Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
This is a randomized, controlled, double-blind, placebo-controlled trial of intranasal Avastin (bevacizumab) injection versus saline control for control of HHT-related epistaxis when used in conjunction with bipolar electrocautery.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder characterized by systemic vascular malformations that result from mutations of the ENG gene, which encodes for factors in the vascular endothelial growth factor (VEGF) pathway. HHT is diagnosed by the Curacao Criteria including the presence of epistaxis; telangiectasias or vascular malformations in the lungs, liver, or nervous system; and a positive family history involving a first-degree relative. One of the most common presentations of this disease is recurrent and profound epistaxis, with many patients reporting more than 4 epistaxis episodes in a day, many lasting up to an hour. HHT-related epistaxis often results in severe anemia requiring intravenous iron and repeated blood transfusions, and also carries significant psychosocial disability relating to impaired quality of life and work absenteeism. Multiple approaches to treatment have been described, including electrocautery, laser treatment, embolization, septodermoplasty, and as a last resort, Young's procedure, involving closure of the nasal vestibule. These approaches are largely palliative, with variable effectiveness, and almost always require repeated procedures for chronic management of bleeding. There is a great need for the development of new treatment options for reducing the medical morbidity and quality of life impairment associated with refractory epistaxis in HHT.
Recently there has been promising data suggesting that inhibition of angiogenesis may be an effective strategy for managing HHT-related bleeding. Circulating concentrations of VEGF are significantly elevated in HHT, making VEGF an attractive therapeutic target. Preliminary studies suggest that bevacizumab, a recombinant monoclonal antibody that inhibits the biologic activity of VEGF, can significantly improve epistaxis severity when topically applied, locally injected, or intravenously administered. However, these early pilot studies of bevacizumab have been limited exclusively to retrospective case series. As yet, there has been no prospective double-blind placebo controlled trial with serial follow up time points to establish the role of bevacizumab in the treatment of HHT-related epistaxis.
Based on existing level 4 evidence that suggests that bevacizumab injection is beneficial in the management of HHT-related epistaxis, we hypothesize that patients who receive intranasal injection with bevacizumab at the time of electrocautery treatment will have an improvement in the frequency and severity of epistaxis compared to patients who receive injection of saline control.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bevacizumab | Experimental | The Stanford Hospital Investigational Pharmacy will perform all randomization, drug storage and management, as well as mixing and packaging for double-blinded injection of bevacizumab or saline control. Patients will undergo standard-of-care bipolar electrocautery of nasal telangiectasias in the Stanford Surgery Center operating room. At the time of electrocautery, patients will receive intranasal injection of either study drug or saline control. The surgeon performing the injection will be blinded to whether injection is composed of bevacizumab or saline control. Bevacizumab will be mixed by the Stanford Hospital Pharmacy to a total dose of 100mg in 4mL, and 50mg (2mL) will be injected into each side of the nose. Injections will be performed according to the standardized four-point injection protocol (0.5mL/site) based on the vascular anatomy of the nose published in 2012 by Dheyauldeen et al. |
|
| Saline Control | Placebo Comparator | The Stanford Hospital Investigational Pharmacy will perform all randomization, drug storage and management, as well as mixing and packaging for double-blinded injection of bevacizumab or saline control. Patients will undergo standard-of-care bipolar electrocautery of nasal telangiectasias in the Stanford Surgery Center operating room. At the time of electrocautery, patients will receive intranasal injection of either study drug or saline control. The surgeon performing the injection will be blinded to whether injection is composed of bevacizumab or saline control. The saline control placebo will be mixed by the Stanford Hospital Pharmacy to a total dose of 4mL in order to be identical in quantity and appearance to the mixed doses of bevacizumab, and 2mL will be injected into each side of the nose. Injections will be performed according to the standardized four-point injection protocol (0.5mL/site) based on the vascular anatomy of the nose published in 2012 by Dheyauldeen et al. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bevacizumab | Drug | Bevacizumab will be mixed by the Stanford Hospital Pharmacy to a total dose of 100mg in 4mL, and 50mg (2mL) will be injected into each side of the nose |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Epistaxis Severity Score (ESS) | ESS is a standardized and reproducible outcome measure for the control of epistaxis. It is composed of six factors that are independent predictors of self-described epistaxis severity. The range is 0 to 13. The higher the score worse is epistaxis severity. | Baseline and month 1, month 2, month 4, month 6 |
| Measure | Description | Time Frame |
|---|---|---|
| Short Form-12 (SF-12) Physical Component Summary (PCS) Score | PCS of the SF-12 is a self-reported measure of mental health-related quality of life. PCS is calculated using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | Baseline and month 1, month 2, month 4, month 6 |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Peter H Hwang, MD | Stanford University, Department of Otolaryngology- Head and Neck Surgery | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University Department of Otolaryngology- Head and Neck Surgery | Stanford | California | 94305 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 10751092 | Background | Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000 Mar 6;91(1):66-7. doi: 10.1002/(sici)1096-8628(20000306)91:13.0.co;2-p. | |
| 10485021 | Background |
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Bevacizumab | Bevacizumab mixed by the Stanford Hospital Pharmacy to a total dose of 100mg in 4mL, and 50mg (2mL), injected into each side of the nose |
| FG001 | Saline Control | Placebo (4mL of saline) mixed by the Stanford Hospital Pharmacy as a control. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
1 participant did not complete the baseline questionnaires.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Bevacizumab | Bevacizumab mixed by the Stanford Hospital Pharmacy to a total dose of 100mg in 4mL, and 50mg (2mL), injected into each side of the nose |
| BG001 | Saline Control | Placebo (4mL of saline) mixed by the Stanford Hospital Pharmacy as a control. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Epistaxis Severity Score (ESS) | ESS is a standardized and reproducible outcome measure for the control of epistaxis. It is composed of six factors that are independent predictors of self-described epistaxis severity. The range is 0 to 13. The higher the score worse is epistaxis severity. | Participants with available data were included in the analysis. | Posted | Mean | 95% Confidence Interval | score on a scale | Baseline and month 1, month 2, month 4, month 6 |
|
6 months.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Bevacizumab | Bevacizumab mixed by the Stanford Hospital Pharmacy to a total dose of 100mg in 4mL, and 50mg (2mL), injected into each side of the nose. |
Not provided
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Peter H. Hwang, MD | Stanford University | (650) 723-5281 | hwangph@stanford.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 19, 2014 | Jan 22, 2021 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D013683 | Telangiectasia, Hereditary Hemorrhagic |
| D004844 | Epistaxis |
| ID | Term |
|---|---|
| D020141 | Hemostatic Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D013684 | Telangiectasis |
Not provided
Not provided
| ID | Term |
|---|---|
| D000068258 | Bevacizumab |
| D012965 | Sodium Chloride |
| D005457 | Fluoridation |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Placebo (Saline) | Drug | 4mL of saline will be mixed by the Stanford Hospital Pharmacy as a control |
|
|
| Short Form-12 (SF-12) Mental Component Summary (MCS) Score | MCS of the SF-12 is a self-reported measure of mental health-related quality of life. MCS is calculated using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | Baseline and month 1, month 2, month 4, month 6 |
| Reduction in Epistaxis-related Costs (Direct and Indirect) | Evaluate the effect of bevacizumab injection on direct and indirect costs in USD associated with care and management of epistaxis as well as productivity lost after treatment. The cost of caring in USD for nasal bleeding was evaluated with two surveys, the Work Productivity and Activity Impairment Questionnaire, and the HHT Costing Data Sheet. | Baseline, Month 2, Month 6 |
| Lund VJ, Howard DJ. A treatment algorithm for the management of epistaxis in hereditary hemorrhagic telangiectasia. Am J Rhinol. 1999 Jul-Aug;13(4):319-22. doi: 10.2500/105065899782102890. |
| 15951295 | Background | Sadick H, Riedel F, Naim R, Goessler U, Hormann K, Hafner M, Lux A. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high ALK1 tissue expression. Haematologica. 2005 Jun;90(6):818-28. |
| 19194865 | Background | Simonds J, Miller F, Mandel J, Davidson TM. The effect of bevacizumab (Avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 2009 May;119(5):988-92. doi: 10.1002/lary.20159. |
| 21344445 | Background | Karnezis TT, Davidson TM. Efficacy of intranasal Bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope. 2011 Mar;121(3):636-8. doi: 10.1002/lary.21415. Epub 2010 Dec 16. |
| 21805356 | Background | Rohrmeier C, Sachs HG, Kuehnel TS. A retrospective analysis of low dose, intranasal injected bevacizumab (Avastin) in hereditary haemorrhagic telangiectasia. Eur Arch Otorhinolaryngol. 2012 Feb;269(2):531-6. doi: 10.1007/s00405-011-1721-9. Epub 2011 Jul 31. |
| 21344447 | Background | Chen S 4th, Karnezis T, Davidson TM. Safety of intranasal Bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope. 2011 Mar;121(3):644-6. doi: 10.1002/lary.21345. Epub 2010 Nov 11. |
| 22565282 | Background | Dheyauldeen S, Ostertun Geirdal A, Osnes T, Vartdal LS, Dollner R. Bevacizumab in hereditary hemorrhagic telangiectasia-associated epistaxis: effectiveness of an injection protocol based on the vascular anatomy of the nose. Laryngoscope. 2012 Jun;122(6):1210-4. doi: 10.1002/lary.23303. Epub 2012 May 7. |
| 22147664 | Background | Karnezis TT, Davidson TM. Treatment of hereditary hemorrhagic telangiectasia with submucosal and topical bevacizumab therapy. Laryngoscope. 2012 Mar;122(3):495-7. doi: 10.1002/lary.22501. Epub 2011 Dec 6. |
| 20087969 | Background | Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA. An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope. 2010 Apr;120(4):838-43. doi: 10.1002/lary.20818. |
| 1593914 | Background | Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473-83. |
| 15794078 | Background | Lennox PA, Hitchings AE, Lund VJ, Howard DJ. The SF-36 health status questionnaire in assessing patients with epistaxis secondary to hereditary hemorrhagic telangiectasia. Am J Rhinol. 2005 Jan-Feb;19(1):71-4. |
| 21743869 | Background | Ingrand I, Ingrand P, Gilbert-Dussardier B, Defossez G, Jouhet V, Migeot V, Dufour X, Klossek JM. Altered quality of life in Rendu-Osler-Weber disease related to recurrent epistaxis. Rhinology. 2011 Jun;49(2):155-62. doi: 10.4193/Rhino09.138. |
| 17021315 | Background | Steinbrook R. The price of sight--ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1409-12. doi: 10.1056/NEJMp068185. No abstract available. |
| 23641023 | Background | Smith KA, Rudmik L. Cost collection and analysis for health economic evaluation. Otolaryngol Head Neck Surg. 2013 Aug;149(2):192-9. doi: 10.1177/0194599813487850. Epub 2013 May 2. |
| 19807557 | Background | Koopmanschap MA. PRODISQ: a modular questionnaire on productivity and disease for economic evaluation studies. Expert Rev Pharmacoecon Outcomes Res. 2005 Feb;5(1):23-8. doi: 10.1586/14737167.5.1.23. |
| 11939242 | Background | Brazier J, Roberts J, Deverill M. The estimation of a preference-based measure of health from the SF-36. J Health Econ. 2002 Mar;21(2):271-92. doi: 10.1016/s0167-6296(01)00130-8. |
| 15319610 | Background | Brazier JE, Roberts J. The estimation of a preference-based measure of health from the SF-12. Med Care. 2004 Sep;42(9):851-9. doi: 10.1097/01.mlr.0000135827.18610.0d. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Epistaxis Severity Score (ESS) | ESS is a standardized and reproducible outcome measure for the control of epistaxis. It is composed of six factors that are independent predictors of self-described epistaxis severity. The range is 0 to 13. The higher the score worse is epistaxis severity. | Median | Inter-Quartile Range | units on a scale |
|
| SF-12 Physical Component Summary (PCS) Score | PCS of the SF-12 is a self-reported measure of mental health-related quality of life. PCS is calculated using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | Median | Inter-Quartile Range | units on a scale |
|
| SF-12 Mental Component Summary (MCS) Score | MCS of the SF-12 is a self-reported measure of mental health-related quality of life. MCS is calculated using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | Median | Inter-Quartile Range | units on a scale |
|
Placebo (4mL of saline) mixed by the Stanford Hospital Pharmacy as a control.
|
|
|
| Secondary | Short Form-12 (SF-12) Physical Component Summary (PCS) Score | PCS of the SF-12 is a self-reported measure of mental health-related quality of life. PCS is calculated using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | Participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | score on a scale | Baseline and month 1, month 2, month 4, month 6 |
|
|
|
|
| Secondary | Short Form-12 (SF-12) Mental Component Summary (MCS) Score | MCS of the SF-12 is a self-reported measure of mental health-related quality of life. MCS is calculated using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | Participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | score on a scale | Baseline and month 1, month 2, month 4, month 6 |
|
|
|
|
| Secondary | Reduction in Epistaxis-related Costs (Direct and Indirect) | Evaluate the effect of bevacizumab injection on direct and indirect costs in USD associated with care and management of epistaxis as well as productivity lost after treatment. The cost of caring in USD for nasal bleeding was evaluated with two surveys, the Work Productivity and Activity Impairment Questionnaire, and the HHT Costing Data Sheet. | Participants with available data are included in the analysis. | Posted | Median | Inter-Quartile Range | US Dollars | Baseline, Month 2, Month 6 |
|
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 0 |
| 20 |
| EG001 | Saline Control | Placebo (4mL of saline) mixed by the Stanford Hospital Pharmacy as a control. | 0 | 20 | 0 | 20 | 0 | 20 |
Not provided
Not provided
Not provided
| D006474 |
| Hemorrhagic Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D054079 | Vascular Malformations |
| D018376 | Cardiovascular Abnormalities |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D009668 | Nose Diseases |
| D012140 | Respiratory Tract Diseases |
| D010038 | Otorhinolaryngologic Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| D011313 | Preventive Dentistry |
| D003813 | Dentistry |
| D011636 | Public Health Dentistry |
| D004778 | Environment and Public Health |
| Month 4 |
|
| Month 6 |
|
Analysis between groups at month 2 |
| Regression, Linear |
| 0.914 |
| Mean Difference (Net) |
| 0.29 |
| 2-Sided |
| 95 |
| -5.02 |
| 5.61 |
| Other |
Linear regression model with repeated measures, controlling for patient's demographic factors, smoking status, and baseline level of PCS. The analysis is weighted by inverse probability treatment weight (IPTW). |
| Analysis between groups at month 4. | Regression, Linear | 0.592 | Mean Difference (Net) | 1.55 | 2-Sided | 95 | -4.17 | 7.28 | Other | Linear regression model with repeated measures, controlling for patient's demographic factors, smoking status, and baseline level of PCS. The analysis is weighted by inverse probability treatment weight (IPTW). |
| Analysis between groups at month 6 | Regression, Linear | 0.31 | Mean Difference (Net) | 3.1 | 2-Sided | 95 | -2.92 | 9.12 | Other | Linear regression model with repeated measures, controlling for patient's demographic factors, smoking status, and baseline level of PCS. The analysis is weighted by inverse probability treatment weight (IPTW). |
| Mean at 4 month |
|
| Mean at 6 month |
|
Analysis between groups at month 2 |
| Regression, Linear |
| 0.816 |
| Mean Difference (Net) |
| 0.82 |
| 2-Sided |
| 95 |
| -6.12 |
| 7.76 |
| Other |
Linear regression model with repeated measures, controlling for patient's demographic factors, smoking status, and baseline level of MCS. The analysis is weighted by inverse probability treatment weight (IPTW). |
| Analysis between groups at month 4. | Regression, Linear | 0.247 | Mean Difference (Net) | -4.3 | 2-Sided | 95 | -11.61 | 3.02 | Other | Linear regression model with repeated measures, controlling for patient's demographic factors, smoking status, and baseline level of MCS. The analysis is weighted by inverse probability treatment weight (IPTW). |
| Analysis between groups at month 6 | Regression, Linear | 0.035 | Mean Difference (Net) | -8.18 | 2-Sided | 95 | -15.76 | -0.6 | Other | Linear regression model with repeated measures, controlling for patient's demographic factors, smoking status, and baseline level of MCS. The analysis is weighted by inverse probability treatment weight (IPTW). |
| Month 6 |
|
| 0.719 |
| Other |
| Analysis of intergroup difference at month 6. | Wilcoxon rank sum test, 2-sided | 0.467 | Other |