Overall Frequency Of Adverse Events Research Articles

Effect of Avenciguat on Albuminuria in Patients with CKD: Two Randomized Placebo-Controlled Trials.

Avenciguat is a novel, potent soluble guanylate cyclase activator in development for CKD. Two trials investigated avenciguat in diabetic (NCT04750577) and non-diabetic (NCT04736628) CKD. A prespecified pooled analysis of two randomized, double-blind, placebo-controlled trials of identical design. Adults with CKD (eGFR ≥20 and <90 mL/min/1.73 m2, urine albumin-to-creatinine ratio [UACR] ≥200 and <3500 mg/g) were randomized to 20 weeks of placebo or avenciguat 1, 2, or 3 mg three times daily (TID; adjunctive to angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker. Primary endpoint: change from baseline in UACR in 10-hour urine at week 20, analyzed per protocol. Secondary endpoint: UACR change from baseline in first morning void urine at week 20. Safety was monitored throughout. Overall 500 patients (mean age 62 years [SD 13]; mean eGFR 44 mL/min/1.73 m2 [SD 18] and median 10-hour UACR 719 [interquartile range 379-1285] mg/g ) received placebo (n=122) or avenciguat 1 mg (n=125), 2 mg (n=126), or 3 mg (n=127) TID. All 243 patients in study one and 27/261 patients in study two had diabetes. Avenciguat 1, 2, and 3 mg TID reduced UACR in 10-hour and first morning void urine versus placebo throughout the treatment period. At week 20, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UACR in 10-hour urine with avenciguat 1, 2, and 3 mg TID were -15.5% (-26.4, -3.0), -13.2% (-24.6, -0.1), and -21.5% (-31.7, -9.8), respectively, analyzed per protocol. Corresponding changes in first morning void urine were -19.4% (-30.0, -7.3), -15.5% (-26.9, -2.5), and -23.4% (-33.5, -11.8), respectively. Avenciguat was well tolerated, overall frequency of adverse events was low and similar to placebo. The number of patients who discontinued study drug due to adverse events with avenciguat 1, 2, and 3 mg TID were 5 (4%), 11 (9%), and 11 (9%), respectively, compared with 4 (3%) in the placebo group. Avenciguat lowered albuminuria, and was well tolerated in patients with CKD.

Safety and Tolerability of Six Months of Isoniazid Plus Pyridoxine or Three Months of Rifampicin for Tuberculosis among Subjects with Diabetes Mellitus: A Randomized Trial.

Tuberculosis (TB) associated with diabetes mellitus (DM) is a growing problem, particularly in low- and medium-resource countries. We conducted an open-label, parallel-group, randomized, and controlled trial in a tertiary care center in Mexico City to assess TB preventive treatment (TPT) with isoniazid (INH) or rifampicin (RIF) in people with type 2 DM. Participants were assigned six months of INH 300 mg/day plus pyridoxine 75 mg or three months of RIF 600 mg/day. The primary outcomes were adverse events resulting in permanent treatment cessation and considered possibly or probably related to study drugs. We included 130 subjects, 68 randomized to INH and 62 to RIF. We prematurely halted the study based on recommendations of the Adverse Event Safety Panel. There was no difference between arms in the overall frequency of adverse events. However, the INH group had significantly more permanent treatment interruptions due to grade 2 recurrent or grade 3 or 4 hepatoxicity. In comparison, the RIF arm had more treatment interruptions due to grade 3 or 4 gastrointestinal intolerance. TPT using INH or RIF is not safe enough to be considered a universal indication to patients with type 2 DM and TB infection. These results underline the need to search for alternative TB preventions with better safety profiles for type 2 DM patients.

The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease

The ASCEND-NHQ trial evaluated the effects of daprodustat on hemoglobin and the Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality score (fatigue) in a multicenter, randomized, double-blind, placebo-controlled trial. Adults with chronic kidney disease (CKD) stages 3-5, hemoglobin 8.5-10.0 g/dl, transferrin saturation 15% or more, and ferritin 50 ng/ml or more without recent erythropoiesis-stimulating agent use were randomized (1:1) to oral daprodustat or placebo to achieve and maintain target hemoglobin of 11-12 g/dl over 28 weeks. The primary endpoint was the mean change in hemoglobin between baseline and the evaluation period (Weeks 24-28). Principal secondary endpoints were proportion of participants with a 1 g/dl or more increase in hemoglobin and mean change in the Vitality score between baseline and Week 28. Outcome superiority was tested (1-sided alpha level of 0.025). Overall, 614 participants with non-dialysis-dependent CKD were randomized. The adjusted mean change in hemoglobin from baseline to the evaluation period was greater with daprodustat (1.58 vs 0.19 g/dl). The adjusted mean treatment difference (AMD) was significant at 1.40 g/dl (95% confidence interval 1.23, 1.56). A significantly greater proportion of participants receiving daprodustat showed a 1 g/dl or greater increase in hemoglobin from baseline (77% vs 18%). The mean SF-36 Vitality score increased by 7.3 and 1.9 points with daprodustat and placebo, respectively; a clinically and statistically significant 5.4 point Week 28 AMD increase. Adverse event rates were similar (69% vs 71%); relative risk 0.98, (95% confidence interval 0.88, 1.09). Thus, in participants with CKD stages 3-5, daprodustat resulted in a significant increase in hemoglobin and improvement in fatigue without an increase in the overall frequency of adverse events.

309 Tralokinumab demonstrated a consistent safety profile with up to 42 months of treatment in moderate-to-severe atopic dermatitis: including adverse events of special interest

Abstract As atopic dermatitis (AD) is a chronic and potentially life-long disease, it is important to determine the long-term safety of new treatments. Tralokinumab, which specifically targets interleukin-13, is approved in Europe, Canada and the United States for the treatment of adults with moderate-to-severe AD. During the initial 12–16 week placebo-controlled treatment period of Phase 2 and 3 trials, tralokinumab was well-tolerated with an overall frequency of adverse events (AEs) similar to the placebo. An ongoing open-label extension trial, ECZTEND (NCT03587805), is assessing the safety and efficacy of tralokinumab up to 5 years after parent trials (PT). To report an interim safety analysis of patients treated with tralokinumab for up to 42 months (≤ 1 year in PT and ≤ 2.5 years in the open-label extension ECZTEND), including AEs of special interest (AESI). In ECZTEND, moderate-to-severe AD patients who completed the previous tralokinumab PT received subcutaneous tralokinumab 300 mg every 2 weeks after a 600 mg loading dose; topical corticosteroid use was optional. All AEs were recorded, coded, and classified by severity, causality and outcome. AESIs were predefined in PT based on areas of safety interest for monoclonal antibodies in AD, including eye disorders (e.g. conjunctivitis), skin infections requiring systemic treatment, eczema herpeticum and malignancies diagnosed after dosing. Event rates are presented as the number of events (nE) per 100 patient-years of exposure (PYE). All AEs described were treatment-emergent AEs, defined as AEs reported after the first dosing of the study drug. As of 30 April 2021, the interim safety analysis included 1442 patients from the PT ECZTRA 1, 2, 3, 4, 5 and 7 who had received ≥1 dose of tralokinumab in ECZTEND, with 121.0 weeks mean exposure time on tralokinumab [median 131.5 weeks (IQR 83.4–161.8); min 0.0, max 186.4 weeks]. Total exposure time in ECZTEND was 2446.2 PYE. Overall, 1127 patients experienced an AE (198.7 nE/100 PYE), the majority of which were mild (132.6 nE/100 PYE). The most frequently reported AEs (≥5.0% of patients) were the same as in the PT, including viral upper respiratory tract infection (18.2 nE/100 PYE, mainly reported as the common cold), atopic dermatitis (17.9 nE/100 PYE), upper respiratory tract infection (5.8 nE/100 PYE), headache (4.4 nE/100 PYE) and conjunctivitis (3.8 nE/100 PYE). The rates of AEs were generally lower as compared to short-term rates in the PT. Most of the serious AEs (SAEs; 4.9 nE/100 PYE) were reported as single events without clustering on the type. No events of conjunctivitis AEs were SAEs, and only five patients discontinued due to conjunctivitis AEs. AESI eye disorders, skin infections requiring systemic treatment, eczema herpeticum and malignancies were observed at rates similar to or lower than reported in PT. Consistent safety was demonstrated during up to 42 months of tralokinumab treatment in patients with moderate-to-severe AD. Exposure-adjusted incidence rates of AESIs, including eczema herpeticum and skin infections requiring systemic treatment, were generally lower than rates reported during the short-term, placebo-controlled period up to week 16. Exposure-adjusted incidence rates of conjunctivitis were lower with long-term exposure, and only five patients discontinued due to conjunctivitis. This analysis supports the long-term benefit-risk profile of targeted IL-13 inhibition with tralokinumab for patients with moderate-to-severe AD.

Comparison of negative pressure wound therapy and moist wound care in patients with diabetic foot ulcers: A protocol for systematic review and meta-analysis of randomized controlled trials.

Background:This study conducted a meta-analysis to compare the effectiveness and safety of the negative pressure wound therapy (NPWT) with the moist wound care (MWC) in the treatment of diabetic foot ulcers (DFUs).Methods:The PubMed, EMBASE, and CENTRAL were searched by 2 of the authors, to identify randomized controlled trials comparing the clinical outcomes of patients treated with NPWT versus MWC for DFUs. Meta-analyses were performed for several outcomes, including wound healing results, amputation or resection incidence, and risk of adverse events, utilizing the “meta” package of R language version 4.0.3.Results:A total of 10 trials (619 patients in NPWT group and 625 in MWC group) and 8 trials were included for the qualitative and quantitative syntheses, respectively. As a result, significantly lower risk of non-closure of the wound (risk ratio [RR] = 0.74, 95% confidence interval [CI]: 0.63–0.87; P = .001), lower average wound area (standard mean difference = −0.80, 95% CI: −1.54 to −0.06; P = .034), more wound area decrease (standard mean difference = 0.81, 95% CI: 0.36–1.26; P = .001), increased appearance rate of granulation tissue (RR = 1.61, 95% CI: 1.07–2.41; P-0.021), and lower risk of amputation or resection (RR = 0.70, 95% CI: 0.50–0.99; P = .045), were demonstrated for the NPWT group when compared to MWC group. However, no statistically significant difference was found for the disappearance rate of wound discharge at 8 weeks, the rate of blood culture positivity, VAS-pain score, and the overall frequency of adverse events between the 2 treatment groups (P = .05).Conclusion:NPWT could accelerate process of the wound healing, and decrease the risk of post-treatment amputation or resection, without any additional frequency of adverse events, when compared with MWC, in patients with DFUs.

The efficacy and safety study of the combined use of platelet-rich plasma and fractional radiofrequency ablation in the treatment of post-acne scars

Introduction. So far, a large number of skin scars treating methods have been proposed and tested. The use of platelet-rich plasma (PRP) is currently being considered as one of the most promising approaches to skin scar treatment.Aim. Clinical efficacy and safety evaluation of complex treatment of post-acne scars using PRP.Materials and methods. An open, randomized, prospective study was conducted in parallel groups. The study included 78 patients with post-acne scars, then randomized into 2 groups. Group 1: 36 patients receiving platelet-rich plasma (PRP); group 2: 42 patients receiving complex treatment with PRP and fractional radiofrequency ablation (PRP + FRF). PRP procedures using the micro-papular technique in group 1 were carried out 5 times with an interval of 2 weeks. The combination of PRP + FRF in group 2 was performed according to the following: the first procedure – FRF, two weeks later – PRP using the micro-papular technique. Then after 2 weeks FRF was performed again, and so on. The total number of procedures of both techniques was 10.Results and discussion. As a result of the treatment, in all patients with post-acne, the clinical indicators of the severity of skin scarring changes decreased significantly, while the most noticeable dynamics were common for patients in group 2. The scars assessment using the Vancouver scale showed that 6 and 12 months after treatment, the severity of objective components and the severity of subjective sensations decreased in most patients. The severity of their own attitude to persistent defects also decreased. Analysis of the frequency of adverse reactions during treatment and in the early period showed that there were no significant intergroup differences in individual adverse reactions. The overall frequency of adverse events in the long-term period also did not significantly differ.Conclusion. The results of the study indicate that the use of PRP in the complex treatment of scarring is a clinically effective and safe method of treatment and allows you to expand the range of therapeutic approaches for scarring skin deformities.

Safety and efficacy of mass drug administration with a single-dose triple-drug regimen of albendazole + diethylcarbamazine + ivermectin for lymphatic filariasis in Papua New Guinea: An open-label, cluster-randomised trial.

BackgroundPapua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG.MethodologyAll consenting, eligible residents of 24 villages in Bogia district, Madang Province, PNG were enrolled, screened for W. bancrofti antigenemia and microfilaria (Mf) and randomised to receive IDA (N = 2382) or DA (N = 2181) according to their village of residence. Adverse events (AE) were assessed by active follow-up for 2 days and passive follow-up for an additional 5 days. Antigen-positive participants were re-tested one year after MDA to assess treatment efficacy.Principal findingsOf the 4,563 participants enrolled, 96% were assessed for AEs within 2 days after treatment. The overall frequency of AEs were similar after either DA (18%) or IDA (20%) treatment. For those individuals with AEs, 87% were mild (Grade 1), 13% were moderate (Grade 2) and there were no Grade 3, Grade 4, or serious AEs (SAEs). The frequency of AEs was greater in Mf-positive than Mf-negative individuals receiving IDA (39% vs 20% p<0.001) and in Mf-positive participants treated with IDA (39%), compared to those treated with DA (24%, p = 0.023). One year after treatment, 64% (645/1013) of participants who were antigen-positive at baseline were re-screened and 74% of these participants (475/645) remained antigen positive. Clearance of Mf was achieved in 96% (52/54) of infected individuals in the IDA arm versus 84% (56/67) of infected individuals in the DA arm (relative risk (RR) 1.15; 95% CI, 1.02 to 1.30; p = 0.019). Participants receiving DA treatment had a 4-fold higher likelihood of failing to clear Mf (RR 4.67 (95% CI: 1.05 to 20.67; p = 0.043). In the DA arm, a significant predictor of failure to clear was baseline Mf density (RR 1.54; 95% CI, 1.09 to 2.88; p = 0.007).ConclusionIDA was well tolerated and more effective than DA for clearing Mf. Widespread use of this regimen could accelerate LF elimination in PNG.Trial registrationRegistration number NCT02899936; https://clinicaltrials.gov/ct2/show/NCT02899936.

Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes

BackgroundFinerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear.MethodsIn this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m2 of body-surface area (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of at least 60 ml per minute per 1.73 m2 (stage 1 or 2 CKD). Patients were treated with renin–angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer’s label that did not cause unacceptable side effects. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The first secondary outcome was a composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes. Safety was assessed as investigator-reported adverse events.ResultsA total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P=0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%).ConclusionsAmong patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD ClinicalTrials.gov number, NCT02545049.)

Efficacy and safety of chiglitazar, a novel peroxisome proliferator-activated receptor pan-agonist, in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, phase 3 trial (CMAP)

Chiglitazar (Carfloglitazar) is a novel non-thiazolidinedione (TZD) structured peroxisome proliferator-activated receptor (PPAR) pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies. This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone. Eligible patients were randomly assigned to receive chiglitazar 32 mg (n = 167), chiglitazar 48 mg (n = 166), or placebo (n = 202) once daily. The primary endpoint was the change in glycosylated hemoglobin A1c (HbA1c) at week 24 with superiority of chiglitazar over placebo. The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA1c, and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were −0.87% (95% confidential interval (CI): −1.10 to −0.65; P < 0.0001) and −1.05% (95% CI: −1.29 to −0.81; P < 0.0001), respectively. Secondary efficacy parameters including glycemic control, insulin sensitivity and triglyceride reduction were also significantly improved in the chiglitazar groups. The overall frequency of adverse events and study discontinuation attributable to adverse events were similar among the groups. Low incidences of mild edema and body weight gain were reported in the chiglitazar dose groups. The results from this phase 3 trial demonstrated that the PPAR pan-agonist chiglitazar possesses an overall good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions, thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.

Reactogenicity after the first and second doses of BNT162b2 mRNA coronavirus disease vaccine: a single-center study.

PurposeThis study was conducted to determine differences in adverse events associated with the first and second doses of the BNT162b2 coronavirus disease 2019 vaccine based on the age and sex of recipients.Materials and MethodsAn online survey on the post-vaccination adverse events of healthcare workers was conducted from March 2021 to April 2021. The differences in the types of adverse events, including severity, onset time, and duration of symptoms, and how the adverse events were dealt with by the patient were analyzed based on the age and sex. The profiles of adverse events were compared after the first and second vaccination doses.ResultsAmong the 131 participants who participated in the online survey out of 208 vaccine recipients, 43 and 80 recipients of the BNT162b2 vaccine experienced adverse events after the first and second dose, respectively. No sex-related differences were observed in the profiles of adverse events in vaccinated recipients. The overall frequency of adverse events did not differ based on age after the first dose. After the second dose, the frequency of adverse events, including both local and systemic reactions was significantly higher in the younger age group than in the older age group.ConclusionThe BNT162b2 vaccine resulted in a higher frequency of adverse events after the second dose than after the first dose especially in the younger age group; however, no sex-related differences associated with these adverse events were observed.

Side effects among healthcare workers from a large Milan university hospital after second dose of BNT162b2 mRNA COVID-19 vaccine.

Background:In Italy, healthcare workers (HCWs) were among the first to receive COVID-19 vaccination. Aim of the present study is to evaluate frequency and severity of adverse events (AEs) following the second dose of BNT162b2 vaccine among HCWs of a large university hospital in Milan, Italy.Methods:One month after having received the second dose of vaccine, HCWs filled-in a form about type, severity, and duration of post-vaccination local and systemic symptoms. We calculated the overall frequency of AEs and used multivariable Poisson regression models (adjusted for sex, age, BMI, smoking, allergy history, previous SARS-CoV-2 infection, anti-hypertensive therapy, and occupation) to calculate risk ratios (RR) and 95% confidence intervals (CI) of AEs according to selected variables.Results:We included 3659 HCWs. Overall, 2801 (76.6%) experienced at least one local event, with pain at injection site being the most frequent (2788, 76.2%). Systemic events were reported by 2080 (56.8%) HCWs, with fatigue (52.3%), muscle pain (42.2%), headache (37.7%), joint pain (31.9%), and fever (26.2%) being the most frequent. Risks of systemic events were associated with female gender (RR=1.14, CI: 1.06-1.24), age (strong decrease with increasing age, p-trend<0.001), allergy history (RR=1.13, CI: 1.05-1.20), SARS-CoV-2 infection more than 180 days before second dose (RR=1.16, CI:1.01-1.32), and current smoking (RR=0.90, CI: 0.84-0.97).Conclusions:Both local and systemic acute effects after second dose of BNT162b2 vaccine were frequently reported. However, symptoms were mostly light/mild and of short duration. Thus, our findings support the safety of COVID-19 vaccination in adults in relatively good health.

EFFICACY AND SAFETY OF SOME ETIOTROPIC THERAPEUTIC SCHEMES FOR TREATING PATIENTS WITH NOVEL CORONAVIRUS INFECTION (COVID-19)

The aim of the study is to assess the efficacy and safety of the Favipiravir (Areplivir) drug, compared to the standard etiotropic therapy in the patients hospitalized with COVID-19.Material and methods. The research was conducted as a part of an open, randomized, multicenter comparative study of the efficacy and safety of Areplivir, 200 mg film-coated tablets (“PROMOMED RUS” LLC, Russia), in the patients hospitalized with COVID-19. The dosing regimen of Favipiravir was 1600 mg twice a day on the 1st day and 600 mg twice a day on days 2–14. Thirty nine patients were enrolled into the study with a laboratory-established diagnosis of a new type of Coronavirus infection caused by SARS-CoV-2 (confirmed) of moderate severity, with pneumonia. The group of comparison (22 patients) received standard etiotropic therapy, prescribed in accordance with the current version of the temporary guidelines for the diagnosis and treatment of COVID-19, represented mainly by Hydroxychloroquine with the dosage regimen of 800 mg on the 1st day, then 400 mg on days 2–7, and Azithromycin 500 mg once a day for 5 days. The main group (17 patients) received Favipiravir (Areplivir) as etiotropiс therapy.Results. In the main group, the time period until fever disappeared was found to be 1.36 days shorter than in the group of comparison (p&lt;0.05); there was a higher rate of the reduction of inflammatory changes in the lungs according to the computer tomography data (38.4% vs 14.9%, p&lt;0.05). By the end of the treatment, there was also a lower lactate level in the blood (27.1%, p&lt;0.05) than in the patients of the group of comparison. The evaluation of the drug efficacy ассording to the Categorical Ordinal Scale of Clinical Improvement and measurements of oxygen saturation in the blood, manifested similar positive dynamics in the patients treated ассording to various etiotropic therapy regimens. By the end of the treatment, the RNA SARS-CoV-2 tests were also negative in all the patients. As for the overall frequency of adverse events (AEs), no relevant distinctions were found between the groups. A greater part of AEs was related to hepatotoxicity, with a predominantly clinically relevant increase in alanine aminotransferase (ALT). A clinically relevant prolongation of the corrected QT interval on the standard ECG was found to occur in the standard-therapy group on day 5, while no serious AEs were registered in the main group. No serious adverse reactions were registered in patients of the main group.Conclusion. The efficacy of the Favipiravir (Areplivir) therapy for the novel coronavirus infection has proved to be superior to the efficacy of the standard etiotropic therapy in a number of aspects. Basing on the obtained findings, Favipiravir (Areplivir) drug can be recommended for treating patients with the novel coronavirus infection of moderate severity.

Long-term safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis: Results from the TOWER extension study

BackgroundIn the phase 3 TOWER core study (NCT00751881), the efficacy and safety of teriflunomide compared with placebo were demonstrated in patients with relapsing forms of multiple sclerosis (RMS). Here, the long-term safety and efficacy outcomes from the TOWER extension study (NCT00751881) are reported. MethodsAll patients who entered the extension (N = 751) were assigned to teriflunomide 14 mg and assessed for long-term safety and efficacy. ResultsOf 751 patients in the TOWER extension study, 253, 265, and 233 patients received placebo/teriflunomide 14 mg, teriflunomide 7 mg/14 mg, and teriflunomide 14 mg/14 mg, respectively. Median teriflunomide exposure was 4.25 years (maximum 6.3 years). The overall frequency of adverse events (AEs) was comparable across treatment groups, but a higher proportion of patients in the teriflunomide 7 mg/14 mg (12.4%) and 14 mg/14 mg (12.4%) groups had serious AEs compared with the placebo/teriflunomide 14 mg group (6.4%). Alanine aminotransferase increase and hair thinning occurred at a higher frequency in the placebo/teriflunomide 14 mg group (11.2% and 14.3%, respectively) compared with the teriflunomide 7 mg/14 mg (3.0% and 4.5%, respectively) and 14 mg/14 mg groups (5.2% and 4.3%, respectively). The incidences of AEs of interest (hematologic and hepatic effects, peripheral neuropathy, hypertension, and malignancy) were low and comparable across treatment arms. Disability worsening and adjusted annualized relapse rates were low and stable over time, and mean Expanded Disability Status Scale scores were unchanged over time, for all treatment groups. ConclusionIn the TOWER extension study, the efficacy of teriflunomide 14 mg was maintained in patients with RMS. No new or unexpected AEs were observed with teriflunomide treatment, supporting a safety profile in the extension that was consistent with the core trial. These findings support the positive benefit:risk profile of teriflunomide as a long-term immunomodulatory therapy.

Impact of renal function-based anti-tuberculosis drug dosage adjustment on efficacy and safety outcomes in pulmonary tuberculosis complicated with chronic kidney disease

BackgroundDosages of anti-tuberculosis (TB) drugs are recommended to be adjusted according to renal function for patients complicated with chronic kidney disease (CKD). However, the efficacy and safety outcomes of such renal function-based dosage adjustments are not fully elucidated.MethodsWe retrospectively reviewed cases of pulmonary TB susceptible to first-line drugs that were treated at Jikei University Daisan Hospital between 2005 and 2014 with standard regimens based on dosage adjustments according to renal function recommended by international guidelines. Patients were divided into four groups, those with no, mild, moderate or severe CKD. In-hospital TB-related mortality, the rate of sputum culture conversion at 2 months, the frequency of adverse events (AEs), for which at least the temporal discontinuation of the suspect drug was required for patient improvement, and the rate of regimen change due to AEs were assessed.ResultsIn the 241 enrolled patients (mean age, 64.1 years; 143 men), fourteen patients (5.8%) died due to TB during their hospitalization. The rate of sputum culture conversion at 2 months was 78.0%. The frequency of in-hospital TB-related death and the conversion rate in the groups did not vary significantly according to CKD severity including those in the non-CKD group (P = 0.310 and P = 0.864). Meanwhile, a total of 70 AEs were observed in 60 patients (24.9%) and the difference between the groups in the overall frequency of AEs was almost significant (P = 0.051). Moreover, for the 154 patients with CKD, severe CKD stage was a significant risk factor for regimen change (OR = 5.92, 95% CI = 1.08–32.5, P = 0.041), as were drug-induced hepatitis and cutaneous reaction (OR = 35.6, 95% CI = 8.70–145, P < 0.001; OR = 17.4, 95% CI = 3.16–95.5, P = 0.001; respectively).ConclusionsAdjusting the dosage of TB treatment for CKD patients according to the guidelines was efficient in terms of similar therapeutic outcome to that of the non-CKD group. However, AEs warrant attention to avoid regimen change in patients with severe CKD, even if the renal function-based dosage adjustment is performed.

Systematic Review of Efficacy and Safety of Newer Antidiabetic Drugs Approved from 2013 to 2017 in Controlling HbA1c in Diabetes Patients

Type 2 Diabetes Mellitus (T2DM) is the most common form of diabetes mellitus and accounts for about 95% of all diabetes cases. Many newer oral as well as parenteral antidiabetic drugs have been introduced in to the market in recent years to control hyperglycemic conditions in diabetes patients and many of these drugs produce potential side effects in diabetes patients. Hence, this systematic review was aimed to analyze and compare the efficacy and safety of oral antidiabetic agents in controlling HbA1c in T2DM patients, that were approved by the United States-Food and Drug Administration (US-FDA) from 2013 to 2017. All randomized controlled, double-blind trials published in English during the search period involving the newer antidiabetic agents were selected. In the outcome assessment comparison, semaglutide demonstrated the highest efficacy in lowering HbA1c, with a 1.6% reduction (p < 0.0001) when given at a dose of 1.0 mg. The safety profile of all the agents as compared to placebo or control were similar, with no or slight increase in the occurrence of adverse events (AEs) but no fatal reaction was reported. The most common AEs of all the antidiabetic agents were gastrointestinal in nature, with several cases of hypoglycemic events. However, among all these agents, semaglutide seems to be the most efficacious drug to improve glycemic control in terms of HbA1c. Alogliptin has the least overall frequency of AEs compared to other treatment groups.

Methylene blue MMX® tablets for chromoendoscopy. Bioavailability, colon staining and safety in healthy volunteers undergoing a full colonoscopy

Methylene blue-MMX® tablets are proposed as an aid for detection and visualisation of adenomas and carcinomas in patients undergoing colonoscopy, by improving their detection rate and highlighting the presence of the intestinal dysplastic lesions.Single total doses of 100 and 200 mg were administered to healthy volunteers undergoing a bowel cleansing preparation and a full colonoscopy to investigate the colonic staining. The pharmacokinetics of methylene blue and the safety after exposure to the tablets were also investigated.With 200 mg, the best staining, assessed as the sum of acceptable and good staining, was achieved in the ascending colon and rectosigmoid (75% subjects each), the transverse and the descending colon (approximately 63% each). Absence of staining or overstaining were reported for no colonic region of interest in any subject. Similar results were observed in the 100 mg dose group.Methylene blue blood concentrations reached a peak (Cmax) in a median time (Tmax) of 12 h with 100 mg and 16 h with 200 mg. AUC0-t was 10.7 ± 6.7 μg/mLxh after 100 mg and 25.2 ± 7.4 μg/mLxh after 200 mg. Half-life ranged between 9 and 22 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative urinary excretion was about 28% after 100 mg and about 39% after 200 mg up to 60 h post-dose.The overall frequency of adverse events after single dose of the test product administered along with a bowel cleansing preparation was 39%, but only one was related to the test product: abnormal transaminases. The most frequent adverse event was a transient polyuria (17%). One serious adverse event (gastrointestinal haemorrhage) led the subject to study discontinuation and hospitalisation and another subject withdrew the study due to one adverse event (haematemesis). Either event was not related to methylene blue.

Modern tocolysis and adverse effects of tocolytics

Relevance. Toсolytic therapy is the only method that is used in the treatment of pregnant women with preterm labor. However, the effectiveness and safety of this therapy is still a matter of debate. One of the least studied issues of this problem is the safety of therapy, which is primarily manifested by the frequency of side effects. The aim is to carry out a comparative study of the safety of the most common tocolytic agents - atosiban, nifedipine and hexoprenaline sulfate. Material and methods. The study included 173 pregnant women with threatening premature births in a period of 28 to 34 weeks. In 54 cases, tocolysis with nifedipinum, 57 with atosiban, 62 with hexoprenaline was performed. To assess the effectiveness of tocolysis, clinical and instrumental methods of control (ultrasound with cervicometry) were used. The primary outcome points were the frequency of prolongation of pregnancy at 48 h and the incidence of side effects, including those requiring the termination of tocolysis. Results. Prolongation of pregnancy at 48 h was achieved in groups of nifedipine, atosiban and hexoprenaline sulfate, respectively in 46 (85.19%), 55 (96.49%) and 53 (77.40%) pregnant. Atosiban showed significantly higher efficacy. In 8 cases of tocolysis with nifedipine and 3 - hexoprenaline, the tocolysis protocol was not performed due to intolerance of treatment. In these observations, the highest frequency of preterm labor occurred. After excluding these observations from the analysis of differences in the frequency of prolongation of pregnancy was not. The overall frequency of adverse events in the groups was 38.9, 12.3 and 82.3%, and was significantly lower in the atosiban group than nifedipine and hexoprenaline sulfate. Conclusions. The effectiveness of tocolysis is affected by the tolerability of the drugs. Atosiban showed the best of the three drug safety profile. With comparable efficacy, atosiban has proven to be a drug that, to a greater extent than nifedipine and hexoprenaline sulfate, meets the current requirements for tocolytic drugs.

Severe eosinophilic fasciitis: comparison of treatment with d-penicillamine plus corticosteroids vs. corticosteroids alone

Objectives: To compare the therapeutic effectiveness of corticosteroids (CS) alone vs. CS plus d-penicillamine (d-Pen) in severe eosinophilic fasciitis.Method: A long-term prospective non-randomized trial of d-Pen plus CS vs. CS alone in patients with severe eosinophilic fasciitis, defined as clinically apparent cutaneous fibrotic involvement affecting more than 15% body surface area (BSA) or more than 10% BSA with joint flexion contractures.Results: Sixteen patients with severe eosinophilic fasciitis entered the study. Ten patients received d-Pen plus CS and six received CS alone. Affected BSA decreased from an average of 29% to 8.9% in the d-Pen plus CS group compared to a decrease in affected BSA from 28% to 22.83% in the CS-alone group. The reduction in affected BSA in the d-Pen plus CS group was significantly greater than in the CS-alone group (p = 0.038). Clinical improvement occurred in all d-Pen plus CS patients compared to only 33.3% of CS-alone patients (p = 0.008). There was no difference in overall frequency of adverse events between the groups (p = 0.60). The most common adverse event in the d-Pen plus CS group was proteinuria (33.3%). However, proteinuria also occurred in 16.6% in the CS-alone group.Conclusions: Treatment with CS alone failed to induce clinical improvement in the majority of the severe eosinophilic fasciitis patients. By contrast, d-Pen plus CS resulted in significantly greater clinical improvement. These results suggest that initial treatment of severe eosinophilic fasciitis with CS alone is not sufficient for optimal therapeutic response and that addition of an antifibrotic agent results in an improved outcome.

O1-10-3 - Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer

a b s t r a c t Objectives: Three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. Materials and methods: We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Results: Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n = 457) received gefitinib, those in 5 trials (n = 513) received erlotinib, and those in 3 trials (n = 498) received afatinib. Rash and diarrhea of grade ≥3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade ≥3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade ≥3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Conclusion: Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity.

Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer.

Three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n=457) received gefitinib, those in 5 trials (n=513) received erlotinib, and those in 3 trials (n=498) received afatinib. Rash and diarrhea of grade ≥3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade ≥3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade ≥3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity.