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

Objectives The Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT) is a Phase IIb randomized, placebo-controlled clinical trial, testing doxycycline (100 mg bid) for inhibition of growth in the greatest transverse, orthogonal diameter of small abdominal aortic aneurysms (AAA). Methods We will enroll 258 patients, ≥ 55 years of age who have AAA, men: 3.5–5.0 cm and women: 3.5–4.5 cm 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. Results Participant average age = 70.9 years, (SD = 7.6 years) and maximum transverse diameter = 4.3 cm for men (SD = 0.4) and 4.0 cm for women (SD = 0.3). Conclusion N-TA3CT 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%. Registration: clinicaltrials.gov #NCT01756833.

Variation in center-level frailty burden and the impact of frailty on long-term survival in patients undergoing elective repair for abdominal aortic aneurysms

“…Our analysis revealed that 45.0% of patients underwent elective AAA repair at less than the recommended 5.5 cm diameter threshold. In frail patients, 35.6% underwent EVAR and 22.2% underwent OAR with aneurysms measuring <5.5 cm. The Society for Vascular Surgery Clinical Practice Guidelines recommend elective repair for patients at low or acceptable surgical risk with a fusiform AAA that is 5.5 cm.…”

“…33 Development of medical therapies for slowing AAA growth, such as the ongoing work in doxycycline and metformin, also has the potential to produce a paradigm shift in our management of AAAs, especially for frail patients. 34,35 Age and comorbidities are associated with poor outcomes but are not useful as tools for determining candidacy for surgery given the heterogeneity of outcomes. 36,37 Frailty, however, has consistently been shown to predict poor outcomes, and more evidence continues to accumulate that frailty is multidimensional and goes beyond merely comorbidities and functional status.…”

Pentagalloyl Glucose and Its Functional Role in Vascular Health: Biomechanics and Drug-Delivery Characteristics

“…106,115 Currently, another clinical trial with a higher dosage of doxycycline is underway in the U.S. and its results are anticipated. 11 Further, AAA patients undergoing treatments with nonsteroidal anti-inflammatory drugs, diuretics, mast cell inhibitors, β blockers, calcium channel blockers, and ACE inhibitors have not exhibited any noteworthy accomplishments. 17,57,155 Other concerns about oral medication therapy for AAA include limitations with respect to current AAA animal models, correct drug dosage, etc .…”

Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small Abdominal Aortic Aneurysm

“…2 Although pharmaceuticals such as doxycycline are currently in trial for AAA treatment, no FDA approved medical treatment currently exists for those who do not qualify for operative repair. 3 While the etiology of AAA formation and growth is unclear at this time, we do know that an intense local inflammatory response leads to the eventual loss of vessel wall integrity. 4 The therapeutic benefit of mesenchymal stem cells (MSCs) in pathologies with substantial inflammatory responses such as graft vs host disease (GVHD), chronic obstructive pulmonary disease (COPD), and myocardial remodeling after infarction are well established.…”