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

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ClinicalTrials.gov Identifier: NCT03152019
Recruitment Status : Completed
First Posted : May 12, 2017
Last Update Posted : July 23, 2019
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

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.


Condition or disease Intervention/treatment Phase
Hemorrhagic Hereditary Telangiectasia (HHT) Drug: Protopic® (Tacrolimus) 0.1% ointment Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : May 22, 2017
Actual Primary Completion Date : November 8, 2018
Actual Study Completion Date : November 8, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus

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.




Primary Outcome Measures :
  1. Percentage of patients experiencing an improvement in their nosebleeds [ Time Frame: up to 12 weeks ]
    Efficacy of tacrolimus nasal ointment on nosebleeds when administered for 6 weeks


Secondary Outcome Measures :
  1. adverse events [ Time Frame: up to 12 weeks ]
    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.

  2. number of epistaxis [ Time Frame: up to 12 weeks ]
    Evaluate efficacy on clinical criteria : epistaxis frequency before and after treatment.

  3. epistaxis duration [ Time Frame: up to 12 weeks ]
    To evaluate efficacy of tacrolimus nasal ointment on duration of nosebleeds before and after treatment.

  4. Hemoglobin level [ Time Frame: up to 12 weeks ]
    before and after treatment.

  5. ferritin level [ Time Frame: up to 12 weeks ]
    before and after treatment.

  6. quality of life assessed by SF36 questionnaire [ Time Frame: up to 12 weeks ]
    To evaluate efficacy on quality of life with SF36 before and after treatment

  7. severity epistaxis score assessed by ESS questionnaire [ Time Frame: up to 12 weeks ]
    To evaluate efficacy on severity epistaxis score with ESS before and after treatment.

  8. The percentage of patient with tacrolimus detection in the blood [ Time Frame: up to 6 weeks ]
    To evaluate systemic absorption after tacrolimus nasal administrations.

  9. the level of exposure of patient with tacrolimus detection in the blood. [ Time Frame: up to 6 weeks ]
    To evaluate systemic absorption after tacrolimus nasal administrations.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03152019


Locations
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France
Hôpital Femme Mère Enfant
Bron, France
CHU Estaing
Clermont-Ferrand, France
CHU de Montpellier
Montpellier, France
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
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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
Principal Investigator: Sophie DUPUIS-GIROD Hospices Civils de Lyon

Additional Information:
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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT03152019    
Other Study ID Numbers: 69HCL16_0705
2017-000085-30 ( EudraCT Number )
First Posted: May 12, 2017    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospices Civils de Lyon:
Hemorrhagic Hereditary Telangiectasia (HHT)
Antiangiogenic therapy
Tacrolimus
Additional relevant MeSH terms:
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Epistaxis
Telangiectasis
Vascular Diseases
Cardiovascular Diseases
Nose Diseases
Respiratory Tract Diseases
Otorhinolaryngologic Diseases
Hemorrhage
Pathologic Processes
Signs and Symptoms, Respiratory
Signs and Symptoms
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action