Clinical Trial In Chinese Patients Research Articles

Pharmacokinetic and safety profiles of mesalazine enema in healthy Chinese subjects: A single- and multiple-dose study.

Mesalazine is a well-established treatment for ulcerative colitis by oral or topical administration. However, the pharmacokinetic (PK) and safety profiles of mesalazine administered by an enema has not been clarified in Chinese population. We conducted an open-label study to assess the PK and safety profiles of mesalazine in 11 healthy Chinese subjects after receiving mesalazine enema (1 g/100 mL) once daily for 7 consecutive days. Blood and urine samples were collected for assay of mesalazine and N-acetyl mesalazine by liquid chromatography-tandem mass spectrometry. The PK and safety data were summarized using descriptive statistics. The mean (standard deviation) maximum plasma concentration (Cmax), area under plasma drug concentration-time curve from time 0 to the last measurable plasma concentration time point (AUC0-t) and elimination half-life (t1/2) of mesalazine were 1007.64 (369.00) ng/mL, 9608.59 (3533.08) h·ng/mL and 3.33 (1.99) h, respectively after the first dose administration. In multiple-dose study, the estimated accumulation factor of mesalazine was 1.09. The cumulative urinary excretion rate of parent and major metabolite of mesalazine was 27.77%. After the last doe administration, 2.21% of the administered dose was excreted as mesalazine and 24.47% as N-acetyl mesalazine in urine within 24 h. Overall, 9 adverse events (AEs) were reported in 4 of the 11 subjects (36.4%), including oral ulcer, toothache, upper respiratory tract infection (1 each) and laboratory abnormalities (6 cases). All AEs were mild and recovered spontaneously without treatment, and were not considered as related to mesalazine. Mesalazine enema (1 g/100 mL) was safe and well tolerated in healthy Chinese subjects. These findings support further clinical trials in Chinese patients. Trial registration: This trial was registered to Chinese Clinical Trial Registry (ChiCTR) at https://www.chictr.org.cn (registration number: ChiCTR2300073148).

Efficacy and safety of tafolecimab in Chinese patients with heterozygous familial hypercholesterolemia: a randomized, double-blind, placebo-controlled phase 3 trial (CREDIT-2)

BackgroundHeterozygous familial hypercholesterolemia (HeFH) is largely underdiagnosed and undertreated in China where few patients achieved recommended target levels of low density lipoprotein cholesterol (LDL-C). We conducted the first randomized, placebo-controlled clinical trial in Chinese patients with HeFH to assess the efficacy and safety of tafolecimab, a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody.MethodsPatients diagnosed with HeFH by Simon Broome criteria and on a stable lipid-lowering therapy for at least 4 weeks were randomized 2:2:1:1 to receive subcutaneous tafolecimab 150 mg every 2 weeks (Q2W), tafolecimab 450 mg every 4 weeks (Q4W), placebo Q2W or placebo Q4W in the 12-week double-blind treatment period. After that, participants received open-label tafolecimab 150 mg Q2W or 450 mg Q4W for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. Secondary endpoints included proportion of participants achieving ≥50% LDL-C reductions and proportion of participants with LDL-C <1.8 mmol/L at week 12 and 24, the change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and lipoprotein(a) levels, as well as the change from baseline to week 24 in lipid levels.ResultsIn total, 149 participants were randomized and 148 received at least one dose of the study treatment. At week 12, tafolecimab treatment induced significant reductions in LDL-C levels (treatment difference versus placebo [on-treatment estimand]: −57.4% [97.5% CI, −69.2 to −45.5] for 150 mg Q2W; −61.9% [−73.4 to −50.4] for 450 mg Q4W; both P <0.0001). At both dose regimens, significantly more participants treated with tafolecimab achieved ≥50% LDL-C reductions or LDL-C <1.8 mmol/L at week 12 as compared with corresponding placebo groups (all P <0.0001). Meanwhile, non-HDL-C, apolipoprotein B and lipoprotein(a) levels were significantly reduced in the tafolecimab groups at week 12. The lipid-lowering effects of tafolecimab were maintained till week 24. During the double-blind treatment period, the most commonly-reported adverse events in the tafolecimab groups included upper respiratory tract infection, increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase and hypertension.ConclusionsTafolecimab administered either 150 mg Q2W or 450 mg Q4W yielded significant and persistent reductions in LDL-C levels and showed a favorable safety profile in Chinese patients with HeFH.Trial registrationClinicalTrials.gov, NCT04179669.

The clinical efficacy and limitations of dutasteride-regulated abiraterone metabolism in abiraterone-resistant patients: a prospective single-arm clinical trial in Chinese patients.

BackgroundThe steroidal metabolism of abiraterone has been proposed to be involved in abiraterone resistance and limited approaches are available for abiraterone-resistant patients. Dutasteride regulates abiraterone metabolism in patients and might enhance the clinical efficacy of abiraterone. However, the function of dutasteride to overcome abiraterone resistance has not been investigated in clinic. Here we investigated the clinical efficacy and limitations of dutasteride in patients with abiraterone-resistant prostate cancer.MethodsAbiraterone-resistant patients with metastatic castration-resistant prostate cancer (mCRPC) were enrolled in this single-arm, open-label study, patients were treated with dutasteride (0.5 mg/day), abiraterone (1,000 mg/day), and prednisone (5 mg twice daily), prostate-specific antigen (PSA) was tested monthly. The primary objective was PSA response, and the secondary objectives were to assess symptom relief and safety. Kaplan-Meier analysis was used to assess the PSA progression free survival (PSA-PFS) of patients.ResultsTwenty-two patients (median age: 75 years) were enrolled, and 19 patients completed the treatment. After a median treatment of 4.0 months, 7 (37%) patients showed a slight PSA reduction (−2% to −32%), and the median PSA-PFS was 2.0 months (1–7 months). No significant improvement was observed in Eastern Cooperative Oncology Group (ECOG) performance status. Bone pain was relieved in 6 patients after 1 month of treatment, but the improvement was not significant. No grade 3 or grade 4 adverse events were observed.ConclusionsThe combination of dutasteride and abiraterone showed a mild effect in patients with abiraterone-resistant. The small sample size was the limitation of this study.

Effectiveness of PD-1/PD-L1 inhibitors in the treatment of lung cancer: Brightness and challenge

Immune checkpoint inhibitors (ICIs), especially inhibitors of the PD-1/PD-L1 axis, have significantly affected the outcomes of patients with lung cancer. Nivolumab and pembrolizumab have been approved as PD-1 blocking antibodies, whereas atezolizumab, avelumab, and durvalumab are approved as PD-L1 blocking antibodies by the United States Food and Drug Administration. However, which patient may benefit the most and how to identify patients at risk of primary or acquired resistance has not been completely defined. Meanwhile, close attention has been paid to the ongoing international and domestic clinical trials in Chinese patients with lung cancer. This review aimed to provide deep insight into the effectiveness of PD-1/PD-L1 inhibitors in patients with lung cancer, including the current settings for varied disease status, the predictive biomarkers, the resistance to ICIs, and the ongoing clinical trials in Chinese patients.

Anatomic Suitability of Iliac Branched Devices for Chinese Patients with Abdominal-Iliac Aortic Aneurysm

Preserving internal iliac flow is the key to preventing ischemic complications during endovascular aneurysm repair (EVAR). The aim of this study is to determine the morphological features of abdominal aortic aneurysms (AAAs) that have been reported in clinical trials in Chinese patients to identify unique features of iliac branched systems. The data for patients who had common iliac aneurysms suitable for imaging review from 2014 to 2017 at 1 institution in China were reviewed. Three-dimensional workstations were used to measure the centerline diameters and lengths of aortoiliac structures, which were screened for suitability for both Cook iliac branch devices (IBD) and Gore iliac branch endoprosthesis (IBE). A total of 102 lesions of common iliac aneurysms were suitable for imaging review. The anatomic standards for the Gore IBE and Cook IBD were met by 13.7% (14/102) and 9.8% (10/102) of the cases, respectively, and 3 cases were suitable for both devices. The most common cause of not meeting the criteria was the same for both the Cook IBD (78.4%) and Gore IBE (48.03%), which was a limitation of the diameter of the target internal iliac artery. Of the 92 lesions excluded from the Cook IBD trial, 11 (11.9%) were eligible for the Gore IBE trial. Likewise, 7.95% (7/88) of the lesions excluded from the Gore IBE trial would have been eligible for the Cook IBD graft. In a practice that is able to enroll patients in both trials, a total of 20.6% (21/102) of the patients would be eligible for treatment, based on the anatomic criteria. The high incidence of iliac artery involvement in AAAs makes EVAR more complicated. Cook IBD and Gore IBE are only suitable for the treatment of a total of 20.6% Chinese patients based on the anatomic criteria. A limitation in the diameter of the target internal iliac artery is the most common cause of failure to meet the criteria for both devices. Future generations of iliac branch technologies should be designed with diameter accommodations for the hypogastric branch stent to reach a wider group of patients with aortoiliac aneurysmal disease.

The Effect of LM25 and LM50 on Hypoglycemia in Chinese T2DM Patients: Post Hoc Analysis of a Randomized Crossover Trial.

IntroductionTo investigate the safety of insulin lispro Mix 25 and 50 (LM25 and LM50) in hypoglycemia in patients with type 2 diabetes mellitus (T2DM).MethodsThis was a post hoc analysis of a phase IV, randomized, crossover clinical trial in Chinese patients with T2DM switching from premixed human insulin 70/30 (PHI70/30) to LM25 or LM50. Eighty-one subjects received a two-stage crossover protocol of either LM25 or LM50 twice daily for 16 weeks. Habitual diet was taken, and self-monitoring of blood glucose (SMBG) was performed throughout the study period. High-carbohydrate diet (HCD), high-fat diet (HFD) and habitual diet patterns were taken, and 72 h continuous glucose monitoring (CGM) was performed at the last 3 days of each treatment stage.ResultsThe frequencies of nocturnal hypoglycemia in LM50 were lower than those in LM25 under a Chinese habitual diet pattern. The related factors of hypoglycemia in patients with T2DM treated with a LM25 or LM50 regimen were the weight-based daily mean insulin dose and the type of combined oral hypoglycemic agents. Under both HCD and habitual diet patterns, the optimal cut point values of bedtime glucose predicting nocturnal hypoglycemia in LM50 were lower than those in LM25.ConclusionsThe risk of nocturnal hypoglycemia in the LM50 regimen was lower than that in the LM25 regimen under the HCD pattern, and the safety range of bedtime glucose for the LM50 regimen was wider than that of the LM25 regimen in Chinese T2DM patients. Premixed insulin analogs combined with acarbose were more helpful to reduce the incidence of hypoglycemia.Trial Registrationhttp://www.chictr.org.cn #ChiCTR-TTRCC-12002516.

Chinese expert consensus on the use of Zhibitai capsules

The components of Zhibitai capsules are based on classic Chinese traditional medicinal formula, including natural statin, statin homologue, triterpenes and flavonoids. Zhibitai capsules is effective on dyslipidemia by inhibiting cholesterol synthesis and absorption. Several randomized clinical trials in Chinese patients have shown that Zhibitai capsules could reduce low density lipoprotein cholesterol (LDL-C) by 18%-34% and triglycerin (TG) by 30%.Zhibitai capsules had less side effects compared to statins, which interpreted a synergistic effect with Zhibitai capsules. Although no evidence has been proved to use Zhibitai capsules as prophylaxis of cardiovascular diseases, Zhibitai capsules is still an alternative choice of both primary and secondary prophylaxis of cardiovascular diseases.

Clinical Value of Circulating Tumor Cells in Monitoring Treatment Response in Chinese Patients with Small Cell Lung Cancer

Aim: Although several small-sized retrospective studies have suggested the clinical value of circulating tumor cells (CTCs) in small cell lung cancer (SCLC) patients, its proper application still need further exploration and validation. In a phase III clinical trial in Chinese patients with extensive-stage SCLC, we explored the clinical value of CTCs in predictive and prognostic value. Methods: Blood samples were collected from eighty five patients in this clinical trial, which were randomized to accept etoposide plus lobaplatin (EL) or etoposide plus cisplatin(EP). CTCs from 7.5 ml of blood were analyzed using the CellSearch system at different time points, including prior to the treatment (baseline), after 2 cycles of treatment and disease progression. The relationship between CTC counts and overall survival (OS) was investigated, as well as the clinical significance of CTCs and other validated serum markers. Results: At baseline, ≥5 CTCs/7.5mL blood were 64.7% in the overall patients with 61.7% in the EL arm and 68.4% in the EP arm, however the total rate was decreased to 33.3% after two cycles of treatment with 41.9% in the EL and 23.7% in the EP arms, respectively. The data of CTC counts at disease progression were not mature yet. At baseline as well as after 2 cycles of chemotherapy, the counts of CTC were related with overall survival (OS), the median OS of patients with ≥5 CTCs was significantly shorter than those with 26 months, log rank p 26 months, log rank p<0.0124). In a multivariate analyses, CTCs were demonstrated to be an independent prognostic marker for OS at both baseline (adjusted hazard ratio=0.081, p=0.018) and after 2 cycles of therapy (adjusted HR=0.206; p=0.0249).Moreover statistical significant was found in CA125 after 2 cycles of therapy (adjusted HR=0.208; p=0.0142), but not in CEA and NSE at either time points. Conclusions: This study demonstrated that CTC counts at both baseline and after 2 cycles of chemotherapy are an independent prognostic marker in Chinese patients with extensive-stage SCLC. Compared with conventionally validated serum markers, CTCs may have a superior clinical significant in monitoring therapeutic outcomes of Chinese SCLC patients after chemotherapy. Disclosure: All authors have declared no conflicts of interest.

A cyclic fluctuation model for 24-h ambulatory blood pressure monitoring in Chinese patients with mild to moderate hypertension

The conventional method for analyzing 24-h ambulatory blood pressure monitoring (24-h ABPM) is insufficient to deal with the large amount of data collected. The aim of this study was to develop a novel cyclic fluctuation model for 24-h ABPM in Chinese patients with mild to moderate hypertension. The data were obtained from 4 independent antihypertensive drug clinical trials in Chinese patients with mild to moderate hypertension. The measurements of 24-h ABPM at the end of the placebo run-in period in study 1 were used to develop the cyclic fluctuation model. After evaluated, the structural model was used to analyze the measurements in the other 3 studies. Models were fitted using NONMEM software. The cyclic fluctuation model, which consisted of 2 cosine functions with fixed-effect parameters for rhythm-adjusted 24-h mean blood pressure, amplitude and phase shift, successfully described the blood pressure measurements of study 1. Model robustness was validated by the bootstrap method. The measurements in the other 3 studies were well described by the same structural model. Moreover, the parameters from all the 4 studies were very similar. Visual predictive checks demonstrated that the cyclic fluctuation model could predict the blood pressure fluctuations in the 4 studies. The cyclic fluctuation model for 24-h ABPM deepens our understanding of blood pressure variability, which will be beneficial for drug development and individual therapy in hypertensive patients.

Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial

The efficacy and safety of bevacizumab with modified irinotecan, leucovorin bolus, and 5-fluorouracil intravenous infusion (mIFL) in the first-line treatment of metastatic colorectal cancer (mCRC) has not been well evaluated in randomized clinical trials in Chinese patients. We conducted a phrase III trial in which patients with previously untreated mCRC were randomized 2:1 to the mIFL [irinotecan (125 mg/m2), leucovorin (20 mg/m2) bolus, and 5-fluorouracil intravenous infusion (500 mg/m2) weekly for four weeks every six weeks] plus bevacizumab (5 mg/kg every two weeks) group and the mIFL group, respectively. Co-primary objectives were progression-free survival (PFS) and 6-month PFS rate. In total, 214 patients were enrolled. Our results showed that addition of bevacizumab to mIFL significantly improved median PFS (4.2 months in the mIFL group vs. 8.3 months in the bevacizumab plus mIFL group, P < 0.001), 6-month PFS rate (25.0% vs. 62.6%, P < 0.001), median overall survival (13.4 months vs. 18.7 months, P = 0.014), and response rate (17% vs. 35%, P = 0.013). Grades 3 and 4 adverse events included diarrhea (21% in the mIFL group and 26% in the bevacizumab plus mIFL group) and neutropenia (19% in the mIFL group and 33% in the bevacizumab plus mIFL group). No wound-healing complications or congestive heart failure occurred. Our results suggested that bevacizumab plus mIFL is effective and well tolerated as first-line treatment for Chinese patients with mCRC. Clinical benefit and safety profiles were consistent with those observed in pivotal phase III trials with mainly Caucasian patients.