Influence of MMP on Brain AVM Hemorrhage

Influence of Matrix Metalloproteinase on Brain Arteriovenous Malformation Hemorrhage

Brain vascular malformations, including arteriovenous malformations (AVM), cavernous malformations (CVM) and aneurysms, are a source of life-threatening risk of intracranial hemorrhage. The etiology and pathogenesis are unknown. There is no medical therapy presently available. Prevention of spontaneous intracerebral hemorrhage (ICH) is the primary reason to treat brain vascular malformations. The goal of this study is to: begin pilot studies to lay the groundwork for future clinical trials to develop medical therapy to decrease ICH risk.

Matrix metalloproteinases (MMPs) regulate the extracellular matrix in association with various hemorrhagic brain disorders. MMP-9 has been most consistently associated with vascular wall instability and hemorrhagic brain disorders. Doxycycline, a non-specific MMP inhibitor, may enhance vascular stability, thus reducing the risk of spontaneous hemorrhage in brain vascular malformations by decreasing MMP-9 activity.

Study Overview

• Status: Completed
• Conditions: Arteriovenous Malformations; Cavernous Angiomas; Brain Aneurysms
• Intervention / Treatment: Drug: Doxycycline or Placebo

Detailed Description

• Doses will be randomized by the Pharmacy Department at UCSF for Doxycycline 100 mg/BID and Placebo BID. These will be prepared in blister-packs.
• Depending on enrollment/surgery date, patients will take medication either one to two weeks before surgery. Patients will be assigned to a treatment group according to a random table.
• Each patient will be initially provided with a 1 or 2-week supply of drug in blister packs. The patient will take the final dose of study drug on the morning of surgery.

Baseline labs will be obtained and then again at time of surgery along with a piece of surgical tissue.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 13 years or older
• Female patients of child bearing age using barrier-type birth control
• Creatinine no greater than 2.0 mg/di
• Alanine aminotransferase (ALT) no greater than 2 times upper limit of normal
• WBC count at least 3,800/mm3
• BMI within 50% of normal

Exclusion Criteria:

• Allergy to tetracycline
• Unstable medical illness (unstable angina, advanced cancer, etc) over the last 30 days
• Female patients of child-bearing age not using effective birth control (barrier)
• History of vestibular disease (except benign positional vertigo)
• History of noncompliance with treatment or other experimental protocols
• Patients taking other antibiotics
• History of systemic lupus erythematosis
• Patients who are immunocompromised Patients with clinically significant hepatic dysfunction

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Doxycycline; Patients undergoing elective vascular malformation surgery will receive doxycycline100 mg twice a day, a dose shown to effectively decrease MMP or placebo, treatment for two weeks prior to surgery	Drug: Doxycycline or Placebo; Randomized to Doxycycline 100mg 2x/day or Placebo 2x/day for 1 or2-weeks pre-operatively.; Other Names: Placebo; Doxycycline
PLACEBO_COMPARATOR: Placebo; Patients undergoing elective vascular malformation surgery will receive doxycycline100 mg twice a day, a dose shown to effectively decrease MMP or placebo, treatment for two weeks prior to surgery	Drug: Doxycycline or Placebo; Randomized to Doxycycline 100mg 2x/day or Placebo 2x/day for 1 or2-weeks pre-operatively.; Other Names: Placebo; Doxycycline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Our primary aim is to perform a pilot study to document the effect of doxycycline therapy to decrease MMP expression in the vascular malformation tissue.	1 to 2-week pre-operative

Secondary Outcome Measures

Outcome Measure	Time Frame
Our secondary aims are: (1) To explore whether plasma MMP-9 levels can be used as a marker for MMP-9 inhibition in the vascular malformation lesional tissue	1 to 2-week pre operative

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Chanhung Lee, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (ACTUAL): December 1, 2010
• Study Completion (ACTUAL): December 1, 2010

Study Registration Dates

• First Submitted: October 30, 2008
• First Submitted That Met QC Criteria: October 30, 2008
• First Posted (ESTIMATE): October 31, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): August 9, 2013
• Last Update Submitted That Met QC Criteria: August 6, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Cardiovascular Abnormalities; Neoplasms, Vascular Tissue; Vascular Malformations; Intracranial Arterial Diseases; Hemorrhage; Congenital Abnormalities; Hemangioma; Arteriovenous Malformations; Aneurysm; Intracranial Aneurysm; Hemangioma, Cavernous; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline
• Other Study ID Numbers: H42145-30334-02; AHA #0730360N