Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial

Hospices Civils de Lyon, Hopital Femme-Mere-Enfants, Service de Genetique et Centre de Reference de la Maladie de Rendu-Osler, F-69677 Bron, France. Inserm, CEA, Laboratory Biology of Cancer and Infection, University, Grenoble Alpes, F-38000 Grenoble, France. Service de Medecine Interne, CHU Estaing, 63100 Clermont-Ferrand, France. Service de Medecine Interne CHU de Montpellier, Hopital St Eloi, and Centre d'Investigation Clinique, Inserm, CIC 1411, F-34295 Montpellier CEDEX 7, France. Hospices Civils de Lyon, Pole Sante Publique, F-69003 Lyon, France. Universite Lyon 1, 69008 Lyon, France. Hospices Civils de Lyon, Pharmacie, Hopital Louis Pradel, F-69677 Bron, France. Hospices Civils de Lyon, Hopital de la Croix Rousse, Service ORL, F-69317 Lyon, France. Hospices Civils de Lyon, Hopital E. Herriot, Service ORL, F-69437 Lyon, France.

J Clin Med. 2020;9(5)
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Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment (p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment (p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time.
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