Equivalence Margin Research Articles

Examining the Measurement Equivalence of Alzheimer Disease Research Centers' Neuropsychological Test Battery (Version 3) Between Singapore and US Samples.

Standardization of neuropsychological tests is crucial for consistency in cognitive assessment, as well as for validity and comparability of results across different populations. We examined the applicability and measurement equivalence of the Alzheimer Disease Research Centers' Neuropsychological Test Battery (version 3) (ADRC-NTB3) in Singapore. The ADRC-NTB3 was administered to 978 older persons with normal cognition in Singapore. To provide comparison between Singapore and US samples, a US sample with similar profile was retrieved from the National Alzheimer Coordinating Center (NACC) database. Scores were compared with 1853 participants with similar profile from the United States. Score-difference between the populations was computed using multiple linear regression (adjusted for covariates), with equivalent score considered present when 90% CI of the score-difference fell within the predefined margin of equivalence. Tasks assessing for memory, processing speed, and executive functioning showed equivalence in scores between US and Singapore samples (adjusted-score difference=-0.94 to 0.09). Singapore sample performed marginally better on the visuospatial task (adjusted-score difference=0.50), but poorer on the language task (adjusted-score difference=-3.22). Nonequivalence of visuospatial and language tasks, which may increase potential misinterpretation of cognitive profiles and misdiagnosis, are related to educational and cultural differences. This highlights the need for different normative data for more accurate diagnostic accuracy as well as research priorities.

Comparison between local-made and imported porous polyethylene orbital implant: a randomized controlled equivalence trial and multicenter study.

To compare the exposure rate, infection rate, percentage of enhancement, and success rate between Medpor and the three-dimensional printed polyethylene (3DP-PE) orbital implant in a preliminary report. This prospective, randomized, equivalence, controlled trial was conducted at two institutes. The equivalent margin was ±10%. The sample size for the equivalence trial was 174 participants per group. Patients who were eligible for enucleations received either Medpor or 3DP-PE implants based on a randomized block of six. The surgeries were performed by five oculoplastic surgeons. The assessor and patients were masked. The magnetic resonance imaging (MRI) of the orbit was performed at least 6mo after operation and the fibrovascular ingrowth was analyzed using the Image J software. Follow-up continued at least 1y after surgery. The intention to treat and per protocol approaches were used. Totally 128 patients met the criteria in the report. Fifty Medpor and 55 3DP-PE cases completed the trial. The most common cause of blindness was trauma. The mean follow-up times of Medpor and 3DP-PE were 33 and 40mo respectively. The exposure rate was not statistically significant between two groups (6.0% and 7.3%), P<0.05, 95%CI (-9.8%, +12.0%). The success rates were 94% (Medpor) and 92.7% (3DP-PE). No postoperative infection was reported. Nine patients had MRI tests and two had implant exposures with 66.3% enhancement at 75mo (Medpor) and 58% enhancement at 57mo (3DP-PE) postoperatively. There is no statistically significant difference in exposure rate and success rate between Medpor and 3DP-PE in enucleation in the report. However, we cannot conclude that they are equivalent in terms of the exposure rate and success rate because the 95%CI is wider than ±10%. The infection rate is equivalent in both groups.

Pharmacokinetics and Safety of Intravenous Candidate Biosimilar CT-P47 and Reference Tocilizumab: A Randomized, Double-Blind, Phase 1 Study.

CT-P47 is a candidate biosimilar of tocilizumab. This 12-week, randomized, double-blind, parallel-design, phase 1 study aimed to demonstrate pharmacokinetic (PK) equivalence of CT-P47 and reference tocilizumab. Participants were healthy Japanese adults aged 18-55 years. Participants were randomized (1:1:1) to receive a single intravenous dose (8 mg/kg) of CT-P47, EU-approved tocilizumab (EU-tocilizumab), or US-licensed tocilizumab (US-tocilizumab). Primary PK endpoints were area under the concentration-time curve (AUC) from time zero to infinity, AUC from time zero to the last quantifiable concentration, and maximum serum concentration. Additional PK variables, safety, and immunogenicity were evaluated. The study was conducted from January 20 to May 26, 2023, in three centers in Japan. In total, 133 male participants were randomized (n = 45 to CT-P47, n = 44 to EU-tocilizumab, and n = 44 to US-tocilizumab). For all primary PK variables, 90% confidence intervals of the ratio of geometric least squares means were within the predefined equivalence margin of 0.80-1.25. Secondary PK variables were similar across groups. The most common treatment-emergent adverse event (TEAE) was neutrophil count decreased, occurring in 15 (33.3%), 13 (30.2%), and 12 (27.3%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively. There were no serious TEAEs, deaths, or study drug discontinuations due to TEAEs. Few participants were anti-drug antibody (ADA)- or neutralizing antibody (NAb)-positive. At the end of study, four (8.9%), one (2.3%), and two (4.5%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively, were ADA-positive; two (4.4%), zero (0%), and one (2.3%) in the respective groups were NAb-positive. CT-P47 demonstrated PK equivalence and comparable safety to EU- and US-tocilizumab.

Safety management within the scope of teaching practical clinical skills: framing errors for cardiopulmonary resuscitation training – a multi-arm randomized controlled equivalence trial

Introduction Cardiopulmonary resuscitation (CPR) is among the most important skills in clinical practice. Errors can happen here, just like everywhere, and potentially have severe consequences. Two common error handling strategies known from practice are Error Management (EM) and Error Avoidance (EA). However, its effects on medical performance outcomes remain unclear. This study aimed to examine the role of error framing in basic life support (BLS) training for future healthcare professionals. Materials and Methods In an equivalence trial (N = 430), first-year medical, dentistry, physiotherapy, and midwifery students underwent BLS training. In the three study arms, participants received either (1) instructions framing errors positively (EM), (2) instructions framing errors to be avoided (EA), or (3) no further instructions (Control). CPR performance was assessed using a resuscitation manikin measuring compression depth (CD) and compression rate (CR). The self-confidence ratings were assessed using a questionnaire. Equivalence margins for the outcome parameters and sample size calculations were based on previous standard BLS studies, using two-sided 95% confidence intervals to determine significance of equivalence. Results The results regarding CD revealed equivalence with a trend toward superiority of EM over EA (proportional difference 23.3%-points; 95% CI 11.4%–34.2%) and EM over control (proportional difference 23.4%-points; 95% CI 11.5%–34.2%.) and significant equivalence of EA and control (proportional difference 0.1%-points; 95% CI −11.6%–11.7%). Significant equivalence was determined for all study arms with respect to CR and self-confidence. Conclusion Our study revealed that EM was not detrimental to learners’ CPR performance. Given existing research on long-term beneficial effects of EM on patient safety, coupled with the proven equivalence of EM and EA concerning short-term performance, we argue that EM is a promising approach for future medical education purposes. Raising awareness of error framing and teaching error-handling strategies is expected to benefit ongoing safety management efforts in medical education and beyond.

Pharmacokinetic comparison of subcutaneously administered CT-P13 (biosimilar of infliximab) via autoinjector and pre-filled syringe in healthy participants.

CT-P13, a biosimilar of infliximab, is used to treat inflammatory diseases that arise from immune system complications, resulting in excessive and persistent inflammation. The subcutaneous (SC) formulation of CT-P13 overcomes the drawback of prolonged administration associated with the intravenous (IV) infliximab biosimilar, necessitating autoinjector (AI) administration. This randomized, open-label, two-arm, parallel-group, single-dose clinical pharmacology study aimed to evaluate the pharmacokinetics (PK) and safety of CT-P13 SC administration via AI compared with the existing pre-filled syringe (PFS) method. A total of 147 healthy participants were randomized into two groups, of which 139 completed the study. Blood samples were collected from before CT-P13 SC administration to 2016 h after the start of the administration. Serum concentrations were analyzed using the Meso Scale Discovery electrochemiluminescence method. Geometric mean ratios (90% confidence interval) of the AUCinf (areas under the concentration-time curve from zero to infinity) and Cmax (The maximum serum concentration) for CT-P13 SC AI versus CT-P13 SC PFS groups, were 94.15% (85.02%-104.26%), 92.48% (84.66%-101.01%), respectively. CT-P13 SC AI and CT-P13 SC PFS achieved comparable PK because the 90% CI was within the predefined equivalence margin. At the end of the study, immunogenicity results revealed that 70 (97.22%) and 73 (98.65%) participants tested positive for anti-drug antibody (ADA) in the CT-P13 SC AI and CT-P13 SC PFS groups, respectively. They were tested positive for neutralizing antibodies. No other significant safety differences were observed between the treatment groups. In conclusion, both administrations demonstrated PK equivalence and were both safe and well-tolerated.

Efficacy and safety of CT-P47 versus reference tocilizumab: 32-week results of a randomised, active-controlled, double-blind, phase III study in patients with rheumatoid arthritis, including 8 weeks of switching data from reference tocilizumab to CT-P47

ObjectivesTo demonstrate efficacy equivalence of CT-P47 and EU-approved reference tocilizumab (r-TCZ) in patients with rheumatoid arthritis (RA).MethodsThis double-blind, phase III study randomised (1:1) patients to receive CT-P47 or r-TCZ (8...

The Validity of Apple Watch Series 9 and Ultra 2 for Serial Measurements of Heart Rate Variability and Resting Heart Rate.

The widespread use of wearable devices has enabled continuous monitoring of biometric data, including heart rate variability (HRV) and resting heart rate (RHR). However, the validity of these measurements, particularly from consumer devices like Apple Watch, remains underexplored. This study aimed to validate HRV measurements obtained from Apple Watch Series 9 and Ultra 2 against the Polar H10 chest strap paired with the Kubios HRV software, which together served as the reference standard. A prospective cohort of 39 healthy adults provided 316 HRV measurements over a 14-day period. Generalized Estimating Equations were used to assess the difference in HRV between devices, accounting for repeated measures. Apple Watch tended to underestimate HRV by an average of 8.31 ms compared to the Polar H10 (p = 0.025), with a mean absolute percentage error (MAPE) of 28.88% and a mean absolute error (MAE) of 20.46 ms. The study found no significant impact of RHR discrepancies on HRV differences (p = 0.156), with RHR showing a mean difference of -0.08 bpm, an MAPE of 5.91%, and an MAE of 3.73 bpm. Equivalence testing indicated that the HRV measurements from Apple Watch did not fall within the pre-specified equivalence margin of ±10 ms. Despite accurate RHR measurements, these findings underscore the need for improved HRV algorithms in consumer wearables and caution in interpreting HRV data for clinical or performance monitoring.

Pharmacokinetics, Safety, and Immunogenicity of a Biosimilar of Nivolumab (LY01015): A Randomized, Double-Blind, Parallel-Controlled Phase I Clinical Trial in Healthy Chinese Male Subjects.

Nivolumab (Opdivo®) is the first anti-PD-1 antibody approved in the world. LY01015 is a potential biosimilar of nivolumab. This phase I study aimed to establish the pharmacokinetic equivalence between LY01015 and the original investigational nivolumab (Opdivo®) in healthy Chinese male subjects. Additionally, safety and immunogenicity were assessed. A randomized, double-blind, parallel-controlled, phase I trial was conducted with 176 healthy male adults receiving a single intravenous infusion of LY01015 or nivolumab at 0.3mg/kg. Pharmacokinetics, safety, and immunogenicity were evaluated over a 99-day period. The primary pharmacokinetics endpoint was AUC0-∞, and the secondary pharmacokinetic endpoints included AUC0-t and Cmax. Pharmacokinetic bioequivalence was confirmed using standard equivalence margins of 80.00-125.00%. This study is the first to report on the pharmacokinetics, safety, and immunogenicity of Opdivo® in healthy individuals. The pharmacokinetics profiles of LY01015 and Opdivo® were found to be comparable. The geometric mean ratios (90% confidence intervals) for the AUC0-∞, AUC0-t, and Cmax of LY01015 to Opdivo® were 94.49% (90.29-98.88%), 94.92% (88.73-101.54%), and 96.55% (93.32-99.90%), respectively, falling within the conventional bioequivalence criteria of 80.00-125.00%. The safety and immunogenicity were also comparable between the two groups. LY01015 demonstrated highly similar pharmacokinetics to nivolumab in healthy Chinese male subjects. Both drugs exhibited comparable safety and immunogenicity profiles. This trial is registered at the Chinese Clinical Trial Registry website ( https://www.chictr.org.cn/ #ChiCTR2200064771).

Aflibercept Biosimilar MYL-1701P vs Reference Aflibercept in Diabetic Macular Edema

Biosimilars may be lower-cost alternatives to originator biologic products, potentially offering expanded access or reduced economic burden, but have not been evaluated with aflibercept in diabetic macular edema (DME). To compare efficacy and safety of MYL-1701P, an aflibercept biosimilar, with reference aflibercept (Eylea [Regeneron]) in DME. This was a double-masked, randomized clinical trial that included participants at 77 centers across the US, Europe, Japan, and India. Included in the analysis were individuals 18 years and older with type 1 or type 2 diabetes with central DME and best-corrected visual acuity (BCVA) letter score of 73 to 38 in the study eye using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Study data were analyzed from October to December 2021. Formulations of MYL-1701P (0.5-mg vial) or reference aflibercept every 4 weeks for 5 consecutive intravitreal injections, followed by every 8 weeks through week 52. The primary outcome was the adjusted difference in least squares mean (SE) change from baseline BCVA letter score at week 8 with an equivalence margin of -3 to +3 letters. Secondary outcomes included change in central subfield thickness (CST), BCVA, number of injections over 52 weeks, incidence of adverse events (AEs), and antidrug antibodies (ADAs). A total of 355 participants (mean [SD] age, 62.2 [9.2] years; 216 male [60.8%]) were randomized to MYL-1701P (179 participants [50.4%]) and aflibercept (176 participants [49.6%]). At week 8, mean (SE) change in BCVA was 6.60 (0.55) letters vs 6.56 (0.55) letters in the MYL-1701P vs aflibercept groups. The adjusted mean difference of 0.04 letters (90% CI, -1.16 to 1.24 letters) met the primary outcome. At week 8, mean (SE) change in CST was -112 (7) μm vs -124 (7) μm in the MYL-1701P vs aflibercept groups (adjusted mean difference, 12 μm; 90% CI, -3 to 26 μm). The incidence of treatment-emergent AEs in the MYL-1701P and aflibercept arms were ocular (30.9% [55 of 178] vs 29.5% [52 of 176]), serious ocular (0.6% [1 of 178] vs 1.1% [2 of 176]), nonocular (65.2% [116 of 178] vs 65.3% [115 of 176]), and serious nonocular (16.9% [30 of 178] vs 11.9% [21 of 176]). The mean (SD) total number of injections was 8.4 (2.1) vs 8.7 (1.8) in the MYL-1701P vs aflibercept groups. The incidence of treatment-induced or treatment-boosted ADAs was 2.8% (5 of 177) vs 5.7% (10 of 176) in the MYL-1701P vs aflibercept arms. MYL-1701P demonstrated clinical equivalence in regard to efficacy, with comparable safety and immunogenicity, to reference aflibercept. These findings support use of MLY-1701P as an alternative to reference aflibercept. ClinicalTrials.gov Identifier: NCT03610646.

Telehealth vs In-Person Early Palliative Care for Patients With Advanced Lung Cancer

Numerous studies show that early palliative care improves quality of life and other key outcomes in patients with advanced cancer and their caregivers, although most lack access to this evidence-based model of care. To evaluate whether delivering early palliative care via secure video vs in-person visits has an equivalent effect on quality of life in patients with advanced non-small cell lung cancer (NSCLC). Randomized, multisite, comparative effectiveness trial from June 14, 2018, to May 4, 2023, at 22 US cancer centers among 1250 patients within 12 weeks of diagnosis of advanced NSCLC and 548 caregivers. Participants were randomized to meet with a specialty-trained palliative care clinician every 4 weeks either via video visit or in person in the outpatient clinic from the time of enrollment and throughout the course of disease. The video visit group had an initial in-person visit to establish rapport, followed by subsequent virtual visits. Equivalence of the effect of video visit vs in-person early palliative care on quality of life at week 24 per the Functional Assessment of Cancer Therapy-Lung questionnaire (equivalence margin of ±4 points; score range: 0-136, with higher scores indicating better quality of life). Participants completed study questionnaires at enrollment and at weeks 12, 24, 36, and 48. By 24 weeks, participants (mean age, 65.5 years; 54.0% women; 82.7% White) had a mean of 4.7 (video) and 4.9 (in-person) early palliative care encounters. Patient-reported quality-of-life scores were equivalent between groups (video mean, 99.7 vs in-person mean, 97.7; difference, 2.0 [90% CI, 0.1-3.9]; P = .04 for equivalence). Rate of caregiver participation in visits was lower for video vs in-person early palliative care (36.6% vs 49.7%; P < .001). Study groups did not differ in caregiver quality of life, patient coping, or patient and caregiver satisfaction with care, mood symptoms, or prognostic perceptions. The delivery of early palliative care virtually vs in person demonstrated equivalent effects on quality of life in patients with advanced NSCLC, underscoring the considerable potential for improving access to this evidence-based care model through telehealth delivery. ClinicalTrials.gov Identifier: NCT03375489.

Quality-of-Life Outcomes from NRG/NSABP B-39/RTOG 0413: Whole-breast Irradiation vs Accelerated Partial-breast Irradiation after Breast Conserving Surgery.

NRG Oncology (NRG)/NSABP B-39/RTOG 0413 compared whole-breast irradiation (WBI) to accelerated partial-breast irradiation (APBI). APBI was not equivalent to WBI in local tumor control. Secondary outcome was Quality-of-life (QOL). The QOL sub-study used validated self-report questionnaires including the Breast Cancer Treatment Outcome Scale (BCTOS) and SF-36 vitality scale. Assessments occurred: before randomization, at treatment completion (chemotherapy or radiotherapy), 4-weeks later, at 6-, 12-, 24-, and 36-months. Primary aims: cosmesis change equivalency (baseline to 3 years; a priori margin of equivalence 0.4 standard deviations) and fatigue change superiority (baseline to end-of-treatment (EOT)) for APBI vs WBI, by patient groups treated with or without chemotherapy when appropriate. From 3/21/05-5/25/09, 975 patients enrolled in this sub-study; 950 had follow-up data. APBI had 3-year cosmesis equivalent to WBI (95%CI,-0.0001-0.16; equivalence margin -0.22-0.22) in all patients. The APBI group without chemotherapy had less EOT fatigue (p = .011; mean score APBI 63 vs WBI 59); APBI group receiving chemotherapy had worse EOT fatigue (p = .011; APBI 43 vs WBI 49). The APBI group reported less pain (BCTOS) at EOT (WBI 2.29 vs APBI 1.97), but worse pain at 3-years (WBI 1.62 vs APBI 1.71). APBI patients reported greater convenience of care than with WBI and reported less symptom severity at EOT and 4-weeks later. Cosmetic outcomes were similar for APBI and WBI groups, with small statistically significant differences in other outcomes that varied over time. Differences in fatigue and other symptoms appeared to resolve by ≥ 6 months. APBI may be preferred by some patients, for whom extended treatment is burdensome.

Efficacy and Safety of Biosimilar SCT510 Compared with Bevacizumab for the First-Line Treatment of Advanced Non-Squamous Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study.

SCT510 is a biosimilar to bevacizumab (Avastin) reference product (RP) that is approved for various metastatic cancers. In this study, we aimed to demonstrate the equivalence of SCT510 and bevacizumab in terms of efficacy, safety, immunogenicity and pharmacokinetics (PK) in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Patients with non-squamous NSCLC were randomized equally to the SCT510 group (comprising SCT510, paclitaxel, and carboplatin) and the bevacizumab group (comprising bevacizumab, paclitaxel, and carboplatin) for 4-6 cycles, followed by maintenance monotherapy with SCT510. The primary endpoint was the objective response rate (ORR) at week 12. Secondary endpoints included 18-week ORR, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and 1-year survival rate, as well as assessments of safety, immunogenicity, and multi-dose PK analysis. Between March 29, 2019, and April 27, 2021, 989 patients were screened and 567 eligible patients were randomly assigned to the SCT510 group (285 patients) and the bevacizumab group (282 patients). The ORR at week 12 was 52.6% [95% confidence interval (CI) 46.66-58.55%] in the SCT510 group and 52.5% (95% CI 46.47-58.47%) in the bevacizumab group. The ORR at week 18 was 55.4% (95% CI 49.46-61.30%) for SCT510 and 55.7% (95% CI 49.68-61.62%) for bevacizumab. The ORR risk ratio (RR) at weeks 12 and 18 was 0.99 (90% CI 0.873-1.133) and 0.99 (90% CI 0.872-1.114), respectively, both within the pre-specified equivalence margin of 0.75-1.33. There were no differences between the two groups in relation to other secondary endpoints, specifically DCR, DOR, PFS, OS, and 1-year survival rate. The overall safety findings were similar between the two treatment groups, and both SCT510 and bevacizumab RP exhibited low immunogenicity. SCT510 is similar to bevacizumab in clinical efficacy, safety, immunogenicity, and PK in patients with advanced non-squamous NSCLC. The totality of the evidence supports the clinical equivalence of SCT510 and bevacizumab. NCT03792074.

Efficacy of eHealth Versus In-Person Cognitive Behavioral Therapy for Insomnia: Systematic Review and Meta-Analysis of Equivalence.

Insomnia is a prevalent condition with significant health, societal, and economic impacts. Cognitive behavioral therapy for insomnia (CBTI) is recommended as the first-line treatment. With limited accessibility to in-person-delivered CBTI (ipCBTI), electronically delivered eHealth CBTI (eCBTI), ranging from telephone- and videoconference-delivered interventions to fully automated web-based programs and mobile apps, has emerged as an alternative. However, the relative efficacy of eCBTI compared to ipCBTI has not been conclusively determined. This study aims to test the comparability of eCBTI and ipCBTI through a systematic review and meta-analysis of equivalence based on randomized controlled trials directly comparing the 2 delivery formats. A comprehensive search across multiple databases was conducted, leading to the identification and analysis of 15 unique randomized head-to-head comparisons of ipCBTI and eCBTI. Data on sleep and nonsleep outcomes were extracted and subjected to both conventional meta-analytical methods and equivalence testing based on predetermined equivalence margins derived from previously suggested minimal important differences. Supplementary Bayesian analyses were conducted to determine the strength of the available evidence. The meta-analysis included 15 studies with a total of 1083 participants. Conventional comparisons generally favored ipCBTI. However, the effect sizes were small, and the 2 delivery formats were statistically significantly equivalent (P<.05) for most sleep and nonsleep outcomes. Additional within-group analyses showed that both formats led to statistically significant improvements (P<.05) in insomnia severity; sleep quality; and secondary outcomes such as fatigue, anxiety, and depression. Heterogeneity analyses highlighted the role of treatment duration and dropout rates as potential moderators of the differences in treatment efficacy. eCBTI and ipCBTI were found to be statistically significantly equivalent for treating insomnia for most examined outcomes, indicating eCBTI as a clinically relevant alternative to ipCBTI. This supports the expansion of eCBTI as a viable option to increase accessibility to effective insomnia treatment. Nonetheless, further research is needed to address the limitations noted, including the high risk of bias in some studies and the potential impact of treatment duration and dropout rates on efficacy. PROSPERO CRD42023390811; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=390811.

Cervical orthosis does not improve postoperative pain following posterior cervical fusion: a randomized controlled trial.

To determine whether postoperative neck pain in the first 4 weeks following multi-level posterior cervical fusion (PCF) with orthosis is equivalent to multi-level PCF without orthosis. Patients were randomly assigned in a 1:1 ratio to postoperative orthosis (CO) for 6 weeks or no orthosis (NO). Randomization was stratified by indication (traumatic vs. degenerative), and preoperative opioid use. A model of longitudinal regression for repeated measures was used. The two-sided 95% confidence interval (CI) was used to test equivalence. If the CI lay between the pre-determined margin of equivalence (-2.0 to + 2.0 pain score) the two groups were considered equivalent. A multiple imputation procedure was used to replace missing data. Thirty-one patients were enrolled in each group. At baseline, the CO group had more neck pain (5.3 vs. 3.2, p = 0.013). The Four week post-operative neck pain intensity score was 4.6 ± 0.3 for the CO group vs. 4.9 ± 0.3 for the NO group. The 95% confidence interval (-1.2 to 0.6) was within the pre-determined equivalence margin. Neck Disability Index, quality-of-life scores, and arm pain were similar. Eleven patients in the CO group and 12 patients in the NO group had an adverse event. The CO group had reduced range of motion at 6 weeks. Pain scores over the first 4 weeks after surgery were equivalent for patients undergoing multi-level PCF treated with or without a cervical orthosis. Our findings do not support the routine use of a postoperative cervical orthosis for postoperative pain control. Clinical Trials Registration Number NCT04308122, April 22, 2020.

A Population Pharmacokinetic Model of Tocilizumab in Kidney Transplant Patients Treated for Chronic Active Antibody-Mediated Rejection: Comparison of Plasma Exposure Between Intravenous and Subcutaneous Administration Schemes.

Tocilizumab prevents the clinical worsening of chronic active antibody-mediated rejection (CAAMR) in kidney transplant recipients. Following a global shortage of the intravenous pharmaceutical form in 2022, patients were switched from monthly intravenous administration of 8 mg/kg to weekly subcutaneous injection of 162 mg, raising the question of bioequivalence between these schemes of administration. We aimed to compare the areas under the curve (AUC) of tocilizumab in virtual simulations of populations treated with the two administration schemes and to identify the covariates that could contribute to pharmacokinetic variability of tocilizumab in kidney transplant patients with CAAMR who received tocilizumab as salvage treatment. This retrospective monocentric study included 43 kidney transplant patients (202 tocilizumab concentrations) with CAAMR treated with intravenous or subcutaneous tocilizumab between December 2020 and January 2023. We developed a population pharmacokinetic model using nonlinear mixed effects modeling and identified the covariates that could contribute to tocilizumab AUC variability. Monte Carlo simulations were then performed to assess the subcutaneous and intravenous tocilizumab AUC for 0-28 days (M1), 56-84 days (M3), 140-168 days (M6), and 308-336 days (M12). Bioequivalence was defined by SC/IV AUC geometric mean ratios (GMRs) between 0.80 and 1.25. A two-compartment model with parallel linear and nonlinear elimination best described the concentration-time data. Significant covariates for tocilizumab clearance were body weight, urinary albumin-to-creatinine ratio (ACR), and inflammation status [C-reactive protein (CRP) ≥5 mg/L]. The GMR values and their 90% confidence intervals at M3, M6, and M12 were within the 0.8-1.25 margin for equivalence. Conversely, the 90% prediction intervals of the GMR were much wider than the 90% confidence intervals and did not fall within 0.8 and 1.25. From month 3 of treatment, the subcutaneous and intravenous tocilizumab administration schemes provided average bioequivalent pharmacokinetic exposure at the population level but not at the individual level. Body weight, inflammation, ACR, and administration scheme should be considered to personalize the dose of tocilizumab for patients with CAAMR. Further studies are required to determine the target of tocilizumab exposure in kidney transplant patients with CAAMR.

Equivalence tests under the non mixture and mixture cure fraction models

In this article, we propose equivalence tests for the difference of two survival functions in the presence of cure fraction. We consider both the non mixture cure model (NMCM) and mixture cure model (MCM). We first demonstrate that the existing tests can be used to test equivalence of two improper survival functions under the class of log transformation (LT) and Box-Cox transformation (BCT) NMCM. For the MCM, a logistic regression model is assumed for the probability of being uncured and the class of LT or BCT models are used to describe the distribution of event time for the uncured subjects. Under the MCM, we consider testing separately the null hypothesis of identical cure rate and that of equivalence of two survival functions of the uncured subjects. We also develop a Wald statistic for simultaneously testing whether or not both the maximal difference between cure rates and that between two short-term survival functions fall within some equivalence margins. Simulation results indicate that the proposed tests have a satisfactory size and an adequate power in finite sample.

Exploring TNFi drug-levels and anti-drug antibodies during tapering among patients with inflammatory arthritis: secondary analyses from the randomised BIODOPT trial

To evaluate tumour necrosis factor inhibitor (TNFi) drug-levels and presence of anti-drug antibodies (ADAb) in patients with inflammatory arthritis who taper TNFi compared to TNFi continuation. Patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis on stable TNFi dose and in low disease activity ≥ 12 months were randomised (2:1) to disease activity-guided tapering or control. Blood samples at baseline, 12- and 18-months were evaluated for TNFi drug-levels and ADAb. In total, 129 patients were randomised to tapering (n = 88) or control (n = 41). Between baseline and month 18, a significant shift in TNFi drug-levels were observed in the tapering group resulting in fewer patients with high drug-levels (change: − 14% [95% CI − 27 to − 1%]) and more with low drug-levels (change: 18% [95% CI 5–31%]). Disease activity was equivalent between groups at 18 months, mean difference: RA − 0.06 (95% CI − 0.44 to 0.33), PsA 0.03 (95% CI − 0.36 to 0.42), and axSpA 0.16 (− 0.17 to 0.49), equivalence margins ± 0.5 disease activity points. ADAb were detected in eight patients, all from the tapering group. TNFi drug-level category or ADAb were not predictive for achieving successful tapering at 18 months. TNFi drug-levels decreased during tapering which indicate adherence to the tapering algorithm. Despite the difference in TNFi drug-levels at 18 months, disease activity remained equivalent, and only few tapering patients had detectable ADAb. These data do not support using TNFi drug-level and/or ADAb to guide the tapering decision but future research with larger trials is needed.Trial registration: EudraCT: 2017-001970-41, December 21, 2017.

Efficacy and safety of candidate biosimilar CT-P41 versus reference denosumab: a double-blind, randomized, active-controlled, Phase 3 trial in postmenopausal women with osteoporosis

SummaryThis 78-week (18-month) study conducted in 479 postmenopausal women with osteoporosis evaluated the efficacy, pharmacodynamics, pharmacokinetics, safety, and immunogenicity of candidate biosimilar CT-P41 relative to US reference denosumab. CT-P41 had equivalent efficacy and pharmacodynamics to US-denosumab, with similar pharmacokinetics and comparable safety and immunogenicity profiles. PurposeTo demonstrate equivalence of candidate biosimilar CT-P41 and US reference denosumab (US-denosumab) in postmenopausal women with osteoporosis. MethodsThis 78-week (18-month), double-blind, randomized, active-controlled Phase 3 study (NCT04757376) comprised two treatment periods (TPs). In TPI, patients (N = 479) were randomized 1:1 to 60 mg subcutaneous CT-P41 or US-denosumab. At Week 52, those who had received CT-P41 in TPI continued to do so. Those who had received US-denosumab were randomized (1:1) to continue treatment or switch to CT-P41 in TPII. The primary efficacy endpoint was percent change from baseline in lumbar spine bone mineral density at Week 52. Efficacy equivalence was concluded if associated 95% confidence intervals (CI) for least squares (LS) mean group differences fell within ± 1.503%. The primary pharmacodynamic (PD) endpoint was area under the effect curve for serum carboxy-terminal cross-linking telopeptide of type I collagen through the first 26 weeks, with an equivalence margin of 80–125% (for 95% CIs associated with geometric LS mean ratios). ResultsEquivalence was demonstrated for CT-P41 and US-denosumab with respect to primary efficacy (LS mean difference [95% CI]: − 0.139 [− 0.826, 0.548] in the full analysis set and − 0.280 [− 0.973, 0.414] in the per-protocol set) and PD (geometric LS mean ratio [95% CI]: 94.94 [90.75, 99.32]) endpoints. Secondary efficacy, PD, pharmacokinetics, and safety results were comparable among all groups up to Week 78, including after transitioning to CT-P41 from US-denosumab. ConclusionsCT-P41 was equivalent to US-denosumab in women with postmenopausal osteoporosis, with respect to primary efficacy and PD endpoints.

Comparing cervical cerclage, pessary and vaginal progesterone for prevention of preterm birth in women with a short cervix (SuPPoRT): A multicentre randomised controlled trial.

Cervical cerclage, cervical pessary, and vaginal progesterone have each been shown to reduce preterm birth (PTB) in high-risk women, but to our knowledge, there has been no randomised comparison of the 3 interventions. The SuPPoRT "Stitch, Pessary, or Progesterone Randomised Trial" was designed to compare the rate of PTB <37 weeks between each intervention in women who develop a short cervix in pregnancy. SuPPoRT was a multicentre, open label 3-arm randomised controlled trial designed to demonstrate equivalence (equivalence margin 20%) conducted from 1 July 2015 to 1 July 2021 in 19 obstetric units in the United Kingdom. Asymptomatic women with singleton pregnancies with transvaginal ultrasound cervical lengths measuring <25 mm between 14+0 and 23+6 weeks' gestation were eligible for randomisation (1:1:1) to receive either vaginal cervical cerclage (n = 128), cervical pessary (n = 126), or vaginal progesterone (n = 132). Minimisation variables were gestation at recruitment, body mass index (BMI), and risk factor for PTB. The primary outcome was PTB <37 weeks' gestation. Secondary outcomes included PTB <34 weeks', <30 weeks', and adverse perinatal outcome. Analysis was by intention to treat. A total of 386 pregnant women between 14+0 and 23+6 weeks' gestation with a cervical length <25 mm were randomised to one of the 3 interventions. Of these women, 67% were of white ethnicity, 18% black ethnicity, and 7.5% Asian ethnicity. Mean BMI was 25.6. Over 85% of women had prior risk factors for PTB; 39.1% had experienced a spontaneous PTB or midtrimester loss (>14 weeks gestation); and 45.8% had prior cervical surgery. Data from 381 women were available for outcome analysis. Using binary regression, randomised therapies (cerclage versus pessary versus vaginal progesterone) were found to have similar effects on the primary outcome PTB <37 weeks (39/127 versus 38/122 versus 32/132, p = 0.4, cerclage versus pessary risk difference (RD) -0.7% [-12.1 to 10.7], cerclage versus progesterone RD 6.2% [-5.0 to 17.0], and progesterone versus pessary RD -6.9% [-17.9 to 4.1]). Similarly, no difference was seen for PTB <34 and 30 weeks, nor adverse perinatal outcome. There were some differences in the mild side effect profile between interventions (vaginal discharge and bleeding) and women randomised to progesterone reported more severe abdominal pain. A small proportion of women did not receive the intervention as per protocol; however, per-protocol and as-treated analyses showed similar results. The main study limitation was that the trial was underpowered for neonatal outcomes and was stopped early due to the COVID-19 pandemic. In this study, we found that for women who develop a short cervix, cerclage, pessary, and vaginal progesterone were equally efficacious at preventing PTB, as judged with a 20% equivalence margin. Commencing with any of the therapies would be reasonable clinical management. These results can be used as a counselling tool for clinicians when managing women with a short cervix. EU Clinical Trials register. EudraCT Number: 2015-000456-15, clinicaltrialsregister.eu., ISRCTN Registry: ISRCTN13364447, isrctn.com.

Efficacy and Safety of BP02 (Trastuzumab Biosimilar) in HER2-Positive Metastatic Breast Cancer: A Multicenter Phase III Study.

Trastuzumab targets human epidermal growth factor receptor 2 (HER2) receptors and is indicated for treating HER2-positive metastatic breast cancer. BP02,a recombinant IgG1 kappa humanized monoclonal antibody, is being developed as atrastuzumab biosimilar. The objective of this study was to evaluate the equivalence of BP02 with reference trastuzumab (RT: Herceptin®-EU) in patients withHER2-positive metastatic breast cancer. This double-blinded, 1:1 randomized, parallel-group, active-controlled, phase III equivalence trial recruited women aged 18-75 years with histologically/cytologically confirmed HER2- positive, locally recurrent or metastatic breast cancer with systemic metastasis, from 59 sites in India. Patients were randomly allocated 1:1 stratified by estrogen receptor/progesterone receptor status to receive BP02/RT (8-mg/kg loading dose on day 1-cycle 1, 6 mg/kg on day 1-cycles 2-8, of each 3-week cycle) combined with docetaxel (75mg/m2 on day 1-cycles 1-8) [induction phase]. Participants with complete or partial response, or stable disease at the end of the induction phase continued the study drug until disease progression/treatment discontinuation [maintenance phase]. The primary efficacy endpoint was the objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Between 23 September, 2020 and 16 September, 2022, 690 patients were recruited (n = 345 each to BP02/RT). At the end of the induction phase (intent-to-treat population), a similar proportion of patients achieved an objective response rate with BP02 (n = 231 [67.0%], 95% confidence interval [CI] 62.0, 71.9) and RT (n = 238 [69.0%], 95% CI 64.1, 73.9). The 95% CI of risk difference (-2.03, 95% CI -9.15, 5.09) and 90% CI of risk ratio (0.97, 90% CI 0.89, 1.06) were within equivalence margins of ±13% and (0.80, 1.25), respectively. Treatment-emergent adverse events leading to treatment withdrawal were reported in 2.9% and 3.2% patients with BP02 and RT, respectively. BP02 showed an equivalent efficacy and similar safety profile to RT at the end of 24 weeks. CTRI Number: CTRI/2020/04/024456.