Clinical Trials Register

Summary
EudraCT Number:	2019-001699-12
Sponsor's Protocol Code Number:	205019
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-07-30
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2019-001699-12

A.3

Full title of the trial

An open-label, randomized three period cross-over relative bioavailability study to compare the pharmacokinetic parameters of a lower dose formulation of ambrisentan (GSK1325760) with marketed ambrisentan in healthy adult participants

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Relative bioavailability study of marketed and lower dose ambrisentan in healthy adult participants

A.4.1

Sponsor's protocol code number

205019

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GlaxoSmithKline Research and Development Ltd
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GlaxoSmithKline Research & Devlopment Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline Research & Development Ltd
B.5.2	Functional name of contact point	GSK Clinical Support Help Desk
B.5.3	Address:
B.5.3.1	Street Address	1-3 Iron Bridge Road, Stockley Park West
B.5.3.2	Town/ city	Uxbridge, Middlesex
B.5.3.3	Post code	UB11 1BT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 (0)80 0 783 9733
B.5.5	Fax number	Not applicable
B.5.6	E-mail	GSKClinicalSupportHD@gsk.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ambrisentan Tablet
D.3.2	Product code	GSK1325760
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AMBRISENTAN
D.3.9.1	CAS number	177036-94-1
D.3.9.3	Other descriptive name	(S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropanoic acid
D.3.9.4	EV Substance Code	SUB25424
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Volibris
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Ltd
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ambrisentan 5mg film-coated tablets [marketed product]
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AMBRISENTAN
D.3.9.1	CAS number	177036-94-1
D.3.9.3	Other descriptive name	(S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropanoic acid
D.3.9.4	EV Substance Code	SUB25424
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pulmonary arterial hypertension

E.1.1.1

Medical condition in easily understood language

Pulmonary arterial hypertension (a narrowing of the arteries connecting the lungs to the heart that leads to an increase in blood pressure)

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10064911
E.1.2	Term	Pulmonary arterial hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the relative bioavailability of AMB (1 mg x 5 tablets) administered as tablets dispersed in water or administered orally, with marketed AMB (5 mg x 1 tablet) administered orally, in healthy adult participants under fasted conditions.

E.2.2

Secondary objectives of the trial

To monitor the safety and tolerability of AMB (1 mg x 5 tablets) administered as tablets dispersed in water or administered orally, compared with marketed AMB
(5 mg x 1 tablet) administered orally, in healthy adult participants.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Participants are eligible to be included in the study only if all of the following criteria apply:
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed consent
2. Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, vital signs and cardiac monitoring (refer to Section 5.4 for information about rescreening).
3. Average systolic blood pressure between 100-160 mmHg and diastolic between 55-90 mmHg (inclusive) over 3 readings at screening
4. Body weight >50 kg for men and ≥ 45kg for women, and body mass index (BMI) within the range 18-30 kg/m2 (inclusive).
5. Male or Female
a. Male Participants
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):
●Refrain from donating sperm
PLUS either:
●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 in Appendix 4 of the study protocol.
b. Female participants
A female participant is eligible to participate if she is not a woman of childbearing potential (WOCBP), as defined in Appendix 4 of the study protocol
6. Capable of giving signed informed consent as described in Appendix 1 of the study protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

E.4

Principal exclusion criteria

Participants are excluded from the study if any of the following criteria apply:
1. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, haematological, 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
2. History or presence of palpitations or tachyarrhythmias
3. Haemoglobin (Hb) below the normal range (Hb <133 g/L for male participants; and Hb <114 g/L for female participants)
4. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN)
5. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
6. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
7. QTc >450 msec
NOTES:
●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.
●The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.
8. Past or intended use of over-the-counter or prescription medication (including vitamins and dietary or herbal supplements but excluding paracetamol ≤2 g/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 GSK Medical Monitor.
9. Participation in the study would result in loss of blood or blood products in excess of 500 mL within a 56-day period
10. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day
11. 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
12. Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention
13. Positive Hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
NOTE: Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained
14. Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention.
NOTE: Test is optional and subjects with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing
15. Positive human immunodeficiency virus (HIV) antibody test
16. Positive pre-study drug/alcohol screen
17. Regular use of known drugs of abuse
18. Regular alcohol consumption within 6 months prior to the study defined as:
●An average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
19. Smoking > 5 cigarettes per week (or equivalent) and participants must be able to abstain from smoking for a 24-hour period prior to dose and any time whilst in the clinical unit.
20. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study

E.5 End points

E.5.1

Primary end point(s)

Plasma pharmacokinetic parameters of AMB, as data permit: Cmax, tmax, AUC (0-∞), AUC(0-t) and t½.

E.5.1.1

Timepoint(s) of evaluation of this end point

PK samples collected at the following timepoints in each treatment period: Pre-dose, Post dose (hrs); 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48, 72.

E.5.2

Secondary end point(s)

Adverse events (AE), vital signs, electrocardiogram (ECG), and clinical laboratory values.

E.5.2.1

Timepoint(s) of evaluation of this end point

Adverse Events will be continually assessed throughout the study and at follow up.
Vital signs will be assessed at the following timepoints: Pre-dose, Post-dose (hrs); 0.5, 1, 2, 4, 8, 12, 24, 48, 72.
ECG’s will be conducted at the following timepoints: Pre-dose, Post-dose (hrs); 1, 2, 4, 12, 24, 72.
Clinical chemistry, hematology and urinalysis values will be collected at the following timepoints: Day -1 (admission to unit) and 48 post dose. Additional tests may be performed at any time during the study as determined necessary by the investigator.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Bioavailability of lower dose formulation

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

As this is a healthy participant study, no intervention will be given to participants following the end of study. Participants will receive a follow up visit 7–14 days after their last dose.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-08-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-08-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-12-17

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