A Phase 3, Prospective, Multicenter, Double-blind, Double-dummy, Randomized, Active-controlled, Parallel-group, Group-sequential, Adaptive, Event-driven Study to Compare Efficacy, Safety, and Tolerability of Macitentan 75 mg Versus Macitentan 10 mg in Patients with Pulmonary Arterial Hypertension, Followed by an Open-label Treatment Period With Macitentan 75 mg

Pulmonary arterial hypertension (PAH) is a syndrome of diverse etiology and
pathogenesis, characterized by a persistent increase in pulmonary vascular
resistance (PVR) progressing to right heart failure and death. PAH is
associated with structural changes in the pulmonary vasculature as well as the
right ventricle. The changes in vascular structure involve vasoconstriction,
vascular-wall remodeling, and thrombosis in situ.

It remains a severe and incurable disease despite the availability of multiple
drugs active by four routes of administration (iv, subcutaneously, orally, and
inhaled).
Currently used therapies target three main pathways important in endothelial
function: the prostacyclin and nitric oxide (NO) pathways, which are
under-expressed in PAH patients, and the endothelin pathway, which is
overexpressed in PAH patients.

Published data from the COMPERA registry showed that in a population of
treatment-naïve, newly diagnosed PAH patients, mortality rates at 1 year after
diagnosis varied from 2.8% in the low-risk cohort to 21.2% in the high-risk
cohort according to predefined disease risk criteria comprising the assessment
of patient World Health Organization Functional Class (WHO FC), results of the
6 minute walking distance test (6MWT), b-type natriuretic peptide (BNP) or N
terminal pro BNP (NT-proBNP) values and hemodynamic values (ie, right atrial
pressure, cardiac index and mixed venous oxygen saturation).

Macitentan (JNJ-67896062 [also known as ACT-064992]) is an endothelin receptor
antagonist (ERA) that inhibits the binding of endothelin-1 (ET-1) to both ETA
and ETB receptors. Macitentan 10 mg once daily (qd) is approved worldwide for
the treatment of pulmonary arterial hypertension (PAH, WHO Group 1) to
delay disease progression and reduce rate of hospitalization for PAH as
monotherapy or in combination with other PAH therapies.

Macitentan 10 mg once daily (qd) is approved world-wide for the treatment of
pulmonary arterial hypertension (PAH, WHO Group 1) to delay disease progression
and reduce rate of hospitalization for PAH as monotherapy or in combination
with other PAH therapies. Refer to the local Prescribing Information for more
information.

Given the current need to further improve long term outcome (ie, survival), by
reducing further occurrence of morbidity events and/or improving patient
disease risk status for clinical worsening and death defined by specific
criteria (eg, exercise capacity, WHO FC, NT-proBNP), patients may benefit from
receiving macitentan at a higher dose in order to further block ETB receptors,
which are overexpressed in the lung/vessels of patients with PH related
disease.

This study has been transitioned to CTIS with ID 2024-515669-32-00 check the CTIS register for the current data.

The purpose of this study is to demonstrate superiority of macitentan 75
milligrams (mg) in prolonging the time to the first clinical events committee
(CEC)-adjudicated morbidity or mortality (M/M) event in participants with
symptomatic pulmonary arterial hypertension (PAH) compared to macitentan 10 mg.

This is a Phase 3 prospective, multicenter, double-blind, double-dummy,
randomized, active controlled, parallel-group, group-sequential, adaptive,
event-driven superiority study in patients with PAH (PH group 1), to evaluate
the efficacy, safety, and tolerability of 75 mg macitentan vs 10 mg macitentan.
- Screening period (Max 30 days)
- 4 week run-in period (if applicable)
- randomised dubbel blind period: 1:1 randomisation - 10mg macitentan +
matching placebo / or / 75 mg macitentan + matching placebo.
- safety follow-up period / open label period

1:1 randomisation period
Group 1: macitentan 10mg + matching placebo
Group 2: macitentan 75mg + matching placebo

Macitentan and matching placebo will be provided as film-coated tablets with a
dose strength of 10 mg, 37.5 mg, or 75 mg in childproof bottles. The tablets
are administered orally and should be swallowed whole (ie, not crushed, split
or chewed) with water during meals. Dosing frequency will be once a day.

Extension period open label:
Macitentan 75mg for all subjects fulfilling the criteria.

Overall Benefit/Risk Assessment
The overall benefit/risk assessment for this clinical study is considered
acceptable for the following reasons:
* There is still a clear unmet medical need to further delay disease
progression (and death) and reduce hospitalization for PAH.
* Macitentan 75 mg may offer participants a more potent treatment alternative
option than macitentan 10 mg to further delay disease progression and time to
death (see Section 4.3).
* Only participants who meet all inclusion criteria and none of the exclusion
criteria (specified in Section 5) will be allowed to participate in this study.
The selection criteria include adequate provisions to minimize the risk and
protect the well-being of participants in the study, in particular with the
requirement for initially restricted exclusion criteria.
* Safety will be closely monitored throughout the study:
* In general, safety evaluations (see Section 8.3) will be performed at
scheduled visits during the study, as indicated in the Schedule of Activities.
Frequency of visits and planned study assessments are deemed adequate to ensure
a close safety monitoring of study participants and assess their disease
progression.
* The investigator or the designee will document unsolicited AEs as indicated
in Appendix 4.
* Any clinically significant abnormalities (including those persisting at the
end of the study/early withdrawal) will be followed by the investigator until
resolution or until a clinically stable condition is reached.
* Safety measures are included in this protocol to minimize the potential risk
to participants, including the following:
* Run-in period with macitentan 10 mg for pre-defined participants (see Section
4.1)
* Initially restricted inclusion criteria (see Section 5)
* Initial safety monitoring (see Section 8.3)
* Special attention will be paid to the AEs of special interest as defined in
Section 8.4.5
* Specific recommendations are provided for study treatment interruption and
discontinuation (Section 7)
* The study will be closely monitored by an external IDMC throughout its
conduct.
* Serious hepatic AEs of special interest (HAESIs) will be reviewed by the
ILSDRB (see Section 8.4.5)
It is the investigator*s responsibility to monitor the individual benefit/risk
of study intervention administration, as well as the degree of distress caused
by study procedures at an individual participant level, and to discontinue
study intervention or the study if he/she considers that continuation would be
detrimental to the participant*s well-being.
More detailed information about the known and expected benefits and risks of
macitentan may be found in the IB21 and local Prescribing Information.