An open-label phase IIIb study of riociguat in patients with in-operable CTEPH, or recurrent or persisting PH after surgical treatment who are not satisfactorily treated and cannot participate in any other CTEPH trial

Chronic thromboembolic pulmonary hypertension (CTEPH) is a chronic disease with
high mortality. Surgery (PEA) is treatment of choice but cannot be done in all
patients. These inoperable patients require drugs which are not available
(approved). The study will
collect more data for riociguat in CTEPH.

Objectives of the study are to assess safety, tolerability and clinical effects
of riociguat and provide access to inoperable patients for a condition (CTEPH)
with unmet medical need.

The study will be conducted as an open-label, uncontrolled long-term
surveillance study to assess safety, tolerability, and clinical effects while
providing early access of riociguat to patients with inoperable CTEPH, or
recurrent or persisting PH after surgical treatment that are not satisfactorily
treated and cannot participate in any other CTEPH trial.

In the dose titration, the starting dose will be 1 mg riociguat tid. The
individual riociguat dose will be titrated every 2 weeks according to the
peripheral systolic blood pressure (SBP) and patient*s well-being measured
before intake of the next morning dose. At each Titration Visit (with the
exemption of Week 0 (Visit 1) the investigator needs to decide, based on the
patient*s systolic blood pressure, whether the study medication dose should be
modified.
The investigators will apply the following blood pressure based titration rules
for their dose decision:
The individual study medication dose of the next titration step will be
determined every 2 weeks according to patient*s well-being and the peripheral
SBP measured and at trough before intake of the morning dose under
consideration of the following algorithm (= individual dose titration scheme):
* If trough SBP * 95 mmHg, increase dose (+0.5 mg tid)
* If trough SBP 90 - 94 mmHg, maintain dose
* If trough SBP <90 mmHg without symptoms of hypotension, reduce dose (-0.5 mg
tid)
* If any SBP <90 mmHg with clinical symptoms of hypotension such as dizziness
or presyncope, stop study treatment; restart after 24 hours with reduced dose
(-0.5 mg tid).
The individual dose titration scheme is based on the patient*s systolic blood
pressure and patient*s well-being. It is allowed in case of study medication
side effects, to suspend a foreseen up-titration step and to maintain the dose.
In the main study phase, riociguat should be continued at the optimal dose as
determined at the end of the titration phase. Dose reductions or stop of study
medication for safety reasons are allowed at any time. Increases or
re-increases in 0.5 mg steps (maximum dose 2.5 mg) are possible at the
investigator*s discretion weighing the benefit with potential risks implied,
e.g. hypotension.

The burden of participation will be to meet the frequent and time-consuming
visits for the study. The risks involved are mainly those related to
vasodilatory effects of riociguat (like hypotension) but benefits include
improvement in pulmonary hemodynamics and functional capacity (eg exercise
tolerance/6 MWD) as already proven with riociguat in a recent trial (CHEST).
The benefit-risk assessment for riociguat has been shown to be positive.