Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT)

Overview

Status: Recruiting
Keywords: Seniors Ages 55+ , Abdominal Aortic Aneurysm , Doxycycline , Vascular Surgery
IRB Number: 00052437
Specialty: Radiology, Vascular Surgery, Surgery, General, Geriatrics
Sub Specialties: Computed Tomography - CT,

Brief Summary

STUDY OBJECTIVES

The overall goal of the proposed study is to determine whether treatment with doxycycline 100 mg p.o., b.i.d., in patients with small abdominal aortic aneurysms (3.5 to 5.0 cm in diameter among men, 3.5 to 4.5 cm among women) is associated with reduced growth of the aneurysm in diameter compared to growth with treatment with placebo over the course of two years.

2.1       PRIMARY AIM

1.   Determine if doxycycline (100 mg bid) will inhibit 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.

2.2       SECONDARY AIMS

  1. Determine if doxycycline will inhibit circulating MMP-9 levels compared to a control (placebo) group.
  2. Determine if doxycycline (100 mg bid) will prevent the increase in aneurysm volume 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.
  3. Determine if doxycycline (100 mg bid) will inhibit the increase in greatest transverse diameter or volume of small aortic aneurysms (3.5-5.0 cm in men, 3.5-4.5 cm in women) using CT data from all 6 month time points according to the numbers of patients whose follow-up has not been censored by the common termination date.
  4. Determine the relationship between MMP-9 levels and interval aneurysm expansion rate.
  5. Determine if doxycycline treatment will adversely affect perceived quality of life.

2.3       EXPLORATORY AIMS

  1. Determine if doxycycline will reduce circulating interferon gamma levels compared to a placebo-treated group.
  2. Determine the relationship between interferon gamma and aneurysm expansion rate.

2.4      ACCOMPLISHING OBJECTIVES

      Pools of over nine hundred patients likely to be eligible have been identified at the 15 clinical sites. CT images obtained serially at 6 month intervals at the clinical sites will be transmitted for central reading to a specialized Imaging Core Laboratory (ICL). The blood samples collected at 6 month intervals will be shipped to the Biomarkers Core Laboratory (BCL) for MMP-9 and Interferon-γ levels. The Data Coordinating Center (DCC) will receive and process data from the clinical sites, the IAC and the BCL for analysis. A brief description of how the aims will be accomplished follows:

            Primary Aim- This aim will be accomplished by quantitative assessment and comparison of the greatest transverse diameter on CT scan obtained at baseline and at 24-month follow-up. The data will be compared by methods that account for all patients ranking them based on aneurysm diameter and informative outcomes such as aneurysm repair, aneurysm rupture and death.

Secondary Aim 1- This aim will be accomplished by quantitative assessment (mg/ml) of plasma MMP-9 levels obtained at baseline and during follow-up at six month intervals in the doxycycline and placebo treated patients. Data analysis will be accomplished with longitudinal methods for comparison of the multiple values at different time points for time by treatment interactions.

Secondary Aim 2- This aim will be accomplished by quantitative assessment and comparison of aneurysm volume on CT scan obtained at baseline and at 24-month follow-up. The data will be compared by methods that account for all patients ranking them based on aneurysm volume and other informative outcomes such as aneurysm repair, aneurysm rupture and death.

Secondary Aim 3- This aim will use CT images obtained at each six month time point rather than using only baseline and 24 month values as described for the primary aim. Analysis will be done with longitudinal methods for comparison of the multiple follow-up points for time by treatment interactions. 

Specific Aim 4- This aim will use the plasma MMP-9 levels obtained at baseline and 6 month intervals and analyze these levels in relationship to change in transverse diameter during the corresponding periods. Data will be analyzed with longitudinal methods for comparison of the multiple follow-up points.

Specific Aim 5- This aim will be accomplished by comparing the results of the Medical Outcomes Study (MOS) Short Form 36 (SF-36) questionnaire assessed at baseline and during treatment comparing the doxycycline and placebo-treated groups. Data analysis will be accomplished with longitudinal methods for comparison of the multiple follow-up points for time by treatment interactions.

Exploratory Aims 1 and 2 - This aim will be accomplished by quantitative assessment (mg/ml) of plasma interferon-gamma levels obtained at baseline and during follow-up at six-month intervals in the doxycycline and placebo groups. Data analysis will be the accomplished with longitudinal methods for comparison of the multiple values at different time points for time by treatment interactions.

Detailed Description

The Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT) is a randomized, double-blind, placebo-controlled clinical trial designed to test the hypothesis that doxycycline 100 mg p.o., b.i.d., 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 in the largest diameter) abdominal aortic aneurysms. Maximum transverse diameter will be determined by Computer Tomography (CT) scans. Men who are found on CT scan to have 3.5-5.0 cm abdominal aortic aneurysms and women who are found on CT scan to have 3.5 to 4.5 cm aortic aneurysms that do not involve the renal arteries are eligible. Patients will be randomly assigned to receive doxycycline capsules, 100 mg, p.o., b.i.d., or indistinguishable placebo capsules p.o., b.i.d. The primary outcome is abdominal aortic aneurysm maximum transverse diameter at two-year follow-up with allowance for baseline (pre-randomization) diameter. Secondary outcomes will determine if doxycycline decreases other measures of aneurysm status, MMP-9 levels in plasma and whether this decrease corresponds to inhibition of aneurysm growth.

Principal Investigator: Larry Kraiss
Department: Vascular Surgery Development
Co Investigator:

Contact Information

Name:Maria Maloney
Phone: 801-585-3663
Email: maria.maloney@hsc.utah.edu

Inclusion Criteria

Inclusion Criteria

The study population will include patients

 1. Patients 55 years of age or older, women post-surgical menopause or at least two years since last menses if natural menopause.

2. 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.

 

There are no differences in the inclusion and exclusion criteria between VA and University populations.

 

 

 

Exclusion Criteria

Exclusion Criteria

Patients will be excluded from the study if : 

 1. Prior repair of the abdominal aortic aneurysm.

2. Renal artery involvement or suprarenal extension of the aneurysm.

3. Documented failure of the aneurysm to increase in size over the two years prior to enrollment if the aneurysm is < 4.0 cm in maximal transverse diameter.

4. Iliac artery aneurysm > 2.9 cm in diameter.

5. Iliac artery occlusive disease planned for repair.

6. Renal artery stenosis with planned open repair.

7. Known thoracic aortic aneurysm > 3.5 cm, for aneurysms that are saccular or observed to be expanding at a rate greater than ordinary and > 4.0 cm, for aneurysms that are not saccular and are expanding at accustomed rates.

8. Known connective tissue disease (e.g., collagen vascular disorder), heritable or genetic syndrome (e.g., Marfan Syndrome, Ehlers-Danlos Syndrome) underlying the abdominal aortic aneurysm.

9. Stage II hypertension (patients whose blood pressure is persistently in the range of systolic > 160 mm Hg or diastolic > 100 mm Hg despite personal physician’s best effort to achieve adequate therapy).

10. Creatinine > 2.0 g/dL or creatinine clearance < 30 ml/min.

11. Allergy or intolerance of tetracyclines.

12. Use of tetracyclines within past six months.

13. Taking anti-epileptic pharmaceutical agents (e.g., carbamazepine, diphenylhydantoin).

14. Current or planned treatment with chemotherapy or radiation therapy for cancer other than squamous cell cancer of the skin.

15. Current or planned treatment with systemic immunosuppressive agents (e.g., prednisone, azathioprine, methotrexate, cyclosporine for autoimmune disease or following transplantation of bone marrow, heart, liver, lung or other solid organ).

16. Chronic infection managed with long-term antibiotics, frequent courses of antibiotic therapy or self-administration of antibiotic therapy.

17. Personal physician/surgeon is not willing to follow the protocol.

18. Prognosis less than two-year survival or other reason the Clinical Site director believes the patient is not a suitable candidate for N-TA3CT (e.g., history of repeatedly missing follow-up appointments or regular residence outside of the U.S.)

19. Enrollment in another, concurrent clinical trial study.

20. Refusal or inability of patient to provide written informed consent.

There are no differences in the inclusion and exclusion criteria between VA and University populations.