Early Signs of Efficacy Study With Riociguat in Adult Homozygous Delta F508 Cystic Fibrosis Patients

The study consists of two parts. The first part is double-blind, randomized and
placebo-controlled. The second part has an open-label study design. In part 1 patients on
Orkambi or other CFTR-modulators are excluded. In part 2 patients on Orkambi are allowed to
be included under certain conditions.

Inclusion Criteria:

- Signed informed consent available before any study specific tests or procedures are
performed

- Patients must be at least 18 years of age at time of inclusion (i.e. upon signature of
informed consent)

- Patient diagnosed with Cystic Fibrosis according to standard criteria (i.e. either
elevated sweat chloride content above 60 mmol/ L and/ or genetic testing)

- Patient is homozygous for the deltaF508 mutation

- Patient has a mild-to-moderate stage of lung disease as determined by FEV1 (FEV1
between 40 and 100% predicted)

- Patient has a stable condition of lung disease (no ongoing or recent pulmonary
exacerbation and no change in current treatment) within the last 4 weeks prior to
screening

- Ability and willingness to understand and follow study procedures for the entire study

- Patients do not smoke. Patients with a history of smoking can be included, if they
have refrained from smoking for the last 3 months. If a patients starts smoking during
the study participation, he/ she needs to be excluded and considered to be a drop out

- Body mass index (BMI): ≥ 16 kg/ m² (calculated by dividing the patient's weight by the
square of his/ her height [kg/ m2])

Inclusion criterion valid for study part 1 only:

- Women of childbearing potential must agree to use adequate contraception when sexually
active. 'Adequate contraception' is defined as one highly effective form of contraception
(intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a
combination of methods (hormone method with a barrier method ). If a partner's vasectomy is
the chosen method of contraception or if a partner has documented azoospermia, a hormone or
barrier method must be used in combination. Adequate contraception is required from the
signing of the informed consent form up until 4 weeks after the last study drug
administration

Inclusion criteria valid for study part 2 only:

- Women of childbearing potential must agree to use adequate contraception when sexually
active. 'Adequate contraception' is defined as one highly effective form of
contraception (intrauterine devices [IUD], contraceptive implants or tubal
sterilization) or a combination of methods (hormone method with a barrier method). For
patients on Orkambi hormonal methods (including hormonal oral contraceptives) cannot
be accepted in this study. They need to choose non-hormonal methods. If a partner's
vasectomy is the chosen method of contraception or if a partner has documented
azoospermia, a hormone or barrier method must be used in combination. Adequate
contraception is required from the signing of the informed consent form up until 4
weeks after the last study drug administration

- Patients receiving Orkambi (Lumcaftor + Ivacaftor) as part of their standard care need
to be on stable Orkambi treatment for at least 3 months prior to screening (patients
on Lumacaftor and/or Ivacaftor are excluded in part 1)

Exclusion Criteria:

- Patients with Cystic Fibrosis with any background other than homozygous deltaF508
mutation

- Exclusion criterion only valid for study part 1: Patients receiving treatment with
Lumacaftor and/ or Ivacaftor

- Active state of hemoptysis or pulmonary hemorrhage, including those events managed by
bronchial artery embolization. Also any history of moderate hemoptysis within the 3
months prior to inclusion

- Any history of pneumothorax, bronchial artery embolization or massive hemoptysis.
Massive hemoptysis being defined as acute bleeding >240 mL in a 24-hour period or
recurrent bleeding >100 mL/ d over several days

- A positive sputum culture for Burkholderia cenocepacia, Burkholderia dolosa, and/ or
Mycobacterium abscessus either currently or within the previous year

- Active allergic broncho-pulmonary aspergillosis

- Current pulmonary exacerbation

- Known history of solid organ transplantation

- Known history of any form of pulmonary hypertension

- Clinically relevant deviations of the screened laboratory parameters from reference
ranges outside of expected changes for Cystic Fibrosis patients, especially a
hemoglobin value below 110 g/L or a creatinine clearance based on the Cockcroft-Gault
formula < 15 ml/ min