Trial Outcomes & Findings for Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (NCT NCT01756833)

Last Updated: 2021-11-26

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

261 participants

Primary outcome timeframe

Baseline and two years from randomization (when patients were late in returning for visits, their data were used up to three years).

Results posted on

2021-11-26

Participant Flow

Participant milestones

Participant milestones
Measure	Doxycycline 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
Overall Study STARTED	133	128
Overall Study COMPLETED	129	125
Overall Study NOT COMPLETED	4	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Doxycycline 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
Overall Study Withdrawal by Subject	4	3

Baseline Characteristics

Aneurysm diameter (cm) measured in men

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Doxycycline n=129 Participants 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 Participants 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule	Total n=254 Participants Total of all reporting groups
Age, Continuous	71.0 years STANDARD_DEVIATION 7.5 • n=129 Participants	70.9 years STANDARD_DEVIATION 7.3 • n=125 Participants	71.0 years STANDARD_DEVIATION 7.4 • n=254 Participants
Sex: Female, Male Female	18 Participants n=129 Participants	17 Participants n=125 Participants	35 Participants n=254 Participants
Sex: Female, Male Male	111 Participants n=129 Participants	108 Participants n=125 Participants	219 Participants n=254 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=129 Participants	4 Participants n=125 Participants	10 Participants n=254 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	122 Participants n=129 Participants	119 Participants n=125 Participants	241 Participants n=254 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=129 Participants	2 Participants n=125 Participants	3 Participants n=254 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=129 Participants	1 Participants n=125 Participants	1 Participants n=254 Participants
Race (NIH/OMB) Asian	1 Participants n=129 Participants	4 Participants n=125 Participants	5 Participants n=254 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	2 Participants n=129 Participants	0 Participants n=125 Participants	2 Participants n=254 Participants
Race (NIH/OMB) Black or African American	3 Participants n=129 Participants	4 Participants n=125 Participants	7 Participants n=254 Participants
Race (NIH/OMB) White	120 Participants n=129 Participants	113 Participants n=125 Participants	233 Participants n=254 Participants
Race (NIH/OMB) More than one race	1 Participants n=129 Participants	1 Participants n=125 Participants	2 Participants n=254 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=129 Participants	2 Participants n=125 Participants	4 Participants n=254 Participants
Region of Enrollment United States	129 participants n=129 Participants	125 participants n=125 Participants	254 participants n=254 Participants
Smoking Status Current Smoker	44 Participants n=129 Participants	43 Participants n=125 Participants	87 Participants n=254 Participants
Smoking Status Former Smoker	75 Participants n=129 Participants	73 Participants n=125 Participants	148 Participants n=254 Participants
Smoking Status Never Smoked	10 Participants n=129 Participants	9 Participants n=125 Participants	19 Participants n=254 Participants
Clinical History Hypercholesterolemia	98 Participants n=129 Participants	98 Participants n=125 Participants	196 Participants n=254 Participants
Clinical History Coronary artery disease	51 Participants n=129 Participants	53 Participants n=125 Participants	104 Participants n=254 Participants
Clinical History Cancer	44 Participants n=129 Participants	38 Participants n=125 Participants	82 Participants n=254 Participants
Clinical History Chronic obstructive pulmonary disease	30 Participants n=129 Participants	29 Participants n=125 Participants	59 Participants n=254 Participants
Clinical History Diabetes	35 Participants n=129 Participants	22 Participants n=125 Participants	57 Participants n=254 Participants
Clinical History Family history of abdominal aortic aneurysm	27 Participants n=129 Participants	20 Participants n=125 Participants	47 Participants n=254 Participants
Clinical History Atrial fibrillation	16 Participants n=129 Participants	17 Participants n=125 Participants	33 Participants n=254 Participants
Clinical History Stroke	13 Participants n=129 Participants	15 Participants n=125 Participants	28 Participants n=254 Participants
Clinical History Congestive Heart Failure	11 Participants n=129 Participants	9 Participants n=125 Participants	20 Participants n=254 Participants
Medications Statin	104 Participants n=129 Participants	103 Participants n=125 Participants	207 Participants n=254 Participants
Medications Any antihypertensive	105 Participants n=129 Participants	94 Participants n=125 Participants	199 Participants n=254 Participants
Medications B-Blocker	68 Participants n=129 Participants	63 Participants n=125 Participants	131 Participants n=254 Participants
Medications Diuretics	43 Participants n=129 Participants	40 Participants n=125 Participants	83 Participants n=254 Participants
Medications Angiotensin-converting enzyme inhibitor	51 Participants n=129 Participants	37 Participants n=125 Participants	88 Participants n=254 Participants
Medications Calcium channel blocker	26 Participants n=129 Participants	34 Participants n=125 Participants	60 Participants n=254 Participants
Medications Angiotensin receptor blocker	20 Participants n=129 Participants	25 Participants n=125 Participants	45 Participants n=254 Participants
Medications Aspirin or other antiplatelet	95 Participants n=129 Participants	92 Participants n=125 Participants	187 Participants n=254 Participants
Medications Daily aspirin	86 Participants n=129 Participants	89 Participants n=125 Participants	175 Participants n=254 Participants
Medications Other antiplatelet	19 Participants n=129 Participants	25 Participants n=125 Participants	44 Participants n=254 Participants
Aneurysm Diameter (Overall)	4.3 cm STANDARD_DEVIATION 0.4 • n=129 Participants	4.3 cm STANDARD_DEVIATION 0.4 • n=125 Participants	4.3 cm STANDARD_DEVIATION 0.4 • n=254 Participants
Aneurysm Diameter (Men)	4.3 cm STANDARD_DEVIATION 0.4 • n=111 Participants • Aneurysm diameter (cm) measured in men	4.4 cm STANDARD_DEVIATION 0.4 • n=108 Participants • Aneurysm diameter (cm) measured in men	4.4 cm STANDARD_DEVIATION 0.4 • n=219 Participants • Aneurysm diameter (cm) measured in men
Aneurysm Diameter (Women)	4.1 cm STANDARD_DEVIATION 0.3 • n=18 Participants • Aneurysm diameter (cm) measured in women	3.9 cm STANDARD_DEVIATION 0.3 • n=17 Participants • Aneurysm diameter (cm) measured in women	4.0 cm STANDARD_DEVIATION 0.3 • n=35 Participants • Aneurysm diameter (cm) measured in women
Aneurysm Volume (Overall)	97.0 cm^3 STANDARD_DEVIATION 24.0 • n=129 Participants	95.8 cm^3 STANDARD_DEVIATION 24.0 • n=125 Participants	96.4 cm^3 STANDARD_DEVIATION 24.0 • n=254 Participants
Aneurysm Volume (Men)	99.0 cm^3 STANDARD_DEVIATION 24.3 • n=111 Participants • Aneurysm volume (cm3) measured in men	99.2 cm^3 STANDARD_DEVIATION 23.3 • n=108 Participants • Aneurysm volume (cm3) measured in men	99.1 cm^3 STANDARD_DEVIATION 23.8 • n=219 Participants • Aneurysm volume (cm3) measured in men
Aneurysm Volume (Women)	84.9 cm^3 STANDARD_DEVIATION 18.5 • n=18 Participants • Aneurysm volume (cm3) measured in women	74.3 cm^3 STANDARD_DEVIATION 15.9 • n=17 Participants • Aneurysm volume (cm3) measured in women	79.6 cm^3 STANDARD_DEVIATION 16.7 • n=35 Participants • Aneurysm volume (cm3) measured in women
MMP-9 Levels (ng/ml)	54.6 ng/ml STANDARD_DEVIATION 53.2 • n=128 Participants • MMP-9 levels (ng/ml) measured at baseline	55.0 ng/ml STANDARD_DEVIATION 51.1 • n=124 Participants • MMP-9 levels (ng/ml) measured at baseline	54.8 ng/ml STANDARD_DEVIATION 52.1 • n=252 Participants • MMP-9 levels (ng/ml) measured at baseline
CRP Levels, mg/l	5.4 mg/l STANDARD_DEVIATION 13.6 • n=128 Participants • CRP Levels (mg/l) measured at baseline	3.6 mg/l STANDARD_DEVIATION 4.9 • n=124 Participants • CRP Levels (mg/l) measured at baseline	4.5 mg/l STANDARD_DEVIATION 10.3 • n=252 Participants • CRP Levels (mg/l) measured at baseline

PRIMARY outcome

Timeframe: Baseline and two years from randomization (when patients were late in returning for visits, their data were used up to three years).

Population: The number of participants refers to the number for whom CT scans were available.

Outcome measures

Outcome measures
Measure	Doxycycline n=129 Participants 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 Participants 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
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).	0.0262 z-score Standard Deviation 1.0	-0.0258 z-score Standard Deviation 1.0

SECONDARY outcome

Timeframe: Six months, one year, and two years (when patients were late in returning for visits their data were used up to three years).

Population: All patients for whom any follow-up CT scans of the abdomen and pelvis were obtained.

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.

Outcome measures

Outcome measures
Measure	Doxycycline n=129 Participants 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 Participants 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
Maximum Transverse Diameter, cm Maximum Transverse Diameter, cm 6 months	4.40 cm Standard Deviation 0.44	4.40 cm Standard Deviation 0.43
Maximum Transverse Diameter, cm Maximum Transverse Diameter, cm 1 year	4.49 cm Standard Deviation 0.48	4.48 cm Standard Deviation 0.44
Maximum Transverse Diameter, cm Maximum Transverse Diameter, cm 2 year	4.61 cm Standard Deviation 0.52	4.61 cm Standard Deviation 0.53
Maximum Transverse Diameter, cm Maximum Transverse Diameter, cm Baseline to 2 year change	0.36 cm Standard Deviation 0.21	0.36 cm Standard Deviation 0.28

SECONDARY outcome

Timeframe: Six months, one year, and two years (when patients were late in returning for visits their data were used up to three years).

Population: All patients for whom any follow-up CT scans of the abdomen and pelvis were obtained.

Outcome measures

Outcome measures
Measure	Doxycycline n=129 Participants 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 Participants 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
Volume, cm^3 Volume, cm^3 2 year	113.60 cm^3 Standard Deviation 34.91	111.20 cm^3 Standard Deviation 33.14
Volume, cm^3 Volume, cm^3 6 months	102.90 cm^3 Standard Deviation 26.19	100.40 cm^3 Standard Deviation 26.27
Volume, cm^3 Volume, cm^3 1 year	106.00 cm^3 Standard Deviation 29.13	105.00 cm^3 Standard Deviation 28.28
Volume, cm^3 Volume, cm^3 Baseline to 2 year change	18.60 cm^3 Standard Deviation 14.38	19.16 cm^3 Standard Deviation 15.75

SECONDARY outcome

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).

Population: All patients for whom any follow-up CT scans of the abdomen and pelvis were obtained.

Outcome measures

Outcome measures
Measure	Doxycycline n=129 Participants 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 Participants 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
MMP-9, ng/ml MMP-9, ng/ml 6 months	60.9 ng/ml Standard Deviation 85.3	61.9 ng/ml Standard Deviation 61.8
MMP-9, ng/ml MMP-9, ng/ml 1 year	63.0 ng/ml Standard Deviation 90.1	61.0 ng/ml Standard Deviation 91.5
MMP-9, ng/ml MMP-9, ng/ml 1 year, 6 months	48.8 ng/ml Standard Deviation 43.9	68.3 ng/ml Standard Deviation 86.7
MMP-9, ng/ml MMP-9, ng/ml 2 year	53.8 ng/ml Standard Deviation 54.8	52.8 ng/ml Standard Deviation 41.9

SECONDARY outcome

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).

Population: All patients for whom any follow-up CT scans of the abdomen and pelvis were obtained.

Outcome measures

Outcome measures
Measure	Doxycycline n=129 Participants 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 Participants 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
CRP, mg/l CRP, mg/l 1 year, 6 months	3.5 mg/l Standard Deviation 6.5	5.7 mg/l Standard Deviation 15.1
CRP, mg/l CRP, mg/l 2 year	5.9 mg/l Standard Deviation 15.6	4.0 mg/l Standard Deviation 5.3
CRP, mg/l CRP, mg/l 6 months	5.4 mg/l Standard Deviation 12.7	4.5 mg/l Standard Deviation 10.7
CRP, mg/l CRP, mg/l 1 year	3.5 mg/l Standard Deviation 4.8	4.1 mg/l Standard Deviation 6.9

OTHER_PRE_SPECIFIED outcome

Timeframe: Two years

Population: Full analysis population.

Clinically reported rupture events.

Outcome measures

Outcome measures
Measure	Doxycycline n=129 Participants 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 Participants 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
Number of Participants With Aneurysm Rupture	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Two years

Population: Full analysis population.

Clinically reported aneurysm repair.

Outcome measures

Outcome measures
Measure	Doxycycline n=129 Participants 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 Participants 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
Number of Participants With Surgical Intervention	13 Participants	9 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Two years

Population: Full analysis population.

Clinically reported deaths.

Outcome measures

Outcome measures
Measure	Doxycycline n=129 Participants 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 Participants 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
Number of Participants Who Died	3 Participants	4 Participants

Adverse Events

Doxycycline

Serious events: 70 serious events

Other events: 121 other events

Deaths: 3 deaths

Placebo

Serious events: 71 serious events

Other events: 111 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Doxycycline n=129 participants at risk 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 participants at risk 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
Musculoskeletal and connective tissue disorders Frequent joint pain	65.1% 84/129 • Number of events 84 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	63.2% 79/125 • Number of events 79 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Gastrointestinal disorders Frequent gastric or intestinal upset	45.0% 58/129 • Number of events 58 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	44.8% 56/125 • Number of events 56 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Blood and lymphatic system disorders Frequent bleeding or bruising	36.4% 47/129 • Number of events 47 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	43.2% 54/125 • Number of events 54 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
General disorders Frequent spells of dizziness	26.4% 34/129 • Number of events 34 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	29.6% 37/125 • Number of events 37 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Skin and subcutaneous tissue disorders Skin rash or hives	31.8% 41/129 • Number of events 41 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	23.2% 29/125 • Number of events 29 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Eye disorders Visual disturbance	20.2% 26/129 • Number of events 26 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	34.4% 43/125 • Number of events 43 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Skin and subcutaneous tissue disorders Moderate to severe sunburn	29.5% 38/129 • Number of events 38 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	11.2% 14/125 • Number of events 14 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
General disorders Frequent headaches	20.9% 27/129 • Number of events 27 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	16.0% 20/125 • Number of events 20 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
General disorders Tooth discoloration	9.3% 12/129 • Number of events 12 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	14.4% 18/125 • Number of events 18 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
General disorders Fever	8.5% 11/129 • Number of events 11 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	14.4% 18/125 • Number of events 18 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
General disorders Other symptom requiring study drug dose adjustment or discontinuation	20.9% 27/129 • Number of events 27 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	21.6% 27/125 • Number of events 27 • Two years Adverse Events were classified without regard to specific Adverse Event Term.

Additional Information

Michael L. Terrin, MDCM, MPH, Contact Principal Investigator

University of Maryland School of Medicine

Phone: 410-706-6139

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Doxycycline n=129 participants at risk 100 mg capsules, twice a day, for a period of two years. Doxycycline: 100 mg po bid	Placebo n=125 participants at risk 100 mg capsules, twice a day, for a period of two years. Placebo: capsule identical to the doxycycline capsule
Cardiac disorders Serious or Unexpected Adverse Events	10.9% 14/129 • Number of events 18 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	8.8% 11/125 • Number of events 16 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Gastrointestinal disorders Serious or Unexpected Adverse Events	10.9% 14/129 • Number of events 27 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	12.8% 16/125 • Number of events 24 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
General disorders Serious or Unexpected Adverse Events	7.8% 10/129 • Number of events 13 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	8.8% 11/125 • Number of events 18 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Infections and infestations Serious or Unexpected Adverse Events	9.3% 12/129 • Number of events 15 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	4.8% 6/125 • Number of events 6 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Injury, poisoning and procedural complications Serious or Unexpected Adverse Events	4.7% 6/129 • Number of events 9 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	5.6% 7/125 • Number of events 10 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Metabolism and nutrition disorders Serious or Unexpected Adverse Events	3.1% 4/129 • Number of events 4 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	1.6% 2/125 • Number of events 6 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Musculoskeletal and connective tissue disorders Serious or Unexpected Adverse Events	4.7% 6/129 • Number of events 6 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	6.4% 8/125 • Number of events 11 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Serious or Unexpected Adverse Events	5.4% 7/129 • Number of events 9 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	4.8% 6/125 • Number of events 6 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Nervous system disorders Serious or Unexpected Adverse Events	7.8% 10/129 • Number of events 21 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	4.8% 6/125 • Number of events 8 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Renal and urinary disorders Serious or Unexpected Adverse Events	3.9% 5/129 • Number of events 9 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	4.8% 6/125 • Number of events 6 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Respiratory, thoracic and mediastinal disorders Serious or Unexpected Adverse Events	9.3% 12/129 • Number of events 23 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	9.6% 12/125 • Number of events 22 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Surgical and medical procedures Serious or Unexpected Adverse Events	24.8% 32/129 • Number of events 36 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	30.4% 38/125 • Number of events 45 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Vascular disorders Serious or Unexpected Adverse Events	3.9% 5/129 • Number of events 7 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	5.6% 7/125 • Number of events 8 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Reproductive system and breast disorders Serious or Unexpected Adverse Events	1.6% 2/129 • Number of events 2 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	0.80% 1/125 • Number of events 1 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Psychiatric disorders Serious or Unexpected Adverse Events	2.3% 3/129 • Number of events 3 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	1.6% 2/125 • Number of events 2 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Skin and subcutaneous tissue disorders Serious or Unexpected Adverse Events	0.00% 0/129 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	2.4% 3/125 • Number of events 3 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Social circumstances Serious or Unexpected Adverse Events	0.78% 1/129 • Number of events 1 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	0.00% 0/125 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Blood and lymphatic system disorders Serious or Unexpected Adverse Events	0.00% 0/129 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	0.80% 1/125 • Number of events 1 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Endocrine disorders Serious or Unexpected Adverse Events	0.00% 0/129 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	0.80% 1/125 • Number of events 1 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Eye disorders Serious or Unexpected Adverse Events	0.78% 1/129 • Number of events 1 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	0.00% 0/125 • Two years Adverse Events were classified without regard to specific Adverse Event Term.
Hepatobiliary disorders Serious or Unexpected Adverse Events	0.78% 1/129 • Number of events 1 • Two years Adverse Events were classified without regard to specific Adverse Event Term.	2.4% 3/125 • Number of events 3 • Two years Adverse Events were classified without regard to specific Adverse Event Term.