NOrth American Study for the Treatment of Recurrent epIstaxis With DoxycycLine: The NOSTRIL Trial

Study Overview
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Brief Summary
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The purpose of this research study is to determine whether Doxycycline can be used to control nosebleeds (epistaxis) for patients with Hereditary Hemorrhagic Telangiectasia (HHT). Patients with HHT will be randomized to one of 2 study arms: Doxycycline or Placebo for a period of 2 months followed by a 1-month washout period before switching treatments for a further 2 months period. Observation and evaluation will continue for a period of one month after treatment is completed.

Detailed Description
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This study will analyze the effect of doxycycline on nosebleeds in hereditary hemorrhagic telangiectasia (HHT), a rare and debilitating medical condition. Patients with HHT have a variety of vascular abnormalities, including changes in their nasal vasculature that result in chronic, severe nosebleeds. These nosebleeds have been shown to significantly reduce the quality of life in HHT and can be severe enough to require emergent blood transfusion. Current therapies to control nosebleeds in HHT, which include both medications and surgical treatments, are inconsistently effective and associated with a variety of problematic side effects and complications. Doxycycline is a common, FDA-approved antibiotic medication that has been used by physicians for decades. It is a safe medication that can be used on an outpatient basis for extended periods of time with minimal side effects. Recent research has shown that doxycycline is a potent inhibitor of angiogenesis, the process of new blood vessel development. Since the vascular abnormalities in HHT form due to uncontrolled angiogenesis, it follows that doxycycline may have potential in treating HHT. A growing body of research demonstrates the efficacy of doxycycline in treating a variety of vascular conditions, including cancer of the breast, duodenum, liver prostate, and lung. Our trial will be the first to analyze the efficacy of doxycycline in treating HHT epistaxis. This a randomized, double-blind, crossover study design. Each patient will take both placebo and doxycycline. Since this is a cross-over study, half the participants will start out with taking placebo and half start with doxycyline and then switch halfway through. After a baseline observation period, participants will be given doxycycline at 100 mg twice a day, or an identical-appearing placebo, for a period of three months. Each month they will be seen be a physician, who will take a detailed clinical history and perform a physical examination. Further, each month the patient will have blood testing to assess blood loss, and fill out scientifically validated surveys to assess quality of life and the severity of bleeding. Following this three month treatment period, participants will be observed for one additional month, with one additional blood test and clinical assessment performed after this month.

Official Title
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NOrth American Study for the Treatment of Recurrent epIstaxis With DoxycycLine: The NOSTRIL Trial

Conditions
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Epistaxis

Intervention / Treatment
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* Drug: Doxycycline
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of definite HHT by the Curacao criteria or genetic diagnosis of HHT Epistaxis severity during observation month at least moderate by Epistaxis Severity Score (ESS) evaluation For female participants, a negative pregnancy test at Day -1 and agree to use birth control during treatment and for 28 days following cessation of Doxycycline Exclusion Criteria: Use of medication(s) contraindicated with doxycycline use within 14 days prior to the study (including barbiturates, tegretol, dilantin, warfarin, isotretinoin)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxycycline, then Placebo<br>Doxycycline for a period of 2 months followed by a 1-month washout period, and then placebo for a further 2 months period followed by a 1-month washout period. | Drug: Doxycycline<br>* Doxycycline, 100 mg twice a day for 2 months<br>Other: Placebo<br>* Matching placebo, twice a day for 2 months<br>|
| Experimental: Placebo, then Doxycycline<br>Placebo for a period of 2 months followed by a 1-month washout period, and then Doxycycline for a further 2 months period followed by a 1-month washout period. | Drug: Doxycycline<br>* Doxycycline, 100 mg twice a day for 2 months<br>Other: Placebo<br>* Matching placebo, twice a day for 2 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Epistaxis | Change in number of bleeding episodes per week by participant self-report via nosebleed diary | Baseline, post-washout - approximately 6 months | 
| Duration of Epistaxis | Change in duration of bleeding per week by patient self-report via nosebleed diary | Baseline, post-washout - approximately 6 months | 
| Change in Severity of Epistaxis | Epistaxis Severity Scale (ESS) for Hereditary Hemorrhagic Telangiectasia, is based on 6 nosebleed variables such as frequency and duration which are reported by patients.The ESS has a minimum value of 0 and maximum value of 10, with 10 representing more severe epistaxis. | Baseline, post-washout - approximately 6-months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quality of Life | The 12-item Short Form (SF-12) is a survey designed for use with patients with multiple chronic conditions. This 12-item scale can be used to assess the physical and mental health of respondents. 10 of the 12 questions are answered on a 5-point Likert scale and 2 are answered on a 3-point Likert scale. The questions are then scored and weighted into 2 subscales, physical health and mental health. Respondents can have a score that ranges from 0-100 with 100 being the best score and indicating high physical or mental health. | Baseline, post-washout - approximately 6 months | 
| Change in Ferritin Level |  | Baseline, post-washout - approximately 6 months | 
| Change in Hemoglobin Level |  | Baseline, post-washout (approximately 6 months) | 
| Change in Monthly Units of Packed Red Blood Cells (PRBCs) Transfused |  | Baseline, post-washout (approximately 6 months) | 
| Incidence of Treatment Failure | Treatment failure, defined as need for nasal surgery or other epistaxis treatments | Baseline, post-washout (approximately 6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epistaxis, Hereditary Hemorrhagic Telangiectasia, HHT, Doxycycline, Nosebleed