Back to resultsNon-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA^3CT)
Primary Purpose
Aneurysm
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Doxycycline
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Aneurysm focused on measuring abdominal, aortic, aneurysm
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.
Sites / Locations
- University of Arizona Medical Center
- Carondelet Heart & Vascular Institute
- University of Southern California
- Stanford University
- Miami Cardiac and Vascular Institute
- University of South Florida Health Center
- Northwestern University Memorial Hospital
- University of Maryland Medical Center
- Beth Israel Deaconness Medical Center
- University of Michigan Medical Center
- McLaren Northern Michigan
- Washington University School of Medicine
- Omaha VAMC
- University of Nebraska Medical Center
- Columbia University Medical Center
- Oregon Health Sciences University
- Portland VAMC
- Geisinger Medical Center
- Vanderbilt University Medical Center
- University of Texas Southwestern Medical Center
- University of Utah Health Sciences Center
- Utah VAMC
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Doxycycline
Placebo
Arm Description
100 mg capsules, twice a day, for a period of two years.
100 mg capsules, twice a day, for a period of two years.
Outcomes
Primary Outcome Measures
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).
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
Maximum Transverse Diameter, cm
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
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
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
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).
Full Information
NCT ID
NCT01756833
First Posted
December 20, 2012
Last Updated
October 29, 2021
Sponsor
University of Maryland, Baltimore
Collaborators
National Institute on Aging (NIA)
1. Study Identification
Unique Protocol Identification Number
NCT01756833
Brief Title
Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial
Acronym
N-TA^3CT
Official Title
Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA^3CT)
Study Type
Interventional
2. Study Status
Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
May 2013 (Actual)
Primary Completion Date
July 23, 2019 (Actual)
Study Completion Date
July 23, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Maryland, Baltimore
Collaborators
National Institute on Aging (NIA)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aneurysm
Keywords
abdominal, aortic, aneurysm
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
261 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Doxycycline
Arm Type
Active Comparator
Arm Description
100 mg capsules, twice a day, for a period of two years.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
100 mg capsules, twice a day, for a period of two years.
Intervention Type
Drug
Intervention Name(s)
Doxycycline
Other Intervention Name(s)
doxycycline hyclate, Vibramycin, Oracea, Adoxa, Atridox and others
Intervention Description
100 mg po bid
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
capsule containing inert filler
Intervention Description
capsule identical to the doxycycline capsule
Primary Outcome Measure Information:
Title
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).
Description
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.
Time Frame
Baseline and two years from randomization (when patients were late in returning for visits, their data were used up to three years).
Secondary Outcome Measure Information:
Title
Maximum Transverse Diameter, cm
Description
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.
Time Frame
Six months, one year, and two years (when patients were late in returning for visits their data were used up to three years).
Title
Volume, cm^3
Description
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.
Time Frame
Six months, one year, and two years (when patients were late in returning for visits their data were used up to three years).
Title
MMP-9, ng/ml
Description
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).
Time Frame
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).
Title
CRP, mg/l
Description
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).
Time Frame
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 Pre-specified Outcome Measures:
Title
Number of Participants With Aneurysm Rupture
Description
Clinically reported rupture events.
Time Frame
Two years
Title
Number of Participants With Surgical Intervention
Description
Clinically reported aneurysm repair.
Time Frame
Two years
Title
Number of Participants Who Died
Description
Clinically reported deaths.
Time Frame
Two years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael L Terrin, MD
Organizational Affiliation
University of Maryland, Baltimore
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Bernard T Baxter, MD
Organizational Affiliation
University of Nebraska
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jonathan Matsumura, MD
Organizational Affiliation
University of Wisconsin Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
John Curci, MD
Organizational Affiliation
Vanderbilt University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Arizona Medical Center
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
Carondelet Heart & Vascular Institute
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85745
Country
United States
Facility Name
University of Southern California
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Miami Cardiac and Vascular Institute
City
Miami
State/Province
Florida
ZIP/Postal Code
33176
Country
United States
Facility Name
University of South Florida Health Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Facility Name
Northwestern University Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Maryland Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Beth Israel Deaconness Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Michigan Medical Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
McLaren Northern Michigan
City
Petoskey
State/Province
Michigan
ZIP/Postal Code
49770
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Omaha VAMC
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Oregon Health Sciences University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Portland VAMC
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Geisinger Medical Center
City
Danville
State/Province
Pennsylvania
ZIP/Postal Code
17822
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37212
Country
United States
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75216
Country
United States
Facility Name
University of Utah Health Sciences Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Utah VAMC
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
Citations:
PubMed Identifier
27018941
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.
Results Reference
background
PubMed Identifier
32986071
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.
Results Reference
background
PubMed Identifier
32453350
Citation
Lachin JM. Nonparametric Statistical Analysis. JAMA. 2020 May 26;323(20):2080-2081. doi: 10.1001/jama.2020.5874. No abstract available.
Results Reference
background
PubMed Identifier
32453369
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.
Results Reference
result
PubMed Identifier
34655683
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.
Results Reference
derived
PubMed Identifier
33957227
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.
Results Reference
derived
PubMed Identifier
33595625
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.
Results Reference
derived
Learn more about this trial
Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial
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