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Pharmaceutical Aneurysm Stabilisation Trial


- candidate number3449
- NTR NumberNTR1345
- ISRCTNISRCTN wordt niet meer aangevraagd
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR16-jun-2008
- Secondary IDsP07.152 
- Public TitlePharmaceutical Aneurysm Stabilisation Trial
- Scientific TitleDoxycycline treatment for the stabilization of abdominal aortic aneurysms (AAA), a randomized placebo controlled trial
- ACRONYMPHAST
- hypothesisAAA is a common disease and a major cause of death due to rupture. Preventive surgical aneurysm repair is costly and associated with considerable morbidity and mortality. Doxycycline has been shown to attenuate the expansion of aneurysm in animal models of AAA and results from two small clinical trials show that 12 months doxycycline treatment is well tolerated and may arrested AAA growth.
We hypothesize that standard dose doxycycline treatment is a cost effective and well-tolerated means of stabilizing AAA. Thus providing a pharmaceutical means of stabilizing AAA, and reducing the need for AAA repair.
- Healt Condition(s) or Problem(s) studiedInflammation, Cardiovascular disease, Abdominal Aortic Aneurysm, Doxycycline, Metalloproteinases
- Inclusion criteriaPatients under surveillance with small aneurysms (i.e. 3.5-5.0 cm), and in larger AAA in patients who are unfit for or refuse open operation or endovascular intervention of their larger AAA (i.e. exceeding 5.0 cm).
- Exclusion criteria1. Unable to comply with follow up.
2. Contra-indications for doxycycline:
- known impaired liver function (ALAT >3-fold normal values)
- known renal failure (estimate clearance below 40 ml/min)
- excessive sun exposure.
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingDouble
- controlPlacebo
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-jul-2008
- planned closingdate1-jan-2011
- Target number of participants300
- InterventionsDoxycycline 100mg or placebo daily, 18 mo
- Primary outcome* Aneurysm growth at t=18 months as determined by ultrasound
- Secondary outcome* Secondary outcome measures are:
- growth at 6 and 12 months
- need for elective aneurysm repair
- rupture
- death
- an inventory of possible side effects (questionnaire).

Moreover, posible effect on atherosclerosis will be evaluated by:
- assesment of intima media thickness (carotid artery)
- plasma inflmmatory markers
- endothelial cell markers
- spirometric testing.
- TimepointsBaseline measurements, follow up at 6 months (6, 12 and 18 mo)
- Trial web siteN/A
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESMD, PhD Jan H. Lindeman
- CONTACT for SCIENTIFIC QUERIESMD, PhD Jan H. Lindeman
- Sponsor/Initiator Leiden University Medical Center (LUMC)
- Funding
(Source(s) of Monetary or Material Support)
Nuts/Ohra
- PublicationsN/A
- Brief summaryAn abdominal aortic aneurysm (AAA) affects 5-7% of people over 60, and is responsible for more than 15.000 deaths annually in the US alone. For unknown reasons, the incidence has been steadily increasing over the last two decades, and a further increase is anticipated. Current approaches towards AAA are surveillance, and preventive surgical elimination ('repair') of AAA over 5.5 cm. Unfortunately, traditional (open) elective AAA repair is associated with a relatively high morbidity and mortality. Although short-term results of endovascular repair appear more favourable, mid- and long-term mortality is similar to that of conventional repair. Moreover, the high incidence of endograft failure repair requires life-long follow-up. According to the available studies, including a Dutch randomized trial, endovascular repair is currently not cost-effective. Hence availability of medical therapy, inhibiting aneurysmal growth and reducing the need for invasive treatment, could have major advances both from patients' as well as from socio-economical perspective.
Increased activities of the matrix metalloproteinases, in particular MMP-9, are considered a key-factor in AAA development and growth. The tetracycline analogue doxycycline attenuates both MMP expression and activity. It was thus hypothesised that doxycycline may prevent AAA growth. Indeed, doxycycline has been shown to prevent aneurysm formation in animal models of the disease. Results from two small clinical studies suggest that doxycycline treatment may also arrest AAA growth in patients with medium sized aneurysm.
We evaluated the effect of pre-operative doxycycline treatment in patients undergoing conventional AAA repair (NHS 2000B165), and confirmed the effects of doxycycline on expression of the gelatinase MMP-9. Our results also revealed remarkable suppression of MMP-8 (neutrophil collagenase) protein expression. These findings are new and remarkable. MMP-8 is a stored secondary granule protein that is only expressed during the late myeloid maturation pathway of neutrophils, but not in mature, infiltrating neutrophils. This suggests that the effect of doxycycline on aneurysm growth may extend beyond the effect on MMP expression and involves attenuation of neutrophil influx. We confirmed the effect on neutrophil influx by immunohistochemical analysis and explored the mechanism underlying reduced neutrophil influx. This analysis showed that that doxycycline, via its effects on the transcription factors AP-1 and C/EBP, profoundly reduces IL-6 and IL-8 hyperexpression in AAA. This not only results in reduced neutrophil influx, but also in attenuation of cytotoxic T-cell activation.
Doxycycline has a well-established safety record, is generally well tolerated and is inexpensive. Doxycycline should thus be considered a promising lead-candidate for the pharmaceutical stabilization of AAA. Yet, its efficiency remains to be established in a prospective, sufficiently powered clinical trial. We therefore propose to evaluate the effects of doxycycline (standard dose, 100 mg/day) on AAA growth in a double blind placebo controlled multi-centre study in patients under surveillance for a small (3,5-5,0 cm) or patients with larger (over 5,5 cm) AAA who are unfit for or refuse intervention.
- Main changes (audit trail)
- RECORD16-jun-2008 - 25-jul-2008


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