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

Publication ,  Journal Article
Gladwin, MT; Gordeuk, VR; Desai, PC; Minniti, C; Novelli, EM; Morris, CR; Ataga, KI; De Castro, L; Curtis, SA; El Rassi, F; Ford, HJ; Liles, D ...
Published in: Lancet Haematol
May 2024

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.

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Published In

Lancet Haematol

DOI

EISSN

2352-3026

Publication Date

May 2024

Volume

11

Issue

5

Start / End Page

e345 / e357

Location

England

Related Subject Headings

  • Treatment Outcome
  • Pyrimidines
  • Pyrazoles
  • Proteinuria
  • Middle Aged
  • Male
  • Hypertension
  • Humans
  • Female
  • Double-Blind Method
 

Citation

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ICMJE
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Gladwin, M. T., Gordeuk, V. R., Desai, P. C., Minniti, C., Novelli, E. M., Morris, C. R., … Abebe, K. Z. (2024). 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. https://doi.org/10.1016/S2352-3026(24)00045-0
Gladwin, Mark T., Victor R. Gordeuk, Payal C. Desai, Caterina Minniti, Enrico M. Novelli, Claudia R. Morris, Kenneth I. Ataga, et al. “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, no. 5 (May 2024): e345–57. https://doi.org/10.1016/S2352-3026(24)00045-0.
Gladwin MT, Gordeuk VR, Desai PC, Minniti C, Novelli EM, Morris CR, et al. 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. 2024 May;11(5):e345–57.
Gladwin, Mark T., et al. “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, vol. 11, no. 5, May 2024, pp. e345–57. Pubmed, doi:10.1016/S2352-3026(24)00045-0.
Gladwin MT, Gordeuk VR, Desai PC, Minniti C, Novelli EM, Morris CR, Ataga KI, De Castro L, Curtis SA, El Rassi F, Ford HJ, Harrington T, Klings ES, Lanzkron S, Liles D, Little J, Nero A, Smith W, Taylor JG, Baptiste A, Hagar W, Kanter J, Kinzie A, Martin T, Rafique A, Telen MJ, Lalama CM, Kato GJ, Abebe KZ. 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. 2024 May;11(5):e345–e357.
Journal cover image

Published In

Lancet Haematol

DOI

EISSN

2352-3026

Publication Date

May 2024

Volume

11

Issue

5

Start / End Page

e345 / e357

Location

England

Related Subject Headings

  • Treatment Outcome
  • Pyrimidines
  • Pyrazoles
  • Proteinuria
  • Middle Aged
  • Male
  • Hypertension
  • Humans
  • Female
  • Double-Blind Method