Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. METHODS: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). FINDINGS: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21-11·53, p<0·0001). 65 (77%) of 84 patients in the efgartigimod group and 70 (84%) of 83 in the placebo group had treatment-emergent adverse events, with the most frequent being headache (efgartigimod 24 [29%] vs placebo 23 [28%]) and nasopharyngitis (efgartigimod ten [12%] vs placebo 15 [18%]). Four (5%) efgartigimod-treated patients and seven (8%) patients in the placebo group had a serious adverse event. Three patients in each treatment group (4%) discontinued treatment during the study. There were no deaths. INTERPRETATION: Efgartigimod was well tolerated and efficacious in patients with generalised myasthenia gravis. The individualised dosing based on clinical response was a unique feature of ADAPT, and translation to clinical practice with longer term safety and efficacy data will be further informed by the ongoing open-label extension. FUNDING: argenx.

Etiologic agents of central nervous system infections among febrile hospitalized patients in the country of Georgia.

OBJECTIVES: There is a large spectrum of viral, bacterial, fungal, and prion pathogens that cause central nervous system (CNS) infections. As such, identification of the etiological agent requires multiple laboratory tests and accurate diagnosis requires clinical and epidemiological information. This hospital-based study aimed to determine the main causes of acute meningitis and encephalitis and enhance laboratory capacity for CNS infection diagnosis. METHODS: Children and adults patients clinically diagnosed with meningitis or encephalitis were enrolled at four reference health centers. Cerebrospinal fluid (CSF) was collected for bacterial culture, and in-house and multiplex RT-PCR testing was conducted for herpes simplex virus (HSV) types 1 and 2, mumps virus, enterovirus, varicella zoster virus (VZV), Streptococcus pneumoniae, HiB and Neisseria meningitidis. RESULTS: Out of 140 enrolled patients, the mean age was 23.9 years, and 58% were children. Bacterial or viral etiologies were determined in 51% of patients. Five Streptococcus pneumoniae cultures were isolated from CSF. Based on in-house PCR analysis, 25 patients were positive for S. pneumoniae, 6 for N. meningitidis, and 1 for H. influenzae. Viral multiplex PCR identified infections with enterovirus (n = 26), VZV (n = 4), and HSV-1 (n = 2). No patient was positive for mumps or HSV-2. CONCLUSIONS: Study findings indicate that S. pneumoniae and enteroviruses are the main etiologies in this patient cohort. The utility of molecular diagnostics for pathogen identification combined with the knowledge provided by the investigation may improve health outcomes of CNS infection cases in Georgia.

Correlation between MMP-9 and extracellular cytokine HMGB1 in prediction of human ischemic stroke outcome.

Ischemic stroke (IS) outcome predictors include clinical features, biochemical parameters and some risk factors. The relations between two main players in the ischemic brain, MMPs and HMGB1, were estimated in the plasma of ischemic stroke patients stratified according to the Glasgow Outcome Scale and the Oxfordshire Community Stroke Project classification. IS patients exhibited higher plasma concentration of MMP-9 and the inflammatory cytokine HMGB1 compared with healthy controls. A full-blown correlation between MMP-9 activation and increased plasma MMP-9 concentration was observed in case of IS patients. A similar activity of MMP-2 and MMP-12 was characteristic of healthy volunteers and IS patients. In patients with ischemic stroke increased plasma levels of MMP-9 and HMGB1 are associated with a poor functional outcome and are significantly correlated with each other (P=0.0054). We suggest that diagnostic benefits will be obtained if plasma HMGB1 levels are measured for IS patients in addition to MMP-9.

Incidence rates of the primary brain tumours in Georgia--a population-based study.

BACKGROUND: To determine the incidence rate and to describe other basic epidemiological data of primary brain tumours in a population-based study in Georgia, performed between March 2009 and March 2011. METHODS: Active case ascertainment was used to identify brain tumour cases by searching neuroradiology scan reports and medical records from all participating medical institutions, covering almost 100% of the neurooncology patients in the country. RESULTS: A total of 980 new cases were identified during the two-year period. For a population of almost 4.5 million, the overall annual incidence rate was 10.62 per 100,000 person-years, age-standardized to the year 2000 US population (ASR). Non-malignant tumours constituted about 65.5% of all tumours. Males accounted for 44% and females for 56% of the cases. Among classified tumours, age-standardized incidence rates by histology were highest for meningiomas (2.65/100,000), pituitary adenoma (1.23/100,000) and glioblastomas (0.51/100,000). ASR were higher among females than males for all primary brain tumours (10.35 vs. 9.48/100,000) as well as for main histology groups except for neuroepithelial, lymphomas and germ cell tumours. CONCLUSIONS: The annual incidence rate of all primary brain tumours in Georgia, though comparable with some European registry data, is low in comparison with the 2004-2005 Central Brain Tumor Registry of the United States (CBTRUS) database, which may reflect variations in reporting and methodology. The higher percentage of unclassified tumours (37.8%) probably also affects the discrepancies between our and CBTRUS findings. However, the most frequently reported tumour was meningioma with a significant predominance in females, which is consistent with CBTRUS data.

Primary brain tumour epidemiology in Georgia: first-year results of a population-based study.

A population-based cohort study was initiated in Georgia in March 2009 to collect epidemiologic data of malignant and non-malignant primary brain tumours. During the first year, 473 incident cases were identified. For a population of 4.3 million, the annual incidence rate was 10.25 per 100,000 inhabitants, age-standardized to the year 2000 US population. Non-malignant tumours constituted about 66 % of all tumours. Males accounted for 40 % and females for 60 % of the cases. Crude incidence rates by histology were highest for meningiomas (2.92/100,000), pituitary adenoma (1.16/100,000) and glioblastomas (0.64/100,000), which was in agreement with the frequency of reported histology: meningiomas--45.2 %, pituitary adenoma--18.0 % and glioblastomas--9.9 %. The age-standardized incidence rates were higher among females than males for all primary brain tumours (11.05 vs. 8.44/100,000) as well as for individual histologies except for glioblastoma and several other neuroepithelial tumours. Some differences compared with 2004-2005 Central Brain Tumor Registry of the United States data may be explained by a higher percentage of unclassified tumours (37 %) in our study. We suggest further studies to clarify the nature of this discrepancy.

Selected acute phase CSF factors in ischemic stroke: findings and prognostic value.

BACKGROUND: Study aimed at investigation of pathogenic role and prognostic value of several selected cerebrospinal fluid acute phase factors that can reflect the severity of ischemic brain damage. METHODS: Ninety five acute ischemic stroke patients were investigated. Ischemic region visualized at the twenty fourth hour by conventional Magnetic Resonance Imaging. Stroke severity evaluated by National Institute Health Stroke Scale. One month outcome of disease was assessed by Barthel Index. Cerebrospinal fluid was taken at the sixth hour of stroke onset. CSF pro- and anti-inflammatory cytokines were studied by Enzyme Linked Immunosorbent Assay. Nitric Oxide and Lipoperoxide radical were measured by Electron Paramagnetic Resonance. CSF Nitrate levels were detected using the Griess reagent. Statistics performed by SPSS-11.0. RESULTS: At the sixth hour of stroke onset, cerebrospinal fluid cytokine levels were elevated in patients against controls. Severe stroke patients had increased interleukin-6 content compared to less severe strokes (P < 0.05). Cerebrospinal fluid Electron Paramagnetic Resonance signal of nitric oxide was increased in patients against controls. Severe stroke group had an elevated Electron Paramagnetic Resonance signal of lipoperoxiradical compared to less severe stroke. Cerebrospinal fluid nitrate levels in less severe stroke patients were higher than those for severe stroke and control. Positive correlation was established between the initial interleukin-6 content and ischemic lesion size as well as with National Institute Health Stroke Scale score on the seventh day. Initial interleukin-6 and nitrate levels in cerebrospinal fluid found to be significant for functional outcome of stroke at one month. CONCLUSION: According to present study the cerebrospinal fluid contents of interleukin-6 and nitrates seem to be the most reliable prognostic factors in acute phase of ischemic stroke.

Stroke incidence and 30-day case-fatality in a suburb of Tbilisi: results of the first prospective population-based study in Georgia.

BACKGROUND AND PURPOSE: Although stroke is one of the main public health problems worldwide, no study of stroke incidence has been performed in Georgia, and therefore, a population-based registry was established to determine the incidence and case-fatality rates of first-ever stroke. METHODS: We identified all first-ever strokes between November 2000 and July 2003 in a defined population of 51,246 residents in the Sanzona suburb of Tbilisi, the capital of Georgia, using overlapping sources of information and standard diagnostic criteria. RESULTS: A total of 233 first-ever strokes occurred during the study period. The crude annual incidence rate was 165 (95% CI, 145 to 188) per 100,000 residents. The corresponding rate adjusted to the standard "world" population was 103 (95% CI, 89 to 117). In terms of stroke subtype, the crude annual incidence rate per 100,000 inhabitants was 89 (95% CI, 74 to 106) for ischemic stroke, 44 (95% CI, 34 to 57) for intracerebral hemorrhage, 16 (95% CI, 10 to 25) for subarachnoidal hemorrhage, and 16 (95% CI, 10 to 25) for unspecified stroke, and the corresponding case-fatality rates at 1 month were 19.2%, 48.4%, 47.8%, and 69.6%. CONCLUSIONS: The overall stroke incidence rate in an urban population of Georgia is comparable to those reported in developed countries. As for the stroke subtypes, there is an excess of hemorrhagic strokes compared with other registries. Geographical and lifestyle variations may explain these findings, whereas inadequacy of the stroke care system in Georgia might contribute to the high case-fatality.