Role of cerebral hypoperfusion in multiple sclerosis (ROCHIMS): study protocol for a proof-of-concept randomized controlled trial with bosentan

Multiple sclerosis (MS) is a chronic neurodegenerative and inflammatory disorder of the central nerve system (CNS) mainly affecting young adults [1]. Disease pathology is characterized by two key players: intermittent bursts of focal inflammatory demyelination and widespread progressive axonal degeneration. The clinical course is highly variable. Most individuals start with a relapsing-remitting pattern, in which newly formed clinical deficits restore partially or completely over time, but after several years they often develop a secondary progressive phase of slower but continuous neurological worsening. Other patients experience primary progressive disease from onset [2].

MS relapses are triggered by the formation of focal inflammatory lesions in which auto-immune reactions against CNS myelin play a paramount role. In contrast, the steadier decline mainly results from progressive axonal loss [3]. The exact underlying mechanism of the latter remains unclear and degenerative features do not seem to correlate well with inflammatory activity, particularly in the later stages of the disease [4]. Recognition is growing that mitochondrial energy failure and oxidative stress are involved in this axonal degeneration process of MS [5, 6]. Levels of N-acetylasparate (NAA), an amino acid synthesized by mitochondria in neurons and their axons, are a marker of both axonal mitochondrial activity and axonal integrity [7] and were found to be reduced in several ¹H-magnetic resonance spectroscopy (MRS) studies of centrum semiovale normal-appearing white matter (NAWM) in patients with MS compared to controls [8].

Perfusion-weighted magnetic resonance imaging (MRI) research conducted over the past decade has found that cerebral blood flow (CBF) is globally impaired in the NAWM of patients with relapsing-remitting MS (RRMS), primary progressive MS, and even clinically isolated syndromes suggestive for MS (CIS-MS) [9‐11]. Similar observations have been made in the thalamus of CIS-MS and RRMS individuals [12]. These findings suggest that cerebral hypoperfusion is an early and integral feature of MS pathology, regardless of the clinical subtype [5]. It is unknown whether this phenomenon contributes to the progressive loss of axons, but chronically induced cerebral hypoperfusion in animal models leads to mitochondrial energy failure, oxidative stress, and eventually axonal degeneration [13]. In addition, reduced CBF has been associated with cognitive dysfunction and fatigue in patients with MS [14], which are both disabling but poorly understood disease manifestations. Reduced cerebral perfusion in small rodents resulted in neuronal loss in the hippocampal CA1 sub region, while MRI studies in MS patients revealed selective and progressive hippocampal atrophy localized initially to this CA1 sub region, which may contribute, among other factors, to cognitive impairment that occurs in many of these individuals [15, 16].

Reduced CBF in MS appears to be mediated by elevated levels of the potent vasoconstrictive agent endothelin-1 (ET-1) in the cerebral circulation, most likely derived from reactive astrocytes in focal lesions. In a previous study, the administration of a single 62.5 mg dose of bosentan, which is an ET-1 receptor antagonist, increased CBF in patients with MS up to the levels obtained in controls [5]. The main goal of the present study is to investigate in NAWM of patients with RRMS whether prolonged treatment with bosentan results in a sustained restoration of CBF and whether this enhances NAA levels, reflecting improvement of axonal mitochondrial metabolism. Our secondary aim is to explore whether CBF restoration ameliorates clinical disability (fatigue, cognition, motor function, and depression) and hippocampal volume in these patients.

Cerebral perfusion appears to be unequivocally and globally decreased in all subtypes of MS. Pathological repercussions have hitherto received little attention but might include fatigue, cognitive impairment, and contribution to the hallmark process of axonal degeneration, possibly by compromising mitochondrial energy production. In a previous study, a single dose of 62.5 mg bosentan was able to restore reduced CBF in patients with MS up to the levels measured in healthy controls, revealing a potential new therapeutic target [5]. The ROCHIMS study is the first proof-of-concept clinical trial evaluating the effects of CBF restoration in patients with MS over a longer treatment period. We hypothesize that countering cerebral hypoperfusion in MS patients for one month improves axonal metabolism, as reflected by NAA levels measured with ¹H-MRS. Beneficial effects may also be noticeable on clinical (fatigue, cognition, motor function, depression) and other imaging outcome parameters (hippocampal volume).

There is a medical need for drugs that can halt or slow down progressive axonal degeneration in MS. Repurposing drugs for proof-of-concept trials in this indication is therefore of considerable interest. Bosentan is already widely available for other medical conditions than MS and the side effects, which in general are rather mild, are well known. A limitation of this trial is the short treatment period. The results of this proof-of-concept trial will form the basis for further trials with a longer period of treatment and more focused on clinical outcome measures, especially progression of disability.

The ROCHIMS study is currently recruiting patients. The protocol “Versie 2.0 ROCHIMS” dated 16 August 2017 was approved by the FAGG and the local ethics committee of the UZ Brussel. We started recruiting on the first of September 2017 and will approximately end the recruitment in April 2019.