Intranasal Bevacizumab for HHT-Related Epistaxis

NCT ID: NCT02389959

Last Updated: 2021-09-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-08-04
• Study Completion Date: 2020-01-23

Brief 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.

Detailed 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.

Conditions

HHT; Hereditary Hemorrhagic Telangiectasia; Epistaxis; Nose Bleeds; Nasal Bleeding

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Bevacizumab

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.

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: 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

Saline Control

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.

Group Type: PLACEBO_COMPARATOR

Placebo (Saline)

Intervention Type: DRUG

4mL of saline will be mixed by the Stanford Hospital Pharmacy as a control

Interventions

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

Intervention Type: DRUG

Placebo (Saline)

4mL of saline will be mixed by the Stanford Hospital Pharmacy as a control

Intervention Type: DRUG

Other Intervention Names

Avastin; Salt water

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stanford University

OTHER

Sponsor Role: lead

Responsible Party

Peter Hwang

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Peter H Hwang, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University, Department of Otolaryngology- Head and Neck Surgery

Locations

Stanford University Department of Otolaryngology- Head and Neck Surgery

Stanford, California, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 10751092 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10485021 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15951295 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19194865 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21344445 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21805356 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21344447 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22565282 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22147664 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20087969 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1593914 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15794078 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21743869 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17021315 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23641023 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19807557 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11939242 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15319610 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

29501

Identifier Type: -

Identifier Source: org_study_id