Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hemorrhagic Hereditary Telangiectasia (HHT)

NCT03152019 | Completed Phase 2 Results DMC

• 2 other identifiers: 69HCL16_07052017-000085-30
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Hemorrhagic Hereditary Telangiectasia (HHT)

Keywords

Hemorrhagic Hereditary Telangiectasia (HHT); Antiangiogenic therapy; Tacrolimus

Outcome Measures

Primary Outcomes (1)

• Percentage of Patients Experiencing an Improvement in Their Nosebleeds

  Efficacy of tacrolimus nasal ointment on nosebleeds when administered for 6 weeks

  up to 12 weeks

Secondary Outcomes (9)

• Adverse Events

  up to 12 weeks

• Number of Epistaxis

  up to 12 weeks

• Epistaxis Duration

  up to 12 weeks

• Hemoglobin Level

  up to 12 weeks

• Ferritin Level

  up to 12 weeks

Study Arms (2)

Protopic® 0.1% (Tacrolimus) ointment

ACTIVE COMPARATOR

Protopic® 0.1% ointment, packed in blinded tube of 30g.

Drug: Protopic® (Tacrolimus) 0.1% ointment

Placebo ointment

PLACEBO COMPARATOR

Same formulation as the Protopic® 0.1% ointment but without tacrolimus, packed in blinded tube of 30g.

Drug: Placebo

Interventions

Protopic® (Tacrolimus) 0.1% ointment DRUG

About 0,1g of ointment is administered by the patient on nasal mucosa of each nostril twice a day for 6 weeks.

Protopic® 0.1% (Tacrolimus) ointment

Placebo DRUG

About 0,1g of ointment is administered by the patient on nasal mucosa of each nostril twice a day for 6 weeks.

Placebo ointment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).
• 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 with ongoing immunosuppressive treatment.
• Patients with known and symptomatic immune deficiency

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (3)

Hôpital Femme Mère Enfant

Bron, France

Location

CHU Estaing

Clermont-Ferrand, France

Location

CHU de Montpellier

Montpellier, France

Location

Related Links

• Related Info

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic

Interventions

Tacrolimus; Ointments

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Telangiectasis; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: Dr Dupuis Girod
• Organization: Hospices Civils de Lyon

sophie.dupuis-girod@chu-lyon.fr

427856522

Study Officials

• Sophie DUPUIS-GIROD

  Hospices Civils de Lyon Centre de Référence pour la maladie de Rendu-Osler Service de génétique Clinique Bâtiment A1 - HFME

  PRINCIPAL INVESTIGATOR

• Sophie DUPUIS-GIROD

  Hospices Civils de Lyon

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 11, 2017
• First Posted: May 12, 2017
• Study Start: May 22, 2017
• Primary Completion: November 8, 2018
• Study Completion: November 8, 2018
• Last Updated: July 1, 2020
• Results First Posted: July 1, 2020

Record last verified: 2019-07

Locations

FR (3)