Intranasal Bevacizumab for HHT-Related Epistaxis

Phase 4

Completed

• Conditions: Nasal Bleeding; HHT; Hereditary Hemorrhagic Telangiectasia; Epistaxis; Nose Bleeds
• Interventions: Drug: Placebo (Saline); Drug: Bevacizumab

• Registration Number: NCT02389959
• Lead Sponsor: Stanford University

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.

Study Timeline

• Study Start: 2014-08-04
• Study First Submitted: 2015-03-11
• Study First Submitted QC: 2015-03-11
• Study First Posted: 2015-03-17
• Primary Completion: 2020-01-23
• Study Completion: 2020-01-23
• Results First Submitted: 2021-01-23
• Results First Submitted QC: 2021-01-23
• Results First Posted: 2021-02-15
• Status Verified: 2021-08
• Last Update Submitted: 2021-08-06
• Last Update Posted: 2021-09-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Saline Control	Placebo (Saline)	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.
Bevacizumab	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.

Primary Outcome Measures

Name	Time	Method
Change in Epistaxis Severity Score (ESS)	Baseline and month 1, month 2, month 4, month 6	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.

Secondary Outcome Measures

Name	Time	Method
Short Form-12 (SF-12) Physical Component Summary (PCS) Score	Baseline and month 1, month 2, month 4, month 6	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.
Short Form-12 (SF-12) Mental Component Summary (MCS) Score	Baseline and month 1, month 2, month 4, month 6	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.
Reduction in Epistaxis-related Costs (Direct and Indirect)	Baseline, Month 2, Month 6	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.

Trial Locations

Locations (1)

Stanford University Department of Otolaryngology- Head and Neck Surgery; 🇺🇸 Stanford, California, United States