The recognized manifestations of HHT are all due to abnormalities in vascular structure. Epistaxis due to telangiectases formation is spontaneous, very variable, recurrent in 90% of patients, and associated with severe anemia in 2-10%. They also significantly reduce quality of life.

Improvement in epistaxis has been shown in HHT patients after a liver transplantation. It was hypothesized that the immunosuppressive treatment (FK506) used to prevent rejection may have an anti-angiogenic effect.

The results of Albiñana et al suggest that the mechanism of action of FK506 involves a partial correction of endoglin and ALK1 haplosufficiency, genes responsible for 90% of HHT case.

Tacrolimus ointment is available on the market for the treatment of eczema and can therefore readily be used as it is for nasal administration. Topical nasal administration of tacrolimus may be an easy local ENT treatment that is non-aggressive and results in little trauma for the patient in relation to other first line treatment possibilities.

The main objective of this trial is to evaluate, at 6 weeks after the end of the treatment, the efficacy on the duration of nosebleeds, of 6 weeks tacrolimus nasal ointment application, in patients with HHT complicated by nosebleeds (30 min/6 weeks). Secondary objectives are to evaluate the tolerance throughout the study, the efficacy on anemia and on clinical parameters (nosebleeds, quality of life, epistaxis severity score questionnaire and blood transfusions) and the systemic absorption of nasal administration.

This is a multicenter prospective and double blinded phase I/II trial. A total of 48 patients will be randomized versus placebo using an allocation ratio of 1:1. The ointment (Protopic® at 0.1% or placebo) will be self-administered by the patient with one administration in each nostril twice a day for 6 consecutive weeks.

Inclusion Criteria:

• Age ≥ 18 years.
• Patients who have given their free, informed and signed consent.
• Patients affiliated to a social security scheme or similar.
• Patients monitored for clinically confirmed HHT (presence of at least 3 Curaçao criteria) and/or confirmed by molecular biology.
• Patient presenting nosebleeds with total duration > 30 minutes for 6 weeks prior to the time of inclusion justified by completed follow-up grids.

Exclusion Criteria:

• Women who are pregnant or nursing (lactating), women of child-bearing potential without reliable contraception.
• Patients not affiliated to a social security scheme.
• Patients who are protected adults under the terms of the law (French Public Health Code).
• Refusal to consent.
• Patients for whom the diagnosis of HHT has not been confirmed clinically and/or by molecular biology.
• Participation in another clinical trial which may interfere with the proposed trial (judgment of the investigator).
• Patients who have undergone nasal surgery in the 6 weeks prior to inclusion.
• Known hypersensitivity to macrolides in general, to tacrolimus or to any of the excipients.
• Patient with an inherited skin barrier disease such as Netherton's syndrome, lamellar ichtyosis, generalized erythroderma, graft-versus-host skin disease, or suffering from generalized erythroderma.
• Patient with CYP3A4 inhibitors treatment, e.g. erythromycin, itraconazole, ketoconazole and diltiazem.
• Patients who have incompletely filled in the nosebleed grids in the 10 weeks preceding the treatment. If there is missing data for more than 7 days, the patient cannot be included.
• Patients who do not present nosebleeds with a total duration of > 30 minutes for 6 weeks prior to the time of inclusion.
• Patients with ongoing immunosuppressive treatment.
• Patients with known and symptomatic immune deficiency