Abdominal Aortic Aneurysm (AAA)
Conditions
Keywords
Abdominal Aortic Aneurysm, AAA, IL-1b, Abdominal ultrasound
Brief summary
This study was designed to assess the safety, tolerability and efficacy of ACZ885 on aneurysmal growth rate in subjects with abdominal aortic aneurysms (AAA). The purpose of the study was to provide data to enable decisions regarding the further development of ACZ885 for subjects with abdominal aortic aneurysms. The design of this study addressed the primary objective of evaluating the change in aneurysmal size in subjects with AAA as a result of treatment with ACZ885.
Interventions
DRUGACZ885
ACZ885 150 mg liquid pre-filled syringes were administered s.c..
DRUGPlacebo
Matching placebo liquid pre-filled syringes were administered s.c..
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Male and female subjects age ≥45 years of age 2. Infrarenal abdominal aortic aneurysm with maximum diameter: for men ≥40mm and ≤50mm; for women ≥38mm and ≤48mm. 3. On a stable medical regimen for at least 2 weeks prior to dosing, per investigator assessment. 4. Have an evaluable ultrasound image at screening for the quantitative determination of the AAA size, per imaging core lab assessment. 5. At screening, vital signs should be within the following ranges: (a) oral body temperature between 35.0-37.5°C; (b) systolic blood pressure, 90-170 mm Hg; (c) diastolic blood pressure, 50-100 mm Hg; (d) pulse rate, 40 - 100 bpm. Key
Exclusion criteria
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment. 2. Known diabetes by medical history, an HbA1c of ≥6.5% at screening, or on an active diabetic medical regimen. 3. History of malignancy of any organ system other than localized basal cell carcinoma of the skin, treated or untreated, within the past 5 years. 4. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing and 30-day follow up period of the study. 5. Donation or loss of 400 ml or more of blood within eight (8) weeks prior to initial dosing, or longer if required by local regulation. 6. Subjects on the following medications: (a) Chronic systemic steroid treatment or other systemic immunosuppression; (b) Any biologic drugs targeting the immune system, along with a history of any previous use of such drugs. 7. Presence of a non-healing wound or infection, including active urinary tract infections, or any recent process requiring significant tissue healing per investigator assessment. 8. Significant illness which has not resolved within four (4) weeks prior to initial dosing or with a life expectancy less than 2 years. 9. Any of the following concomitant hepatic or renal conditions or diseases: (a) Nephrotic syndrome, or eGFR less than 30 mL/min/1.73 m2 per CRCL formula; (b) Prior organ transplant requiring immunosuppressive therapy; (c) Known active or recurrent hepatic disorder. 10. Previous infra-renal aortic surgery 11. Planned major surgery 12. Known aortic dissection 13. Subjects with eligible AAA diameter, but with known slow growth (\<2mm/year) or known stable AAA size over the prior one year of surveillance per investigator assessment. 14. Subjects should exhibit no signs of clinically concerning unstable acceleration of AAA size or growth rate at the time of enrollment per investigator assessment. 15. Known or suspected inherited connective tissue disorders (e.g., Marfan or Vascular Ehlers Danlos syndrome). 16. Recently unstable clinically significant cardiac disease within 3 months of screening, including but not limited to, unstable angina, acute myocardial infarction, and congestive heart failure (NYHA class IV). 17. Uncontrolled or refractory hypertension per Investigator determination. 18. Live vaccinations within 3 months prior to randomization, or live vaccinations planned during the study. 19. History of untreated tuberculosis infection or evidence of active tuberculosis (TB) infection. 20. History of multiple and recurring allergies or allergy to the investigational compound/compound class being used in this study. 21. History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result. 22. A positive Hepatitis B surface antigen or Hepatitis C test result whether at screening or historically. 23. For USA sites utilizing CT angiograms, subjects with a history of a previous reaction to contrast agent, a known sensitivity to iodine and known allergies (e.g, shellfish allergy), or other hypersensitivities to contrast agents. 24. Underlying immune disorders, autoimmunity or immunodeficiency. 25. History of drug or alcohol abuse within the 12 months prior to dosing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Abdominal Aortic Aneurysm (AAA) Size Per Year | month 3, month 12 | Size of the AAA was determined using an abdominal ultrasound technique at baseline, 3 months, and 12 months after treatment with study drug. Growth rate (in mm/year) was calculated from the change in AAA size compared to baseline |
Countries
Denmark, Netherlands, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 65 participants were randomized in a 1:1 ratio to one of the two treatment groups. One participant discontinued prior to taking any study medication. As such, the participant flow is based on 64 randomized participants.
Participants by arm
| Arm | Count |
|---|---|
| ACZ885 Participants received ACZ885 150 mg subcutaneously (s.c.) once per month for 12 months. | 31 |
| Placebo Participants received matching placebo to ACZ885 s.c. once per month for 12 months. | 33 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 1 | 0 |
| Overall Study | Administrative problems | 3 | 7 |
| Overall Study | Adverse Event | 7 | 4 |
Baseline characteristics
| Characteristic | ACZ885 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 69.4 Years STANDARD_DEVIATION 7.44 | 70.8 Years STANDARD_DEVIATION 5.84 | 70.1 Years STANDARD_DEVIATION 6.65 |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 27 Participants | 26 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 31 | 28 / 33 |
| serious Total, serious adverse events | 2 / 31 | 0 / 33 |
Outcome results
Primary
Change From Baseline in Abdominal Aortic Aneurysm (AAA) Size Per Year
Size of the AAA was determined using an abdominal ultrasound technique at baseline, 3 months, and 12 months after treatment with study drug. Growth rate (in mm/year) was calculated from the change in AAA size compared to baseline
Time frame: month 3, month 12
Population: The pharmacodynamic analysis set, which included randomized participants who received at least one dose of study drug, was considered for the analysis. However, only participants with values at each time point were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| ACZ885 | Change From Baseline in Abdominal Aortic Aneurysm (AAA) Size Per Year | Month 3 (n=23,31) | 0.781 millimeter/year |
| ACZ885 | Change From Baseline in Abdominal Aortic Aneurysm (AAA) Size Per Year | Month 12 (n=20,23) | 2.538 millimeter/year |
| Placebo | Change From Baseline in Abdominal Aortic Aneurysm (AAA) Size Per Year | Month 3 (n=23,31) | 2.519 millimeter/year |
| Placebo | Change From Baseline in Abdominal Aortic Aneurysm (AAA) Size Per Year | Month 12 (n=20,23) | 2.581 millimeter/year |
Comparison: Month 3p-value: =0.1037ANCOVA
Comparison: Month 12p-value: =0.4806ANCOVA