Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial

Phase 2

Completed

Conditions: Aneurysm

Interventions: Drug: Doxycycline
Drug: Placebo

Registration Number: NCT01756833

Lead Sponsor: University of Maryland, Baltimore

Brief Summary: The primary aim of this study is to determine if doxycycline (100 mg bid) will inhibit (by at least 40%) the increase in greatest transverse diameter of small abdominal aortic aneurysms (3.5-5.0 cm in men, 3.5-4.5 cm in women) over a 24-month period of observation in comparison to a placebo-treated control group.

Detailed Description: N-TA\^3CT is a randomized, double-blind, placebo-controlled test of the hypothesis that doxycycline 100 mg bid, will reduce the rate of increase of maximum transverse diameter of small (3.5-5.0 cm among men and 3.5 to 4.5 cm among women) abdominal aortic aneurysms. The primary outcome is abdominal aortic aneurysm (AAA) maximum transverse diameter determined by CT scans at two-year follow-up with allowance for baseline (pre-randomization) diameter. Based on an anticipated growth rate of 2.5 mm per year in the placebo group and the current threshold at which surgical intervention will be offered to trial participants, (5.5 cm in men, 5.0 cm in women), the upper limit of AAA size for inclusion has been set at 5.0 cm for men and 4.5 cm for women. Among these subjects, the threshold for repair would be exceeded only by those exhibiting persistent growth. Secondary outcomes will determine if doxycycline affects other measures, e.g., MMP-9 levels in plasma and whether these effects are related to aneurysm growth. Nineteen clinical sites have identified pools of over 1600 patients with small aneurysm who meet the proposed inclusion/exclusion criteria. Two hundred fifty-eight patients will be randomized to placebo or doxycycline and their aneurysms followed for change in diameter at six-month intervals using CT imaging. The alternative hypothesis is that doxycycline will inhibit the expansion rate by 40% during the two years of observation. Patients enrolling in N-TA\^3CT must be able to give consent for their participation themselves and meet study eligibility criteria.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 261

Inclusion Criteria

Patients 55 years of age or older, women post-surgical menopause or at least two years since last menses if natural menopause.
CT scan documented infrarenal abdominal aortic aneurysm with maximum transverse diameter larger than 35 mm and no greater than 50 mm, in men, and larger than 35 mm and no greater than 45 mm in women.

Exclusion Criteria

Patients will be excluded from the study if they are unable to give their own informed consent to participate.
have symptoms related to abdominal aortic aneurysm.
have other intra-abdominal vascular pathology that may require repair within 24 months (e.g., renal artery stenosis, large iliac artery aneurysms, iliac occlusive disease, aneurysmal involvement of the renal artery).
have had previous abdominal aortic aneurysm repair by open surgical or endovascular technique.
have an active malignancy with life expectancy less than two years.
have an allergy to tetracycline.
are currently or have been recently treated (previous six months) with tetracycline derivatives.
they are currently taking anti-seizure medicines metabolized by pathways influenced by doxycycline (e.g., carbamazepine, phenytoin, and barbiturates).
stage II hypertension (patients whose blood pressure is persistently in the range of systolic > 160 mm Hg or diastolic > 100 mm Hg despite primary physician's best effort to achieve adequate therapy.
have dialysis dependent renal failure or impending dialysis treatment for renal insufficiency.
have a chronic infection requiring long-term (> 2 weeks) antibiotics.
have known genetic syndromes responsible for the abdominal aortic aneurysm (e.g., Marfan's Syndrome).
are under treatment with systemic immunosuppressive agents.
could become pregnant.
are not good candidates for clinical trial participation.
are enrolled in another clinical trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Doxycycline	Doxycycline	100 mg capsules, twice a day, for a period of two years.
Placebo	Placebo	100 mg capsules, twice a day, for a period of two years.

Primary Outcome Measures

Name	Time	Method
Difference in Z-score for Rank of Maximum Transverse Diameter (MTD) Regressed on Z-score at Baseline to Assess Growth in Abdominal Aortic Aneurysm MTD Determined by CT Scans at Two-year Follow-up and Baseline (Pre-randomization).	Baseline and two years from randomization (when patients were late in returning for visits, their data were used up to three years).	Diameters were ranked from smallest to largest. Worse ranks were assigned to surviving patients who underwent aneurysm repair (in order of longest to shortest time from randomization to repair), and worst ranks were assigned to patients who died (in order likewise). Each rank was converted to a z-score corresponding to the value on the standard normal curve of its percentile. The primary analysis was based on linear regression of the change in z-scores from baseline to 2 years. Independent variables were baseline z-score, sex, and a dichotomous variable for the randomly assigned treatment group (0 for placebo, 1 for doxycycline). Missing values were multiply imputed. Higher score corresponds to less favorable outcome. There is no scale associated with these z-scores; the absolute z-scores have no biological meaning or clinically relevant threshold. A z-score of 0 corresponds to the median rank. The maximum and minimum z-scores are +2.41 and -2.41. See References in Protocol Section.

Secondary Outcome Measures

Name	Time	Method
Maximum Transverse Diameter, cm	Six months, one year, and two years (when patients were late in returning for visits their data were used up to three years).	Secondary outcomes will derive from central, Imaging Core Laboratory analyses of the CT scans performed every six months on patients and from the clinical follow-up of randomized patients, from clinical observation, local laboratory findings, study visit quality of life assessments, and from biomarker analyses to be performed in the Biomarkers Core Laboratory (e.g., changes from initial matrix metalloproteinase (MMP-9) levels, and matrix metalloproteinase (MMP-9) levels at 24 months). When patients were late in returning for visits their data were used up to three years.
Volume, cm^3	Six months, one year, and two years (when patients were late in returning for visits their data were used up to three years).	Secondary outcomes will derive from central, Imaging Core Laboratory analyses of the CT scans performed every six months on patients and from the clinical follow-up of randomized patients, from clinical observation, local laboratory findings, study visit quality of life assessments, and from biomarker analyses to be performed in the Biomarkers Core Laboratory (e.g., changes from initial matrix metalloproteinase (MMP-9) levels, and matrix metalloproteinase (MMP-9) levels at 24 months). When patients were late in returning for visits their data were used up to three years.
MMP-9, ng/ml	Six months, one year, 18 months, and two years (when patients were late in returning for visits their data were used up to three years).	Secondary outcomes will derive from central, Imaging Core Laboratory analyses of the CT scans performed every six months on patients and from the clinical follow-up of randomized patients, from clinical observation, local laboratory findings, study visit quality of life assessments, and from biomarker analyses to be performed in the Biomarkers Core Laboratory (e.g., changes from initial matrix metalloproteinase (MMP-9) levels, and matrix metalloproteinase (MMP-9) levels at 24 months). When patients were late in returning for visits their data were used up to three years. Analysis of hs-CRP will be performed using an immunoturbidimetric latex agglutination method (K-assay \[KAI-60\], Kamiya Biomedical Co., Seattle, WA).
CRP, mg/l	Six months, one year, 18 months, and two years (when patients were late in returning for visits their data were used up to three years).	Secondary outcomes will derive from central, Imaging Core Laboratory analyses of the CT scans performed every six months on patients and from the clinical follow-up of randomized patients, from clinical observation, local laboratory findings, study visit quality of life assessments, and from biomarker analyses to be performed in the Biomarkers Core Laboratory (e.g., changes from initial matrix metalloproteinase (MMP-9) levels, and matrix metalloproteinase (MMP-9) levels at 24 months). When patients were late in returning for visits their data were used up to three years. Plasma MMP-9 concentrations will be measured by an ELISA, two-site sandwich method that is commercially available (R \& D Systems, Quantikine, DMP900).

Trial Locations

Locations (22): Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
Omaha VAMC
🇺🇸
Omaha, Nebraska, United States
University of South Florida Health Center
🇺🇸
Tampa, Florida, United States
Portland VAMC
🇺🇸
Portland, Oregon, United States
Geisinger Medical Center
🇺🇸
Danville, Pennsylvania, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
University of Arizona Medical Center
🇺🇸
Tucson, Arizona, United States
Miami Cardiac and Vascular Institute
🇺🇸
Miami, Florida, United States
Carondelet Heart & Vascular Institute
🇺🇸
Tucson, Arizona, United States
University of Southern California
🇺🇸
Los Angeles, California, United States
Stanford University
🇺🇸
Stanford, California, United States
Northwestern University Memorial Hospital
🇺🇸
Chicago, Illinois, United States
McLaren Northern Michigan
🇺🇸
Petoskey, Michigan, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Beth Israel Deaconness Medical Center
🇺🇸
Boston, Massachusetts, United States
University of Michigan Medical Center
🇺🇸
Ann Arbor, Michigan, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Oregon Health Sciences University
🇺🇸
Portland, Oregon, United States
Utah VAMC
🇺🇸
Salt Lake City, Utah, United States
University of Utah Health Sciences Center
🇺🇸
Salt Lake City, Utah, United States
University of Maryland Medical Center
🇺🇸
Baltimore, Maryland, United States