title
stringlengths 1
1.19k
| keywords
stringlengths 0
668
| concept
stringlengths 0
909
| paragraph
stringlengths 0
61.8k
| PMID
stringlengths 10
11
|
|---|---|---|---|---|
Study procedure | A participant’s intravenous cannula was inserted into a vein in the right arm (dose escalation group) or a vein catheter (dose expansion group) for administration or top-up of the study drug. Only patients in the ciprofol group required an open vein in the left arm for blood collection for PK analysis. A simultaneous arterial catheter was only placed in the radial artery of 4 patients in the 0.4 mg/kg ciprofol group for arterial blood collection.Standard monitoring was applied including a 12-lead ECG, pulse oxygen saturation (SpO | PMC10147789 |
||
End points | SECONDARY | The primary end-point was the success rate of induction of general anesthesia produced by the initial bolus dose, i.e. the percentage of patients who achieved successful induction after the initial bolus dose, without requiring a top-up dose.The secondary end-points were: (1) the time to reach a MOAA/S ≤ 1, defined as the time from the first administration of ciprofol or propofol to the first occurrence of MOAA/S ≤ 1; (2) the time for loss of the eyelash reflex, defined as the time from the first administration of ciprofol or propofol to disappearance of the eyelash reflex; (3) emergence time, defined as the time from the completion of surgery to the first occurrence of MOAA/S = 5; (4) number of top-up doses; (5) incidence and severity of AEs during the whole study, number of corresponding treatments, and the accumulated doses of rescue medication for AEs within 15 min after the initiation of induction. | PMC10147789 |
|
Measurements | DBP and mean arterial blood pressure, pain | The pain associated with a ciprofol or propofol injection was assessed approximately 15 s after initiation of the bolus injection. MOAA/S scores were recorded every 1 min and the eyelash reflex every 30 s.Hemodynamic parameters including HR, SBP, DBP and mean arterial blood pressure (MAP) were recorded at intervals of 1 min within the first 10 min, and at intervals of 5 min thereafter. SpO | PMC10147789 |
|
Emergence time | Once surgery was completed, the MOAA/S score was assessed every 2 min until patients’ MOAA/S scores reached 5. | PMC10147789 |
||
Drugs | PMC10147789 |
|||
Investigational drugs | Ciprofol emulsion (20 mL: 200 mg in part 1, and 20 mL: 50 mg in part 2 (Liaoning Haisco Pharmaceutical Group Co., Ltd., China) and Diprivan® (20 mL: 200 mg, AstraZeneca, UK).Midazolam (Jiangsu Nhwa Pharmaceutical Co., Ltd., China), sufentanil (Yichang Humanwell Pharmaceutical Co., Ltd., China) and rocuronium bromide (Esmeron, N.V. Organon, The Netherlands) were given in combination during the induction of general anesthesia. | PMC10147789 |
||
Statistical analysis | Wilson’s | IBM SPSS (ver. 25) was used for all statistical analyses. The demographic characteristics were analyzed using analysis of variance (ANOVA), chi-square, Fisher or Kruskal–Wallis tests. The primary outcome was also analyzed using Wilson’s and/or Fisher tests. Time to MOAA/S ≤ 1 and loss of the eyelash reflex were evaluated using the Kruskal–Wallis test, followed by Student's The sample size calculation was based on the data from our previous clinical experience. Assuming that the success rate of induction with propofol injection was 100% and the difference in the success rate of induction with a ciprofol equally potent dose was not > 3%, a sample size of 23 patients in each group would produce a two-sided 95% confidence interval (CI) of − 0.1 to 0.1. Considering that the dropout rate would be about 25%, the sample size was rounded to 30 patients in the dose escalation + expansion study. Therefore, we started with 10 patients in each group in the part 1 dose escalation and planned to add another 20 patients in the part 2 dose expansion. | PMC10147789 |
|
Results | PMC10147789 |
|||
Demographic characteristics of patients in the dose escalation and dose expansion groups | From December 2016 to July 2018, a total of 109 patients for inclusion in both part 1 and part 2 were enrolled and the flow chart is shown in Fig. Flow chart of patient enrollment | PMC10147789 |
||
Efficacy | PMC10147789 |
|||
Primary outcome | The success rates of anesthesia induction in patients who received one initial bolus dose of ciprofol-0.5 mg/kg, propofol-2.0 and 2.5 mg/kg were all 100%. However, 1 patient in the ciprofol-0.4 mg/kg group (part I) and one in the ciprofol-0.3 mg/kg group (part II) required one top-up dose and then achieved successful induction. No patient failed the induction and no patient received more than one top-up dose (Table Efficacy of sedation in all patients with ciprofol or propofol including dose escalation and dose expansionSuccessful time of anesthesia induction = the time when MOAA/S ≤ 1 occurred—the time when the study drug was first administered; Time to loss of the eyelash reflex = eyelash reflex disappearance time—the time when the study drug was first administered; Emergence time was defined as the period from surgery completion to a MOAA/S score = 5* | PMC10147789 |
||
Secondary outcomes | All of the patients who received an initial bolus reached MOAA/S scores ≤ 1 at the end of the first min of administration except for 2 patients (1 in the 0.4 mg/kg ciprofol group and the other in the 2.0 mg/kg propofol group), who achieved MOAA/S scores ≤ 1 at the end of the second min of drug administration).As shown in Table Furthermore, no significant differences were found between the time to loss of the eyelash reflex and the time to emergence after the operation among the 5 groups, even when the patients who required one top-up dose were included in the analysis (all | PMC10147789 |
||
Discussion | pain | Propofol has been reported to have a narrow therapeutic index and the guidelines recommend usage only by experienced anesthesiologists, with close monitoring and individual dose adjustments [The main finding of the present study was that the success rates of induction with ciprofol-0.5 mg/kg as an i.v. bolus was comparable to that of propofol-2.0 mg/kg. When lower doses of ciprofol (0.3 or 0.4 mg/kg) were given, a top-up dose was occasionally needed after the initial bolus injection to achieve a 100% success rate of induction. The results also showed that patients in ciprofol-0.5 mg/kg group had the shortest time of loss of the eyelash reflex and that the 0.4 mg/kg group had the longest duration for successful induction and the shortest emergence times. In terms of safety, there were no significant differences among the ciprofol and propofol groups in the incidence of AEs. Vital signs were relatively stable during induction of general anesthesia and even during intubation, and no significant differences were found in term of the accumulated dose of the rescue drugs used to treat AEs. Considering the efficacy and safety endpoints, ciprofol 0.5 mg/kg for induction of general anesthesia was as effective and safe as propofol at a dose of 2.0 mg/kg. No difference in hemodynamic stability during the induction period among the 5 groups was due to prompt treatment with rescue drugs.There is another potential advantage of ciprofol, namely less injection pain on administration compared to propofol. This conjecture is based on the fact that the injection pain produced by propofol is attributable to the absolute drug concentration in the aquatic phase [There were a number of limitations to the study. First, patients were not randomly assigned to groups and a future randomized study will be conducted. In addition, selection bias might have existed as the differences in ASA statuses between the 5 groups were significant (Supplementary Table 1). Second, the administration of the premedication midazolam and sufentanil, but the study design was intended to reflect real clinical practice as much as possible. It should however be noted that the use of a combination of midazolam and sufentanil as premedication has been standard practice in clinical anesthesia for a number of years [ | PMC10147789 |
|
Conclusion | The efficacy and safety of a single i.v. bolus dose of 0.5 mg/kg ciprofol for the induction of general anesthesia in patients undergoing selective surgery was comparable to propofol administered at a dose of 2.0 mg/kg. Lower doses of ciprofol, 0.3 mg/kg or 0.4 mg/kg, could also achieve the same efficacy but occasionally an additional top-up dose was required. | PMC10147789 |
||
Acknowledgements | We would like to thank other investigators Yuan Zeng, Tingting Jiang, ZhaoTing Meng, Rufeng Zeng, Huacheng Liu, Dingxin Kang, Li Yang, Yunxia Hu, Weixiang Min, Lu Jiang, Qiang Xu, Qingping Wu, Zhenghua Zhao, Yanling Jin, Fang Wang, Lili Wang, Saiying Wang, Huan Chang, and Kaiming Duan for their great assistance with the study. | PMC10147789 |
||
Funding | This work was supported by the Sichuan Haisco Pharmaceutical Group Co., Ltd. The funder had no role in the design of the study, collection, analysis or interpretation of the data or in writing the manuscript. | PMC10147789 |
||
Conflicts of interest | The authors have no relevant financial or non-financial interests to disclose. | PMC10147789 |
||
References | PMC10147789 |
|||
Background | NKTL, PTCL, Natural killer/T-cell lymphoma, peripheral T-cell lymphoma, NHL | PERIPHERAL T-CELL LYMPHOMA, NHL | Natural killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with a poor prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit potential novel therapeutic targets for the treatment of NKTL. Histone deacetylase (HDAC) inhibitor chidamide was recently approved for treating relapsed/refractory peripheral T-cell lymphoma (PTCL) patients. However, its therapeutic efficacy in NKTL remains unclear.
| PMC9900953 |
Methods | NKTL, tumors | TUMORS | We performed a phase II clinical trial to evaluate the efficacy of chidamide in 28 relapsed/refractory NKTL patients. Integrative transcriptomic, chromatin profiling analysis and functional studies were performed to identify potential predictive biomarkers and unravel the mechanisms of resistance to chidamide. Immunohistochemistry (IHC) was used to validate the predictive biomarkers in tumors from the clinical trial.
| PMC9900953 |
Results | NKTL, hyperactivity | We demonstrated that chidamide is effective in treating relapsed/refractory NKTL patients, achieving an overall response and complete response rate of 39 and 18%, respectively. In vitro studies showed that hyperactivity of JAK-STAT signaling in NKTL cell lines was associated with the resistance to chidamide. Mechanistically, our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect in vitro and in vivo. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of the JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide.
| PMC9900953 |
|
Supplementary Information | The online version contains supplementary material available at 10.1186/s13148-023-01436-6. | PMC9900953 |
||
Keywords | PMC9900953 |
|||
Introduction | Natural killer/T-cell lymphoma, NKTL, Barr virus-associated T-cell lymphoma | EPSTEIN | Natural killer/T-cell lymphoma (NKTL) is an aggressive Epstein–Barr virus-associated T-cell lymphoma (TCL) that accounts for 10% of all TCLs [Histone acetylation is an important mode of epigenetic regulation controlled by the antagonistic actions of two classes of enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs acetylate histones, leading to open chromatin regions that promote gene transcription. On the other hand, HDACs deacetylate histones, resulting in chromatin condensation, which induces transcriptional repression [Multiple HDAC inhibitors, such as vorinostat (SAHA), romidepsin (FK-228) and belinostat, have shown promising clinical efficacy in TCL patients [In this study, we evaluated the therapeutic effects of chidamide in 28 relapsed/refractory NKTL patients, and a remarkable ORR of 39% was achieved. We identified potential biomarkers to predict the clinical response to chidamide. Moreover, we deciphered the underlying mechanisms of primary resistance to chidamide mediated by aberrant JAK-STAT signaling and found that JAK-STAT inhibitors can effectively overcome this resistance in the treatment of NKTL.
| PMC9900953 |
Methods | PMC9900953 |
|||
Patients and cell lines | NKTL, tumor, Cancer | MYCOPLASMA, MYCOPLASMA, TUMOR, CANCER | A phase II clinical trial to evaluate chidamide monotherapy in relapsed/refractory NKTL was conducted at Sun Yat-sen University Cancer Center (SYSUCC). The study was approved by the institutional review board of SYSUCC in accordance with the Declaration of Helsinki, and applicable regulations according to Good Clinical Practice guidelines. Written informed consent was obtained from all patients before enrollment in the trial. This trial was registered at ClinicalTrials.gov, number NCT02878278. Research protocols for tumor collection and analysis were approved by the ethical committees of SYSUCC. The details for the patients and cell lines are described in the Supplementary Methods. We routinely tested mycoplasma contamination in cell culture using Myco-Blue® Mycoplasma Detector (Vazyme) monthly. | PMC9900953 |
Drugs | ALDRICH | Chidamide was provided by Shenzhen Chipscreen Biosciences Ltd. SAHA was obtained from Sigma–Aldrich. Trichostatin A (TSA), belinostat and tofacitinib were purchased from Selleckchem. Romidepsin was obtained from MedChemExpress. Ruxolitinib and Stattic were purchased from Axon Medchem and Millipore, respectively. | PMC9900953 |
|
Cell viability assays | Tecan | PROLIFERATION | A total of 2000 cells were seeded in 96-well plates in triplicate and treated with the indicated drugs at various concentrations or not treated for 96 h. Cell viability was measured by the CellTiter-Glo Luminescent Cell Viability Assay (Promega) according to the manufacturer’s instructions, and luminescence was read using an Infinite M200 plate reader (Tecan, Switzerland). Half maximal inhibitory concentration (IC50) values were calculated, and proliferation curves were plotted using GraphPad Prism. | PMC9900953 |
Calculation of the combination index (CI) | CI values were determined by the inhibition rate of the cells treated with drugs and computed using CalcuSyn [ | PMC9900953 |
||
Cell cycle assays | 2 × 10 | PMC9900953 |
||
Cell apoptosis assay | 2 × 10 | PMC9900953 |
||
H&E staining and immunohistochemistry (IHC) | NKTL | EPSTEIN | H&E staining, IHC for TNFRSF8 (CD30) and Epstein–Barr encoding region in situ hybridization (EBER ISH) were performed with formalin-fixed, paraffin-embedded (FFPE) tissues from NKTL patients using standard procedures [ | PMC9900953 |
ChIP-qPCR, ChIP-seq and ChIP-seq data analyses | The primer sequences used for ChIP-qPCR are listed in Additional File | PMC9900953 |
||
Real-time RT–qPCR, RNA-seq and RNA-seq data analyses | The primer sequences used for RT–qPCR are listed in Additional File | PMC9900953 |
||
In vivo studies | In vivo studies were conducted in compliance with animal protocols approved by the SingHealth Institutional Animal Care and Use Committee. Five- to eight-week-old female NOD/SCID/IL2rγnull (NSG) mice were kept under standard laboratory conditions according to the National Advisory Committee for Laboratory Animal Research guidelines. The details are provided in the Supplementary Methods. | PMC9900953 |
||
Statistical analysis | SD | Graphs include results that are expressed as the mean ± SD of three independent experiments. Statistical differences between the two groups were evaluated by a two-tailed Student’s | PMC9900953 |
|
Results | PMC9900953 |
|||
Clinical efficacy of chidamide, a novel HDAC inhibitor, in relapsed/refractory NKTL patients | NKTL | DISEASE PROGRESSION | To evaluate the efficacy of chidamide, a single-arm, phase II clinical trial was performed in 28 NKTL patients who relapsed after or were refractory to chemoradiotherapy and/or autologous stem cell transplantation (ASCT). The patients were treated with chidamide until disease progression or intolerance. The demographic and clinical characteristics of the 28 patients are summarized in Additional File Efficacy of chidamide in 28 relapsed/refractory NKTL patients. | PMC9900953 |
Characterization of NKTL cell line sensitivity to chidamide in vitro | NKTL, death | PROLIFERATION | To assess the in vitro efficacy of chidamide in NKTL, we evaluated the IC50 of the drug in 11 NKTL cell lines (Fig. Chidamide inhibits cell proliferation and selectively induces the death of NKTL cells. | PMC9900953 |
Enhancer landscapes in chidamide-resistant and chidamide-sensitive cells | NKTL | To investigate the underlying mechanism of resistance to chidamide in NKTL cells, we performed chromatin immunoprecipitation sequencing (ChIP-seq) for H3K27ac and H3K4me3 in two resistant cell lines (HANK1 and SNK6) and two sensitive cell lines (KHYG1 and MEC04). Epigenetic changes in H3K27ac and H3K4me3, which are associated with gene enhancers and promoters, respectively, have been shown to modulate gene activities and confer resistance to drug treatment [Chromatin and transcriptomic profiling of chidamide-resistant and chidamide-sensitive NKTL cells. To gain further insights into the altered transcriptional pathways resulting from epigenetic dysregulation, RNA-seq was performed in two chidamide-resistant (HANK1 and SNK6) and two chidamide-sensitive (KHYG1 and MEC04) cell lines. Integrative transcriptomic and chromatin profiling analyses revealed that the differential H3K27ac peaks were positively correlated with gene expression in NKTL cells (Fig. | PMC9900953 |
|
Aberrant activation of the JAK-STAT pathway in NKTL | NKTL | As the JAK-STAT pathway was found to be implicated in resistance to chidamide, we examined the activity of its effector molecules, STAT3 and STAT5 in both sensitive and resistant NKTL cell lines. High levels of phospho-STAT3 and STAT5 were detected in resistant cell lines compared to sensitive cell lines (Fig. The JAK-STAT pathway is constitutively activated in chidamide-resistant NKTL. | PMC9900953 |
|
Pharmacologically targeting the JAK-STAT pathway overcomes resistance to chidamide in NKTL | NKTL | We hypothesized that targeting the JAK-STAT pathway could reverse chidamide resistance in NKTL cell lines. To test this hypothesis, we treated the chidamide-resistant NKTL cell lines (HANK1 and SNK6) with tofacitinib (JAK inhibitor), chidamide or a combination of both drugs for 96 h and determined the combination index (Fig. JAK-STAT inhibitors overcome chidamide resistance in NKTL cells. | PMC9900953 |
|
The JAK inhibitors tofacitinib/ruxolitinib induce chromatin remodeling at JAK-STAT genes | NKTL | To understand how JAK inhibitors reverse chidamide resistance in NKTL cells, we performed RNA-seq of HANK1 cells treated with DMSO, tofacitinib or ruxolitinib. Compared to the control treatment, tofacitinib and ruxolitinib treatment remarkably upregulated 131 common genes and downregulated 141 common genes in HANK1 cells (Fig. The JAK inhibitors tofacitinib and ruxolitinib reverse chidamide resistance by altering chromatin remodeling. | PMC9900953 |
|
Clinical efficacy of JAK-STAT inhibition and chidamide in chidamide-resistant NKTL | NKTL, death | EPSTEIN, VIRUS, DISEASE | We next assessed whether JAK-STAT inhibition could be a potential therapeutic strategy to overcome resistance to chidamide in the clinic. A 48-year-old Chinese male patient who was initially diagnosed with stage IIA extranodal NKTL of the nasal type was recruited. He was refractory to first-line asparaginase-based chemotherapy. Salvage therapy with a combination of chidamide (30 mg orally, twice a week, continuous) and the anti-programmed death protein 1 (PD-1) antibody sintilimab (200 mg intravenously, on Day 1) was given, but the disease progressed with multiple new lesions accompanied by a dramatic increase in the peripheral blood Epstein–Barr virus (EBV) viral load after four 21-day cycles (Fig. The benefit of combinatorial therapy in relapsed/refractory NKTL patient. | PMC9900953 |
Discussion | NKTL, tumor, H3Y41, PTCL | DISORDER, REGRESSION, DISEASE, TUMOR | In the current management of NKTL, a substantial proportion of patients still experience treatment failures, and salvage options are severely limited. Increasing evidence suggests that PTCL is characteristically an epigenetic disorder, with several HDAC inhibitors receiving regulatory approvals for the treatment of relapsed/refractory disease. Here, we conducted the first focused trial of chidamide, an oral HDAC inhibitor, in relapsed/refractory NKTL. Chidamide induced durable tumor regression, with a complete response rate of 18% and a partial response rate of 21%. Compared with other HDAC inhibitors, chidamide is the first selective oral HDAC inhibitor to show effective and increased immunomodulatory effects and convenient administration [We further found that aberrant JAK-STAT signaling contributes to primary resistance to chidamide, and inhibiting this oncogenic pathway can resensitize resistant NKTL cells to chidamide. We have previously demonstrated the prevalence of JAK-STAT pathway alterations in NKTL and discovered frequent Interestingly, we found that JAK-STAT signaling mediates resistance to chidamide through chromatin remodeling of enhancer elements. We demonstrated that drug resistance to chidamide was correlated with chromatin remodeling alterations, which could be reversed by targeting the JAK-STAT pathway. Enhancer but not promoter alterations were significantly correlated with the response to chidamide in NKTL. In addition, STAT motifs were enriched at gained enhancers over lost enhancers, which was consistent with the enrichment of JAK-STAT target genes in resistant cells. Previous studies have demonstrated that the JAK-STAT pathway can regulate chromatin accessibility and influence the chromatin landscape through different mechanisms. For example, JAK2 can directly phosphorylate Tyr41 in histone H3 (H3Y41), preventing the binding of heterochromatin protein 1α (HP1α) with chromatin and destabilizing heterochromatin in hematopoietic cells [Importantly, chromatin-mediated drug resistance is often reversible, as demonstrated by JAK-STAT inhibitor reprogramming of the chromatin state from a resistant to a sensitive state. JAK-STAT inhibition suppresses H3K27ac marks of JAK-STAT target genes, such as Furthermore, JAK-STAT target genes can also serve as predictive or therapeutic biomarkers of chidamide resistance. Frequent overexpression of TNFRSF8 (CD30) in NKTL has been reported previously [ | PMC9900953 |
Conclusions | NKTL | In summary, our study shows favorable clinical outcomes of chidamide in treating relapsed/refractory NKTL patients. JAK-STAT inhibitors may further expand the clinical utility of HDAC inhibitors, including chidamide, romidepsin and belinostat, by remodeling the resistant enhancer landscape toward a sensitive state. The combined use of JAK-STAT and HDAC inhibitors is a promising new treatment option for relapsed/refractory NKTL patients. We believe that our study could promote the clinical application of HDAC inhibitor chidamide in NKTL, provide personalized and precision treatments for NKTL patients and improve their survival rate.
| PMC9900953 |
|
Acknowledgements | We thank Shenzhen Chipscreen Biosciences Ltd. for providing us with chidamide for our work. We thank Dr. Yoshitoyo Kagami, Dr. C. Clayberger, Dr. Norio Shimizu, Dr. Paul Coppo and Dr. Philippe Gaulard for kindly providing the cell lines used in this study. | PMC9900953 |
||
Author contributions | PD | PATHOLOGY | JC, HH, CKO and JT conceived, designed and supervised the study; JC, YG, ZL, YW and KXYC performed the experiments; JC, ZZ, YG, XY, PG, ZL, JH, PD, JYC, JL, BKHC, HH, CKO and JT analyzed and interpreted the data; YG, XL and HH provided samples; XY, JH, DC, JWP, JK, DH, HH, YS, LL, SL, XW, HY, NFG, JB, TK, STL and BTT provided material and technical support; SAS, JYC and YH provided pathology expertise; JC, HH, CKO and JT prepared the manuscript with help from all coauthors. | PMC9900953 |
Funding | Cancer | CANCER | This work was supported by the National Natural Science Foundation of China (81970176, 81972596 and 81772963), Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S638 and 2016ZT06S252), Sci-Tech Project Foundation of Guangzhou City (201707020039), Medical Scientific Research Foundation of Guangdong Province of China (A2016013), Singapore National Medical Research Council (NMRC-TCR-12Dec005, NMRC-OFIRG-16Nov090 and NMRC-OFLCG-18May0028), National Cancer Centre Research Fund (NCCRF-OACPCCS-YR2015-AUG2), Neighborhood Funders Group Fund (NMRC/TA/0051/2016), and Tanoto Foundation, Ling Foundation and New Century Foundation. | PMC9900953 |
Availability of data and materials | The datasets supporting the conclusions of this article are available at GEO under accession number GSE152185. | PMC9900953 |
||
Declarations | PMC9900953 |
|||
Ethics approval and consent to participate | tumor | TUMOR | The study was approved by the institutional review board of SYSUCC in accordance with the Declaration of Helsinki, and applicable regulations according to Good Clinical Practice guidelines. Written informed consent was obtained from all patients before enrollment in the trial. This trial was registered at ClinicalTrials.gov, number NCT02878278. Research protocols for tumor collection and analysis were approved by the ethical committees of the SYSUCC. In vivo studies were conducted in compliance with animal protocols approved by the SingHealth Institutional Animal Care and Use Committee. | PMC9900953 |
Consent for publication | All authors have agreed to publish this manuscript. | PMC9900953 |
||
Competing interests | The authors declare that they have no competing interests. | PMC9900953 |
||
References | PMC9900953 |
|||
Background | HGP1705, acid-related disorders | EROSIVE ESOPHAGITIS | Proton-pump inhibitors (PPIs) are the most effective drugs for treating acid-related disorders. However, once-daily dosing with conventional PPIs fail to fully control acid secretion over 24 h. This study aimed to compare the efficacy and safety of HIP1601 (dual delayed-release esomeprazole) and HGP1705 (delayed-release esomeprazole) in patients with erosive esophagitis (EE). | PMC10729464 |
Methods | treatment-emergent adverse, HGP1705, GERD-related | We enrolled 213 patients with EE randomized in a 1:1 ratio to receive 40 mg HIP1601 (n = 107) or HGP1705 (n = 106) once daily for 4 or 8 weeks. The primary endpoint was the EE healing rate, confirmed by endoscopy up to week 8. GERD-related symptoms and treatment-emergent adverse events were compared between both groups. | PMC10729464 |
|
Results | HGP1705 | By week 8, the estimated healing rates of EE were 97.8% and 96.8% in the HIP1601 and HGP1705 groups, respectively, with a 95% confidence interval of -4.7 to 7.2. After 4 or 8 weeks of treatment, the EE healing rate at week 4, complete resolution rate of symptoms, time to sustained resolution of symptoms, and number of rescue medications used were similar in both groups. The proportion of heartburn- and acid regurgitation-free nights by week 4 were higher in the HIP1601 group compared to the HGP1705 group, but the difference did not reach clinical significance (87.7% vs. 85.8%, | PMC10729464 |
|
Conclusions | HGP1705 | GERD | The efficacy and safety of HIP1601 40 mg were comparable to those of HGP1705 40 mg for the treatment of EE and symptomatic improvement of GERD. | PMC10729464 |
Trial registration | NCT04080726 ( | PMC10729464 |
||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12876-023-03087-6. | PMC10729464 |
||
Keywords | PMC10729464 |
|||
Background | chronic disorder, heartburn, GERD, acid regurgitation, Barrett’s esophagus [HIP1601, esophagitis, Barrett’s esophagus, reflux of gastric | CHRONIC DISORDER, ESOPHAGEAL STRICTURE, GERD, ESOPHAGITIS, GASTROESOPHAGEAL REFLUX DISEASE (GERD), COMPLICATIONS | Gastroesophageal reflux disease (GERD) is a chronic disorder caused by the reflux of gastric contents, resulting in symptoms such as heartburn and acid regurgitation as well as potential complications such as esophagitis and Barrett’s esophagus [Proton pump inhibitors (PPIs) are the most commonly prescribed class of medications to treat GERD. They function by inhibiting the secretion of hydrogen ions through the inhibition of H+/K+-ATPase (a proton pump) located on the secretory surface of gastric parietal cells, resulting in a potent inhibition of gastric acid secretion and a sustained increase of intragastric pH. Previous studies have consistently demonstrated the superiority of PPIs over other acid blockers and placebo in controlling GERD symptoms and preventing complications such as esophagitis, esophageal stricture, and Barrett’s esophagus [HIP1601 is a newly developed esomeprazole formulation with dual delayed-release emission. It comprises a mixture of two types of enteric-coated granules designed to dissolve at different pH levels. Compared to conventional delayed-release PPIs, HIP1601 has an extended duration of therapeutic plasma drug concentration and is expected to improve the efficacy of GERD treatment [This study aimed to demonstrate that the clinical efficacy and safety of HIP1601 40 mg are non-inferior to those of HGP1705 (delayed-release esomeprazole, Nexium®) 40 mg in patients with GERD. | PMC10729464 |
Materials and methods | PMC10729464 |
|||
Study design | treatment-emergent adverse, HGP1705, GERD-related | EROSIVE ESOPHAGITIS, HEART | This study was designed as a multicenter, double-blind, randomized controlled, non-inferiority trial involving patients with erosive esophagitis (EE). Patients with EE were randomly assigned to receive either HIP1601 40 mg or HGP1705 40 mg for 4 or 8 weeks. Complete EE healing rates, GERD-related symptoms, and treatment-emergent adverse events (TEAE) were investigated and compared between both drugs. This study was conducted at 20 hospitals in Republic of Korea between October 2018 and November 2019. The study protocol was approved by the ethics committees of all participating hospitals, and written informed consent was obtained from each patient before enrollment (Asan Medical Center Institutional Review Board [A2018-1391], CMC Institutional Review Board [KC18MDDT0645], GangNeung Asan Hsopital Institutional Review Board [GNAH 2018-09-012], Kangbuk Samsung Hospital Institutional Review Board [KBSMC 2018-08-040], Korea University Guro Hospital Institutional Review Board [2018GR0399], Kosin University Gospel Hospital Institutional Review Board [KUGH 2018-08-029], Pusan National University Hospital Institutional Review Board [D-1809-003-081], Seoul National University Hospital Institutional Review Board [H-1808-183-970], Severance Hospital Institutional Review Board [4-2018-1229], Soonchunhyang University Hospital Bucheon Institutional Review Board [SCHBC 2018-09-005], Ajou University Hospital Institutional Review Board [AJIRB-MED-CT3-18-327], Yeungnam University Hospital Institutional Review Board [2018-08-045], Wonkwang University Hospital Institutional Review Board [WKUH 2018-09-008], Ewha womans university medical center Institutional Review Board [EUMC 2018-09-004], Inje University Seoul Paik Hospital Institutional Review Board [PAIK 2018-09-003], Chonnam National University Hospital Institutional Review Board [CNUH-2018-237], Chungnam National University Hospital Institutional Review Board [CNUH-2018-063], Kyungpook National University Chilgok Hospital Institutional Review Board [KNUCH 2018-08-035], Hallym University Sacred Heart Hospital Institutional Review Board [HALLYM 2018-08-033] & Seoul National University Bundang Hospital Institutional Review Board [B-1904-532-405]). This trial has been registered in Clinical Trials. (NCT04080726, registration date: 25/10/2018, | PMC10729464 |
Study subject | primary esophageal motility disorders, heartburn, malignancy, acid regurgitation, active gastric or, Zollinger-Ellison syndrome, Barrett’s esophagus, duodenal ulcer | ESOPHAGEAL DYSPLASIA, GASTROINTESTINAL BLEEDING, ZOLLINGER-ELLISON SYNDROME, INFLAMMATORY BOWEL DISEASE | Male and female patients aged 19–75 years were eligible for inclusion if they had endoscopically confirmed EE based on the Los Angeles (LA) Classification (grades A–D). Additionally, patients had to experience symptoms of acid regurgitation and/or heartburn 7 days prior to the screening visit.The exclusion criteria for the study were as follows: (1) patients who had taken PPI and histamine receptor 2 blocking agent within 2 weeks before the screening endoscopy, (2) patients with active gastric or duodenal ulcer, gastrointestinal bleeding, primary esophageal motility disorders, Zollinger-Ellison syndrome, inflammatory bowel disease, malignancy, and endoscopic Barrett’s esophagus more than 3 cm or esophageal dysplasia, (3) patients who had undergone previous major abdominal surgery, and (4) patients with abnormal laboratory findings at the screening (MDRD eGFR ≤ 59 mL/min/1.73 m | PMC10729464 |
Study protocol | Figure
Randomization protocol and patient disposition | PMC10729464 |
||
Efficacy and safety assessment | GERD, death, TEAEs, disability | ADVERSE EVENTS, ADVERSE EVENT, GERD, REMISSION, ADVERSE EVENT | The primary endpoint of the study was the complete healing rate of EE confirmed endoscopically up to week 8 in the per-protocol set (PPS) population. The complete healing of EE was defined as the LA Classification criterion “Not Present” in endoscopy after administration of the clinical trial drug [Patients were instructed to rate the severity of their worst GERD symptom episodes experienced in the previous 24 h. This information was recorded in a diary every morning using a 4-point scale: 0 (no symptoms), 1 (symptoms with spontaneous remission, not significantly affecting normal activities or sleep), 2 (symptoms with spontaneous but slow remission, somewhat impeding normal activities or sleep), and 3 (symptoms with no spontaneous remission, remarkably impeding normal activities or sleep). Complete resolution of symptoms was defined as patients reporting no symptoms (score 0) during the 7 days before the follow-up visit. Sustained resolution was defined as 7 consecutive days of GERD symptoms recorded as a score of 0 (no symptoms), and the time to sustained resolution of symptoms was determined as the first day of the symptom-free period. To assess the proportion of symptom-free days and nights, the percentage of days without daytime or night-time symptoms during treatment was calculated. Similarly, the percentage of nights without night-time symptoms was assessed using a daily diary.All safety assessments, including frequency and severity of adverse events, clinical laboratory evaluations, 12-lead electrocardiogram results, vital sign measurements, and physical examination findings, were monitored throughout the study. A TEAE was defined as an adverse event that occurred during treatment and represented a change from baseline. All TEAEs were graded by the investigator as mild, moderate, or severe. Adverse events were considered drug related if they were deemed by the investigator to be possibly related to or related to the study drug. Serious TEAEs were defined as adverse events that could potentially cause death, hospitalization, disability, or life-threatening adverse events. | PMC10729464 |
Statistical analyses | HGP1705 | For estimating the necessary number of subjects, the complete healing rate of EE by week 8 was assumed to be 93.7% in the HGP1705 40 mg group [Safety analysis was conducted among those who took at least one dose of the clinical trial drugs after random assignment, for whom data on safety assessments could be obtained. All patients who received at least one dose of investigational drugs and underwent efficacy assessments at least once until the end of the clinical trial were included in the full analysis set (FAS). Among the patients included in the FAS, those who completed the clinical trial in accordance with the protocol were included in the PPS. Patients with major protocol violations or poor compliance (taking less than 70% of the total medications) were excluded from the PPS. Compliance was assessed by counting the unused medications at the completion of 4 or 8 weeks of treatment. For the primary efficacy evaluation, in principle, the PPS was the main analysis set, and the FAS was the supportive analysis set. Secondary efficacy analysis was performed using both PPS and FAS.The chi-square test or Fisher’s exact test was used to test for associations among various categorical variables, and the independent samples t-test or Wilcoxon’s rank-sum test was used for non-categorical variables. Comparisons between the two groups at weeks 4 or 8 were performed using the Cochran–Mantel–Haenszel test to analyze stratified categorical data (LA Classification, grades A/B and C/D). Statistical analyses were performed using SAS® Version 9.4, SAS Institute, Cary, NC, USA), and a | PMC10729464 |
|
Results | PMC10729464 |
|||
Study population and baseline characteristics | GASTROESOPHAGEAL REFLUX DISEASE | In total, 213 patients were enrolled in this clinical trial (Fig. Table
Baseline patient demographics and characteristics according to treatment groupGERD, Gastroesophageal reflux disease; LA, Los Angeles; SD, standard deviation | PMC10729464 |
|
Primary endpoint | HGP1705 | EROSIVE ESOPHAGITIS | Based on the PPS analysis by week 8, the complete healing rate of EE in the HIP1601 group was 97.8% (91/93), which was higher than the rate of 96.8% (91/94) in the HGP1705 group (Table
Healing rate of erosive esophagitis by weeks 8 and 4EE, erosive esophagitis; CI, confidence interval; FAS, full analysis set; PPS, per protocol set* Furthermore, after 8 weeks of treatment, the complete healing rate of EE was 97.7% for LA Classification grades A/B and 100% for grades C/D in the HIP1601 group. In the HGP1705 group, the rates were 96.7% for grades A/B and 100% for grades C/D. There was no significant difference between both groups (
Healing rate of erosive esophagitis at week 4 and up to week 8 according to the Los Angeles Classification (per protocol set) | PMC10729464 |
Secondary endpoints | PMC10729464 |
|||
Healing rate of erosive esophagitis at week 4 | HGP1705 | In PPS analysis at week 4, the complete healing rate of EE in the HIP1601 and HGP1705 groups were 91.4% (85/93) and 92.6% (87/94), respectively, and the 95% CI of the difference between the two groups ranged from − 8.9 to 6.6 (Table | PMC10729464 |
|
Complete resolution rate of GERD symptoms at week 4 or 8 | dysphagia, HGP1705, heartburn, GERD, acid regurgitation, pain | DYSPHAGIA, GERD | After 4 weeks of treatment, the complete resolution rate of overall GERD symptoms, including heartburn, acid regurgitation, dysphagia, and epigastric pain, was 49.5% (46/93) in the HIP1601 group and 48.9% (46/94) in the HGP1705 group (Table
Complete resolution rate of symptoms after treatment (per protocol set)46(49.5%)48(51.6%)46(48.9%)47(50.0%)28(46.7%)30(50.0%)37(57.8%)37(57.8%)49(63.6%)50(64.9%)55(72.4%)55(72.4%)51(68.0%)52(69.3%)51(66.2%)52(67.5%)4(36.4%)4(36.4%)10(55.6%)10(55.6%)25(69.4%)26(72.2%)29(69.0%)30(71.4%)The complete resolution rate was defined proportion of patients with ‘score 0’ of severity during the last 7 days prior to the visit*Cumulative complete resolution rate of symptoms by week 8***** **** The complete resolution rate of GERD symptoms at week 8 was analyzed in 15 patients who did not achieve complete EE healing at week 4. There were no statistically significant differences in any GERD symptoms between the two groups. | PMC10729464 |
Proportion of heartburn- and acid regurgitation-free days and nights by week 1, 2, 4, 8 (per protocol set) | HGP1705 | The proportions of heartburn- and acid regurgitation-free days by week 4 were 68.1% and 68.7% in HIP1601 group, and 71.9% and 69.3% in HGP1705 group, respectively (Fig.
The proportion of symptoms-free days and nights after 1, 2, 4 weeks of treatment (per protocol set). A, the proportion of heartburn-free days after 1, 2, 4 weeks of treatment. B, the proportion of acid regurgitation-free days after 1, 2, 4 weeks of treatment. C, the proportion of heartburn-free nights after 1, 2, 4 weeks of treatment. D, The proportion of acid regurgitation-free nights after 1, 2, 4 weeks of treatmentThe proportion of symptom-free days and nights by week 8 was analyzed in 15 patients who did not achieve complete healing of the EE at week 4. There were no statistically significant differences between the two groups. | PMC10729464 |
|
Time to sustained resolution of heartburn and acid regurgitation (per protocol set) | HGP1705, heartburn | The median time to sustained resolution of heartburn was 7 days (95% CI: 3.0–16.0) in the HIP1601 group and 8 days (95% CI: 5.0–11.0) in the HGP1705 group (Supplementary Table The proportion of patients who achieved sustained resolution of nocturnal heartburn and nocturnal acid regurgitation was 87.2% (34/39) and 81.8% (27/33) in the HIP1601 group and 83.3% (35/42) and 86.8% (33/38) in the HGP1705 group, respectively (Supplementary Table | PMC10729464 |
|
Number of rescue medication use | HGP1705 | The mean number of rescue medications administered in the HIP1601 (7.8 per subject) was lower than that (9.3 per subject) in the HGP1705 group. However, there was no significant difference between the two groups ( | PMC10729464 |
|
Tolerability and safety | HGP1705, TEAEs | ADVERSE EVENTS, EVENTS, ADVERSE EVENT | The incidence of TEAEs was 14.3% (15/105; 22 events) in the HIP1601 group and 14.2% (15/106; 20 events) in the HGP1705 group (Table
Summary of treatment-emergent adverse events (safety analysis set)TEAE: treatment-emergent adverse events*TEAEs: Adverse events with start date on or after administration of the study drug, or pre-existing conditions that worsened during or after study drug administration | PMC10729464 |
Discussion | GERD, fracture, TEAEs, erosions, hypomagnesemia, reflux disease, NERD, community-acquired pneumonia, Barrett’s esophagus, esophageal and extraesophageal symptoms, gastric acid | ADVERSE EVENTS, GERD, HYPOMAGNESEMIA, CLOSTRIDIUM DIFFICILE INFECTION, COMMUNITY-ACQUIRED PNEUMONIA, COMPLICATIONS | The goal of GERD treatment is to alleviate symptoms and prevent complications. Although currently approved delayed-release PPIs have shown benefits in the treatment of GERD, unmet needs remain [Although a new class of drugs, such as potassium-competitive acid blockers (P-CABs), has recently been developed, PPIs remain the first-line drug for GERD treatment [The spectrum of GERD includes EE, nonerosive reflux disease (NERD), and Barrett’s esophagus. EE is characterized by the presence of erosions in the esophageal mucosa and is commonly graded using the LA Classification system, which has a high level of inter-observer reliability among experienced endoscopists [GERD has a significant impact on the quality of life of affected individuals, as both esophageal and extraesophageal symptoms can be bothersome and affect daily functioning [Nocturnal symptoms of GERD can significantly disrupt sleep and reduce the quality of life in patients with GERD. Nocturnal acid breakthrough (NAB), a trop in gastric pH below 4 that lasts for more than 1 h during night, is the main cause of nocturnal symptoms in patients with GERD. NAB presents in a high proportion (75%) of healthy subjects, and a once-daily dose of PPIs, owing to their short half-life, could not eliminate this phenomenon [In addition to effectiveness, the safety of new drugs remains an important issue. Recent reports have highlighted the potential long-term adverse events associated with gastric acid suppression, such as community-acquired pneumonia, clostridium difficile infection, hip fracture, or hypomagnesemia [This study has several limitations. First, most enrolled patients had LA Classification grades A/B EE, with only a small number having LA Classification grades C/D EE. None of the patients had LA grade D EE. Consequently, these findings may not represent the clinical effects in the entire GERD population, particularly in those with more severe EE. Secondly, validated questionnaires specifically designed to assess the severity and improvement of GERD symptoms were not included. However, we analyzed the severity and improvement of GERD symptoms using objective indicators, and the improvement in GERD symptoms was assessed based on dichotomous endpoints (complete resolution or not). Third, the analysis of the complete resolution of GERD symptoms and TEAEs by week 8 was limited to a small subgroup of 15 patients who did not achieve complete healing of the EE at week 4. | PMC10729464 |
Conclusions | GERD, HGP1705 | GERD | In conclusion, the findings of this study support the efficacy and safety of HIP1601 40 mg as a treatment option for EE healing and alleviating GERD symptoms. The results indicate that HIP1601 is not inferior to HGP1705 40 mg in terms of both efficacy and safety, as demonstrated by comparable healing rates and tolerability profiles. Based on these results, it can be concluded that HIP1601 is effective and well tolerated in patients with GERD. | PMC10729464 |
CONSORT guidelines | The study adheres to the CONSORT guidelines and a completed CONSORT has been submitted separately. | PMC10729464 |
||
Electronic supplementary material | Below is the link to the electronic supplementary material.
Supplementary Material 1 | PMC10729464 |
||
Acknowledgements | Not applicable. | PMC10729464 |
||
Author contributions | Hwoon-Yong Jung: Study concept and design, study supervision, acquisition of data, revision of the manuscript, statistical analysis, interpretation of data, verified the underlying data. Hyun Lim: Acquisition of data, drafting of the manuscript, revision of the manuscript, interpretation of data,. Jae Myung Park, Jong Kyu Park, Jung Ho Park, Moo In Park, Gwang Ha Kim, Hyunsoo Chung, Sung Kwan Shin, Kwang Jae Lee, Si Hyung Lee, Suck Chei Choi, Hye-Kyung Jung, Jeong Seop Moon, Hyun-Soo Kim, Jae Kyu Sung, Seong Woo Jeon, Nayoung Kim, and Jong-Jae Park: Acquisition of data, revision of the manuscript. Sung Hee Hong and Na Young Kim: Study supervision, statistical analysis, revision of the manuscript, interpretation of data, verified the underlying data. | PMC10729464 |
||
Funding | This work was supported by Hanmi Pharmaceuticals Co., Ltd., Seoul, Republic of Korea (HM-ESOM-301). | PMC10729464 |
||
Data availability | Relevant data have been presented in the main manuscript. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10729464 |
||
Declarations | PMC10729464 |
|||
Ethics approval and consent to participate | The study protocol was approved by the ethics committees of all participating hospitals. | PMC10729464 |
||
Consent for publication | Informed consent was obtained from all individual participants included in the study. | PMC10729464 |
||
Competing interests | The authors declare no competing interests. | PMC10729464 |
||
References | PMC10729464 |
|||
Background | fibrosis, IUA | INTRAUTERINE ADHESIONS, FIBROSIS | Intrauterine adhesion (IUA) is a frequent acquired endometrial condition, for which there is no effective preventive or treatment. Previous studies have found that vaginal microbiota dysregulation is closely related to endometrial fibrosis and IUA. Therefore, we wondered whether restoration of vaginal microbiota by vaginal administration of | PMC10032012 |
Results | IUA | First, we created a mechanically injured mouse model of IUA and restored the mice’s vaginal microbiota by the addition of | PMC10032012 |
|
Conclusions | This study confirmed that | PMC10032012 |
||
Clinical trial registration | : | PMC10032012 |
||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12866-023-02823-y. | PMC10032012 |
||
Keywords | PMC10032012 |
|||
Results | PMC10032012 |
|||
Discussion | TGF-β1, inflammation, fibrosis, intrauterine inflammation, infection, IUA, endometrial basal layer damage | ENDOMETRITIS, INTRAUTERINE ADHESION, INFLAMMATION, FIBROSIS, INFECTION | Finally, 10 vaginal secretion samples were selected in the group C, I, E and L, a total of 40 samples were used for high-throughput sequencing. In α-diversity, there are significant differences in Shannon (P < 0.01) and Simpson (P < 0.005) (Fig.
The effect of We allow visitors to reproduce images with permission and/or creditA combination of TCRA supplemented with IUD [Nowadays, the antagonistic and synergistic effects between vaginal microbiota are significant in keeping the female reproductive system in good condition [It is well known that the constant stimulation of infection and inflammation impairs the repair of endometrial basal layer damage, leading to intrauterine inflammation and fibrosis, and ultimately to IUA [The purpose of IUA treatment is to reduce endometrial fibrosis and boost endometrial regeneration. TGF-β1 and MMP-9 are two profibrotic and antifibrotic cytokines whose interactions control the damaged endometrial healing process [In high-throughput sequencing results, the composition and diversity of vaginal microflora in mice with IUA were significantly changed, as shown by PCoA in Fig. In the clinical investigation, 27.08% of patients with IUA had endometritis, which were positive for CD38 and CD138, which was consistent with previous studies on the etiology of intrauterine adhesion [After TCRA, by comparing with estrogen, we found that the effect of estrogen in promoting endometrial growth is better than that of Although This study confirmed that the supplementation of | PMC10032012 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.