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Methods | PMC10337346 | |||
Procedures | EMA | The sample included participants who met trial eligibility criteria and attended the first treatment visit where half of the sample was randomized to a standard course of varenicline treatment (12 weeks initiated 1 week prior to their target quit day) and half to an extended course (15 weeks initiated 4 weeks prior to their target quit day). Participants in the standard course received a placebo during the 3 weeks prior to varenicline initiation. Participants received up to 6 in-person smoking cessation counseling sessions during the 9-week EMA protocol (see [Daily data collection was completed using mobile EMA software (ilumivu), a smartphone-based EMA platform that operates on Android and Apple devices. Participants could use their personal smartphone or a loaned Samsung Galaxy “study phone” running on Android. Assessment schedules were based on the participant’s usual wake-up time. Participants completed a brief (~15 minutes) training including an overview of the application and a practice assessment. Participants were given a “frequently asked questions” handout and a “check-in” call was completed during the first week of the EMA period (the baseline week) for troubleshooting and compliance review. Technical problems and compliance were also reviewed at each in-person visit (up to 7 visits occurring every 1-2 weeks), and participants could call the study office if they had any technical problems.Two types of brief EMA were administered: morning assessments (1 per day) and random assessments (4 per day). Participants earned US $1 per assessment completed and were paid at each in-person visit. To be eligible for the study, participants were required to achieve 40% compliance for morning assessments and 50% for random assessments during the baseline week. Participants who did not meet the minimum compliance completed a second baseline week (n=17) and were excluded if they continued to fall below the requirement (n=8; only the second baseline week data were included in the present analyses for participants who were eligible after the second attempt). During the study, the eligibility criterion for the random assessments was dropped to reduce participant burden; 27% (n=70) of participants in this sample were recruited after this criterion was removed. A supplemental analysis suggested that removing this eligibility criterion did not contribute to significant differences in compliance rates ( | PMC10337346 | |
Measures | PMC10337346 | |||
Morning Assessments | Participants were instructed to complete the morning assessment within 60 minutes of waking and before their first cigarette of the day (if still smoking). The morning assessments were available 1 hour before and 2 hours following the participant’s usual wake time. See | PMC10337346 | ||
Random Assessments | Participants received four pseudorandomly timed survey prompts. The random assessments occurred over a 12-hour window divided into four 3-hour blocks with 1 assessment occurring in each block. The first block began 2 hours after the participant’s usual wake time. Participants received an initial notification and 2 reminder notifications to complete each random assessment. Surveys had to be initiated within 15 minutes of the initial notification and completed within 5 minutes of initiation. On average, the random assessments took 1.1 (SD 0.7) minutes to complete. | PMC10337346 | ||
Data Reduction | EMA | Of the 320 participants who met the baseline compliance eligibility criteria and attended the first treatment visit, 60 participated in an optional substudy that varied the frequency and amount of reinforcement for completing EMA (data to be presented in a separate report), and 3 participants were removed from the sample due to software problems with the mobile EMA app (data loss from a server crash), leaving a sample size of 257. Race, employment status, household income, and education were dichotomized as in the primary outcome paper of the parent trial [Within-subject percent compliance was computed for each of the 9 weeks, separately for morning assessments (up to 7 observations per week on each participant) and random assessments (up to 28 observations per week on each participant). Thirty (12%) participants dropped out of the study (withdrew or withdrawn or missed 3 visits in a row) during the EMA period. These participants were retained in the final sample, with data after their final week of study participation set to missing (not 0), and study dropout status (dropped out or completed) was examined as a predictor of EMA compliance rates. | PMC10337346 | |
Data Analysis | EMA | All analyses were conducted in SPSS (version 28; IBM Corp). A series of multilevel models (MLMs) were estimated to assess changes in weekly EMA compliance over time and to evaluate participant and study characteristics as predictors of compliance. Morning and random assessment compliance rates were analyzed in the same model to allow direct comparisons between assessment types. This yielded a data set with up to 18 repeated measures per participant (2 assessment types×9 weeks).First, a series of unconditional MLMs were used to establish the basic shape of trajectories of change. We started with an intercept-only model (with random intercept) to estimate the interclass correlation coefficient (ICC), then linear and quadratic slopes were added to examine the shape of change. Unconditional models were run using a maximum-likelihood estimator to compare model fit using likelihood ratio tests and to determine the structure of random effects. All other models used the default estimator (restricted maximum likelihood).Second, after determining the best fitting model to characterize change, predictors of compliance were evaluated. Assessment type was included in all predictor models. Additional predictors were mean-centered age, employment status (full-time vs not full-time, which included part-time employed, unemployed, retired, homemakers, and disabled participants), EMA phone type (study phone vs participant’s personal phone), COVID-19 context (enrolled before vs after March 22, 2020), treatment group (extended vs standard varenicline run-in), as well as additional participant demographics, including race (Black or African American vs White), sex (male vs female), income (<US $50,000 vs ≥ US $50,000 yearly), education (high school or less vs some college or greater), and study dropout (study completers vs study dropouts). Predictors were first considered in separate individual models evaluating the first-order effect of the predictor, the interaction with the slope over time, the interaction with assessment type (morning vs random assessments), and the 3-way interaction between the predictor, slope, and assessment type. After assessing predictors of compliance individually, a single model including all significant effects from the individual models assessed the unique effects of each predictor on EMA compliance. Simple slopes and effects were used to probe significant interactions [ | PMC10337346 | |
Ethics Approval | Procedures were approved by the University at Buffalo’s institutional review board (IRB ID:RNI00000386). | PMC10337346 | ||
Results | PMC10337346 | |||
Baseline Model: Unconditional MLMs | EMA | Table S2 in Adding a random linear slope (with intercept representing the baseline week of the EMA period) improved model fit (Observed and model implied morning and random assessment compliance trends across the 9-week ecological momentary assessment period. | PMC10337346 | |
Discussion | PMC10337346 | |||
Principal Findings | EMA | Building on prior short-term EMA studies of health behavior [A methodological concern for EMA studies lasting several months is markedly lower EMA compliance occurring in the latter weeks of assessment, which could seriously undermine the validity of those data [ | PMC10337346 | |
Predictors of EMA Compliance | EMA | As hypothesized, initial compliance was substantially higher for the morning assessments than for the random assessments (see Based on the present results and prior literature, compliance can be improved for random assessments by expanding the assessment window, using less stringent time-to-initiation/completion criteria, or incorporating a “snooze” feature for delaying initiating the survey [As predicted, the rate of decline in EMA compliance was negatively associated with participant age. Despite younger participants having higher rates of random assessment compliance at the start of the EMA period, compliance in the final week was approximately 20% higher for older participants (64 years old) than for younger participants (44 years old; see We initially conceptualized age as a predictor based on the perspective that compliance would be both higher initially and better maintained among participants with fewer competing demands and greater flexibility in their schedules (eg, retired participants [The most striking declines in EMA compliance (7%-10% per week) occurred among participants who eventually dropped out of the study. It is important to note that EMA compliance was coded as missing (not 0%) once a participant was no longer in the study. Consequently, declines in EMA compliance preceded study dropout. It seems plausible that either the burden of EMA contributed directly to study dropout or third variables (eg, general motivation or stress) contributed to both poor EMA adherence and study dropout. Either way, future studies may seek to replicate the relationship between study attrition and EMA compliance. Detection of early noncompliance or rapid declines in EMA compliance may be helpful for identifying participants who need extra support to be retained in long-term health behavior studies, a novel twist on using EMA to trigger just-in-time, adaptive interventions [Consistent with other smoking research, compliance was lower among African American participants than among White participants [Importantly, the predictors of EMA compliance discussed above (except for the COVID-19 context) all remained significant when included in a single, multiple predictor model, demonstrating that the effects discussed above were each uniquely and additively predictive of EMA compliance. However, because the effects are additive, it is also reasonable to consider them in combination. For example, the present findings suggest EMA compliance would be particularly low among younger African Americans who work full-time. Given the need to better capture the experiences of marginalized groups described above, these findings raise concerns about adequate representation in EMA data across individuals. This, in turn, raises the question: what constitutes “adequate” EMA compliance? | PMC10337346 | |
“Adequate” EMA Compliance | EMA | What level of EMA compliance should we strive for in long-term studies of health behavior and at what level is the validity of EMA seriously threatened? Certainly, when there are long periods of 0% compliance in the majority of the sample [Ultimately, “acceptable” compliance depends in large part on the particular questions being asked and analyses being performed. Greater temporal precision and representativeness of momentary changes is needed to test complex within-day mediational analyses involving changes in multiple processes (eg, affect, self-efficacy, and momentary changes in health behavior) than to examine week-to-week changes in health behavior and related processes. However, even for complex mediational analyses, statistical approaches to address missing data (eg, imputation strategies and full-information estimation) can mitigate bias even at high levels of missingness [These results may be useful in optimizing approaches to deal with missing EMA data and addressing issues of noncompliance. Our findings suggest adding variables associated with compliance including assessment type, age, employment status, and race into statistical models can help to reduce bias from missing data. Additional quantitative and qualitative work is also needed to better understand the mediating mechanisms that cause these groups to have reduced compliance (eg, increased demands, lowered research engagement, and stress). Such information can help inform EMA protocols to better meet the needs of participants and increase compliance. | PMC10337346 | |
Summary | MM, Cancer | CANCER, EMA | EMA has allowed health behavior researchers to collect large amounts of real-time, real-world data with excellent temporal precision, providing insights into the processes that drive health behavior change and maintenance over weeks or even months. The present study provided an initial evaluation of the degree to which compliance, critical for the validity of EMA, is maintained over 9 weeks in the context of a randomized controlled trial for smoking cessation among community adults. Primary findings generally replicated and extended prior work attempting to identify compliance predictors in clinical samples [Together with prior work, these data suggest that, under most circumstances and for most participants, EMA can reasonably be used to monitor health behavior and related processes over periods of at least 2 months. However, the rate of decline was greater among younger people, people employed full-time, and particularly among people who eventually dropped out of the study. The present data call attention to the need to develop targeted strategies for maintaining long-term EMA compliance, including further work on the mechanistic processes that drive compliance; conversely, the data raise the possibility that marked declines in EMA compliance over time may be useful triggers of just-in-time, adaptive interventions for enhancing retention in long-term studies of health behavior.We thank Adam Ferkin, Robert Cooper, Schuyler Lawson, Nicolas Schlienz, and CeCe Duerr for their support with the EMA data collection. Additionally, we appreciate the contribution of Jennifer Betts for her comments and support throughout this project. We would also like to acknowledge the participants who contributed their time and effort to this research.Conflicts of Interest: LWH Jr reported receiving grant funding from the National Cancer Institute (NCI) and National Center for Advancing Translational Sciences (NCATS) and nonfinancial support from Pfizer Inc during the conduct of the study. MM reported receiving nonfinancial support from Pfizer Inc during the conduct of the study and serving as former speaker/content expert on smoking cessation for Pfizer Inc outside the submitted work.Supplemental materials. | PMC10337346 |
Abbreviations | ecological momentary assessmentinterclass correlation coefficientmultilevel model | PMC10337346 | ||
Purpose | ® | The study was aimed at evaluating the bioequivalence and safety of oseltamivir phosphate for suspension, provided by Shenzhen Beimei Pharmaceutical Co. Ltd. and manufactured by Hetero Labs Limited, and the reference product TAMIFLU® in healthy Chinese subjects. | PMC9942619 | |
Methods | A single-dose, randomized, two-phase, self-crossed model was adopted. Among 80 healthy subjects, 40 subjects in the fasting group and 40 subjects in the fed group. Subjects in the fasting group were randomized into two sequences according to the proportion of 1:1, each given 75 mg/12.5 mL of Oseltamivir Phosphate for Suspension or TAMIFLU®, and cross-administered after 7 days. Postprandial group is the same as fasting group. | PMC9942619 | ||
Results | The T | PMC9942619 | ||
Conclusion | Two Oseltamivir phosphate for suspensions are safe and bioequivalent. | PMC9942619 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s40360-023-00646-1. | PMC9942619 | ||
Keywords | PMC9942619 | |||
Introduction | fever illness | RESPIRATORY DISEASE, VIRUS, INFLUENZA, INFLUENZA | Influenza, a contagious respiratory disease, which induced by the influenza virus that resulting in high morbidity and mortality worldwide. Outbreaks of influenza are usually earliest detected in children with fever illness [Currently, four classes of antiviral drugs are approved for influenza treatment in several countries, mainly including adamantane, neuraminidase inhibitors, membrane fusion inhibitors, and RNA-dependent RNA polymerase inhibitors [Oseltamivir carboxylate, which is a neuraminidase inhibitor (NAI), is produced by hydrolysis of oseltamivir through the ester bond and inhibits the isolation of mature influenza virus from host cells by inhibiting neuraminidase, thereby inhibiting virus transmission in humans [TAMIFLU® was jointly developed by Roche Registration Ltd and Gilead Sciences, Inc. The capsule was first approved for marketing by the FDA in October 1999, and the oral suspension was approved for marketing by the US FDA in December 2000. It has been marketed in many countries and regions around the world, and is recognized as one of the most effective drugs against influenza in the world. The purpose of this study was to assess the bioequivalence of oseltamivir phosphate for suspension (Hetero Labs Limited, 6 mg/ml after reconstitution, dose: 75 mg/12.5 mL) and TAMIFLU® (F. Hoffmann-La Roche AG, strength 6 mg/mL, dose: 75 mg/12.5 mL) in Healthy Chinese volunteers. | PMC9942619 |
Subjects and methods | PMC9942619 | |||
Study Design | This study was developed in healthy subjects in the fasting or postprandial state, using a single-dose, randomized, open-label, two-period, two-sequence, self-crossover design. It authorized by the Ethics Committee of the First Affiliated Hospital of Bengbu Medical College. The ethical approval process complies with the requirements of Good Clinical Practice (GCP), the Declaration of Helsinki and relevant Chinese laws and regulations. Registration number CTR20200764 at 26-Apr-2020. According to "the Guiding Principles for Human Bioavailability and Bioequivalence test of Pharmaceutical Preparations (2015 Edition)", "the Guiding Principles for Human Bioequivalence Research of Chemical Drug Imitations with Pharmacokinetic Parameters as the End Point Evaluation Indicators", and recommended dose in Tamiflu® instructions, the single oral dose of 75 mg/12.5 mL was determined for the reference preparation and test preparation of this study. According to the data in the relevant literature [ | PMC9942619 | ||
Study participants | depression, psychiatric, epilepsy | DISEASES, GENETIC DISEASE, EPILEPSY | Subjects participating in the study: all aged between 18 and 65 years old (including the boundary values), with an appropriate gender ratio of males and females; men and women need to meet the standard weight of not less than 50 kg and 45 kg respectively, as well body mass index (BMI) ranged from 19.0–26.0 kg/mSubjects with the following situations need to be excluded: women who are breastfeeding, or subjects and their partners who are planning to become pregnant or donating sperm or eggs, unwilling or unable to voluntarily use effective contraception from the screening date to 6 months after the end of the trial; or subjects with history of psychiatric or neurological related diseases such as epilepsy or depression or family history of genetic diseases; or subjects taking any drugs or food supplements or herbal medicines within 14 days before screening or not longer than their 5 times half-life. | PMC9942619 |
Assessment and analysis | PMC9942619 | |||
Pharmacokinetics | Pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate were calculated using Phoenix WinNonlin (Pharsight Corporation, 8.3.1) based on individual blood concentrations and sampling time (calculated by actual sampling time) using non-compartmental analysis (NCA), C | PMC9942619 | ||
Safety | ADVERSE EVENTS, ADVERSE EVENT | Adverse events (AEs), serious adverse events (SAEs), concomitant medications, clinical laboratory tests, vital signs, 12-lead electrocardiogram and physical examination were recorded. | PMC9942619 | |
Results | PMC9942619 | |||
Participants characteristics and baseline | vomiting | ADVERSE EVENT | A total of 205 subjects were screened, of which 125 failed in screening for not meeting the inclusion criteria/for meeting exclusion criteria. Among the 80 qualified subjects, there were 40 in the fasting group and 40 in the fed group. In the fed trial, 2 subjects withdrew early. Among them, Subject S107 (C001) voluntarily withdrew early from the trial during the washout period after completing the first period of blood sample collection; and subject S152 (C021) voluntarily withdrew early from the trial 4.5 h after the first period of dosing. In the fasting trial, one subject voluntarily withdrew early. Subject S082 (K033) withdrew early from the trial due to an adverse event of severe vomiting with high volume, which occurred 1.75 h after the second period of dosing. The baseline characteristics of the subjects are shown in Table Summary of demography and its baseline characteristicsData are Mean ± SD | PMC9942619 |
Pharmacokinetics | The mean oseltamivir and oseltamivir carboxylate in the fasting and fed groups had similar plasma concentration–time profiles (Figs. Mean (mean ± SD) plasma concentration vs. time profiles of oseltamivir and oseltamivir carboxylic under fasting conditions (pharmacokinetic concentration sets). Mean (mean ± SD) plasma concentration vs. time profiles of oseltamivir and oseltamivir carboxylic underfed conditions (pharmacokinetic concentration sets). The pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate in fasting or fed administration subjects included in the pharmacokinetic parameter analysis are shown in Table Statistical results of pharmacokinetic parameters of oseltamivirTStatistical results of pharmacokinetic parameters of oseltamivir carboxylateTAll were within the range of 80.00–125.00%, and the conclusion of bioequivalence was established (Additional file Statistical results of fasting oseltamivir pharmacokinetic parameters—sensitivity analysisC(ng/mL)AUC(h*ng/mL)AUC(h*ng/mL)CV (%) Intraindividual variation, Coefficient of variation, C | PMC9942619 | ||
Safety | nausea, Gastrointestinal adverse, gastrointestinal adverse, treatment-emergent adverse, TEAEs, vomiting, blood and coagulation | ADVERSE EVENTS, ADVERSE EVENT, EVENT | Among the 40 subjects in the fed trial, a total of 9 subjects reported 14 adverse events, all of which were TEAEs, including elevated blood triglycerides, positive bacterial test (urine), positive urinary leukocyte esterase, urine sediment detection, abnormal urinalysis, elevated gamma-glutamyl transferase, elevated alanine aminotransferase, increased human chorionic gonadotropin, abnormal electrocardiogram QRS wave complex, and nausea. Of which 3 cases in 3 subjects were grade 2 in severity and the rest were grade 1 in severity. Adverse events of severity grade 2 are mainly elevated blood triglycerides. Vital signs and physical examination were all normal and no clinically significant. For the 12-lead ECG, 1 subject showed abnormalities with clinical significance; for laboratory tests, 4 subjects showed abnormalities with clinical significance after taking the drug for blood biochemistry tests, 3 subjects showed abnormalities with clinical significance after taking the drug for routine urine tests, 1 subject showed abnormalities with clinical significance after taking the drug for blood pregnancy tests, and no abnormalities with clinical significance after taking the drug for routine blood and coagulation tests. There were no abnormalities and clinically significant blood tests. Of the 27 cases of TEAEs in this trial, 14 were cured, 12 had an unknown outcome, 1 had a persistent outcome, and there were no serious adverse events (Additional file Subject with a positive pregnancy test (screening number S117, random number: C004), who had normal pregnancy test during the screening period and two-period enrollment examination, was suspected to be pregnant based on human chorionic gonadotropin (β-HCG) of 435.62 IU/L during the second-period exit examination on July 01, 2020, and was asked whether sexual intercourse has occurred, the subject explained that she once had sexual intercourse and took contraception before enrollment. The β-HCG doubled two days later and pregnancy was highly suspected. Pregnancy was confirmed by gynecological color Doppler ultrasonography, and the pregnancy event was reported and followed up. On March 12, 2021, the subject delivered a female infant at 39-week gestation, and the newborn was born naturally in good condition with an Apgar score of 10.The more frequently reported adverse events after subjects took the test product and the reference product, ranked by system organ classification (SOC), were mainly elevated blood triglycerides in various tests, positive bacterial tests and positive urinary leukocyte esterase. The main gastrointestinal adverse event was nausea (Additional file Among the 40 subjects in the fasting trial, a total of 9 subjects reported 13 adverse events, all of which were treatment-emergent adverse events (TEAEs), this includes elevated C-reactive protein, decreased mean cell volume, elevated neutrophil count, nausea, and, as in the postprandial group, also elevated blood triglycerides, abnormal urinalysis, and vomiting. Of which 3 cases in 3 subjects were grade 2 in severity and the rest were grade 1 in severity. Vital signs, physical examination, and 12-lead electrocardiogram were all normal and no clinically significant; in terms of laboratory tests, after medication, 6 subjects showed abnormal and clinically significant blood biochemical tests, 2 subjects showed abnormal and clinically significant routine blood tests, 2 subjects showed abnormal and clinically significant routine urine tests, and pregnancy tests and coagulation tests were normal and clinically significant. Of the 13 cases of TEAEs in this trial, 8 were cured, 5 had an unknown outcome, and there were no serious adverse events (Additional file The more frequently reported adverse events after subjects took the test product and the reference product, ranked by SOC, were mainly elevated blood triglycerides in various tests, abnormal urinalysis, and elevated alanine aminotransferase. Gastrointestinal adverse events included vomiting and nausea (Additional file | PMC9942619 |
Discussion | nausea, cardiac arrhythmias, critically ill, ®, diarrhea, abdominal pain, confusion, epilepsy, allergy, vomiting, dizziness, hepatitis, insomnia, headache, erythema multiforme, rhinorrhagia | ADVERSE REACTIONS, CARDIAC ARRHYTHMIAS, CRITICALLY ILL, EPILEPSY, GASTROINTESTINAL BLEEDING, ALLERGY, INFLUENZA PNEUMONIA, TOXIC EPIDERMAL NECROLYSIS, INFLUENZA A, CONJUNCTIVITIS, ERYTHEMA MULTIFORME, EVENTS, HEPATITIS | Oseltamivir phosphate, an antiviral drug, which used in the treatment of influenza A and B, and early treatment with oseltamivir was associated with a significant 33% reduction in ICU mortality compared with late treatment. It may be related to enhanced survival in critically ill patients with influenza pneumonia, at the same time, it may decrease the ICU length of stay and duration of mechanical ventilation [In this study, the oseltamivir phosphate for suspension produced by Hetero Labs Limited was compared with the originator TAMIFLU® to evaluate the absorption rate and degree of absorption in healthy humans, and to investigate the human bioequivalence of the two drugs. The difference between the test product and the reference product TAMIFLU® under fasting and fed conditions in the pharmacokinetic parameters between was not significant, which was similar to the results of previous studies [This study confirmed the interchangeability of the test product and TAMIFLU® by verifying their bioequivalence, and that food intake did not affect the pharmacokinetics and bioequivalence of the two products. For patients, it is possible to achieve the same therapeutic effect by choosing a drug with a relatively good price.In terms of adverse reactions, the most common side effects of oseltamivir phosphate were nausea (incidence 10%), vomiting (2–15%), abdominal pain, diarrhea, headache, insomnia and dizziness. Other side effects included conjunctivitis, rhinorrhagia, allergy, cardiac arrhythmias, gastrointestinal bleeding, erythema multiforme, toxic epidermal necrolysis, confusion, hepatitis, epilepsy, and neuropsychiatric events, but the incidence was < 1%. Oseltamivir is generally well tolerated [The limitation of this study is as follows, the study is a bioequivalence trial in healthy Chinese subjects, the pharmacokinetic parameter data express the absorption distribution and elimination in Chinese subjects, and the bioequivalence in other races has not been evaluated yet, so it is not known whether there are differences between different races, which will be further verified in later trials. | PMC9942619 |
Conclusions | ® | This study showed that oseltamivir phosphate for suspension (6 mg/ml after reconstitution, 75 mg/12.5 ml) and TAMIFLU® (6 mg/mL, 75 mg/12.5 ml) met bioequivalence criteria in the matter of the absorption rate and the degree of absorption of oseltamivir phosphate and oseltamivir carboxylate, and had good safety. Food had no effect on the pharmacokinetics and bioequivalence of oseltamivir phosphate for suspension and TAMIFLU® in healthy subjects. | PMC9942619 | |
Acknowledgements | Thanks to all the nurses of the Clinical Research Center of the First Affiliated Hospital of Bengbu Medical College for their contributions in blood collection and subject care. | PMC9942619 | ||
Author contributions | HZ designed and implemented the study. YW, JX, XQW, BZT, PR, GMW, collected and processed the trial data. CXH, MHZ, LF, QG, YS pretreatment of blood samples. JZ, RFS were responsible for the quality control of the study. JXD, YYX, wrote the article. BYL, YZD provided valuable comments on the analysis and writing of the article. The authors read and approved the final manuscript. | PMC9942619 | ||
Funding | This study was supported by the 512 Talent Cultivation Program of Bengbu Medical College [by51201313]. | PMC9942619 | ||
Availability of data and materials | A signed confidential document, dataset generated and/or analyzed during the current study is not publicly available, but can be obtained directly from the author upon reasonable request. To obtain data for this study, please contact Ms. Ying Wang or Mr. Bangzhong Tang. | PMC9942619 | ||
Declarations | PMC9942619 | |||
Ethics approval and consent to participate | This research was approved by the Ethics Committee of the First Affiliated Hospital of Bengbu Medical College. The ethical approval process complies with the requirements of Good Clinical Practice (GCP), the Declaration of Helsinki and relevant Chinese laws and regulations. All volunteers signed informed consent when participating in the study. The trial has been registered on the Drug Clinical Trial Registration and Information Publicity Platform. Registration number CTR20200764 at 26-Apr-2020. | PMC9942619 | ||
Consent for publication | Not applicable. | PMC9942619 | ||
Competing interests | All authors declare that they have no conflicts of interest. | PMC9942619 | ||
References | PMC9942619 | |||
Methods | This is a pilot study in which 36 consecutive patients undergoing living-donor kidney transplantation were randomly assigned to receive either 4.5 mg/kg (n = 19) or 6.0 mg/kg (n = 17) of ATG; all patients had corticosteroid withdrawal within 7 days. The primary end point was a composite of biopsy-proven acute rejection, | PMC9976999 | ||
Results | At 12 months post-transplant, biopsy-proven acute rejection was more common in the ATG4.5 group (21.1%) than in the ATG6.0 group (0%)( | PMC9976999 | ||
Conclusions | Compared with ATG 6.0 mg/kg, ATG 4.5 mg/kg with early corticosteroid withdrawal and low dose maintenance regimen was associated with higher rates of acute rejection in non-sensitized Asian living-donor kidney recipients. | PMC9976999 | ||
Trial registration | ClinicalTrials.gov: | PMC9976999 | ||
Data Availability | All relevant data are within the paper and its | PMC9976999 | ||
Introduction | T-cell depletion | ADHESION | In recent decades, rabbit anti-thymocyte globulin (ATG) was the most commonly used induction agent for kidney transplantation worldwide. ATG was found to induce T-cell depletion and modulate cell surface molecules and adhesion molecules that regulate T-cell function and leukocyte-endothelial interaction, respectively [Several studies have reported the dose optimization of ATG as induction therapy in kidney transplantation [The aim of this study was to compare the efficacies of 4.5 mg/kg ATG and 6.0 mg/kg ATG in non-sensitized living-donor kidney recipients with early steroid withdrawal in an Asian population, and to investigate the immunologic profiles thereof during follow-up. | PMC9976999 |
Research design and methods | PMC9976999 | |||
Study design, patient selection, and randomization | EVENTS | The study design was an a prospective, open-label, randomized, non-blinded, non-inferiority pilot study in which 36 consecutive adult patients undergoing living-donor kidney transplantation were randomly assigned to receive either 4.5 mg/kg (n = 19) or 6.0 mg/kg (n = 17) of ATG at Asan Medical Center (Seoul, South Korea); the enrollment of patients was initiated in January 2016. The data safety monitoring board at our center ceased the trial in September 2017, which was due to the more frequently observed composite events of biopsy-proven acute rejection (BPAR) and All patients were randomly assigned in a computer-generated 1:1 variable-block randomization performed by a study coordinator at our center to receive ATG (Thymoglobuline | PMC9976999 | |
Induction and maintenance immunosuppression and prophylaxis against infection | thrombocytopenia, neutropenia | THROMBOCYTOPENIA, NEUTROPENIA | Before the administration of ATG (1.5 mg/kg/day intravenously), chlorpheniramine and acetaminophen were given intravenously as a premedication. The dose of ATG was reduced by 50% in patients with thrombocytopenia (platelet count 50,000–75,000 per cubic millimeter) or neutropenia (absolute neutrophil count 2000–3000 per cubic millimeter). ATG was discontinued when the patiet developed severe thrombocytopenia (platelet count < 50,000 per cubic millimeter) or severe neutropenia (absolute neutrophil count < 2000 per cubic millimeter).The maintenance immunosuppressants consisted of tacrolimus, mycophenolate mofetil, and seven-day methylprednisolone taper. Tacrolimus was initiated two days before kidney transplantation at a dose of 0.05 mg/kg twice a day, and the target trough level was 6–8ng/ml until one year post-transplant. Mycophenolate mofetil was given 750 mg twice a day in both groups. Methylprednisolone was administered at a dose of 500 mg intravenously on day 0, 250 mg on day 1, and 125 mg on day 2 and 3. Thereafter, a fast taper was carried out with oral prednisone in the first week post-transplant.All recipients received oral doses of trimethoprim 80 mg-sulfamethoxazole 400 mg daily for six months for bacterial and | PMC9976999 |
HLA antibody testing and HLA typing | ® | HLA antibody testing and HLA typing were performed before transplantation. Specificities of antibodies were reported by LABScreen® Single Antigen Class I and Class II assay (One Lambda Inc., Canoga Park, CA). Single antigen beads were used to test for antibodies against HLA-A, -B, -C, -DRB1, -DRB3, -4 and -5, and -DQB1. Using BioSewoom™, typing of low-to-medium resolution HLA-A, -B, -C and DR was done. PCR/SSP kit (BioSewoom Inc., Seoul, Korea) and high resolution HLA-DQB1 typing was performed by AVITA™ plus HLA-DQB1 SBT kits (BioWithus Inc., Seoul, Korea).After transplantation, LABScreen® Single Antigen Class I and Class II assay was performed every one or two months and when there was an acute deterioration of renal function. | PMC9976999 | |
Peripheral blood mononuclear cells (PBMC) isolation and flow cytometry and data analysis | REA110 | STERILE | We acquired blood samples from the recipients at two days before transplantation, one-week post-transplant, and one, three, and six months post-transplant. PBMCs were separated by density-gradient centrifugation using lymphocyte isolation sterile solution Ficoll-PaqueIn flow cytometry analysis, subsets of natural killer (NK) cells were stained with the following antibodies: PE-conjugated anti-CD56 antibody (5.1H11, IgG1κ, BioLegend), FITC-conjugated anti-CD3 antibody (UCHT1, IgG1κ, BioLegend), PerCP/Cy5.5-conjugated anti-CD57 antibody (HNK1, IgM, BioLegend), PE/Cy7-conjugated anti-NKG2D (CD159c) antibody (1D11, IgG1κ, BioLegend), APC-conjugated anti-NKG2A (CD159a) antibody (REA110, IgG1κ, Miltenyi Biotec), and APC/Cy7-conjugated anti-CD16 antibody (B73.1, IgG1κ, BioLegend). Lymphocytes that were CD3 | PMC9976999 |
End points | The primary efficacy end point was a composite of BPAR, | PMC9976999 | ||
Statistical analysis and data availability | Mann-Whitney U test was used to compare continuous variables between the two groups. Categorical variables were compared using the chi-squared test. Survival rates related to the composite outcomes were calculated using the Kaplan-Meier method and compared using the log-rank test. A linear mixed model was applied to analyze the difference in the pattern of time-dependent change according to the dose of ATG. Time was entered as a categorical fixed-effects variable and the patient identity as a random effect. We first analysed the effect of time on expression of each immune cell separately. Thereafter we constructed a model to look at the effect of the dose of ATG on expression of each immune cell, taking time into account. All covariates for models were chosen For the primary endpoint, it is judged whether the upper limit of the 90% two-sided confidence interval for the difference between the two groups exceeds the non-inferiority margin (10%). In addition, a one-sided Z test for non-inferiority was performed. | PMC9976999 | ||
Results | PMC9976999 | |||
Characteristics of the enrolled patients | A total of 478 patients were screened for potential enrollment in this study. Among the 478 recipients, 394 were excluded due to age≤18 or ≥70 (n = 9), ABO incompatible KT (n = 117), HLA incompatible KT (n = 31), re-transplantation (n = 7), pre-transplant DSA (n = 94), HLA identical donor (n = 28), panel reactive antibody>20% (n = 108), and declination to participate (n = 48) ( | PMC9976999 | ||
Flow diagram of enrollment, randomization, follow-up, and analysis. | ATG, anti-thymocyte globulin; KT, kidney transplantation. | PMC9976999 | ||
Baseline characteristics according to the dosage of antithymocyte globulin. | ESRD | END-STAGE RENAL DISEASE, ESRD | IQR, Interquartile range; ESRD, end-stage renal disease. | PMC9976999 |
Efficacy end points | At 12 months post-transplant, BPAR was more common in the ATG4.5 group (21.1%) than in the ATG6.0 group (0%)(log-rank test, | PMC9976999 | ||
Efficacy end points. | Kaplan-Meier curves for BPAR (A) and a composite end point of BPAR, | PMC9976999 | ||
Adverse events | ADVERSE EVENTS | There were no significant differences in adverse events between the two groups ( | PMC9976999 | |
Adverse outcomes according to the dosage of anti-thymocyte globulin. | PMC9976999 | |||
Histopathologic characteristics | During the follow-up period, six patients in the ATG4.5 group and three patients in the ATG6.0 group underwent a for-cause biopsy ( | PMC9976999 | ||
Comparison of histopathologic characteristics according to the dosage of anti-thymocyte globulin. | tubular atrophy, ABMR, SD | ANTIBODY-MEDIATED REJECTION, INTERSTITIAL FIBROSIS | NR, no rejection; TCMR, T-cell-mediated rejection; ABMR, antibody-mediated rejection; IFTA, interstitial fibrosis and tubular atrophy; SD, standard deviation. | PMC9976999 |
Comparison of reconstitution of peripheral lymphocytes and monocytes | At pre-transplantation, the two groups did not show significant differences in the proportions of lymphocytes and monocytes among PBMCs and the proportions of T, B, NK, and NKT cells among lymphocytes ( | PMC9976999 | ||
Changes in the proportions of immune cell populations. | Total lymphocytes (A), T cells (B), B cells (C), NK cells (D), NKT cells (E), and monocytes (F) during follow-up after kidney transplantation are shown according to the dosage of ATG.We performed flow cytometry analysis to identify the specific subsets of lymphocytes and monocytes that are differentially expressed according to the dosage of ATG. The linear mixed model revealed that the proportion of NKG2D | PMC9976999 | ||
Proportion of NKG2D | ATG, anti-thymocyte globulin. | PMC9976999 | ||
Proportion of CD25 | ATG, anti-thymocyte globulin. | PMC9976999 | ||
Proportion of CD25 | ATG, anti-thymocyte globulin. | PMC9976999 | ||
Discussion | EVENTS | Our study results showed that compared with kidney transplant recipients who received ATG 6.0 mg/kg as an induction regimen with early steroid withdrawal, those who received ATG 4.5 mg/kg were more likely to show composite outcomes of biopsy-proven acute rejection, The dose of ATG ranged from 5.4 to 10 mg/kg in previous randomized trials that compared ATG with IL-2 receptor antagonist as an induction regimen in kidney transplant recipients [Our results are in line with those of previous reports that the degree of T cell depletion and reconstitution did not significantly differ according to ATG dosage [The following limitations of our study should be addressed. First, this study was ceased earlier than expected due to concerns regarding the observed risks of the composite outcome in the ATG4.5 group; also, the number of enrolled patients was less than the designated sample size. This limitation stands out because the study cohort were low risk live donor transplants in which the targeted events would be predictably low frequency compared to higher immunological risk or deceased donor subjects. Therefore, our results fall short of being able to draw confirmative conclusions. Second, only for-cause biopsies were performed in this study. To exclude subclinical rejection, it would be better if a protocol biopsy was performed. Third, the occurrence of early composite outcomes might have affected the reconstitution of immune cells because physicians often re-used steroids when patients developed the composite outcomes. Fourth, the trough level of tacrolimus and the MMF dose were relatively low which could have contributed to a higher rate of composite outcomes in the ATG4.5 group. Fifth, we could not find significant differences in the proportion of specific immune cells at each time between the groups which may be due to the small number of PBMC samples.In conclusion, we compared ATG 4.5 mg/kg regimen with ATG 6.0 mg/kg as an induction regimen in non-sensitized Asian recipients undergoing kidney transplantation from living donors, and found that ATG 4.5 mg/kg and early corticosteroid withdrawal in association with a low dose maintenance regimen resulted in higher rates of biopsy-proven acute rejection and | PMC9976999 | |
Supporting information | PMC9976999 | |||
Raw data of this study (SPSS). | (SAV)Click here for additional data file. | PMC9976999 | ||
Raw data of this study (EXCEL). | (XLS)Click here for additional data file. | PMC9976999 | ||
CONSORT checklist. | (DOC)Click here for additional data file. | PMC9976999 | ||
The study protocol (Korean version). | (DOCX)Click here for additional data file. | PMC9976999 | ||
Informed consent for clinical research (for living donors). | (DOCX)Click here for additional data file. | PMC9976999 | ||
Comparison of estimated GFR after kidney transplantation according to the dosage of ATG. | ATG, anti-thymocyte globulin; GFR, glomerular filtration rate.(TIF)Click here for additional data file. | PMC9976999 | ||
Gating strategy using single color compensation controls. | (PDF)Click here for additional data file. | PMC9976999 | ||
The study protocol (English version). | (DOCX)Click here for additional data file.We do not have any declaration relating to employment, consultancy, patents, products in development, and marketed products. We thank Dr. Joon Seo Lim from the Scientific Publications Team at Asan Medical Center for his editorial assistance in preparing this manuscript. | PMC9976999 | ||
References | PMC9976999 | |||
Background | PsA, psoriatic arthritis, PsA., enthesitis | DISEASE, PSORIATIC ARTHRITIS, ENTHESITIS | Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post hoc analysis assessed tofacitinib efficacy on enthesitis by baseline location and severity, and impact on disease activity and patient-reported outcomes (PROs), in patients with PsA. | PMC10464128 |
Methods | PsA, Spondyloarthritis, enthesitis | ENTHESITIS, SPONDYLOARTHRITIS, ENTHESITIS | Data were pooled from two phase 3 studies (NCT01877668/NCT01882439) in patients with PsA receiving tofacitinib 5 or 10 mg twice daily to month (M)6 or placebo to M3. Endpoints were: change from baseline in Leeds Enthesitis Index (LEI) or Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC); proportions of patients with enthesitis, relapsed enthesitis after resolution, de novo enthesitis | PMC10464128 |
Results | arthritis pain, enthesitis | ENTHESITIS, HAND ARTHRITIS, ENTHESITIS | Seven hundred ten patients from two studies were included: 479 had LEI > 0; 545 had SPARCC > 0; and 136 had LEI = 0 and SPARCC = 0 at baseline. At baseline, among patients with LEI > 0 or SPARCC > 0, mean LEI and SPARCC across treatments and enthesitis locations/severities ranged from 1.0–4.4 and 1.3–9.4, respectively. Across several baseline enthesitis locations/severities, changes from baseline in LEI and SPARCC up to M3 were greater with tofacitinib (-2.0–0.4 and -3.5–0.2) vs placebo (-0.9–0.4 and -1.5–1.1). Enthesitis at M6 was more common in patients with greater baseline enthesitis severity. At M6, ≤ 40% of patients with baseline LEI > 0 or SPARCC > 0 whose enthesitis had resolved by M1/M3 experienced a relapse, and < 14% of patients with baseline LEI = 0 and SPARCC = 0 had de novo enthesitis. LDA/remission rates generally increased with tofacitinib over time. Baseline LEI location was significantly associated with change from baseline in arthritis pain score, while baseline SPARCC severity was significantly associated with change from baseline in FACIT-F total and arthritis pain scores. | PMC10464128 |
Conclusion | PsA, enthesitis | ENTHESITIS | Tofacitinib treatment resulted in improvements in enthesitis in patients with PsA, regardless of baseline location or severity. | PMC10464128 |
Trial registration | NCT01877668;NCT01882439. | PMC10464128 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13075-023-03108-5. | PMC10464128 | ||
Keywords | PMC10464128 | |||
Background | PsA, musculoskeletal and dermatologic manifestations, Psoriatic arthritis, PsA., PsA disease, enthesitis | PSORIATIC ARTHRITIS, ENTHESITIS, CHRONIC INFLAMMATORY DISEASE | Psoriatic arthritis (PsA) is a chronic inflammatory disease with musculoskeletal and dermatologic manifestations [Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Efficacy and safety of tofacitinib 5 mg twice daily (BID; recommended dosage) [In this post hoc analysis, the effects of tofacitinib on enthesitis, its impact on PsA disease activity, and patient-reported outcomes (PROs) in patients with vs without enthesitis at baseline, were further evaluated. Development of de novo enthesitis was also investigated. | PMC10464128 |
Patients and methods | PMC10464128 | |||
Study design | PsA, tumor necrosis | TUMOR NECROSIS | This post hoc analysis included pooled data from two phase 3 studies of tofacitinib for the treatment of active PsA: OPAL Broaden (NCT01877668) [OPAL Broaden was a 12-month study of tofacitinib in tumor necrosis factor inhibitor (TNFi)-naïve patients with an inadequate response to a conventional synthetic disease-modifying antirheumatic drug (csDMARD). Patients received tofacitinib 5 or 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks, or placebo (advancing to tofacitinib 5 or 10 mg BID at month 3) [This post hoc analysis included patients receiving tofacitinib 5 or 10 mg BID to month 6, or placebo to month 3.Both studies were conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. The study protocols were reviewed and approved by the Institutional Review Boards and/or an Independent Ethics Committee at each study center, and all patients provided written, informed consent. | PMC10464128 |
Assessment | Chronic Illness, fatigue, Spondyloarthritis, Psoriatic Arthritis, low disease activity, criteria)/very low disease, enthesitis | ENTHESITIS, CHRONIC ILLNESS, DISEASE, REMISSION, SPONDYLOARTHRITIS, PSORIATIC ARTHRITIS, DISEASE, ENTHESITIS | In OPAL Broaden and Beyond, presence of enthesitis in patients was determined at baseline, and at months 1, 3, and 6, by a blinded, qualified assessor using the Leeds Enthesitis Index (LEI) [Enthesitis sites evaluated by LEI or SPARCC. LEI, Leeds Enthesitis Index; SPARCC, Spondyloarthritis Research Consortium of Canada Enthesitis Index. Adapted from Mease PJ, et al. J Rheumatol. 2017;44:599–608. Reproduced with permissionPatients were categorized based on the presence (LEI > 0 or SPARCC > 0) or absence (LEI = 0 and SPARCC = 0) of enthesitis at baseline. Patients with enthesitis were further stratified by enthesitis location and severity at baseline. Enthesitis location was determined as the individual sites assessed for LEI (Fig. Data at baseline and months 1, 3, and 6, from OPAL Broaden and Beyond, were included in this analysis. Individual patient-level data across the two studies were pooled, and data-handling conventions that were utilized in each study, including the handling of missing data, were also applied across the pooled data.The following endpoints were assessed in patients with LEI > 0 or SPARCC > 0 at baseline: change from baseline in LEI or SPARCC, and the proportions of patients with enthesitis or with relapsed enthesitis (assessed at months 3 and 6 only) after resolution at months 1 or 3. The development of de novo enthesitis in patients with LEI = 0 and SPARCC = 0 at baseline was also assessed.Disease activity measures assessed were: the proportion of patients achieving low disease activity (LDA) and remission, based on minimal disease activity (MDA; ≥ 5/7 criteria)/very low disease activity (7/7 MDA criteria), Psoriatic Arthritis Disease Activity Score (PASDAS; > 1.9– < 3.2/ ≤ 1.9 [near remission]), Disease Activity Index for Psoriatic Arthritis (DAPSA; > 4– ≤ 14/ ≤ 4), and Composite Psoriatic Disease Activity in Psoriatic Arthritis (CPDAI; > 2– ≤ 4/ ≤ 2). Detailed descriptions of the disease activity measures are presented in Supplementary Table 1 (see Additional file PROs included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score (range 0–52; higher scores indicate less fatigue) [ | PMC10464128 |
Statistical analyses | femoral condyle, enthesitis | REGRESSION, HAND ARTHRITIS, DISEASE CHARACTERISTIC, ENTHESITIS | Demographics and baseline disease characteristics were reported for patients who received ≥ 1 dose of study treatment. Descriptive statistics were generated for each endpoint by visit and treatment arm. Binary endpoints were analyzed using Cochran-Mantel–Haenszel statistics, with non-responder imputation for missing values. The 95% confidence intervals (CIs) were derived based on normal approximation. When compared with placebo, tofacitinib responses were defined as “greater,” “lower,” or “higher” if the corresponding 95% CIs did not overlap.Multivariate linear regression analyses based on backward selection criteria were conducted to determine the effects of baseline enthesitis location and severity on change from baseline in FACIT-F total score and arthritis pain (VAS) at months 3 and 6. Baseline covariates included were: the respective PRO being assessed; enthesitis in LEI locations (lateral epicondyle humerus [yes/no], medial femoral condyle [yes/no], Achilles tendon insertion [yes/no]); enthesitis severity based on LEI (0 vs 1, 2, or 3–6 affected sites); enthesitis in SPARCC locations (upper sites only [yes/no], lower sites only [yes/no], both upper and lower sites [yes/no]); and enthesitis severity based on SPARCC (0 vs 1–2, > 2– ≤ 5, or > 5 affected sites). In the pooled tofacitinib analysis, a variable for dose group (tofacitinib 5 mg BID vs 10 mg BID) was included in the model as a covariate. Statistical significance was defined as | PMC10464128 |
Results | PMC10464128 | |||
Improvements in patients with enthesitis at baseline | enthesitis | ENTHESITIS | Compared with placebo, improvements from baseline in LEI scores were greater with tofacitinib 10 mg BID at month 3 in patients with enthesitis at the lateral epicondyle humerus or medial femoral condyle, and greater with tofacitinib 5 mg BID in patients with 3–6 affected LEI sites at baseline (Fig. Change from baseline in LEI/SPARCC (patients with LEI > 0/SPARCC > 0 at baseline). *Indicates a comparison where the 95% CI for tofacitinib does not overlap with the 95% CI for placebo. | PMC10464128 |
Trajectory of enthesitis over time in patients with enthesitis at baseline | tofacitinib-treated, enthesitis | ENTHESITIS, ENTHESITIS | Regardless of baseline location or severity, the proportion of patients with enthesitis (LEI > 0 or SPARCC > 0) generally decreased over time with tofacitinib treatment (Fig. Enthesitis presences/relapse of resolved enthesitis (patients with LEI > 0/SPARCC > 0 at baseline). *Indicates a comparison where the 95% CI for tofacitinib does not overlap with the 95% CI for placebo. At month 6, the proportions of tofacitinib-treated patients with enthesitis assessed by LEI were reduced by 40–50% across baseline locations (Fig. For patients with LEI > 0 at baseline whose enthesitis had resolved (LEI = 0) at month 1, 26.3%, 15.6%, and 30.8% of patients treated with tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo, respectively, had relapsed at month 3 (Fig. At month 3, for patients with SPARCC > 0 at baseline who had resolved enthesitis (SPARCC = 0) at month 1, 45.5%, 17.4%, and 41.2% of patients treated with tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo, respectively, had relapsed (Fig. | PMC10464128 |
De novo enthesitis in patients without enthesitis at baseline | enthesitis | ENTHESITIS | For patients without enthesitis (LEI = 0 and SPARCC = 0) at baseline, ≤ 6.4% and ≤ 15.6% of patients receiving tofacitinib or placebo developed enthesitis across locations (LEI and SPARCC) at months 1 and 3, respectively (Fig. De novo enthesitis development (patients with LEI = 0 and SPARCC = 0 at baseline). The dashed line indicates < 14% of patients without enthesitis (LEI = 0 and SPARCC = 0) at baseline with enthesitis at month 6. At months 1 and 3, the proportions of patients without enthesitis at baseline who developed de novo enthesitis were similar with tofacitinib and placebo, regardless of enthesitis location (LEI and SPARCC; Fig. | PMC10464128 |
Disease activity in patients with or without enthesitis at baseline | tofacitinib-treated, enthesitis | REMISSION, ENTHESITIS | Overall, regardless of baseline enthesitis location or severity, the proportion of tofacitinib-treated patients with enthesitis (LEI > 0 or SPARCC > 0) at baseline who achieved LDA or remission increased over time, though there were some fluctuations from months 1 to 6 (Supplementary Figs. 1, 2 [see Additional file Among patients with LEI > 0 at baseline, at month 3, MDA (≥ 5/7 criteria) rates were greater with tofacitinib vs placebo in patients with enthesitis at the lateral epicondyle humerus (5 mg BID only) and medial femoral condyle at baseline (both 5 and 10 mg BID; Supplementary Fig. 1a [see Additional file Among patients with SPARCC > 0 at baseline, at month 1, the proportion of patients who achieved MDA was greater with tofacitinib 10 mg BID vs placebo in patients with enthesitis at the lower sites only at baseline; at month 3, a greater proportion of patients with enthesitis at the upper and lower sites at baseline achieved MDA with tofacitinib 5 mg BID vs placebo (Supplementary Fig. 2a [see Additional file Across baseline enthesitis severity (LEI or SPARCC), some differences in MDA (≥ 5/7 criteria) or PASDAS/DAPSA LDA (> 1.9– < 3.2/ > 4– ≤ 14, respectively) rates between patients treated with tofacitinib vs placebo were observed at months 1 and 3 (Supplementary Fig. 1a–c, 2a–c [see Additional file Through month 3, remission rates were similar in patients with enthesitis at baseline treated with tofacitinib and placebo, except CPDAI remission (≤ 2) rates were higher at month 3 in patients with 2 affected LEI sites or ≥ 2– > 5 affected SPARCC sites at baseline who received tofacitinib 10 mg BID (Supplementary Figs. 1e–h, 2e–h [see Additional file The proportions of patients without enthesitis (LEI = 0 and SPARCC = 0) at baseline reporting LDA or remission were similar across treatments (Supplementary Fig. 3a–h [see Additional file | PMC10464128 |
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