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Pharmacokinetics, Safety, and Tolerability of Tenapanor in Healthy Chinese and Caucasian Volunteers: A Randomized, Open-Label, Single-Center, Placebo-Controlled Phase 1 Study.
Yuan, G, Chen, Y, Li, L, Wang, X, Wei, G, Zeng, J, Hui, AM, Jiang, Y, Zhao, H, Diao, L, et al
International journal of clinical practice. 2024;:1386980
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BACKGROUND Tenapanor is a locally acting selective sodium-hydrogen exchanger 3 inhibitor with the potential to treat sodium/phosphorus and fluid overload in various cardiac-renal diseases, which has been approved for constipation-predominant irritable bowel syndrome in the US. The pharmacokinetics (PK) of tenapanor and its metabolite tenapanor-M1 (AZ13792925), as well as the safety and tolerability of tenapanor, were investigated in healthy Chinese and Caucasian subjects. METHODS This randomized, open-label, single-center, placebo-controlled phase 1 study (https://www.chinadrugtrials.org.cn; CTR20201783) enrolled Chinese and Caucasian healthy volunteers into 4 parallel cohorts (3 cohorts for Chinese subjects, 1 cohort for Caucasian subjects). In each cohort, 15 subjects were expected to be included and received oral tenapanor (10 or 30 mg as single dose, or 50 mg as a single dose followed by a twice-daily repeated dose from Day 5 to 11, with a single dose in the morning on Day 11) or placebo in a 4 : 1 ratio. RESULTS 59 healthy volunteers received tenapanor 10 mg (n = 12 Chinese), 30 mg (n = 12 Chinese), or 50 mg (n = 12 (Chinese), n = 11 (Caucasian)) or placebo (n = 12, 3 per cohort). After single and twice-daily repeated doses, tenapanor plasma concentrations were all below the limit of quantitation; tenapanor-M1 appeared slowly in plasma. In single-ascending dose evaluation (10 to 50 mg) of Chinese subjects, the mean Cmax, AUC0-t, and AUC0-∞ of tenapanor-M1 increased with increasing dose level, and AUC0-t increased approximately dose proportionally. The Cmax accumulation ratio was 1.55 to 6.92 after 50 mg repeated dose in Chinese and Caucasian subjects. Exposure to tenapanor-M1 was generally similar between the Chinese and Caucasian subjects. Tenapanor was generally well-tolerated and the safety profile was similar between the Chinese and Caucasian participants receiving tenapanor 50 mg, as measured by vital signs, physical and laboratory examination, 12-lead ECG, and adverse events. No serious adverse event or adverse event leading to withdrawal occurred. CONCLUSION Tenapanor was well-tolerated, with similar PK and safety profiles between Chinese and Caucasian subjects. This trial is registered with CTR20201783.
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DIALIZE China: A Phase IIIb, Randomized, Placebo-Controlled Study to Reduce Predialysis Hyperkalemia With Sodium Zirconium Cyclosilicate in Chinese Patients.
Ni, Z, Lu, R, Xu, X, Bian, X, Zhou, Z, Yang, J, Luo, Q, Chen, M, Chen, C, Sun, X, et al
Clinical therapeutics. 2023;(7):633-642
Abstract
PURPOSE The DIALIZE China study (Reduce Incidence of Pre-Dialysis Hyperkalaemia With Sodium Zirconium Cyclosilicate in Chinese Subjects) (NCT04217590) evaluated sodium zirconium cyclosilicate (SZC) for the management of hyperkalemia in Chinese patients undergoing hemodialysis. METHODS In the double-blind, Phase IIIb DIALIZE China study, Chinese adults with kidney failure and predialysis hyperkalemia (predialysis serum potassium [sK+] concentration >5.4 mmol/L after the long interdialytic interval [LIDI] and >5.0 mmol/L after ≥1 short interdialytic interval) who were receiving hemodialysis 3 times weekly were randomized to placebo or SZC 5 g once daily on nondialysis days. Doses were titrated towards maintaining normokalemia for 4 weeks (titration period) in 5-g increments up to 15 g. Primary efficacy was the proportion of responders during the 4-week evaluation period following the titration period (ie, those with a predialysis sK+ of 4.0-5.0 mmol/L for at least 3 of 4 hemodialysis visits following the LIDI) who did not require urgent rescue therapy. FINDINGS Overall, 134 adults (mean [SD] age, 55 [11.3] years) were randomized to SZC or placebo (n = 67 each). There were significantly more responders with SZC (37.3%) versus placebo (10.4%; estimated odds ratio [OR] = 5.10; 95% CI, 1.90-15.12; P < 0.001). The probability of all predialysis sK+ concentrations being 3.5 to 5.5 mmol/L was significantly higher with SZC versus placebo (estimated OR = 6.41; 95% CI, 2.71-15.12; P < 0.001). A greater proportion of patients achieved an sK+ of 3.5 to 5.5 mmol/L on at least 3 of 4 LIDI visits during evaluation with SZC (73.1%) versus placebo (29.9%). Serious adverse events occurred in 9.1% and 11.9% of patients in the SZC and placebo groups, respectively. IMPLICATIONS SZC treatment for predialysis hyperkalemia is effective and well tolerated in Chinese patients with kidney failure receiving hemodialysis. CLINICALTRIALS gov identifier: NCT04217590.
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Lenvatinib, Toripalimab plus FOLFOX Chemotherapy in Hepatocellular Carcinoma Patients with Extrahepatic Metastasis: A Biomolecular Exploratory, Phase II Trial (LTSC).
He, M, Huang, Y, Du, Z, Lai, Z, Ouyang, H, Shen, J, Wen, D, Li, Q, Zhang, Y, Wei, W, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;(24):5104-5115
Abstract
PURPOSE To investigate the efficacy, safety, and biomarkers of systemic chemotherapy with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) in combination with lenvatinib and toripalimab as the first-line treatment for advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis. PATIENTS AND METHODS In this biomolecular exploratory, phase II trial, eligible patients underwent the triple combination therapy of lenvatinib, toripalimab, plus FOLFOX chemotherapy. Primary endpoint was progression-free survival (PFS) rate at 6 months by RECIST v1.1. Single-nucleus RNA sequencing (snRNA-seq) of tumor biopsy samples was performed for exploratory biomarker analyses. RESULTS Between November 19, 2019, and July 4, 2021, 30 patients were enrolled. The primary endpoint was a 6-month PFS rate of 66.7%, with a median PFS of 9.73 months [95% confidence interval (CI), 2.89-16.58]. The median overall survival (OS) was 14.63 months (95% CI, 11.77-17.50), with an objective response rate of 43.3%. Twenty-four (80.0%) patients exhibited high-risk features, among whom the median OS and PFS were 13.7 months (95% CI, 9.24-18.16) and 8.3 months (95% CI, 3.02-13.58), respectively. The most common adverse events were neutropenia, and increased aspartate aminotransferase and alanine aminotransferase levels. Exploratory analyses of snRNA-seq profiles suggested that patients with higher abundance of tumor-infiltrating immune cells were more likely to benefit from this combination. In addition, two subtypes of hepatocytes (AKR1C2+ and CFHR4+ malignant hepatocytes) were associated with reduced clinical benefits. CONCLUSIONS FOLFOX chemotherapy in combination with lenvatinib and toripalimab showed promising antitumor activity with manageable toxicities in advanced HCC with extrahepatic metastasis. AKR1C2+ and CFHR4+ hepatocyte subtypes may be predictive biomarkers of resistance to the combination therapy.
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Upadacitinib Induction and Maintenance Therapy for Crohn's Disease.
Loftus, EV, Panés, J, Lacerda, AP, Peyrin-Biroulet, L, D'Haens, G, Panaccione, R, Reinisch, W, Louis, E, Chen, M, Nakase, H, et al
The New England journal of medicine. 2023;(21):1966-1980
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BACKGROUND Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn's disease. METHODS In two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn's disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn's Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]). RESULTS A total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib. CONCLUSIONS Upadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn's disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.).
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Efficacy and Safety of Ivarmacitinib in Patients With Moderate-to-Severe, Active, Ulcerative Colitis: A Phase II Study.
Chen, B, Zhong, J, Li, X, Pan, F, Ding, Y, Zhang, Y, Chen, H, Liu, F, Zhang, Z, Zhang, L, et al
Gastroenterology. 2022;(6):1555-1568
Abstract
BACKGROUND & AIMS Current therapies for ulcerative colitis (UC) fail to achieve satisfactory disease control. Selective inhibition of Janus kinase (JAK) type 1 may improve clinical outcomes in patients with UC while avoiding the side effects associated with pan-JAK inhibition. The safety and efficacy of the selective JAK1 inhibitor ivarmacitinib (formerly SHR0302) were evaluated in patients with moderate-to-severe, active UC. METHODS AMBER2 was a double-blind, placebo-controlled, phase II trial conducted at 63 clinical centers in China, the United States, and Europe. Patients (N = 164) were randomized 1:1:1:1 to receive oral ivarmacitinib 8 mg once daily (QD), 4 mg twice daily (BID), or 4 mg QD, or placebo for 8 weeks, followed by an 8-week extension period. The primary endpoint was clinical response rate at week 8. Hochberg's procedure was used to control the study-wise type 1 error at alpha=0.1. RESULTS A total of 146 (89.0%) patients completed 8 weeks of treatment. Week 8 clinical response rates were significantly higher in the 8 mg QD (46.3%; P = .066), 4 mg BID (46.3%; P = .059), and 4 mg QD (43.9%; P = .095) groups vs placebo (26.8%). Week 8 rates of clinical remission were 22.0% (P = .020), 24.4% (P = .013), and 24.4% (P = .011) in the 3 ivarmacitinib treatment groups, respectively, vs 4.9% for placebo. During the initial 8-week period, treatment-emergent adverse events occurred in 43.9% to 48.8% of ivarmacitinib-treated patients and in 39.0% of the placebo group, and were predominantly mild. There were no deaths, or major adverse cardiovascular or thromboembolic events. CONCLUSION Ivarmacitinib demonstrated clinical efficacy and was well tolerated in patients with moderate-to-severe, active, UC. Ivarmacitinib represents a promising new treatment for moderate-to-severe UC. CLINICALTRIALS gov number, NCT03675477.
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Lenvatinib, toripalimab plus hepatic arterial infusion chemotherapy in patients with high-risk advanced hepatocellular carcinoma: A biomolecular exploratory, phase II trial.
Lai, Z, He, M, Bu, X, Xu, Y, Huang, Y, Wen, D, Li, Q, Xu, L, Zhang, Y, Wei, W, et al
European journal of cancer (Oxford, England : 1990). 2022;:68-77
Abstract
INTRODUCTION The combination of lenvatinib, toripalimab and hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) suggested encouraging antitumour activity in our retrospective study. We hereby prospectively establish the efficacy, safety and predictive biomarkers of the combination therapy as a first-line treatment in patients with high-risk advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS This phase II, single-centre, single-arm trial enrolled advanced HCC participants with high-risk. Of 51 screened participants, 36 received lenvatinib, toripalimab plus FOLFOX-HAIC. Participants received 21-day treatment cycles of lenvatinib, toripalimab, and FOLFOX-HAIC. The primary end-point was the progression-free survival (PFS) rate per RECIST at six months. RESULTS Thirty-six participants (86.1% with high-risk features) were enrolled in our study. The primary end-point was met with a PFS rate of 80.6% (95% CI, 64.0%-91.8%) at six months. The median PFS was 10.4 months (95% CI, 5.8-15.0), and the median OS was not reached at the prespecified final analysis and was 17.9 months (95% CI, 14.5-21.3) after follow-up was extended. The ORR per RECIST was 63.9%, and per mRECIST was 66.7%. The median duration of response was 14.4 months (95% CI, 8.9-19.9). The most common adverse events were thrombocytopenia, elevated aspartate aminotransferase, and hypertension, and no treatment-related death was reported. Participants with low levels of both CCL28 and BTC had unsatisfactory prognosis. CONCLUSIONS Lenvatinib, toripalimab and FOLFOX-HAIC showed safe and encouraging antitumour activity for advanced HCC with high-risk features. The levels of CCL28 and BTC might be the predictive biomarkers for the triple combination therapy.
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Rationale for and design of a multicenter, placebo-controlled, phase 3 study to assess efficacy and safety of intranasal etripamil for the conversion of paroxysmal supraventricular tachycardia.
Stambler, BS, Plat, F, Sager, PT, Lubkov, V, Shardonofsky, S, Wight, D, Chen, M, Camm, AJ
American heart journal. 2022;:20-29
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Presently, acute pharmacological termination of paroxysmal supraventricular tachycardia (PSVT) unresponsive to patient-initiated vagal maneuvers requires in-hospital intervention. Etripamil, a fast-acting, nondihydropyridine, L-type calcium channel blocker, is formulated as an intranasal spray to rapidly terminate atrioventricular (AV) nodal-dependent PSVT in a medically unsupervised setting. The NODE-301 study did not meet its prespecified primary end point of PSVT conversion over 5 hours following a single dose of etripamil 70 mg. However, analysis at earlier time points demonstrated etripamil treatment effect during the first 30 minutes, consistent with its expected rapid onset and short duration of action. This led to the design of the RAPID study, which includes a new dosing regimen (up to 2 etripamil 70 mg doses separated by 10 minutes) to increase the exposure and pharmacodynamic effect of etripamil. The primary objective of RAPID (NCT03464019) is to determine if etripamil self-administered by patients is superior to placebo in terminating PSVT in an at-home setting. The secondary objective is to evaluate the safety of etripamil when self-administered by patients without medical supervision. Additional efficacy end points include the proportion of patients requiring additional medical intervention in an emergency department to terminate PSVT and patient-reported outcomes. After successfully completing a test dose to assess the safety of 2 70 mg doses of etripamil during sinus rhythm, approximately 500 patients will be randomized 1:1 to etripamil or placebo to accrue 180 positively adjudicated AV nodal-dependent PSVT events for treatment with the study drug. Etripamil may offer a new alternative to the current in-hospital treatment modality, providing for safe and effective at-home termination of PSVT.
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Cryoablation Without Excision for Low-Risk Early-Stage Breast Cancer: 3-Year Interim Analysis of Ipsilateral Breast Tumor Recurrence in the ICE3 Trial.
Fine, RE, Gilmore, RC, Dietz, JR, Boolbol, SK, Berry, MP, Han, LK, Kenler, AS, Sabel, M, Tomkovich, KR, VanderWalde, NA, et al
Annals of surgical oncology. 2021;(10):5525-5534
Abstract
BACKGROUND The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. METHODS The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. RESULTS Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. CONCLUSIONS Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.
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Toripalimab plus intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma: an open-label single-arm, phase II trial.
Hua, Y, You, R, Wang, Z, Huang, P, Lin, M, Ouyang, Y, Xie, Y, Zou, X, Liu, Y, Duan, C, et al
Journal for immunotherapy of cancer. 2021;(11)
Abstract
BACKGROUND Toripalimab is a humanized immunoglobulin G4 monoclonal antibody against programmed death 1. We aimed to investigate the efficacy and safety of toripalimab in combination with intensity-modulated radiotherapy (IMRT) for recurrent nasopharyngeal carcinoma (rNPC). METHODS We conducted a single-arm, phase II trial with patients with rNPC who had biopsy-proven disease and were unsuitable for local surgery. Eligible patients received IMRT in combination with toripalimab administered via intravenous infusion of 240 mg once every 3 weeks for a maximum of seven cycles. The primary endpoint was the objective response rate at 3 months post radiotherapy. The secondary endpoints included safety profiles, progression-free survival (PFS). RESULTS Between May 2019 and January 2020, a total of 25 patients with rNPC were enrolled (18 men (72.0%) and 7 women (28.0%); median (IQR) age, 49.0 (43.5-52.5) years). With a median (IQR) follow-up duration of 14.6 months (13.1-16.2) months, 19 patients (79.2%) achieved an overall response, and disease control was achieved in 23 (95.8%) patients at 3 months post radiotherapy. The 12-month PFS was 91.8% (95% CI 91.7% to 91.9%). The incidences of acute (grade ≥3) blood triglyceride elevation, creatine kinase elevation, skin reaction, and mucositis were 1 (4.0%), 1 (4.0%), 2 (8.0%), and 1 (4.0%), respectively. The incidences of late severe (grade ≥3) nasopharyngeal wall necrosis, nasal bleeding, and trismus were 28.0%, 12.0%, and 4.0%, respectively. CONCLUSIONS Toripalimab combined with IMRT was tolerable and showed promising antitumor activity in patients with rNPC. TRIAL REGISTRATION NUMBER NCT03854838.
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Flash Glucose Monitoring Improves Glucose Control in People with Type 2 Diabetes Mellitus Receiving Anti-diabetic Drug Medication.
Chen, M, Li, H, Shen, Y, Liu, B, Yan, R, Sun, X, Ye, L, Lee, KO, Ma, J, Su, X
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2021;(12):857-863
Abstract
OBJECTIVE To investigate the effects of Flash Glucose Monitoring (FGM) on glucose profile in people with Type 2 Diabetes Mellitus (T2DM) receiving anti-diabetic drug medication. METHODS This is a prospective non-randomized uncontrolled study. 111 people with T2DM were enrolled and received FGM for 14 days. There was no change of anti-diabetic medication during the 14 days. The plasma glucose concentration on day 2 was used as baseline and the day 13 was considered as study end point. The parameters to compare were mean plasma glucose (MPG), glucose variations, and incidence of hypoglycemia during the FGM period. The multivariate linear stepwise regression analysis was applied to determine the independent factors that affect MPG difference. RESULTS This study analyzed the data of a total of 111 people with T2DM (male 60 and female 51). The general clinical data of these patients were as follows: age: 65.0±6.7 years old; duration of diabetes: 11.6±6.8 years; HbA1c: 61.2±13.3 mmol/mol; body mass index (BMI): 25.2±3.2 kg/m². Using FGM, people with T2DM were able to change daily diet and exercise through which significant reductions in MPG on days 12 or 13 were achieved as compared with that of day 2 (P=0.04 or P=0.003, respectively). The glucose variations, such as standard deviation (SD) of plasma glucose, coefficient of variation (CV), and mean amplitude of glycemic excursion (MAGE), progressively declined starting from day 6 as compared with baseline (P=0.016, P=0.003, or P=0.012, respectively). The incremental area over the curve (AOC) of the hypoglycemia (<3.9 mmol/L) had a significant reduction starting from the day 3 (P=0.001). When people with T2DM were divided into 3 groups based on the tertile of HbA1c (high, middle, and low concentrations), the reduction of MPG in patients with high concentration of HbA1c were much larger than that in middle and low concentration group patients (P=0.001 for both). The incidence of hypoglycemia was improved in the low concentration group (P=0.017). The optimal frequency of scanning time required to maintain euglycemia was 11.7 times/day as calculated by the receiver operating characteristic (ROC) analysis. CONCLUSION Using FGM to monitor glucose concentration at 11.7 times/day, people with T2DM can achieve a better glucose control in addition to anti-diabetic drug medication through changing daily diet and exercise, especially in patients with high concentration of HbA1c (>66.1 mmol/mol).