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

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

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.

Study Overview

• Status: Completed
• Conditions: Hemorrhagic Hereditary Telangiectasia (HHT)
• Intervention / Treatment: Drug: Protopic® (Tacrolimus) 0.1% ointment; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bron, France
    • Hôpital Femme Mère Enfant
  • Clermont-Ferrand, France
    • CHU Estaing
  • Montpellier, France
    • CHU de Montpellier

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Protopic® 0.1% (Tacrolimus) ointment; Protopic® 0.1% ointment, packed in blinded tube of 30g.	Drug: Protopic® (Tacrolimus) 0.1% ointment; About 0,1g of ointment is administered by the patient on nasal mucosa of each nostril twice a day for 6 weeks.
Placebo Comparator: Placebo ointment; Same formulation as the Protopic® 0.1% ointment but without tacrolimus, packed in blinded tube of 30g.	Drug: Placebo; About 0,1g of ointment is administered by the patient on nasal mucosa of each nostril twice a day for 6 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Tolerance will be evaluated by recording adverse reactions and adverse events during the treatment period and the follow up period and by clinical examinations during the follow-up period.	up to 12 weeks
Number of Epistaxis	Evaluate efficacy on clinical criteria : epistaxis frequency before and after treatment.	up to 12 weeks
Epistaxis Duration	To evaluate efficacy of tacrolimus nasal ointment on duration of nosebleeds before and after treatment.	up to 12 weeks
Hemoglobin Level	before and after treatment.	up to 12 weeks
Ferritin Level	before and after treatment.	up to 12 weeks
Quality of Life Assessed by SF36 Questionnaire	To evaluate efficacy on quality of life with SF36 before and after treatment	up to 12 weeks
Severity Epistaxis Score Assessed by ESS Questionnaire	To evaluate efficacy on severity epistaxis score with ESS before and after treatment.	up to 12 weeks
The Percentage of Patient With Tacrolimus Detection in the Blood	To evaluate systemic absorption after tacrolimus nasal administrations.	up to 6 weeks
the Level of Exposure of Patient With Tacrolimus Detection in the Blood.	To evaluate systemic absorption after tacrolimus nasal administrations.	up to 6 weeks

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Sophie DUPUIS-GIROD, Hospices Civils de Lyon; Principal Investigator: Sophie DUPUIS-GIROD, Hospices Civils de Lyon Centre de Référence pour la maladie de Rendu-Osler Service de génétique Clinique Bâtiment A1 - HFME

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2017
• Primary Completion (Actual): November 8, 2018
• Study Completion (Actual): November 8, 2018

Study Registration Dates

• First Submitted: May 11, 2017
• First Submitted That Met QC Criteria: May 11, 2017
• First Posted (Actual): May 12, 2017

Study Record Updates

• Last Update Posted (Actual): July 1, 2020
• Last Update Submitted That Met QC Criteria: June 12, 2020
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Tacrolimus; Antiangiogenic therapy; Hemorrhagic Hereditary Telangiectasia (HHT)
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Hemorrhage; Otorhinolaryngologic Diseases; Signs and Symptoms, Respiratory; Nose Diseases; Epistaxis; Telangiectasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: 69HCL16_0705; 2017-000085-30 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No