A Randomized, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension
This Phase iii/iV, randomised, double-blind study will compare the safety and efficacy of first-line combination therapy (ambrisentan and tadalafil) to first-line monotherapy (ambrisentan or tadalafil) in subjects with WHo/nYHa functional class ii and iii PaH.
enrolment of 545 subjects is planned with 228 subjects in the combination arm and 228 in the monotherapy arm.
Subjects must have a confirmed diagnosis of PaH with documented mean pulmonary arterial pressure (mPaP) [GreaterThanorequalTo]25 mmHg, pulmonary vascular resistance (PVR) [GreaterThanorequalTo]240 dyne [and] #8901;sec/cm5, and pulmonary capillary wedge pressure (PCWP) or left ventricle end diastolic pressure (LVeDP) of [LessThanorequalTo]15 mmHg based on a right heart catheterization (RHC) prior to Screening.
eligible subjects will be stratified based on the underlying aetiology of PaH (iPaH/HPaH and non-iPaH) and WHo Functional Class (ii and iii). Subjects will be randomised 2:1:1 to either the combination therapy arm (ambrisentan and tadalafil) or to the monotherapy arm (ambrisentan and placebo or tadalafil and placebo). Subjects will also be randomly assigned in a 1:1 allocation within each treatment group to peak or trough 6MWD assessment at week 16.
The target doses of the study medication will be 10mg ambrisentan (aBS) once daily and 40mg tadalafil (TaD) once daily.
Monotherapy arm: ambrisentan group: Subjects randomised to ambrisentan monotherapy will receive both one tablet of 5mg aBS and one tablet of aBS-matching placebo for the first 8 weeks and, if well tolerated, two tablets of 5mg aBS (10mg once daily), thereafter Two tablets of TaD-matching placebo
Monotherapy arm: tadalafil group: Subjects randomised to tadalafil monotherapy will receive both Two tablets of aBS-matching placebo one tablet of 20mg TaD and one tablet of TaD-matching placebo for the first 4 weeks and two tablets of 20mg TaD (40mg once daily), thereafter Subjects with mild to moderate renal impairment (creatinine clearance [Greater Than]30mL/min and [Less Than]80mL/min) should be carefully assessed for tolerability at the week 4 visit and a risk:benefit decision made by the investigator whether the subject remain on tadalafil 20mg od or up-titrate to tadalafil 40mg od (see section 188.8.131.52 for details). Subjects will be assessed for efficacy and safety at Screening, Randomisation, Weeks 4, 8, 16, 24, and every 12 weeks thereafter. Subjects will also have monthly liver function and pregnancy safety assessments, which may be performed by a local phlebotomy laboratory or at the investigator clinic (or by the central lab with Sponsor permission).
The primary endpoint of the study is time to the first clinical failure event. Criterion for clinical failure will be adjudicated by a blinded study-specific Clinical endpoint Committee (CeC).
amendment 2 clarifies the primary endpoint, along with second and fourth endpoint components. The amendment allows any hospitalization due to worsening PaH, not just non-elective hospitalization. also, to clarify that unsatisfactory long term clinical response requires WHo function class iii sytmpoms at two clinic visits separated by at least 6 months, not sustained WHo functional class iii symptoms for 6 months.
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Subject must be between 18 and 75 years of age, inclusive, at the Screening Visit
2. Subject must weigh great than or equal to 40 kg at the Screening Visit
PAH Diagnosis and Classification
3. Subjects must have a diagnosis of PAH due to the following:
a) idiopathic or heritable PAH
b) PAH associated with:
i. connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed CTD,
systemic lupus erythematosus, or overlap syndrome)
ii. drugs or toxins
iii. HIV infection
iv. congenital heart defects repaired greater than 1 year prior to screening (i.e., atrial septal
defects, ventricular septal defects, and patent ductus arteriosus)
NB: subjects with portopulmonary hypertension and PVOD are NOT eligible for the study
4. Subject must have a current diagnosis of being in WHO Functional Class II or III.
5. Subject with a diagnosis of HIV must have stable disease status. For this study, stable HIV
status is defined as:
i. No addition of medications for treatment of HIV for at least 8 weeks prior to screening
ii. No active opportunistic infection during the Screening Period
iii. No hospitalizations due to HIV for at least 4 weeks prior to screening
6. Subject must meet all of the following haemodynamic criteria by means of a RHC prior to
i. mPAP of >=25 mmHg
ii. PVR >=240 dyne⋅sec/cm5
iii. PCWP or LVEDP of <=15 mmHg
7. Subject must meet all of the following pulmonary function tests completed no more than 24
weeks before the Screening visit:
i. Total lung capacity (TLC) >=60% of predicted normal and
ii. Forced expiratory volume in one second (FEV1) >=55% of predicted normal
8. Subject must walk a distance of >=125m and <=500m at the screening visit. In addition the screening and baseline 6MWD tests must not vary by greater than 10%
9. Subject, with or without supplemental oxygen, must have a resting arterial oxygen saturation
(SaO2) >=88% as measured by pulse oximetry at the Screening Visit.
10. Subjects with a confirmed VQ scan that demostrates low probability for CTEPH.
11. Subject has not enrolled in an exercise training program for pulmonary 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 24 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 24 weeks of the study.
12. Female subject of childbearing potential, if sexually active, 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). Subjects who have had a Copper T 380A IUD or LNg 20 IUD inserted are not required to use additional methods of contraception
13. Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study
14. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved 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.
15. Patients must 2 or fewer risk factors for left heart disease.
16. Patients with a documented VQ scan showing negative results for pulmonary embolism.