Safety Trial Research Articles

Testosterone and the risk of incident atrial fibrillation in older men: further analysis of the ASPREE study

A cardiovascular safety trial of testosterone in men with cardiovascular risk factors or disease found no difference in rates of major adverse cardiovascular events (MACE) or death but noted more atrial fibrillation (AF) events in testosterone-treated men. We investigated the relationship between endogenous testosterone concentrations with risk of developing AF in healthy older men. Post-hoc analysis of 4570 male participants in the ASPirin in Reducing Events in the Elderly (ASPREE) study. Men were aged ≥ 70 years, had no history of cardiovascular disease (including AF), thyroid disease, prostate cancer, dementia, or life-threatening illnesses. Risk of AF was modelled using Cox proportional hazards regression. Median (IQR) age was 73.7 (71.6-77.1) years and median (IQR) follow-up 4.4 (3.3-5.5) years, during which 286 men developed AF (15.3 per 1000 participant-years). Baseline testosterone was higher in men who developed incident AF compared men who did not [17.0 (12.4-21.2) vs 15.7 (12.2-20.0) nmol/L]. There was a non-linear association of baseline testosterone with incident AF. The risk for AF was higher in men with testosterone in quintiles (Q) 4&5 (Q4:Q3, HR=1.91; 95%CI=1.29-2.83 and Q5:Q3HR=1.98; 95%CI=1.33-2.94). Results were similar after excluding men who experienced MACE or heart failure during follow-up. Circulating testosterone concentrations within the high-normal range are independently associated with an increased risk of incident AF amongst healthy older men. This suggests that AF may be an adverse consequence of high-normal total testosterone concentrations. National Institute on Aging and National Cancer Institute at the National Institutes of Health; Australian Government (NHMRC, CSIRO); Monash University; and AlfredHealth.

Results from a first-in-human phase I safety trial to evaluate the use of a vascularized pericranial/temporoparietal fascial flap to line the resection cavity following resection of newly diagnosed glioblastoma

PurposeThe efficacy of systemic therapies for glioblastoma (GBM) remains limited due to the constraints of systemic toxicity and blood–brain barrier (BBB) permeability. Temporoparietal fascial flaps (TPFFs) and vascularized peri cranial flaps (PCF) are not restricted by the blood–brain barrier (BBB), as they derive their vascular supply from branches of the external carotid artery. Transposition of a vascularized TPFF or PCF along a GBM resection cavity may bring autologous tissue not restricted by the BBB in close vicinity to the tumor bed microenvironment, permit ingrowth of vascular channels fed by the external circulation, and offer a mechanism of bypassing the BBB. In addition, circulating immune cells in the vascularized flap may have better access to tumor-associated antigens (TAA) within the tumor microenvironment. We conducted a first-in-human Phase I trial assessing the safety of lining the resection cavity with autologous TPFF/PCF of newly diagnosed patients with GBM.Methods12 patients underwent safe, maximal surgical resection of newly diagnosed GBMs, followed by lining of the resection cavity with a pedicled, autologous TPFF or PCF. Safety was assessed by monitoring adverse events. Secondary analysis of efficacy was examined as the proportion of patients experiencing progression-free disease (PFS) as indicated by response assessment in neuro-oncology (RANO) criteria and overall survival (OS). The study was powered to determine whether a Phase II study was warranted based on these early results. For this analysis, subjects who were alive and had not progressed as of the date of the last follow-up were considered censored and all living patients who were alive as of the date of last follow-up were considered censored for overall survival. For simplicity, we assumed that a 70% PFS rate at 6 months would be considered an encouraging response and would make an argument for further investigation of the procedure.ResultsMedian age of included patients was 57 years (range 46–69 years). All patients were Isocitrate dehydrogenase (IDH) wildtype. Average tumor volume was 56.6 cm3 (range 14–145 cm3). Resection was qualified as gross total resection (GTR) of all of the enhancing diseases in all patients. Grade III or above adverse events were encountered in 3 patients. No Grade IV or V serious adverse events occurred in the immediate post-operative period including seizure, infection, stroke, or tumor growing along the flap. Disease progression at the site of the original tumor was identified in only 4 (33%) patients (median 23 months, range 8–25 months), 3 of whom underwent re-operation. Histopathological analyses of those implanted flaps and tumor bed biopsy at repeat surgery demonstrated robust immune infiltrates within the transplanted flap. Importantly, no patient demonstrated evidence of tumor infiltration into the implanted flap. At the time of this manuscript preparation, only 4/12 (33%) of patients have died. Based on the statistical considerations above and including all 12 patients 10/12 (83.3%) had 6-month PFS. The median PFS was 9.10 months, and the OS was 17.6 months. 4/12 (33%) of patients have been alive for more than two years and our longest surviving patient currently is alive at 60 months.ConclusionsThis pilot study suggests that insertion of pedicled autologous TPFF/PCF along a GBM resection cavity is safe and feasible. Based on the encouraging response rate in 6-month PFS and OS, larger phase II studies are warranted to assess and reproduce safety, feasibility, and efficacy.Trial registration number and date of registration for prospectively registered trialsClinicalTrials.gov ID NCT03630289, dated: 08/02/2018.

Polymeric Microneedles for Health Care Monitoring: An Emerging Trend.

Bioanalyte collection by blood draw is a painful process, prone to needle phobia and injuries. Microneedles can be engineered to penetrate the epidermal skin barrier and collect analytes from the interstitial fluid, arising as a safe, painless, and effective alternative to hypodermic needles. Although there are plenty of reviews on the various types of microneedles and their use as drug delivery systems, there is a lack of systematization on the application of polymeric microneedles for diagnosis. In this review, we focus on the current state of the art of this field, while providing information on safety, preclinical and clinical trials, and market distribution, to outline what we believe will be the future of health monitoring.

Phase I/II clinical trial of efficacy and safety of EGCG oxygen nebulization inhalation in the treatment of COVID-19 pneumonia patients with cancer

BackgroundThe antiviral drug Nirmatrelvir was found to be a key drug in controlling the progression of pneumonia during the infectious phase of COVID-19. However, there are very few options for effective treatment for cancer patients who have viral pneumonia. Glucocorticoids is one of the effective means to control pneumonia, but there are many adverse events. EGCG is a natural low toxic compound with anti-inflammatory function. Thus, this study was designed to investigate the safety and efficacy of epigallocatechin-3-gallate (EGCG) aerosol to control COVID-19 pneumonia in cancer populations.MethodsThe study was designed as a prospective, single-arm, open-label phase I/II trial at Shandong Cancer Hospital and Institute, between January 5, 2023 to March 31,2023 with viral pneumonia on radiographic signs after confirmed novel coronavirus infection. These patients were treated with EGCG nebulization 10 ml three times daily for at least seven days. EGCG concentrations were increased from 1760-8817umol/L to 4 levels with dose escalation following a standard Phase I design of 3–6 patients per level. Any grade adverse event caused by EGCG was considered a dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) is defined as the highest dose with less than one-third of patients experiencing dose limiting toxicity (DLT) due to EGCG. The primary end points were the toxicity of EGCG and CT findings, and the former was graded by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. The secondary end point was the laboratory parameters before and after treatment.ResultA total of 60 patients with high risk factors for severe COVID-19 pneumonia (factors such as old age, smoking and combined complications)were included in this phase I-II study. The 54 patients in the final analysis were pathologically confirmed to have tumor burden and completed the whole course of treatment. A patient with bucking at a level of 1760 umol/L and no acute toxicity associated with EGCG has been reported at the second or third dose gradients. At dose escalation to 8817umol/L, Grade 1 adverse events of nausea and stomach discomfort occurred in two patients, which resolved spontaneously within 1 hour. After one week of treatment, CT showed that the incidence of non-progression of pneumonia was 82% (32/39), and the improvement rate of pneumonia was 56.4% (22/39). There was no significant difference in inflammation-related laboratory parameters (white blood cell count, lymphocyte count, IL-6, ferritin, C-reactive protein and lactate dehydrogenase) before and after treatment.ConclusionAerosol inhalation of EGCG is well tolerated, and preliminary investigation in cancer population suggests that EGCG may be effective in COVID-19-induced pneumonia, which can promote the improvement of patients with moderate pneumonia or prevent them from developing into severe pneumonia.Trial registrationClinicalTrials.gov Identifier: NCT05758571. Date of registration: 8 February 2023.

Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation, with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth, but current evidence on dosing, candidacy and outcomes is limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP. This single-center, open-label, pilot phase-1 safety and feasibility clinical trial included 25 pregnant individuals with a diagnosis of fetal SVP. Participants self-administered continuous MSO using medical-grade oxygen concentrators for up to 24 h per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation using echocardiography and late-gestation cardiovascular magnetic resonance imaging. Early outcomes were assessed, including perinatal growth and preoperative brain injury, and neurodevelopmental outcomes were assessed at 18 months using the Bayley Scales of Infant and Toddler Development 3rd edition, and compared with those of a contemporary fetal SVP cohort (n = 217) that received the normal standard of care (SOC). Among the 25 participants, the median maternal age at conception was 35 years, and fetal SVP diagnoses included 16 with right ventricle dominant, eight with left ventricle dominant and one with indeterminate ventricular morphology. Participants started the trial at approximately 29 + 2 weeks' gestation and self-administered MSO for a median of 16.1 h per day for 63 days, accumulating a median of 1029 h of oxygen intake from enrolment until delivery. The only treatment-associated adverse events were nasal complications that were resolved typically by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio or head-circumference-to-abdominal-circumference ratio Z-scores over gestation compared with SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over the study period compared with SOC (P = 0.02), this was probably due to initial baseline differences in placental resistance. At late-gestation cardiovascular magnetic resonance imaging, MSO was not associated with an increase in fetal cerebral oxygen delivery. Similarly, no differences were observed in neonatal outcomes, including preoperative brain weight Z-score and brain injury, mortality by 18 months of age and neurodevelopmental outcomes at 18 months of age. This pilot phase-1 clinical trial indicates that low-dose MSO therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with an increase in fetal cerebral oxygen delivery or improvements in early neurological or neurodevelopmental outcomes. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Stereotactic Radiation for Ultra-Central Non-Small Cell Lung Cancer: A Safety and Efficacy Trial (SUNSET)

The use of stereotactic body radiotherapy (SBRT) for tumors in close proximity to the central mediastinal structures has been associated with a high risk of toxicity. This study (BLINDED FOR REVIEW) aimed to determine the maximally tolerated dose (MTD) of SBRT for ultra-central (UC) non-small cell lung carcinoma (NSCLC), using a time-to-event continual reassessment methodology (TITE-CRM). Patients with T1-3N0M0 (≤ 6 cm) NSCLC were eligible. The MTD was defined as the dose of radiotherapy associated with a ≤ 30% rate of grade (G) 3-5 pre-specified treatment-related toxicity occurring within 2 years of treatment. The starting dose level was 60 Gy in 8 daily fractions. The dose-maximum hotspot was limited to 120% and within the planning tumor volume (PTV); tumors with endobronchial invasion were excluded. This primary analysis occurred two years after completion of accrual. Between March 2018 and April 2021, 30 patients were enrolled at 5 institutions. The median age was 73 years (range: 65-87) and 17 (57%) were female. PTV was abutting proximal bronchial tree in 19 (63%), esophagus 5 (17%), pulmonary vein 1 (3.3%) and pulmonary artery 14 (47%). All patients received 60 Gy in 8 fractions. The median follow-up was 37 months (range: 8.9-51). Two patients (6.7%) experienced G3-5 adverse events related to treatment: 1 patient with G3 dyspnea and 1 G5 pneumonia; the latter had CT findings consistent with a background of interstitial lung disease. Three-year overall survival was 72.5% (95% confidence interval [CI]: 52.3-85.3%), progression-free survival 66.1% (95% CI: 46.1-80.2%), local control 89.6% (95% CI: 71.2-96.5%), regional control 96.4% (95% CI: 77.2-99.5%) and distant control 85.9% (95% CI: 66.7-94.5%). Quality of life scores declined numerically over time, but the decreases were not clinically or statistically significant. 60 Gy in 8 fractions, planned and delivered with only a moderate hotspot, has a favorable adverse event rate within the pre-specified acceptability criteria, and results in excellent control for UC tumors.

Topical Versus Intravenous Tranexamic Acid in Patients Undergoing Cardiac Surgery: The DEPOSITION Randomized Controlled Trial.

Although intravenous tranexamic acid is used in cardiac surgery to reduce bleeding and transfusion, topical tranexamic acid results in lower plasma concentrations compared with intravenous tranexamic acid, which may lower the risk of seizures. We aimed to determine whether topical tranexamic acid reduces the risk of in-hospital seizure without increasing the risk of transfusion among cardiac surgery patients. We conducted a multicenter, double dummy, blinded, randomized controlled trial of patients recruited by convenience sampling in academic hospitals undergoing cardiac surgery with cardiopulmonary bypass. Between September 17, 2019, and November 28, 2023, a total of 3242 patients from 16 hospitals in 6 countries were randomly assigned (1:1 ratio) to receive either intravenous tranexamic acid (control) through surgery or topical tranexamic acid (treatment) at the end of surgery. The primary outcome was seizure, and the secondary outcome was red blood cell transfusion. After the last planned interim analysis, when 75% of anticipated participants had completed follow up, the data and safety monitoring board recommended to terminate the trial, and upon unblinding, the operations committee stopped the trial for safety. Among 3242 randomized patients (mean age, 66.0 years; 77.7% male), in-hospital seizure occurred in 4 of 1624 patients (0.2%) in the topical group, and 11 of 1628 patients (0.7%) in the intravenous group (absolute risk difference, -0.5% [95% CI, -0.9 to 0.03]; P=0.07). Red blood cell transfusion occurred in 570 patients (35.1%) in the topical group and in 433 (26.8%) in the intravenous group (absolute risk difference, 8.3% [95% CI, 5.2-11.5]; P=0.007). The absolute risk difference in transfusion of ≥4 units of red blood cells in the topical group compared with the intravenous group was 8.2% (95% CI, 3.4-12.9). Among patients undergoing cardiac surgery, topical administration of tranexamic acid resulted in an 8.3% absolute increase in transfusion without reducing the incidence of seizure, compared with intravenous tranexamic acid. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03954314.

Clinical trial of tolerability, safety and immunogenicity of influenza inactivated split-vaccine Flu-M in children aged 6 to 17 years

Purpose. To evaluate the tolerability, safety and immunogenicity of influenza inactivated split flu vaccine Flu-M during single immunization of children aged 6 to 17 years.Materials and methods. A multicentre double-blind comparative randomised clinical trial of influenza inactivated split vaccine Flu-M for immunisation of children aged 6 to 17 years (the reference agent – Ultrix vaccine) was conducted. Children aged 12 to 17 years inclusive (300 children) were studied at stage I, and children aged 6 to 12 years (300 children) at stage II. Volunteers of each age category were randomised 1:1 into 2 groups comparable in sex and age, one was vaccinated with Flu-M vaccine and the other with Ultrix vaccine. The follow-up, including various laboratory and clinical tests, lasted for 28 days from the time of vaccination.Results. Both vaccines were well tolerated by children aged 12 to 17 years and by children aged 6 to 12 years. There were no severe or serious adverse events. By all criteria of immunogenicity evaluation, vaccine Flu-M was not inferior to the comparison vaccine Ultrix.Conclusion. Influenza inactivated split Flu-M vaccine produced by SPbNIIVS is approved for use for specific prophylaxis of influenza in children aged 6 to 17 years in the Russian Federation, the Republic of Belarus, Latin America and the Caribbean.The trial is registered at ClinicalTrials. gov (NCT 05317767).

Perceptions, attitudes, and willingness of healthcare and frontline workers to participate in an Ebola vaccine trial in Uganda

BackgroundUnderstanding the knowledge, perception and attitudes towards Ebola vaccines is an important factor in ensuring future use of these vaccines. A qualitative methods study embedded in an Ebola vaccine immunogenicity and safety trial (NCT04028349) was conducted to explore the knowledge and perceptions of healthcare (HCWs) and frontline workers (FLWs), about Ebola vaccines and their willingness to participate or recommend participation in Uganda. MethodWe carried out focus group discussions and semi-structured interviews before and after vaccination, with 70 HCWs and FLWs who consented to participate in the trial, and in the qualitative component, from August to September 2019. Data were analysed using thematic content analysis. ResultsRespondents showed good knowledge about Ebola and the vaccines in general, and had wide access to information through several channels, including the study team. On prevention, particular attention was given to effective communication within health facilities. Misconceptions were mainly around route of transmission, animal origin and types of vaccines. Previous fears were based on rumours circulating in the community, mainly about the presence of the virus in the vaccine, side effects and intention to harm (e.g. by “the whites”), ultimately insisting on transparency, trust and involvement of local leaders. Acceptability of participation was motivated by the need to protect self and others, and the willingness to advance research. Majority were willing to recommend participation to their community. ConclusionsOverall, information sharing leads to a better understanding and acceptance of vaccine trials and a positive vaccination experience can be a deciding factor in the acceptance of others. Particular attention should be paid to involving the community in addressing misconceptions and fears, while ensuring that participants have access to vaccination sites in terms of transport, and that they are properly accommodated at the study site including staying for a reasonable period of time.

A phase IIa, randomized, double-blind, safety, immunogenicity and efficacy trial of Plasmodium falciparum vaccine antigens merozoite surface protein 1 and RTS,S formulated with AS02 adjuvant in healthy, malaria-naïve adults

BackgroundTo improve the efficacy of Plasmodium falciparum malaria vaccine RTS,S/AS02, we conducted a study in 2001 in healthy, malaria-naïve adults administered RTS,S/AS02 in combination with FMP1, a recombinant merozoite surface-protein-1, C-terminal 42kD fragment. MethodsA double-blind Phase I/IIa study randomized N = 60 subjects 1:1:1:1 to one of four groups, N = 15/group, to evaluate safety, immunogenicity, and efficacy of intra-deltoid half-doses of RTS,S/AS02 and FMP1/AS02 administered in the contralateral (RTS,S + FMP1-separate) or same (RTS,S + FMP1-same) sites, or FMP1/AS02 alone (FMP1-alone), or RTS,S/AS02 alone (RTS,S-alone) on a 0-, 1-, 3-month schedule. Subjects receiving three doses of vaccine and non-immunized controls (N = 11) were infected with homologous P. falciparum 3D7 sporozoites by Controlled Human Malaria Infection (CHMI). ResultsSubjects in all vaccination groups experienced mostly mild or moderate local and general adverse events that resolved within eight days. Anti-circumsporozoite antibody levels were lower when FMP1 and RTS,S were co-administered at the same site (35.0 µg/mL: 95 % CI 20.3–63), versus separate arms (57.4 µg/mL: 95 % CI 32.3–102) or RTS,S alone (62.0 µg/mL: 95 % CI: 37.8–101.8). RTS,S-specific lymphoproliferative responses and ex vivo ELISpot CSP-specific interferon-gamma (IFN-γ) responses were indistinguishable among groups receiving RTS,S/AS02. There was no difference in antibody to FMP1 among groups receiving FMP1/AS02. After CHMI, groups immunized with a RTS,S-containing regimen had ∼ 30 % sterile protection against parasitemia, and equivalent delays in time-to-parasitemia. The FMP1/AS02 alone group showed no sterile immunity or delay in parasitemia. ConclusionCo-administration of RTS,S and FMP1/AS02 reduced anti-RTS,S antibody, but did not affect tolerability, cellular immunity, or efficacy in a stringent CHMI model. Absence of efficacy or delay of patency in the sporozoite challenge model in the FMP1/AS02 group did not rule out efficacy of FMP1/AS02 in an endemic population. However, a Phase IIb trial of FMP1/AS02 in children in malaria-endemic Kenya did not demonstrate efficacy against natural infection. ClinicalTrials.gov identifier: NCT01556945.

A population pharmacokinetic model using allometric scaling for baricitinib in patients with juvenile idiopathic arthritis.

Baricitinib is approved for the treatment of rheumatoid arthritis (RA) in more than 70 countries, and juvenile idiopathic arthritis (JIA) in the European Union. Population pharmacokinetic (PK) models were developed in a phase 3 trial to characterize PK in pediatric patients with JIA and identify weight-based dosing regimens. The phase 3, randomized, double-blind, placebo-controlled withdrawal, efficacy and safety trial, JUVE-BASIS, enrolled patients (aged 2 to <18 years) with polyarticular course JIA. During a safety/PK period, baricitinib concentration data from age-based dose cohorts were compared to concentrations from adult patients receiving 4-mg QD. PK data were used to develop a population PK model with allometric scaling to determine a weight-based posology in pediatric patients with JIA that matched the adult 4-mg exposure. Baricitinib plasma concentrations from 217 pediatric patients were used to characterize PK. Based on the adult model, pediatric PK was best described using a 2-compartment model with allometric scaling on clearance and volume of distribution and renal function (estimated with glomerular filtration rate [GFR], a known covariate affecting PK of baricitinib) on clearance. The PK modeling suggested the optimal dosing regimen based on weight for pediatric patients as: 2-mg QD for patients 10 to <30 kg and 4-mg QD for patients ≥30 kg. The use of a population PK model of baricitinib treatment in adult patients with RA, with the addition of allometric scaling for weight on clearance and volume terms, was useful to predict exposures and identify weight-based dosing in pediatric patients with JIA.

Phase IV Drug Trials With a Canadian Site: A Comparison of Industry-Funded and Non-Industry-Funded Trials.

Recent regulatory reforms have favored expedited drug marketing and increased reliance on Phase IV clinical trials for safety and efficacy assurance. This study, utilizing ClinicalTrials.gov, assesses the characteristics of Phase IV trials, with at least one site in Canada, examining those funded by industry sponsors and those lacking industry funding. Additionally, it compares the publication status of industry-funded and non-industry-funded trials through a manual review of the medical literature. Between 2000 and 2022, 864 Phase IV trials were completed, with 480 (55.6%) receiving industry funding and 384 (44.4%) funded solely by non-industry sources. Industry-funded clinical trials were larger (mean 204 enrollees versus 70), more likely to be international (57.7% versus 9.6%) and reported results more promptly (1.21 years after completion versus 1.85 years), yet both types shared similar designs, outcomes, and completion times. Publication rates were 81.8% for industry-funded and 65.8% for non-industry-funded trials. The ClinicalTrials. gov registry displayed 48 inaccuracies in publication associations, raising concerns about its accuracy. Our findings underscore the existing institutional limitations in ensuring comprehensive reporting and publication of Phase IV trial results funded by both industry and non-industry sources.

Safety and tolerability of atogepant for the preventive treatment of migraine: a post hoc analysis of pooled data from four clinical trials

BackgroundConventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene–related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders.MethodsThis post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM).ResultsThe safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation.ConclusionsOverall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults.Trial registrationClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309).Graphical

A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss

Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proof-of-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I (N = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa (N = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change −0.87 dB; 95% CI −2.37 to 0.63; P = 0.252 and −0.46 dB; 95% CI −1.94 to 1.03; P = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial’s primary endpoint was not met.

Biosimilars in the practice of modern oncologist

Currently, genetically engineered drugs are widely used in oncological clinical practice which has significantly increased treatment cost. One of the most effective ways to decrease cost is substitution of an innovative drug after patent expiration with a reproduced compound – biosimilar.In this article, a problem of biosimilars is actualized both worldwide and in Russia, characteristics of these products are described, and the path of the agents from the moment of reproduction through preclinical and clinical trials to introduction into real clinical practice is traced, examples of such trials are presented.The results of clinical trials of effectiveness and safety of Pembroria® in patients with various oncological pathologies are described in detail. The first data from the multicenter prospective post-marketing trial PERFECTION are presented demonstrating similar effectiveness and tolerability results for the biosimilar in a multicohort patient category compared to pembrolizumab molecule.Manufacturing of high-quality analogs and their introduction into clinical practice create a possibility to provide more patients in need with modern highly effective and safe drugs as well as increases effectiveness of the state healthcare system.

Effects and Mechanisms of Luteolin, a Plant-Based Flavonoid, in the Prevention of Cancers via Modulation of Inflammation and Cell Signaling Molecules.

Luteolin, a flavonoid, is mainly found in various vegetables and fruits, including carrots, cabbages, onions, parsley, apples, broccoli, and peppers. Extensive research in vivo and in vitro has been performed to explore its role in disease prevention and treatment. Moreover, this compound possesses the ability to combat cancer by modulating cell-signaling pathways across various types of cancer. The studies have confirmed that luteolin can inhibit cancer-cell survival and proliferation, angiogenesis, invasion, metastasis, mTOR/PI3K/Akt, STAT3, Wnt/β-catenin, and cell-cycle arrest, and induce apoptosis. Further, scientific evidence describes that this compound plays a vital role in the up/down-regulation of microRNAs (miRNAs) in cancer therapy. This review aims to outline the anti-cancer mechanisms of this compound and its molecular targets. However, a knowledge gap remains regarding the studies on its safety and efficacy and clinical trials. Therefore, it is essential to conduct more research based on safety, efficacy, and clinical trials to explore the beneficial role of this compound in disease management, including cancer.

Characteristics and Outcomes of Patients on Tofacitinib for Alopecia Areata or Rheumatoid Arthritis: A Retrospective Cohort Study

Tofacitinib is a Janus kinase inhibitor (JAKi) that is used off-label for the treatment of alopecia areata (AA). Its boxed warning includes an increased risk of serious adverse events (SAEs) based on the results of a safety trial in rheumatoid arthritis (RA) patients taking the medication. The purpose of this study was to investigate the differences in patients’ characteristics and SAEs profiles between RA and AA populations taking tofacitinib. The cohorts were constructed using the TrinetX database to identify the patients who were prescribed tofacitinib for RA or AA between October 2012 and October 2023. A total of 22,873 patients were included in this analysis, with 21,080 individuals in the RA cohort and 1793 individuals in the AA cohort. After matching for age, sex, and race, each cohort had a sample size of 1482. Data on the patients’ sex, age, race, comorbidities, concomitant medications, and associated SAEs were collected. The cohorts were compared by calculating the odds ratios and tested for significance associations using Fisher’s Exact Tests. Both the RA and AA cohorts were predominantly female (RA 79%, AA 70%), with mean ages of 61 ± 14 years and 38 ± 19 years (p-value &lt; 0.0001), respectively. Both the groups showed similar racial distributions. The RA cohort had increased rates of hypertension, obesity, type 2 diabetes mellitus, and nicotine dependence compared to those of the AA cohort (p-value &lt; 0.0001). With the exception of cyclosporine and azathioprine, the percentage of concomitant medication use was higher in all the categories in the RA cohort than those in the AA cohort (p-value &lt; 0.0001). Higher rates of adverse events were seen in the RA cohort across all the categories, except myocardial infarction, stroke, and lymphomas/hematopoietic malignancies. Our findings show that the SAEs on the boxed warning of tofacitinib should be strongly considered when being used off-label for the treatment of AA. Clinicians must carefully assess the individual patient factors when determining the appropriateness of tofacitinib use.

Peripheral nerve regeneration following scaffold-free conduit transplant of autologous dermal fibroblasts: a non-randomised safety and feasibility trial

BackgroundThe use of Bio 3D nerve conduits is a promising approach for peripheral nerve reconstruction. This study aimed to assess their safety in three patients with peripheral nerve defects in their hands.MethodsWe describe a single institution, non-blinded, non-randomised control trial conducted at Kyoto University Hospital. Eligibility criteria included severed peripheral nerve injuries or a defect in the region distal to the wrist joint not caused by a congenital anomaly; a defect with a length of ≤20 mm in a nerve with a diameter ≤2 mm; failed results of sensory functional tests; ability to register in the protocol within 6 months from the day of injury; refusal of artificial nerve or autologous nerve transplantation; age 20–60 years; and willingness to participate and provide informed written consent. Six weeks before transplantation, skin was harvested, dermal fibroblasts were isolated and expanded, and Bio 3D nerve conduits were created using a Bio 3D printer. Bio 3D nerve conduits were transplanted into the patients’ nerve defects. The safety of Bio 3D nerve conduits in patients with a peripheral nerve injury in the distal part of the wrist joint were assessed over a 48-week period after transplantation.ResultsNo adverse events related to the use of Bio 3D nerve conduits were observed in any patient, and all three patients completed the trial.ConclusionsBio 3D nerve conduits were successfully used for clinical nerve reconstruction without adverse events and are a possible treatment option for peripheral nerve injuries.

Safety assessment and determination of a maximally tolerated dose of an RAS-GTPase inhibitor (iRAS) in the treatment of gastrointestinal tumors: preliminary results of the phase I trial

Background: Ras oncogene mutations leading to hyperactivation of the MAPK/ERK signaling pathway occur in 25% of all human tumors, and for gastrointestinal tumors, the frequency of Ras mutations amounts to 60%. The introduction of a Ras-GTPase inhibitor into clinical practice would increase the effectiveness of the treatment of socially significant diseases such as stomach and intestinal cancer.&#x0D; Aim: To select the optimal dose with a subsequent assessment of the safety of iRAS when administered to patients with gastrointestinal tract tumors, including those with peritoneal carcinomatosis.&#x0D; Materials and methods: This was a prospective open-label non-randomized phase I study for the assessment of safety and tolerability, with an adaptive design and determination of the maximally tolerated dose of the iRAS. Three dose levels were used (0.45 mg/kg, 0.9 mg/kg, 1.8 mg/kg) according to the "3 + 3" scheme. The study included 11 patients after surgery for stomach or colorectal cancer. The patients were administered PIPAC therapy with iRAS twice with a 7-days interval. The study duration was 28 ± 1 days. During the study, the patient monitoring included physical examination, assessment of vital signs, electrocardiography and echocardiography, laboratory parameters (hematology, clinical chemistry, coagulation tests, and urine analysis).&#x0D; Results: The anti-tumor iRAS agent demonstrated satisfactory tolerability of all doses studied, including the maximal 1.8 mg/kg dose. Vital sign and laboratory abnormalities were clinically non-significant and did not require additional therapeutic interventions. Statistically significant abnormalities were registered for total protein (p = 0.00028), white blood cell counts (p = 0.007), lymphocyte counts (p = 0.0008), and a number of other blood parameters; however, most of these abnormalities were within the physiological normal ranges. Vital signs such as electrocardiography and echocardiography parameters remained stable throughout the entire follow-up period (28 days after administration of the drug). There were short-term rises in body temperature, minor pains in the postoperative scar area.&#x0D; Conclusion: This trial of safety and tolerability of iRAS showed that no cases of dose-limiting toxicity in the studied dose range. The 1.8 mg/kg dose can be recommended for further clinical studies.

Depressive Syndromes in Men With Hypogonadism in the TRAVERSE Trial: Response to Testosterone-Replacement Therapy.

The effect of testosterone on depressive symptoms in men with hypogonadism remains incompletely understood. We assessed the effects of testosterone-replacement therapy (TRT) in improving depressive symptoms in hypogonadal men with and without depressive symptoms enrolled in the TRAVERSE cardiovascular safety trial. A randomized, placebo-controlled, double-blind study was conducted at 316 trial sites. Participants included men, aged 45 to 80 years, with 2 fasting testosterone levels less than 300 ng/dL, 1 or more hypogonadal symptoms, cardiovascular disease (CVD), or increased risk of CVD. We evaluated 3 subgroups of participants: (1) men with rigorously defined, late-life-onset, low-grade persistent depressive disorder (LG-PDD, previously "dysthymia"); (2) all men with significant depressive symptoms (Patient Health Questionnaire-9 Score >4); and (3) all randomly assigned men. Intervention included 1.62% transdermal testosterone or placebo gel. Outcome measures included the proportions of participants (1) meeting criteria for LG-PDD or (2) with significant depressive symptoms; and changes in depressive symptoms, energy, sleep quality, and cognition in testosterone-treated vs placebo-treated men in the 3 subgroups. Of 5204 randomly assigned participants, 2643 (50.8%) had significant depressive symptoms, but only 49 (1.5%) met rigorous criteria for LG-PDD. Among those with LG-PDD, there was no significant difference in any outcome measure between the TRT and placebo groups, possibly reflecting low statistical power. In men with significant depressive symptoms (n = 2643) and in all randomly assigned participants (n = 5204), TRT was associated with modest but significantly greater improvements in mood and energy but not cognition or sleep quality. Depressive symptoms are common in middle-aged and older men with hypogonadism but LG-PDD is uncommon. TRT is associated with small improvements in mood and energy in hypogonadal men with and without significant depressive symptoms.