RESUMEN

BACKGROUND: Mediation analysis, often completed as secondary analysis to estimating the main treatment effect, investigates situations where an exposure may affect an outcome both directly and indirectly through intervening mediator variables. Although there has been much research on power in mediation analyses, most of this has focused on the power to detect indirect effects. Little consideration has been given to the extent to which the strength of the mediation pathways, i.e., the intervention-mediator path and the mediator-outcome path respectively, may affect the power to detect the total effect, which would correspond to the intention-to-treat effect in a randomized trial. METHODS: We conduct a simulation study to evaluate the relation between the mediation pathways and the power of testing the total treatment effect, i.e., the intention-to-treat effect. Consider a sample size that is computed based on the usual formula for testing the total effect in a two-arm trial. We generate data for a continuous mediator and a normal outcome using the conventional mediation models. We estimate the total effect using simple linear regression and evaluate the power of a two-sided test. We explore multiple data generating scenarios by varying the magnitude of the mediation paths whilst keeping the total effect constant. RESULTS: Simulations show the estimated total effect is unbiased across the considered scenarios as expected, but the mean of its standard error increases with the magnitude of the mediator-outcome path and the variability in the residual error of the mediator, respectively. Consequently, this affects the power of testing the total effect, which is always lower than planned when the mediator-outcome path is non-trivial and a naive sample size was employed. Analytical explanation confirms that the intervention-mediator path does not affect the power of testing the total effect but the mediator-outcome path. The usual effect size consideration can be adjusted to account for the magnitude of the mediator-outcome path and its residual error. CONCLUSIONS: The sample size calculation for studies with efficacy and mechanism evaluation should account for the mediator-outcome association or risk the power to detect the total effect/intention-to-treat effect being lower than planned.

Asunto(s)

Simulación por Computador , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Tamaño de la Muestra , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Análisis de Mediación , Análisis de Intención de Tratar , Resultado del Tratamiento , Interpretación Estadística de Datos , Modelos Lineales , Modelos Estadísticos

RESUMEN

BACKGROUND: The efficacy and safety of risankizumab as compared with ustekinumab in patients with Crohn's disease are unknown. METHODS: In this phase 3b, multicenter, open-label, randomized, controlled trial with blinded assessment of end points, patients with moderate-to-severe Crohn's disease who had had an inadequate response to anti-tumor necrosis factor (TNF) therapy or unacceptable side effects with such therapy were randomly assigned to receive risankizumab or ustekinumab at standard doses for 48 weeks. The two primary end points, which were tested sequentially, were clinical remission at week 24 (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]), which was analyzed in the first 50% of patients to complete the week 24 visit, with a noninferiority margin of 10 percentage points; and endoscopic remission at week 48 (defined as a score of ≤4, a decrease of ≥2 points from baseline, and no subscore >1 in any individual variable on the Simple Endoscopic Score for Crohn's Disease [range, 0 to 56, with higher scores indicating more severe disease]), which was analyzed for superiority in 100% of the patients. Safety was assessed in all patients who received at least one dose of risankizumab or ustekinumab. RESULTS: In the full intention-to-treat population for the efficacy analysis, 230 of 255 patients (90.2%) who received risankizumab and 193 of 265 patients (72.8%) who received ustekinumab completed all the assigned treatments. Both primary end points were met; risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 (58.6% vs. 39.5%; adjusted difference, 18.4 percentage points; 95% confidence interval [CI], 6.6 to 30.3) and superior to ustekinumab with respect to endoscopic remission at week 48 (31.8% vs. 16.2%; adjusted difference, 15.6 percentage points; 95% CI, 8.4 to 22.9; P<0.001). The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: In this head-to-head clinical trial of risankizumab and ustekinumab involving patients with moderate-to-severe Crohn's disease who had had unacceptable side effects with anti-TNF therapy or an inadequate response to such therapy, risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 and superior with respect to endoscopic remission at week 48. (Funded by AbbVie; ClinicalTrials.gov number, NCT04524611.).

Asunto(s)

Anticuerpos Monoclonales , Enfermedad de Crohn , Ustekinumab , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Análisis de Intención de Tratar , Inducción de Remisión , Índice de Severidad de la Enfermedad , Ustekinumab/uso terapéutico , Ustekinumab/efectos adversos , Endoscopía Gastrointestinal

RESUMEN

BACKGROUND: Waitlist and posttransplant outcomes have been widely reported for pediatric liver transplantation. Yet, analyzing these metrics individually fails to provide a holistic perspective for patients and their families. Intent-to-treat (ITT) analysis fills this gap by studying the associations between waitlist outcomes, organ availability, and posttransplant outcomes. Our study aimed to construct a predictive index utilizing ITT analysis for pediatric liver transplant recipients (Pedi-ITT). METHODS: We performed a retrospective analysis utilizing de-identified data provided by the United Network for Organ Sharing (UNOS) from March 1, 2002, to December 31, 2021. We analyzed data for 12 926 pediatric recipients (age <18). We conducted a univariate and multivariable logistic regression to find the significant predictive factors affecting ITT survival. A scoring index was constructed to stratify outcome risk on the basis of the significant factors identified by regression analysis. RESULTS: Multivariable analysis found the following factors to be significantly associated with death on the waitlist or after transplant: gender, diagnosis, UNOS region, ascites, diabetes mellitus, age at the time of listing, serum sodium at the time of listing, total bilirubin at the time of listing, serum creatinine at the time of listing, INR at the time of listing, history of ventilator use, and history of re-transplantation. Using receiver operator characteristic analysis, the Pedi-ITT index had a c-statistic of 0.79 (95% confidence interval [CI]: 0.76-0.82). The c-statistics of the Model for End-Stage Liver Disease/Pediatric for End-Stage Liver Disease and pediatric version of the Survival Outcomes Following Liver Transplantation score indices were 0.74 (CI: 0.71-0.76) and 0.69 (CI: 0.66-0.72), respectively. CONCLUSIONS: The Pedi-ITT index provides an additional prognostic model with moderate predictive power to assess outcomes associated with pediatric liver transplantation. Further analysis should focus on increasing the predictive power of the index.

Asunto(s)

Trasplante de Hígado , Listas de Espera , Humanos , Femenino , Masculino , Estudios Retrospectivos , Niño , Adolescente , Preescolar , Lactante , Listas de Espera/mortalidad , Análisis de Intención de Tratar , Enfermedad Hepática en Estado Terminal/cirugía , Enfermedad Hepática en Estado Terminal/mortalidad , Modelos Logísticos , Recién Nacido , Pronóstico , Factores de Riesgo

RESUMEN

BACKGROUND: Observational studies suggest that voluntary medical male circumcision (VMMC) may lower HIV risk among men who have sex with men (MSM). A randomized controlled trial (RCT) is needed to confirm this. OBJECTIVE: To assess the efficacy of VMMC in preventing incident HIV infection among MSM. DESIGN: An RCT with up to 12 months of follow-up. (Chinese Clinical Trial Registry: ChiCTR2000039436). SETTING: 8 cities in China. PARTICIPANTS: Uncircumcised, HIV-seronegative men aged 18 to 49 years who self-reported predominantly practicing insertive anal intercourse and had 2 or more male sex partners in the past 6 months. INTERVENTION: VMMC. MEASUREMENTS: Rapid testing for HIV was done at baseline and at 3, 6, 9, and 12 months. Behavioral questionnaires and other tests for sexually transmitted infections were done at baseline, 6 months, and 12 months. The primary outcome was HIV seroconversion using an intention-to-treat analysis. RESULTS: The study enrolled 124 men in the intervention group and 123 in the control group, who contributed 120.7 and 123.1 person-years of observation, respectively. There were 0 seroconversions in the intervention group (0 infections [95% CI, 0.0 to 3.1 infections] per 100 person-years) and 5 seroconversions in the control group (4.1 infections [CI, 1.3 to 9.5 infections] per 100 person-years). The HIV hazard ratio was 0.09 (CI, 0.00 to 0.81; P = 0.029), and the HIV incidence was lower in the intervention group (log-rank P = 0.025). The incidence rates of syphilis, herpes simplex virus type 2, and penile human papillomavirus were not statistically significantly different between the 2 groups. There was no evidence of HIV risk compensation. LIMITATION: Few HIV seroconversions and limited follow-up period. CONCLUSION: Among MSM who predominantly practice insertive anal intercourse, VMMC is efficacious in preventing incident HIV infection; MSM should be included in VMMC guidelines. PRIMARY FUNDING SOURCE: The National Science and Technology Major Project of China.

Asunto(s)

Circuncisión Masculina , Infecciones por VIH , Homosexualidad Masculina , Humanos , Masculino , Adulto , Infecciones por VIH/prevención & control , Infecciones por VIH/epidemiología , Adulto Joven , Adolescente , Persona de Mediana Edad , China/epidemiología , Incidencia , Conducta Sexual , Análisis de Intención de Tratar

RESUMEN

Importance: Obesity has become a global public health concern and China has the largest number of affected people worldwide. Objective: To assess the efficacy and safety of treatment with tirzepatide for weight reduction in Chinese adults with obesity or overweight and weight-related comorbidities. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 29 centers in China from September 2021 to December 2022 included Chinese adults (aged ≥18 years) with a body mass index (BMI) greater than or equal to 28 or greater than or equal to 24 and at least 1 weight-related comorbidity, excluding diabetes. Interventions: Participants were randomly assigned (1:1:1) to receive once-weekly, subcutaneous 10-mg (n = 70) or 15-mg (n = 71) tirzepatide or placebo (n = 69), plus a lifestyle intervention, for 52 weeks. Main Outcomes and Measures: Co-primary end points were the percent change in body weight from baseline and weight reduction of at least 5% at week 52. Efficacy and safety analyses were performed on an intention-to-treat population. Results: Of 210 randomized participants (103 [49.0%] female; mean [SD] age, 36.1 [9.1] years; body weight, 91.8 [16.0] kg; BMI, 32.3 [3.8]), 201 (95.7%) completed the trial. The mean change in body weight at week 52 was -13.6% (95% CI, -15.8% to -11.4%) with tirzepatide 10 mg, -17.5% (95% CI, -19.7% to -15.3%) with tirzepatide 15 mg, and -2.3% with placebo (difference between 10 mg and placebo, -11.3% [95% CI, -14.3% to -8.3%; P < .001]; difference between 15 mg and placebo, -15.1% [95% CI, -18.2% to -12.1%; P < .001]). The percentage of participants achieving body weight reductions of 5% or greater was 87.7% with tirzepatide 10 mg, 85.8% with tirzepatide 15 mg, and 29.3% with placebo (P < .001 for comparisons with placebo). The most frequent treatment-emergent adverse events with tirzepatide were gastrointestinal. Most were mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Conclusions and Relevance: In Chinese adults with obesity or overweight, once-weekly treatment with tirzepatide 10 mg or 15 mg resulted in statistically significant and clinically meaningful weight reduction with an acceptable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT05024032.

Asunto(s)

Fármacos Antiobesidad , Polipéptido Inhibidor Gástrico , Receptor del Péptido 2 Similar al Glucagón , Obesidad , Sobrepeso , Pérdida de Peso , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/efectos adversos , Índice de Masa Corporal , China , Método Doble Ciego , Polipéptido Inhibidor Gástrico/administración & dosificación , Polipéptido Inhibidor Gástrico/efectos adversos , Receptor del Péptido 2 Similar al Glucagón/agonistas , Inyecciones Subcutáneas , Análisis de Intención de Tratar , Obesidad/tratamiento farmacológico , Sobrepeso/tratamiento farmacológico , Pérdida de Peso/efectos de los fármacos

RESUMEN

Importance: For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. Objective: To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled. Interventions: Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed. Main Outcomes and Measures: The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported. Results: Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Conclusions: Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT05184712.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatino , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Pemetrexed , Supervivencia sin Progresión , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Método Doble Ciego , Receptores ErbB/genética , Análisis de Intención de Tratar , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Mutación , Pemetrexed/administración & dosificación , Pemetrexed/efectos adversos , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos

RESUMEN

OBJECTIVE: Multimorbidity or the co-occurrence of multiple health conditions is increasing globally and is associated with significant psychological complications. It is unclear whether digital mental health (DMH) interventions for patients experiencing multimorbidity are effective, particularly given that this patient population faces more treatment resistance. The goal of the current study was to examine the impact of smartphone-delivered DMH interventions for patients presenting with elevated internalizing symptoms that have reported multiple lifetime medical conditions. METHODS: This preregistered (see https://osf.io/vh2et/ ) retrospective cohort intent-to-treat study with 2819 patients enrolled in a therapist-supported DMH intervention examined the associations between medical multimorbidity (MMB) and mental health outcomes. RESULTS: Results indicated that more MMB was significantly associated with greater presenting mental health symptom severity. MMB did not have a deleterious influence on depressive symptom trajectories across treatment, although having one medical condition was associated with a steeper decrease in anxiety symptoms compared to patients with no medical conditions. Finally, MMB was not associated with time to dropout, but was associated with higher dropout and was differentially associated with fewer beneficial treatment outcomes, although this is likely attributable to higher presenting symptom severity, rather than lesser symptom reductions during treatment. CONCLUSIONS: Overall, the Meru Health Program was associated with large effect size decreases in depressive and anxiety symptoms regardless of the number of MMB. Future DMH treatments and research might investigate tailored barrier reduction and extended treatment lengths for patients experiencing MMB to allow for greater treatment dose to reduce symptoms below clinical outcome thresholds.

Asunto(s)

Multimorbilidad , Humanos , Estudios Retrospectivos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Telemedicina , Teléfono Inteligente , Anciano , Ansiedad/terapia , Ansiedad/epidemiología , Depresión/terapia , Depresión/epidemiología , Análisis de Intención de Tratar , Psicoterapia/métodos , Evaluación de Resultado en la Atención de Salud

RESUMEN

CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2-74.2%) and 46.5% (95%CI 37.6-57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1-44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3-75.8) and 55.3% (95%CI 43.6-70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival.

Asunto(s)

Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Quiméricos de Antígenos , Niño , Humanos , Adolescente , Análisis de Intención de Tratar , Estudios Retrospectivos , Receptores de Antígenos de Linfocitos T , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inmunoterapia Adoptiva/efectos adversos , Antígenos CD19

RESUMEN

BACKGROUND: Non-inferiority trials comparing different active drugs are often subject to treatment non-adherence. Intention-to-treat (ITT) and per-protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non-adherence. METHODS: The REMoxTB trial evaluated two 4-month experimental regimens compared with a 6-month control regimen for newly diagnosed drug-susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post-randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non-adherence in non-inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse-probability-of-treatment weighting (IPTW), and a doubly-robust (DR) estimator. RESULTS: When non-adherence differed between trial arms, ITT, and PP analyses often resulted in non-trivial bias in the estimated treatment effect, which consequently under- or over-inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non-adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power. CONCLUSIONS: When non-adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches.

Asunto(s)

Simulación por Computador , Análisis de Intención de Tratar , Humanos , Estudios de Equivalencia como Asunto , Cumplimiento de la Medicación/estadística & datos numéricos , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Tuberculosis/tratamiento farmacológico , Resultado del Tratamiento , Sesgo , Modelos Estadísticos

RESUMEN

Living donor liver transplantation (LDLT) offers the opportunity to decrease waitlist time and mortality for patients with autoimmune liver disease (AILD), autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. We compared the survival of patients with a potential living donor (pLDLT) on the waitlist versus no potential living donor (pDDLT) on an intention-to-treat basis. Our retrospective cohort study investigated adults with AILD listed for a liver transplant in our program between 2000 and 2021. The pLDLT group comprised recipients with a potential living donor. Otherwise, they were included in the pDDLT group. Intention-to-treat survival was assessed from the time of listing. Of the 533 patients included, 244 (43.8%) had a potential living donor. Waitlist dropout was higher for the pDDLT groups among all AILDs (pDDLT 85 [29.4%] vs. pLDLT 9 [3.7%], p < 0.001). The 1-, 3-, and 5-year intention-to-treat survival rates were higher for pLDLT versus pDDLT among all AILDs (95.7% vs. 78.1%, 89.0% vs. 70.1%, and 87.1% vs. 65.5%, p < 0.001). After adjusting for covariates, pLDLT was associated with a 38% reduction in the risk of death among the AILD cohort (HR: 0.62, 95% CI: 0.42-0.93 [ p <0.05]), and 60% among the primary sclerosing cholangitis cohort (HR: 0.40, 95% CI: 0.22-0.74 [ p <0.05]). There were no differences in the 1-, 3-, and 5-year post-transplant survival between LDLT and DDLT (AILD: 95.6% vs. 92.1%, 89.9% vs. 89.4%, and 89.1% vs. 87.1%, p =0.41). This was consistent after adjusting for covariates (HR: 0.97, 95% CI: 0.56-1.68 [ p >0.9]). Our study suggests that having a potential living donor could decrease the risk of death in patients with primary sclerosing cholangitis on the waitlist. Importantly, the post-transplant outcomes in this population are similar between the LDLT and DDLT groups.

Asunto(s)

Colangitis Esclerosante , Hepatitis Autoinmune , Análisis de Intención de Tratar , Trasplante de Hígado , Donadores Vivos , Listas de Espera , Humanos , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Trasplante de Hígado/estadística & datos numéricos , Femenino , Masculino , Donadores Vivos/estadística & datos numéricos , Estudios Retrospectivos , Persona de Mediana Edad , Listas de Espera/mortalidad , Adulto , Resultado del Tratamiento , Colangitis Esclerosante/cirugía , Colangitis Esclerosante/mortalidad , Colangitis Esclerosante/complicaciones , Hepatitis Autoinmune/cirugía , Hepatitis Autoinmune/mortalidad , Enfermedad Hepática en Estado Terminal/cirugía , Enfermedad Hepática en Estado Terminal/mortalidad , Enfermedad Hepática en Estado Terminal/diagnóstico , Cirrosis Hepática Biliar/cirugía , Cirrosis Hepática Biliar/mortalidad , Enfermedades Autoinmunes/cirugía , Enfermedades Autoinmunes/mortalidad , Anciano , Factores de Tiempo , Supervivencia de Injerto

RESUMEN

Randomized controlled trials and intent-to-treat analyses are important for infertility clinical studies. Dropouts or crossovers during the study process will disrupt the randomization design and affect the intent-to-treat analysis. In this review, we have briefly introduced the occurrence of dropout and crossover from our previous Reproductive Medicine Network and other related studies and provided some experience obtained from these studies on how to minimize and reduce the occurrence of dropout and crossover for infertility randomized clinical studies.

Asunto(s)

Estudios Cruzados , Infertilidad , Pacientes Desistentes del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Infertilidad/terapia , Infertilidad/diagnóstico , Infertilidad/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Femenino , Técnicas Reproductivas Asistidas , Masculino , Resultado del Tratamiento , Análisis de Intención de Tratar

RESUMEN

OBJECTIVES: Patients undergoing revascularization for chronic limb-threatening ischemia experience a high burden of target limb reinterventions. We analyzed data from the Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) randomized trial comparing initial open bypass (OPEN) and endovascular (ENDO) treatment strategies, with a focus on reintervention-related study endpoints. METHODS: In a planned secondary analysis, we examined the rates of major reintervention, any reintervention, and the composite of any reintervention, amputation, or death by intention-to-treat assignment in both trial cohorts (cohort 1 with suitable single-segment great saphenous vein [SSGSV], n = 1434; cohort 2 lacking suitable SSGSV, n = 396). We also compared the cumulative number of major and all index limb reinterventions over time. Comparisons between treatment arms within each cohort were made using univariable and multivariable Cox regression models. RESULTS: In cohort 1, assignment to OPEN was associated with a significantly reduced hazard of a major limb reintervention (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.28-0.49; P < .001), any reintervention (HR, 0.63; 95% CI, 0.53-0.75; P < .001), or any reintervention, amputation, or death (HR, 0.68; 95% CI, 0.60-0.78; P < .001). Findings were similar in cohort 2 for major reintervention (HR, 0.53; 95% CI, 0.33-0.84; P = .007) or any reintervention (HR, 0.71; 95% CI, 0.52-0.98; P = .04). In both cohorts, early (30-day) limb reinterventions were notably higher for patients assigned to ENDO as compared with OPEN (14.7% vs 4.5% of cohort 1 subjects; 16.6% vs 5.6% of cohort 2 subjects). The mean number of major (mean events per subject ratio [MR], 0.45; 95% CI, 0.34-0.58; P < .001) or any target limb reinterventions (MR, 0.67; 95% CI, 0.57-0.80; P < .001) per year was significantly less in the OPEN arm of cohort 1. The mean number of reinterventions per limb salvaged per year was lower in the OPEN arm of cohort 1 (MR, 0.45; 95% CI, 0.35-0.57; P < .001 and MR, 0.66; 95% CI, 0.55-0.79; P < .001 for major and all, respectively). The majority of index limb reinterventions occurred during the first year following randomization, but events continued to accumulate over the duration of follow-up in the trial. CONCLUSIONS: Reintervention is common following revascularization for chronic limb-threatening ischemia. Among patients deemed suitable for either approach, initial treatment with open bypass, particularly in patients with available SSGSV conduit, is associated with a significantly lower number of major and minor target limb reinterventions.

Asunto(s)

Amputación Quirúrgica , Procedimientos Endovasculares , Isquemia , Recuperación del Miembro , Reoperación , Humanos , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Masculino , Femenino , Anciano , Isquemia/cirugía , Isquemia/mortalidad , Isquemia/fisiopatología , Isquemia/diagnóstico , Resultado del Tratamiento , Factores de Tiempo , Factores de Riesgo , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Enfermedad Arterial Periférica/cirugía , Enfermedad Arterial Periférica/mortalidad , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/fisiopatología , Isquemia Crónica que Amenaza las Extremidades/cirugía , Enfermedad Crónica , Injerto Vascular/efectos adversos , Injerto Vascular/mortalidad , Análisis Multivariante , Enfermedad Crítica , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Vena Safena/trasplante , Vena Safena/cirugía

RESUMEN

ABSTRACT: This review presents a comprehensive summary and critical evaluation of intention-to-treat analysis, with a particular focus on its application to randomized controlled trials within the field of rehabilitation. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a methodological review that encompassed electronic and manual search strategies to identify relevant studies. Our selection process involved two independent reviewers who initially screened titles and abstracts and subsequently performed full-text screening based on established eligibility criteria. In addition, we included studies from manual searches that were already cataloged within the first author's personal database. The findings are synthesized through a narrative approach, covering fundamental aspects of intention to treat, including its definition, common misconceptions, advantages, disadvantages, and key recommendations. Notably, the health literature offers a variety of definitions for intention to treat, which can lead to misinterpretations and inappropriate application when analyzing randomized controlled trial results, potentially resulting in misleading findings with significant implications for healthcare decision making. Authors should clearly report the specific intention-to-treat definition used in their analysis, provide details on participant dropouts, and explain upon their approach to managing missing data. Adherence to reporting guidelines, such as the Consolidated Standards of Reporting Trials for randomized controlled trials, is essential to standardize intention-to-treat information, ensuring the delivery of accurate and informative results for healthcare decision making.

Asunto(s)

Análisis de Intención de Tratar , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Investigación Biomédica , Proyectos de Investigación

RESUMEN

Aim: Social isolation in cancer patients is correlated with prognosis and is a potential mediator of treatment completion. Black women with endometrial cancer (EC) are at increased risk for social isolation when compared with White patients. We developed the Social Interventions for Support during Treatment for Endometrial Cancer and Recurrence (SISTER) study to compare and evaluate interventions to address social isolation among Black women with high-risk EC in USA. The primary objective of the SISTER study is to determine whether virtual support interventions improve treatment completion compared with Enhanced Usual Care. Secondary objectives include comparing effectiveness virtual evidence-based interventions and evaluating barriers and facilitators to social support delivery. Patients & methods: This is a multi-site prospective, open-label, community-engaged randomized controlled trial, consisting of three intervention arms: enhanced usual care, facilitated support group and one-to-one peer support. Primary outcome will be measured using relative dose. Qualitative semi-structured interviews will be conducted with a subset of participants to contextualize the relative degree or lack thereof of social isolation, over time. Data analysis: Primary analysis will be based on an intent-to-treat analysis. Multivariable analysis will be performed to determine the effect of the intervention on the primary and secondary outcomes of interest, relative dose and social isolation score. Semi-structured interviews will be qualitatively analyzed using inductive and deductive approaches of content analysis. Discussion/conclusion: Endometrial cancer mortality disproportionately affects Black women, and social isolation contributes to this disparity. The SISTER study aims to identify whether and to what extent differing social support vehicles improve key outcomes for Black women in the United States with high-risk EC. Clinical Trial Registration: NCT04930159 (ClinicalTrials.gov).

Asunto(s)

Neoplasias Endometriales , Femenino , Humanos , Neoplasias Endometriales/terapia , Análisis de Intención de Tratar , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Investigación , Servicio Social

RESUMEN

INTRODUCTION: Adenoma per colonoscopy (APC) has recently been proposed as a quality measure for colonoscopy. We evaluated the impact of a novel artificial intelligence (AI) system, compared with standard high-definition colonoscopy, for APC measurement. METHODS: This was a US-based, multicenter, prospective randomized trial examining a novel AI detection system (EW10-EC02) that enables a real-time colorectal polyp detection enabled with the colonoscope (CAD-EYE). Eligible average-risk subjects (45 years or older) undergoing screening or surveillance colonoscopy were randomized to undergo either CAD-EYE-assisted colonoscopy (CAC) or conventional colonoscopy (CC). Modified intention-to-treat analysis was performed for all patients who completed colonoscopy with the primary outcome of APC. Secondary outcomes included positive predictive value (total number of adenomas divided by total polyps removed) and adenoma detection rate. RESULTS: In modified intention-to-treat analysis, of 1,031 subjects (age: 59.1 ± 9.8 years; 49.9% male), 510 underwent CAC vs 523 underwent CC with no significant differences in age, gender, ethnicity, or colonoscopy indication between the 2 groups. CAC led to a significantly higher APC compared with CC: 0.99 ± 1.6 vs 0.85 ± 1.5, P = 0.02, incidence rate ratio 1.17 (1.03-1.33, P = 0.02) with no significant difference in the withdrawal time: 11.28 ± 4.59 minutes vs 10.8 ± 4.81 minutes; P = 0.11 between the 2 groups. Difference in positive predictive value of a polyp being an adenoma among CAC and CC was less than 10% threshold established: 48.6% vs 54%, 95% CI -9.56% to -1.48%. There were no significant differences in adenoma detection rate (46.9% vs 42.8%), advanced adenoma (6.5% vs 6.3%), sessile serrated lesion detection rate (12.9% vs 10.1%), and polyp detection rate (63.9% vs 59.3%) between the 2 groups. There was a higher polyp per colonoscopy with CAC compared with CC: 1.68 ± 2.1 vs 1.33 ± 1.8 (incidence rate ratio 1.27; 1.15-1.4; P < 0.01). DISCUSSION: Use of a novel AI detection system showed to a significantly higher number of adenomas per colonoscopy compared with conventional high-definition colonoscopy without any increase in colonoscopy withdrawal time, thus supporting the use of AI-assisted colonoscopy to improve colonoscopy quality ( ClinicalTrials.gov NCT04979962).

Asunto(s)

Adenoma , Inteligencia Artificial , Pólipos del Colon , Colonoscopía , Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Colonoscopía/métodos , Masculino , Persona de Mediana Edad , Femenino , Adenoma/diagnóstico , Adenoma/diagnóstico por imagen , Estudios Prospectivos , Pólipos del Colon/diagnóstico , Pólipos del Colon/diagnóstico por imagen , Pólipos del Colon/patología , Detección Precoz del Cáncer/métodos , Anciano , Neoplasias Colorrectales/diagnóstico , Estados Unidos , Valor Predictivo de las Pruebas , Análisis de Intención de Tratar

RESUMEN

BACKGROUND & AIMS: There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US. METHODS: From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates. RESULTS: The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p = 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant. CONCLUSIONS: Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC. IMPACT AND IMPLICATIONS: The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation.

Asunto(s)

Colangitis Esclerosante , Trasplante de Hígado , Adulto , Humanos , Tacrolimus/uso terapéutico , Ciclosporina/uso terapéutico , Inhibidores de la Calcineurina , Estudios Retrospectivos , Trasplante de Hígado/efectos adversos , Colangitis Esclerosante/tratamiento farmacológico , Colangitis Esclerosante/cirugía , Colangitis Esclerosante/etiología , Análisis de Intención de Tratar , Puntaje de Propensión , Inmunosupresores/uso terapéutico , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto

RESUMEN

BACKGROUND: Issues with specification of margins, adherence, and analytic population can potentially bias results toward the alternative in randomized noninferiority pragmatic trials. To investigate this potential for bias, we conducted a targeted search of the medical literature to examine how noninferiority pragmatic trials address these issues. METHODS: An Ovid MEDLINE database search was performed identifying publications in New England Journal of Medicine, Journal of the American Medical Association, Lancet, or British Medical Journal published between 2015 and 2021 that included the words "pragmatic" or "comparative effectiveness" and "noninferiority" or "non-inferiority." Our search identified 14 potential trials, 12 meeting our inclusion criteria (11 individually randomized, 1 cluster-randomized). RESULTS: Eleven trials had results that met the criteria established for noninferiority. Noninferiority margins were prespecified for all trials; all but two trials provided justification of the margin. Most trials did some monitoring of treatment adherence. All trials conducted intent-to-treat or modified intent-to-treat analyses along with per-protocol analyses and these analyses reached similar conclusions. Only two trials included all randomized participants in the primary analysis, one used multiple imputation for missing data. The percentage excluded from primary analyses ranged from ∼2% to 30%. Reasons for exclusion included randomization in error, nonadherence, not receiving assigned treatment, death, withdrawal, lost to follow-up, and incomplete data. CONCLUSION: Specification of margins, adherence, and analytic population require careful consideration to prevent bias toward the alternative in noninferiority pragmatic trials. Although separate guidance has been developed for noninferiority and pragmatic trials, it is not compatible with conducting a noninferiority pragmatic trial. Hence, these trials should probably not be done in their current format without developing new guidelines.

Asunto(s)

Proyectos de Investigación , Estados Unidos , Humanos , Sesgo , Análisis de Intención de Tratar

RESUMEN

BACKGROUND: Systemic chemotherapy is the initial treatment strategy for borderline resectable and locally advanced pancreatic cancer to facilitate curative resection. The aim of this study was to investigate the resection rates and overall survival in patients with borderline resectable pancreatic cancer and locally advanced pancreatic cancer. METHODS: Consecutive patients with borderline resectable pancreatic cancer/locally advanced pancreatic cancer discussed by Oslo University Hospital multidisciplinary team between 2018 and 2020, serving a population of 3.1 million within a geographically defined area in south-eastern Norway, were included in this prospective Norwegian Pancreatic Cancer Trial-2 study, according to intention-to-treat principles. The total number of patients with pancreatic cancer was sought from the Cancer Registry of Norway. RESULTS: A total of 1178 patients were diagnosed with pancreatic cancer, of whom 618 were referred to Oslo University Hospital. After multidisciplinary team evaluation, 230 patients were considered to have borderline resectable pancreatic cancer/locally advanced pancreatic cancer. The final study group consisted of 188 patients (borderline resectable pancreatic cancer n = 96, locally advanced pancreatic cancer n = 92) who were fit to receive primary chemotherapy. Resection rates were 46.9% (45 of 96) for borderline resectable pancreatic cancer and 13% (12 of 92) for locally advanced pancreatic cancer (P <0.001). Median overall survival was 14.6 months (borderline resectable pancreatic cancer 16.4 months; locally advanced pancreatic cancer 13.7 months, (P = 0.2)). Adjusted for immortal time bias, median overall survival for patients undergoing resection versus only chemotherapy was 24.4 months versus 10.1 months (P <0.001) for borderline resectable pancreatic cancer and 28.4 months versus 12.6 months for locally advanced pancreatic cancer (P = 0.001). CONCLUSION: Resection rates and survival in patients with borderline resectable pancreatic cancer and locally advanced pancreatic cancer treated at a high-volume centre in a universal healthcare system compare well with those treated at international expert centres.Registration number: NCT04423731 (http://www.clinicaltrials.gov).

Asunto(s)

Terapia Neoadyuvante , Neoplasias Pancreáticas , Humanos , Estudios Prospectivos , Análisis de Intención de Tratar , Neoplasias Pancreáticas/cirugía , Pancreatectomía

Asunto(s)

COVID-19 , Humanos , Análisis de Intención de Tratar

Asunto(s)

Intención , Proyectos de Investigación , Humanos , Análisis de Intención de Tratar , Sesgo , Resultado del Tratamiento