Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy

Data from a previous single arm study (RESPITE) indicate that transition from PDE5i to
riociguat may be feasible, safe and beneficial in patients not adequately responding to
PDE5i.

REPLACE is a randomized controlled study to confirm the potential clinical benefit of
transition from PDE5i to riociguat. Satisfactory clinical response in patients who are on a
stable dose of phosphodiesterase-5inhibitors (PDE-5i) with or without endothelin receptor
antagonist (ERA), but not at treatment goal will be compared between one group of patients
randomized to maintain current treatment and another group where the PDE5i is replaced by
riociguat.

Inclusion Criteria:

- Male and female patients aged 18 to 75 years.

- Patients with symptomatic PAH with a pulmonary vascular resistance (PVR) > 400
dyn*sec*cm-5, mean pulmonary artery pressure ≥ 25 mmHg, and pulmonary capillary wedge
pressure (PCWP) ≤ 15 mmHg as assessed by the most recent right heart catheterization
(RHC) from medical history prior to screening to confirm the diagnosis. Alternatively,
PCWP can be replaced by left ventricular end-diastolic pressure (≤ 15 mmHg). PAH of
the following types:

- Idiopathic

- Hereditary

- Drug and toxin induced PAH

- Associated with PAH due to:

- Connective tissue disease (CTD)

- Congenital heart disease, but only if the patient underwent surgical repair
more than one year before enrolment

- Portal hypertension with liver cirrhosis (Note: patients with clinical
relevant hepatic dysfunction are excluded; see exclusions related to
disorders in organ function)

- Patients who are on stable doses of a PDE-5i and ERA combination therapy or on stable
PDE-5i monotherapy 6 weeks prior to and at randomization but not at treatment goal
(tadalafil 20 to 40 mg once daily or sildenafil at least 60 mg daily dose).

- WHO FC III at screening and at randomization.

- 6MWD test between 165 m and 440 m at screening and at randomization.

- Stable dose of diuretics, if used, for at least 30 days prior to and at randomization.

- Patients who are able to understand and follow instructions and who are able to
participate in the study for the entire study.

- Women of childbearing potential must agree to use adequate contraception when sexually
active. Adequate contraception is defined as any combination of at least 2 effective
methods of birth control, of which at least 1 is a physical barrier (e.g. condom with
hormonal contraception like implants or combined oral contraceptives, condom with
intrauterine devices). This applies beginning with signing of the informed consent
form until 30 (+5) days after the last administration of study drug.

- Patients must have given their written informed consent to participate in the study
after having received adequate previous information and prior to any study-specific
procedures.

Exclusion Criteria:

- Participation in another interventional clinical study within 30 days prior to
screening.

- All types of PH (including PH-IIP) except subtypes of Dana Point Group I specified in
the inclusion criteria.

- Previous treatment with riociguat.

- Pregnant women (i.e., positive serum ß-human-chorionic-gonadotropin test or other
signs of pregnancy), or breast feeding women, or women with childbearing potential not
using a combination of 2 effective contraception methods (as laid out in inclusion
criterion) throughout the study.

- Patients with a medical disorder, condition, or history of such that would impair the
patient's ability to participate or complete this study, in the opinion of the
investigator.

- Relevant obstructive and restrictive or other lung diseases.

- Patients with underlying medical disorders with an anticipated life expectancy below 2
years (e.g., active cancer disease with localized and/or metastasized tumor mass).

- Cardiovascular exclusion criteria like left ventricular disease, coronary heart
disease or stroke within previous 3 months.

- Patients with hypersensitivity to the investigational drug or any of the excipients.

- Patients unable to perform a valid 6MWD test (e.g., orthopedic disease, peripheral
artery occlusive disease, which affects the patient's ability to walk). Note:
Patients, who require walking aids, may be included if in the opinion of the
investigator the walking distance is not impaired. Patients with a variance of more
than 15% between the screening and the randomization (i.e., baseline) 6MWD test.