**5. Conclusions**

In HHT patients with epistaxis, tacrolimus nasal ointment, administered twice daily compared with a placebo, did not reduce monthly epistaxis duration in the six consecutive weeks after treatment compared to the six weeks immediately before the start of treatment. However, 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.

**Author Contributions:** Conceptualization, S.D.-G., E.D., and A.-E.F.; methodology, E.D. and L.B.; software, E.D. and L.B.; validation, S.D.-G., A.-E.F., and R.H.; formal analysis, S.D.-G., E.D., and L.B.; investigation, S.D.G., A.-E.F., M.B., V.G., and S.R.; resources, E.D.; data curation, S.D.-G., E.D., M.B., and A.-E.F.; writing—original draft preparation, S.D.-G.; writing—review and editing, S.D.-G., A.E.F., M.B., V.G., S.R., E.D., L.B., V.B., B.C., R.H., F.F., P.P., and S.B.; visualization, S.D.-G., A.-E.F., M.B., V.G., S.R., E.D., L.B., V.B., B.C., R.H., F.F., P.P., and S.B.; supervision, S.D.-G.; project administration, S.D.-G., A.-E.F., and M.B.; funding acquisition, S.D.-G. and R.H.; All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was financed by the institution (Hospices Civils de Lyon) gran<sup>t</sup> supported by the National Research Programme (PHRC 2016) and by the patients' association (AMRO-France). Neither the funding organization (National Research Program) nor the patients' association (AMRO) played any role in designing or conducting the study; collecting, managing, analyzing, or interpreting the data; or preparing, reviewing, or approving the manuscript.

**Acknowledgments:** We would like to thank all the patients who participated in this study, the Association of patients, and all the members of the French HHT Network, particularly Nicolas Saroul (CHU Clermont-Ferrand) and Cesar Cartier (CHU Montpellier). We would also like to thank the members of the independent data and safety monitoring committee (IDMC), Yves Donazzolo (EUROFINS/OPTIMED Clinical Research, Gières, France), Elisabetta Buscarini (HHT center, Crema, Italy), and Xavier Lassartesse (ENT surgeon, Avignon, France). They did not receive any compensation for this contribution.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Trial Registration:** ClinicalTrials.gov Identifier #NCT 03152019 (TACRO study).
