ABSTRACT
Background: The tolerability of mRNA COVID-19 vaccines among people living with HIV (PLWH) has been understudied in vaccine trials. CoVPN 3008 (Ubuntu) is the largest multicenter Phase 3 efficacy trial of mRNA vaccines in sub-Saharan Africa. Method(s): We enrolled adults age >=18 years living with HIV or another comorbidity associated with severe COVID-19. Previously vaccinated individuals were excluded. Baseline testing included HIV, CD4 count and HIV viral load (VL) (if HIV+), anti-SARS-CoV-2 antibodies, and nasal swab SARS-CoV-2 nucleic acid amplification test (NAAT). All participants receive vaccinations at months 0 and 6, and SARS-CoV-2 seronegative individuals also receive vaccination at month 1. This analysis includes mRNA-1273 vaccinations at months 0 and 1. Reactogenicity (solicited adverse events [AEs]) was assessed among a representative subset of participants (Safety Subset, SS) for 7 days post-vaccination. Baseline characteristics associated with moderate/severe reactogenicity events were assessed by univariate and multivariate logistic regression. Result(s): 14002 participants were enrolled in the trial (1510 into the SS) at 46 sites from 2 Dec 2021 to 9 Sep 2022. At baseline in the SS, 71% (1065) were female, median age 38 years (IQR 32-46), and median BMI 25.0 (IQR 20.7-30.2). 73% (1108) were SARS-CoV-2 seropositive, and 8.7% (131) had a positive nasal NAAT swab. 16% (197) had a history of tuberculosis. 84% (1267) were PLWH, with median CD4 count of 614 cells/muL (IQR 414-861);7.8% had CD4 count < 200. 21% (238) had detectable HIV VL (>=50 copies/mL), with median VL 1660 (IQR 182-23932). 14% (172/1262) and 12% (64/542) of PLWH reported moderate/severe reactogenicity after the 1st and 2nd vaccination (Figure), with no hospitalizations. Female PLWH and CD4 count >500 had 35% (p=0.03) and 44% (p=0.04) increased odds of moderate/severe reactogenicity, respectively. Other baseline characteristics were not associated with the odds of reporting moderate/severe reactogenicity among PLWH after 1st vaccination. Similar trends were seen after the 2nd vaccination, but none reached statistical significance. In multivariate models, female sex remained associated with increased odds of moderate/severe reactogenicity after the 2nd vaccination. Conclusion(s): Similar to observations in HIV-negative populations, mRNA-1273 was well tolerated by PLWH with more reactogenicity in females. Impaired inflammatory responses among participants with CD4 counts < 500 cell/muL may explain less moderate/severe reactions.
ABSTRACT
Evaluate the safety and tolerability of losmapimod in the treatment for FSHD. FSHD is a relentless, variably progressive disease leading to accumulation of disability over decades. Fulcrum is developing losmapimod, a small molecule p38 alpha/beta MAPK inhibitor, to treat FSHD. Losmapimod has been generally well-tolerated in more than 3,600 subjects across multiple clinical studies, including >100 subjects with FSHD. Fulcrum has assessed losmapimod in FSHD in one completed phase 1 study (FIS 001-2018) and two ongoing Phase 2 studies in the open label extension period (FIS 001-2019 and FIS 002-2019). Subjects aged 18-65 years with genetically confirmed FSHD1, clinical severity score 2-4, and MRI-eligible muscles for biopsy were exposed to losmapimod 7.5 or 15 mg twice daily PO for 14 days and up to 76 weeks. In study FIS 001-2018, 6 subjects were exposed to 7.5 mg and 11 subjects to 15 mg twice daily dosing for 14 consecutive days. In studies FIS 001-2019 and FIS 002-2019, 14 and 77 subjects respectively, received at least one dose of losmapimod 15 mg twice daily for up to 76 weeks. A total of 108 subjects with FSHD1 have been exposed to losmapimod, with approximately 131 patient-years of exposure. Fifty-seven subjects have been exposed to losmapimod for 12 to 18 months, and 30 have been exposed for over 18 months. Most adverse events (AEs) observed during the studies were considered of mild to moderate in severity. The most common AEs were alanine aminotransferase (ALT) increase, headache, dizziness, dry skin, eczema and gastrointestinal disorders. The majority of AEs resolved with continued dosing. Dosing has been paused for 14 days in four subjects (3 in FIS 001-2019 and 1 in FIS 002-2019) subjects due to COVID-19 infection. There were no reported drug related SAEs, deaths, discontinuations due to AEs, or clinically significant changes in vital signs, clinical laboratory results, or ECG parameters. Losmapimod given as up to 15 mg twice daily in >100 subjects with FSHD1 for up to 76 weeks has been generally well-tolerated, consistent with that previously reported in other patient populations. Therefore, the benefit-risk profile of losmapimod for the treatment of FSHD remains favorable.Copyright © 2022
ABSTRACT
Objective. To comparatively assess the early toxicity of treatment, its tolerability, 1-, 2-, 3-year overall survival, and local regional control rates in a group of patients receiving a radical cycle of accelerated or conventional fractionation chemoradiotherapy. Subjects and methods. The paper presents the interim results of a prospective study that included 115 patients with locally advanced cancer of the oropharynx, tongue root, and larynx who received a radical cycle of conformal chemoradiotherapy using accelerated (the single focal dose (SFD) was 2.4 Gy for 25-26 fractions) or conventional (SFD was 2.0 Gy for 32-33 fractions) fractionation in the period from 2015 to 2020. Results. An analysis comparing the study group with the control one revealed no statistically significant differences in the level of early toxicity of treatment (p=0.41). Complete tumor reversal was achieved in 57 (86.3%) patients in the study group and in 39 (79.5%) in the comparison group (p=0.23). The 1-, 2-, and 3-year local regional control rates in the accelerated fractionation group was 78.3+/-5.3%;65.9+/-6.8%, and 54.5+/-9.2%, respectively. The 3-year overall survival rate was 80.4+/-7.4%. These rates did not differ statistically from those in the conventional radiotherapy group (p=0.12-0.82);53 (80.3%) patients in the study group and 37 (75.5%) in the standard fractionation group received a radiation cycle without a forced interval. The treatment interval in the patients of both groups reduced the 2-year local regional control rates by 30.2% compared to that in the continuous cycle group (p=0.02). Conclusion. Accelerated fractionation chemoradiotherapy (SFD was 2.4 Gy for 25-26 fractions, the daily focal dose was 60.0- 62.4 Gy) is a procedure comparable with conventional radiation in its direct efficiency and safety. During the COVID-19 pandemic, this regimen can be considered to be a mainstay for patients with locally advanced oropharyngeal cancer in order to preserve the previous volumes of specialized healthcare.Copyright © A.V. SEMENOV I.A. GULIDOV O.G. LEPILINA M.U. RADZHAPOVA F.E. SEVRYUKOV K.B. GORDON.
ABSTRACT
Background: ASC10 is an oral double prodrug of the active antiviral ribonucleoside analog, ASC10-A (also known as beta-d-N4-hydroxycytidine), which is a potent inhibitor of SARS-CoV-2. ASC10 is rapidly metabolized into ASC10-A in vivo after oral dosing. Here, we report the results of the first-in-human, phase 1 study to determine the safety, tolerability, and pharmacokinetics (PK) of ASC10 in healthy subjects, and to assess the food effect on the pharmacokinetics. Method(s): This study included 2 parts. Part 1 (multiple-ascending-dose) consisted of 6 cohorts (8 or 12 subjects per cohort). Eligible subjects were randomized in a 3:1 ratio to receive either twice-daily (BID) doses of 50 to 800 mg ASC10 or placebo for 5.5 days, and were then followed for 7 days for safety. In Part 2 (food effect), 12 subjects were randomized in a 1:1 ratio to either 800 mg ASC10 in the fed state followed by 800 mg in the fasted state, or vice versa, with a 7-day washout period between doses. PK blood samples were collected and measured for ASC10-A along with ASC10 and molnupiravir. Safety assessments included monitoring of adverse events (AEs), measurement of vital signs, clinical laboratory tests, and physical examinations. Result(s): ASC10-A was the major circulating metabolite ( >99.94%) in subjects after oral dosing of ASC10. ASC10-A appeared rapidly in plasma, with a median Tmax of 1.00 to 2.00 h, and declined with a geometric t1/2 of approximately 1.10 to 3.04 h. After multiple dosing for 5.5 days, both Cmax and AUC of ASC10-A increased in a dose-proportional manner from doses of 50 to 800 mg BID without accumulation. of ASC10-A in the fed state occurred slightly later, with a median of 3.99 h postdose versus 2.00 h (fasted state). However, Cmax and AUC were very similar or the same between fed and fasted states. Thus, administration of ASC10 with food is unlikely to have an effect on exposure. The incidence of AEs was similar between subjects receiving ASC10 or placebo (both 66.7%) and 95.0% of AEs were mild. There were no serious adverse events as well as no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Conclusion(s): Results of this study showed that ASC10 was well tolerated, and the increase in plasma exposure of ASC10-A was dose proportional across the range of doses tested with no accumulation and no food effect. 800 mg ASC10 BID is selected for further studies in patients infected with SARS-CoV-2.
ABSTRACT
Background: The currently approved vaccines do not induce sterilizing immunity against SAR-CoV-2 infection, and immunity wanes over time. A robust broad spectrum topical prophylaxis strategy could protect vulnerable populations in the face of continuous evolution of SARS-CoV-2. The algal antiviral lectin Griffithsin (GRFT), and an engineered oxidation-resistant variant Q-GRFT have robust entry inhibitory activity against SARS-CoV variants of concern, in addition to other respiratory viruses with pandemic potential. We designed a nasal spray to deliver Q-GRFT to the upper respiratory tract mucosa for on-demand use as a broad-spectrum prophylactic. Two clinical trials (Phase 1a and 1b) were conducted to assess safety, tolerability, and pharmacokinetics of Q-GRFT nasal spray in healthy adults. Method(s): Healthy adult volunteers were enrolled in a Phase 1a double blinded, randomized study to receive a single dose of either intranasal Q-GRFT (3.0 mg, 2 sprays per nostril) or placebo at 2:1 ratio. Following a safety review, the Phase 1b study was initiated. Eleven volunteers in Group 1 received 3.0 mg dose once daily, for 7 days. After a safety review, 11 volunteers in Group 2 received a total of 6.0 mg Q-GRFT (3.0 mg twice daily for 7 days). Topical Q-GRFT concentrations were measured by ELISA in collected nasal and nasopharyngeal fluids. Drug levels in plasma were assayed to determine systemic exposure. Viral microneutralization cytopathic effect (CPE) assays were performed against SARS-CoV-2 Omicron BA-5 and MERS-CoV. Result(s): Eighteen adults (24-54 years;Males 58.3%, Females 41.7%;12 Q-GRFT, 6 Placebo), and 22 adults (aged 23-59 years;Males 52.4%, Females 47.6%) were enrolled in Phase 1a and 1b, respectively. In Phase 1a, a single dose of Q-GRFT maintained quantifiable levels in nasal passages and nasopharynx for up to 24 hours. Similarly, Q-GRFT was quantifiable in nasal and nasopharyngeal regions in the Phase 1b study. No dose accumulation effect or systemic exposure was observed. Nasal and nasopharyngeal swab eluates inhibited SARS-CoV-2 Omicron BA.5 and MERS-CoV in CPE assays. Q-GRFT did not modify olfactory sensation. No severe adverse events were reported. Thus, the nasal spray was deemed safe. Conclusion(s): Intranasal Q-GRFT was safe and enhanced mucosal SARSCoV-2 inhibitory activity in human volunteers. The results support further development of Q-GRFT as a broad-spectrum prophylactic against coronaviruses to curb ongoing infections, and for future pandemic preparedness.
ABSTRACT
Background: Ensitrelvir is a SARS-CoV-2 3CL protease inhibitor approved in Japan under emergency regulatory approval system as an oral treatment for COVID-19. Here we report the key analysis results of 125 mg group of phase3 part (SCORPIO-SR). Method(s): This study was a multicenter, randomized, double-blind, placebocontrolled study. Regardless of SARS-CoV-2 vaccination status and presence of risk factors for severe disease, patients with mild-to-moderate COVID-19 within 120 hours from onset were randomized to oral administration of ensitrelvir 125 mg (375 mg loading dose on Day1), ensitrelvir 250 mg (750 mg loading dose on Day1), and placebo once daily, for 5 days. The primary endpoint was time to resolution of 5 symptoms of COVID-19 (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness), and the key secondary endpoints include change from baseline on Day4 in the amount of SARS-CoV-2 viral RNA and time to first negative of viral titer. The primary population for the primary and key secondary endpoints was patients with <72 hours from onset to randomization. Result(s): Median time to resolution of 5 symptoms was significantly shorter in 125 mg group (n=336, 167.9 hours) than placebo group (n=321, 192.2 hours) (p=0.0407). Mean change of viral RNA levels from baseline (log10 copies/mL) on Day4 was significantly greater in 125 mg group (-2.48) than in placebo group (-1.01) (p< 0.0001). The time to first negative of viral titer was significantly shorter in 125 mg group (n=199, 36.2 hours) compared to placebo group (n=211, 65.3 hours) (p< 0.0001). Mean changes from baseline in viral titers [log10(TCID50)/mL] were significantly greater in 125mg group on Day2 (-0.807, n=196) and Day4 (-1.108, n=197) than in the placebo group (-0.395, n=208 and -0.850, n=207, respectively) (p< 0.0001). (Table Presented) In the patients randomized within 120 hours of onset, median time to resolution of 5 symptoms was 189.7 hours in 125 mg group (n=582) and 200.3 hours in placebo group (n=572) (p=0.4352). No deaths or serious adverse drug reactions were reported in either group, and the incidence of serious adverse events between the two groups was comparable. Conclusion(s): Ensitrelvir demonstrated a significant reduction in the time to resolution of 5 typical symptoms of COVID-19, robust antiviral effects and good tolerability.
ABSTRACT
Clinical parameters characterizing the efficacy and safety of favipiravir were examined in a multicenter, non-interventional (before-and-after study design) trial in 264 patients with mild COVID-19. It is shown that on the background of 14-day therapy with favipiravir body temperature normalized, blood oxygen saturation improved, and the frequency of tachycardia detection reduced by 16% (p < 0.0001). A statistically significant decrease by 91,3% (p 0.0001) in the frequency of SARS-nCoV-2 RNA detection in the nasopharyngeal mucosa discharge was revealed. A decrease in the concentration of ferritin (by 69% compared to initial values), blood glucose (by 21%), creatinine (by 10%), C-reactive protein (by 36%) (p 0.0001), and D-dimer by 61% (p = 0.016) was noted. The results of the SF-36 health survey questionnaire revealed a significant (p 0.05) improvement in the quality of life in terms of physical functioning (by 35%), and role functioning associated with physical and emotional state by 107% and 160%, respectively. Analysis of the COV19-QoL questionnaire revealed a decrease by 24% in negative perception of the disease (p < 0,01). Among the identified adverse events, elevated level of ALT (in 39.47% of patients), hyperuricemia (in 28.95% of patients), and elevated AST (in 23.68% of patients) prevailed. All the adverse events occurred with mild or moderate severity. There were no lethal outcomes in the studied sample of patients. The analysis showed a satisfactory level of the tolerability of the treatment.Copyright © 2023 Izdatel'stvo Meditsina. All rights reserved.
ABSTRACT
Background. Pandemic caused by severe acute respiratory syndrome coronavirus 2 (COVID19) raises a smash barrier for clinicians and patients since 2 years. Limited information is available on disease course after COVID19 infection or vaccination in patients with idiopathic inflammatory myopathies (IIM). Objective(s): The primary goals of the current research were to assess frequency and outcome of COVID19 disease and to determine the vaccination rate and effect in our IIM cohort. Secondary objectives were to search for risk factors of infection, predictive factors of hospitalization and to assess incidence of pots-vaccination adverse events and breakthrough infections. Methods. We identified the confirmed COVID19 positive patients and assessed disease course and outcome on 01/06/2021 in our cohort then patients were prospectively followed. Incidence and complications of infection and vaccination were determined by questionnaires and using the database. Anti-SARS-CoV-2 spike protein electrochemiluminescent immunoassay has been used to assess seroconversion. Disease activity was determined by physician global activity. Results. A total of 176 patients were screened and 101 participated in the study. By 01/06/2021, the COVID infection rate was 34.7%, which was significantly higher than the national prevalence at that time (8.2%). A third of these infections occurred asymptomatically or mild, but 20% of the infected patients were hospitalized, one patient died. Longer disease duration (8.67 vs. 17.87 years;p=0.003) and higher incidence of anti-Jo-1 antibody (57% vs. 10%;p=0.018) were significantly associated with hospitalization. All patients became seropositive after COVID19 infection regardless of immunosuppressive therapy or symptoms severity, meanwhile 72.3% of patients became seropositive after vaccination. Different vaccines induced various titer of antibody against the spike protein. Significantly higher antibody titers was detected after Pfizer-BioNTech (177.1 U / ml vs. 81.1 U / ml;p=0.001) and numerically lower ones after AstraZeneca (45.05 U/ml vs. 126.93 U/ml p=0.054) vaccination compared to others. Patients receiving steroid therapy had significantly decreased post-vaccination antibody response compared to those without steroid treatment (94.03 U/ml vs. 165.6 U/ ml;p=0.008). We did not found short term vaccine related major adverse events. Long term data by 15/02/2022 revealed more infections (42.57%), where anti-Jo1 positivity still showed significant association with hospitalization (50% vs. 9%;p=0.0103). Breakthrough infection was detected in 9,25 % of the vaccinated patients, which was significantly more often after Astra Zeneca vaccination (40 % vs. 7%, p=0.017). All the fatal (n=3) COVID infections occurred in patients with seronegativity to anti-spike protein regardless vaccination. We identified 7,4 % post vaccination disease relapse needing therapy changes and 24,7% new autoantibody positivity. Conclusions. Based on our results, myositis may be associated with an increased risk of COVID19 disease. Independent risk factor for hospitalization for unvaccinated people is anti-Jo1 positivity. Anti-SARS-CoV2 vaccines are safe, tolerable, could prevent complicated infections and strongly recommended for IIM population. Further investigation is required to assess clinical significance of post-vaccination disease flare.
ABSTRACT
Background Taletrectinib is a potent, next-generation, CNS-active, ROS1 tyrosine kinase inhibitor (TKI) with selectivity over TRKB. In previous reports from TRUST-I, taletrectinib showed meaningful clinical efficacy and was well tolerated in pts with ROS1+ NSCLC (n = 109) regardless of crizotinib (CRZ) pretreatment status. We report updated efficacy and safety data with ~1.5 yr follow-up. Methods TRUST-I is a multicenter, open-label, single-arm study with two cohorts: ROS1 TKI-naive and CRZ-pretreated. Pts in both cohorts received taletrectinib 600 mg QD. Key study endpoints included IRC-confirmed ORR (cORR), DoR, disease control rate (DCR), PFS, and safety. A pooled analysis of ORR, PFS, and safety including pts from additional clinical trials was also conducted. Results In the 109 pts from TRUST-I (enrolled prior to Feb 2022) the median follow-up was 18.0 mo in TKI-naive (n = 67) and 16.9 mo in CRZ-pretreated pts (n = 42). cORR was 92.5% in TKI-naive and 52.6% in CRZ-pretreated pts (table). Median DoR (mDoR) and mPFS were not reached. Intracranial-ORR was 91.6%;ORR in pts with G2032R was 80.0%. In a pooled analysis with phase I studies, ORR was 89.5% and 50.0% for TKI-naive and CRZ-pretreated pts, respectively;mPFS was 33.2 mo and 9.8 mo. In 178 pts treated at 600 mg QD, treatment-emergent adverse events (TEAEs) were 92.7%;most (64.0%) were grade 1-2. The most common TEAEs were increased AST (60.7%), increased ALT (55.6%), and diarrhea (55.6%). Neurological TEAEs (dizziness, 18.5%;dysgeusia, 12.4%) and discontinuations due to TEAEs (3.4%) were low. Further updated results will be presented. [Formula presented] Conclusions With additional follow-up, taletrectinib continued to demonstrate meaningful efficacy outcomes including high response rates, prolonged PFS, robust intracranial activity, activity against G2032R, and tolerable safety with low incidence of neurological AEs. Clinical trial identification NCT04395677. Editorial acknowledgement Medical writing and editorial assistance were provided by Arpita Kulshrestha of Peloton Advantage, LLC, an OPEN Health company, and funded by AnHeart Therapeutics, Inc Legal entity responsible for the study AnHeart Therapeutics, Inc. Funding AnHeart Therapeutics, Inc. Disclosure S. He: Financial Interests, Personal, Other, Employment: AnHeart Therapeutics. T. Seto: Financial Interests, Institutional, Research Grant: AbbVie, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kissei Pharmaceutical, MSD, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical;Financial Interests, Personal, Other, Employment: Precision Medicine Asia;Financial Interests, Personal, Speaker's Bureau, Honoraria for lectures: AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical, Towa Pharmaceutical. C. Zhou: Financial Interests, Personal, Other, Consulting fees: Innovent Biologics Qilu, Hengrui, TopAlliance Biosciences Inc;Financial Interests, Personal, Speaker's Bureau, Payment or honoraria: Eli Lilly China, Sanofi, BI, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone LUYE Pharma, TopAlliance Biosciences Inc, Amoy Diagnositics, AnHeart. All other authors have declared no conflicts of interest.Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc.
ABSTRACT
Background: Allergic rhinitis, one of the most common chronic allergic diseases, commonly associated with asthma, has a disease modifying therapy, allergen-specific immunotherapy (AIT). AIT can play a significant role in the reduction of clinical and immunological reaction to the culprit allergen, decreasing the onset of new sensitizations, preventing the onset of asthma, and reducing use of pharmacological treatments. This latter aspect is highly relevant for adolescents, a category of patients that frequently prefer to use "as few drugs as possible". AIT continuation may be difficult in some situations, such as the COVID-19 pandemic. Difficulty in accessing hospitals was experienced by many leading to a discontinuation of therapies for chronic conditions, such as allergic rhinitis. Method(s): We report our experience on the management, safety and adherence to sublingual immunotherapy (SLIT) prescribed to 25 adolescents affected by allergic rhinitis (house dust mite (HDM) -8 patients, SLIT grass pollen -12 patients, SLIT parietaria -5 patients), during the COVID-19 pandemic, following EAACI recommendations. The first administration of SLIT was carried out under medical supervision. We used a personalized monitoring approach according to the type of SLIT prescribed and according to the needs presented by each patient, advising them how to recognize and manage a possible reaction. Result(s): No immediate severe adverse reactions were reported by patients. Between the 2nd and 5th day of SLIT, 4 patients in therapy with HDM SLIT, experienced an exacerbation of rhinitis symptoms, with resolution after the use of oral antihistamine and topical cortisone+antihistamine before taking the daily dose of SLIT (for 30 days). Two patients on grass pollen SLIT and 2 patients on HDM SLIT, with gastric upset after taking SLIT daily while fasting, presented a resolution of the symptom after we advised them to take the daily dose in the morning after breakfast. Five patients interrupted SLIT for COVID-19 infection, until complete resolution. To date, all 25 patients are continuing SLIT, with good tolerability, with an improvement of rhinitis symptoms. Conclusion(s): We have reported real-life SLIT adherence and safety in adolescents that started SLIT during the COVID-19 pandemic to confirm how SLIT is a winning strategy and the only modifying treatment for allergic conditions.
ABSTRACT
Background: Disease-modifying drugs (DMDs) are an inseparable part of multiple sclerosis (MS) management, which have dramatically changed the prognosis and course of the disease. A change during DMD therapy, which includes switching or stopping (temporary or permanent) medication, can manipulate the goals and has various causes such as side effects, ineffectiveness of treatment, patient's preference, presence of concurrent diseases and pregnancy. Therefore, we aimed to investigate the patterns and causes of DMD change in patients with MS (PwMS) in Tehran, Iran. The understanding will help us identify opportunities to improve adherence and ultimately patient outcomes and health system efficiency through effective education, and recognition of more tolerable or simpler regimens. The aim of this study is to identify rate and pattern of DMDs among PwMS in Tehran. Material(s) and Method(s): The study population of this cross-sectional was all PwMS in Tehran province who had changed their DMD for any reason in the last 5 years until June 2, 2022. The basic information was extracted through nationwide MS registry of Iran (NMSRI), Tehran, where all MS data including diagnosis had been confirmed by trained neurologists based on the 2017 revisions of the McDonald criteria. Moreover, supplementary unregistered data were gathered through telephone follow-ups carried out by 6 trained physicians with precise quality checks. The questionnaires covered 5 aspects of MS including demographics, disease history, diagnosis, progress and treatment. DMDs were classified into 10 general classes. All participants were asked to attribute the change to distinct categories following a written pre-existing consent. IBM SPSS (version 23) was used for statistical analysis. All the steps taken were in complete adherence with the tenets of the declaration of Helsinki. Result(s): Among 1999 enrolled patients with a mean age of 36.9+/-9.4 and total disease duration of 7.06+/-5.8 years, 1315 experienced change (Group 1) during study period, while 684 did not (Group 2). There was no difference in terms of demographic characteristics between the two groups. On the other hand, Group 1 had longer disease durations and more comorbidities (P <0.001). Getting infected with COVID-19 more than 4 times was observed to be significantly higher in Group 1 (P =0.032). Unlike Patients with PPMS and RRMS, SPMS patients showed higher EDSS scores when experiencing no DMD change. The most widely used DMDs were interferons, while ocrelizumab was the least used drug. Corona virus had the most effect on the change of ocrelizumab. Conclusion(s): DMD change generally occurs independent of socioeconomic level. Since most of the patients (65.8%) experienced DMD change, which serves as the biggest cost component in PwMS, the economic aspects of MS management in this field should be considered in the future.Copyright © 2022
ABSTRACT
Clinical parameters characterizing the efficacy and safety of favipiravir were examined in a multicenter, non-interventional (before-and-after study design) trial in 264 patients with mild COVID-19. It is shown that on the background of 14-day therapy with favipiravir body temperature normalized, blood oxygen saturation improved, and the frequency of tachycardia detection reduced by 16% (p < 0.0001). A statistically significant decrease by 91,3% (p 0.0001) in the frequency of SARS-nCoV-2 RNA detection in the nasopharyngeal mucosa discharge was revealed. A decrease in the concentration of ferritin (by 69% compared to initial values), blood glucose (by 21%), creatinine (by 10%), C-reactive protein (by 36%) (p 0.0001), and D-dimer by 61% (p = 0.016) was noted. The results of the SF-36 health survey questionnaire revealed a significant (p 0.05) improvement in the quality of life in terms of physical functioning (by 35%), and role functioning associated with physical and emotional state by 107% and 160%, respectively. Analysis of the COV19-QoL questionnaire revealed a decrease by 24% in negative perception of the disease (p < 0,01). Among the identified adverse events, elevated level of ALT (in 39.47% of patients), hyperuricemia (in 28.95% of patients), and elevated AST (in 23.68% of patients) prevailed. All the adverse events occurred with mild or moderate severity. There were no lethal outcomes in the studied sample of patients. The analysis showed a satisfactory level of the tolerability of the treatment.Copyright © 2023 Izdatel'stvo Meditsina. All rights reserved.
ABSTRACT
Introduction & Objectives: Bladder preservation is routinely used as an alternative to radical cystectomy in the UK and is becoming more accepted elsewhere globally. The gold standard is for patients to receive radiotherapy with a radiosensitiser most commonly concurrent chemotherapy e.g. 5FU/mitomycin C, gemcitabine or cisplatin. Patients with poor performance status or comorbidities may be unable to be offered concurrent treatment with chemotherapy but alternative treatment with concurrent carbogen +/- nicotinamide as a hypoxic modifier may be of benefit. Our aim therefore was to retrospectively review patients with bladder TCC treated with radical radiotherapy alone in the last 5 years who may have benefited from carbogen +/- nicotinamide radiosensitisation at a large cancer centre in the north of England. Material(s) and Method(s): In this single institution retrospective case note review, electronic records were reviewed for 175 patients who had received radiotherapy to the bladder for TCC between 2017-2022. Patients who had radical radiotherapy (RT) alone without radiosensitisation were scrutinised to ascertain whether they would have been candidates for carbogen and nicotinamide using the inclusion/exclusion criteria previously defined in the Bladder Carbogen Nicotinamide (BCON) Randomised Phase 3 trial. Result(s): We analysed 175 patients. Of these, 133 received had radical RT without radiosensitisation. The most common reason for not offering radiosensitisation was the presence of co-morbidities (27.8%). Of interest, the proportion of patients having chemotherapy radiosensitisation did not change after COVID19 in March 2020 (21.5% pre- vs 27.5% post;p=0.32 chi2). Conversely, the proportion of patients receiving neo-adjuvant chemotherapy reduced though failed to reach significance (12.6% pre- vs 5% post;p=0.08 chi2). After review of the notes and criteria from the original BCON trial, 106 patients (79.6%) could have benefited from carbogen +/- nicotinamide. Of these, 14 patients (13.2%) could have been offered carbogen alone due to poor renal function. The most common reason for not being eligible for BCON was respiratory disease with reduced respiratory drive (44%). Conclusion(s): The National Institute for Health and Care Excellence (NICE) state that all radical RT for bladder TCC should be with a radiosensitiser. Due to logistical and departmental issues, the BCON regimen is not currently offered as a standard alternative to radiosensitisation with chemotherapy. BCON has been demonstrated to be tolerable and, whilst updated follow-up data failed to demonstrate statistical significance for overall survival (OS), meta-analysis of hypoxia modification has shown significant improvement in OS compared to RT alone. Hypoxia modification with carbogen +/- nicotinamide should be considered for all patients unsuitable for chemotherapy radiosensitisation.Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.
ABSTRACT
Background: aPAP is a rare lung disease characterized by surfactant build-up for which there is no approved pharmacologic treatment. aPAP patients typically present with shortness of breath due to impaired oxygen transfer in the lung . Objective(s): To report the long-term safety of inhaled molgramostim nebulizer solution (MOL) administered intermittently in aPAP patients: open-label IMPALA-X extension study (NCT03482752). Method(s): Patients who completed IMPALA (NCT02702180) were eligible for IMPALA-X. MOL (300 mug;once daily) was administered in cycles of 7 days on/7 days off treatment. The primary endpoint included adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and discontinuations. Result(s): Safety data from 59 patients were analyzed;44 (74.6%) and 15 (25.4%) patients had >=12 and >=24 months of exposure, respectively. Forty (67.8%) patients reported 165 AEs;138 AEs in 38 (64.4%) patients were treatmentemergent AEs (TEAEs). Eight patients had SAEs that were considered unlikely related to treatment. Seven patients had severe TEAEs and 3 were considered treatment-related/ADRs. Most common AEs (7 patients each, 11.9%) were cough and nasopharyngitis. Respiratory tract infection, arthralgia, alveolar proteinosis, and COVID-19 were each reported by 6.8% patients. No TEAEs led to treatment discontinuation/withdrawal. One subject died following COVID-19 infection 24 days after the last MOL dose. Conclusion(s): IMPALA-X was discontinued early as intermittent dosing did not show a benefit vs placebo in the IMPALA study. The phase 3 IMPALA-2 study of continuous daily MOL vs placebo in patients with aPAP is ongoing.
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Currently, there are data that that make it possible to speak about a high clinical efficacy of the use of succinic salt of tyrosylD-alanyl-glycyl-phenylalanyl-leucyl-arginine (hexapeptide succinate) for the COVID-19 treatment. This article is devoted to the results of clinical trials of the original Russian drug based on it. The aim of the study was to evaluate a clinical efficacy, safety and tolerability of intramuscular and inhalation use of hexapeptide succinate in complex therapy in comparison with standard therapy in patients with moderate COVID-19. Materials and methods. The research was conducted from February 28, 2022 to November 22, 2022 based on 10 research centers in the Russian Federation. The study included hospitalized patients (n=312) over 18 years of age with moderate COVID-19 who had undergone a screening procedure and were randomized into 3 groups: group 1 received standard therapy in accordance with the Interim Guidelines in force at the time of the study, within 10 days;group 2 received hexapeptide succinate (Ambervin Pulmo) intramuscularly at the dose of 1 mg once a day for 10 days;group 3 received hexapeptide succinate (Ambervin Pulmo) 10 mg once a day by inhalation for 10 days. Results. According to the results of the study, therapy with the drug hexapeptide succinate, both intramuscular and inhaled, provided an acceleration of recovery up to the complete absence of the disease signs in more than 80% of hospitalized COVID-19 patients. By the end of the therapy course with the drug, more than 60% of patients had met the criteria for discharge from hospital and could continue the treatment on an outpatient basis. About 70% of patients in the inhalation group and 80% in the intramuscular hexapeptide succinate injection group had concomitant diseases (hypertension - 28%, obesity - 14%), which indicates the effectiveness of this drug use in comorbid patients. The use of the drug contributed to the restoration of damaged lung tissues, normalization of oxygenation, the disappearance of shortness of breath and a decrease in the duration of the disease symptoms compared with standard therapy. As a result of a comparative analysis of adverse events in terms of their presence, severity, causal relationship with the therapy and outcome, there were no statistically significant differences between the treatment groups. Conclusion. Thus, the results of the clinical study of the succinate hexapeptide efficacy and safety showed the feasibility of using the drug in pathogenetic therapy COVID-19 regimens.Copyright © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.
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ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient chimpanzee adenovirus vectored vaccine developed by Oxford and AstraZeneca for a disease we all know as Coronavirus, or COVID-19. Ongoing clinical studies reveal that the ChAdOx1 nCoV-19 vaccine has a tolerable safety profile and is effective against symptomatic COVID-19. This vaccine may prove crucial in boosting herd immunity, averting life threatening illness, and relieving the current pandemic. In this mini review, we performed a thorough literature search through PubMed and Google Scholar and reported various case reports associated with complications of the adenovirus-vectored COVID-19 vaccine. Various adverse effects of the ChAdOx1 nCoV-19 vaccine were reported around the globe, which were often serious but rare and developed into life-threatening pathologies such as GBS, thrombocytopenia, demyelinating neuropathies, progressive dementia, cerebral infarction, IgA vasculitis, hemophagocytic lymphohistiocytosis, herpes zoster, cutaneous reactions, and vein thrombosis. These worldwide reported complications, which are usually rare and severe, will aid clinicians in understanding and managing unforeseen situations. There is a need for more research to find out more about these complications and their etiopathogenesis. However, the benefits of these vaccinations for stopping the spread of the outbreak and lowering the fatality rate outweigh the potential risk of the uncommon complications.Copyright © The Author(s) 2023.
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Background: Patients with HR- advanced/metastatic breast cancer (a/mBC) with a low level of HER2 (immunohistochemistry [IHC] score 1+ or IHC 2+ and negative in situ hybridization [ISH]) have poor prognosis. Combining 1L chemotherapy with immune checkpoint inhibitors can modestly improve outcomes vs chemotherapy alone, but treatment benefit is largely seen in patients with PD-L1+ disease. BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study, evaluating safety and efficacy of D, an anti-PD-L1 antibody, combined with other novel therapies in 1L triple-negative a/mBC, including HR-, HER2-low disease. T-DXd is a trastuzumab-topoisomerase I inhibitor antibody-drug conjugate that improves survival in patients with previously treated HR-, HER2-low mBC (NCT03734029;Modi NEJM 2022). Here, we report updated results of the T-DXd + D combination from BEGONIA. Method(s): Patients with unresectable HR-, HER2-low (per local testing, IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested) a/mBC were enrolled in the T-DXd + D arm. Patients eligible for 1L treatment, regardless of PD-L1 status, received intravenous T-DXd 5.4 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. PD-L1, assessed using the VENTANA PD-L1 (SP263) Assay, was defined as high if >= 5% of the tumor area was populated by PDL1-expressing tumor or immune cells. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed objective response rate (ORR;RECIST v1.1);progressionfree survival [PFS];and response duration. Patients included in the efficacy analysis had >= 2 ontreatment disease assessments, progressed, died, or withdrew from the study. Result(s): As of April 8, 2022, 56 patients received T-DXd + D (34 ongoing) and 46 were included in the efficacy analysis. Median (range) follow-up was 10.1 (0-22) months. Median age was 53.5 years, 71% had received prior treatment for early stage BC, and 64% had visceral metastases at baseline. Confirmed ORR was 26/46 (57% 95% CI, 41-71) and unconfirmed ORR was 33/54 (61% 95% CI, 47-74);1/46 patients (2%) had complete and 25/46 (54%) had partial responses. Confirmed response occurred irrespective of PD-L1 expression (PD-L1 high ORR, 5/7 [71%];PD-L1 low, 13/21 [62%];PD-L1 missing, 8/18 [44%]). Median duration of response was not reached;however, 64% of patients remained in response at 12 month follow-up and 73% had an ongoing response at data cutoff. Median PFS was 12.6 months (95% CI, 8-not reached). Adverse events (AEs) were consistent with the agents' known safety, with treatment-related AEs occurring in 49 patients (88%), any Grade 3/4 AEs in 18 patients (32%), and any serious AEs in 10 patients (18%). The most common all-Grade AEs were nausea (41 [73%]), fatigue (26 [46%]), and vomiting (17 [30%]). Adjudicated treatment-related interstitial lung disease/pneumonitis occurred for 5 patients (9%), which were mostly Grade 1 or 2 and 1 case of Grade 5 associated with COVID pneumonia. Seven patients (13%) and 21 patients (38%) had T-DXd dose reduction and dose delay, respectively;22 (39%) had D dose delay. Seven patients (13%) discontinued treatment due to AEs. Conclusion(s): For patients with HR-, HER2-low a/mBC, T-DXd in combination with D in the 1L setting shows manageable safety and promising efficacy including durable responses and an encouraging PFS. Although subgroups were small, responses were observed irrespective of PD-L1 expression. Analysis of additional translational data is ongoing. Funding(s): AstraZeneca/Daiichi Sankyo.
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BACKGROUND: Upadacitinib is a Janus kinase inhibitor that has been approved for the treatment of adults and adolescents with moderate to severe atopic dermatitis (AD). The objective of this study was to characterize the pharmacokinetics (PK), safety, and tolerability of upadacitinib in children with severe atopic dermatitis. METHOD(S): This is an open-label, multiple-dose study. AD patients (n = 35) were enrolled into four cohorts (Cohort 1, 6 to <12 years, low dose;Cohort 2, 6 to <12 years, high dose;Cohort 3, 2 to <6 years, low dose;Cohort 4, 2 to <6 years, high dose). The low and high doses were selected based on body weight to provide comparable plasma exposure in pediatrics to 15 mg and 30 mg QD doses in adults, respectively. All patients continued on the low dose after the PK assessment on Study Day 7. Safety and exploratory efficacy parameters are assessed in the study. RESULT(S): Geometric mean Cmax and AUC over 0-24 hours at steady state were 33.1 ng/mL and 249 ng.h/mL, respectively, in Cohort 1, 95.5 ng/mL and 523 ng.h/mL, respectively, in Cohort 2, 35.2 ng/mL and 264 ng.h/mL, respectively, in Cohort 3, and 101 ng/mL and 625 ng.h/mL, respectively, in Cohort 4. Upadacitinib was generally safe and well tolerated. The most common AEs were COVID infection, headache, and abdominal discomfort. No new safety risks were identified compared to the known safety profile for upadacitinib. In the 29 subjects with available interim efficacy results at week 12, 34.5% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 and 69.0% achieved Eczema Area and Severity Index by at least 75% at Week 12 with treatment of upadacitinib. CONCLUSION(S): The findings supported the use of current dosing regimens for further investigation of upadacitinib in upcoming phase 3 clinical trials in pediatric AD patients.
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Introduction: We report results on immunogenicity of the recombinant adenovirus (rAd) 26 and rAd5 vector-based COVID-19 vaccine Gam-COVID-Vac (Sputnik V, developed by Gamaleya National Research Centre, Russia) in patients, receiving maintenance hemodialysis (HD). We aimed to compare the dynamics of humoral and cellular immunity after 2 doses of Gam-COVID-Vac in patients receiving HD and individuals with normal kidney function. Method(s): We recruited 23 patients treated with maintenance HD and 28 volunteers with normal kidney function (control group). All participates were adult, had been vaccinated twice with Gam-COVID-Vac vaccine and had no prior history of confirmed COVID-19. In all participants, the levels of anti-SARS-CoV-2-specific IgG were quantified at 1 month and 6 months from the second vaccine shot using ELISA. Specific T-cell responses (CD4+ and CD8+ cytotoxic T-lymphocytes) were evaluated using the TIGRA-test (Generium, Russia) at the same timepoints. [Formula presented] Results: Participant's characteristics and tolerability data are summarized in Table 1. Patients receiving HD were older and had more comorbidities compared with the control group. The seropositivity rate declined in both groups over time and was 100% vs 68% in non-renal controls and 91% vs 50% in HD group at months 1 and 6, respectively. In both groups, IgG levels decreased from month 1 to 6, however, antibodies did not vanish more rapidly in the HD group (analysis of variance p = 0.709 for the "time x group" interaction, age-adjusted model) - Figure 1. [Formula presented] IgG levels correlated inversely with age of HD patients (rho= -0.42 [95% CI: -0.64;-0.13], p=0.0047), whereas no correlation was observed in control group. Initially, the T-test result was positive in 79% non-renal and 73% HD subjects. At the end of the study, 48% non-renal and 64% HD participants showed T-cell positivity. T-spot responses to SARS-CoV-2 structural peptides S did not differ in the control group and in patients receiving HD at month 1 (p = 0.75) and 6 (p = 0.6) after vaccination. However, T-spot counts dropped over time in non-renal controls, but not in HD subjects (p=0.008 and p=0.18, respectively) - Figure 2. Over the course of the study, there were 2 confirmed cases of COVID-19 reinfection in control group, and 1 case in HD group. Conclusion(s): Patients receiving hemodialysis maintain significant long-term humoral response after vaccination with Gam-COVID-Vac vaccine, which is comparable to that in subjects with normal kidney function. Cellular response turned up to be more sustained over time in HD group. [Formula presented] No conflict of interestCopyright © 2023
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Background: Intravenous (IV) infliximab (IFX) monotherapy is associated with significant loss of response. Therapeutic drug monitoring shows an association with low serum trough drug levels and development of anti-IFX antibodies. Combination therapy with immunomodulators is not always possible, and IFX dose escalation leads to higher drug costs and time pressure on infusion units. Both approaches have raised heightened patient safety concerns due to the Covid-19 pandemic. Subcutaneous (SC) IFX pharmacokinetics lead to improved drug trough levels, which could lead to better clinical outcomes. Method(s): The NHS Greater Glasgow and Clyde biologics database was used to identify selected patients currently treated with IV IFX for IBD for suitability for SC switch. Patients were contacted to allow informed choice to opt in or out of switch. Baseline clinical data was collected, and patients were reviewed at week 8 and week 24 for assessment of clinical disease activity scores, IFX trough levels/anti-drug antibody levels, and faecal calprotectin. Patient experience outcomes were assessed using a quality of life questionnaire (CUCQ-8). Result(s): 31 patients consented to switch;F:M = 17:14. The majority of patients (16) had Crohn's disease, with 13 with UC and 2 IBDU. Mean duration of disease was 9.1 years and duration of prior IV therapy was 3.3 years. 28 patients were reviewed at week 8 and 24 at week 24. At week 24, 71% of patients were in clinical remission (Harvey-Bradshaw index score <5 or partial Mayo score <2), 96% had CRP <5 mg/Land 87% had FCP <250mug/g. 21% of patients had subtherapeutic IFX trough levels at baseline, all had increased by week 8 and there were no subtherapeutic levels measured by week 24. One patient had detectable antibodies at week 24, compared with 9 patients at baseline. Three patients required oral steroid therapy during the 24-week follow up period. There were no hospital admissions, significant infections or adverse reactions within the cohort. 15 patients submitted CUCQ-8 scores, of these 7 patients' scores had worsened at week 8 but by week 24 13/15 were stable or improved compared to baseline. Conclusion(s): Switching from IV to SC infliximab is welcomed by most patients. The efficacy, tolerability, increased drug level and safety which has previously been demonstrated is reproduced in our cohort. This study is the first to explore patient experience outcomes. The finding of initial worsening of the CUCQ-8 score, but overall improvement by week 24 opens further opportunity for engaging patient involvement in switch programmes.