掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.ekir.2023.08.034

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掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

In this article, we propose two variable selection methods for adjusting the censoring information for survival times, such as the restricted mean survival time. To adjust for the influence of censoring, we consider an inverse probability of censoring weighted for subjects with events. We derive a least absolute shrinkage and selection operator (lasso)-type variable selection method, which considers an inverse weighting for of the squared losses, and an information criterion-type variable selection method, which applies an inverse weighting of the survival probability to the power of each density function in the likelihood function. We prove the consistency of the inverse probability of censoring weighted lasso estimator and the maximum inverse probability of censoring weighted likelihood estimator. The performance of the inverse probability of censoring weighted lasso and inverse probability of censoring weighted information criterion are evaluated via a simulation study with six scenarios, and then their variable selection ability is demonstrated using data from two clinical studies. The results confirm that inverse probability of censoring weighted lasso and the inverse probability of censoring weighted likelihood function produce good estimation accuracy and consistent variable selection. We conclude that our two proposed methods are useful variable selection tools for adjusting the censoring information for survival time analyses.

DOI： 10.1177/09622802231199335

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/09622802231199335

掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.cct.2023.107265

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1200/PO.23.00087

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/sim.9626

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/sim.9626

掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

I propose a data-dependent early completion of dose-finding trials for drug combinations. Early completion is determined when the dose retainment probability using both the trial data and the number of remaining patients is high. An early completion method in which the dose retainment probability is adjusted by a bivariate isotonic regression is also proposed. Early completion is demonstrated for a virtual trial. The performance of the early completion method is evaluated by simulation studies with 12 scenarios. I have shown that, compared with non-early completion designs, the proposed early completion methods reduce the number of patients treated while maintaining similar performance. The number of patients for determining early completion before a trial start is determined and the program code for calculating the dose retainment probability is provided.

Abstract

Purpose

Model-assisted designs for drug combination trials have been proposed as novel designs with simple and superior performance. However, model-assisted designs have the disadvantage that the sample size must be set in advance, and trials cannot be completed until the number of patients treated reaches the pre-set sample size. Model-assisted designs have a stopping rule that can be used to terminate the trial if the number of patients treated exceeds the predetermined number, there is no statistical basis for the predetermined number. Here, I propose two methods for data-dependent early completion of dose-finding trials for drug combination: (1) an early completion method based on dose retainment probability, and (2) an early completion method in which the dose retainment probability is adjusted by a bivariate isotonic regression.

Methods

Early completion is determined when the dose retainment probability using both trial data and the number of remaining patients is high. Early completion of a virtual trial was demonstrated. The performances of the early completion methods were evaluated by simulation studies with 12 scenarios.

Results

The simulation studies showed that the percentage of early completion was an average of approximately 70%, and the number of patients treated was 25% less than the planned sample size. The percentage of correct maximum tolerated dose combination selection for the early completion methods was similar to that of non-early completion methods with an average difference of approximately 3%.

Conclusion

The performance of the proposed early completion methods was similar to that of the non-early completion methods. Furthermore, the number of patients for determining early completion before the trial starts was determined and a program code for calculating the dose retainment probability was proposed.

DOI： 10.1177/09622802231155094

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/09622802231155094

掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Purpose

The early identification of maximum tolerated dose (MTD) in phase I trial leads to faster progression to a phase II trial or an expansion cohort to confirm efficacy.

Methods

We propose a novel adaptive design for identifying MTD early to accelerate dose-finding trials. The early identification of MTD is determined adaptively by dose-retainment probability using a trial data via Bayesian analysis. We applied the early identification design to an actual trial. A simulation study evaluates the performance of the early identification design.

Results

In the actual study, we confirmed the MTD could be early identified and the study period was shortened. In the simulation study, the percentage of the correct MTD selection in the early identification Keyboard and early identification Bayesian optimal interval (BOIN) designs was almost same from the non-early identification version. The early identification Keyboard and BOIN designs reduced the study duration by about 50% from the model-assisted designs. In addition, the early identification Keyboard and BOIN designs reduced the study duration by about 20% from time-to-event model-assisted designs.

Conclusion

We proposed the early identification of MTD maintaining the accuracy to be able to short the study period.

DOI： 10.1186/s12874-022-01584-y

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その他リンク： https://link.springer.com/article/10.1186/s12874-022-01584-y/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

ABSTRACT

Background

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), but currently available treatments do not improve kidney function or prevent the initiation of dialysis/kidney replacement therapy. A previous study demonstrated that bardoxolone methyl improves the estimated glomerular filtration rate (eGFR), but the study was prematurely terminated because of an imbalance in heart failure between treatment groups. The subsequent phase 2 TSUBAKI study demonstrated no incidence of heart failure and an improved eGFR and GFR as determined by inulin clearance in DKD patients.

Methods

This randomized, double-blind, placebo-controlled multicentre phase 3 study was designed to assess the efficacy and safety of bardoxolone methyl in DKD patients with an eGFR ≥15.0–<60.0 ml/min/1.73 m2 and a urinary albumin:creatinine ratio (UACR) ≤3500 mg/g but without risk factors for heart failure. The primary endpoint is the time to onset of a ≥30% decrease in the eGFR or ESKD. Randomized patients (1:1) have been under treatment with once-daily oral bardoxolone methyl (5, 10 or 15 mg by intrapatient dose adjustment) or placebo for at least 3 years.

Results

The mean age of the 1013 patients is 65.9 years, 21.5% are female, the mean eGFR is 37.84 ml/min/1.73 m2 and the median UACR is 351.80 mg/g.

Conclusions

Appropriate patients are enrolled in this study. This study will investigate the long-term efficacy and safety of bardoxolone methyl in DKD patients covering a wider range of eGFR (≥15.0–<60.0 ml/min/1.73 m2) and albuminuria (≤3500 mg/g) compared with previous studies.

DOI： 10.1093/ndt/gfac242

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その他リンク： https://academic.oup.com/ndt/article-pdf/38/5/1204/50195017/gfac242.pdf

掲載種別：研究論文（学術雑誌）   出版者・発行元：The Endocrine Society  

Abstract

Objective

Burosumab, an anti-fibroblast growth factor 23 antibody, was recently approved for the treatment of X-linked hypophosphatemia (XLH).

We evaluated the safety and efficacy of burosumab in pediatric XLH patients.

Methods

This open-label, phase 3/4 trial of ≤ 124 weeks’ duration was conducted at 4 Japanese medical centers. Fifteen children aged 1 to 12 years with XLH were included. All had previously been treated with phosphorus or vitamin D. Subcutaneous burosumab was administered every 2 weeks, starting with 0.8 mg/kg, and adjusted based on serum phosphorus levels and any safety concerns (maximum 2 mg/kg). Safety assessments included the frequency of treatment-emergent adverse events (TEAEs). Efficacy of burosumab on biochemical markers, clinical markers of rickets, motor function, and growth was also evaluated.

Results

The average treatment duration was 121.7 weeks. Frequently reported TEAEs were nasopharyngitis (46.7%), dental caries (40.0%), and influenza (33.3%). At baseline, patients had low serum phosphorus concentrations (2.6 ± 0.3 mg/dL) and low-to-normal 1,25-dihydroxyvitamin D concentrations (24.7 ± 12.7 pg/mL), which increased with burosumab treatment and were maintained during the study period. Alkaline phosphatase decreased continuously. At baseline, the mean ± SD total Thacher Rickets Severity Score (RSS) was 1.3 ± 1.2, and 4 patients (26.7%) had an RSS ≥ 2.0. Mean Radiographic Global Impression of Change and RSS tended to improve, particularly in patients with higher baseline RSS. There was a trend toward increased 6-minute walk test distance. No apparent changes in growth rate were observed.

Conclusion

Burosumab has a good safety profile and is effective in pediatric patients with XLH.

DOI： 10.1210/jendso/bvac021

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その他リンク： https://academic.oup.com/jes/article-pdf/6/5/bvac021/43058351/bvac021.pdf

掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Clinical Oncology ({ASCO})  

PURPOSE

We propose a novel early completion method for phase I dose-finding trials using model-assisted designs. The trials can halt when a maximum tolerated dose (MTD) is estimated with sufficient accuracy. Early completion can reduce the average number of patients treated relative to the planned number, thereby allowing the trial to proceed to enrolling an expansion cohort for efficacy and enabling the trial to reach the next phase faster.

METHODS

Early completion is conducted on the basis of a dose-retainment probability using dose-assignment decisions. We evaluated early the completion for two actual trials. In addition, we performed a computer simulation to confirm the percentage of correctly selected MTDs, the early completion percentage, and the average number of patients treated.

RESULTS

In the evaluation of the two actual trials, we confirmed that the trials completed early. In the simulation results, we confirmed that the percentages of correct MTD selection were maintained relative to the original model-assisted designs. The early completion percentages ranged from 50% to 90%, and the number of patients treated reduced from 20%-60% relative to the planned number of patients.

CONCLUSION

We conclude that the early completion method can be applied unproblematically to the model-assisted design of phase I dose-finding trials.

DOI： 10.1200/PO.21.00192

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/sim.8886

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/sim.8886

掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

ABSTRACT

Patients with tumor‐induced osteomalacia (TIO), an acquired paraneoplastic condition characterized by osteomalacia due to hypophosphatemia, exhibit a similar clinical picture to those with X‐linked hypophosphatemic rickets/osteomalacia (XLH). The human monoclonal anti‐fibroblast growth factor 23 (FGF23) antibody burosumab (KRN23) increases serum phosphate and improves bone turnover, fracture healing, pain, and physical function in XLH patients by inhibiting circulating FGF23; thus, burosumab is expected to be an effective treatment for TIO. We report here an interim analysis of a multicenter, open‐label, intraindividual dose‐adjustment study of burosumab (0.3 to 2.0 mg/kg every 4 weeks) in Japanese and Korean TIO patients. The primary endpoint was the fasting serum phosphate level at each visit. Key secondary endpoints were changes over time in bone biomarkers, pharmacodynamic markers, bone histomorphometric parameters, motor function, and patient‐reported outcomes. Safety was assessed based on treatment‐emergent adverse events (TEAEs). Thirteen patients received burosumab treatment, of whom 4 underwent bone biopsy. The mean dose after week 112 was approximately 1.0 mg/kg. After the first burosumab administration, mean serum phosphate levels increased and remained above the lower limit of normal and in the normal range from weeks 14 to 112. Bone biomarkers initially increased, reaching maximum values at week 16 or 24, and then gradually decreased. After burosumab treatment, patients were able to walk further (evaluated by the 6‐minute walk test), reported decreased pain levels, and showed a tendency toward healing of baseline fractures and pseudofractures. Two patients discontinued, one each due to disease progression and consent withdrawal. Burosumab was generally well tolerated, with no treatment‐related TEAEs of grade ≥3 and no treatment‐related serious AEs. In conclusion, the interim results of this first study of burosumab to treat TIO patients indicate that this drug has the potential to provide clinical benefit for patients with unresectable tumors. The full study results are eagerly anticipated. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

DOI： 10.1002/jbmr.4184

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jbmr.4184

掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jmva.2013.07.016

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