Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hemorrhagic Hereditary Telangiectasia (HHT)
Condition: Hemorrhagic Hereditary Telangiectasia (HHT)
MeSH terms: Epistaxis; Telangiectasis
Intervention: Protopic® (Tacrolimus) 0.1% ointment; Placebo
Intervention description: About 0,1g of ointment is administered by the patient on nasal mucosa of each nostril twice a day for 6 weeks.; About 0,1g of ointment is administered by the patient on nasal mucosa of each nostril twice a day for 6 weeks.
Intervention MeSH terms: Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hemorrhagic Hereditary Telangiectasia (HHT); Antiangiogenic therapy; Tacrolimus

Summary:

      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.
    

Eligibility criteria:

        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