Intranasal Bevacizumab for HHT-Related Epistaxis

Epistaxis Clinical Trial

Official title:

Intranasal Bevacizumab for HHT-Related Epistaxis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02389959
• Other study ID #: 29501
• Status: Completed
• Phase: Phase 4
• Start date: August 4, 2014
• Est. completion date: January 23, 2020

Study information

• Verified date: August 2021
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: January 23, 2020
• Est. primary completion date: January 23, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. The patient carries a diagnosis of hereditary hemorrhagic telangiectasia (HHT)

2. The patient is to undergo treatment with electrocautery in the operating room under endoscopic visualization

3. The patient is able to give informed consent

4. The patient is at least 18 years old

Exclusion Criteria:

1. The patient has had prior treatment with systemic or nasal bevacizumab within the past year

2. The patient has undergone electrocautery for epistaxis within the 6 months prior to study enrollment

3. The patient is a minor

4. The patient is pregnant

5. The patient is incapable of understanding the consent process

6. The patient has a history of HIV or another known cause of immunosuppression, or is actively taking immunosuppressive medications due to organ transplantation, rheumatoid disease, or other medical conditions.

Related Conditions & MeSH terms

• Epistaxis
• Hemorrhage
• Hereditary Hemorrhagic Telangiectasia
• HHT
• Nasal Bleeding
• Nose Bleeds
• Telangiectasia, Hereditary Hemorrhagic
• Telangiectasis

Intervention

Drug:
• Bevacizumab
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
• Placebo (Saline)
4mL of saline will be mixed by the Stanford Hospital Pharmacy as a control

Locations

Country	Name	City	State
United States	Stanford University Department of Otolaryngology- Head and Neck Surgery	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Stanford University

Country where clinical trial is conducted

United States, 

References & Publications (18)

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. — View Citation

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. — View Citation

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. — View Citation

Dheyauldeen S, Østertun 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Sadick H, Riedel F, Naim R, Goessler U, Hörmann 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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline and month 1, month 2, month 4, month 6
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.	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.	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.	Baseline, Month 2, Month 6