Metformin in Patients With Unruptured Vertebrobasilar Dissecting Aneurysms (METTLE)

Dissecting Aneurysm of Cerebral Artery Clinical Trial

— METTLE  

Official title:

Metformin in Patients With Unruptured Vertebrobasilar Dissecting Aneurysms: a Prospective, Randomized Study (METTLE)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06405971
• Other study ID #: Ming Lv
• Status: Not yet recruiting
• Phase: N/A
• Start date: June 1, 2024
• Est. completion date: June 1, 2025

Study information

• Verified date: May 2024
• Source: Beijing Tiantan Hospital
• Contact: Linggen Dong, MD
• Phone: 18844738529
• Email: donglinggen[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Vertebrobasilar dissecting aneurysms (VBDAs) are one of the most important causes of stroke in young and middle-aged people, and the natural history of VBDAs is complex and varied, often leading to high rates of disability and mortality. For some patients with VBDAs who are not suitable for surgical entrapment and intervention, pharmacologic therapy may be used to slow the progression of VBDAs. Metformin (MET) has been shown to act as an anti-inflammatory, anti-oxidative stress and improve vascular endothelial function by inhibiting smooth muscle cell phenotypic transformation, proliferation, migration and apoptosis, thereby reducing the incidence of intracranial aneurysms and rupture rates, and MET may be a suitable candidate. Inflammatory response plays an important role in the occurrence, development and rupture of VBDAs. Inflammatory response in the aneurysm wall can cause endothelial and smooth muscle cell injury and apoptosis, leading to degenerative changes in the vessel wall and increasing the risk of rupture of VBDAs. High-resolution magnetic resonance vessel wall imaging (HR-VWI), which can clearly show the structure of the vessel wall and reflect the active degree of inflammatory reaction in the aneurysm wall, has been widely used in the assessment of intracranial aneurysm instability. In this study, we propose to conduct a multicenter, prospective, randomized study to investigate whether MET reduces the degree of aneurysm wall inflammatory response in VBDAs by performing HR-VWI scans in patients with VBDAs and obtaining quantitative parameters reflecting the inflammatory response of the aneurysm wall.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: June 1, 2025
• Est. primary completion date: January 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Age =18 years and =75 years, gender is not limited;

2. Patients with previously untreated, unruptured stable VBDAs clearly diagnosed by DSA, CTA or MRA;

3. Patients with aneurysm wall enhancement as shown by HR-VWI of 3.0T high field strength MRI whole body scanner at Tsinghua University;

4. Baseline mRS score =2;

5. Patients voluntarily participated in this study and signed an informed consent form.

Exclusion Criteria:

1. Patients with aneurysms located in non-vertebral basilar artery sites (mainly referring to bifurcation saccular aneurysms);

2. Patients with combined diabetes or its complications;

3. Patients who are allergic to any components in MET;

4. Pregnant and lactating female patients;

5. Patients with other immune diseases in combination, patients taking immunosuppressants or anti-inflammatory drugs (such as long-term use of aspirin, statin, hormones and other drugs);

6. Target aneurysm-related symptoms were severe at the time of diagnosis, and the mRS score was =3;

7. VBDAs have received interventional or surgical treatment;

8. Those with severe allergy to the contrast agent gadolinium terlumate glucosamine (Gd-DTPA) (skin rash not counted);

9. Those with severe renal disease resulting in renal insufficiency (glomerular filtration rate <30ml/(min·1.73m2));

10. Patients with metal implants in the body (e.g., cardiac stents, cardiac prosthetic valves, pacemakers, metal joints, steel plates, non-removable metal dentures, etc.);

11. Patients known to suffer from dementia or psychiatric disorders and claustrophobia who are unable to complete the magnetic resonance examination;

12. Patients with other serious diseases combined at the time of diagnosis and with an expected survival time of less than 1 year;

13. Patients who are participating in clinical trials of other drugs or devices.

14. Other conditions judged by the investigator to exist that are unsuitable for enrollment.

Related Conditions & MeSH terms

• Aneurysm
• Aortic Dissection
• Dissecting Aneurysm of Cerebral Artery

Intervention

Drug:
• Metformin
Patients in the drug group took one tablet of metformin hydrochloride enteric capsule orally each day after breakfast and dinner, and the dose of each tablet was 250mg.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Ming Lv

References & Publications (13)

Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, McNeilly AD, Balfour DJ, Savinko T, Wong AK, Viollet B, Sakamoto K, Fagerholm SC, Foretz M, Lang CC, Rena G. Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status. Circ Res. — View Citation

Debette S, Compter A, Labeyrie MA, Uyttenboogaart M, Metso TM, Majersik JJ, Goeggel-Simonetti B, Engelter ST, Pezzini A, Bijlenga P, Southerland AM, Naggara O, Bejot Y, Cole JW, Ducros A, Giacalone G, Schilling S, Reiner P, Sarikaya H, Welleweerd JC, Kapp — View Citation

Etminan N, Rinkel GJ. Unruptured intracranial aneurysms: development, rupture and preventive management. Nat Rev Neurol. 2016 Dec;12(12):699-713. doi: 10.1038/nrneurol.2016.150. Epub 2016 Nov 3. Erratum In: Nat Rev Neurol. 2017 Feb 1;13(2):126. — View Citation

He J, Li N, Fan Y, Zhao X, Liu C, Hu X. Metformin Inhibits Abdominal Aortic Aneurysm Formation through the Activation of the AMPK/mTOR Signaling Pathway. J Vasc Res. 2021;58(3):148-158. doi: 10.1159/000513465. Epub 2021 Feb 18. — View Citation

Larsen N, von der Brelie C, Trick D, Riedel CH, Lindner T, Madjidyar J, Jansen O, Synowitz M, Fluh C. Vessel Wall Enhancement in Unruptured Intracranial Aneurysms: An Indicator for Higher Risk of Rupture? High-Resolution MR Imaging and Correlated Histolog — View Citation

Li S, Shi Y, Liu P, Song Y, Liu Y, Ying L, Quan K, Yu G, Fan Z, Zhu W. Metformin inhibits intracranial aneurysm formation and progression by regulating vascular smooth muscle cell phenotype switching via the AMPK/ACC pathway. J Neuroinflammation. 2020 Jun — View Citation

Lv N, Karmonik C, Chen S, Wang X, Fang Y, Huang Q, Liu J. Wall Enhancement, Hemodynamics, and Morphology in Unruptured Intracranial Aneurysms with High Rupture Risk. Transl Stroke Res. 2020 Oct;11(5):882-889. doi: 10.1007/s12975-020-00782-4. Epub 2020 Jan — View Citation

Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Me — View Citation

Quan K, Song J, Yang Z, Wang D, An Q, Huang L, Liu P, Li P, Tian Y, Zhou L, Zhu W. Validation of Wall Enhancement as a New Imaging Biomarker of Unruptured Cerebral Aneurysm. Stroke. 2019 Jun;50(6):1570-1573. doi: 10.1161/STROKEAHA.118.024195. Epub 2019 Ap — View Citation

Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017 Sep;60(9):1577-1585. doi: 10.1007/s00125-017-4342-z. Epub 2017 Aug 3. — View Citation

Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med. 2001 Mar 22;344(12):898-906. doi: 10.1056/NEJM200103223441206. No abstract available. — View Citation

Shimonaga K, Matsushige T, Ishii D, Sakamoto S, Hosogai M, Kawasumi T, Kaneko M, Ono C, Kurisu K. Clinicopathological Insights From Vessel Wall Imaging of Unruptured Intracranial Aneurysms. Stroke. 2018 Oct;49(10):2516-2519. doi: 10.1161/STROKEAHA.118.021 — View Citation

Sikkema T, Uyttenboogaart M, Eshghi O, De Keyser J, Brouns R, van Dijk JM, Luijckx GJ. Intracranial artery dissection. Eur J Neurol. 2014 Jun;21(6):820-6. doi: 10.1111/ene.12384. Epub 2014 Feb 22. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	3-dimensional wall enhancement volume rate (3D-WEVR)	Changes in the degree of wall enhancement of VBDAs at the time of patient enrollment and after 6 months of oral drug administration were measured by HR-VWI, i.e., the quantitative wall enhancement parameters 3D-WEVR was compared between the drug group and the placebo group at the end of the 6-month treatment period. The unit of 3D-WEVR is percentage (%).	6 months after taking the drug
Secondary	Morphological changes in VBDAs	change in the maximum diameter of the aneurysm by =1 mm or the presence of a daughter aneurysm was defined as a morphologic change	6 months after taking the drug
Secondary	Characteristic changes in the internal lumen of VBDAs	change of intramural hematoma by =1 mm or disappearance of false lumen defined as characteristic changes in the internal lumen	6 months after taking the drug
Secondary	Changes in C-reactive protein	The unit of C-reactive protein is mg/dL.	6 months after taking the drug
Secondary	changes in serum inflammatory markers	e.g., IL-1ß, IL-2R, IL-6, IL-8, IL-10, TNF-a. The unit of serum inflammatory markers is pg/ml.	6 months after taking the drug
Secondary	changes in serum inflammatory markers	e.g., MMP-3, MMP-9. The unit of serum inflammatory markers is ng/ml.	6 months after taking the drug
Secondary	Proportion of patients with VBDAs who developed cerebral infarction, transient ischemic attack, cerebral hemorrhage, and symptoms of compression in the drug and placebo groups were recorded	To record patients with VBDAs who developed cerebral infarction, transient ischemic attack, cerebral hemorrhage, and pressure symptoms in the drug and placebo groups, and to clarify whether MET suppresses ischemic events, hemorrhagic events, and pressure-occupying events (defined as ischemic events, hemorrhagic events, and pressure-occupying events if the patient's mRS scores are increased and associated with a target aneurysm)	6 months after taking the drug
Secondary	Wall enhancement index (WEI)	Changes in the degree of wall enhancement of VBDAs at the time of patient enrollment and after 6 months of oral drug administration were measured by HR-VWI, i.e., the quantitative wall enhancement parameters WEI was compared between the drug group and the placebo group at the end of the 6-month treatment period. Quantitative parameter WEI has no units.	6 months after taking the drug