Pharmacokinetics, Pharmacodynamics, and Safety of Evocalcet (KHK7580), a Novel Calcimimetic Agent: An Open-Label, Single- and Multiple-Dose, Phase I Trial in Healthy Chinese Subjects.

Purpose: This study explored the pharmacokinetics (PK), pharmacodynamics (PD), and safety of evocalcet (KHK7580), a new calcimimetic agent, in healthy Chinese subjects following single and multiple doses. Methods: This was a single-center, open-label phase I trial conducted in China. The study started from the single-dose cohorts (1, 3, 6, 12 mg evocalcet, step-by-step administration) and proceeded to the multiple-dose cohort (6 mg evocalcet once daily for eight days). Blood and urine samples were collected at the designated time points for pharmacokinetic and pharmacodynamic analysis. Safety was evaluated by treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, electrocardiograms (ECGs), and ophthalmological examination. Results: Among 42 enrolled subjects, eight in each single-dose cohort and 10 in multiple-dose cohort, 40 subjects completed the study. In single-dose cohorts, tmax was 1.00-2.00 h and declined biphasically. The mean t1/2 was 15.99-20.84 h. Evocalcet exposure in AUC0-inf, AUC0-t, and Cmax showed a dose-proportional increase. In the multiple-dose cohort, tmax was 2.00 h and declined biphasically after multiple administrations. The accumulation was negligible. Ctrough levels were similar across days and steady from 24 hours after the first administration. The mean t1/2 was 15.59 h. PD analysis showed that evocalcet decreased intact parathyroid hormone and corrected calcium levels in a dose-dependent manner. Seventeen (40.5%) subjects reported TEAEs. No serious or severe TEAE occurred. Conclusion: In healthy Chinese subjects, evocalcet demonstrated dose-dependent PK and PD properties and was well-tolerated.

Frailty model with change points for survival analysis.

We propose a novel frailty model with change points applying random effects to a Cox proportional hazard model to adjust the heterogeneity between clusters. In the specially focused eight Empowered Action Group (EAG) states in India, there are problems with different survival curves for children up to the age of five in different states. Therefore, when analyzing the survival times for the eight EAG states, we need to adjust for the effects among states (clusters). Because the frailty model includes random effects, the parameters are estimated using the expectation-maximization (EM) algorithm. Additionally, our model needs to estimate change points; we thus propose a new algorithm extending the conventional estimation algorithm to the frailty model with change points to solve the problem. We show a practical example to demonstrate how to estimate the change point and the parameters of the distribution of random effect. Our proposed model can be easily analyzed using the existing R package. We conducted simulation studies with three scenarios to confirm the performance of our proposed model. We re-analyzed the survival time data of the eight EAG states in India to show the difference in analysis results with and without random effect. In conclusion, we confirmed that the frailty model with change points has a higher accuracy than the model without a random effect. Our proposed model is useful when heterogeneity needs to be taken into account. Additionally, the absence of heterogeneity did not affect the estimation of the regression parameters.

Comparison of baseline covariate adjustment methods for restricted mean survival time.

The restricted mean survival time provides a straightforward clinical measure that dispenses with the need for proportional hazards assumptions. We focus on two strategies to directly model the survival time and adjust covariates. Firstly, pseudo-survival time is calculated for each subject using a leave-one-out approach, followed by a model analysis that adjusts for covariates using all pseudo-values. This method is used to reflect information of censored subjects in the model analysis. The second approach adjusts for covariates for those subjects with observed time-to-event while incorporating censored subjects using inverse probability of censoring weighting (IPCW). This paper evaluates these methods' power to detect group differences through computer simulations. We find the interpretation of pseudo-values challenging with the pseudo-survival time method and confirm that pseudo-survival times deviate from actual data in a primary biliary cholangitis clinical trial, mainly due to extensive censoring. Simulations reveal that the IPCW method is more robust, unaffected by the balance of censors, whereas pseudo-survival time is influenced by this balance. The IPCW method retains a nominal significance level for the type-1 error rate, even amidst group differences concerning censor incidence rates and covariates. Our study concludes that IPCW and pseudo-survival time methods differ significantly in handling censored data, impacting parameter estimations. Our findings suggest that the IPCW method provides more robust results than pseudo-survival time and is recommended, even when censor probabilities vary between treatment groups. However, pseudo-survival time remains a suitable choice when censoring probabilities are balanced.

Application of multi-armed bandits to dose-finding clinical designs.

Multi-armed bandits are very simple and powerful methods to determine actions to maximize a reward in a limited number of trials. An early phase in dose-finding clinical trials needs to identify the maximum tolerated dose among multiple doses by repeating the dose-assignment. We consider applying the superior selection performance of multi-armed bandits to dose-finding clinical designs. Among the multi-armed bandits, we first consider the use of Thompson sampling which determines actions based on random samples from a posterior distribution. In the small sample size, as shown in dose-finding trials, because the tails of posterior distribution are heavier and random samples are too much variability, we also consider an application of regularized Thompson sampling and greedy algorithm. The greedy algorithm determines a dose based on a posterior mean. In addition, we also propose a method to determine a dose based on a posterior mode. We evaluate the performance of our proposed designs for nine scenarios via simulation studies.

Comparison of the Oral Calcimimetics Evocalcet and Cinacalcet in East Asian Patients on Hemodialysis with Secondary Hyperparathyroidism.

Introduction: Evocalcet is an oral calcimimetic agent with proven efficacy and safety in treating secondary hyperparathyroidism (SHPT) in Japanese patients on dialysis. Methods: This randomized, double-blind, intrapatient dose-adjustment, parallel-group, international multicenter study compared the efficacy and safety of evocalcet versus cinacalcet for 52 weeks in East Asian hemodialysis patients with SHPT. Results: In total, 203 and 200 patients were randomized to receive evocalcet or cinacalcet, respectively (overall, 70.1% had baseline intact parathyroid hormone (PTH) levels ≥500 pg/ml, with no between-group difference). Mean percentage changes in intact PTH levels from baseline were -34.7% and -30.2% in the evocalcet and cinacalcet groups at 52 weeks (between-group difference -4.4%, 95% confidence interval [CI] -13.1%, 4.3%, below the predefined 15% noninferiority margin). Overall, 67.3% and 58.7% of patients in the evocalcet and cinacalcet groups, respectively, achieved ≥30% decrease in intact PTH levels from baseline (between-group difference 8.6%; 95% CI -1.8%, 19.1%). No major safety concerns were observed. Gastrointestinal adverse events (AEs) were significantly less frequent with evocalcet compared with cinacalcet (33.5% vs. 50.5%, P = 0.001), whereas the incidence of hypocalcemia did not differ. Conclusion: Evocalcet might be a better alternative to cinacalcet for East Asian patients on hemodialysis with SHPT.

Variable selection using inverse probability of censoring weighting.

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.

Adaptive Cohort Size Determination Method for Bayesian Optimal Interval Phase I/II Design to Shorten Clinical Trial Duration.

PURPOSE: Recently, the strategy for dose optimization in oncology has shifted toward conducting phase II randomized controlled trials with multiple doses. Optimal biologic dose (OBD) selection from phase I trial data to determine candidate doses for phase II trials has been gaining attention. Trials to identify the OBD have a fixed cohort size, which increases the trial duration. We propose a method to increase the cohort size using trial data and shorten the trial duration while maintaining accuracy. METHODS: We propose a novel adaptive cohort size determination method in which the increase of cohort size is determined using desirability probability on the basis of toxicity and efficacy data. The desirability probability is a measure of how desirable a dose is and thus how close it is to the OBD. However, during the trial, the desirability probability does not need to be calculated. Instead, the cohort size expansion can be determined by a simple table generated in advance from toxicity and efficacy data. An illustrated example is provided and the performance was evaluated in a simulation study with 16 scenarios. RESULTS: In the simulation study, the trial duration was reduced by an average of 20% compared with the conventional design. The percentages of correct OBD selection are almost the same as those with the conventional design. CONCLUSION: The proposed adaptive cohort size determination method described in this study reduces trial duration while maintaining accuracy.

Data-dependent contrast test for dose-finding clinical trials.

We propose a simple and powerful data-dependent contrast test with ordinal-constraint contrast coefficients of the dose response determined from observed responses. The contrast coefficients are easily calculated using a pool-adjacent-violators algorithm and making assumptions for the contrast coefficients. Once the dose response is determined for p < 0.05 in the data-dependent contrast test, the best dose-response model is selected from multiple dose-response models. Using the best model, a recommended dose is identified. We demonstrate the data-dependent contrast test for sample data. In addition, we calculate the ordinal-constraint contrast coefficients and test statistic for an actual study, and we obtain a recommended dose. Finally, we perform a simulation study with 11 scenarios to evaluate the performance of the data-dependent contrast test by comparing multiple comparison procedures with modeling techniques. We confirm the dose response for both the sample data and the actual study. In the simulation study, the data-dependent contrast test is more powerful than the conventional method on the simulation datasets generated using non-dose-response models. In addition, the type-1 error rate of the data-dependent contrast test remains at a significant level when there is no difference between the treatment groups. We conclude that the data-dependent contrast test can be applied unproblematically in a dose-finding clinical trial.

Catalytic Enantioselective Amination of Enol Silyl Ethers Using a Chiral Paddle-Wheel Diruthenium Complex.

A chiral paddle-wheel dinuclear ruthenium catalyst was applied to a catalytic asymmetric nitrene-transfer reaction with enol silyl ethers. The ruthenium catalyst was applicable to aliphatic enol silyl ethers as well as aryl-containing enol silyl ethers. The substrate scope of the ruthenium catalyst was superior to that of analogous chiral paddle-wheel rhodium catalysts. α-Amino ketones derived from aliphatic substrates were obtained in up to 97% ee with the ruthenium catalyst, while analogous rhodium catalysts resulted in only moderate enantioselectivity.

Enantioselective Synthesis of 1,2-Benzothiazine 1-Imines via RuII /Chiral Carboxylic Acid-Catalyzed C-H Alkylation/Cyclization.

Sulfondiimines are diaza-analogues of sulfones with a chiral sulfur center. Compared to sulfones and sulfoximines, their synthesis and transformations have so far been studied to a lesser extent. Here, we report the enantioselective synthesis of 1,2-benzothiazine 1-imines, i.e., cyclic sulfondiimine derivatives from sulfondiimines and sulfoxonium ylides via C-H alkylation/cyclization reactions. The combination of [Ru(p-cymene)Cl2 ]2 and a newly developed chiral spiro carboxylic acid is key to achieving high enantioselectivity.

Synthesis of Polysubstituted Enamides by Hydrogen Atom Transfer Alkene Isomerization Using Dual Cobalt/Photoredox Catalysis.

M-HAT isomerization is a highly reliable method to access thermodynamically stable alkenes with high functional group tolerance. However, synthesis of heteroatom-substituted alkenes by M-HAT isomerization reaction is still underdeveloped. Herein, we report an enamide synthesis using M-HAT via a combination of cobalt and photoredox catalysis. This method tolerates a variety of functional groups including haloarenes, heteroarenes, free hydroxy groups, non-protected indoles, and drug derivatives. Furthermore, this method can isomerize styrene derivatives in good yield and E/Z selectivity.

Formation of Isolable Dearomatized [4 + 2] Cycloadducts from Benzenes, Naphthalenes, and N-Heterocycles Using 1,2-Dihydro-1,2,4,5-tetrazine-3,6-diones as Arenophiles under Visible Light Irradiation.

We report that the dearomative [4 + 2] cycloaddition between 1,2-dihydro-1,2,4,5-tetrazine-3,6-diones (TETRADs) and benzenes, naphthalenes, or N-heteroaromatic compounds under visible light irradiation affords the corresponding isolable cycloadducts. Several synthetic transformations including transition-metal-catalyzed allylic substitution reactions using the isolated cycloadducts at room temperature or above were demonstrated. Computational studies revealed that the retro-cycloaddition of the benzene-TETRAD adduct proceeds via an asynchronous concerted mechanism, while that of the benzene-MTAD adduct (MTAD = 4-methyl-1,2,4-triazoline-3,5-dione) proceeds via a synchronous mechanism.

An Electron-Deficient CpE Iridium(III) Catalyst: Synthesis, Characterization, and Application to Ether-Directed C-H Amidation.

The synthesis, characterization, and catalytic performance of an iridium(III) catalyst with an electron-deficient cyclopentadienyl ligand ([CpE IrI2 ]2 ) are reported. The [CpE IrI2 ]2 catalyst was synthesized by complexation of a precursor of the CpE ligand with [Ir(cod)OAc]2 , followed by oxidation, desilylation, and removal of the COD ligand. The electron-deficient [CpE IrI2 ]2 catalyst enabled C-H amidation reactions assisted by a weakly coordinating ether directing group. Experimental mechanistic studies and DFT calculations suggested that the high catalytic performance of [CpE IrI2 ]2 is due to its electron-deficient nature, which accelerates both C-H activation and IrV -nitrenoid formation.

Noble-Metal-Free C-H Allylation of Tetrahydroisoquinolines Using a Cobalt-Organophotoredox Dual Catalyst System.

Metallaphotoredox-catalyzed allylation represents an emerging synthetic methodology that enables allylic substitution using nucleophilic radical species. The C-H allylation of N-aryl tetrahydroisoquinolines is an innovative example in this area and allows access to synthetically useful precursors for the further derivatization of tetrahydroisoquinolines. However, previous methods have required the use of noble metals, which has hampered their application due to concerns over their sustainability. Here we report the C-H allylation of N-aryl tetrahydroisoquinolines using a cobalt/organophotoredox dual catalyst system. Based on precedent, control experiments and controlled irradiation experiments, a mechanism for the cobalt/photoredox-catalyzed allylation that involves a π-allyl cobalt complex is proposed.

Data-dependent early completion of dose-finding trials for drug-combination.

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.

Inhibitory Effects of a Novel µ-Opioid Receptor Nonpeptide Antagonist, UD-030, on Morphine-Induced Conditioned Place Preference.

Although opioids are widely used to treat moderate to severe pain, opioid addiction and the opioid overdose epidemic are becoming more serious. Although opioid receptor antagonists/partial agonists, such as naltrexone and buprenorphine, have relatively low selectivity for the µ-opioid receptor (MOP), they have been used for the management of opioid use disorder. The utility of highly selective MOP antagonists remains to be evaluated. Here, we biologically and pharmacologically evaluated a novel nonpeptide ligand, UD-030, as a selective MOP antagonist. UD-030 had more than 100-fold higher binding affinity for the human MOP (Ki = 3.1 nM) than for δ-opioid, κ-opioid, and nociceptin receptors (Ki = 1800, 460, and 1800 nM, respectively) in competitive binding assays. The [35S]-GTPγS binding assay showed that UD-030 acts as a selective MOP full antagonist. The oral administration of UD-030 dose-dependently suppressed the acquisition and expression of morphine-induced conditioned place preference in C57BL/6J mice, and its effects were comparable to naltrexone. These results indicate the UD-030 may be a new candidate for the treatment of opioid use disorder, with characteristics that differ from traditional medications that are in clinical use.

Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: design and baseline characteristics of the AYAME study.

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.

Photocatalytic Deuterium Atom Transfer Deuteration of Electron-Deficient Alkenes with High Functional Group Tolerance.

Due to its mild reaction conditions and unique chemoselectivity, hydrogen atom transfer (HAT) hydrogenation represents an indispensable method for the synthesis of complex molecules. Its analog using deuterium, deuterium atom transfer (DAT) deuteration, is expected to enable access to complex deuterium-labeled compounds. However, DAT deuteration has been scarcely studied for synthetic purposes, and a method that possesses the favorable characteristics of HAT hydrogenations has remained elusive. Herein, we report a protocol for the photocatalytic DAT deuteration of electron-deficient alkenes. In contrast to the previous DAT deuteration, this method tolerates a variety of synthetically useful functional groups including haloarenes. The late-stage deuteration also allows access to deuterated amino acids as well as donepezil-d2 . Thus, this work demonstrates the potential of DAT chemistry to become the alternative method of choice for preparing deuterium-containing molecules.

Adjusted closed-form confidence interval formulas for network meta-analysis with a small number of studies.

We derive simple formulas for closed-form confidence intervals for the Wald statistic, likelihood ratio statistic, and score statistic for network meta-analysis (NMA). Additionally, we consider resolutions of concerns that network meta-analyzes with a small number of studies cannot maintain a nominal confidence level. For bias adjustment in analyzes with a small number of studies, the Bartlett-type adjustment is a well-known method. Many Bartlett-type adjustment-type methods are based on maximum likelihood estimators (MLEs). However, NMA often uses restricted MLEs that have not been extensively discussed with respect to the Bartlett-type adjustment. In this article, we propose a Bartlett-type adjustment method for the Wald statistic, likelihood ratio statistic, and score statistic when nuisance parameters are estimated by not only the maximum likelihood method but also the restricted maximum likelihood method. We can compute closed-form confidence intervals adjusted using the Bartlett-type adjustment immediately without any numerical calculations (eg, bootstrap method). Additionally, we propose a higher-order adjustment by applying the bootstrap method to Bartlett-type adjusted statistics. Using a computer simulation, we confirmed that the adjusted confidence intervals maintained a nominal confidence level. Additionally, we confirmed that the confidence intervals of the Wald statistic, likelihood ratio statistic, and score statistic based on the restricted maximum likelihood method performed well without further bootstrap adjustment and the performances of the three adjusted confidence intervals were comparable. Finally, we demonstrated that confidence intervals were adjusted for actual NMA. In the actual NMA, the adjusted confidence intervals of the Wald statistic were wider, the adjusted confidence intervals of the likelihood ratio statistic were also wider, and the adjusted confidence intervals of the score statistic were narrower. We recommend using the likelihood ratio test statistic with the restricted maximum likelihood estimator; however, just in case, we recommend applying the Bartlett-type adjustment to remove the second order bias. From demonstrations in actual studies, we confirmed that the adjusted confidence intervals improved compared with the naive confidence intervals.

Native Amide-Directed C(sp3 )-H Amidation Enabled by Electron-Deficient RhIII Catalyst and Electron-Deficient 2-Pyridone Ligand.

Trivalent group-9 metal catalysts with a cyclopentadienyl-type ligand (CpMIII ; M=Co, Rh, Ir, Cp=cyclopentadienyl) have been widely used for directed C-H functionalizations, albeit that their application to challenging C(sp3 )-H functionalizations suffers from the limitations of the available directing groups. In this report, we describe directed C(sp3 )-H amidation reactions of simple amide substrates with a variety of substituents. The combination of an electron-deficient CpE Rh catalyst (CpE =1,3-bis(ethoxycarbonyl)-substituted Cp) and an electron-deficient 2-pyridone ligand is essential for high reactivity.