Hemorrhagic Hereditary Telangiectasia (HHT)
Conditions
Keywords
Hemorrhagic Hereditary Telangiectasia (HHT), Antiangiogenic therapy, Tacrolimus
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.
Interventions
DRUGProtopic® (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.
DRUGPlacebo
About 0,1g of ointment is administered by the patient on nasal mucosa of each nostril twice a day for 6 weeks.
Sponsors
Hospices Civils de Lyon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Experiencing an Improvement in Their Nosebleeds | up to 12 weeks | Efficacy of tacrolimus nasal ointment on nosebleeds when administered for 6 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Epistaxis | up to 12 weeks | Evaluate efficacy on clinical criteria : epistaxis frequency before and after treatment. |
| Epistaxis Duration | up to 12 weeks | To evaluate efficacy of tacrolimus nasal ointment on duration of nosebleeds before and after treatment. |
| Hemoglobin Level | up to 12 weeks | before and after treatment. |
| Ferritin Level | up to 12 weeks | before and after treatment. |
| Adverse Events | 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. |
| Severity Epistaxis Score Assessed by ESS Questionnaire | up to 12 weeks | To evaluate efficacy on severity epistaxis score with ESS before and after treatment. |
| The Percentage of Patient With Tacrolimus Detection in the Blood | up to 6 weeks | To evaluate systemic absorption after tacrolimus nasal administrations. |
| the Level of Exposure of Patient With Tacrolimus Detection in the Blood. | up to 6 weeks | To evaluate systemic absorption after tacrolimus nasal administrations. |
| Quality of Life Assessed by SF36 Questionnaire | up to 12 weeks | To evaluate efficacy on quality of life with SF36 before and after treatment |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Protopic® 0.1% (Tacrolimus) Ointment Protopic® 0.1% ointment, packed in blinded tube of 30g.
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. | 26 |
| Placebo Ointment Same formulation as the Protopic® 0.1% ointment but without tacrolimus, packed in blinded tube of 30g.
Placebo: About 0,1g of ointment is administered by the patient on nasal mucosa of each nostril twice a day for 6 weeks. | 24 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Ointment | Total | Protopic® 0.1% (Tacrolimus) Ointment |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 49 Participants | 26 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment France | 24 participants | 50 participants | 26 participants |
| Sex: Female, Male Female | 14 Participants | 23 Participants | 9 Participants |
| Sex: Female, Male Male | 10 Participants | 27 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 24 |
| other Total, other adverse events | 11 / 26 | 8 / 24 |
| serious Total, serious adverse events | 1 / 26 | 2 / 24 |
Outcome results
Primary
Percentage of Patients Experiencing an Improvement in Their Nosebleeds
Efficacy of tacrolimus nasal ointment on nosebleeds when administered for 6 weeks
Time frame: up to 12 weeks
Population: n=26 included in per protocol analysis because of a wrong allocation: 1 patient in placebo group who received tacrolimus
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protopic® 0.1% (Tacrolimus) Ointment | Percentage of Patients Experiencing an Improvement in Their Nosebleeds | 10 Participants |
| Placebo Ointment | Percentage of Patients Experiencing an Improvement in Their Nosebleeds | 9 Participants |
p-value: <0.05Chi-squared
Secondary
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.
Time frame: up to 12 weeks
Secondary
Epistaxis Duration
To evaluate efficacy of tacrolimus nasal ointment on duration of nosebleeds before and after treatment.
Time frame: up to 12 weeks
Secondary
Ferritin Level
before and after treatment.
Time frame: up to 12 weeks
Secondary
Hemoglobin Level
before and after treatment.
Time frame: up to 12 weeks
Secondary
Number of Epistaxis
Evaluate efficacy on clinical criteria : epistaxis frequency before and after treatment.
Time frame: up to 12 weeks
Secondary
Quality of Life Assessed by SF36 Questionnaire
To evaluate efficacy on quality of life with SF36 before and after treatment
Time frame: up to 12 weeks
Secondary
Severity Epistaxis Score Assessed by ESS Questionnaire
To evaluate efficacy on severity epistaxis score with ESS before and after treatment.
Time frame: up to 12 weeks
Secondary
the Level of Exposure of Patient With Tacrolimus Detection in the Blood.
To evaluate systemic absorption after tacrolimus nasal administrations.
Time frame: up to 6 weeks
Secondary
The Percentage of Patient With Tacrolimus Detection in the Blood
To evaluate systemic absorption after tacrolimus nasal administrations.
Time frame: up to 6 weeks