To assess the effect of ACZ885 on AAA size and growth rate as measured with ultrasound at 12 months.Secondary Objectives * To assess the safety and tolerability of monthly 150 mg subcutaneousdoses of ACZ885 in subjects with AAA over a treatment…
ID
Source
Brief title
Condition
- Aneurysms and artery dissections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy variables will be the AAA size and growth rate (change from
baseline AAA size per year) from the ultrasound assessment.
Secondary outcome
Volumetric and biophysical profiling data from CT scan of AAA, as well as
hs-CRP, IL-6, total IL-1* and immunoglobulins.
The number and percentage of subjects with major cardiovascular events (MACE),
acute or
elective aneurysm repair, aneurysm rupture, death (any cause) and any other
clinical events of
special interest over the 12-month treatment period.
Safety parameters: all vital signs data, ECG data, laboratory data, adverse
events and immunogenicity data.
Background summary
Abdominal aortic aneurysm (AAA) is a condition characterized by abnormal
dilation of the abdominal aorta. As the AAA grows, the risk of aortic rupture
and death also grows. AAA affects ~3.5 million individuals in the USA alone,
resulting in ~55,000 deaths annually in the USA and EU. The incidence of AAA is
expected to increase with the world*s aging population, and it remains vastly
undertreated. Current clinical management of AAA relies on appropriately timed
endovascular stent graft procedures or open surgery, usually triggered by a
critical AAA size. Assessing aneurysm size and growth rate are the foundations
for clinical decision making at this time, since both are associated with AAA
rupture rate. While surgical intervention for AAA remains the standard of care
and new technologies such as endovascular stent grafts appear promising, these
options are not without detriment. Surgical mortality is high (~5% open repair,
up to 1.7% endovascular), late complications are frequent (25-40% for
endovascular), and procedures are costly. The pathophysiology of AAA involves
three main processes: inflammation, proteolysis, and apoptosis. Substantial
evidence suggests that the IL-1* protein plays a role in each of these
processes. Preclinical data data support a hypothesis that IL-1* is important
in AAA pathogenesis. In AAA patients, inhibition of systemic IL-1* should
decrease inflammation, reduce proteolysis, and diminish smooth muscle cell
apoptosis. These effects should, in turn, structurally stabilize the aneurysm
and ultimately slow or halt its growth. If clinically meaningful effects are
observed, ACZ885 therapy in AAA may delay or obviate the need for risky and
expensive procedures and surgeries. At the present time, there are no efficacy
or safety studies in humans with AAA for any anit-IL-1* therapies.
Study objective
To assess the effect of ACZ885 on AAA size and growth rate as measured with
ultrasound at 12 months.
Secondary Objectives * To assess the safety and tolerability of monthly 150 mg
subcutaneous
doses of ACZ885 in subjects with AAA over a treatment period of 12months.
Study design
This is a non-confirmatory, double-blind, randomized, placebo-controlled,
two-arm parallel group study in subjects who have been diagnosed with AAA.
Eligible subjects will receive 12 monthly doses of 150mg of ACZ885 or placebo
administered subcutaneously as randomized in a 1:1 ratio. The size of the AAA
will be followed using ultrasonography over the course of the study. The study
will consist of an up to 30-day screening period, a 12-month treatment period,
and an End of Study evaluation approximately 1 month after the last study drug
administration.
Intervention
Monthly subcutaneous doses of 150 mg ACZ885
Monthly subcutaneous doses of placebo to 150 mg ACZ885
Study burden and risks
Before starting the study, patients will have a screening visit and will be
asked about their health and your medical history and concomitant medication.
They will be physically examined and vital signs will be measured. Patients
will have an ECG and blood and urine will be taken for laboratory testing.
Females will have a pregnancy test. An ultrasound will also be performed. Tests
will also be done for illegal *street* drugs, for HIV/AIDS, hepatitis B and C,
and tuberculosis but the results of these tests will not be captured in the
study database. If patients test positive for any of these tests, they will not
be allowed to enroll in the study.
Patients that join the study will be asked to come to the study site
approximately 14 times over about 14 months. Each visit should take about 2-3
hours.
Patients will be administered the study medicine once a month for 12 months.
During the site visits, they will be clinically examined and vital signs will
be measured. The patients* ongoing smoking status will also be discussed and
recorded. Blood samples will be taken pre-dose at each visit. Patients will
have monthly urine tests for pregnancy, if appropriate. There will be a total
of 5 ultrasounds during the study: during the screening period, after 3, 6, 9
and 12 months of treatment. The ultrasounds after 3 and 9 months of treatment
are for safety purposes only. At visits on months 1, 2, 3, 4, 5, 6, 9, and 12,
patients will have an ECG.
For every visit, patients should fast overnight for at least 10 hours. For
overnight fasts, no food or fluids are permitted (except water). Patients
should take their medications as per their regular schedule for all visits,
including fasted visits.
Patients will be asked to give some blood, which can make them feel faint or
sick. It can also be uncomfortable and cause local bruising. All blood samples
will be taken by direct needle stick. Rarely, a small blood clot may form or
infection could occur at the site where the blood was taken. Blood will be
taken 15 times during the study and approximately 610 mL (about 2 and a half
cups) of blood will be collected in total over the 14 months of the study.
When patients are given a dose of ACZ885 or placebo this will be injected just
under the surface of the skin. This may cause some reddening of the skin,
itching, swelling or pain. Identified risks with ACZ885 (canakinumab) and other
IL-1 receptor blockers include an increased risk of infections, injection site
reactions, decreased white blood cell and platelet count, increases in ALT or
AST, immunogenicity, and vertigo. Predominantly upper respiratory tract
infections have been reported in subjects treated with canakinumab.
Theoretical risks of ACZ885 include reduced wound healing and reduced response
to vaccines.
As a result of the ECG, the skin may become a little itchy and red where the
sticky pads are placed.
Ultrasound imaging (sonography) uses high-frequency sound waves to view soft
tissues and does not involve ionizing radiation. There are no known adverse
safety risks but ultrasound use does produce slight bioeffects on the body as
the tissue heats slightly when the acoustic waves enter the body and can also
produce small pockets of gas in tissue. A hand-held transducer is placed on the
skin to produce the image and its application will be limited to the region of
interest (abdomen for AAA) to minimize any discomfort and risk of cavitation.
Novartis Campus - Forum 1
Basel 4056
CH
Novartis Campus - Forum 1
Basel 4056
CH
Listed location countries
Age
Inclusion criteria
* Male and female subjects age *45 years of age
* Infrarenal abdominal aortic aneurysm with maximum diameter:
* for men *40mm and *50mm
* for women *38mm and *48mm
* On a stable medical regimen for at least 2 weeks prior to dosing
* Have an evaluable ultrasound image at screening for thequantitative determination of the AAA size
* At screening and pre-dose on Day 1, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes.
Sitting vital signs should be within the following ranges:
oral body temperature between 35.0-37.5°C
systolic blood pressure, 90-170 mm Hg
diastolic blood pressure, 50-100 mm Hg
pulse rate, 40 - 100 bpm
Exclusion criteria
*Known diabetes by medical history, a HbA1c of *6.5% at screening, or on an active diabetic medical regimen
* Women of child bearing potential unless using effective methods of contraception
* Subjects on the following medications:
1) Chronic systemic steroid treatment or other systemic immunosuppression. Use oftopical, ophthalmic or inhaled steroids at doses not considered to have systemic effects is allowed. Temporary use of steroids (e.g., for asthma exacerbations) are allowed if last steroid use is more than 1 month prior to screening and the anticipated frequency of requiring such steroids are less than once per year.
2) Any biologic drugs targeting the immune system, e.g., TNF blockers, anakinra, rituximab, abatacept, tocilizumab. Any previous history of the use of such biologics is also an excluded.
* Presence of a non-healing wound or infection, including active urinary tract infections, or any recent process requiring significant tissue healing per investigator assessment. Other active infections
within 2 weeks will be excluded.
* Previous infra-renal aortic surgery
* Known aortic dissection
* Subjects should exhibit no signs of clinically concerning unstable acceleration of AAA size or growth rate at the time of enrollment per investigator assessment
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-002088-25-NL |
| CCMO | NL46059.060.13 |