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BACKGROUND: Multiple sclerosis (MS) is a prevalent, disabling, inflammatory, neurodegenerative disease that typically manifests during a highly productive stage of life. Interferon beta-1a was among the first approved disease-modifying therapies for MS and remains among the first-line treatment options. Pegylation of the interferon beta-1a molecule prolongs its half-life while maintaining its efficacy and safety profile. In PEGINTEGRITY study, we aimed to compare peginterferon beta-1a with interferon beta-1a in terms of efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: This study was a randomized, active-controlled, parallel-group, multi-center Phase 3 trial conducted in Iran in participants with RRMS. Participants received 125 µg of subcutaneous peginterferon beta-1a every two weeks or 30 µg of intramuscular interferon beta-1a once a week for up to 96 weeks. The primary outcome was the non-inferiority of peginterferon beta-1a to interferon beta-1a in reducing annualized relapse rate (ARR). Other outcomes included the number of patients with 12-week confirmed disability progression, the number of new or newly-enlarging T2 hyperintense lesions, the number of gadolinium-enhancing lesions, the number of new T1 hypointense lesions, the volume of new or newly-enlarging T2 hyperintense lesions, changes in brain volume, immunogenicity, and safety assessments. RESULTS: A total of 168 patients who met the eligibility criteria were enrolled and assigned to two arms of the study, each consisting of 84 participants. Totally, 41 participants (24 patients in the peginterferon beta-1a group and 17 patients in the interferon beta-1a group) were withdrawn from the study. The withdrawn patients were included in the per-protocol analysis for the period of time they were in the study. In 96 weeks, in the per-protocol population, the ARR was 0.05 in the peginterferon beta-1a group versus 0.11 in the interferon beta-1a group, which does not reflect a statistically significant difference (p=0.09; 95 % CI, 0.18-1.14). Considering the upper limit of the one-sided 95 % CI of the rate ratio of peginterferon beta-1a compared to interferon beta-1a, as well as the non-inferiority margin, it can be concluded that the primary outcome was met. The results were also comparable for other efficacy and safety outcomes. CONCLUSION: The results demonstrate the non-inferiority of peginterferon beta-1a to interferon beta-1a with similar efficacy in 96-week ARR in RRMS patients. Both arms were also comparable in other efficacy outcomes and safety profiles with no statistically significant differences. These findings support considering peginterferon beta-1a as a safe and efficient option in patients with RRMS. This study was registered on Iranian Registry of Clinical Trials (IRCT201612306135N8) and clinicaltrials.gov (NCT05242133).
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Interferón beta-1a , Esclerosis Múltiple Recurrente-Remitente , Polietilenglicoles , Humanos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Masculino , Femenino , Interferón beta-1a/administración & dosificación , Interferón beta-1a/farmacología , Interferón beta-1a/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Polietilenglicoles/farmacología , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/farmacología , Persona de Mediana Edad , Interferón beta/administración & dosificación , Interferón beta/efectos adversos , Interferón beta/farmacología , Adulto JovenRESUMEN
Background: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration: This trial is registered as ISRCTN06473203. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.
Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients' disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient's quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible.
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Carcinoma de Células Renales , Neoplasias Renales , Inhibidores de Proteínas Quinasas , Años de Vida Ajustados por Calidad de Vida , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Reino Unido , Privación de Tratamiento , Sunitinib/uso terapéutico , Evaluación de la Tecnología Biomédica , Adulto , Antineoplásicos/uso terapéuticoRESUMEN
Background: DS-5670 is a messenger ribonucleic acid (mRNA) vaccine platform targeting the receptor-binding domain (RBD) of the spike protein derived from severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Booster vaccination against coronavirus disease 2019 (COVID-19) with monovalent DS-5670a (incorporating mRNA encoding the RBD from the original SARS-CoV-2 strain) or bivalent DS-5670a/b (original and omicron BA.4-5 RBD antigens) is effective and safe in adults. Data from a phase 2/3 active-controlled, non-inferiority, pediatric study evaluating a third booster dose of DS-5670a/b are reported here. Methods: Children aged 5-11 years who had completed the two-dose primary vaccination series with monovalent BNT162b2 (original strain) at least 3 months prior to enrolment were randomly assigned to receive DS-5670a/b (20 µg of mRNA) or bivalent BNT1 62b2 (original/omicron BA.4-5; 10 µg of mRNA) on Day 1. The primary efficacy endpoint was blood neutralization geometric mean titer (GMT) against SARS-CoV-2 (omicron variant BA.5.2.1) and immune response rate (≥ 4-fold increase in post-vaccination circulating anti-SARS-CoV-2 neutralizing activity) on Day 29. Results: Among evaluable participants (DS-5670a/b, n = 74; bivalent BNT162b2, n = 75), the adjusted GMT ratio of DS-5670a/b to bivalent BNT162b2 on Day 29 was 1.636 (95% CI, 1.221, 2.190). Immune response rates were ≥ 89% with both study vaccines; adjusted difference 2.6% (95% CI, -7.8, 13.8). The prespecified non-inferiority margins were exceeded, and the study met the primary endpoint. DS-5670a/b also demonstrated broad neutralization activity across recent omicron sublineages and no cases of COVID-19 between Days 8-29 post-administration were reported. There were no novel safety concerns in the pediatric population at data cut-off. Conclusions: Bivalent DS-5670a/b was non-inferior to bivalent BNT162b2 in terms of immunogenicity, and had a manageable safety profile, when administered as a heterologous booster in children aged 5-11 years. Clinical trial registration: https://jrct.niph.go.jp/, identifier jRCT2031220665.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , SARS-CoV-2/inmunología , COVID-19/prevención & control , COVID-19/inmunología , Masculino , Femenino , Preescolar , Niño , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Glicoproteína de la Espiga del Coronavirus/inmunología , Inmunogenicidad Vacunal , Vacuna BNT162/inmunología , Vacunación/métodosRESUMEN
BACKGROUND: The evolving oncology treatment paradigm has created an unmet need for administration options that improve patient experiences and healthcare efficiencies. PATIENTS AND METHODS: CheckMate 67T (NCT04810078) was a phase 3, open-label, multicenter, noninferiority trial in which patients with advanced/metastatic clear cell renal cell carcinoma were randomized to subcutaneous nivolumab (1200 mg every 4 weeks; coformulated with recombinant human hyaluronidase PH20 20,000 units) or intravenous nivolumab (3 mg/kg every 2 weeks). Primary objective was to assess the noninferiority of subcutaneous versus intravenous nivolumab by coprimary endpoints determined from a population pharmacokinetics analysis (time-averaged serum concentration over the first 28 days [Cavgd28], and minimum steady-state serum concentration [Cminss]; noninferiority threshold: lower boundary of 90% confidence interval (CI) of the geometric mean ratios [GMR] ≥0.8). Objective response rate (ORR) was a key secondary endpoint powered for noninferiority (noninferiority threshold: lower boundary of 95% CI of relative risk of ORR [subcutaneous versus intravenous nivolumab] ≥0.60). RESULTS: Overall, 495 patients were randomized. Relative exposure in the subcutaneous versus intravenous arm reported by the GMR of Cavgd28 and Cminss was 2.098 (90% CI, 2.001-2.200) and 1.774 (90% CI, 1.633-1.927), respectively. After 8 months minimum follow-up, ORR was 24.2% with subcutaneous nivolumab (95% CI, 19.0-30.0) versus 18.2% with intravenous nivolumab (95% CI, 13.6-23.6; relative risk: 1.33 [95% CI, 0.94-1.87]). Coprimary endpoints and ORR met noninferiority thresholds. Additional efficacy and safety measures were similar. CONCLUSION: Subcutaneous nivolumab was noninferior to intravenous nivolumab based on pharmacokinetics and ORR. No new safety signals were observed.
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BACKGROUND: Opioid abuse and mortality are ravaging American society, highlighting the need to find alternative effective analgesics with fewer side effects. FDA-approved topical analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs), are commonly used to treat musculoskeletal pain but can cause adverse effects. Natural compounds, including essential oils, are potential therapeutic alternatives for managing musculoskeletal pain. If these compounds can provide comparable analgesia to FDA-approved products, it will increase the available options for people with pain, improving quality of life with minimal morbidity and mortality. OBJECTIVE: This study assesses the effectiveness and onset of action of Bonipar, a topical analgesic formulated with camphor, methyl salicylate, and oils of coconut, eucalyptus, nutmeg, and rosemary, in managing musculoskeletal pain compared to 1.5 % diclofenac solution, an FDA-approved topical non-steroidal anti-inflammatory drug. METHODS: One hundred sixty-four adult patients with localized musculoskeletal pain were randomly assigned to twice-daily applications of either Bonipar or Diclofenac for one week. The primary outcome measure was a 50 % reduction in pain after one week. Secondary outcomes included the change in pain from baseline and onset of action, defined as the first reduction in pain by 20 %. RESULTS: All patients completed the initial pain assessment to determine the onset of action. One-week data was available for 74 patients treated with diclofenac and 72 patients treated with Bonipar. Data for 18 patients were incomplete. The proportion of patients achieving a 50 % reduction in pain was statistically similar between the two groups. The success rates of achieving a 50 % pain reduction with Bonipar were found to be non-inferior to those treated with diclofenac. All follow-up time points showed roughly similar results between the groups. Regression models adjusted for age and sex revealed no significant effects on pain changes. Secondary analyses demonstrated no significant differences between the groups. DISCUSSION: The topical analgesic Bonipar demonstrates a comparable onset of action, with efficacy non-inferior to diclofenac in the management of musculoskeletal pain, while showing fewer adverse effects compared to diclofenac. These findings highlight the potential of Bonipar as a valuable alternative for the treatment of localized pain.
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BACKGROUND: The non-inferiority of the efficacy of subcutaneous (SC) vs intravenous (IV) administration of natalizumab (NTZ) once every 4 weeks in relapsing-remitting multiple sclerosis (RRMS) was recently demonstrated on the primary outcome of the REFINE study, i.e. MRI "combined unique active lesions number" (CUAL). To provide further evidence on the comparative efficacy of the two NTZ formulations, the effect of NTZ-SC vs NTZ-IV on annualized relapse rate (ARR) was investigated re-analysing the REFINE dataset. METHODS: Post-hoc analysis of the REFINE study dataset aimed at exploring the non-inferiority of the efficacy of NTZ-SC vs NTZ-IV on ARR, i.e. the main secondary outcome of the REFINE study. Robustness of the non-inferiority analysis on CUAL with respect to the presence of cases from the SC arm who received a rescue treatment, including NTZ-IV, was also assessed by sensitivity analyses. Three non-inferiority margins were selected, corresponding to 25 %, 33 %, and 50 % fractions of the effect size of NTZ-IV vs placebo observed in the AFFIRM study on ARR (i.e. 0.125, 0.170, and 0.250). RESULTS: Ninety-nine RRMS patients were included. The mean difference in the effect of NTZ-SC vs NTZ-IV on ARR was close to 0. The lower bound of the 95 % confidence interval (worst case scenario) was -0.119, corresponding to 25 % (p = 0.025) of the effect of NTZ-IV vs placebo on ARR. Sensitivity analyses confirmed the results of the primary non-inferiority analysis on the outcome CUAL. CONCLUSIONS: NTZ-SC resulted not inferior to NTZ-IV on ARR for all the non-inferiority margins. The non-inferiority analysis of the efficacy of NTZ-SC vs NTZ-IV on CUAL was demonstrated to be robust with respect to rescued patients.
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Purpose: This study aimed to determine the therapeutic effectiveness of different machines in intense pulsed light (IPL) treatment of meibomian gland dysfunction (MGD). Methods: 213 subjects diagnosed with MGD underwent three sessions of IPL treatment in a control (M22) treatment group or experimental (OPL-I) treatment group and were followed up three to four weeks after each session. Tear breakup time (TBUT), meibomian gland secretion scores (MGSS), meibomian gland meibum scores (MGMS), corneal fluorescein staining (CFS) scores, and the Standard Patient Evaluation of Eye Dryness (SPEED) was used to assess eye dryness signs and symptoms at baseline and follow-up visits. Results: Two machines had the same working principles except that experimental (OPL-I) group consist of a dual filter system. Both groups showed significant improvements (P â< â0.0001) in TBUT, MGSS, MGMS, CFS scores and SPEED scores. Non-inferiority analysis showed no statistically significant differences in any result between the two groups. Various defects appeared on the filter with the extension of usage time. Spectrophotometry showed that light intensity decreased to 93.5% â± â0.46% past the first filter. Conclusions: IPL treatment completed with different machines have the same effect on improving the symptoms and signs of MGD. The dual filter system in the IPL machine reduces light intensity by approximately 6.5% without affecting its therapeutic effect. It is a feasible measure to ensure double safety and has the significance of popularization not only for MGD but also in other IPL treatment scenarios.
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BACKGROUND: High and increasing expenses on pembrolizumab ask for more cost-effective and sustainable treatment strategies to improve affordability of healthcare. Therefore, a part of the Dutch hospitals implemented an alternative, partially lower, weight-based dosing protocol for pembrolizumab. This provided the unique opportunity to compare the overall survival (OS) of the alternative pembrolizumab dosing protocol to standard dosing using a nationwide registry in non-small cell lung cancer (NSCLC) patients. METHODS: This is a retrospective cohort study with a non-inferiority primary objective. Forty hospitals in the Dutch Medication Audit and Dutch Lung Cancer Audit treated 1966 patients with NSCLC with first line pembrolizumab (mono- or combination therapy) between Jan 1st 2021, and Mar 31st, 2023. Alternative weight-based pembrolizumab dosing (100/150/200 mg Q3W or 200/300/400 mg Q6W) was administered to 604 patients, and 1362 patients received standard pembrolizumab dosing (200 mg Q3W or 400 mg Q6W). A Cox proportional hazard model with selected covariates was used to compare the OS between alternative and standard dosing protocols. The non-inferiority margin was set at a hazard ratio (HR) of 1.2 for OS. Non-inferiority is established by showing that the upper limit of the 95 % confidence interval (CI) of the HR of OS is smaller or equal to 1.2. RESULTS: Distribution of age (66.7 years +/-9.4), sex (45 % female) and treatment combinations were similar for both groups, comorbidity score was higher in the standard group. Median daily dose in the alternative dosing group was 22 % lower compared to the standard dosing group, 7.14 mg/day (interquartile range (IQR):5.48-8.04 mg/day) vs. 9.15 mg/day (IQR:8.33-9.52 mg/day), respectively. Alternative dosing was non-inferior to standard dosing regarding overall survival (adjusted HR 0.83, 95 %CI:0.69-1.003). CONCLUSION: This large, retrospective real-world analysis supports the hypothesis that the alternative, partially lower pembrolizumab dosing protocol in NSCLC maintains treatment effectiveness while reducing treatment costs.
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BACKGROUND: One-fourth of men older than 70 years have lower urinary tract symptoms (LUTS) that impair their quality of life. Transurethral resection of the prostate (TURP) is considered the gold standard for surgical treatment of LUTS caused by benign prostatic hyperplasia (BPH) that cannot be managed conservatively or pharmacologically. However, TURP is only an option for patients fit for surgery and can result in complications. Transurethral microwave thermotherapy (TUMT) and prostatic artery embolisation (PAE) are alternative minimally invasive surgical therapies (MISTs) performed in an outpatient setting. Both treatments have shown to reduce LUTS with a similar post-procedure outcome in mean International Prostate Symptom Score (IPSS). It is however still unknown if TUMT and PAE perform equally well as they have never been directly compared in a randomised clinical trial. The objective of this clinical trial is to assess if PAE is non-inferior to TUMT in reducing LUTS secondary to BPH. METHODS: This study is designed as a multicentre, non-inferiority, open-label randomised clinical trial. Patients will be randomised with a 1:1 allocation ratio between treatments. The primary outcome is the IPSS of the two arms after 6 months. The primary outcome will be evaluated using a 95% confidence interval against the predefined non-inferiority margin of + 3 points in IPSS. Secondary objectives include the comparison of patient-reported and functional outcomes at short- and long-term follow-up. We will follow the patients for 5 years to track long-term effect. Assuming a difference in mean IPSS after treatment of 1 point with an SD of 5 and a non-inferiority margin set at the threshold for a clinically non-meaningful difference of + 3 points, the calculated sample size was 100 patients per arm. To compensate for 10% dropout, the study will include 223 patients. DISCUSSION: In this first randomised clinical trial to compare two MISTs, we expect non-inferiority of PAE to TUMT. The most prominent problems with MIST BPH treatments are the unknown long-term effect and the lack of proper selection of candidates for a specific procedure. With analysis of the secondary outcomes, we aspire to contribute to a better understanding of durability and provide knowledge to guide treatment decisions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05686525. Registered on January 17, 2023, https://clinicaltrials.gov/study/NCT05686525 .
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Embolización Terapéutica , Estudios de Equivalencia como Asunto , Síntomas del Sistema Urinario Inferior , Próstata , Hiperplasia Prostática , Humanos , Masculino , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/terapia , Embolización Terapéutica/métodos , Embolización Terapéutica/efectos adversos , Síntomas del Sistema Urinario Inferior/etiología , Síntomas del Sistema Urinario Inferior/terapia , Síntomas del Sistema Urinario Inferior/diagnóstico , Resultado del Tratamiento , Próstata/irrigación sanguínea , Factores de Tiempo , Microondas/uso terapéutico , Microondas/efectos adversos , Resección Transuretral de la Próstata , Índice de Severidad de la Enfermedad , Hipertermia Inducida/métodos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , AncianoRESUMEN
BACKGROUND: Colorectal surgery still experiences high rates of infectious complications, such as anastomotic leakage (AL) and surgical site infections (SSIs). Therefore, oral antibiotic bowel decontamination (OABD) has experienced a renaissance. However, data on perioperative selective digestive tract decontamination (SDD)-based regimens or combined bowel preparation are inconsistent. Nonetheless, with widespread use of Enhanced Recovery After Surgery concepts, the ideal length for perioperative SDD treatment has to be reconsidered. METHODS: Perioperative outcome was analyzed in a cohort of patients undergoing minimally invasive surgery for left-sided colorectal cancer in a retrospective study. Additional to usual perioperative outcome measures, including AL, SSIs, and overall infectious complications, the efficacy of a shortened 3-day perioperative OABD treatment was compared with the efficacy of a 7-day perioperative OABD treatment based on a noninferiority analysis. RESULTS: Overall, 256 patients were included into analysis, of whom 84 and 172 patients were treated by 3-day and 7-day perioperative OABD regimens, respectively. AL occurred in 1.2% of patients in the 3-day group and 5.2% of patients in the 7-day group, and SSIs occurred in 3.6% of patients in the 3-day group and 5.8% of patients in the 7-day group, without significant difference. The shortened 3-day perioperative SDD-based regimen was noninferior to the regular 7-day perioperative SDD-based regimen concerning the rates of AL, SSIs, and infectious complications. CONCLUSION: Our data demonstrated noninferiority of a shortened 3-day SDD-based treatment vs a 7-day SDD-based treatment for AL, SSIs, and overall infectious complications.
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Background: We compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen. Methods: This study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150 mg plus lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (ANV/3TC/TDF), or cobicistat (Cobi) 150 mg boosted EVG plus emtricitabine (FTC) 200 mg, and tenofovir alafenamide (TAF) 10 mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605. Findings: Between October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n = 381) or EVG/Cobi/FTC/TAF (n = 381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI -1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05 kg, ETD -0.90 kg, 95% CI, -1.43 to -0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF. Interpretation: In virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF. Funding: Jiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.
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Most published applications of the estimand framework have focused on superiority trials. However, non-inferiority trials present specific challenges compared to superiority trials. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use notes in their addendum on estimands and sensitivity analysis in clinical trials that there may be special considerations to the implementation of estimands in clinical trials with a non-inferiority objective yet provides little guidance. This paper discusses considerations that trial teams should make when defining estimands for a clinical trial with a non-inferiority objective. We discuss how the pre-addendum way of establishing non-inferiority can be embraced by the estimand framework including a discussion of the role of the Per Protocol analysis set. We examine what clinical questions of interest can be formulated in the context of non-inferiority trials and outline why we do not think it is sensible to describe an estimand as 'conservative'. The impact of the estimand framework on key considerations in non-inferiority trials such as whether trials should have more than one primary estimand, the choice of non-inferiority margin, assay sensitivity, switching from non-inferiority to superiority and estimation are discussed. We conclude by providing a list of recommendations, and important considerations for defining estimands for trials with a non-inferiority objective.
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Background: Noninferiority trials are increasingly common in cardiovascular medicine, but their reporting and interpretation are challenging, particularly when an absolute risk difference is used as noninferiority margin. Objectives: This study aimed to investigate the effect of using absolute rather than relative noninferiority margins in cardiovascular trials. Methods: We reviewed noninferiority trials presented at major cardiovascular conferences from 2015 to 2022 and published within the same period. Based on the actual versus anticipated event rates in the control group, we recalculated the absolute noninferiority margin and re-assessed the trial results. The primary outcome of interest was the proportion of trials with a different interpretation after recalculation. Additionally, we analyzed the conclusion statements of these trials to determine if cautionary notes for the interpretation of study results were included. Results: We analyzed a total of 768 trials, of which 88 had a noninferiority design and 66 used an absolute noninferiority margin. Of 48 comparisons from 45 trials qualifying for the analysis, 11 (22.9%) had divergent results after recalculation of the absolute noninferiority margin based on the observed rather than anticipated event rate. Ten trials originally claiming noninferiority, did not meet it after the margin recalculation. All of them did not include statements suggesting cautionary interpretation of the study results in the conclusion section. Compared with the other trials, these displayed a larger median difference between anticipated and recalculated noninferiority margins (44.7% [IQR: 38.6%-56.7%] vs 15.3% [IQR: -1.5% to 28.9%]; P < 0.001). Conclusions: Recalculating noninferiority margins based on actual event rates, rather than anticipated ones, led to different outcomes in approximately 1 out of 4 cardiovascular trials, with most divergent trials lacking cautionary interpretation. These findings emphasize the importance of using or supplementing the relative noninferiority margin, particularly in studies with significant deviations between observed and expected event rates. This underscores the critical need for enhanced methodological and reporting standards in noninferiority trials, especially those employing absolute margins.
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OBJECTIVES: In this study, we aimed to evaluate the non-inferiority of a quadrivalent influenza vaccine (QIV) developed by Sinovac Biotech Co., Ltd. (Sinovac, Beijing, China) by comparing its immunogenicity and safety with a comparator QIV (Vaxigrip Tetra®) in a population aged 3 years and older in Chile and the Philippines. METHODS: A phase 3, non-inferiority, double-blind, randomized controlled, multicenter clinical trial was conducted in the southern hemisphere (SH) 2023 influenza season. Participants aged ≥ 3 years old with stable health were randomized 1:1 to receive either Sinovac QIV or comparator QIV. The co-primary outcomes were immunological non-inferiority for Sinovac QIV versus the comparator against each strain contained in the vaccines in terms of seroconversion rates (SCRs) and geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies 28 days after final vaccination. RESULTS: A total of 2039 participants were vaccinated (1019 Sinovac QIV; 1020 comparator QIV). Sinovac QIV induced non-inferior immune responses to all four strains as compared to comparator QIV, with slightly higher GMTs than those of comparator QIV: GMT ratios (lower limit 95% confidence interval (CI)) were 1.8 (1.6) for A(H1N1), 1.4 (1.3) for A (H3N2), 1.3 (1.1) for B Victoria and 1.2 (1.1) for B Yamagata; observed seroconversion rate differences (lower limit 95% CI) were 9.6% (6.7) for A(H1N1), 7.0% (3.5) for A(H3N2), 2.4% (-0.03) for B Victoria and 6.8% (3.0) for B Yamagata. Adverse reactions were similar across the two groups and no vaccine-related serious adverse events were reported. CONCLUSIONS: The immunogenicity of Sinovac QIV was non-inferior to that of the comparator QIV in these populations aged 3 years and older, and safety was comparable.
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A non-inferiority trial is usually conducted to investigate whether a new drug/treatment is no worse than a reference drug/treatment by a small, pre-specified, non-inferiority margin. This study aimed to assess the non-inferiority of the difference between two binary-outcome treatments in a matched-pairs design based on the method of variance of estimates recovery (MOVER). The processes for estimating the confidence interval of a single proportion included in the MOVER are the Wilson score interval, Agresti - Coull interval, Jeffreys interval, modified Jeffreys interval, score method with continuity correction, and arcsin interval. The performance of the six MOVER tests, the fiducial test, and the restricted maximum likelihood estimation test were evaluated by comparing their type I error rates and power at different pre-assigned levels and with varying combinations of parameters. The evaluation results showed that the modified Jeffreys MOVER test can be a competitive alternative to the other recommended tests. It can control type I errors well, and its power is not inferior to other methods. The proposed tests were illustrated with three real-world examples.
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Noninferiority clinical trials are crucial for evaluating the effectiveness of new interventions compared to standard interventions. By establishing statistical and clinical comparability, these trials can be conducted to demonstrate that a new intervention is not significantly inferior to the standard intervention. However, selecting appropriate noninferiority margins and study designs are essential to ensuring valid and reliable results. Moreover, employing the Consolidated Standards of Reporting Trials (CONSORT) statement for reporting noninferiority clinical trials enhances the quality and transparency of research findings. This article addresses key considerations and challenges faced by investigators in planning, conducting, and interpreting the results of noninferiority clinical trials.
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Estudios de Equivalencia como Asunto , Proyectos de Investigación , Humanos , Proyectos de Investigación/normas , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/normasRESUMEN
INTRODUCTION: To evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of ZRC-3277 (pertuzumab biosimilar) with Perjeta® (pertuzumab) in previously untreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: This phase III, multicenter, double-blind study across 38 sites in India randomized (1:1) patients with HER2-positive MBC in either the ZRC-3277 or Perjeta® group. Both groups also received trastuzumab and docetaxel. Of 268 enrolled patients, mITT population had 243 patients (119 and 124 in the ZRC-3277 and Perjeta® groups, respectively). The primary objective was to compare the between-group objective response rate (ORR) after 6 cycles of treatment. ORR was determined by evaluating scans of computed tomography or magnetic resonance imaging following Response Evaluation Criteria in Solid Tumor (RECIST 1.1). Two-sided 95% confidence interval (95% CI) for the difference in ORR was determined to evaluate the noninferiority of ZRC-3277 to Perjeta®. The secondary outcomes included the assessment of PK, immunogenicity, and safety between the 2 groups. RESULTS: In the mITT population, 104 (87.39%) and 114 (91.94%) participants achieved the ORR in the ZRC-3277 and Perjeta® groups, respectively. For predefined -15% noninferiority margin, obtained 2-sided 95% CIs (-12.19%, 3.11%) for the difference in ORR (-4.55%) between the 2 groups demonstrated the noninferiority of ZRC-3277 to Perjeta®. PK, immunogenicity, and safety were not significantly different between the 2 groups. CONCLUSION: Efficacy, PK, immunogenicity, and safety profiles of ZRC-3277 was found to be similar to those of Perjeta®.
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Anticuerpos Monoclonales Humanizados , Biosimilares Farmacéuticos , Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Persona de Mediana Edad , Método Doble Ciego , India , Biosimilares Farmacéuticos/uso terapéutico , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/efectos adversos , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/efectos adversos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacocinética , Resultado del Tratamiento , Trastuzumab/uso terapéutico , Trastuzumab/administración & dosificación , Docetaxel/uso terapéutico , Docetaxel/administración & dosificaciónRESUMEN
As genomic selection emerges as a promising breeding method for both plants and animals, numerous methods have been introduced and applied to various real and simulated data sets. Research suggests that no single method is universally better than others; rather, performance is highly dependent on the characteristics of the data and the nature of the prediction task. This implies that each method has its strengths and weaknesses. In this study, we exploit this notion and propose a different approach. Rather than comparing multiple methods to determine the best one for a particular study, we advocate combining multiple methods to achieve better performance than each method in isolation. In pursuit of this goal, we introduce and develop a computational method of the stacked generalization within ensemble methods. In this method, the meta-model merges predictions from multiple base models to achieve improved performance. We applied this method to plant and animal data and compared its performance with currently available methods using standard performance metrics. We found that the proposed method yielded a lower or comparable mean squared error in predicting phenotypes compared to the current methods. In addition, the proposed method showed greater resistance to overfitting compared to the current methods. Further analysis included statistical hypothesis testing, which showed that the proposed method outperformed or matched the current methods. In summary, the proposed stacked generalization integrates currently available methods to achieve stable and better performance. In this context, our study provides general recommendations for effective practices in genomic selection.