardiac monitoring (ECG and 24 hour Holter). A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator, in consultation with Medical Monitor if required, judges and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • Body weight >= 50 Kilogram (kg) (110 pounds [lbs]) for men and >= 45 kg (99lbs) for women and body mass index (BMI) within the range 18 - 30 kg per square metre (m^2) (inclusive)
  • Male or Female. Female with non-reproductive potential defined as, Pre-menopausal females with one of the following: Documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or Hysterectomy or Documented Bilateral Oophorectomy, Documented Postmenopausal defined as 12 months of spontaneous amenorrhea
  • Capable of giving signed informed consent.

Exclusion Criteria:

  • A blood pressure <100/55 millimetre of Mercury (mm Hg).
  • Haemoglobin (Hb) below normal range: Hb <133 (gram per litre) g/L for males and Hb <114 g/L for females
  • Alanine amino transferase (ALT) and bilirubin >1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35 percentage [%]).
  • 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 (QTc) >450 milliseconds (msec). The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read.
  • Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (~240 millilitre [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
  • Smoking more than 5 cigarettes per week and subjects must be able to abstain from smoking for a 24 hour period prior to dose and any time whilst in the clinical unit.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
  • Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment.
  • A positive test for human immuno-deficiency virus (HIV) antibody
  • A positive pre-study drug/alcohol screen.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within previous 3 months
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02688387

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
United Kingdom
GSK Investigational Site Recruiting
London, United Kingdom, NW10 7EW
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Sponsors and Collaborators
GlaxoSmithKline
Covance Harrogate
Hammersmith Medicines Research
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02688387     History of Changes
Other Study ID Numbers: 201964 
Study First Received: February 18, 2016
Last Updated: July 21, 2016
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by GlaxoSmithKline:
Ambrisentan
Bioavailability
Tadalafil
Fixed Dose combination

Additional relevant MeSH terms:
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Tadalafil
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents

ClinicalTrials.gov processed this record on August 28, 2016