Back to resultsEfficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hemorrhagic Hereditary Telangiectasia (HHT) (TACRO)
Primary Purpose
Hemorrhagic Hereditary Telangiectasia (HHT)
Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Protopic® (Tacrolimus) 0.1% ointment
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Hemorrhagic Hereditary Telangiectasia (HHT) focused on measuring Hemorrhagic Hereditary Telangiectasia (HHT), Antiangiogenic therapy, Tacrolimus
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
Sites / Locations
- Hôpital Femme Mère Enfant
- CHU Estaing
- CHU de Montpellier
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Protopic® 0.1% (Tacrolimus) ointment
Placebo ointment
Arm Description
Protopic® 0.1% ointment, packed in blinded tube of 30g.
Same formulation as the Protopic® 0.1% ointment but without tacrolimus, packed in blinded tube of 30g.
Outcomes
Primary Outcome Measures
Percentage of Patients Experiencing an Improvement in Their Nosebleeds
Efficacy of tacrolimus nasal ointment on nosebleeds when administered for 6 weeks
Secondary Outcome Measures
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.
Number of Epistaxis
Evaluate efficacy on clinical criteria : epistaxis frequency before and after treatment.
Epistaxis Duration
To evaluate efficacy of tacrolimus nasal ointment on duration of nosebleeds before and after treatment.
Hemoglobin Level
before and after treatment.
Ferritin Level
before and after treatment.
Quality of Life Assessed by SF36 Questionnaire
To evaluate efficacy on quality of life with SF36 before and after treatment
Severity Epistaxis Score Assessed by ESS Questionnaire
To evaluate efficacy on severity epistaxis score with ESS before and after treatment.
The Percentage of Patient With Tacrolimus Detection in the Blood
To evaluate systemic absorption after tacrolimus nasal administrations.
the Level of Exposure of Patient With Tacrolimus Detection in the Blood.
To evaluate systemic absorption after tacrolimus nasal administrations.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03152019
Brief Title
Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hemorrhagic Hereditary Telangiectasia (HHT)
Acronym
TACRO
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
May 22, 2017 (Actual)
Primary Completion Date
November 8, 2018 (Actual)
Study Completion Date
November 8, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospices Civils de Lyon
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemorrhagic Hereditary Telangiectasia (HHT)
Keywords
Hemorrhagic Hereditary Telangiectasia (HHT), Antiangiogenic therapy, Tacrolimus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
50 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Protopic® 0.1% (Tacrolimus) ointment
Arm Type
Active Comparator
Arm Description
Protopic® 0.1% ointment, packed in blinded tube of 30g.
Arm Title
Placebo ointment
Arm Type
Placebo Comparator
Arm Description
Same formulation as the Protopic® 0.1% ointment but without tacrolimus, packed in blinded tube of 30g.
Intervention Type
Drug
Intervention Name(s)
Protopic® (Tacrolimus) 0.1% ointment
Intervention Description
About 0,1g of ointment is administered by the patient on nasal mucosa of each nostril twice a day for 6 weeks.
Intervention Type
Drug
Intervention Name(s)
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.
Primary Outcome Measure Information:
Title
Percentage of Patients Experiencing an Improvement in Their Nosebleeds
Description
Efficacy of tacrolimus nasal ointment on nosebleeds when administered for 6 weeks
Time Frame
up to 12 weeks
Secondary Outcome Measure Information:
Title
Adverse Events
Description
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.
Time Frame
up to 12 weeks
Title
Number of Epistaxis
Description
Evaluate efficacy on clinical criteria : epistaxis frequency before and after treatment.
Time Frame
up to 12 weeks
Title
Epistaxis Duration
Description
To evaluate efficacy of tacrolimus nasal ointment on duration of nosebleeds before and after treatment.
Time Frame
up to 12 weeks
Title
Hemoglobin Level
Description
before and after treatment.
Time Frame
up to 12 weeks
Title
Ferritin Level
Description
before and after treatment.
Time Frame
up to 12 weeks
Title
Quality of Life Assessed by SF36 Questionnaire
Description
To evaluate efficacy on quality of life with SF36 before and after treatment
Time Frame
up to 12 weeks
Title
Severity Epistaxis Score Assessed by ESS Questionnaire
Description
To evaluate efficacy on severity epistaxis score with ESS before and after treatment.
Time Frame
up to 12 weeks
Title
The Percentage of Patient With Tacrolimus Detection in the Blood
Description
To evaluate systemic absorption after tacrolimus nasal administrations.
Time Frame
up to 6 weeks
Title
the Level of Exposure of Patient With Tacrolimus Detection in the Blood.
Description
To evaluate systemic absorption after tacrolimus nasal administrations.
Time Frame
up to 6 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sophie DUPUIS-GIROD
Organizational Affiliation
Hospices Civils de Lyon Centre de Référence pour la maladie de Rendu-Osler Service de génétique Clinique Bâtiment A1 - HFME
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sophie DUPUIS-GIROD
Organizational Affiliation
Hospices Civils de Lyon
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Femme Mère Enfant
City
Bron
Country
France
Facility Name
CHU Estaing
City
Clermont-Ferrand
Country
France
Facility Name
CHU de Montpellier
City
Montpellier
Country
France
12. IPD Sharing Statement
Links:
URL
http://www.rendu-osler.fr
Description
Related Info
Learn more about this trial
Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hemorrhagic Hereditary Telangiectasia (HHT)
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