Study of a drug to treat chronic thromboembolic pulmonary hypertension (CTEPH)

• Register: EUCTR
• Last refreshed on: 10 July 2015
• Main ID: EUCTR2012-001646-18-ES
• Date of registration: 09/04/2013
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline, S.A.
• Public title: Study of a drug to treat chronic thromboembolic pulmonary hypertension (CTEPH)
• Scientific title: A randomised, multicentre, double-blind, placebo-controlled study of ambrisentan in subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH)
• Date of first enrolment: 25/04/2013
• Target sample size: 275
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-001646-18
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Argentina, Austria, Brazil, Canada, China, Czech Republic, France, Germany, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Russian Federation, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Clinical Trials HelpDesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

• Name: Clinical Trials HelpDesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
Demographics
1. Subject must be between 18 and 75 years of age, inclusive, at the Screening Visit

CTEPH Diagnosis and Classification
2. Subjects must have a diagnosis of CTEPH at an expert centre* with a positive V/Q and CT angiogram and a pulmonary angiogram if available within 3 months prior to screening
*Expert centre is an expert multidisciplinary team which must include at least one cardiology or respiratory consultant, and one consultant PEA surgeon
3. Subject must meet all of the following haemodynamic criteria by means of a RHC within 4 weeks prior to screening:
i. mPAP of >25 mmHg
ii. PVR > 400 dynes.sec/cm5
iii. PCWP or LVEDP of <15 mmHg
4. Subjects must have previously been judged inoperable due to the obstruction being surgically inaccessible (i.e. distal disease) by an expert multidisciplinary team which must include at least one cardiology or respiratory consultant, and one consultant PEA surgeon. For countries with CTEPH expert centers (including at least a surgeon with sound experience performing PEAs) the expert team will be the local expert
centre. For countries without a CTEPH surgical expert center a central adjudication committee will assess the operability of the subjects during the screening period. See Section 6.1.1 of the protocol.
5. Subject must walk a distance of >=150m and <=475m at the screening visit. See Section 6.2.1.
6. Subject must have a current diagnosis of being in WHO Functional Class II or III.
7. Subject, with or without supplemental oxygen, must have a resting arterial oxygen saturation (SaO2) =>92% as measured by pulse oximetry at the Screening Visit.
8. Subjects must have received anticoagulation for a minimum of 3 months prior to Screening.

General
9. Female subject of childbearing potential must agree 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 Investigational Product (reliable methods of contraception are described in Appendix 1 of the protocol.
10. Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study.
11. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form (ICF)and must sign the form prior to the initiation of any study procedures.

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the investigational product that may impact subject eligibility is provided in the IB and product label.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore,
adherence to the criteria as specified in the protocol is essential.

French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 137
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 138

Exclusion criteria:
CTEPH Treatments
1. Subject received previous PAH therapy (PDE5i, ERA, chronic prostanoid use*) within 12 weeks prior to the screening visit
*Chronic prostanoid use is considered >7 days of treatment
2. Subject has previously discontinued other ERA in either another clinical study or commercial product for safety or tolerability reasons other than for liver function abnormalities.
3. Subject has a known hypersensitivity to the Investigational Products, the metabolites, or formulation excipients.

Other Therapies
4. Subject has previously undergone a pulmonary endartorectamy.
5. Subject receiving intravenous inotropes within 2 weeks prior to the Screening Visit (e.g. dopamine, dobutamine)
6. Subjects receiving Calcium Channel Blockers or HMG-CoA reductase inhibitors (i.e., statins) on an unstable dose 4 weeks prior to the Screening Visit (to be eligible subjects must not have changed their dose <4 weeks prior to the screening visit)

Exercise Programmes
7. Subject has not enrolled in an exercise training program for cardiopulmonary rehabilitation within 12 weeks prior to the Screening Visit and must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 16 weeks of the study. Subjects enrolled in an exercise program for pulmonary rehabilitation 12 weeks prior to screening may enter the study if they agree to maintain their current level of rehabilitation for the first 16 weeks of the study.

Laboratory Values at Screening
8. ALT and/or AST ? 3xULN
9. Bilirubin ? 1.5xULN (>35% direct bilirubin)
10. Subject has severe renal impairment (creatinine clearance <30 mL/min) at the Screening Visit
NOTE: if serum bilirubin is elevated at screening it will need to be fractionated to exclude liver injury and determine if the patient is able to be included in the trial.

Liver
11. Subject has moderate - severe hepatic impairment (Child-Pugh class B-C with or without cirrhosis) at the Screening Visit
Haematology and bleeding disorders
12. Subject has clinically significant anaemia: Hb < 10g/dL
13. Subjects with bleeding disorders or significant active peptic ulceration in the opinion of the investigator

Cardiovascular
14. Subject has uncontrolled hypertension (>180/110 mmHg) at screening
15. Subject has severe hypotension (<90/50 mmHg) at screening
16. Subject has had an acute myocardial infarction within the last 90 days prior to screening
17. Subject has, in the opinion of the investigator, clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction (ejection fraction <50% of normal); left ventricular outflow obstruction; symptomatic coronary artery disease; autonomic
hypotension; fluid depletion.

General Medical Conditions
18. Subject with significant pulmonary disease (FEV1<70% of predicted): COPD, Emphysema, evidence of fibrotic lung disease on imaging
19. Subject has clinically significant fluid retention in the opinion of the investigator
20. Subject with significant obesity (BMI ? 35), cardiovascular, musculoskeletal or any other condition that in the opinion of the investigator may involve an impairment of exercise capacity or the performance of the 6MWD test (e.g. previous history of hip/knee surgery, lower limb ulcers associated with autoimmune diseases)
21. Subject with cardiovascular, liver, renal, haematologic, gastrointestinal,

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).
MedDRA version: 14.1 Level: LLT Classification code 10068739 Term: Chronic thromboembolic pulmonary hypertension System Organ Class: 100000004855

Intervention(s)

Trade Name: Volibris
Product Name: GSK1325760
Product Code: GSK1325760
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Ambrisentan
CAS Number: 177036-94-1
Current Sponsor code: GSK1325760
Other descriptive name: ambrisentan
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 16

Secondary Objective: The secondary objectives are safety and tolerability of ambrisentan 5mg.

Main Objective: The primary objective of this study is to assess the efficacy of ambrisentan 5mg after treatment period of 16 weeks, in subjects with inoperable CTEPH.

Primary end point(s): Change from baseline in 6MWD measured at week 16.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Baseline and week 16

Secondary end point(s): Secondary endpoints include change from baseline to week 16 in:
? Pulmonary Vascular Resistance (PVR)
? WHO Functional Class (FC)
? Borg CR10 Scale (BCR10S) immediately following exercise
? Clinical worsening of CTEPH, as defined by the time from randomization to the first occurrence of death, lung transplantation, hospitalization for CTEPH, atrial septostomy, addition of parenteral prostanoids, or study withdrawal due to two or more early escape criteria*
*Early escape criteria to consider:
1. A decrease from baseline of at least 20 percent in the distance walked during the six-minute walk test;
2. An increase of one or more WHO Functional Class;
3. Worsening right ventricular failure (e.g., as indicated by increased jugular venous pressure; new/worsening hepatomegaly, ascites, or peripheral edema; worsening echocardiographic parameters such as tricuspid annulus plane systolic excursion (TAPSE) and TDI of the tricuspid annulus);Rapidly progressing cardiogenic, hepatic, or renal failure;
4. Refractory systolic hypotension (systolic blood pressure less than 85 mmHg).
? Other haemodynamics: Right atrial pressure (mm Hg), pulmonary artery pressure (mm Hg) and cardiac index (L/min/m2)
? N-terminal pro-B-type natriuretic peptide (NT-proBNP)
Health outcomes endpoints include:
? Change from baseline to week 16 in Quality of Life as measured by the Short Form 36 Health Survey (SF-36)
Safety endpoints include:
? Incidence of Adverse events and Serious Adverse events
? Change from baseline in haemoglobin or haematocrit levels
? Liver Testing abnormalities
? Vital signs (i.e. supine blood pressure and heart rate)
? Laboratory test: clinical chemistry, haematology, testicular function (males only)

Secondary ID(s)

AMB115811

Source(s) of Monetary Support

GSK Pharma & R&D