Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.

BACKGROUND AND OBJECTIVES: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. METHODS: In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. RESULTS: Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. DISCUSSION: Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among adults with active RRMS and ≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).

A double-blind, randomized, placebo-controlled phase 2 trial evaluating the selective dihydroorotate dehydrogenase inhibitor vidofludimus calcium in relapsing-remitting multiple sclerosis.

OBJECTIVE: Inhibition of dihydroorotate dehydrogenase suppresses magnetic resonance imaging brain lesions and disease activity in multiple sclerosis but has limiting tolerability. We assessed the safety and efficacy of vidofludimus calcium, a novel, selective dihydroorotate dehydrogenase inhibitor, in patients with relapsing-remitting multiple sclerosis. METHODS: This double-blind, 24 weeks, placebo-controlled, phase 2 trial (EMPhASIS) enrolled patients 18-55 years with relapsing-remitting multiple sclerosis. Eligible patients were randomly assigned (1:1:1) to once-daily vidofludimus calcium (30 mg or 45 mg) or placebo. The primary endpoint was the cumulative number of combined unique active lesions to week 24 between vidofludimus calcium 45 mg and placebo (clinicalTrials.gov number NCT03846219; EudraCT 2018-001896-19). RESULTS: After 24 weeks, the mean cumulative number of combined unique active lesions was 6.4 (95% CI: 2.8-13.9) with placebo compared to 2.4 (95% CI: 1.1-4.9) with vidofludimus calcium 45 mg (rate ratio 0.38, 95% CI: 0.22-0.64; p = 0.0002); the rate ratio between vidofludimus calcium 30 mg and placebo was 0.30 (95% CI: 0.17-0.53; p < 0.0001). Treatment-emergent adverse events occurred in 30 (44%) of patients assigned placebo and 60 (43%) of patients assigned vidofludimus calcium. Serious adverse events occurred in one (1%) assigned placebo and two (1%) assigned vidofludimus calcium. No increased incidence of infectious, hepatic, or renal treatment-emergent adverse events or serious adverse events was observed. INTERPRETATION: Treatment with vidofludimus calcium led to a reduction in new magnetic resonance imaging lesions in patients with relapsing-remitting multiple sclerosis and was well tolerated with a favorable safety profile. Assessment in longer, larger trials is justified.

CLINICAL AND NEUROPHYSIOLOGICAL PARALLELS OF THE BRACHIAL PLEXOPATHY IN THE STRUCTURE OF NEUROGENIC THORACIC OUTLET SYNDROME.

OBJECTIVE: The aim: Was assessment of the neurophysiological data and features of clinical picture in patients with neurogenic thoracic outlet syndrome (TOS). PATIENTS AND METHODS: Materials and methods: 103 patients with upper extremity pain and/or paresthesia or hypotrophy, or a combination of these symptoms were examined. The examination algorithm included: cervical spine radiography, cervical spine and brachial plexuses magnetic resonance imaging (MRI), upper extremity soft tissues and vessels ultrasonic examination, stimulation electroneuromiography with F-waves registration. RESULTS: Results: Neurogenic TOS was diagnosed in 29 patients. A significant relationship between the following complaints and neurophysiological parameters was observed: pain, numbness during physical activity and decreased medial anrebrachial cutaneous nerve response amplitude by ≥25% compared to the contralateral side; hypothenar hypotrophy and decrease of ulnar nerve motor/sensory response amplitude; the 4-5th fingers hypoesthesia and decrease of ulnar nerve sensory response amplitude. CONCLUSION: Conclusions: Medial antebrachial cutaneous nerve amplitudes asymmetry indices of ≥25% or lack of response may be considered to be a marker of true neurogenic TOS.

CLINICAL CASE OF NEUROMYELITIS OPTICA SPECTRUM DISORDERS IN YOUNG WOMAN TREATED WITH RITUXIMAB.

We report a case of a 28-year-old female who had the clinical manifestation of Neuromyelitis optica spectrum disorders with the area postrema syndrome at 24 years old. The patient presented with decreased vision due to acute optic neuritis, gait impairment, tetraplegia, sensory, and bladder disturbances. Magnetic resonance imaging of the spinal cord showed longitudinal high-intensity signals on a T2-weighted image in cervical and thoracic parts. Her serum and cerebrospinal fluid were positive for the anti-AQP4 antibody. The patient received high-dose methylprednisolone, plasmapheresis, but she remained free from relapses only after prescribing Rituximab. Prophylactic treatment of Neuromyelitis optica spectrum disorders recurrence must be immediately performed when it is identified because the progression of disability is related to the severity of attacks.

ASSOCIATIONS BETWEEN THE UPPER EXTREMITY FUNCTION AND COGNITION IN POST-STROKE PATIENTS.

OBJECTIVE: The aim: Was to determine the relations between the the upper extremity function and cognition in post-stroke patients. PATIENTS AND METHODS: Materials and methods: Totally there were 86 patients examined in the 1-year period after first-ever anterior circulation ischemic stroke. Examination of the upper extremity function was performed with the Fugl-Meyer assessment (FMA). Cognitive function was assessed with the Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Trail-making Test A and B (TMT) and the Clock Drawing Test (CDT). RESULTS: Results: Motor dysfunction mostly manifested in low "Wrist" and "Hand" subtests scores (5 and 7 , respectively) and therefore resulted in decreased "Total motor function" score of 40 . The most significant relations were found out between the FMA "Hand", "Total motor function" subtests and CI indices. MoCA score correlated with FMA "Wrist" (r=0.34; p=0.021), "Hand" (r=0.52; p=0.001) and "Total motor function" (r=0.48; p=0.003) scores. "Hand" score also correlated with the FAB (r=0.43; p=0.012), CDT (r=0.22; p=0.016), TMT-A (r=-0.31; p=0.023) and TMT-B (-0.48; p=0.009) scores. There was no significant correlation between the sensory FMA subtests. CONCLUSION: Conclusion: Our findings suggest that upper extremity motor impairment, especially hand and wrist dysfunction, are associated with cognitive impairment and executive functions disorder in particular.