Clinical trial NCT01756833: Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial
Official title: Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA^3CT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aneurysm
Keywords: abdominal
aortic
aneurysm
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2012-12-28
Enrollment: 261
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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).
timeFrame: Baseline and two years from randomization (when patients were late in returning for visits, their data were used up to three years).
Secondary outcomes:
measure: Maximum Transverse Diameter, cm
timeFrame: Six months, one year, and two years (when patients were late in returning for visits their data were used up to three years).
measure: Volume, cm^3
timeFrame: Six months, one year, and two years (when patients were late in returning for visits their data were used up to three years).
measure: MMP-9, ng/ml
timeFrame: 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).
measure: CRP, mg/l
timeFrame: 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).
Other outcomes:
measure: Number of Participants With Aneurysm Rupture
timeFrame: Two years
measure: Number of Participants With Surgical Intervention
timeFrame: Two years
measure: Number of Participants Who Died
timeFrame: Two years
Locations:
city: Tucson
country: United States
facility: University of Arizona Medical Center
state: Arizona
city: Tucson
country: United States
facility: Carondelet Heart & Vascular Institute
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Miami
country: United States
facility: Miami Cardiac and Vascular Institute
state: Florida
city: Tampa
country: United States
facility: University of South Florida Health Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University Memorial Hospital
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconness Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Petoskey
country: United States
facility: McLaren Northern Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Omaha VAMC
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Portland
country: United States
facility: Portland VAMC
state: Oregon
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Salt Lake City
country: United States
facility: Utah VAMC
state: Utah
Study officials:
affiliation: University of Maryland, Baltimore
name: Michael L Terrin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Nebraska
name: Bernard T Baxter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin Medical Center
name: Jonathan Matsumura, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University
name: John Curci, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baxter BT, Matsumura J, Curci J, McBride R, Blackwelder WC, Liu X, Larson L, Terrin ML; N-TA(3)CT Investigators. Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT): Design of a Phase IIb, placebo-controlled, double-blind, randomized clinical trial of doxycycline for the reduction of growth of small abdominal aortic aneurysm. Contemp Clin Trials. 2016 May;48:91-8. doi: 10.1016/j.cct.2016.03.008. Epub 2016 Mar 25.
citation: Lachin JM. Worst-Rank Score Methods-A Nonparametric Approach to Informatively Missing Data. JAMA. 2020 Oct 27;324(16):1670-1671. doi: 10.1001/jama.2020.7709. No abstract available.
citation: Lachin JM. Nonparametric Statistical Analysis. JAMA. 2020 May 26;323(20):2080-2081. doi: 10.1001/jama.2020.5874. No abstract available.
citation: Baxter BT, Matsumura J, Curci JA, McBride R, Larson L, Blackwelder W, Lam D, Wijesinha M, Terrin M; N-TA3CT Investigators. Effect of Doxycycline on Aneurysm Growth Among Patients With Small Infrarenal Abdominal Aortic Aneurysms: A Randomized Clinical Trial. JAMA. 2020 May 26;323(20):2029-2038. doi: 10.1001/jama.2020.5230.
citation: Olson SL, Panthofer AM, Blackwelder W, Terrin ML, Curci JA, Baxter BT, Weaver FA, Matsumura JS; Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial Investigators. Role of volume in small abdominal aortic aneurysm surveillance. J Vasc Surg. 2022 Apr;75(4):1260-1267.e3. doi: 10.1016/j.jvs.2021.09.046. Epub 2021 Oct 14.
citation: Panthofer AM, Olson SL, Rademacher BL, Grudzinski JK, Chaikof EL, Matsumura JS; N-TA(3)CT Investigators. Anatomic eligibility for endovascular aneurysm repair preserved over 2 years of surveillance. J Vasc Surg. 2021 Nov;74(5):1527-1536.e1. doi: 10.1016/j.jvs.2021.04.044. Epub 2021 May 4.
citation: Olson SL, Wijesinha MA, Panthofer AM, Blackwelder WC, Upchurch GR Jr, Terrin ML, Curci JA, Baxter BT, Matsumura JS. Evaluating Growth Patterns of Abdominal Aortic Aneurysm Diameter With Serial Computed Tomography Surveillance. JAMA Surg. 2021 Apr 1;156(4):363-370. doi: 10.1001/jamasurg.2020.7190.