Dimethyl fumarate treatment for unruptured intracranial aneurysms: a study protocol for a double-blind randomised controlled trial

Abstract

Introduction

Intracranial aneurysm (IA) is a common cerebrovascular disease. Considering the risks and benefits of surgery, a significant proportion of patients with unruptured IA (UIA) choose conservative observation. Previous studies suggest that inflammation of aneurysm wall is a high-risk factor of rupture. Dimethyl fumarate (DMF) acts as an anti-inflammatory agent by activating nuclear factor erythroid 2-related factor 2 (Nrf2) and other pathways. Animal experiments found DMF reduces the formation and rupture of IAs. In this study, DMF will be evaluated for its ability to reduce inflammation of the aneurysm wall in high-resolution vessel wall imaging.

Methods and analysis

This is a multi-centre, randomised, controlled, double-blind clinical trial. Three hospitals will enrol a total of 60 patients who have UIA with enhanced wall. Participants will be assigned randomly in a 1:1 proportion, taking either 240 mg DMF or placebo orally every day for 6 months. As the main result, aneurysm wall enhancement will be measured by the signal intensity after 6 months of DMF treatment. Secondary endpoints include morphological changes of aneurysms and factors associated with inflammation. This study will provide prospective data on the reduction of UIA wall inflammation by DMF.

Ethics and dissemination

This study has been approved by Medical Ethics Committee of the Beijing Tiantan Hospital, Capital Medical University (approval no: KY2022-064-02). We plan to disseminate our research findings through peer-reviewed journal publication and relevant academic conferences.

Trial registration number

NCT05959759.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• MRI high-resolution vessel wall imaging is a valuable method to predict the aneurysm rupture and expansion.

• Inflammatory factors in peripheral blood are affected by multiple factors and may not accurately reflect the inflammation within the aneurysm wall.

• The sample size is relatively small.

• Although this study is multicentre, it will be conducted at facilities in China only, which may limit its generalisability.

Introduction

Intracranial aneurysm (IA) is a common cerebrovascular disease in neurosurgery and the incidence rate of the population is about 3%–5%.¹ IA is the main cause of nontraumatic subarachnoid haemorrhage. Once ruptured, it will cause a high mortality rate, and nearly half of the survivors will be disabled.² The current treatment methods for aneurysms include surgical clipping and endovascular treatment. However, for some patients, the risk of aneurysm rupture is low, or the risk of treatment outweighs the risk of rupture. So conservative treatment should be considered, and regular imaging follow-up should be conducted to observe whether the aneurysm is growing. Conservative treatment generally reduces risk factors by quitting smoking, controlling hypertension and hyperlipidaemia and other methods but cannot eliminate aneurysms.

The initial stage of IA development at the pathological and molecular levels involves the breakdown of the elastic laminae and the demise of the medial smooth muscle cells.³ Then, the aneurysm protrudes from the artery wall and inflammatory cells infiltrate.⁴ Inflammatory cells promote matrix degradation. As the aneurysm sac grows, there is an equilibrium between the mending of the vessel wall and the breakdown of the extracellular matrix.⁵ The inflammation of the IA wall can eventually cause aneurysm rupture by inducing apoptosis of endothelial cells and smooth muscle cells.⁶ The role of inflammation is significant in development, expansion and rupture of aneurysms.

In 2017, by histopathological studies, Shimonaga et al revealed that vessel wall imaging (VWI) enables the visualisation of aneurysm wall thickening and enhancement corresponding to histological neovascularisation and macrophage infiltration.⁷ By using high-resolution VWI (HR-VWI), it could potentially identify smaller or more inconspicuous signal enhancement, thereby providing a more accurate comprehension of the pathology.⁸ Previous studies have demonstrated that aneurysms exhibiting wall enhancement on HR-VWI are more likely to rupture or grow or change morphology.⁹ Hence, the characterisation of aneurysm wall enhancement holds great potential as a biomarker for aneurysm rupture and expansion.⁸

Kang et al found statin can reduce the level of aneurysm wall enhancement and circulating inflammatory biomarkers, which may have the potential to alleviate aneurysm wall inflammation.¹⁰

Dimethyl fumarate (DMF) is mainly used for the treatment of autoimmune diseases, such as multiple sclerosis and psoriasis.^{11 12} Previous studies found DMF and its metabolite monomethyl fumarate inhibit cytokine-induced nuclear translocation of the nuclear factor kappa B,¹³ promote the programmed cell death of activated T-cells¹⁴ and enhance the synthesis of interleukin (IL)-4 and IL-5 in stimulated T cells while increasing the production of the interferon gamma (IFN-γ).¹⁵ DMF also exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.¹⁶ Consequently, this results in an increase in the synthesis and recycling of glutathione in neuronal cells. This process suppresses the production of proinflammatory cytokines and reduces oxidative stress without affecting neuronal network activity.¹⁷

Pascale et al demonstrated that the DMF therapy reduced the occurrence of aneurysm development and rupture in mice while increasing Nrf2 levels.¹⁸ In mice, DMF showed neuroprotective effects by inhibiting oxidative stress, inflammation and fibrosis in the cerebrovascular system.¹⁸

Thus, we hypothesis that DMF can suppress the inflammation in the aneurysm wall and then inhibit the development of IA. This protocol designed a prospective clinical trial to validate this hypothesis. In the study, DMF will be evaluated for its ability to reduce inflammation of the aneurysm wall in HR-VWI.

Methods and design

Study design

The clinical trial is a multicentre, randomised, controlled and blinded (participants, care providers, investigators and outcome assessors). A total of 60 participants with UIA showing aneurysm wall enhancement will be recruited in a competitive approach from Beijing Tiantan Hospital, Beijing Chao-Yang Hospital and Henan Provincial People’s Hospital. Study recruitment began in July 2023 and this study is anticipated to end in September 2024.

Inclusion criteria

1. Must be at least 18 years old, gender neutral.

2. Individuals have UIAs ≥3 mm, identified through imaging (CT, MRI or digital subtraction angiography).

3. Pretreatment HR-VWI shows enhanced aneurysm wall.

4. Participants must have the ability to comprehend the purpose of the trial and sign informed consent.

Exclusion criteria

1. Contraindications for MRI, such as having metallic implants, allergy to contrast agents or claustrophobia.

2. Patients who have aneurysm treatment plans within the next 6 months.

3. Currently taking medications with anti-inflammatory effects or vasoactive medicines, such as aspirin, statins or angiotensin converting enzyme.

4. Severe impairment of liver or renal function.

5. Retreatment of recurrent aneurysm.

6. Pregnant or lactating women.

7. Presence of malignant diseases (liver disease, kidney disease, congestive heart failure, malignant tumors, etc).

8. Poor compliance with treatment or follow-up (patients who refuse to take medication as prescribed, patients who decline imaging follow-up or blood test, etc).

Study description

A total of 60 patients will be enrolled in this study. Randomly divide the patients into experimental group and control group in a 1:1 ratio, and seal them. The patients with IA will be numbered and randomly divided into two groups, 30 patients in each group. Through blind method, experimental group will be given DMF enteric capsule (Tecfidera, Janssen Cilag SpA, Italy) (the initial dose is 120 mg two times per day, after 7 days, the dose will be increased to the maintenance dose of 240 mg two times per day, for 6 months). The dosage of DMF for treating IA remains unclear. This dosage is based on previous clinical trials^19–21 and the drug label information of Tecfidera²² and has been proven to be safe and effective in treating multiple sclerosis. The control group will take placebo with the same appearance (colour, taste, size, shape).

Follow-up

Follow-up visits will be conducted at 6 months after the patient has taken drugs. In the follow-up visits, MRI HR-VWI will be performed using the same modality and sequences as the baseline imaging examination. Blood tests will be conducted to assess the disease status. In addition, during medication period, monthly telephone follow-up will be conducted to report possible adverse reactions.

Primary endpoint

The main outcome will be the changes in the aneurysm wall inflammation as observed on MRI HR-VWI. At the end of 6 months, Wall enhancement index (WEI) and wall enhancement volume rate (WEVR) on MRI HR-VWI will be quantitatively compared between the DMF group and placebo group. The WEVR is determined through the following calculations.²³

$${\displaystyle \mathrm{W}\mathrm{E}\mathrm{V}\mathrm{R}=\frac{\mathrm{a}\mathrm{n}\mathrm{e}\mathrm{u}\mathrm{r}\mathrm{y}\mathrm{s}\mathrm{m}\mathrm{e}\mathrm{n}\mathrm{h}\mathrm{a}\mathrm{n}\mathrm{c}\mathrm{e}\mathrm{m}\mathrm{e}\mathrm{n}\mathrm{t}\mathrm{v}\mathrm{o}\mathrm{l}\mathrm{u}\mathrm{m}\mathrm{e}}{\mathrm{w}\mathrm{h}\mathrm{o}\mathrm{l}\mathrm{e}\mathrm{a}\mathrm{n}\mathrm{e}\mathrm{u}\mathrm{r}\mathrm{y}\mathrm{s}\mathrm{m}\mathrm{v}\mathrm{o}\mathrm{l}\mathrm{u}\mathrm{m}\mathrm{e}}\times 100\mathrm{\%}}$$

The WEI is determined using the methods from previous studies.²³

$${\displaystyle \mathrm{W}\mathrm{E}\mathrm{I}=\frac{\frac{\mathrm{S}\mathrm{I}\mathrm{W}\mathrm{a}\mathrm{l}\mathrm{l}\mathrm{p}\mathrm{o}\mathrm{s}\mathrm{t}\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{s}\mathrm{t}}{\mathrm{S}\mathrm{I}\mathrm{\_}\mathrm{W}\mathrm{h}\mathrm{i}\mathrm{t}\mathrm{e}\mathrm{m}\mathrm{a}\mathrm{t}\mathrm{t}\mathrm{e}\mathrm{r}\mathrm{p}\mathrm{o}\mathrm{s}\mathrm{t}\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{s}\mathrm{t}}-\frac{\mathrm{S}\mathrm{I}\mathrm{\_}\mathrm{W}\mathrm{a}\mathrm{l}\mathrm{l}\mathrm{p}\mathrm{r}\mathrm{e}\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{s}\mathrm{t}}{\mathrm{S}\mathrm{I}\mathrm{\_}\mathrm{W}\mathrm{h}\mathrm{i}\mathrm{t}\mathrm{e}\mathrm{m}\mathrm{a}\mathrm{t}\mathrm{t}\mathrm{e}\mathrm{r}\mathrm{p}\mathrm{r}\mathrm{e}\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{s}\mathrm{t}}}{\frac{\mathrm{S}\mathrm{I}\mathrm{\_}\mathrm{W}\mathrm{a}\mathrm{l}\mathrm{l}\mathrm{p}\mathrm{r}\mathrm{e}\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{s}\mathrm{t}}{\mathrm{S}\mathrm{I}\mathrm{\_}\mathrm{W}\mathrm{h}\mathrm{i}\mathrm{t}\mathrm{e}\mathrm{m}\mathrm{a}\mathrm{t}\mathrm{t}\mathrm{e}\mathrm{r}\mathrm{p}\mathrm{r}\mathrm{e}\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{s}\mathrm{t}}}}$$

The secondary endpoints

The proportion of aneurysm morphological growth from pretreatment to the 6 months follow-up. Aneurysm morphological growth is defined as an increase ≥1 mm in any direction in the same image modality or appearance of a daughter sac.

Changes in C reactive protein (CRP), tumour necrosis factor-α (TNF-α), IL-1β and IL-6 in patients with UIA from pretreatment to the 6 months follow-up. We will conduct a turbidimetric immunoassay to measure the CRP level. ELISA will be employed to measure the levels of TNF-α, IL-1β and IL-6. A blood sample will be collected from the brachial vein at a fixed morning time, before breakfast.

Randomisation and masking

Patients will be randomly assigned (1:1) to DMF group and placebo group. To ensure the blindness and integrity of this study, an independent third party will perform stratified randomisation by centre using the SAS PLAN Procedure (V.9.4; SAS Institute). Participants, care providers, investigators and outcome assessors will be masked to group allocation. The allocation information will be independently maintained by the third party who provides the study drugs.

Sample size estimation

We hypothesise that DMF can reduce the risk of unruptured aneurysms rupture. Due to the lack of references indicating the WEI of high-risk unruptured aneurysms, we use that of ruptured aneurysms as a substitute. According to earlier studies, the WEI of ruptured aneurysms was found to be higher than that of unruptured aneurysms (1.70±1.06 vs 0.89±0.88).²⁴ At least 24 patients will be required to detect the difference (α value=5%, a β value=20%). We assumed a follow-up loss rate of 10%–20%. The sample size of each group will be around 30 patients.

HR-VWI MRI protocol

The 3.0T MRI system (Prisma, Siemens Healthineers; Erlangen, Germany) with a 32-channel head coil will be used for MRI scanning. Before and after the injection of intravenous gadolinium contrast, VW-MRI will be obtained with complete coverage of the entire head in the sagittal plane, providing a 0.6 mm isotropic resolution.

Sequences include three-dimensional time-of-flight (3D TOF) MR angiography (MRA), 3D T1-weighted imaging (T1WI) sampling perfection with application-optimised contrasts using different flip angle evolutions and contrast-enhanced 3D T1WI. Localisation will be achieved using 3D TOF MRA. The dimensions of the 3D T1 sequences will be 0.7×0.7×0.7 mm. Echo train length=52. Slices=224. Integrated parallel acquisition techniques=2. Table 1 displays the imaging parameters.

Table 1.

Parameters of high-resolution vessel wall imaging

	TR/TE (ms)	Flip angle (°)	Field of view (mm2)	Matrix	Slice thickness (mm)	In-plane resolution (mm2)	Scan time
3D TOF MRA	20/3.2	18	240×240	320×224	0.8	0.75×1.07	1’40”
3D T1WI SPACE	800/22	180	180×180	256×256	0.7	0.70×0.70	5’30”

3D TOF, three-dimensional time-of-flight; MRA, MR angiography; SPACE, sampling perfection with application-optimised contrasts using different flip angle evolutions; T1WI, T1-weighted imaging.

Image analysis

Two neuroradiologists with over 10 years of experience will exclude images with artefacts or low quality. They will independently analyse each image, ensuring they remain unaware of patients’ clinical details and treatment. Aneurysm wall quantitative analysis will be performed using Vessel-MASS software (MEDIS, Version 2014-EXP, Leiden University Medical Center; Leiden, the Netherlands) on a dedicated postprocessing workstation.

The boundaries of lumen and aneurysm wall will be outlined to measure the lumen area, wall area and maximum wall thickness. The volume of lumen and wall will be calculated. The layers of aneurysms will be segmented into four quarters automatically, outlining their contours. Then calculate the average enhancement signal intensity (SI) of each quarter (referred to as quarter SI). The quarter with the highest SI will represent its layer.²³ Researchers will select three layers with the most significant enhancement from the aneurysm images and calculate the average SI of these three layers. The average SI will be used to represent this aneurysm. The WEVR in the HR-VWI will be analysed using 3D Slicer (https://www.slicer.org/). Manually outline the aneurysm at each layer on postcontrast T1WI and then 3D reconstruct the aneurysm wall.

Patient and public involvement

Patients and the public are not involved in the design, implementation or dissemination of this research.

Discussion

This study may demonstrate the anti-inflammatory effect of DMF on the IA wall and validate the anti-inflammatory effects on the inhibiting aneurysm rupture.

Clinicians may recommend conservative management after considering the risks of clipping or endovascular treatment may outweigh the risk of the rupture of UIA. However, the growth of aneurysms is discontinuous and stochastic rather than linear.^{25 26} The rupture of IAs is difficult to predict, so it requires long-term follow-up of UIAs.

HR-VWI has the ability to display thickening of the aneurysm wall. The enhancement of the wall corresponds to degenerative changes that have been histologically confirmed, along with neovascularisation and significant infiltration of macrophages.⁷ Several studies have demonstrated that the enhancement on HR-VWI is inherent inflammation in histopathology. Aneurysm wall enhancement on HR-VWI may help identify UIAs at high risk of rupture and may serve as an imaging biomarker to predict aneurysms growth and rupture.

In our study, we will perform HR-VWI for patients who choose conservative observation before and after DMF/placebo treatment. Our study will provide prospective data to verify the association between aneurysm wall enhancement and aneurysm stability.

DMF, an oral fumaric acid ester, possesses immunomodulatory properties and is regarded as a safe treatment choice for patients with psoriasis and relapsing-remitting multiple sclerosis.¹¹ DMF triggers Nrf2 activation, leading to a decrease of oxidative stress through the induction of the antioxidant response elements which enhance the expression of various detoxification enzymes such as glutathione, hemeoxygenase and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase-1.^27–31 Pascale et al evaluated the effects of DMF both in vitro and vivo. In mice DMF resulted in a notable reduction of aneurysm formation and rupture while simultaneously elevating the levels of Nrf2. It was found that DMF induced a neuroprotective effect in mice by inhibiting oxidative stress, inflammation and fibrosis in the cerebrovascular system.¹⁸

However, previous studies of DMF treatment for IAs were either in vitro or animal experiment. There is currently a lack of prospective clinical study. Therefore, it is necessary to conduct a prospective randomised clinical trial to assess the efficacy and safety of DMF in preventing the growth and rupture of UIAs.

Safety considerations

During the recruitment process, patients with high-risk aneurysms (UIA≥7 mm)^32–34 will be primarily recommended to undergo clipping or endovascular treatment. For patients who refuse surgical treatment and opt for conservative observation, we will recommend this trial to them. Additionally, during the trial, we will alert patients when there are signs indicating an increased risk of aneurysm rupture.

The most common adverse reactions (incidence ≥10% and 2% higher than placebo) of DMF were flushing, abdominal pain, diarrhoea and nausea. Other adverse reactions included lymphopenia, elevations of hepatic transaminases.

van Oosten et al reported a case of psoriasis treated with DMF and the adverse effect was lymphopenia.³⁵ Reich et al collected data of 984 patients regarding the safety and efficacy of DMF for long-term treatment of psoriasis. In over 90% of cases, the changes in laboratory parameters were not significant enough to warrant a modification of treatment plan.³⁶ DMF causes gastrointestinal events (eg, nausea, vomiting, diarrhoea, abdominal pain and dyspepsia). The occurrence of serious gastrointestinal events was reported in 1% of patients receiving DMF.²² For most patients with elevation of hepatic transaminases, the level of hepatic transaminases was below than three times of normal.²²

Complete blood counts including lymphocyte counts were obtained before starting with DMF. Every month thereafter or if clinically indicated, a complete blood count including lymphocyte count will be tested. If the lymphocyte count is less than 0.5×10⁹/L for more than 1 month, consider interrupting the therapy with DMF enteric coated capsules.²²

Monthly monitoring will be conducted to track the plasma levels of creatinine phosphokinase, alanine aminotransferase and aspartate aminotransferase. If there are early signs of hepatitis, myositis or other clinical suspicions, the above indicators will be monitored every 7 days or at any time. If the levels of alanine aminotransferase or aspartate aminotransferase exceed three times the normal level (≥180 U/L), or if the creatinine phosphokinase level is ≥1000 U/L, the administration of the study drug will be discontinued.⁸

Statistical analysis

The association between categorical variables will be evaluated by the χ² test or Fisher’s exact test and continuous variables will be evaluated by non-parametric Mann-Whitney U test. Perform a Wilcoxon signed-ranks test to compare the variables before and after treatment. The reproducibility of interobserver and intraobserver measurements of the WEI, WEVR and aneurysm size will be assessed by calculating the intraclass correlation coefficient. The statistical analyses will be conducted by a statistician using SPSS software (V.26.0; IBM). Statistical significance will be established at two-tailed p<0.05.

Ethics and dissemination

This study has been approved by Medical Ethics Committee of the Beijing Tiantan Hospital, Capital Medical University (approval no: KY2022-064-02). A written informed consent form will be given to every participant before the clinical trial. This clinical trial will follow the requirements of Declaration of Helsinki, International Ethical Guidelines for Biomedical Research Involving Human Subject (CIOMS, 2002) of WHO and The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. We plan to disseminate our research findings through peer-reviewed journal publication and relevant academic conferences.

Ethics statements

Patient consent for publication

Not applicable.