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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.

ABSTRACT: The Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT) is a Phase IIb randomized, placebo-controlled clinical trial, testing doxycycline (100mg bid) for inhibition of growth in the greatest transverse, orthogonal diameter of small abdominal aortic aneurysms (AAA).We will enroll 258 patients, ?55years of age who have AAA, men: 3.5-5.0cm and women: 3.5-4.5cm on CT scans confirmed centrally. The primary outcome is growth in maximal transverse, orthogonal diameter from baseline to 24-month follow-up. Secondary analyses address doxycycline effects on clinical events, aneurysm volume, and biomarkers. Primary analysis will be performed according to the principle of intention-to-treat accounting for death and ruptures by use of normal scores in analysis of covariance. At the time of the data file reported, 200 subjects have been randomized. We started enrollment in mid-2013 and will complete enrollment by mid-2016.Participant average age=70.9years, (SD=7.6years) and maximum transverse diameter=4.3cm for men (SD=0.4) and 4.0cm for women (SD=0.3).N-TA(3)CT is a critical experiment to determine whether doxycycline reduces growth of small AAA and systemic markers of inflammation previously seen in bench experiments and observational human studies to be associated with AAA growth. Our patient population baseline measurements agree with the design assumptions supporting our expectation of 90% power or greater to reject a null hypothesis in favor of an alternative hypothesis when growth is reduced by at least 40%.clinicaltrials.gov #NCT01756833.

SUBMITTER: Baxter BT

PROVIDER: S-EPMC4964873 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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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.

Baxter B Timothy BT Matsumura Jon J Curci John J McBride Ruth R Blackwelder William C WC Liu Xinggang X Larson LuAnn L Terrin Michael L ML

Contemporary clinical trials 20160325

<h4>Objectives</h4>The Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT) is a Phase IIb randomized, placebo-controlled clinical trial, testing doxycycline (100mg bid) for inhibition of growth in the greatest transverse, orthogonal diameter of small abdominal aortic aneurysms (AAA).<h4>Methods</h4>We will enroll 258 patients, ≥55years of age who have AAA, men: 3.5-5.0cm and women: 3.5-4.5cm on CT scans confirmed centrally. The primary outcome is growth in maximal tran ...[more]

PMID: 27018941

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Project description:ImportanceAbdominal aortic aneurysms affect more than 3% of US older adults.ObjectiveTo test whether doxycycline reduces the growth of abdominal aortic aneurysm over 2 years as measured by maximum transverse diameter.Design, setting, and participantsParallel, 2-group, randomized clinical trial that was conducted at 22 US clinical centers between May 2013 and January 2017, and enrolled patients 50 years or older with small (3.5-5.0 cm for men, 3.5-4.5 cm for women) infrarenal aneurysms. The final date of follow-up was July 31, 2018.InterventionsPatients were randomized to receive twice daily for 2 years doxycycline 100 mg orally (as capsules) (n = 133) or placebo (n = 128).Main outcomes and measuresThe primary outcome was change in abdominal aortic aneurysm maximum transverse diameter measured from CT images at baseline and follow-up at 2 years. Patients were assigned ranks based on the maximum transverse diameter (measured or imputed) of the aorta and also if they underwent aneurysm repair or died. The ranks were converted to scores having a normal distribution to facilitate the primary analysis ("normal scores").ResultsOf 261 patients randomized, no follow-up CT scans were obtained on 7 (3%), leaving a final analysis set of 129 patients assigned to doxycycline and 125 to placebo (mean [SD] age, 71.0 years [7.4 years], 35 women [14%]). The outcome normal scores used in the primary analysis were based on maximum transverse diameter (measured or imputed) in 113 patients (88%) in the doxycycline group and 112 patients (90%) in the placebo group; aneurysm repair in 13 (10%) and 9 (7%), and death in 3 (2%) and 4 (3%), respectively. The primary outcome, normal scores reflecting change in aortic diameter, did not differ significantly between the 2 groups, mean change in normal scores, 0.0262 vs -0.0258 (1-sided P = .71). Mean (SD) baseline maximum transverse diameter was 4.3 cm (0.4 cm) for doxycycline and 4.3 cm (0.4 cm) for placebo. At the 2-year follow-up, the change in measured maximum transverse diameter was 0.36 cm (95% CI, 0.31 to 0.40 cm) for 96 patients in the doxycycline group vs 0.36 cm (95% CI, 0.30 to 0.41 cm) for 101 patients in the placebo group (difference, 0.0; 95% CI, -0.07 to 0.07 cm; 2-sided P = .93). No patients were withdrawn from the study because of adverse effects. Joint pain occurred in 84 of 129 patients (65%) with doxycycline and 79 of 125 (63%) with placebo.Conclusions and relevanceAmong patients with small infrarenal abdominal aortic aneurysms, doxycycline compared with placebo did not significantly reduce aneurysm growth at 2 years. These findings do not support the use of doxycycline for reducing the growth of small abdominal aortic aneurysms.Trial registrationClinicalTrials.gov Identifier: NCT01756833.

Project description:BACKGROUND:The late durability of endovascular aneurysm repair (EVAR) has been limited by progressive aortic degeneration believed to be mediated by matrix metalloproteases (MMP). The goal of this study was to evaluate the effect of a MMP inhibitor, doxycycline, on EVAR. METHODS:Patients undergoing EVAR were randomized to doxycycline (100 mg twice daily) or placebo for 6 months following the procedure. Clinical data, blood samples, and computed tomography (CT) scans were obtained preoperatively, postoperatively (blood only), and at 1- and 6-month follow-up. Forty-four subjects were analyzed based on intention-to-treat. RESULTS:Plasma MMP-9 decreased significantly below baseline in the doxycycline (N = 20) treated patients at 6 months (-16.4% +/- 20.7%, P < .05) while there was a nonsignificant increase in the placebo (N = 24) group (128.1% +/- 73.5%). This was primarily related to changes between 1 and 6 months. In patients with endoleaks at 6 months, plasma MMP-9 increased in 83% of the placebo treated patients, but in only 14% of the doxycycline treated group (P < .03). Among endoleak-free patients with AneuRx or Excluder endografts, doxycycline treatment resulted in greater decreases in maximum aortic diameter than placebo treatment (-13.3% +/- 3.3% vs -3.8% +/- 3.0%, P < .05). Furthermore, doxycycline treatment significantly reduced the aortic neck dilatation at 6 months in Excluder treated patients. CONCLUSION:There is evidence of persistent MMP release representing ongoing aortic degradation after endografting which can be inhibited by doxycycline therapy. In analyses based on the endograft used, treatment with doxycycline also demonstrated evidence of increased aortic dimensional stability, a surrogate marker for long-term success of EVAR. Although encouraging, these results require confirmation in larger patient populations. Doxycycline should undergo more thorough evaluation as a potential adjuvant treatment to improve the results of EVAR, particularly in certain subgroups.

Dataset Information

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.

Publications

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.

Similar Datasets

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