Stanford, California 94305


Purpose:

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.


Study summary:

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.


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.


Study is Available At:


Original ID:

29501


NCT ID:

NCT02389959


Secondary ID:


Study Acronym:


Brief Title:

Intranasal Bevacizumab for HHT-Related Epistaxis


Official Title:

Intranasal Bevacizumab for HHT-Related Epistaxis


Overall Status:

Recruiting


Study Phase:

Phase 4


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

Stanford University


Oversight Authority:

United States: Institutional Review Board


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

2


Number of Groups:

0


Total Enrollment:

40


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Peter H Hwang, MD
Principal Investigator
Stanford University, Department of Otolaryngology- Head and Neck Surgery
Primary Contact:Amelia K Clark, MD
akclark@stanford.edu
Backup Contact:Chelsey Perry
(650) 723-6116
CPerry@ohns.stanford.edu

Study Dates

Start Date:August 2014
Completion Date:December 2019
Completion Type:Anticipated
Primary Completion Date:September 2019
Primary Completion Type:Anticipated
Verification Date:December 2018
Last Changed Date:December 19, 2018
First Received Date:March 11, 2015

Study Outcomes

Outcome Type:Secondary Outcome
Measure:Reduction in epistaxis-related costs (direct and indirect)
Time Frame:6 months
Safety Issues:False
Description:Evaluate the effect of bevacizumab injection on direct and indirect costs associated with care and management of epistaxis as well as productivity lost at 1 month, 2 months, 4 months, and 6 months after treatment.
Outcome Type:Secondary Outcome
Measure:Improvement in Quality of Life
Time Frame:6 months
Safety Issues:False
Description:Evaluate the effect of bevacizumab injection on patient quality of life as measured by the Short Form-12 (SF-12) Health Status Questionnaire at 1 month, 2 months, 4 months, and 6 months after treatment.
Outcome Type:Primary Outcome
Measure:Improvement in Epistaxis Severity Score
Time Frame:6 months
Safety Issues:False
Description:Evaluate the effect of bevacizumab injection on Epistaxis Severity Score at 1 month, 2 months, 4 months, and 6 months after treatment.

Study Interventions

Intervention Type:Drug
Name:Bevacizumab
Description: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
Arm Name:Bevacizumab
Other Name:Avastin
Intervention Type:Drug
Name:Placebo (Saline)
Description:4mL of saline will be mixed by the Stanford Hospital Pharmacy as a control
Arm Name:Saline Control
Other Name:Salt water

Study Arms

Study Arm Type:Placebo Comparator
Arm Name:Saline Control
Description: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 blin
Study Arm Type:Experimental
Arm Name:Bevacizumab
Description: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 blin

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Stanford University

Sample and Retention Information

There are no available Sample and Retention Information

Study References

Reference Type:Reference
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PMID:15319610
Reference Type:Reference
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PMID:11939242
Reference Type:Reference
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.
PMID:19807557
Reference Type:Reference
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.
PMID:23641023
Reference Type:Reference
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.
PMID:17021315
Reference Type:Reference
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.
PMID:21743869
Reference Type:Reference
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.
PMID:15794078
Reference Type:Reference
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.
PMID:1593914
Reference Type:Reference
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.
PMID:20087969
Reference Type:Reference
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.
PMID:22147664
Reference Type:Reference
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.
PMID:22565282
Reference Type:Reference
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.
PMID:21344447
Reference Type:Reference
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.
PMID:21805356
Reference Type:Reference
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.
PMID:21344445
Reference Type:Reference
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.
PMID:19194865
Reference Type:Reference
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.
PMID:15951295
Reference Type:Reference
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.
PMID:10485021
Reference Type:Reference
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.
PMID:10751092

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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