Brief 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).
Brief Title
A Multi-Center Study of Riociguat in Patients With Sickle Cell Diseases
Detailed Description
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.
Completion Date
Completion Date Type
Actual
Conditions
Sickle Cell Disease
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
* 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
Inclusion 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.
* 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.
Gender
All
Gender Based
false
Keywords
SCD
Sickle Cell Disease
Riociguat
Adempas
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02633397
Org Class
Other
Org Full Name
University of Pittsburgh
Org Study Id
PRO15110016
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase II Randomized, Double-Blind, Placebo-Controlled Multi-Center Study to Assess the Safety, Tolerability, and Efficacy of Riociguat in Patients With Sickle Cell Diseases
Primary Outcomes
Outcome Description
The primary endpoint was the proportion of participants who experienced at least 1 treatment-emergent serious adverse event (SAE), which was defined as any event occurring after the baseline visit (i.e., after initiation of study drug), adjudicated by a designated committee of protocol investigators and outside experts. SAEs were considered to be treatment-emergent if they started or worsened after the first dose of study medication and up to 7 days after end of study treatment.
Outcome Measure
Overall Incidence of Treatment Emergent Severe Adverse Events (SAE)
Outcome Time Frame
Baseline through 7 days after discontinuation of treatment, up to 13 Weeks
Secondary Outcomes
Outcome Description
The proportion of participants with treatment-emergent SAE for sickle-cell related crises (Vaso-occlusive crises)
Outcome Time Frame
Baseline through 7 days after discontinuation of treatment, up to 13 Weeks
Outcome Measure
Frequency of SAE Due to Sickle Cell Related Painful Crisis
Outcome Description
Proportion of participants that experienced treatment-emergent AEs
Outcome Time Frame
Baseline to Week 12
Outcome Measure
Overall Incidences of Treatment-emergent Adverse Events (AEs)
Outcome Description
Incidence of Vaso-occlusive Crisis (VOC) between baseline and week 12
Outcome Time Frame
Baseline to Week 12
Outcome Measure
Incidences of Sickle Cell Related Clinical Complications
Outcome Description
Brief Pain Inventory (BPI) short form - score ranges from 0 (no pain) to 10 (Pain as bad as you can imagine)
Mean at 12 weeks assessed using ANCOVA adjusting for baseline.
Mean at 12 weeks assessed using ANCOVA adjusting for baseline.
Outcome Time Frame
Baseline, 12 weeks
Outcome Measure
Pain Intensity Using the Brief Pain Inventory
Outcome Description
6-minute walk distance was used to assess functional exercise capacity
Mean at 12 weeks assessed using ANCOVA adjusting for baseline.
Mean at 12 weeks assessed using ANCOVA adjusting for baseline.
Outcome Time Frame
Baseline, 12 weeks
Outcome Measure
6-minute Walk Distance
Outcome Description
Baseline to 12 weeks mean change of the Borg dyspnea scores, post 6MWT, using a linear regression model.
Dyspnea Borg score was used to measure the level of severity of breathlessness perceived by the patient at the end of the 6MWD Test. The severity is measured on a 10-point scale with 0= nothing at all and 10=maximum severity of breathlessness.
Dyspnea Borg score was used to measure the level of severity of breathlessness perceived by the patient at the end of the 6MWD Test. The severity is measured on a 10-point scale with 0= nothing at all and 10=maximum severity of breathlessness.
Outcome Time Frame
Baseline,12 Weeks
Outcome Measure
Changes in the Dyspnea Borg Scale
Outcome Description
Fatigue Borg score was used to rank the participant's exertion at the end of the 6MWD Test. The rate of exertion was given according to a scale ranging from 0 (nothing at all) to 10=maximum severity of exertion
Mean at 12 weeks assessed using ANCOVA adjusting for baseline.
Mean at 12 weeks assessed using ANCOVA adjusting for baseline.
Outcome Time Frame
Baseline,12 weeks
Outcome Measure
Fatigue Borg Scale
Outcome Description
Baseline to 12 weeks mean change of MAP, estimated with a repeated measures analysis (Baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks) using a linear mixed model.
Outcome Time Frame
Baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks
Outcome Measure
Changes in Blood Pressure as the Main Pharmacodynamic (MAP)
Outcome Description
Mean TRV at 12 weeks assessed using ANCOVA, adjusting for baseline.
Outcome Time Frame
Baseline, 12 Weeks
Outcome Measure
Tricuspid Regurgitant Velocity (TRV) Using Non-invasive Echocardiography
Outcome Description
Mean end-systolic volume (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline.
Outcome Time Frame
Baseline,12 weeks
Outcome Measure
End-systolic Volume Using Non-invasive Echocardiography
Outcome Description
Mean ejection fraction (biplane) at 12 weeks, assessed using ANCOVA adjusting for baseline.
Outcome Time Frame
Baseline, 12 weeks
Outcome Measure
Ejection Fraction (Biplane) Using Non-invasive Echocardiography
Outcome Description
Mean Change in the levels of plasma NT-proBNP from baseline to 12 weeks using a linear regression model.
Outcome Time Frame
Baseline,12 weeks
Outcome Measure
Changes in the Levels of Plasma NT-proBNP
Outcome Description
Albumin/Creatinine Ratio (ACR) mean change from baseline to 12 weeks using linear regression model.
Outcome Time Frame
Baseline,12 weeks
Outcome Measure
Changes in Albumin/Creatinine Ratio
Outcome Description
Odds ratio per week of microalbuminuria estimated with a repeated measures analysis (baseline, 12 weeks) using a generalized linear mixed model without random slope
Outcome Time Frame
Baseline,12 weeks
Outcome Measure
Microalbuminuria
Outcome Description
Odds ratio per week of macroalbuminuria estimated with a repeated measures analysis (baseline, 12 weeks) using a generalized linear mixed model without random slope.
Outcome Time Frame
Baseline,12 weeks
Outcome Measure
Macroalbuminuria
Outcome Description
Mean change in GFR to 12 weeks, estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.
Outcome Time Frame
Baseline, 4 weeks, 8 weeks, 12 weeks
Outcome Measure
Changes in Glomerular Filtration Rate
Outcome Description
Odds ratio (OR) per week of low-risk CKD stage versus at least moderately increased risk (includes moderately increased risk CKD, high increased risk CKD, and very high increased risk CKD) estimated with a repeated measures analysis (baseline, 12 weeks) using a generalized linear mixed model without random slope
Outcome Time Frame
Baseline,12 weeks
Outcome Measure
Chronic Kidney Disease (CKD) Stage - Low Risk Versus at Least Moderately Increased Risk
Outcome Description
Mean change in hemoglobin to 12 weeks, estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.
Outcome Time Frame
Baseline, 4 weeks, 8 weeks,12 weeks
Outcome Measure
Changes in Hemoglobin
Outcome Description
Mean change in reticulocyte count to 12 weeks, estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.
Outcome Time Frame
Baseline, 4 weeks, 8 weeks,12 weeks
Outcome Measure
Changes in Reticulocyte Count
Outcome Description
Mean change in White Blood Cell count to 12 weeks estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.
Outcome Time Frame
Baseline, 4 weeks, 8 weeks,12 weeks
Outcome Measure
Changes in White Blood Cell Count
Outcome Description
Mean change in LDH to 12 weeks estimated with a repeated measures analysis (Baseline, 4 weeks, 8 weeks, 12 weeks) a using a linear mixed model.
Outcome Time Frame
Baseline, 4 weeks, 8 weeks,12 weeks
Outcome Measure
Changes in Lactate Dehydrogenase (LDH)
Outcome Description
Mean change in fetal hemoglobin from baseline to 12 weeks using a linear mixed model
Outcome Time Frame
Baseline,12 weeks
Outcome Measure
Changes in Fetal Hemoglobin
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Caterina Minniti
Investigator Email
caterina.minniti@einsteinmed.org
Investigator Phone