Infliximab Therapy for Dolichoectactic Vertebrobasilar Aneurysms

NCT ID: NCT02638701

Last Updated: 2025-07-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-10-01
• Study Completion Date: 2027-12-31

Brief Summary

Patients harboring dolichoectactic vertebrobasilar (DVB) aneurysms are at risk of suffering SAH, ischemic stroke, and/or brainstem compression and many patients are not offered invasive treatment due to the futility of existing surgical methods. Consequently, there is demand for development of medical therapy for DVB aneurysms

Detailed Description

Dolichoectatic vertebrobasilar (DVB) aneurysms are fusiform in geometry and often large (< 10 cm) in size limiting traditional microsurgical clipping or endovascular coiling strategies. Collectively, DVB aneurysms represent ≤ 0.01% of all aneurysms (~ 600 US) and, consequently, their study is limited to a few small series. Despite their rarity, the location and geometry of DVB aneurysms make surgical intervention, microsurgical or endovascular, nearly uniformly fatal. Therefore, most DVB aneurysms are observed providing greater insight into their natural history than many more surgically amenable aneurysms. One series noted 28% of patients manifesting any neurological deficit, ischemic or hemorrhagic, over a 4 year interval with an overall mortality rate of ~ 20%.

Tumor necrosis alpha (TNFα). From the many implicated genetic pathways in aneurysm formation, tumor necrosis alpha (TNFα) has been noted a pivotal actor. In pre-clinical studies, the ability to inhibit TNFα induction prevents aneurysm rupture and even aneurysm growth altogether. In humans, TNFα inhibitor therapy has proven effective for many types of vascular inflammation including carotid wall thickening in the setting of rheumatoid arthritis. Over 12- and 24-month intervals, others have demonstrated significant decreases in carotid intima-media thickness in patients taking the TNFα inhibitor, infliximab. Furthermore, infliximab therapy has proven effective in refractory Kawasaki's disease, a condition characterized by post-infectious coronary artery inflammation in children. There is also evidence that infliximab therapy is effective in treatment of IVIG-refractory Kawasaki's disease including regressing coronary aneurysms. Despite the multitude of agents and indications both on and off-label, TNFα inhibitor therapy has not been used for the treatment of brain aneurysm.

Conditions

Aneurysm; Stroke; Vasculitis; Tumor Necrosis Factor-alpha

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Infliximab treatment

Administer infliximab intravenously to patients with DVB aneurysms (3 mg/kg at 0, 3 and 7 weeks, then at 8-week intervals x 7) for a total of 12-months. Patients will undergo MR imaging at 0, 12, and 24-month time points.

Group Type: EXPERIMENTAL

Infliximab

Intervention Type: DRUG

Please see protocol for details.

Interventions

Infliximab

Please see protocol for details.

Intervention Type: DRUG

Other Intervention Names

Remicade

Eligibility Criteria

Inclusion Criteria

1. Vertebral and/or basilar artery dolichoectactic aneurysm not amenable to microsurgical or endovascular treatment.

2. Age greater than 18 years at time of first study drug administration.

Exclusion Criteria

1. Use of an anti-TNF or other biologic medication (Including but not limited to abatacept, rituximab, or tocilizumab) within the previous 12 months.

2. The following laboratory parameters at the Screening visit: Neutropenia (absolute neutrophil count < 1,500/microliter; Thrombocytopenia (platelets < 100,000/ • Anemia (hemoglobin < 8 g/dL); Greater than or equal to 3 times the upper limit of normal (ULN) for either of the following liver function tests (LFTs): aspartate transaminase (AST) or alanine transaminase (ALT); Renal insufficiency (serum creatinine> 2.0 mg/dL)

3. Purified protein derivative (PPD) test of > 5 mm induration regardless of prior BacilleCalmette Guerin vaccine administration or positive QuantiFERON®-TB Gold In-Tube Test (QFT-G_IT) without documentation of completed treatment or evidence of ongoing treatment of latent tuberculosis (TB) for 30 days. Subjects with active TB infection are excluded.

4. History of positive PPD, positive QuantiFERON®-TB Gold In-Tube Test (QFT-G_IT), or chest x-ray findings indicative of prior TB infection, without documentation of either treatment for TB infection or chemoprophylaxis for TB exposure

5. Presence of open leg ulcers

6. Chronic or persistent infection including but not limited to human immunodeficiency virus [HIV], untreated hepatitis B, listeriosis, TB, or other opportunistic infection). Patients with hepatitis C but without evidence of cirrhosis or significant hepatic dysfunction will be considered for inclusion on a case-by-case basis as will patients with chronic hepatitis B on anti-viral therapy.

7. Active infection or severe infections requiring hospitalization or treatment with intravenous (IV) antibiotics, IV antivirals, or IV antifungals within 30 days prior to randomization, or oral antibiotics, oral antivirals, or oral antifungals within 14 days prior to randomization

8. Receipt of a live vaccine within 4 weeks prior to randomization

9. History of malignancy within the past 5 years other than treated localized carcinoma in situ of the cervix or adequately treated non-metastatic squamous or basal cell skin carcinoma

10. Any medical condition, which, in the opinion of the investigator, would put the subject at risk by participation in the protocol

11. Women of childbearing potential who are sexually active and who do not agree to practice one of the following methods of contraception during the duration of the study: condoms, sponge, foams, jellies, diaphragm or intrauterine device; oral or parenteral contraceptives for 2 months prior to study product administration; a vasectomized partner; abstinence.

12. Pregnant (all women of childbearing potential must have a negative serum pregnancy test) or breastfeeding

13. Any investigational agent within the earlier of 4 weeks or 5 half-lives prior to randomization

14. History of drug or alcohol abuse within 6 months prior to randomization

15. Known allergy or hypersensitivity to any study products

16. Any psychiatric disorder that prevents the subject from providing informed consent

17. Inability or unwillingness to follow the protocol.

18. Unable to undergo MR imaging.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Daniel L. Cooke

Assistant Professor of Radiology and Biomedical Imaging

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Daniel L Cooke, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

UCSF Medical Center

San Francisco, California, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Daniel L Cooke, MD

Role: CONTACT

daniel.cooke@ucsf.edu

415 353 1863

Jonathan Graf, MD

Role: CONTACT

jonathan.graf@ucsf.edu

415 206 6647

Facility Contacts

Daniel Cooke, MD

Role: primary

References

Flemming KD, Wiebers DO, Brown RD Jr, Link MJ, Huston J 3rd, McClelland RL, Christianson TJ. The natural history of radiographically defined vertebrobasilar nonsaccular intracranial aneurysms. Cerebrovasc Dis. 2005;20(4):270-9. doi: 10.1159/000087710. Epub 2005 Aug 22.

Reference Type: BACKGROUND

PMID: 16123548 (View on PubMed)

Mangrum WI, Huston J 3rd, Link MJ, Wiebers DO, McClelland RL, Christianson TJ, Flemming KD. Enlarging vertebrobasilar nonsaccular intracranial aneurysms: frequency, predictors, and clinical outcome of growth. J Neurosurg. 2005 Jan;102(1):72-9. doi: 10.3171/jns.2005.102.1.0072.

Reference Type: BACKGROUND

PMID: 15658099 (View on PubMed)

Starke RM, Raper DM, Ding D, Chalouhi N, Owens GK, Hasan DM, Medel R, Dumont AS. Tumor necrosis factor-alpha modulates cerebral aneurysm formation and rupture. Transl Stroke Res. 2014 Apr;5(2):269-77. doi: 10.1007/s12975-013-0287-9. Epub 2013 Sep 20.

Reference Type: BACKGROUND

PMID: 24323710 (View on PubMed)

Ferrante A, Giardina AR, Ciccia F, Parrinello G, Licata G, Avellone G, Giardina E, Impastato R, Triolo G. Long-term anti-tumour necrosis factor therapy reverses the progression of carotid intima-media thickness in female patients with active rheumatoid arthritis. Rheumatol Int. 2009 Dec;30(2):193-8. doi: 10.1007/s00296-009-0935-2.

Reference Type: BACKGROUND

PMID: 19387646 (View on PubMed)

Del Porto F, Lagana B, Lai S, Nofroni I, Tinti F, Vitale M, Podesta E, Mitterhofer AP, D'Amelio R. Response to anti-tumour necrosis factor alpha blockade is associated with reduction of carotid intima-media thickness in patients with active rheumatoid arthritis. Rheumatology (Oxford). 2007 Jul;46(7):1111-5. doi: 10.1093/rheumatology/kem089. Epub 2007 Apr 20.

Reference Type: BACKGROUND

PMID: 17449484 (View on PubMed)

Burns JC, Best BM, Mejias A, Mahony L, Fixler DE, Jafri HS, Melish ME, Jackson MA, Asmar BI, Lang DJ, Connor JD, Capparelli EV, Keen ML, Mamun K, Keenan GF, Ramilo O. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr. 2008 Dec;153(6):833-8. doi: 10.1016/j.jpeds.2008.06.011. Epub 2008 Jul 30.

Reference Type: BACKGROUND

PMID: 18672254 (View on PubMed)

Hasan DM, Chalouhi N, Jabbour P, Magnotta VA, Kung DK, Young WL. Imaging aspirin effect on macrophages in the wall of human cerebral aneurysms using ferumoxytol-enhanced MRI: preliminary results. J Neuroradiol. 2013 Jul;40(3):187-91. doi: 10.1016/j.neurad.2012.09.002. Epub 2013 Feb 18.

Reference Type: BACKGROUND

PMID: 23428244 (View on PubMed)

Other Identifiers

15-16893

Identifier Type: -

Identifier Source: org_study_id