A Multi-Center Study of Riociguat in Patients With Sickle Cell Diseases
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Intervention: Riociguat; Placebo
Intervention description: Riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks; Matching placebo to riociguat 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg three times a day for 12 weeks
Intervention MeSH terms: Riociguat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 130.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: SCD; Sickle Cell Disease; Riociguat; Adempas

Summary:

      The proposed study is a Phase 2 multi-center, randomized, double-blind, placebo-controlled,
      parallel groups study aimed to evaluate the safety, tolerability and the efficacy of
      riociguat compared with placebo in patients with sickle cell disease (SCD).
    

Eligibility criteria:

        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, L-glutamine,
             crizanlizumab, or voxelotor 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