A Multi-Center Study of Riociguat in Patients With Sickle Cell Diseases

This randomized study involves 12 weeks of treatment with riociguat pills or placebo pills,
and a follow-up period of 30 days after treatment. The dose is adjusted every 2 weeks based
on systolic blood pressure (SBP) and well-being assessed at that visit. Physical
examinations, vital signs, blood tests and questionnaires will be performed at 2 week
intervals during the double blinded study treatment. Echocardiogram, urine testing,
six-minute walk distance and questionnaires will be assessed at the beginning and end of the
treatment phase.

Inclusion Criteria:

- Age ≥ 18 years

- Sickling disorder (HbSS, HbSC, HbSbeta-thalassemia, HbSD, HbSO-Arab documented by
hemoglobin electrophoresis or HPLC fractionation)

- At least one of the following findings: a. Systolic blood pressure ≥ 130 mm Hg on at
least two occasions at least 1 day apart (one of these may be by history), b.
Macroalbuminuria as manifested by urine albumin to creatinine ratio > 300 mg/g, c.
Tricuspid regurgitant velocity (TRV) > 2.9 m/sec measured by echocardiography d.
NT-proBNP level ≥ 160 pg/mL e. Urinalysis protein 1 + or higher.

- Females of reproductive potential (FRP) must have a negative, pre-treatment pregnancy
test. Post-menopausal women (defined as no menses for at least 1 year or post-surgical
from bilateral oophorectomy) are not required to undergo a pregnancy test.

- Females of reproductive potential must agree to use reliable contraception when
sexually active. Adequate contraception is defined as any combination of at least 2
effective methods of birth control, of which at least one is a physical barrier (e.g.
condoms with hormonal contraception or implants or combined oral contraceptives,
certain intrauterine devices). Adequate contraception is required beginning at the
signing of the informed consent form until one month after the last dose of riociguat.

- Patients must be willing to provide a blood sample for DNA analysis.

Exclusion Criteria:

- Pregnant or breast feeding women

- Patients with severe hepatic impairment defined as Child Pugh C

- End stage renal disease requiring dialysis

- Patients with eGFR <30 mL/min/1.73m, where GFR is estimated based on CKD-epi equation

- Patients on phosphodiesterase type 5 inhibitors (PDE-5) (such as sildenafil,
tadalafil, vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or
theophylline) or nitrates

- Patients on strong cytochrome P450 (CYP) and P-glycoprotein 1(P-gp)/BCRP inhibitors
such as systemic azole antimycotics (eg: ketoconazole, itraconazole), or HIV protease
inhibitors (such as ritonavir)

- Patients on St. John's Wort

- If patients are taking antihypertensive drugs, hydroxyurea, or L-glutamine prior to
enrollment, they are excluded until the dose level is stable for at least three months

- Systolic blood pressure <95 mm Hg at Screening Visit 1 or 2 or Week 0 before
randomization

- Current enrollment in an investigational new drug trial. Patients are eligible for
enrollment 30 days after the last dose of an investigational drug has been received

- Evidence of qualitative urine drug test at screening for cocaine, phencyclidine (PCP),
heroin, or amphetamines within three months prior to enrollment

- Patients who have recently (last six months) experienced serious bleeding from the
lung or have undergone a bronchial arterial embolization procedure.

- Pulmonary hypertension associated with Idiopathic Interstitial Pneumonias

- Medical disorder, condition, or history that in the investigator's judgment would
impair the patient's ability to participate or complete this study or render the
patient to be inappropriate for enrollment