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Intranasal Bevacizumab for HHT-Related Epistaxis

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ClinicalTrials.gov Identifier: NCT02389959
Recruitment Status : Recruiting
First Posted : March 17, 2015
Last Update Posted : April 27, 2017
Sponsor:
Information provided by (Responsible Party):
Peter Haichin Hwang, 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.

Condition or disease Intervention/treatment Phase
HHT Hereditary Hemorrhagic Telangiectasia Epistaxis Nose Bleeds Nasal Bleeding Drug: Bevacizumab Drug: Placebo (Saline) Phase 4

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Intranasal Bevacizumab for HHT-Related Epistaxis
Study Start Date : August 2014
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : March 2019


Arm Intervention/treatment
Experimental: 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.
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
Other Name: Avastin

Placebo Comparator: 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.
Drug: Placebo (Saline)
4mL of saline will be mixed by the Stanford Hospital Pharmacy as a control
Other Name: Salt water




Primary Outcome Measures :
  1. Improvement in Epistaxis Severity Score [ Time Frame: 6 months ]
    Evaluate the effect of bevacizumab injection on Epistaxis Severity Score at 1 month, 2 months, 4 months, and 6 months after treatment.


Secondary Outcome Measures :
  1. Improvement in Quality of Life [ Time Frame: 6 months ]
    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.

  2. Reduction in epistaxis-related costs (direct and indirect) [ Time Frame: 6 months ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02389959


Contacts
Contact: Amelia K Clark, MD akclark@stanford.edu
Contact: Chelsey Perry (650) 723-6116 CPerry@ohns.stanford.edu

Locations
United States, California
Stanford University Department of Otolaryngology- Head and Neck Surgery Recruiting
Stanford, California, United States, 94305
Sponsors and Collaborators
Stanford University
Investigators
Principal Investigator: Peter H Hwang, MD Stanford University, Department of Otolaryngology- Head and Neck Surgery

Publications:

Responsible Party: Peter Haichin Hwang, Principle Investigator, Stanford University
ClinicalTrials.gov Identifier: NCT02389959     History of Changes
Other Study ID Numbers: 29501
First Posted: March 17, 2015    Key Record Dates
Last Update Posted: April 27, 2017
Last Verified: April 2017

Keywords provided by Peter Haichin Hwang, Stanford University:
HHT
Hereditary Hemorrhagic Telangiectasia
epistaxis
nose bleeds
nasal bleeding
Avastin
bevacizumab

Additional relevant MeSH terms:
Hemorrhage
Telangiectasis
Epistaxis
Telangiectasia, Hereditary Hemorrhagic
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Nose Diseases
Respiratory Tract Diseases
Otorhinolaryngologic Diseases
Hemostatic Disorders
Hemorrhagic Disorders
Hematologic Diseases
Vascular Malformations
Cardiovascular Abnormalities
Congenital Abnormalities
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents