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

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

Publication date: Mar 14, 2019

Axonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS.

The ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 +/- 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume.

We hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism. Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest.

Clinical Trials Register, EudraCT 2017-001253-13 . Registered on 15 February 2018.

Hostenbach, S., Pauwels, A., , Michiels, Raeymaekers, H., Van Binst, A.M., Van Merhaeghen-Wieleman, A., Van Schuerbeek, P., De Keyser, J., and D’Haeseleer, M. Role of cerebral hypoperfusion in multiple sclerosis (ROCHIMS): study protocol for a proof-of-concept randomized controlled trial with bosentan. 17530. 2019 Trials (20):1.

Concepts Keywords
Acetyl Magnetic resonance imaging
Antagonist White matter
Aspartate MRI
Astrocytic Endothelin
Brain Axon
CBF Thiophenes
Cerebral Blood Flow Sitaxentan
Cognition Isoxazoles
Cognitive Hepatotoxins
Cognitive Dysfunction Chloroarenes
Depression Branches of biology
Disability Organ systems
Double Blind Multiple sclerosis
ET Chemical compounds
Fatigue G fatigue
Hypoperfusion MS
Magnetic Resonance Imaging Axonal energetic dysfunction
Metabolism
Mitochondrial
MRI
Multiple Sclerosis
Placebo
Progressive
Protocol
Randomized Clinical Trial
Randomized Controlled Trial
Receptor
White Matter

Semantics

Type Source Name
pathway BSID Metabolism
disease MESH depression
gene UNIPROT CYREN
disease DOID relapsing-remitting MS
disease MESH cognitive decline
drug DRUGBANK Endothelin-1
gene UNIPROT CEBPZ
disease MESH cerebral blood flow
drug DRUGBANK Bosentan
disease DOID multiple sclerosis
disease MESH multiple sclerosis

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