AAA: ACZ885 for the Treatment of Abdominal Aortic Aneurysm

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02007252
• Collaborator: (none)
• Enrollment: 65
• Locations: 9
• Arms: 2
• Duration (Months): 22
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Abdominal Aortic Aneurysm (AAA)	Drug: ACZ885; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: A Randomized, Double-blind, Placebo-controlled, Multiple Dose Study of Subcutaneous ACZ885 for the Treatment of Abdominal Aortic Aneurysm
• Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ACZ885 Participants received ACZ885 150 mg subcutaneously (s.c.) once per month for 12 months.	Drug: ACZ885; ACZ885 150 mg liquid pre-filled syringes were administered s.c..
Placebo Comparator: Placebo Participants received matching placebo to ACZ885 s.c. once per month for 12 months.	Drug: Placebo; Matching placebo liquid pre-filled syringes were administered s.c..

Outcome Measures

Primary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Charlottesville	Virginia	United States	22903
2	Novartis Investigative Site	Copenhagen		Denmark	DK-2100
3	Novartis Investigative Site	Kolding		Denmark	6000
4	Novartis Investigative Site	Odense C		Denmark	DK-5000
5	Novartis Investigative Site	Amsterdam		Netherlands
6	Novartis Investigative Site	Eindhoven		Netherlands	5623EJ
7	Novartis Investigative Site	Orebro		Sweden	701 16
8	Novartis Investigative Site	Stockholm		Sweden	171 76
9	Novartis Investigative Site	Manchester		United Kingdom	M23 9LT

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02007252
• Other Study ID Numbers: CACZ885X2201; 2013-002088-25
• First Posted: Dec 10, 2013
• Last Update Posted: Jan 5, 2021
• Last Verified: Mar 1, 2019

• Keywords provided by Novartis Pharmaceuticals: Abdominal Aortic Aneurysm; AAA; IL-1b; Abdominal ultrasound
• Additional relevant MeSH terms: Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Abdominal

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Participants received ACZ885 150 mg subcutaneously (s.c.) once per month for 12 months.	Participants received matching placebo to ACZ885 s.c. once per month for 12 months.
Period Title: Overall Study
STARTED	31	33
Safety Analysis Set	31	33
Pharmacodynamic Analysis Set	31	33
COMPLETED	20	22
NOT COMPLETED	11	11

Baseline Characteristics

Arm/Group Title	ACZ885	Placebo	Total
Arm/Group Description	Participants received ACZ885 150 mg subcutaneously (s.c.) once per month for 12 months.	Participants received matching placebo to ACZ885 s.c. once per month for 12 months.	Total of all reporting groups
Overall Participants	31	33	64
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	69.4 (7.44)	70.8 (5.84)	70.1 (6.65)
Sex: Female, Male (Count of Participants)
Female	4 12.9%	7 21.2%	11 17.2%
Male	27 87.1%	26 78.8%	53 82.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Abdominal Aortic Aneurysm (AAA) Size Per Year
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	ACZ885	Placebo
Arm/Group Description	Participants received ACZ885 150 mg subcutaneously (s.c.) once per month for 12 months.	Participants received matching placebo to ACZ885 s.c. once per month for 12 months.
Measure Participants	31	33
Month 3 (n=23,31)	0.781	2.519
Month 12 (n=20,23)	2.538	2.581

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ACZ885, Placebo
	Comments	Month 3
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1037
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ACZ885, Placebo
	Comments	Month 12
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	= 0.4806
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Arm/Group Title	ACZ885		Placebo
Arm/Group Description	Participants received ACZ885 150 mg subcutaneously (s.c.) once per month for 12 months.		Participants received matching placebo to ACZ885 s.c. once per month for 12 months.
All Cause Mortality
	ACZ885		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ACZ885		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/31 (6.5%)		0/33 (0%)
Injury, poisoning and procedural complications
Hip fracture	1/31 (3.2%)		0/33 (0%)
Vascular disorders
Aortic aneurysm	1/31 (3.2%)		0/33 (0%)
Other (Not Including Serious) Adverse Events
	ACZ885		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/31 (90.3%)		28/33 (84.8%)
Blood and lymphatic system disorders
Anaemia	1/31 (3.2%)		0/33 (0%)
Cardiac disorders
Angina pectoris	0/31 (0%)		2/33 (6.1%)
Atrial fibrillation	2/31 (6.5%)		0/33 (0%)
Atrioventricular block second degree	0/31 (0%)		1/33 (3%)
Eye disorders
Cataract	0/31 (0%)		1/33 (3%)
Gastrointestinal disorders
Abdominal pain	3/31 (9.7%)		1/33 (3%)
Abdominal pain upper	2/31 (6.5%)		0/33 (0%)
Diarrhoea	1/31 (3.2%)		1/33 (3%)
Gastric ulcer	0/31 (0%)		1/33 (3%)
Gastrooesophageal reflux disease	0/31 (0%)		2/33 (6.1%)
Haematochezia	0/31 (0%)		1/33 (3%)
Nausea	1/31 (3.2%)		0/33 (0%)
Oesophagitis	0/31 (0%)		1/33 (3%)
Vomiting	0/31 (0%)		1/33 (3%)
General disorders
Energy increased	1/31 (3.2%)		0/33 (0%)
Fatigue	2/31 (6.5%)		0/33 (0%)
Impaired healing	1/31 (3.2%)		1/33 (3%)
Influenza like illness	0/31 (0%)		1/33 (3%)
Injection site hypersensitivity	1/31 (3.2%)		0/33 (0%)
Injection site pain	1/31 (3.2%)		1/33 (3%)
Injection site swelling	3/31 (9.7%)		2/33 (6.1%)
Malaise	1/31 (3.2%)		0/33 (0%)
Oedema peripheral	0/31 (0%)		4/33 (12.1%)
Infections and infestations
Erysipelas	1/31 (3.2%)		0/33 (0%)
Gastroenteritis	0/31 (0%)		1/33 (3%)
Influenza	0/31 (0%)		1/33 (3%)
Nasopharyngitis	5/31 (16.1%)		3/33 (9.1%)
Pneumonia	2/31 (6.5%)		1/33 (3%)
Respiratory tract infection	0/31 (0%)		1/33 (3%)
Rhinitis	2/31 (6.5%)		1/33 (3%)
Sinusitis	1/31 (3.2%)		0/33 (0%)
Tooth infection	0/31 (0%)		1/33 (3%)
Upper respiratory tract infection	2/31 (6.5%)		1/33 (3%)
Urinary tract infection	2/31 (6.5%)		1/33 (3%)
Vestibular neuronitis	1/31 (3.2%)		0/33 (0%)
Injury, poisoning and procedural complications
Contusion	1/31 (3.2%)		1/33 (3%)
Foot fracture	0/31 (0%)		1/33 (3%)
Ligament sprain	1/31 (3.2%)		1/33 (3%)
Wound	0/31 (0%)		1/33 (3%)
Investigations
Alanine aminotransferase increased	0/31 (0%)		2/33 (6.1%)
Aspartate aminotransferase increased	0/31 (0%)		2/33 (6.1%)
Blood creatinine increased	1/31 (3.2%)		0/33 (0%)
Blood glucose increased	0/31 (0%)		1/33 (3%)
International normalised ratio increased	1/31 (3.2%)		0/33 (0%)
Occult blood positive	2/31 (6.5%)		0/33 (0%)
Prostatic specific antigen increased	0/31 (0%)		1/33 (3%)
Metabolism and nutrition disorders
Diabetes mellitus	0/31 (0%)		1/33 (3%)
Hypercholesterolaemia	1/31 (3.2%)		2/33 (6.1%)
Hyperlipidaemia	1/31 (3.2%)		0/33 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/31 (6.5%)		2/33 (6.1%)
Back pain	4/31 (12.9%)		3/33 (9.1%)
Groin pain	1/31 (3.2%)		0/33 (0%)
Musculoskeletal pain	1/31 (3.2%)		0/33 (0%)
Myalgia	1/31 (3.2%)		1/33 (3%)
Osteoarthritis	1/31 (3.2%)		0/33 (0%)
Osteoporosis	1/31 (3.2%)		0/33 (0%)
Pain in extremity	0/31 (0%)		1/33 (3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer stage 0, with cancer in situ	1/31 (3.2%)		0/33 (0%)
Nervous system disorders
Amnesia	1/31 (3.2%)		0/33 (0%)
Dizziness	0/31 (0%)		1/33 (3%)
Headache	2/31 (6.5%)		0/33 (0%)
Sciatica	1/31 (3.2%)		1/33 (3%)
Syncope	1/31 (3.2%)		0/33 (0%)
Transient ischaemic attack	1/31 (3.2%)		0/33 (0%)
Psychiatric disorders
Depression	1/31 (3.2%)		0/33 (0%)
Insomnia	1/31 (3.2%)		1/33 (3%)
Renal and urinary disorders
Urinary retention	1/31 (3.2%)		1/33 (3%)
Reproductive system and breast disorders
Breast cyst	1/31 (3.2%)		0/33 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/31 (3.2%)		2/33 (6.1%)
Cough	3/31 (9.7%)		1/33 (3%)
Dyspnoea	0/31 (0%)		1/33 (3%)
Epistaxis	1/31 (3.2%)		0/33 (0%)
Haemoptysis	0/31 (0%)		1/33 (3%)
Oropharyngeal pain	0/31 (0%)		1/33 (3%)
Skin and subcutaneous tissue disorders
Blister	1/31 (3.2%)		0/33 (0%)
Night sweats	1/31 (3.2%)		0/33 (0%)
Telangiectasia	1/31 (3.2%)		0/33 (0%)
Vascular disorders
Aortic aneurysm	1/31 (3.2%)		2/33 (6.1%)
Hot flush	0/31 (0%)		1/33 (3%)
Hypertension	4/31 (12.9%)		3/33 (9.1%)
Intermittent claudication	1/31 (3.2%)		0/33 (0%)
Thrombophlebitis	1/31 (3.2%)		0/33 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.