Dataset Information

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

ABSTRACT: BACKGROUND: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. METHODS: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. DISCUSSION: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. TRIAL REGISTRATION:Clinical Trials Register, EudraCT 2017-001253-13 . Registered on 15 February 2018.

SUBMITTER: Hostenbach S

PROVIDER: S-EPMC6416892 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Hostenbach Stéphanie S Pauwels Ayla A Michiels Veronique V Raeymaekers Hubert H Van Binst Anne-Marie AM Van Merhaeghen-Wieleman Annick A Van Schuerbeek Peter P De Keyser Jacques J D'Haeseleer Miguel M

Trials 20190314 1

<h4>Background</h4>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 activ ...[more]

PMID: 30871594

Similar Datasets

Project description:IntroductionMultiple sclerosis (MS) is a demyelinating disease of the central nervous system with an underlying immune-mediated and inflammatory pathogenesis. Innate immunity, in addition to the adaptive immune system, plays a relevant role in MS pathogenesis. It represents the immediate non-specific defense against infections through the intrinsic effector mechanism "immunothrombosis" linking inflammation and coagulation. Moreover, decreased cerebral blood volume (CBV), cerebral blood flow (CBF), and prolonged mean transit time (MTT) have been widely demonstrated by MRI in MS patients. We hypothesized that coagulation/complement and platelet activation during MS relapse, likely during viral infections, could be related to CBF decrease. Our specific aims are to evaluate whether there are differences in serum/plasma levels of coagulation/complement factors between relapsing-remitting (RR) MS patients (RRMS) in relapse and those in remission and healthy controls as well as to assess whether brain hemodynamic changes detected by MRI occur in relapse compared with remission. This will allow us to correlate coagulation status with perfusion and demographic/clinical features in MS patients.Materials and methodsThis is a multi-center, prospective, controlled study. RRMS patients (1° group: 30 patients in relapse; 2° group: 30 patients in remission) and age/sex-matched controls (3° group: 30 subjects) will be enrolled in the study. Patients and controls will be tested for either coagulation/complement (C3, C4, C4a, C9, PT, aPTT, fibrinogen, factor II, VIII, and X, D-dimer, antithrombin, protein C, protein S, von-Willebrand factor), soluble markers of endothelial damage (thrombomodulin, Endothelial Protein C Receptor), antiphospholipid antibodies, lupus anticoagulant, complete blood count, viral serological assays, or microRNA microarray. Patients will undergo dynamic susceptibility contrast-enhanced MRI using a 3.0-T scanner to evaluate CBF, CBV, MTT, lesion number, and volume.Statistical analysisANOVA and unpaired t-tests will be used. The level of significance was set at p ≤ 0.05.DiscussionIdentifying a link between activation of coagulation/complement system and cerebral hypoperfusion could improve the identification of novel molecular and/or imaging biomarkers and targets, leading to the development of new effective therapeutic strategies in MS.Clinical trial registrationClinicaltrials.gov, identifier NCT04380220.

Project description:Background: Accumulating evidence indicates that mitochondrial energy failure is involved in the progressive axonal degeneration in multiple sclerosis (MS). In patients with MS, it has been shown that both levels of N-acetylaspartate (NAA), which is a marker of axonal mitochondrial energy, and cerebral blood flow (CBF) are reduced in cerebral normal appearing white matter (NAWM). The latter is likely due to the vasoconstrictive action of endothelin-1 (ET-1) produced by reactive astrocytes, which is triggered by local proinflammatory cytokines. A preliminary study in patients with MS showed that CBF could be restored to normal values after a single dose of 62.5 mg of the ET-1 antagonist bosentan. Objective: To investigate whether restoring CBF in patients with relapsing remitting MS (RRMS) increases levels of NAA in cerebral NAWM and improves clinical symptoms. Methods: 27 RRMS patients were included in a 4 weeks proof-of-concept, randomized, double-blind placebo-controlled trial (ROCHIMS) to investigate whether bosentan 62.5 mg twice daily could increase the NAA/creatine (NAA/Cr) ratio in NAWM of the centrum semiovale. Magnetic resonance imaging (MRI) assessing CBF and NAA/Cr, and clinical evaluations were performed at baseline and at end of study. Separately from the clinical trial, 10 healthy controls underwent the same baseline multimodal brain MRI protocol as the MS patients. Results: Eleven patients in the bosentan arm and thirteen patients in the placebo arm completed the study. Bosentan did not increase CBF. However, we found that CBF in the patients was not different from that of the healthy controls. There were no effects on NAA levels and clinical symptoms. Conclusions: Our study showed that CBF in RRMS patients is not always decreased and that bosentan has no effect when CBF values are within the normal range. We hypothesize that in our patients there was no significant astrocytic production of ET-1 because they had a mild disease course, with minimal local inflammatory activity. Future studies with bosentan in MS should focus on patients with elevated ET-1 levels in cerebrospinal fluid or blood.

Project description:Introduction Multiple sclerosis (MS) is a progressive disease with a fluctuating and unpredictable course that has no curative treatment at present. One of its main characteristics is the variety of signs and symptoms that produce a high percentage of patients who present alterations in balance and gait during the development of the disease, decreased muscle strength, spasticity, or decreased pimax. Rehabilitative therapy, especially physiotherapy, is the main course of the treatment of these alterations using reflex locomotion and the Bobath concept as a form of kinesitherapy that activates the preorganized circuits of the central nervous system. Objective The objective of this study is to evaluate the reflex locomotion and Bobath concept effects on balance, spasticity, reaction time, respiratory parameters, and lacrimal biomolecular markers. Methods and analysis This is a randomized controlled trial on the effectiveness of two neurorehabilitation techniques in patients with multiple sclerosis conducted at the University of Salamanca. The research will take place at the Faculty of Nursing and Physiotherapy, University of Salamanca. The study will be conducted from June 2023 to June 2024. The reflex locomotion group will receive individual sessions of therapy (n = 27), and the Bobath concept group (n = 27) will receive the same number of sessions. Both groups will receive two sessions per week for 12 months. The measurement variables will be the Berg Balance Scale, the Tardieu Scale, the Cognitfit Program, Maximum Inspiratory Pressure, and Lacrimal Biomarkers. Ethics and dissemination This study has been approved by the Ethics Committee of the University of Salamanca on March 2023 (ref: 896). Limitations The main limitations of this study are the selection and number of patients, the delay in implementing the therapy within the initially scheduled period, inadequate sample collection, and inadequate sample processing. Trial registration number ClinicalTrials.gov; identifier: NCT05558683.

Project description:BackgroundAlbumin has potential endothelial protective effects through antioxidant and anti-inflammatory properties. However, the effect of albumin on peripheral tissue perfusion in human sepsis remains poorly known.MethodsBi-centric prospective study included patients with sepsis with or without shock and prolonged CRT > 3 s despite initial resuscitation. Clinicians in charge of the patients were free to infuse either saline 500 mL or human serum albumin 20% 100 mL over 15 min. Global hemodynamic parameters as well as peripheral tissue perfusion were analyzed after 1 (H1) and 4 h (H4). The primary endpoint was CRT normalization (< 3 s) at H1.Results62 patients were screened, and 50 patients (13 sepsis and 37 septic shock) were included, 21 in the saline group and 29 in the albumin group. SOFA score was 8 [5-11], and SAPS II was 53 [45-70]. Median age was 68 [60-76] years with a higher proportion of men (74%). The primary sources of infection were respiratory (54%) and abdominal (24%). At baseline, comorbidities, clinical and biological characteristics were similar between groups. At H1, CRT normalization (< 3 s) was more frequent in patients receiving albumin as compared to patients treated by saline (63 vs 29%, P = 0.02). The decrease in fingertip CRT was more important in the albumin group when compared to saline group (- 1.0 [- 0.3; - 1.5] vs - 0.2 [- 0.1; - 1.1] seconds, P = 0.04) as well as decrease in mottling score. At H4, beneficial effects of albumin on peripheral tissue perfusion were maintained and urinary output trended to be higher in the albumin group (1.1 [0.5-1.8] vs 0.7 [0.5-0.9] ml/kg/h, P = 0.08). Finally, arterial lactate level did not significantly change between H0 and H4 in the saline group but significantly decreased in the albumin group (P = 0.03).ConclusionIn patients with resuscitated sepsis, albumin infusion might lead to greater improvement of tissue hypoperfusion compared to saline.Clinicaltrialsgov Identifier: NCT05094856.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets