Эффективность и безопасность левилимаба в сочетании с метотрексатом при лечении пациентов с активным ревматоидным артритом, устойчивым к монотерапии метотрексатом (двойное слепое рандомизированное плацебо-контролируемое исследование III фазы, SOLAR)

Levilimab is anti-interleukin-6 receptor (IL6R) monoclonal antibody. The article presents data obtained during 24 weeks of the SOLAR phase III study.Objective: to confirm efficacy and safety of levilimab in combination with methotrexate (MTX) in patients with methotrexate resistant active rheumatoid arthritis (RA).Patients and methods. 154 adult patients, aged ≥18 years with the diagnosis of RA (ACR/EULAR 2010) and confirmed disease activity at screening despite treatment with MTX for at least 12 weeks (in a stable dose 15-25 mg/week). Patients were randomized 2:1 in levilimab (162 mg once a week, subcutaneously) + MTX (n=102) or placebo + MTX (n=52) group.The hypothesis of superiority of levilimab over placebo was tested for two co-primary efficacy endpoints: proportion of subjects who achieved ACR20 at week 12 and proportion of subjects who achieved low disease activity (LDA) of RA (DAS28-CRP <3.2) at week 24. Safety was assessed through monitoring of adverse events (AEs).Results and discussion. Seventy (68.6%) subjects who received levilimab and 20 (38.5%) who received placebo achieved ACR20 response at week 12. Fifty three (52%) subjects who received levilimab and 3 (5,8%) subjects who received placebo achieved LDA at week 24. The most common adverse events (reported in ≥5% of subjects) in levilimab and placebo arms, respectively were (by decreasing frequency): blood c holesterol increase (24% vs 12%), alanine aminotransferase elevation (11% vs 8%), lymphocyte count decrease (9% vs 8%), blood total bilirubin increase (11% vs 0%), blood triglycerides increase (10% vs 2%), aspartate aminotransferase elevation (7% vs 4%), positive interferon-gamma release assay (IGRA) with M.tuberculosis antigen blood test (5% vs 6%), absolute neutrophil count decrease (8% vs 0%). No deaths were occurred.Conclusion. The study confirmed superior efficacy of levilimab + MTX over placebo + MTX in subjects with MTX resistant active RA. Levilimab showed favorable safety profile and low immunogenicity. No new important safety risks were detected.Левилимаб – моноклональное антитело к рецептору интерлейкина 6. В статье приведены данные, полученные в ходе 24 нед исследования III фазы SOLAR.Цель исследования – подтвердить эффективность и безопасность левилимаба в комбинации с метотрексатом (МТ) у пациентов с активным ревматоидным артритом (РА), устойчивым к монотерапии МТ.Пациенты и методы. Рандомизировано 154 пациента в возрасте 18 лет и старше с установленным диагнозом РА (критерии ACR/EULAR, 2010) и подтвержденной активностью заболевания, несмотря на терапию МТ (в стабильной дозе 15–25 мг/нед) в течение ≥12 нед. Рандомизация проводилась в соотношении 2:1 в группу левилимаба (162 мг, 1 раз в неделю, подкожно) в комбинации с МТ (n=102) или плацебо в комбинации с МТ (n=52).Превосходство левилимаба над плацебо было оценено по двум ко-первичным конечным точкам: доля пациентов, достигших 20% улучшения в течении РА в соответствии с ACR20 на 12-й неделе исследования; доля пациентов с низкой активностью РА (DAS28-СРБ <3,2) на 24-й неделе. Безопасность лечения левилимабом в сочетании с МТ оценивалась на основании мониторинга нежелательных явлений (НЯ).Результаты и обсуждение. На 12-й неделе терапии ACR20 достигли 70 (68,6%) и 20 (38,5%) пациентов группы левилимаба и группы плацебо соответственно. Низкая активность РА на 24-й неделе исследования выявлена у 53 (52%) пациентов, получавших левилимаб в сочетании с МТ, и у 3 (5,8%) пациентов группы плацебо. Среди наиболее частых (развившихся у ≥5% пациентов) НЯ в группах левилимаба и плацебо соответственно были зарегистрированы (в порядке убывания частоты) следующие отклонения в показателях крови: повышение уровня холестерина (24 и 12%), повышение активности аланинаминотрансферазы (11 и 8%), снижение числа лимфоцитов (9 и 8%), повышение уровня общего билирубина (11 и 0%), повышение уровня триглицеридов (10 и 2%), повышение активности аспартатаминотрансферазы (7 и 4%), положительный тест высвобождения интерферона гамма с антигеном M. tuberculosis (5 и 6%) и снижение абсолютного числа нейтрофилов (8 и 0%). Летальных исходов не было.Заключение. Результаты исследования подтвердили, что у пациентов с РА, устойчивых к монотерапии МТ, левилимаб в комбинации с МТ превосходит по эффективности плацебо с МТ. Левилимаб продемонстрировал благоприятный профиль безопасности и низкую иммуногенность. Не выявлено новых важных рисков, связанных с безопасностью

Долгосрочное влияние нетакимаба на качество жизни, боль в спине и работоспособность пациентов с анкилозирующим спондилитом: результаты международного многоцентрового рандомизированного двойного слепого клинического исследования III фазы BCD-085-5/ASTERA

The article contains the data obtained during the 156-week follow-up of patients with ankylosing spondylitis (AS) in the ASTERA phase III study.Objective: to evaluate the effect impact of netakimab (NTK) on quality of life (QoL), back pain and work capacity in patients with active AS.Material and methods. The study enrolled 228 patients with active AS who were randomized 1:1 to receive NTK 120 mg or placebo. At week 52, patients in Group 1 (NTK) who achieved ASAS20 continued therapy (NTK at a dose of 120 mg once every 2 weeks) until week 156. Patients in Group 2 (placebo/NTK) received the study drug at a dose of 120 mg subcutaneously every 2 weeks from week 20 until week 68, after which the efficacy of therapy was determined (by achieving an ASAS20 response). Patients who achieved ASAS20 received treatment (NTK at a dose of 120 mg once every 2 weeks) until week 172.Results and discussion. Under NTK therapy, a significant improvement in QoL was observed in the assessment of the physical and psychological components of the SF-36 questionnaire, which was maintained during the three years of therapy: increase in indicator by 12.68±9.92; 13.27±10.14; 12.92±10.03; 14.10±10.35; 14.76±9.77 and 6.10±11.59; 5.50±11.82; 6.32±11.01; 5.87±11.45; 5.25±11.98 points at week 52, 76, 104, 128 and 156, respectively. During the extended therapy period, a reduction in the proportion of working hours missed for health reasons, an improvement in work capacity and work efficiency and an increase in daily activity were observed. Back pain (BASDAI question 2) and nocturnal back pain decreased steadily during the entire follow-up period compared to the screening values.Conclusion. NTK is an effective therapy for active AS that improves QoL scores, significantly reduces pain intensity and improves work productivity.В статье приведены данные, полученные в ходе 156 нед наблюдения за пациентами с анкилозирующим спондилитом (АС) в исследовании III фазы ASTERA.Цель исследования – оценить влияние нетакимаба (НТК) на качество жизни (КЖ), боль в спине и работоспособность пациентов с активным АС.Материал и методы. В исследование включено 228 больных активным АС, которые были рандомизированы в соотношении 1:1 в группу НТК 120 мг или группу плацебо. На неделе 52 пациенты группы 1 (НТК), достигшие ASAS20, продолжили получать терапию (НТК в дозе 120 мг 1 раз в 2 нед) до недели 156. Пациенты группы 2 (плацебо/НТК), начиная с недели 20, использовали исследуемый препарат в дозе 120 мг подкожно 1 раз в 2 нед до недели 68, после которой у них была определена эффективность терапии (по достижению ответа ASAS20). Пациенты, достигшие ASAS20, получали лечение (НТК в дозе 120 мг 1 раз в 2 нед) до недели 172.Результаты и обсуждение. На фоне лечения НТК наблюдалось значимое улучшение КЖ при оценке физического и психологического компонентов опросника SF-36, которое сохранялось на протяжении 3 лет терапии: повышение показателя на 12,68±9,92; 13,27±10,14; 12,92±10,03; 14,10±10,35; 14,76±9,77 и 6,10±11,59; 5,50±11,82; 6,32±11,01; 5,87±11,45; 5,25±11,98 балла на неделях 52, 76, 104, 128, 156 соответственно. В течение продленного периода терапии было выявлено снижение доли рабочего времени, пропущенного по состоянию здоровья, улучшение работоспособности и эффективности труда, а также повышение повседневной активности. Боль в спине (вопрос 2 BASDAI) и ночная боль в спине стойко уменьшались на протяжении всего периода наблюдения по сравнению с их показателями на момент скрининга.Заключение. НТК является эффективным методом терапии активного АС. Под действием НТК улучшаются показатели КЖ, в том числе значимо снижается интенсивность боли и улучшается производительность труда

RARE VASCULAR ANOMALY «ARTERIAL FORCEPS» AS A CAUSE OF OBSTRUCTION URETEROPELVIC JUNCTIONOF THE RIGHT KIDNEY

The article describes a clinical case of right renal artery anomalies in the form of «arterial forceps». Patient S., 26 years have seen a university clinic for two years. Complained of heaviness in the right lumbar region, not associated with urination and stoped after taking antispasmodics (drotaverin). In urinalysis revealed no pathological changes, serum creatinine, glomerular filtration rate in the normal range. Palpation in the right flank found kidney, easily movable hand pressure, painless. Ultrasound during supine and standing were identified nephroptosis, yavivsheesya indication for endoscopic surgery nephropexy. However, after the operation the patient's condition has not improved. Pain intensified and gained position hue. The study was revealed complex malformation of the vascular bed of the right kidney . It has been found that the right renal artery divides into two long branches before entering the gates kidney then forward it again bifurcated branch of the upper and lower branches and the same before entering the gates, forming a compression pelvis and causing its dilation

Long-Term Outcomes of Pharmacoinvasive Reperfusion Strategy Depending on the Choice of Thrombolytic Agent in ST-Segment Elevation Myocardial Infarction

There is limited information on the comparative results of using different thrombolytic drugs for pharmacoinvasive reperfusion in acute ST-segment elevation myocardial infarction (STEMI). There is special interest in comparing the efficacy of fibrin-selective and fibrin-non-selective thrombolytics.Aim. To study the prevalence of major adverse cardiovascular events and the status of patients who had STEMI and pharmacoinvasive reperfusion a year ago, depending on the choice of thrombolytic drug.Material and methods. 240 STEMI-patients undergoing pharmacoinvasive reperfusion (reference event) were divided into 4 groups depending on the choice of the thrombolytic drug (alteplase [group 1], teneteplase [group 2], fortetelizin [group 3], streptokinase [group 4]) as well as into 2 groups depending on the fibrin-specificity of thrombolytics. One year after the reference event the prevalence of major cardiovascular events (death, repeated myocardial infarction, stroke, repeated revascularization of the target vessel, and their combination) was assessed. Data of echocardiography and 24-hour ECG monitoring, indicis of rating scale of clinical state in patients with heart failure (RSCS, Mareev V.Y, 2000), results of determination of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and of six-minute walk test were also analyzed.Results. One year after the reference event, patients who received fibrin-selective thrombolytics (groups 1,2, 3) compared with patients treated with fibrin-non-selective drug (group 4) had a higher left ventricular ejection fraction (49.8±7.4% vs 47,4±6.8%; p=0.048), lower index of impaired local contractility (1.19 [1.06; 1.38] vs 1.25 [1.175; 1.5], p=0.029), an end-diastolic volume (1 39.1 ±28.6 ml vs 148.7±23.9 ml; p=0.027), the size of the left atrium (39.0±4.6 mm vs 41.1 ±3.1 mm, p=0.007 ), and insignificantly lower prevalence of atrial fibrillation (1.5% vs 6.7%, p=0.068). They also showed a lower prevalence of supraventricular tachycardia (4.5% vs 13.3%, p=0.049) and ventricular extrasystoles (54.5% vs 76.7%, p=0.022) as well as the daily number of ventricular extrasystoles (4.5 [0; 32.0] vs 34, 0 [2.25; 80.25], p=0.001) with more favorable gradations and indicators of heart rate variability. Statistically significantly lower NT-proBNP level (148 [1 20; 208.5] pg/ml vs 241 [189; 287] pg/ml; p=0.000) and chronic heart failure manifestation according to RSCS (p=0.033), as well as a longer distance in the six-minute walk test (p=0.000) were found in patients treated with fibrin-selective drugs. Statistically significant differences between groups 1, 2, 3 for the study period were not found. Significant differences in the prevalence of hard clinical endpoints (death, repeated myocardial infarction, stroke, repeated revascularization of the target artery) were not found in all groups.Conclusion. More favorable clinical, laboratory and instrumental parameters were found one year after STEMI and pharmacoinvasive reperfusion with fibrin-specific thrombolytic agents as compared with fibrin-non-specific thrombolytic. All groups had no statistically significant differences in the effect on hard clinical endpoints during the entire observation period

Arterial hypertension in tuberculosis patients: clinical course and pharmaceutical control

Aim. To access arterial hypertension (AH) prevalence, pathogenesis, and effectiveness of fixed-dose perindopril and indapamide combination in tuberculosis (TB) patients. Material and methods. In total, 489 case records of patients with TB of various localization were analyzed; 42 patients with TB and AH were examined. Dynamics of 24-hour blood pressure monitoring (BPM) parameters, left ventricular (LV) morphology and function (echocardiography data), vegetative effects on hemodynamics (heart rate variability), and endothelial function (von Willebrand factor level measurement, reactive hyperemia test) were investigated. Results. The rates of AH and TB combination were quite high. These patients were characterized by “non-dipper” and “night-peaker” 24-hour BMP profiles, hypersympathicotonia, LV remodeling, right heart hypertrophy tendency, and endothelial dysfunction. Twelve-week therapy with fixed-dose combination of perindopril (4,0 mg) and indapamide (1,25 mg) was associated with positive dynamics of pathogenetic disturbances in AH and TB patients. Conclusion. AH and TB combination negatively affects cardiovascular system. Treatment with perindopril and indapamide combination provides antihypertensive effect and normalizes main mechanisms of BP regulation

PRACTICAL APPLICATION OF DABIGATRAN ETEXILATE FOR STROKE PREVENTION IN PATIENTS WITH ATRIAL FIBRILLATION

Disadvantages of vitamin K antagonist warfarin and the benefits of new anticoagulants, including dabigatran etexilate, in the stroke prevention in patients with atrial fibrillation are considered. Factors that influence the choice of dabigatran dose in different individuals are discussed. Dabigatran treatment in special conditions is considered: during stroke development; in electrical or pharmacological cardioversion; in invasive or surgical procedures; during bleeding. Possible organizational system of thromboembolic events prevention in patients with atrial fibrillation is presented

THE EFFICACY AND SAFETY OF RITUXIMAB BIOSIMILAR (ACELLBIA®) IN RHEUMATOID ARTHRITIS AS THE FIRST BIOLOGICAL AGENT: RESULTS OF PHASE III (ALTERRA) CLINICAL TRIAL

The Russian biotechnological company «BIOCAD» has designed a chimeric monoclonal antibody against CD20 (BCD-020, Acellbia®) that is a biosimilar of rituximab (RTM; MabThera®, F. Hoffmann-La Roche Ltd., Switzerland). In recent years, there has been evidence that RTM can be used at lower doses than those given in the standard recommendations and instructions for the use of this drug. This serves as the basis for the BCD-020-4/ALTERRA (ALTErnative Rituximab regimen in Rheumatoid Arthritis) trial, the objective of which was to investigate the efficiency and safety of using Acellbia® (at a dose of 600 mg twice at a 2-week interval) as the first biological agent (BA) for methotrexate (MTX)-resistant active rheumatoid arthritis (RA). The investigation enrolled 159 patients aged 18 to 80 years with active RA. After 24 weeks 65.7 and 29.4% of patients achieved 20% improvement by the American College of Rheumatology (ACR) criteria in the Acellbia® + MTX and placebo (PL) + MTX groups, respectively (p<0.0001). The differences in the ACR20 response rate in the two groups were 36.3% (95% CI, 19.27–53.28%). There were significant differences between the groups in the ACR50 response rates: 28.4% and 5.9% (p=0.001) and in the ACR70 ones: 12.8% and only 2.0%, respectively (p=0.036). Analysis of all recorded adverse events (AE) frequency showed no significant differences between the patients in the study and control groups and demonstrates its equivalence with that of RTM (MabThera®); all the AE were expectable. It is noted that antibodies to RTM with binding and neutralizing activities had no impact on the efficiency and safety of therapy

Efficacy and safety of netakimab, anti-IL-17A monoclonal antibody, in patients with ankylosing spondylitis. Results of phase III international, multicenter, randomized double-blind clinical trial BCD-085-5/ASTERA

Netakimab (NTK) is a humanized monoclonal antibody targeting interleukin-17A.Objective. The main objective of BCD-085-5/ASTERA study was to prove superiority of NTK over placebo and assess its’ safety in patients with active AS.Subjects and methods. BCD-085-5/ASTERA was a double-blind, multicenter, randomized, placebo-controlled, phase III study, which included 228 adult patients with active AS, persisting despite active treatment with NSAIDs. AS was considered active at BASDAI score ≥ 4.0. Patients were blindly randomized (1:1) to receive subcutaneous injections of NTK (120 mg) or placebo at weeks 0, 1, 2 and then every other week up to week 14. Starting from week 16 all patients from NTK group and patients from placebo group not achieving ASAS20 were switched to open label 120 mg NTK s/c once every two weeks. The total duration of treatment with NTK was 3 years.Results. Higher proportion of patients had ASAS40 response at week 16 (primary endpoint) in NTK arm compared to placebo (40,4 vs 2,6%, р <0,0001, 95% CI [27,4%; 48,1%]). Spinal pain subsided and laboratory inflammation markers decreased within one week after the first NTK injection. NTK safety profile was comparable to that of placebo. The most common for NTK adverse events were neutropenia (7,0%) and ALT increase (6,1%).Conclusion. Subcutaneous NTK at 120 mg dose demonstrated superior efficacy vs placebo, with fast onset of response and favorable safety profile when used in patients with ankylosing spondylitis

Physicians' guideline adherence is associated with long-term heart failure mortality in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry

Background: Physicians' adherence to guideline-recommended therapy is associated with short-term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer-term outcomes is poorly documented. Here, we present results from the 18-month follow-up of the QUALIFY registry. Methods and results: Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed for five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF-related (191/394) and the same was true for unplanned hospitalizations (1175 CV and 861 HF-related hospitalizations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87–0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalization or CV death (SHR 0.97, 95% CI 0.94–0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all-cause, CV or HF hospitalizations were not (all-cause: SHR 0.99, 95% CI 0.9–1.02; CV: SHR 0.98, 95% CI 0.96–1.01; and HF: SHR 0.99, 95% CI 0.96–1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively). Conclusion: These results suggest that physicians' adherence to guideline-recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians' adherence to guidelines. © 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiolog