Pneumocystis pneumonia in intensive care: clinical spectrum, prophylaxis patterns, antibiotic treatment delay impact, and role of corticosteroids. A French multicentre prospective cohort study.

PURPOSE: Severe Pneumocystis jirovecii pneumonia (PJP) requiring intensive care has been the subject of few prospective studies. It is unclear whether delayed curative antibiotic therapy may impact survival in these severe forms of PJP. The impact of corticosteroid therapy combined with antibiotics is also unclear. METHODS: This multicentre, prospective observational study involving 49 adult intensive care units (ICUs) in France was designed to evaluate the severity, the clinical spectrum, and outcomes of patients with severe PJP, and to assess the association between delayed curative antibiotic treatment and adjunctive corticosteroid therapy with mortality. RESULTS: We included 158 patients with PJP from September 2020 to August 2022. Their main reason for admission was acute respiratory failure (n = 150, 94.9%). 12% of them received antibiotic prophylaxis for PJP before ICU admission. The ICU, hospital, and 6-month mortality were 31.6%, 35.4%, and 40.5%, respectively. Using time-to-event analysis with a propensity score-based inverse probability of treatment weighting, the initiation of curative antibiotic treatment after 96 h of ICU admission was associated with faster occurrence of death [time ratio: 6.75; 95% confidence interval (95% CI): 1.48-30.82; P = 0.014]. The use of corticosteroids for PJP was associated with faster occurrence of death (time ratio: 2.48; 95% CI 1.01-6.08; P = 0.048). CONCLUSION: This study showed that few patients with PJP admitted to intensive care received prophylactic antibiotic therapy, that delay in curative antibiotic treatment was common and that both delay in curative antibiotic treatment and adjunctive corticosteroids for PJP were associated with accelerated mortality.

Assurance methods for designing a clinical trial with a delayed treatment effect.

An assurance calculation is a Bayesian alternative to a power calculation. One may be performed to aid the planning of a clinical trial, specifically setting the sample size or to support decisions about whether or not to perform a study. Immuno-oncology is a rapidly evolving area in the development of anticancer drugs. A common phenomenon that arises in trials of such drugs is one of delayed treatment effects, that is, there is a delay in the separation of the survival curves. To calculate assurance for a trial in which a delayed treatment effect is likely to be present, uncertainty about key parameters needs to be considered. If uncertainty is not considered, the number of patients recruited may not be enough to ensure we have adequate statistical power to detect a clinically relevant treatment effect and the risk of an unsuccessful trial is increased. We present a new elicitation technique for when a delayed treatment effect is likely and show how to compute assurance using these elicited prior distributions. We provide an example to illustrate how this can be used in practice and develop open-source software to implement our methods. Our methodology has the potential to improve the success rate and efficiency of Phase III trials in immuno-oncology and for other treatments where a delayed treatment effect is expected to occur.

Time assessment for final restoration of endodontically treated teeth in a university clinic setting: An observational study.

Background: The aim was to quantify the time elapsed between tooth reconstruction and the end of endodontic treatment, and to assess differences according to sex, age, and tooth group. Material and Methods: A retrospective study was conducted with patient clinical records. Data relating to patient characteristics, treated teeth, endodontic treatment, and subsequent restorative treatment were recorded. Results: For this study, 355 endodontically treated teeth by undergraduate students during 2019 were included. 24 teeth (6.76 %) were not restored, more direct (86.4 %) than indirect (13.6 %) restorations were performed, and the most frequent type of restoration was complex filling. The mean elapsed time from endodontic completion to direct restoration was 7 days, with a minimum of 0 and a maximum of 90 days. For indirect restorations the mean elapsed time was 21 days. Conclusions: The median elapsed time for endodontic tooth reconstruction was 7 days (IQR = 7), however, treatment should not be considered completed until the tooth has been properly restored. In cases where an indirect restoration was also necessary, the median elapsed time was higher (21 days; IQR = 31.5).

Outcomes in children with delayed surgical treatment of medial humeral condyle fractures.

PURPOSE: Medial humeral condyle (MHC) fractures are easily overlooked in young patients. This can lead to delayed or incorrect diagnosis, resulting in delayed treatment, which is often associated with complications such as nonunion, osteonecrosis, fishtail deformity, and cubitus varus. The purpose of this study is to evaluate the clinical and radiographic outcomes in a cohort of paediatric patients who underwent delayed surgery for an untreated MHC fracture. METHODS: From January 2017 to December 2022, we conducted a retrospective study of paediatric patients who underwent delayed treatment for a MHC fracture. In all cases, the initial diagnosis was incorrect and surgery was performed at least one week after injury. Patients were divided into two groups based on the time between trauma and surgery: Group 1 consisted of individuals who underwent early delayed treatment within seven to 30 days of injury, while Group 2 consisted of those who underwent late delayed treatment more than one month after injury. Elbow function was assessed using the Mayo Elbow Performance Score (MEPS) and range of motion (ROM). The related literature was also reviewed (1970-2023). RESULTS: We enrolled 12 patients (7 boys, 5 girls); the average age at the time of surgery was 7.7 years (range, 2-14 years). Six patients underwent early delayed treatment (Group 1) while another six underwent late delayed treatment (Group 2). The mean time from injury to surgery was 17.7 days (range, 7-30 days) and 33.3 months (range, 70 days-9 years) in Groups 1 and 2, respectively. Open reduction and internal fixation were performed via a medial approach in 11 patients, while one patient underwent closing wedge osteotomy and internal fixation to correct cubitus varus deformity. The mean duration of follow-up was 39.4 months (range, 8-60 months). The average MEPS score was 98.3 in Group 1 (range, 95-100) and 94.2 in Group 2 (range, 85-100; P = 0.21). The following postoperative complications were recorded: heterotopic ossification (n = 2), fishtail deformity (n = 1), MHC necrosis (n = 1), and reduction of elbow ROM (n = 1); one complication occurred in Group 1 and five occurred in Group 2 (P = 0.18). We reviewed nine related studies (n = 14 patients). CONCLUSIONS: Diagnosis of MHC fractures can be challenging in paediatric patients, especially in younger individuals with incompletely ossified trochlea. Patients requiring surgery for delayed MHC fractures with an unossified trochlea should undergo ORIF to prevent progressive varus deformity. On the other hand, in patients with cubitus varus and an already ossified trochlea, distal humeral osteotomy should be considered instead of ORIF. This will minimize the potential negative impact on joint mobility.

Ophthalmia neonatorum complicated with neonatal orbital cellulitis: A case series.

Orbital cellulitis is an extremely rare but potentially lethal condition in neonates. The clinical presentation of neonatal orbital cellulitis can be non-specific, and minimal signs of periorbital inflammation may go unrecognised by inexperienced parents or primary care medical personnel, leading to delayed treatment. Herein, we present a case series describing ophthalmia neonatorum complicated with neonatal orbital cellulitis owing to delayed treatment. The clinical presentation, management and outcomes are described. One neonate had orbital cellulitis, while the other had impending orbital cellulitis, with both cases resulting from delayed treatment of ophthalmia neonatorum. Both neonates were hospitalised for systemic antibiotic treatment and fully recovered with good outcomes. Timely identification and treatment of ophthalmia neonatorum are critical to mitigate potential severe sequelae, such as neonatal orbital cellulitis.

Differences in the association of time to treatment initiation and survival according to various head and neck cancer sites in a nationwide cohort.

OBJECTIVES: To assess whether there are differences in the effects of time to treatment interval (TTI) on patient survival for head and neck cancer (HNC) sites in order to provide evidence that can support decision-making regarding prioritizing treatment. MATERIALS AND METHODS: Patients in the Netherlands with a first primary HNC without distant metastasis between 2010 and 2014 were included for analysis (N = 10,486). TTI was defined as the time from pathologic diagnosis to the start of initial treatment. Overall survival (OS), cox regression analyses and cubic spline hazard models were calculated and visualized. RESULTS: Overall, the hazard of dying was higher (HR = 1.003; 95 % CI 1.001-1.005) with each additional day until treatment initiation. The pattern, as visualized in cubic spline graphs, differed by site the hazard increased more steeply with increasing TTI for oral cavity cancer. For oropharyngeal and laryngeal cancer, a slight increase commenced after a longer TTI than for oral cavity cancer, while there was hardly an increase in hazard with increasing TTI for hypopharyngeal cancer. CONCLUSION: The relationship between longer TTI and decreased survival was confirmed, but slight variations in the pattern of the hazard of dying by TTI by tumour site were observed. These findings could support decisions on prioritizing treatment. However, other aspects such as extent of treatment and quality of life should be investigated further so this can also be included.

Group sequential designs for cancer immunotherapy trial with delayed treatment effect.

Cancer immunotherapy trials are frequently characterized by delayed treatment effects such that the proportional hazards assumption is violated and the log-rank test suffers a substantial loss of statistical power. To increase the efficacy of the trial design, a variety of weighted log-rank tests have been proposed for fixed sample and group sequential trial designs. However, in such a group sequential design, it is often not recommended for futility interim monitoring due to possible delayed treatment effect which could result a high false-negative rate. To resolve this problem, we propose a group sequential design using a piecewise weighted log-rank test which provides an event-driven approach based on number of events after the delayed time. That is, the interim looks will not be conducted until the planned number of events observed after the delay time. Thus, it avoids the possibility of false-negative rate due to the delayed treatment effect. Furthermore, with an event-driven approach, the proposed group sequential design is robust against the underlying survival, accrual and censoring distributions. The group sequential designs using Fleming-Harrington-(ρ,γ) weighted log-rank test and a new weighted log-rank test are also discussed.

A qualitative study of clinicians' perspectives on reasons for delays in clozapine initiation.

OBJECTIVES: To elicit mental health clinicians' views on the reasons for delayed initiation of clozapine treatment. METHOD: Thematic analysis of transcripts from a semi-structured interview of 15 mental health clinicians. RESULTS: Four major themes emerged from data analysis: Patient and Carer Factors, Medication factors, Protocol factors, and Prescriber factors. Patient and carer anxiety over side effects and experience of stigma, difficulties in implementing the monitoring protocol, problems with community managing of treatment, prescriber preferences and practices, and gaps in mental health services were some of the reasons identified. CONCLUSION: Education and support to patients and carers, a modified monitoring protocol, establishing clozapine clinics, improved early intervention services, and upskilling of clinicians can promote early clozapine initiation.

Combination therapy with oral antiviral and anti-inflammatory drugs improves the efficacy of delayed treatment in a COVID-19 hamster model.

BACKGROUND: Pulmonary infection with SARS-CoV-2 stimulates host immune responses and can also result in the progression of dysregulated and critical inflammation. Throughout the pandemic, the management and treatment of COVID-19 has been continuously updated with a range of antiviral drugs and immunomodulators. Monotherapy with oral antivirals has proven to be effective in the treatment of COVID-19. However, treatment should be initiated in the early stages of infection to ensure beneficial therapeutic outcomes, and there is still room for further consideration on therapeutic strategies using antivirals. METHODS: We studied the therapeutic effects of monotherapy with the oral antiviral ensitrelvir or the anti-inflammatory corticosteroid methylprednisolone and combination therapy with ensitrelvir and methylprednisolone in a delayed dosing model of hamsters infected with SARS-CoV-2. FINDINGS: Combination therapy with ensitrelvir and methylprednisolone improved respiratory conditions and reduced the development of pneumonia in hamsters even when the treatment was started after 2 days post-infection. The combination therapy led to a differential histological and transcriptomic pattern in comparison to either of the monotherapies, with reduced lung damage and down-regulation of expression of genes involved in the inflammatory response. Furthermore, we found that the combination treatment is effective in case of infection with either the highly pathogenic delta or circulating omicron variants. INTERPRETATION: Our results demonstrate the advantage of combination therapy with antiviral and corticosteroid drugs in COVID-19 treatment from the perspective of lung pathology and host inflammatory responses. FUNDING: Funding bodies are described in the Acknowledgments section.

Sequential monitoring of cancer immunotherapy trial with random delayed treatment effect.

Cancer immunotherapy trials are frequently characterized by a delayed treatment effect that violates the proportional hazards assumption. The log-rank test (LRT) suffers a substantial loss of statistical power under the nonproportional hazards model. Various group sequential designs using weighted LRTs (WLRTs) have been proposed under the fixed delayed treatment effect model. However, patients enrolled in immunotherapy trials are often heterogeneous, and the duration of the delayed treatment effect is a random variable. Therefore, we propose group sequential designs under the random delayed effect model using the random delayed distribution WLRT. The proposed group sequential designs are developed for monitoring the efficacy of the trial using the method of Lan-DeMets alpha-spending function with O'Brien-Fleming stopping boundaries or a gamma family alpha-spending function. The maximum sample size for the group sequential design is obtained by multiplying an inflation factor with the sample size for the fixed sample design. Simulations are conducted to study the operating characteristics of the proposed group sequential designs. The robustness of the proposed group sequential designs for misspecifying random delay time distribution and domain is studied via simulations.

The Inverse Log-Rank Test: A Versatile Procedure for Late Separating Survival Curves.

Often in the planning phase of a clinical trial, a researcher will need to choose between a standard versus weighted log-rank test (LRT) for investigating right-censored survival data. While a standard LRT is optimal for analyzing evenly distributed but distinct survival events (proportional hazards), an appropriately weighted LRT test may be better suited for handling non-proportional, delayed treatment effects. The "a priori" misspecification of this alternative may result in a substantial loss of power when determining the effectiveness of an experimental drug. In this paper, the standard unweighted and inverse log-rank tests (iLRTs) are compared with the multiple weight, default Max-Combo procedure for analyzing differential late survival outcomes. Unlike combination LRTs that depend on the arbitrary selection of weights, the iLRT by definition is a single weight test and does not require implicit multiplicity correction. Empirically, both weighted methods have reasonable flexibility for assessing continuous survival curve differences from the onset of a study. However, the iLRT may be preferable for accommodating delayed separating survival curves, especially when one arm finishes first. Using standard large-sample methods, the power and sample size for the iLRT are easily estimated without resorting to complex and timely simulations.

Transient EDTA-dependent pseudothrombocytopenia and ulcerative colitis recurrence during chemotherapy: A case of misleading platelet count results attributable to a laboratory artifact.

Key Clinical Message: EDTA-dependent pseudothrombocytopenia as well as myelosuppression should be suspected when thrombocytopenia occurs in patients with autoimmune disease during chemotherapy. Abstract: A patient with pancreatic cancer and ulcerative colitis developed transient ethylenediaminetetraacetic acid (EDTA)-dependent pseudothrombocytopenia with exacerbation of ulcerative colitis during chemotherapy. Unfortunately, pseudothrombocytopenia could not be immediately detected because thrombocytopenia was masked by a reasonable time course of adverse events associated with chemotherapy and ulcerative colitis recurrence. When thrombocytopenia occurs during chemotherapy, especially in patients with autoimmune diseases, EDTA-dependent pseudothrombocytopenia and bone marrow suppression caused by anti-cancer agents should be suspected.

Impact of COVID-19 Pandemic on Advanced Non-small Cell Lung Cancer Treatment at a Japanese Hospital.

Background/Aim: The COVID-19 pandemic has forced medical institutions to scale back their practice. Changes in patient behavior seemed to be having an impact. We conducted a survey with the aim of reviewing lung cancer treatment during the pandemic period and identifying problems. Patients and Methods: We examined the medical records of all patients pathologically diagnosed with non-small cell lung cancer (NSCLC) in our hospital from 2017 to 2022. NSCLC patients were divided into two groups: those diagnosed between 2017 and 2019 (first period) and those diagnosed between 2020 and 2022 (second period). Results: Within the study period, 267 NSCLC patients (first period: 147 patients, second period: 121 patients) were diagnosed in our hospital. The patients in the two study periods did not differ significantly in age (p=0.613), ECOG performance status (p=0.125), and clinical stage (p=0.354). Tumor size was significantly larger in the second period with a mean of 5.88 cm ± 3.02, compared to 4.24 cm ± 1.76 in the first period (p<0.001). In the standard treatment group, the median survival time was 457 days in the first period and 313 days in the second period (p=0.063). In the best supportive care group, median survival time was 122 days in the first period and 57 days in the second period (p=0.004). Conclusion: Patients themselves refrained from seeking consultation for lung cancer treatment during the pandemic period. It is inconclusive how to reduce the delay due to the suppression of consultations, but this is an important issue for the future.

Causes of late-presenting developmental dislocation of the hip beyond 12 months of age: A pilot study.

Background & objectives: Developmental dysplasia of the hip (DDH), when detected early, can usually be managed effectively by simple methods. A delayed diagnosis often makes it a complex condition to treat. Late presentation of DDH is fairly common in developing countries, and there is scarcity of literature regarding the epidemiology and reason for late presentation. Through this study, we attempted to identify the reasons for late presentation of DDH in children more than 12 months of age. Methods: Fifty four children with typical DDH and frank dislocation of hip in whom treatment was delayed for 12 months or more were included. Parents were interviewed with a pre-structured questionnaire and data were collected for analysis with Microsoft Excel 2016 and SPSS version 26. Results: Diagnostic delay was the most common reason for late presentation and was observed in 52 children (96.2%). The mean age at diagnosis was 24.7 months. The mean age at treatment was 37.3 months with a mean delay of 12.5 months from diagnosis and 22.1 months from initial suspicion. Physician-related factors contributed 55.3 per cent, while family and social issues accounted for 44.7 per cent of overall reasons for diagnostic and treatment delays. Interpretation & conclusions: Late presentation of DDH in walking age is common. Physician- and family-related factors accounted for most of these cases. Failure or inadequate hip screening at birth by the attending physician is a common reason for late diagnosis. The family members were unaware about the disorder and developed suspicion once child started walking with an abnormal gait.

Sociodemographic Barriers to the Timely Treatment of Pancreatic Cancer.

BACKGROUND/AIM: Pancreatic cancer has a high mortality rate and timely treatment is imperative for favorable patient outcomes. This retrospective study aimed to identify disparities in time to treatment for pancreatic cancer based on sociodemographic factors. PATIENTS AND METHODS: The study used the National Cancer Database from 2004 to 2019. A total of 423,482 patients with pancreatic cancer were included in the study. Time to first treatment, surgery, radiation, and chemotherapy were analyzed in the context of age, sex, race, Hispanic origin, insurance status, income, facility type, geographic setting, grade, stage, and Charlson-Deyo Comorbidity score (CDC). RESULTS: All sociodemographic factors included were found to be significantly associated with disparities for time to treatment in at least one of the categories studied. Minorities, treatment at academic facilities, and patients with a high CDC score had consistently longer times to all treatment classifications. CONCLUSION: The analyzed sociodemographic factors affected time to pancreatic cancer treatment. Disparities in time to treatment for pancreatic cancer must be studied and understood to ameliorate the impact this cancer has on society and assure the best possible care for all communities.

Delayed treatment seeking and its associated factors among people with schizophrenia spectrum disorders who are on follow-up at Dilla University Referral Hospital in the southern region of Ethiopia, 2022: a cross-sectional study.

Background: Delay in psychiatric treatment leads to increased morbidity and mortality, as well as the emergence of several psychiatric and physical comorbidities and the use of life-threatening and life-altering self-treatments (such as licit and illicit substance misuse). Delaying detection and taking preventive measures against its modifiable factors are crucial for a better prognosis. Objective: To assess delayed treatment seeking and its associated factors among people with schizophrenia spectrum disorders who are on follow-up at Dilla University Referral Hospital in the southern region of Ethiopia. Method: An institution-based cross-sectional study was conducted between 8 June and 11 September at Dilla University Referral Hospital in the southern region of Ethiopia in 2022. Epicollect was used to collect data from 414 randomly selected participants using an interviewer-administered questionnaire. Delayed treatment seeking was determined using participants' medical records and a semi-structured questionnaire. The data were analyzed using Statistical Package for Social Sciences (SPSS) version 26. A logistic regression analysis was conducted to identify the explanatory variables for delayed treatment. Results: The magnitude of delayed treatment seeking was 49.8% (95%CI = 44.9, 54.3). Study participants with disengaged family cohesion [AOR = 3.97, 95%CI = (2.999, 7.193)], inflexible family adaptability [AOR = 2.00, 95%CI = (1.686, 4.044)], who lack awareness about the availability of psychiatric treatment [AOR = 1.63, 95%CI = (1.362, 2.626)], high internalized stigma [AOR = 3.24, 95%CI = (2.770, 5.514)], and those with a negative attitude toward psychiatric treatment [AOR = 2.88, 95%CI = (2.034, 4.469)] had delayed seeking treatment. However, the participants whose educational status was higher than diploma [AOR = 0.040, 95%CI = (0.026, 0.077)] and high school [AOR = 0.09, 95%CI = (0.071, 0.204)] were less likely to have delayed seeking treatment. Conclusions: There is a significant delay in seeking modern psychiatric treatment. Stigma, a lack of awareness of where treatment is available, disengaged family cohesion, inflexible family adaptability, distance to a health facility >5 km, and a negative attitude toward psychiatric treatment were barriers to seeking appropriate care.

Pharmacokinetic and Pharmacodynamic Analysis of the 3CL Protease Inhibitor Ensitrelvir in a SARS-CoV-2 Infection Mouse Model.

The small-molecule antiviral drug ensitrelvir targets the 3C-like protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study evaluated its inhibitory effect on viral replication in a delayed-treatment mouse model and investigated the relationship between pharmacokinetic (PK) parameters and pharmacodynamic (PD) effects. SARS-CoV-2 gamma-strain-infected BALB/c mice were orally treated with various doses of ensitrelvir starting 24 h post-infection. Effectiveness was determined 48 h after first administration based on lung viral titers. Ensitrelvir PK parameters were estimated from previously reported plasma concentration data and PK/PD analyses were performed. Ensitrelvir doses ≥ 16 mg/kg once daily, ≥8 mg/kg twice daily, or ≥8 mg/kg thrice daily for two days significantly reduced lung viral titers compared to that of the vehicle. PK/PD analyses revealed that mean AUC0-48h post-first administration, plasma concentration 48 h post-first administration (C48h), and total time above the target plasma concentration (TimeHigh) were PK parameters predictive of viral titer reduction. In conclusion, ensitrelvir dose-dependently reduced lung SARS-CoV-2 titers in mice, suggesting it inhibited viral replication. PK parameters C48h and TimeHigh were associated with sustained ensitrelvir plasma concentrations and correlated with the reduced viral titers. The findings suggest that maintaining ensitrelvir plasma concentration is effective for exerting antiviral activity against SARS-CoV-2.

Intra-articular delivery of micronized dehydrated human amnion/chorion membrane reduces degenerative changes after onset of post-traumatic osteoarthritis.

Background: Micronized dehydrated human amnion/chorion membrane (mdHACM) has reduced short term post-traumatic osteoarthritis (PTOA) progression in rats when delivered 24 h after medial meniscal transection (MMT) and is being investigated for clinical use as a disease modifying therapy. Much remains to be assessed, including its potential for longer-term therapeutic benefit and treatment effects after onset of joint degeneration. Objectives: Characterize longer-term effects of acute treatment with mdHACM and determine whether treatment administered to joints with established PTOA could slow or reverse degeneration. Hypotheses: Acute treatment effects will be sustained for 6 weeks, and delivery of mdHACM after onset of joint degeneration will attenuate structural osteoarthritic changes. Methods: Rats underwent MMT or sham surgery (left leg). mdHACM was delivered intra-articularly 24 h or 3 weeks post-surgery (n = 5-7 per group). Six weeks post-surgery, animals were euthanized and left tibiae scanned using equilibrium partitioning of an ionic contrast agent microcomputed tomography (EPIC-µCT) to structurally quantify joint degeneration. Histology was performed to examine tibial plateau cartilage. Results: Quantitative 3D µCT showed that cartilage structural metrics (thickness, X-ray attenuation, surface roughness, exposed bone area) for delayed mdHACM treatment limbs were significantly improved over saline treatment and not significantly different from shams. Subchondral bone mineral density and thickness for the delayed treatment group were significantly improved over acute treated, and subchondral bone thickness was not significantly different from sham. Marginal osteophyte degenerative changes were decreased with delayed mdHACM treatment compared to saline. Acute treatment (24 h post-surgery) did not reduce longer-term joint tissue degeneration compared to saline. Histology supported µCT findings and further revealed that while delayed treatment reduced cartilage damage, chondrocytes displayed qualitatively different morphologies and density compared to sham. Conclusion: This study provides insight into effects of intra-articular delivery timing relative to PTOA progression and the duration of therapeutic benefit of mdHACM. Results suggest that mdHACM injection into already osteoarthritic joints can improve joint health, but a single, acute mdHACM injection post-injury does not prevent long term osteoarthritis associated with meniscal instability. Further work is needed to fully characterize the durability of therapeutic benefit in stable osteoarthritic joints and the effects of repeated injections.

A change point-based analysis procedure for improving the success rate of decision-making in clinical trials with delayed treatment effects.

A delayed treatment effect is a commonly observed phenomenon in tumor immunotherapy clinical trials. It can cause a loss of statistical power and complicate the interpretation of the analytical findings. This phenomenon also poses challenges for interim analysis in the context of phase II/III seamless design or group sequential design. It shows potential to lead researchers to make incorrect go/no-go decisions. Despite its significance, rare research has explored the impact of delayed treatment effects on the decision success rate of the interim analysis and the methods to compensate for this loss. In this study, we propose an analysis procedure based on change points for improving the decision success rate at the interim analysis in the presence of delayed treatment effects. This procedure primarily involves three steps: I. detecting and testing the number and locations of change points; II. estimating treatment efficacy; and III. making go/no-go decisions. Simulation results demonstrate that when there is a delayed treatment effect with a single change point, using the proposed analysis procedure significantly improves the decision success rate while controlling the type I error rate. Moreover, the proposed method exhibits very little disparity compared to the unadjusted method when the proportional hazards assumption holds. Therefore, the proposed analysis procedure provides a feasible approach for decision-making at the interim analysis when delayed treatment effects are present.

Two-sample inference procedures under nonproportional hazards.

We introduce a new two-sample inference procedure to assess the relative performance of two groups over time. Our model-free method does not assume proportional hazards, making it suitable for scenarios where nonproportional hazards may exist. Our procedure includes a diagnostic tau plot to identify changes in hazard timing and a formal inference procedure. The tau-based measures we develop are clinically meaningful and provide interpretable estimands to summarize the treatment effect over time. Our proposed statistic is a U-statistic and exhibits a martingale structure, allowing us to construct confidence intervals and perform hypothesis testing. Our approach is robust with respect to the censoring distribution. We also demonstrate how our method can be applied for sensitivity analysis in scenarios with missing tail information due to insufficient follow-up. Without censoring, Kendall's tau estimator we propose reduces to the Wilcoxon-Mann-Whitney statistic. We evaluate our method using simulations to compare its performance with the restricted mean survival time and log-rank statistics. We also apply our approach to data from several published oncology clinical trials where nonproportional hazards may exist.