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2.6.4. Sequential effects test. | Independent samples | PMC10553036 | ||
2.7. Experimental flow chart | PMC10553036 | |||
3. Results | PMC10553036 | |||
3.1. Basic information of participants | The Shapiro–Wilk test showed that all dependent variables were normally distributed (Baseline demographics of the study population. | PMC10553036 | ||
3.2. Results of the first trial | According to Table Analysis of variability of relevant indicators in the first trial.Significant difference compared with TimeSignificant difference compared with TimeSignificant difference compared with the Control group at the same time. | PMC10553036 | ||
3.3. Results of the second trial | According to Table Analysis of variability of relevant indicators in the second trial.Significant difference compared with TimeSignificant difference compared with Time | PMC10553036 | ||
3.4. Sequential effect analysis | Further comparisons were made to determine if there were any order effects in the 2 experiments. In Group 1, the first experiment was the speed and accuracy test (X1), and the second experiment (cross-over) was the same test for the exercise group (X2). The difference was calculated as X = |X1 − X2|. In Group 2, the first experiment was the aiming response test for the exercise group (Y1), and the second experiment (cross-over) was the same test for the control group (Y2). The difference was calculated as Y = |Y1 − Y2|. The evaluation method for visual memory and reaction time tests was the same. The difference in results (X and Y) between Group 1 and Group 2 showed no statistically significant differences (Comparison of inter-individual differences in each index after 30 min of exercise. | PMC10553036 | ||
4. Discussion | muscle damage | CARDIOVASCULAR DISEASE, CHRONIC DISEASE | Our study aimed to investigate whether acute aerobic exercise benefits cognitive function in a specific occupational group of eSports players. As the best beneficiaries of cognitive executive function, eSports athletes urgently need an exercise training program that can rapidly improve their cognitive executive performance. At the same time, the unique nature of the eSports profession has led to a series of health problems in eSports athletes due to their sedentary lifestyle, including “stiff and twisted fingers, muscle damage, chronic disease, and cardiovascular disease.” | PMC10553036 |
4.1. Mechanisms of the benefits of exercise | There are currently several mechanisms regarding exercise-induced benefits, which include exercise increases microcirculation and mitochondrial function, which results in a significant ameliorative function for muscle,As “lack of time” is often cited as the most common barrier to increasing habitual physical activity, recent years have seen a renewed interest in “time-efficient” physical activity,Acute aerobic exercise, also known as a 1-time exercise, lasts from 10 to 60 minutes and provides energy in a single session with aerobic metabolism, acute aerobic exercise. | PMC10553036 | ||
4.2. The effects of acute moderate-intensity aerobic exercise on different cognitive tasks vary | This study found that acute moderate-intensity aerobic exercise has varying effects on different cognitive tasks. Based on the results of the 2 experiments, exercise for 30 minutes can improve speed and accuracy, instant visual memory, and shorten reaction time. This is consistent with Peng and Zhou’sThe experiment results did not find a promotion effect of exercise on sequential memory tests and chimpanzee tests, which are tests of sequential memory ability. Tomporowski | PMC10553036 | ||
4.3. Temporal characteristics of the effects of acute moderate-intensity aerobic exercise on cognitive tasks | frontal lobe dysfunction | Two experiments showed that the exercise intervention group had significantly improved speed and accuracy 30 minutes after exercise compared to before exercise. The exercise intervention group also had significantly shorter reaction times 30 minutes after exercise than before in the first experiment, but the second experiment did not show a statistically significant difference. These results indicate that acute moderate-intensity aerobic exercise has temporal characteristics on cognitive tasks. Its effects can last up to 30 minutes after exercise, consistent with Peng and Zhou.In addition to the exercise awakening hypothesis and the neurotrophic factor BDNF, theories about acute aerobic exercise’s effects on cognitive performance include the frontal lobe dysfunction hypothesis, the neuroendocrine model, and the overcompensation theory of self-control strength. | PMC10553036 | |
4.4. Limitation | Our research results were observed only at the macroscopic level, focusing on the actual changes in various cognitive functions of E-athletes. The findings confirmed that acute aerobic exercise contributes to the improvement of certain cognitive functions in E-athletes, providing a basis for further research. However, 1 limitation of our study is that we did not further explain the cellular and molecular biological mechanisms at the micro level. Exercise can significantly increase the levels of biologically active molecules associated with improvements in cognitive function, including insulin-like growth factor 1, growth hormone, vascular endothelial growth factor, and brain-derived neurotrophic factor. Subsequent research could delve into the changes in the content of these relevant biologically active molecules, further elucidating their mechanisms at the cellular and molecular levels. Additionally, near-infrared spectroscopy could be employed to further observe the brain imaging results of E-athletes, thereby investigating the activating effects of acute aerobic exercise on different brain regions of E-athletes. | PMC10553036 | ||
5. Conclusion | shortening visual reaction | Acute moderate-intensity aerobic exercise significantly improves cognitive function in e-sports players and exhibits temporal characteristics. Its characteristics are mainly reflected in improving speed and accuracy, shortening visual reaction time, and improving instantaneous memory ability. The improvement effect can last 30 minutes after the end of the exercise. This suggests that e-sports players can adopt acute moderate-intensity aerobic exercise before competition or daily training to improve their performance. | PMC10553036 | |
Abbreviation: | brain derived neurotrophic factorThe source of funds is provided by the first author Zhang Weichao. The project number is 202202004.The authors have no conflicts of interest to disclose.The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.How to cite this article: Zhang W, Wang X, Li X, Yan H, Song Y, Li X, Zhang W, Ma G. Effects of acute moderate-intensity aerobic exercise on cognitive function in E-athletes: A randomized controlled trial. Medicine 2023;102:40(e35108). | PMC10553036 | ||
References | PMC10553036 | |||
Abstract | PMC10485297 | |||
Background | cancer | CANCER | When cancer treatments have similar oncologic outcomes, the number of days with in-person healthcare contact (“”contact days’’) can help contextualize expected time use with each treatment. We assessed contact days in a completed randomized clinical trial. | PMC10485297 |
Patients and Methods | relapsed/refractory lymphoma | SECONDARY | We conducted a secondary analysis of the CCTG LY.12 RCT that evaluated 2-3 cycles of gemcitabine, dexamethasone, and cisplatin (GDP) vs. dexamethasone, cytarabine, and cisplatin (DHAP) in 619 patients with relapsed/refractory lymphoma prior to stem cell transplant. Primary analyses reported similar response rates and survival. We calculated patient-level “contact days” by analyzing trial forms. The study period was from assignment to progression or transplant. Days without healthcare contact were considered “home days’’. We compared measures of contact days across arms. | PMC10485297 |
Results | The study period was longer in the GDP arm (median 50, vs. 47 days, | PMC10485297 | ||
Conclusions | hematological cancers, cancer | CANCER, SECONDARY | Measures of time use, such as contact days, can be extracted from RCTs. In LY.12, despite comparable oncologic outcomes, GDP was associated with fewer contact days. Such information can guide decision-making for patients with hematological cancers, who already face significant healthcare contact.When cancer treatments have similar oncologic outcomes, the number of days with in-person healthcare contact (“contact days’’) can help contextualize expected time use with each treatment. This secondary analysis of the CCTG LY.12 trial analyzed trial forms to assess days with and without health care contact. | PMC10485297 |
Implications of Practice | ONCOLOGY | We extracted a patient-centered and pragmatic measure of the time spent with healthcare contact from a completed clinical trial. We identified days with in-person healthcare contact (“”contact days’’) and days spent at home (“”home days’’). In the LY.12 trial, we demonstrate that although 2 different chemotherapy regimens were associated with similar short- and long-term oncologic outcomes, one chemotherapy regimen was associated with more contact days and many more hospitalized days. Oncology clinical trial reports that present such data alongside traditional efficacy endpoints can help patients understand expected time use patterns and guide patient-oncologist decision-making regarding pursuing treatment approaches. | PMC10485297 | |
Introduction | lymphoma, cancer, hematological malignancies | COLORECTAL CANCER, CANCER, HEMATOLOGICAL MALIGNANCIES, SOLID TUMORS, MALIGNANCIES, SECONDARY, LYMPHOMA | The time burdens imposed by cancer care are increasingly recognized, especially among persons with advanced solid tumors where the absolute survival benefit offered by a treatment may be small.To optimize patient centeredness (since seemingly short days can turn into all-day affairs) and practicality (dichotomous and easily determined outcome), our proposed measure of this time spent considers a day with in-person healthcare system contact as a healthcare contact day, or a “”contact day’’. We have demonstrated that in a clinical trial in patients with advanced colorectal cancer, the additional 6 weeks of increased overall survival with the experimental agent was offset by an equal number of contact days.While a majority of our initial work has focused on persons with advanced solid tumors, burdens of care are relevant to people with hematological malignancies. Prior work in hematology malignancies has largely focused on inpatient days, or nights spent away from home, and has not consistently accounted for outpatient visits.As with solid tumors, different cancer treatment approaches for hematological malignancies may have similar or marginally different oncologic outcomes. In such cases, their associated contact days can aid patient-oncologist decision making regarding which treatment approach to pursue. We conducted a secondary analysis of a completed randomized controlled trial in patients with relapsed/ refractory lymphoma to assess the feasibility of extracting and comparing contact days and home days between arms. | PMC10485297 |
Methods | PMC10485297 | |||
Study Background, Procedures, and Initial Efficacy/Safety Data | B-cell malignancies, non-Hodgkin’s lymphoma, Cancer | ADVERSE EVENTS, SECONDARY, CANCER | We conducted a secondary analysis of the Canadian Cancer Trials Group LY.12 randomized clinical trial (ClinicalTrials.gov Identifier: NCT00078949). LY.12 recruited participants in Canada, Italy, US, and Australia during 2003-2011. Eligible adults had an aggressive histology relapsed/ refractory non-Hodgkin’s lymphoma that had relapsed after one anthracycline-containing regimen. Patients were randomized 1:1 to receive 2-3 outpatient cycles of gemcitabine, dexamethasone, and cisplatin (GDP) vs. dexamethasone, cytarabine, and cisplatin (DHAP) prior to autologous stem cell transplant. The third cycle was permitted if response to 2 cycles was insufficient. A protocol amendment in 2005 allowed patients with B-cell malignancies in both arms to additionally receive rituximab. The therapies were delivered in 21-day cycles, as presented in Drugs and schedule of chemotherapy administration in both arms of the LY.12 trial.Each regimen was delivered in 21-day cycles. Dose adjustments and deferments, and addition of growth factor support was allowed.The primary trial endpoint was response rate with a non-inferiority design. Secondary endpoints included event-free survival, overall survival, rates of stem-cell mobilization, adverse events, quality-of-life, and healthcare utilization.A total of 619 patients were randomized. Initial primary results published in 2014 reported similar response rates (44%-45%) between arms, confirming the non-inferiority of GDP. Transplantation rates (49%-52%), 4-year event-free-survival (26%), and 4-year overall survival (39%) were also similar between arms. | PMC10485297 |
Study Procedures for the Current Analyses | The study period for the current analysis was the date of assignment to the date of progression or the day before stem cell transplant (whichever was earlier), as in prior work.We considered any day with any amount of in-person healthcare system contact as a “”contact day’’. | PMC10485297 | ||
Statistical Analysis | We compared proportions and medians of time measures across arms by a χ | PMC10485297 | ||
Results | Six-hundred and 10 of the 619 (98.5%) trial participants had data on contact days available and were included in the current analyses. The median age was 55 years, 61% of participants were men, and 86% had an ECOG performance status of 0-1. Detailed baseline characteristics are available in prior publications.Data on contact days and their sources, and home days are presented in Measures of time use in LY.12 for the overall study population, data are median (interquartile range).Data are median (interquartile range). | PMC10485297 | ||
Discussion | aggressive hematological cancers, hematologic malignancies | SECONDARY, HEMATOLOGIC MALIGNANCIES | In this secondary analysis of the LY.12 trial, we demonstrate that measures of time spent in healthcare can be extracted from completed RCTs. In LY.12, despite broadly comparable short- and long-term oncologic outcomes, the GDP arm experienced fewer contact days. The sources of contact days also differed between arms, with the GDP arm spending relatively more days receiving outpatient chemotherapy, and the DHAP arm spending many more days in the hospital. Such information can add help patients and care partners understand expected time use, and guide decision-making for patients with aggressive hematological cancers, who already spend a significant portion of time with healthcare contact.The primary finding of this work is that time spent undergoing treatment can be gleaned from secondary analyses of available data from previously published clinical trials. Our initial approach was to use clinical trial protocols and publications to reconstruct the course of the average patient on the trial arms, but this involved making several assumptions.These data also provide elements of detail that can help improve care for vulnerable patients. First, over the 6-10 week salvage chemotherapy period, participants in both arms spent more than one in 3 days with healthcare contact. While patients often receive extensive logistic support during and after stem cell transplant, this is not always true during salvage regimens.This work has limitations. First, the current measure itself has limitations. It currently does not consider home-based care or telemedicine visits, and does not consider care partner time use. It is currently not quality-weighted. Ongoing qualitative work is addressing this. Second, the exact date of contact for a few outpatient visits was missing. We considered these visits to be on a separate day. We were unable to capture some trial-related contact days, eg, related to screening, prior to the date of assignment. These issues applied to both arms and should not affect comparisons.In conclusion, we demonstrate that secondary analyses of a completed cooperative group trial that prospectively collected resource utilization data can be used to extract measures of time use. Data on patterns of time use in oncology clinical trial reports can supplement oncology efficacy data to aid patient-oncologist decision making, especially when differences in efficacy are small. This work is particularly relevant to people with hematologic malignancies who already face significant time with healthcare contact. | PMC10485297 |
Acknowledgments | We thank the participants in the study for volunteering. Prior presentation: We will present this work in abstract form to the 2023 ASCO Annual Meeting to be held in Chicago, IL, USA (and virtually) on June 2-6, 2023. | PMC10485297 | ||
Funding | Cancer | CANCER | The original LY.12 clinical trial was supported by grants nos. 015469 and 021039 from the Canadian Cancer Society Research Institute, and by Roche Canada and Eli Lilly Canada. Annette Hay has received research funding from Roche, AbbVie, Merck, Seattle Genetics, Janssen, Incyte, Amgen, Novartis. | PMC10485297 |
Conflict of Interest | Annette E. Hay has received research funding from Roche, AbbVie, Merck, Seattle Genetics, Janssen, Incyte, Amgen, Novartis. The other authors indicated no financial relationships. | PMC10485297 | ||
Author Contributions | Conception/design: A.G., A.E.H., M.C.C., C.M.B. Data analysis and interpretation: all authors. Administrative support: A.E.H., M.C., L.E.S., M.C.C. Manuscript writing (first draft): A.G. Manuscript revisions and final approval of manuscript: all authors. | PMC10485297 | ||
Data Availability | The data underlying this article will be shared on reasonable request to the corresponding author. | PMC10485297 | ||
References | PMC10485297 | |||
Background | thrombosis, thrombocytopenia, TTS, coronavirus disease 2019 | THROMBOSIS, THROMBOCYTOPENIA, CORONAVIRUS DISEASE 2019, SYNDROME | Edited by: Jochen Mattner, University of Erlangen Nuremberg, GermanyReviewed by: Qihan Li, Chinese Academy of Medical Sciences and Peking Union Medical College, China; Rezvan Hosseinzadeh, Babol University of Medical Sciences, Iran†These authors have contributed equally to this work and share first authorship‡These authors have contributed equally to this work and share last authorshipBillions of doses of coronavirus disease 2019 (COVID-19) vaccines have been administered and several cases of thrombocytopenia with thrombosis syndrome (TTS) have been reported after the administration of adenoviral vector vaccines. However, the effects of an inactivated COVID-19 vaccine, CoronaVac, on coagulation are not well understood. | PMC10265469 |
Methods | hepatitis A | ADVERSE EVENT, HEPATITIS A, BLOOD | In this randomized, controlled, open-label phase IV clinical trial, 270 participants including 135 adults aged 18–59 years and 135 adults aged 60 years or older, were enrolled and randomized to the CoronaVac group or to the control group in a 2:1 ratio and received two doses of CoronaVac or one dose of the 23-valent pneumococcal polysaccharide vaccine and one dose of inactivated hepatitis A vaccine on days 0 and 28, respectively. Adverse events were collected for 28 days after each dose. Blood samples were taken on days 0, 4, 14, 28, 32, 42, and 56 after the first dose to evaluate neutralizing antibody titers and laboratory parameters of coagulation function and blood glucose. | PMC10265469 |
Results | ADVERSE REACTIONS, SEVERE ACUTE RESPIRATORY SYNDROME, CORONAVIRUS | Fourteen days after the second dose of CoronaVac, the seroconversion rates of neutralizing antibodies against the prototype strain and beta, gamma, and delta variants of concern (VOC) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reached peak values of 89.31%, 23.3%, 45.3%, and 53.5%, respectively. The incidence of adverse reactions was 43.6% and 52.2% in the CoronaVac group and in the control group, respectively. All were mild or moderate in severity. For the laboratory parameters, there was no difference in the means of any parameter between the two groups at any time point, except for the D-dimer on day 14. However, the D-dimer in the CoronaVac group decreased on day 14 compared to the value at baseline, while a higher D-dimer value, instead of a decreased D-dimer value, was a risk factor for TTS. | PMC10265469 | |
Conclusion | CoronaVac showed a good safety profile and could induce a humoral response against the prototype and VOCs of SARS-CoV-2 in adults 18 years or older, with no abnormal effects on laboratory parameters of blood glucose and coagulation function. | PMC10265469 | ||
Introduction | death, coronavirus disease 2019 | ADVERSE REACTIONS, CORONAVIRUS DISEASE 2019, THROMBOCYTOPENIA, ADVERSE EFFECTS, ARTERIAL THROMBOSIS | The coronavirus disease 2019 (COVID-19) pandemic has led to millions of confirmed cases of COVID-19 worldwide and billions of vaccines against SARS-CoV-2 have been administered (TTS is a rare symptom characterized by acute venous or arterial thrombosis, thrombocytopenia, and positive PF4-heparin ELISA. The peak time for symptoms onset is 6 to 14 days after vaccination and the symptoms can range from mild adverse effects to death (Inactivated COVID-19 vaccines have been widely used for vaccination around the world, but there have been few studies on TTS-related safety after vaccination. Therefore, there is an urgent need to study whether inactivated COVID-19 vaccines could affect coagulation function. Here, we report the results of a phase IV clinical trial to evaluate the effects of an inactivated vaccine (CoronaVac) on coagulation function, immunogenicity, and other adverse reactions. Fasting glucose was also detected and evaluated. | PMC10265469 |
Methods | PMC10265469 | |||
Study design and participants | DISEASE | This single-site, randomized, controlled, open-label phase IV clinical trial was conducted by the Shandong Provincial Center for Disease Control and Prevention (CDC) in Rushan, Shandong province, China (NCT04953325). Participants 18 years or older were recruited and randomized to evaluate the immunogenicity and safety of an inactivated COVID-19 vaccine (CoronaVac). The trial was approved by the Shandong Provincial CDC Ethics Committee and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. All participants provided their written informed consent prior to screening. | PMC10265469 | |
Vaccines | hepatitis A | VIRUS, HEPATITIS A | Inactivated SARS-CoV-2 vaccine (CoronaVac), 23-valent pneumococcal polysaccharide vaccine (PPV23) and inactivated hepatitis A vaccine used in this trial were manufactured by Sinovac Biotech Ltd. and approved by the China National Medical Products Administration (NMPA). CoronaVac is an inactivated COVID-19 vaccine. Each dose contains 600SU inactivated virus in 0.5 mL of aluminum hydroxide solution. The 23-valent pneumococcal polysaccharide vaccine contains 23 serotypes of pneumococcal capsular polysaccharide, each of which was 25 μg per dose (0.5 mL). The inactivated hepatitis A (HepA) vaccine contains 500 SU inactivated hepatitis A virus per dose in 1 mL of aluminum hydroxide solution. | PMC10265469 |
Procedures | thrombosis, bleeding, SARS-CoV-2 infection, abnormal fasting blood glucose or diabetes, coagulation abnormalities | THROMBOSIS, BLEEDING, SARS-COV-2 INFECTION, ADVERSE EVENTS, ADVERSE EVENT, CHRONIC DISEASES, DISEASES | Participants aged 18 years or older were selected by an oral consultant according to inclusion and exclusion criteria. Criteria for critical exclusion included participants with 1) a history of SARS-CoV-2 infection or vaccination, 2) severe chronic diseases, 3) abnormal fasting blood glucose or diabetes, or 4) diagnosed coagulation abnormalities or diseases prone to thrombosis or bleeding. Other detailed inclusion and exclusion criteria are listed on ClinicalTrials.gov (NCT04953325).A total of 270 participants were recruited and randomly assigned to the CoronaVac group and the control group in a 2:1 ratio. There were 180 participants in the CoronaVac group (including 90 adults aged 18–59 years and 90 adults aged 60 years or older) who received two doses of CoronaVac in a 28-day interval and 90 participants (including 45 adults aged 18–59 years and 45 adults aged 60 years or older) in the control group who received one dose of PPV23 on day 0 and one dose of inactivated HepA vaccine on day 28.For safety assessment, participants were required to record the solicited adverse events on paper for the first 7 days after each dose and the unsolicited adverse events for 28 days after each dose. Serious adverse events were recorded throughout the trial. Adverse events were classified according to the guidelines released by the China NMPA ( | PMC10265469 |
Outcomes | fasting blood glucose | ADVERSE EVENTS, ADVERSE REACTIONS, SECONDARY | The primary safety outcome was abnormal differences in the means of laboratory parameters between the CoronaVac group and the control group at seven time points. Laboratory parameters included fasting blood glucose, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), international normalized ratio (INR), D-dimer, erythrocyte sedimentation rate (ESR), and anti-heparin/platelet factor 4 antibody. Laboratory parameters adverse events were evaluated according to the China NMPA guidelines and the US HHS tables (The second safety outcome was adverse reactions within 7 and 28 days after each dose. The primary immunogenic outcome was the seroconversion rate of the neutralizing antibody against the prototype strain of SARS-CoV-2 at 28 days after the second dose of CoronaVac. The secondary immunogenic outcomes included geometric mean titers (GMT), geometric mean increases (GMI), seroconversion rates (SCR), and seropositive rates of neutralizing antibodies against the prototype strain and VOCs of SARS-CoV-2 at different time points (days 0, 4, 14, 28, 32, 42, and 56). Seropositivity was defined as neutralizing antibody titer ≥ 8 and seronegative was defined as neutralizing antibody titer < 8. Seroconversion was defined as a change from seronegative at baseline to seropositive ( | PMC10265469 |
Serum-neutralizing antibodies detection | The neutralizing antibodies against the prototype strain of SARS-CoV-2 (SARS-CoV-2/human/CHN/CN1/2020, GenBank number MT407649.1) and variants Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2) were quantified using a microcytopathogenic effect assay according to previous trials ( | PMC10265469 | ||
Anti-platelet factor 4/Heparin antibody detection | SECONDARY | The enzyme-linked immunosorbent assay (ELISA) kit for anti-heparin/platelet factor 4 antibodies (Anti-PF4) was purchased from Cloud-Clone Corp. (Wuhan, China). Serum samples were detected strictly according to the manufacturer’s instructions.Standards or samples were added to the microtiter plate wells, which had been precoated with platelet factor 4/Heparin (PF4/H). Then after adding horseradish peroxidase (HRP) conjugated secondary antibodies, TMB substrate solution, and sulfuric acid solution step by step, the wells that contained anti-PF4/H antibodies would change colors to yellow. The concentrations of the anti-PF4/H antibodies were calculated by the optical density (OD) values, which were measured by a spectrophotometer at 450 nm. | PMC10265469 | |
Glucose detection | The glucose hexokinase reagent kit was purchased from Medicalsystem Biotechnology Co., Ltd. (Ningbo, China). All samples were detected by the hexokinase/glucose-6-phosphate dehydrogenase method according to the manufacturer’s instructions. | PMC10265469 | ||
Statistical analysis | Because there were no previous studies relevant to the primary safety outcome of the three vaccines used in this trial, no statistical methods were used to calculate the sample size. Based on practical considerations and guidelines in China that the minimum sample size for each group in a phase I clinical trial should be 20–30 individuals, 90 participants per CoronaVac age subgroup and 45 participants per control age subgroup (2:1) were determined. Data were entered into EpiData software (version 3.1, EpiData Association). Analysis methods were described in previous trials ( | PMC10265469 | ||
Results | PMC10265469 | |||
Participants | HEPATITIS A | From 30 July to 25 August 2021, a total of 355 participants aged 18 years or older were selected, 270 participants were enrolled and underwent randomization. One hundred and eighty participants were assigned to the CoronaVac group (including 90 adults aged 18 to 59 years and 90 adults aged 60 years or older), and 90 participants were in the control group (including 45 adults aged 18 to 59 years and 45 adults aged 60 years or older). Of these participants, 269 were vaccinated with the first dose of CoronaVac or one dose of PPV23 on day 0, and 249 were vaccinated with the second dose of CoronaVac or a dose of the hepatitis A vaccine (Study flow of the trial. | PMC10265469 | |
Demographic characteristics | At baseline, the demographic characteristics between the control group and the CoronaVac group were generally similar in terms of mean age, height, weight, sex, and ethnicity (Demographic characteristics.*Data are mean (SD) or n (%). | PMC10265469 | ||
Immunogenicity | PMC10265469 | |||
GMTs and seroconversion rates of neutralizing antibodies against the prototype strain | To assess the dynamic changes of neutralizing antibodies before and after immunization, blood samples from participants in the CoronaVac group were detected at seven time points. Four days after the first dose of CoronaVac, GMTs and seroconversion rates (SCR) of neutralizing antibodies against the prototype strain of SARS-CoV-2 showed no differences compared to those on day 0 in both the younger (18-59 years) (pDynamic changes in neutralizing antibody titers against prototype strain of SARS-CoV-2 at different time points. Participants received two doses of CoronaVac on Day 0 and Day 28. Neutralizing antibody titers at seven time points (Day 0, 4, 14, 28, 32, 42, 56) were measured. The neutralizing antibodies increased in a similar pattern after the second dose of CoronaVac. Neutralizing GMTs and seroconversion rates did not show significant differences between day 28 (before the second vaccination) and day 32 (4 days after the second dose) in each age subgroup (pTo further demonstrate the dynamic changes of the neutralizing antibody titers, reverse cumulative distribution plots were drawn ( | PMC10265469 | ||
GMTs and seroconversion rates of neutralizing antibodies against VOCs | To analyze the neutralizing antibody titers against beta, gamma, and delta variants of concern (VOC), blood samples from participants in the CoronaVac group were detected at four time points. All participants were seronegative and susceptible to any VOCs at baseline.The GMTs and seroconversion rates of neutralizing antibodies against SARS-CoV-2 VOC were lower than those against the prototype strain (The dynamic changes of neutralizing antibody titers against SARS-CoV-2 VOCs at different time points. Participants received two doses of CoronaVac on Day 0 and Day 28 respectively and the neutralizing antibody titers were detected at four time points (Day 0, 28, 42, 56). | PMC10265469 | ||
Safety | PMC10265469 | |||
Changes in laboratory parameters before and after vaccination | CHRONIC DISEASES | Ten parameters were detected at seven time points to assess the safety profile of CoronaVac in coagulation activity and blood glucose levels. The nine parameters related to coagulation function were platelet count, PT, APTT, TT, fibrinogen, INR, D-dimer, ESR and anti-heparin/platelet factor 4 antibody.At each time point, the means of each laboratory parameter fell within the laboratory normal ranges (Dynamic changes in the means of laboratory parameters at each time point. To simulate the post-marketing vaccination condition, the oral consultation method was used, rather than laboratory tests, to screen participants. Therefore, subjects unaware of their chronic diseases, which were not contraindicated by vaccination, were recruited. After detecting laboratory parameters of blood samples, physicians evaluated whether laboratory results were laboratory abnormalities and clinically significant.According to the relevant guidelines (Grades Changes in the laboratory parameters between prevaccination and 28 days after the second dose in comparison with prevaccination. | PMC10265469 | |
Adverse reactions | headache, fatigue, pain | ADVERSE REACTIONS, ADVERSE REACTION, INDURATION | A total of 125 (46.5%) of the 269 participants reported at least one adverse reaction within 28 days of either vaccination, of which 78 participants were in the CoronaVac group and 47 participants were in the control group. In addition, 74 (55.2%) of the 134 participants aged 1859 years reported adverse reactions, which was higher than the percentage of participants aged 60 years or older (51 of 135, 37.8%) (p=0.004).All adverse reactions were grade 1 (42.8%) or grade 2 (3.7%) and the most common adverse reactions were injection site pain (28.5% in the CoronaVac group and 36.7% in the control group) and fatigue (6.1% in the CoronaVac group and 8.9% in the control group). There were no significant differences in the percentages of participants with any adverse reaction between the CoronaVac and the control group and between the two subgroups within the same age population. For the CoronaVac group, there were only three cases of grade 2, one case of induration at the vaccination site in participants aged 18–59 years, one case of pain at the vaccination site and one case of headache in participants aged 60 years or older (Local and systemic solicited adverse reactions reported for 28 days after either vaccination. | PMC10265469 |
Discussion | thrombosis, abnormal fasting glucose, HIT, venous or arterial thrombosis, diabetes | THROMBOSIS, ASH, THROMBOCYTOPENIA, HEPARIN-INDUCED THROMBOCYTOPENIA, STREPTOCOCCUS PNEUMONIAE INFECTION, THROMBOEMBOLISM, EVENTS, DIABETES | In this phase IV clinical trial, two doses of CoronaVac with an interval of 28 days exhibited good immunogenicity and safety profiles. CoronaVac did not have any effect on laboratory parameters related to coagulation function and blood glucose.Considering the vaccination policy in China stipulating that all participants who received post-marketing SARS-CoV-2 vaccines must know the lot number, this trial could not be blinded. For control vaccines, some studies have reported that Streptococcus pneumoniae infection could worsen the severity of COVID-19 (As a measure of immune system activation after vaccination, serum SARS-CoV-2 neutralizing antibodies were dynamically analyzed at seven time points after CoronaVac vaccination. Interestingly, we found that 4 days after either dose of CoronaVac, the neutralizing antibody level against the prototype strain did not show any difference compared to the prevaccination level of the corresponding dose. However, antibodies increased significantly 14 or 28 days after each dose. This indicated that it would take more than four days for each dose of CoronaVac to activate the humoral response. Our findings provide evidence supporting the statistical method used in previous studies evaluating the efficacy COVID-19 vaccines, whereby COVID-19 cases counted in the efficacy models occurred at least 14 days after the second dose of CoronaVac (CoronaVac vaccination could also activate neutralizing antibodies against the VOCs, however, it required a longer time. The GMT and seroconversion rate did not increase significantly until 42 days after the first dose (14 days after the second dose). Compared to the prototype strain, the values of GMT and the seroconversion rates against VOC decreased to different degrees. The greatest reduction was against beta VOC, followed by gamma and delta VOCs. Although antibody levels decreased, two doses of CoronaVac vaccines still showed effectiveness against different VOCs in real-world studies (According to the review published by the American Society of Hematology (ASH), five criteria were given to definitively diagnose TTS: 1) COVID-19 vaccination 4 to 42 days before symptom onset, 2) any venous or arterial thrombosis (often cerebral or abdominal), 3) thrombocytopenia, 4) positive for PF4 ‘HIT’ (heparin-induced thrombocytopenia) ELISA, 5) markedly elevated D-dimer (> 4 times the upper limit of normal) (Previous laboratory studies have also shown that CoronaVac did not cause thrombosis or TTS. Signorelli et al. (Previous epidemiological findings in real-world studies did not report an increased risk of thrombocytopenia, thromboembolism, or diabetes associated with CoronaVac vaccinations (Compared to the rigorous screening methods and criteria in typical phase I–III clinical studies, the enrolled population in this trial was closer to the actual vaccination population. Through laboratory test results before vaccination on day 0, we found that 17% of participants had an abnormal fasting glucose value higher than the normal range and some were suspected to be patients with diabetes. This showed that many vaccine recipients may not know their medical conditions well in the real world. Our findings provided the reference baseline data of the real-world population for the assessment of pharmacovigilance risk in China, indicating that some pharmacovigilance events diagnosed after vaccination may already had occurred before vaccination, and the percentage may not be as low as we thought before.This trial has several limitations. Due to the lack of previous studies on laboratory parameters of the CoronaVac vaccine, the sample size of this trial was exploratory and small. As the incidence of TTS is very low, a TTS safety monitoring study in a larger population is required. Epidemiological studies of TTS are also available to further verify the effect of the CoronaVac vaccine on TTS in a larger population in China. Furthermore, in this study, neutralizing antibodies against Omicron VOC were not detected. They will be analyzed in the follow-up booster immunization study.In conclusion, the CoronaVac vaccine could activate humoral responses against SARS-CoV-2 with a good safety profile and did not affect coagulation function and blood glucose levels. | PMC10265469 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10265469 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Shandong Provincial CDC Ethics Committee. The patients/participants provided their written informed consent to participate in this study. | PMC10265469 | ||
Author contributions | RECRUITMENT | QX, XL, XDL, YZ, DS, YG, and LZ designed the clinical trial and the documents used in this trial. QC and HL organized the recruitment and visits of participants at the trial site. XL, XDL, TY, DS, JJL, PX, JS and MX monitored the progress of the trial. YS cleaned and analyzed the data. JL detected serum neutralizing antibodies and anti-PF4/H antibodies. QX, XL, and YZ drafted the manuscript. LZ and YG reviewed the manuscript. All authors contributed to the interpretation of the data and the critical review of the manuscript. | PMC10265469 | |
Acknowledgments | DISEASE | We would like to thank all the investigators from the Rushan Center for Disease Control and Prevention and the People’s Hospital of Rushan City for the contribution to this trial. | PMC10265469 | |
Conflict of interest | Authors XL, TY, YS, and YG are employed by Sinovac Biotech Co., Ltd., YZ, JL, and JS are employed by Sinovac Life Sciences Co., Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The authors declare that this study received funding from Sinovac Life Sciences Co., Ltd. The funder had the following involvement in the study: the study design, on-site monitoring, antibody detection, interpretation of data, the writing and review of this article. | PMC10265469 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10265469 | ||
Supplementary material | The Supplementary Material for this article can be found online at: Click here for additional data file. | PMC10265469 | ||
References | PMC10265469 | |||
Background | renal angiomyolipoma, SEGA, epilepsy, rAML, TSC | RENAL ANGIOMYOLIPOMA, SUBEPENDYMAL GIANT CELL ASTROCYTOMA, EPILEPSY, TUBEROUS SCLEROSIS COMPLEX, ADVERSE EFFECTS | The randomised double-blinded placebo-controlled EXIST-1–3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. | PMC10693167 |
Results | seizure, epilepsy | EPILEPSY | The study included 64 patients with TSC (median age: 19, range 0.9–54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, | PMC10693167 |
Conclusions | Seizure, SEGA | ADVERSE EFFECTS | Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects. | PMC10693167 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s13023-023-02982-1. | PMC10693167 | ||
Keywords | Open access funding provided by University of Oslo (incl Oslo University Hospital) | PMC10693167 | ||
Background | SEGA, rAML, and, epilepsy, TSC, tumour, autosomal dominant genetic disease | TUBEROUS SCLEROSIS COMPLEX, TUMOUR, EPILEPSY | Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease caused by genetic variants in TSC1 [TSC treatment involves mTOR-inhibitors. These drugs block the mTOR-complex activation, reducing tumour growth, and offer a potential disease-modifying approach [The safety and efficacy of the mTOR inhibitor everolimus was studied in a series of randomised, double-blinded, placebo-controlled trials (EXIST-1–3) for the treatment of SEGA, rAML, and epilepsy [Randomized controlled trials (RCT) are the most reliable design to investigate effects on interventions, [However, the stringent trial settings in RCTs with highly selected patients and short follow up differ from the complexities in routine clinical practice [Population-based studies investigating the effectiveness and safety of mTOR inhibitors in clinical practice are limited [The aim of this study was to investigate the effectiveness and safety of treatment with everolimus in patients with TSC in real-world clinical practice. | PMC10693167 |
Results | PMC10693167 | |||
Patient characteristics | Table Patient characteristics | PMC10693167 | ||
Epilepsy | seizure, Seizure, epilepsy | CLONIC SEIZURE, EPILEPSY | Twenty-eight of 64 patients (44%) were treated with everolimus for epilepsy as the primary indication (epilepsy indication group). Further, 17 (27%) had epilepsy but were primarily treated with everolimus for other indications (other indication group). Thus, in total, there were 45 patients in the entire epilepsy group (70% of the study’s patient sample).Seizure frequency per month at the start of treatment was higher in patients treated for epilepsy indication (mean/median: 32/28, SD: 36.6, range 0.25–175) than in patients treated for other indications (mean/median: 3.2/1.5, SD 4.12, range 0–14), and there were more patients with ≥ 3 seizure types (43 vs. 24%) and ≥ 3 ASMs (50 vs. 35%) at the start of treatment among patients treated for epilepsy than in patients treated for other indications. At least 50% seizure reduction occurred in 31% of the entire epilepsy group and was quite similar in both groups (Table Seizure reduction (≥ /< 50%) and related factors*Significant differenceThe proportions of patients with ≥ 50% (Table Figure Change in seizure frequency in patients with epilepsy (n = 45). *Clinically relevant reduction without a given percentage (when percentage change was not available)Forty-four (98%) had exact information about the number of ASMs during treatment. The number of ASMs decreased from baseline in 6 patients, increased in 10 patients in the entire epilepsy group, decreased in 5 patients, and increased in 6 patients in the epilepsy indication group. In the patients with ≥ 50% reduction in seizure frequency, one started vagus stimulation treatment, one changed the vagus stimulator, and one had epilepsy surgery during the treatment period.Seizure reduction was associated with younger age. The proportions of patients with ≥ 50%, ≥ 30%, and any seizure reduction were significantly higher in patients < 18 years of age in the entire epilepsy group (Table Seizure reduction was not associated with the number of seizure types, focal to bilateral tonic clonic seizure, seizure frequency, number of ASMs, or major changes in the use of ASMs (Table | PMC10693167 |
SEGA | SEGA | Five patients were treated with everolimus for SEGA. For two of them, the first available imaging were taken 5 and 7 months after start of treatment, making only three available for evaluation of the effects. The SEGA volume of the largest SEGA decreased from 111.52 mm | PMC10693167 | |
Safety | anaemia, immunodeficiency disorder, leucopoenia, neutropenia, fever, leukopenia, epilepsy, rAML, Hypercholesterolemia, infection, testes infection, skin infections, upper respiratory tract infections, Cancer | ANAEMIA, ADVERSE EFFECTS, IMMUNODEFICIENCY DISORDER, UPPER RESPIRATORY TRACT INFECTIONS, NEUTROPENIA, LEUKOPENIA, EPILEPSY, CNS INFECTIONS, VAGINAL INFECTION, HYPERCHOLESTEROLEMIA, COVID-19 INFECTION, SKIN INFECTION, CEREBRAL OEDEMA, ADVERSE EFFECTS, INFECTION, ULCERATION, ORAL ULCERATION, CANCER | Sixty-one of the 64 (95%) patients reported clinical adverse effects after follow-up periods of 1–12 months (n = 10), 13–24 months (n = 13), 25–36 months (n = 18), and > 36 months (n = 23) (Table Adverse effects with dose modification over time during the treatment period*Genital infection (vaginal infection n = 2, testes infection n = 1)**Cysts: (ovarian, clitoris, pilonidal)***According to the National Cancer Institute Common Terminology Criteria version 5Frequency of the most common adverse effects (stomatitis/oral ulceration, upper respiratory tract infections, fever, and skin infections) declined by ≥ 10% over time. However, a minority of the patients had stomatitis/mouth ulceration (30%) or upper respiratory tract infections (25%) regularly or almost continuously (13%). Hypercholesterolemia (41%), anaemia (30%), and leucopoenia (25%) were the most frequent laboratory abnormalities during the entire treatment period and in the first, second, and after the second treatment year. Hypercholesterolemia was mostly grade 1; only four patients had grade 2 (max cholesterol 10.2 mmol/L). Four patients required statin treatment.Table Fifty percent required dose modifications due to adverse effects. Stomatitis/oral ulceration was the most frequent cause of dose modification. Eighteen patients with symptomatic stomatitis/oral ulceration had no dose modifications.Hospitalisation or prolongation of hospitalisation was required in 34% of the sample, and one patient was diagnosed with immunodeficiency disorder and was hospitalised 10 times during 33 months of treatment. The occurrence of hospitalisation decreased after treatment with immunoglobulin for this patient.Nine patients (14%) discontinued treatment; four due to adverse effects (leukopenia, neutropenia and COVID-19 infection, cerebral oedema, oral ulceration), three due to both adverse effects and loss of effect (infections in two, infection risk due to COVID-19 pandemic in one, epilepsy in two, and rAML in one), and two due to loss of effectiveness (epilepsy).The median duration of treatment was 15 months (range 0–28, mean 13, SD: 7.9, 95% CI 6.9–19.1). The frequency of adverse effects and adverse effects ≥ grade 3 during the entire treatment period was similar in Norway and Denmark [Norway: 34/35 (97%) vs. Denmark: 27/29 (93%), Norway 14/35 (40%) vs. Denmark 9/29 (31%), respectively]. | PMC10693167 |
Discussion | TSC | In this study, we demonstrated the effectiveness and safety aspects of treatment with everolimus in 64 patients with TSC in Norway and Denmark. This is one of few unselected, population-based studies from clinical practice in countries with similar health care systems, characterised by high-quality follow-up and equal access to health care. In the following sections, we compare the outcome measures with results from the randomised, double-blinded, placebo-controlled EXIST studies [ | PMC10693167 | |
Epilepsy effectiveness | rAML, seizure, epilepsy | ADVERSE EFFECTS, INTERACTIONS, ADVERSE EFFECT, EPILEPSY | The effectiveness of epilepsy treatment with everolimus, defined as at least 50% seizure reduction, was observed in one-third of patients with epilepsy in this study. This proportion is similar to the patients treated with a low dose of everolimus in EXIST-3 [This finding might be lower than expected, since most patients also changed ASMs during the study period. Interactions due to concomitant use of enzyme inducers could explain some of the changes, as CYP3A4-mediated metabolism of everolimus is affected by drugs such as carbamazepine, phenytoin, and phenobarbital [In contrast to RCTs studies, it is difficult to know if the seizure frequency reduction is caused by the intervention alone in real world studies [In our study, the proportion of patients with ≥ 50% seizure reduction was higher in Denmark than in Norway.The use of everolimus for epilepsy is restricted in Denmark, to ensure sufficient effect of everolimus, which is an expensive drug with potentially serious adverse effects. Thirty-three and fifty percent seizure reduction, good cooperation, and tolerable adverse effects are required after 4 and 12 months, respectively, to continue treatment. To fulfil these requirements, Danish patients submit seizure diaries for review, and the treating physician submits an evaluation to the Danish Medicines Authorities for documentation after the first treatment year. This is not required in Norway.The observed variability in effectiveness between Norway and Denmark may not reflect a real discrepancy in efficacy, but may be influenced by the requirement to fulfill efficacy criteria in Denmark.Another possible explanation is that patients treated for epilepsy indication were younger at start of treatment in Denmark than in Norway and although the difference were not significant, it is possible that also influenced the difference. In addition, there was not difference in patients with less than 50% reduction between Norway and Denmark.The proportions of patients who reported ≥ 50% seizure reduction varied between 33 and 78% [Patients who started treatment before 2 years did not report a better effect in our study, although seizure reduction was associated with younger age, as also reported previously [The number of ASMs did not decrease under everolimus treatment in our study. The different safety profiles of everolimus compared to other ASMs, gives a higher and different adverse effect load for patients treated with everolimus for epilepsy.In contrast to the results from EXIST-3, which reported higher odds for response in patients treated with high exposure [However, if the efficacy of everolimus is not dose dependent, as it seems in some other studies [No growth or a small reduction in rAML and SEGA lesions might be sufficient to prevent symptoms, whereas a small reduction in seizure frequency might not be as clinically relevant. However, a slight reduction in seizure frequency may make a difference in everyday life for persons with epilepsy [A reasonable effect with regard to seizure reduction and tolerable adverse effects, as requested in Denmark, could, in general, be recommended to continue treatment for the epilepsy indication. | PMC10693167 |
RAML effectiveness | Tumors | TUMORS | About one-third of our patients were responders (> 30% reduction of LD) versus 42% in EXIST-2 [Volume measurement was not feasible for various reasons; it was too time-consuming, the automated method used for volume measurement did not capture accurate volume assessment, and some images were only taken in single sections. The change in size of rAML was measured according to Response Evaluation Criteria in Solid Tumors (RECIST) [ | PMC10693167 |
SEGA effectiveness | SEGA, volume reduction | SEGA volume decreased in all three patients. Our observation (43–71% volume reduction) is in line with or better than results from the EXIST-1 trial, in which 35% [ | PMC10693167 | |
Safety | immunodeficiency disorder, infections, [Immunodeficiency disorder | IMMUNODEFICIENCY DISORDER, PRIMARY IMMUNODEFICIENCY, INFECTIONS, ADVERSE EFFECTS, ADVERSE EVENT, ULCERATION, IMMUNODEFICIENCY DISORDER | The frequency of adverse effects was in line with EXIST-1–3 [Notably, patients with adverse effects ≥ grade 3 were younger than patients without adverse effects ≥ grade 3, this is in line with results in the extension study of EXIST-3 [The frequency of stomatitis/oral ulceration was slightly lower than those reported in EXIST-1–3 [The upper respiratory tract infections in our study were quite similar to those in EXIST-1–3 [Dose reductions and interruptions were reported in 50%, as reported in EXIST-2 [Immunodeficiency disorder was described in one patient. This is a serious condition and is as far as we know not previously described as an everolimus related adverse event. Immunoglobulins were not measured before initiation of everolimus in this patient, and consequently it was not possible to determine for certain whether the patient that developed immunodeficiency disorder has a primary immunodeficiency, or if this is drug related. Clinically infections increased significantly after treatment initiation, making everolimus treatment a probable cause.Data collection was finished for most patients before the outbreak of covid-19, only 14 had follow-up for days up to a month after the outbreak. For two of the nine patients that discontinued everolimus treatment, the COVID-19 pandemic was part of the reason, but apart from that it is not likely that the study result was influenced by the pandemic. | PMC10693167 |
Strengths and limitations | epilepsy, seizure, ’ | DISORDERS, EPILEPSY | The study included unselected patients from two countries with similar health care systems and follow-up from specialists. The patients were recruited from the Norwegian TSC population and from two regions in Denmark. It is possible that some treated patients invited through the National Centre for Rare Epilepsy-Related Disorders in Norway did not respond to the invitation. Only two invited patients treated with everolimus did not want to participate. Due to equal access to health care services and follow-up from specialists, it is likely that most patients with indications for treatment are known and included. In Denmark, everolimus treatment is centralised, and all treated adult patients from Aarhus University Hospital and all paediatric patients from University Hospital Rigshospitalet were invited. The total response rate in Denmark was high (88%), indicating that the included patients were representative and the risk of selection bias low.Due to the observational design, missing data in medical records and data unconformity were important limitations. Patients’ and parents’ interviews were carried out to reduce this limitation, but potential recall bias could not be excluded. Imaging data were not available for all patients and reduced the sample size. Imaging was reevaluated by experienced radiologists, ensuring data conformity.Due to the irregular (multilobular) shape of most of the SEGAs, the simplified method of volume measurement by multiplying diameters in three orthogonal directions and divided the result by 2 was considered too inaccurate. Despite the chosen method, some inaccuracy in volume measurements may persist due to differences in imaging quality across multiple MRI exams from different centres and over the actual time period.Other ASMs were changed in a majority of the patients, and some underwent epilepsy surgery, which made it difficult to draw conclusions on the cause of the change in seizure frequency. Different conditions for epilepsy treatment between Norway and Denmark were also limitations. | PMC10693167 |
Methods | PMC10693167 | |||
Patient selection and inclusion | Patients with a confirmed TSC diagnosis based on recommendations of the 2012 International TSC Consensus Conference [In Norway, 190 TSC patients from the registries were contacted about the use of everolimus: 75 replied, 35 of those were treated with everolimus and were included in the study. Two patients treated with everolimus did not consent to participate. Four were included from the renal, neurological, and rehabilitation departments. In Denmark, everolimus treatment is centralised. Among the users of everolimus, 25 were invited from Aarhus University Hospital, 20 of those were included, and 11 were invited from Rigshopitalet in Copenhagen, 9 of those were included. | PMC10693167 | ||
Study design | epilepsy, lymphangiomyomatosis, seizure | ADVERSE EFFECTS, LYMPHANGIOMYOMATOSIS, EPILEPSY | This was a retrospective observational study. Demography, patient history, indication for and duration of treatment, dosage, serum concentration measurements, dose modifications/discontinuation and adverse effects, and seizure response in epilepsy patients were collected from medical records through a web-based form. Imaging data were re-evaluated by an experienced abdominal and neuro-radiologist. Data related to adverse effects and seizure responses in epilepsy patients were further assessed with a semi-structured patient/parent interview. Patients treated solely for lymphangiomyomatosis (LAM) were only included in the evaluation of adverse effects. In Denmark, the use of everolimus for epilepsy is restricted and requires 33% and 50% seizure reduction, good cooperation, and tolerable adverse effects after 4 and 12 months respectively for permission to continue treatment. To fulfil these requirements, Danish patients submit seizure diaries for review, and the treating physician submits an evaluation to the Danish Medicines Authorities for documentation after the first treatment year. Patients are not obliged to submit seizure registrations in Norway. | PMC10693167 |
Outcome measures of epilepsy | epilepsy, seizure, Seizure, myoclonic, atonic, Epilepsy | EPILEPSY, MINOR, CLONIC SEIZURES, EPILEPSY, ATYPICAL ABSENCE | We investigated changes in seizure frequency from baseline to the last three months of everolimus treatment. We defined seizure frequency during the last three months before treatment as the baseline. Seizure response was divided into seizure freedom, ≥ 50% reduction, ≥ 30% reduction, clinically relevant reduction without a given percentage (when percentage change was not available), no change, or increase. The total reduction in the frequency of focal, tonic, myoclonic, atonic, and focal to bilateral tonic clonic seizures was calculated. Atypical absences were not included. Effectiveness was described in three groups: (a) all everolimus patients with epilepsy using anti-seizure medication (ASM), with ≥ 1 seizure/year (entire epilepsy group), (b) patients with epilepsy treated with everolimus for other indications (other indications group), and (c) patients treated with everolimus for epilepsy indication (epilepsy indication group). Changes in ASM treatment were described as none, minor (dosage adjustments, discontinuing an ASM), or major (adding an ASM, vagus nerve stimulator, or epilepsy surgery).We further investigated the association between epilepsy effectiveness and epilepsy severity, age, and concentration-to-dose ratio (C/D ratio) as a measure of drug exposure. The C/D ratio was calculated from the mean serum concentration/dose in patients with at least three everolimus measurements. Epilepsy severity was investigated by association between the number of seizure types (< 3, ≥ 3), occurrence of focal to bilateral tonic clonic seizures, median weekly seizure frequency (< 7, ≥ 7 in the entire epilepsy group, < 1.5, ≥ 1.5 in the other indication group and < 25, ≥ 25 in the epilepsy indication group), and number of ASMs (< 3, ≥ 3). | PMC10693167 |
Outcome measures of RAML and SEGA | SEGA, rAML, haemorrhage, tumour, SEGA lesions, RAMLs | HAEMORRHAGE, TUMOUR, COMPLICATIONS | We investigated the change in the size of rAML (largest lesion and mean diameter change of largest lesion in both kidneys) from baseline to the last imaging and the change in SEGA volume from baseline to the last imaging. RAMLs with the longest diameter (LD) in both kidneys and overall were identified. The change in size was calculated by subtracting the LD at baseline from the LD at the last imaging. The baseline was defined as imaging closest to the start of treatment. The change in size was defined according to RECIST [SEGA volume was calculated by manually drawing areas along tumour borders on every axial slice (1 mm slice thickness), summing areas and multiplying the result with the slice interval (usually 1 mm), performed on a PACS workstation (SECTRA PACS software). For every exam, a T1-weighted isotropic volume series (MPRAGE) was used, contrast enhanced when available, and alternatively without contrast.The effectiveness of everolimus treatment for rAML (> 1 cm) and SEGA lesions was investigated when imaging was available and when everolimus was prescribed for these indications. The quality of renal imaging was defined as good, moderate, or poor.We further investigated the change in the number of rAML > 1 cm and renal complications (haemorrhage, embolization, nephrectomy) during everolimus treatment. | PMC10693167 |
Outcome measures of adverse effects | Cancer | ADVERSE EFFECTS, ADVERSE EFFECTS, HYPERCHOLESTEROLEMIA, CANCER | We investigated adverse effects possibly or probably related to everolimus treatment mapped and graded by the National Cancer Institute Common Terminology Criteria version 5 [Hypercholesterolemia was not graded using this terminology. Grading was based on total cholesterol levels (grade 1: increased from start or under treatment to above the upper limit of normal (ULN) to 7.75 mmol/L, grade 2: 7.75–10.34 mmol/L, grade 3: 10.34–12 mmol/L). Adverse effects were described every year they occurred. Adverse effects without information of date and without information of grade were described and included in the entire treatment period. We further investigated dose modifications (interruptions, and dose reductions), discontinuation, reason for discontinuation, and association between adverse effects ≥ grade 3 and age. | PMC10693167 |
Statistical analysis | seizure | ADVERSE EVENTS, ADVERSE EFFECTS | The data were coded and analysed with SPSS (version 28.0.1.1 (14)). Continuous variables were analysed with frequency, mean, standard deviation, median, minimum, and maximum. Contingency tables with chi-square test for independence (Pearson’s chi-square and Fisher’s exact test) were used to test group differences between categorical variables (seizure reduction and related factors (≥ 3/< 3 seizure types, GTK, ≥ 3/< 3 ASMs, median weekly seizure frequency, age at start of treatment ≥ 18/< 18, major change in ASMs, and occurrence of adverse effects). Group differences in rAML, seizure reduction, frequency of adverse effects, and grade 3–4 adverse effects between Norway and Denmark were analysed by contingency tables with chi-square test for independence (Pearson’s chi-square and Fisher’s exact test). The Mann–Whitney U test was used to test group differences between continuous not normally distributed variables, occurrence of grade 3–4 adverse events, and group differences between CD/ratio and seizure reduction/rAML reduction. A | PMC10693167 |
Conclusions | autism disorders, intellectual disabilities, seizure, epilepsy | EVENTS, HYDROCEPHALUS, ADVERSE EFFECTS, EPILEPSY | The effectiveness of everolimus in epilepsy was acceptable and in line with EXIST-3. In this study, however, most patients also changed their concomitant ASM treatments. This may suggest that everolimus was not the only cause of the improvement in the seizure situation. Treatment effectiveness with everolimus was associated with a younger age. The results indicate that everolimus treatment reduces or stabilises rAML lesions, reduces risk of renal events, and reduces SEGA volume and risk of hydrocephalus.Most adverse effects were generally mild to moderate, but some tended to be more frequent than in EXIST and other clinical practice studies. Careful monitoring of adverse effects is needed, and benefits against adverse effects should be carefully considered and discussed with patients and parents before the start of treatment and during follow-up. It is our opinion that awareness in vulnerable patients, such as children and patients with intellectual disabilities and autism disorders, is of special importance. | PMC10693167 |
Acknowledgements | Tuberous Sclerosis | TUBEROUS SCLEROSIS | We thank all patients, family members, and others participating in the study. We further thank Arnt Egil Trelsgård from the Norwegian Association of Tuberous Sclerosis for pilot testing the parent/patient interview. | PMC10693167 |
Author contributions | RS, CHH | RECRUITMENT | Responsible/contributed to study design: IC, JC, AIIE, BN, RS, KH, CJL, CL, TN; Recruitment of patients, collection, and interpretation of data: IC, JC, CHH, LH, MGF; Re-evaluation of imaging: AIIE, BN; Data analyses: IC, CL, CJL, TN; Writing/revising of manuscript: IC, JC, CHH, LH, MGF, AIIE, BN, RS, KH, CJL, CL, TN; All authors have given final approval for the submitted version to be published. | PMC10693167 |
Funding | RARE DISORDER | Open access funding provided by University of Oslo (incl Oslo University Hospital) This work was supported by the Norwegian National Advisory Unit on Rare Disorders and KG Jebsen Stiftelsen (SKGJ-MED-021). | PMC10693167 | |
Availability of data and materials | The datasets generated during and/or analysed during the current study are not publicly available due to them containing information that could compromise research participant privacy/consent but are available from the corresponding author on reasonable request. | PMC10693167 | ||
Declarations | PMC10693167 | |||
Ethics approval and consent to participate | The Norwegian Medical Ethics Committee reviewed and approved the study (ethic committee number 2013/176-36). The Central Denmark Region Committees on Health Research Ethics declared the study exempted from notification, as a data processing contract was completed. | PMC10693167 | ||
Consent for publication | Written informed consent was received from patients ≥ 16 years and from parents/guardians of patients < 16 years and of patients without competence to consent. | PMC10693167 | ||
Competing interests | Ine Cockerell gave an unpaid lecture to UCB Nordic. Jakob Christensen has received honoraria from serving on the scientific advisory board of UCB Nordic and Eisai AB, received honoraria for giving lectures from UCB Nordic and Eisai AB, and received funding for a trip from UCB Nordic. Cecilie Johannessen Landmark has received advisory board/speaker’s honoraria from Angelini, Eisai, Jazz, and UCB Pharma. Christina E. Høi-Hansen received speaker’s honoraria from Eisai. Caroline Lund received speaker’s honoraria from Eisai, UCB, and Jazz. | PMC10693167 | ||
References | PMC10693167 |
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