Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study

Eric Hachulla, Pierre-Yves Hatron, Patrick Carpentier, Christian Agard, Emmanuel Chatelus, Patrick Jego, Luc Mouthon, Viviane Queyrel, Anne-Laure Fauchais, Ulrique Michon-Pasturel, Roland Jaussaud, Alexis Mathian, Brigitte Granel, Elisabeth Diot, Dominique Farge-Bancel, Arsène Mekinian, Jérôme Avouac, Hélène Desmurs-Clavel, Pierre Clerson, SEDUCE study group, Thomas Quemeneur, Marie-Hélène Balquet, Géraldine Wojtasik, Marc Lambert, David Launay, Hélène Maillard, Sandrine Morell-Dubois, Noémie Le Gouellec, Isabelle Marie, Nathalie Tieulie, Christophe Deligny, Boris Bienvenu, Alice Berezne, Isabelle Lazareth, Sondess Hadj Khelifa, Kiet Tiev, Jean Cabane, Baptiste Hervier, Zahir Amoura, Yannick Allanore, Jean-Philippe Arnault, Sabine Berthier, Claire Cazalets, Kim Ly, Agnès Sparsa, Jean Sibilia, Jacques Ninet, Eric Hachulla, Pierre-Yves Hatron, Patrick Carpentier, Christian Agard, Emmanuel Chatelus, Patrick Jego, Luc Mouthon, Viviane Queyrel, Anne-Laure Fauchais, Ulrique Michon-Pasturel, Roland Jaussaud, Alexis Mathian, Brigitte Granel, Elisabeth Diot, Dominique Farge-Bancel, Arsène Mekinian, Jérôme Avouac, Hélène Desmurs-Clavel, Pierre Clerson, SEDUCE study group, Thomas Quemeneur, Marie-Hélène Balquet, Géraldine Wojtasik, Marc Lambert, David Launay, Hélène Maillard, Sandrine Morell-Dubois, Noémie Le Gouellec, Isabelle Marie, Nathalie Tieulie, Christophe Deligny, Boris Bienvenu, Alice Berezne, Isabelle Lazareth, Sondess Hadj Khelifa, Kiet Tiev, Jean Cabane, Baptiste Hervier, Zahir Amoura, Yannick Allanore, Jean-Philippe Arnault, Sabine Berthier, Claire Cazalets, Kim Ly, Agnès Sparsa, Jean Sibilia, Jacques Ninet

Abstract

Objective: To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).

Methods: Randomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).

Results: Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12).

Conclusions: The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.

Trial registration number: NCT01295736.

Keywords: Autoimmune Diseases; Patient perspective; Treatment.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Trial profile. (A) Intention-to-treat population. (B) Per protocol subset. *One premature drop out patient in the placebo group had no evaluation of discontinuation beyond inclusion.
Figure 2
Figure 2
Healing rate of digital (DUs) present at entry in the study (intention-to-treat analysis). Hatched columns, placebo group; Solid black columns, sildenafil group.
Figure 3
Figure 3
Example of digital ulcer evolution during the clinical trial in a patient who was assigned to the sildenafil group. (A) at randomisation; (B) at week 4; (C) at week 8; and (D) at week 12.

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