Epistaxis
Conditions
Keywords
Epistaxis, Hereditary Hemorrhagic Telangiectasia, HHT, Doxycycline, Nosebleed
Brief summary
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
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.
Interventions
DRUGDoxycycline
Doxycycline, 100 mg twice a day for 2 months
OTHERPlacebo
Matching placebo, twice a day for 2 months
Sponsors
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Epistaxis | Baseline, post-washout - approximately 6 months | Change in number of bleeding episodes per week by participant self-report via nosebleed diary |
| Duration of Epistaxis | Baseline, post-washout - approximately 6 months | Change in duration of bleeding per week by patient self-report via nosebleed diary |
| Change in Severity of Epistaxis | Baseline, post-washout - approximately 6-months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Monthly Units of Packed Red Blood Cells (PRBCs) Transfused | Baseline, post-washout (approximately 6 months) | — |
| Change in Quality of Life | Baseline, post-washout - approximately 6 months | 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. |
| Incidence of Treatment Failure | Baseline, post-washout (approximately 6 months) | Treatment failure, defined as need for nasal surgery or other epistaxis treatments |
| Change in Ferritin Level | Baseline, post-washout - approximately 6 months | — |
| Change in Hemoglobin Level | Baseline, post-washout (approximately 6 months) | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Doxycycline, Then Placebo 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.
Doxycycline: Doxycycline, 100 mg twice a day for 2 months
Placebo: Matching placebo, twice a day for 2 months | 13 |
| Placebo, Then Doxycycline 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.
Doxycycline: Doxycycline, 100 mg twice a day for 2 months
Placebo: Matching placebo, twice a day for 2 months | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Baseline | Withdrawal by Subject | 2 | 1 |
| Washout (1 Month) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Doxycycline, Then Placebo | Placebo, Then Doxycycline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 6 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 7 Participants | 15 Participants |
| Age, Continuous | 51.3 years STANDARD_DEVIATION 12.9 | 63.6 years STANDARD_DEVIATION 13.8 | 57.4 years STANDARD_DEVIATION 14.5 |
| Epistaxis Severity Scale (ESS) score | 6.3 Score on a scale STANDARD_DEVIATION 1.2 | 5.7 Score on a scale STANDARD_DEVIATION 1.5 | 6.0 Score on a scale STANDARD_DEVIATION 1.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 9 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Ferritin Level | 71.1 ng/ml STANDARD_DEVIATION 83.7 | 98.1 ng/ml STANDARD_DEVIATION 186.3 | 85.1 ng/ml STANDARD_DEVIATION 144.1 |
| Hemoglobin level | 12.8 g/dl STANDARD_DEVIATION 2.5 | 12.3 g/dl STANDARD_DEVIATION 2.4 | 12.5 g/dl STANDARD_DEVIATION 2.4 |
| Number of monthly blood transfusions 0 transfusions | 12 participants | 12 participants | 24 participants |
| Number of monthly blood transfusions 1 transfusion | 0 participants | 1 participants | 1 participants |
| Number of monthly blood transfusions Not reported | 1 participants | 0 participants | 1 participants |
| Number of monthly iron infusions 1 infusion | 2 participants | 1 participants | 3 participants |
| Number of monthly iron infusions 2 infusions | 1 participants | 1 participants | 2 participants |
| Number of monthly iron infusions No infusions | 9 participants | 11 participants | 20 participants |
| Number of monthly iron infusions Not reported | 1 participants | 0 participants | 1 participants |
| Quality of Life SF-12 Mental | 47.0 Score on a scale STANDARD_DEVIATION 12.5 | 54.4 Score on a scale STANDARD_DEVIATION 6.4 | 50.7 Score on a scale STANDARD_DEVIATION 10.4 |
| Quality of Life SF-12 Physical | 43.6 Score on a scale STANDARD_DEVIATION 10.7 | 40.2 Score on a scale STANDARD_DEVIATION 9.7 | 41.9 Score on a scale STANDARD_DEVIATION 10.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 6 Participants | 9 Participants | 15 Participants |
| Region of Enrollment United States | 13 participants | 13 participants | 26 participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 22 |
| other Total, other adverse events | 6 / 23 | 6 / 22 |
| serious Total, serious adverse events | 0 / 23 | 0 / 22 |
Outcome results
Primary
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.
Time frame: Baseline, post-washout - approximately 6-months
Population: All participants who received each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Doxycycline | Change in Severity of Epistaxis | -.095 score on a scale | Standard Deviation 1.55 |
| Placebo | Change in Severity of Epistaxis | -0.32 score on a scale | Standard Deviation 1.3 |
p-value: 0.19Wilcoxon (Mann-Whitney)
Primary
Duration of Epistaxis
Change in duration of bleeding per week by patient self-report via nosebleed diary
Time frame: Baseline, post-washout - approximately 6 months
Population: All participants who received each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Doxycycline | Duration of Epistaxis | -41.17 Minutes per week | Standard Deviation 159.26 |
| Placebo | Duration of Epistaxis | 24.36 Minutes per week | Standard Deviation 58.03 |
p-value: 0.05Wilcoxon (Mann-Whitney)
Primary
Frequency of Epistaxis
Change in number of bleeding episodes per week by participant self-report via nosebleed diary
Time frame: Baseline, post-washout - approximately 6 months
Population: All participants who received each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Doxycycline | Frequency of Epistaxis | -1.68 Nosebleeds per week | Standard Deviation 6.55 |
| Placebo | Frequency of Epistaxis | 1.14 Nosebleeds per week | Standard Deviation 4.44 |
p-value: 0.16Wilcoxon (Mann-Whitney)
Secondary
Change in Ferritin Level
Time frame: Baseline, post-washout - approximately 6 months
Population: All participants who received each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Doxycycline | Change in Ferritin Level | 14.9 ng/ml | Standard Deviation 72.82 |
| Placebo | Change in Ferritin Level | -47.4 ng/ml | Standard Deviation 214.83 |
p-value: 0.5Wilcoxon (Mann-Whitney)
Secondary
Change in Hemoglobin Level
Time frame: Baseline, post-washout (approximately 6 months)
Population: All participants who received each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Doxycycline | Change in Hemoglobin Level | 0.26 g/dl | Standard Deviation 1.09 |
| Placebo | Change in Hemoglobin Level | -0.12 g/dl | Standard Deviation 1.19 |
p-value: 0.3Wilcoxon (Mann-Whitney)
Secondary
Change in Monthly Units of Packed Red Blood Cells (PRBCs) Transfused
Time frame: Baseline, post-washout (approximately 6 months)
Population: All participants who received each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Doxycycline | Change in Monthly Units of Packed Red Blood Cells (PRBCs) Transfused | 0 count of PBRC units | Standard Deviation 0.31 |
| Placebo | Change in Monthly Units of Packed Red Blood Cells (PRBCs) Transfused | 0 count of PBRC units | Standard Deviation 0 |
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Baseline, post-washout - approximately 6 months
Population: All participants who received each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Doxycycline | Change in Quality of Life | SF-12 Physical | 2.21 score on a scale | Standard Deviation 6.94 |
| Doxycycline | Change in Quality of Life | SF-12 Mental | -0.63 score on a scale | Standard Deviation 9.97 |
| Placebo | Change in Quality of Life | SF-12 Physical | -0.83 score on a scale | Standard Deviation 6.72 |
| Placebo | Change in Quality of Life | SF-12 Mental | -0.63 score on a scale | Standard Deviation 9.74 |
Comparison: SF-12 Physicalp-value: 0.24Wilcoxon (Mann-Whitney)
Comparison: SF-12 Mentalp-value: 0.35Wilcoxon (Mann-Whitney)
Secondary
Incidence of Treatment Failure
Treatment failure, defined as need for nasal surgery or other epistaxis treatments
Time frame: Baseline, post-washout (approximately 6 months)
Population: All participants who received each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Doxycycline | Incidence of Treatment Failure | 0 Participants |
| Placebo | Incidence of Treatment Failure | 1 Participants |