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Publications

Journal Article Randomized Controlled Trial Clinical Trial, Phase II Clinical Trial, Phase I Ppublish 4 citations

PubMed: 38554715 DOI: 10.1016/S2352-3026(24)00045-0

Riociguat in patients with sickle cell disease and hypertension or proteinuria (STERIO-SCD): a randomised, double-blind, placebo controlled, phase 1-2 trial.

Lancet Haematol 11(5):e345-e357

Authors: Mark T Gladwin, Victor R Gordeuk, Payal C Desai, Caterina Minniti, Enrico M Novelli, Claudia R Morris, Kenneth I Ataga, Laura De Castro, Susanna A Curtis, Fuad El Rassi, Hubert James Ford, Thomas Harrington, Elizabeth S Klings, Sophie Lanzkron, Darla Liles, Jane Little, Alecia Nero, Wally Smith, James G Taylor, Ayanna Baptiste, Ward Hagar, Julie Kanter, Amy Kinzie, Temeia Martin, Amina Rafique, Marilyn J Telen, Christina M Lalama, Gregory J Kato, Kaleab Z Abebe

Affiliations

  • University of Maryland School of Medicine, Baltimore, MD, USA.
  • Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
  • Levine Cancer Institute, Atrium Health, Wake Forest School of Medicine, Charlotte, NC, USA.
  • Albert Einstein College of Medicine, New York, NY, USA.
  • Department of Medicine, Division of Hematology and Oncology, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
  • Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Department of Pediatric Emergency Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA.
  • Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
  • Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; Georgia Comprehensive Sickle Cell Clinic at Grady Health System, Atlanta, GA, USA.
  • Pulmonary Hypertension Program, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Division of Hematology, Department of Medicine, University of Miami, Miami, FL, USA.
  • The Pulmonary Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
  • Sickle Cell Center for Adults, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Brody School of Medicine East Carolina University, Greenville, NC, USA.
  • University of North Carolina Comprehensive Sickle Cell Disease Program and Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Division of General Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.
  • Center for Sickle Cell Disease, Departments of Medicine (Hematology and Oncology) and Microbiology and Immunology, Howard University College of Medicine, Washington, DC, USA; Department of Food and Human Nutrition Sciences, University of Manitoba, Winnipeg, MB, Canada.
  • Department of Medicine, New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY, USA.
  • Internal Medicine, Department of Pediatrics, University of California San Francisco, Benioff Children's Hospital Oakland, Oakland, CA, USA.
  • Hematology Oncology, Department of Internal Medicine, University of Alabama Birmingham, Birmingham, AL, USA.
  • Sickle Cell Center of Southern Louisiana, Tulane University School of Medicine, New Orleans, LA, USA.
  • Medical University of South Carolina, Charleston, SC, USA.
  • Division of Hematology, Department of Medicine, Duke University School of Medicine, and Duke Comprehensive Sickle Cell Center, Durham, NC, USA.
  • Division of General Internal Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Clinical Trials & Data Coordination, Division of General Internal Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Abstract

BACKGROUND

Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events.

METHODS

This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sβ-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed.

FINDINGS

Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001).

INTERPRETATION

Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials.

FUNDING

Bayer Pharmaceuticals.

MeSH

Cells, Proteinuria, Hypertension, Blood, Anemia, Sickle Cell, Pain, Blood Pressure, Drug-Related Side Effects And Adverse Reactions, Therapeutics, Soluble Guanylyl Cyclase