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Author contributions | MP, FM | EP, MP, JE, and FM: conceptualization and methodology, writing—review and editing, and project administration.. TM: statistics. EP and MP: coordinating clinical investigators. EP, MP, JE, FM, AK, MG, JO-S, IK, JL-A, and ES: writing and original draft preparation. All authors contributed to the writing—review and editing, article, and approved the submitted version.The authors thank Dr. Egmont Zieseniß, Inpharm Consulting, Dortmund, Germany, for performing the study monitoring. | PMC10393266 |
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Conflict of interest | FM | JE, FM, and ESc are employees of Dr. Kurt Wolff GmbH and Co. KG, Bielefeld, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10393266 |
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Publisher's note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10393266 |
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Supplementary material | The Supplementary Material for this article can be found online at: Click here for additional data file. | PMC10393266 |
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References | PMC10393266 |
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1. Introduction | muscle mass, muscle soreness, muscle damage, tissue damage | INFLAMMATORY RESPONSE | The post-exercise inflammatory response, characterized by muscle damage and elevated plasma levels of creatine kinase (CK), is a normal physiological process that is thought to play a vital role in tissue damage repair and enhancing muscle adaptation [Daily dietary protein intake is an important factor for muscle repair by enhancing muscle protein synthesis [This randomized double-blind placebo-controlled trial aimed to assess the effect of pea versus whey protein supplementation in comparison to placebo on exercise-induced increases in muscle damage markers in older adults 1, 2 and 3 days after endurance walking exercise. Secondary outcome measures included differences in changes in muscle soreness, muscle strength and muscle mass among groups after endurance walking exercise. We hypothesized that pea protein supplementation would be able to reduce muscle damage after endurance walking exercise in adults comparable to whey protein supplementation. | PMC9867418 |
2. Materials and Methods | PMC9867418 |
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2.1. Participants | Participants were recruited in July 2021 via the Nijmegen Exercise Study database [ | PMC9867418 |
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2.2. Study Design | In this randomized double-blind placebo-controlled trial, a total of 47 participants were randomly allocated to a whey protein, pea protein or placebo supplement group. Participants were invited for 5 study visits at the department of Physiology of the Radboud university medical center ( | PMC9867418 |
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2.3. Supplementation Protocol | Participants were instructed to consume the assigned supplement twice a day for a period of 13 days (10 days prior to the exercise bout and 3 days post exercise). This pre-loading period was chosen as previous studies have demonstrated its importance [ | PMC9867418 |
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2.4. Measurements | PMC9867418 |
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2.4.1. Blood Samples | muscle damage, tissue damage | Venous blood was drawn from the antecubital vein during each visit, and serum and lithium heparin plasma samples were stored at −80 °C until further analyses. Analyses were performed by trained technicians using standard operating procedures. CK and LDH levels were measured using a C8000 module C720 clinical chemistry analyzer (Roche, Almere, The Netherlands) to identify muscle damage and tissue damage, respectively. | PMC9867418 |
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2.4.2. Habitual Walking Characteristics | The habitual walking activity in the past year (July 2020–July 2021) was assessed at baseline using an online questionnaire. Participants were asked to indicate how frequent they walked per week, the average number of kilometers per walking bout and how many weeks in the past year they performed the reported walking bouts. Hence, the cumulative walking distance was calculated. | PMC9867418 |
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2.4.3. Exercise Intervention | Participants were instructed to perform a single walking bout with a minimum of 20 km and a maximum of 30 km. Walking distance, exercise duration and whether participants suffered from physical discomfort were registered directly following the exercise bout. | PMC9867418 |
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2.4.4. Muscle Soreness | Muscle soreness, pain | Muscle soreness was assessed using a Numeric (pain) Rating Scale (NPRS) where participants could mark a pain score between no pain at all (NRS = 0) and extremely painful (NRS = 10). NPRS scores of 1–5 were considered as mild pain, 6–7 as moderate pain and >8 as severe pain [ | PMC9867418 |
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2.4.5. Dietary Intake | Food consumption patterns were assessed using an online Dutch tool (i.e., ‘Mijn Voedingscentrum’) [ | PMC9867418 |
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2.4.6. Muscle Strength | Handgrip strength of the right hand was measured with a hydraulic, analogue handheld dynamometer (JAMARLeg muscle strength was measured in kilograms with an EN-Dynamic seated leg press (Enraf-Nonius, Rotterdam, The Netherlands). After adjusting the seat and a warm-up, participants had to perform one leg press per fixed step. The weight was increased gradually in seven fixed steps dependent on their body weight to directly determine the 1 repetition maximum (1 RM). There were only 7 attempts to determine the 1 RM to prevent injury and overexerting participants. | PMC9867418 |
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2.4.7. Anthropometrics and Muscle Mass | skeletal muscle mass | Body height and weight of the participants were measured. Total skeletal muscle mass (SMM) of both legs were estimated with bioelectrical impedance analyses (InBody 770 Body Composition Analyzed, Seoul, Republic of Korea) [ | PMC9867418 |
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3. Statistical Analysis | muscle soreness | Statistical analyses were performed using SPSS software (IBM SPSS Statistics for Windows, Version 25.0 IBM Corp., Armonk, NY, USA) and graphs were made using Graphpad Prism 9. All continuous variables and the residuals of the variables used in the linear-effects model were visually inspected and tested for normality with the Kolmogorov–Smirnov test. Logarithmic transformations were applied when data were not normally distributed and subsequently the normality was retested. Logarithmic transformations of CK and LDH were used in the statistical analyses in all cases. Data were displayed as mean ± SD or median (interquartile range [IQR]) for parametric and non-parametric continuous variables, respectively. Group differences were analyzed using a One-Way ANOVA or Kruskal–Wallis for parametric or non-parametric continuous variables, respectively. Repeated observations over days, such as CK, LDH and skeletal muscle mass, were analyzed using linear mixed-effects models with compound symmetry as the repeated covariance type in which group and time (e.g., 24 h, 48 h and 72 h upon walking) were treated as independent variables. The pre-exercise values were used as a covariate in the linear mixed model analyses. When significant main effects or interactions were detected, Bonferroni post hoc comparisons were made in case of parametric variables and Mann–Whitney U tests in case of non-parametric variables. Repeated measures analyses for the non-parametric muscle soreness values were performed using a Friedman analysis. The level of significance was set at | PMC9867418 |
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4. Results | PMC9867418 |
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4.1. Participants | muscle cramps | One participant from the placebo group withdrew from further participation after the baseline measurement due to personal reasons not related to the study protocol. Another participant from the pea supplement group dropped out due to heavy muscle cramps during the walking exercise bout and was therefore unable to complete the minimum walking distance of 20 km. This resulted in 15 participants per subgroup. Participants were predominantly male (80%), aged 70 ± 6 years with a BMI of 24.2 ± 2.8 kg/m | PMC9867418 |
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4.2. Habitual Dietary Intake and Walking Activity | Total energy intake was 2078 ± 528 kcal and comparable across groups ( | PMC9867418 |
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4.3. Exercise Bout Characteristic | Participants covered a walking distance of 24.3 ± 4.9 km with a duration of 5.2 ± 1.1 h. Walking distance and exercise duration did not differ across the three groups ( | PMC9867418 |
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4.4. Muscle Damage | The time-dependent exercise-induced increase in creatine kinase (CK) levels were significantly different between the three groups (Pinteraction = 0.018). Peak CK concentrations (+24 h) were significantly lower in the whey (175 ± 90 U/ | PMC9867418 |
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4.5. Muscle Parameters | Maximum recorded handgrip strength was not different between groups ( | PMC9867418 |
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5. Discussion | muscle soreness, muscle damage, skeletal muscle mass | SECONDARY | The aim of this randomized double-blind placebo-controlled trial was to assess the effect of pea protein and whey protein supplementation versus placebo on exercise-induced increases in muscle damage markers within older adults. We found that long-distance walking exercise provoked muscle damage, with peak CK levels around 24 h post-exercise in physically active older men and women. The CK increase is in line with a previous study who measured CK release in vital elderly after comparable bout of walking exercise [The magnitude of exercise-induced CK elevations was similar in active older adults receiving pea protein supplementation compared to placebo. These findings are contradictory to previous studies using other plant-based proteins, such as soy and oat, as an attenuated exercise-induced increase in CK levels was found compared to the placebo group [In contrast to the pea protein group, an attenuated exercise-induced elevation in CK concentrations was observed for the whey protein group. Whey protein supplementation is known to limit exercise-induced muscle damage [The digestibility of whey protein could be another important factor to explain the difference in exercise-induced elevations of CK concentrations compared to pea protein supplementation. Literature about the bio-availability of pea protein is contradictory. In vitro digestibility values are similar between whey and pea protein [Our study did not show effects of protein or placebo supplementation on changes in serum LDH concentrations, muscle strength, muscle soreness and skeletal muscle mass. The pattern of blood LDH showed a different response to the walking exercise compared to the CK response. This finding in our participants is not in line with most other literature where LDH was used as a marker for muscle damage after short periods of intense exercise (30 min–1.5 h) [Several limitations apply to our study. The protocol used for assessment of 1 RM for leg strength made it difficult to determine 1 RM of participants that reached the maximum of 200 kg or the last attempt. This may have hampered the possible effect of protein supplementation on leg muscle strength. Furthermore, this study also had a relatively small population, which could result in less statistical power and the supplementation period could have been too short to have impact on secondary outcomes. At last, this study had a fixed protein supplementation dose (25 g/day) which increased daily protein intake to >1.0 g/kg/day in 93% of our participants. A personalized protein supplementation dose, based on the individual lean body mass, may therefore be recommended to future studies to achieve a maximal effective dose for all study participants. | PMC9867418 |
6. Conclusions | muscle soreness, muscle damage, skeletal muscle mass | EXERCISE INDUCED MUSCLE DAMAGE | Our randomized double-blind placebo-controlled trial demonstrated that 13 days with 25 g per day of pea protein suppletion did not attenuate exercise-induced muscle damage in older adults compared to placebo. In contrast, the whey protein group showed lower serum CK levels at 24 h post exercise compared to pea protein and placebo group. Furthermore, none of the applied protein supplementation strategies had effect on muscle strength, muscle soreness and skeletal muscle mass, potentially due to the relatively short supplementation period. The effects of long-term plant protein supplementation on exercise induced muscle damage and body composition should be further explored in physically active elderly. Participants may also be exposed to a higher dosage of plant-based protein, whereas the protein quality in terms of digestibility and composition should be taken into account. | PMC9867418 |
Author Contributions | Conceptualization and methodology, M.S., Y.A.W.H., C.C.W.G.B., M.C.A.S. and M.T.E.H.; investigation: M.S., Y.A.W.H., C.C.W.G.B., T.M.H.E. and M.T.E.H.; formal analysis: M.S., M.C.A.S. and T.M.H.E.; writing—original draft preparation: M.S. and L.K.; writing—review and editing: M.S., L.K., Y.A.W.H., C.C.W.G.B., M.C.A.S., T.M.H.E. and M.T.E.H.; visualization: M.S. L.K.; project administration: M.S., Y.A.W.H., C.C.W.G.B. and M.T.E.H. All authors have read and agreed to the published version of the manuscript. | PMC9867418 |
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Institutional Review Board Statement | The study conformed to the principles of the Declaration of Helsinki, was approved by the local Medical Ethical committee (Study-ID: NL77522.091.21) and registered at the Dutch trial registry (#NL9499). | PMC9867418 |
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Informed Consent Statement | All participants gave signed consent to participate in the research study. | PMC9867418 |
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Data Availability Statement | The datasets generated and/or analyzed during the current study are not publicly available due to the fact that study participants can be identified based on age, sex and finish time, but the pseudonymized dataset is available from the corresponding author upon reasonable request. | PMC9867418 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC9867418 |
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Abbreviations | PMC9867418 |
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References | muscle mass | Overview of study timeline and measurements. #1–5 means visit 1–5.Change in Creatine kinase (CK) (Muscle parameters. Changes in handgrip strength (Nutritional composition of whey, pea and placebo supplements.** Branches Chain Amino Acids (BCAA’s).Baseline characteristics of the total group and specified for the whey-, pea- and placebo supplemented group.Data are presented as number (with percentage between brackets) of participants, mean ± SD for parametric data or median with the IQR between square brackets for non-parametric data. Body Mass Index (BMI). Thepercentage skeletal muscle mass was calculated by (skeletal muscle mass/the participant’s bodyweight) × 100. (kg = kilogram; m = meter; m | PMC9867418 |
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INTRODUCTION | B-cell lymphomas, DLBCL of germinal center B-cell, hypophosphatemia, neutropenia, toxicity, treatment-emergent adverse, B-cell lymphoma, lymphoid malignancy, DLBCL, lymphoma, non-Hodgkin’s lymphoma | HYPOPHOSPHATEMIA, NEUTROPENIA, DISEASE, B-CELL LYMPHOMA, SOLID TUMORS, LYMPHOMA, DIFFUSE LARGE B-CELL LYMPHOMA | We report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report).Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60–120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity.A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) and 38% (26/69), respectively. Median duration of response was 28.1 months overall and not reached in DLBCL responders. In subgroups with DLBCL of germinal center B-cell (GCB) and non-GCB origin, ORR was 28% (11/40) and 58% (7/12), respectively. Median progression free survival was 2.0 and 1.6 months in the lymphoma and DLBCL cohorts, respectively. Grade ≥3 treatment-emergent adverse events occurred in 96% of all lymphoma patients, many of which were limited to asymptomatic laboratory abnormalities; the most common were increased amylase (29%), neutropenia (27%), and hypophosphatemia (26%).These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL.Trial registration: ClinicalTrials.gov number: NCT02000934.Diffuse large B-cell lymphoma (DLBCL) is an aggressive histologic subtype of non-Hodgkin’s lymphoma and is the most common adult lymphoid malignancy in the Western world [Multi-agent salvage chemotherapy followed by autologous stem-cell transplant (ASCT) has been the standard treatment for relapsed or refractory DLBCL [Mivavotinib (TAK-659/CB-659) is an investigational, oral, reversible, potent dual inhibitor of spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3) [The safety, tolerability, and preliminary efficacy of mivavotinib were investigated in a phase I first-in-human dose escalation and expansion study conducted in patients with relapsed or refractory solid tumors or B-cell lymphomas, including DLBCL [Mivavotinib demonstrated anti-tumor activity in patients with relapsed or refractory B-cell lymphomas across different histological subtypes, including DLBCL [The current analysis provides updated results for these lymphoma patients with extended follow-up. Also included are data for an additional cohort of patients with DLBCL ( | PMC9882996 |
RESULTS | PMC9882996 |
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Patients | DLBCL | A total of 124 patients were enrolled; 17 patients were enrolled in the dose escalation phase and received mivavotinib at the following doses: 60 mg QD (Of the patients with DLBCL, 12 were enrolled during dose escalation, 41 were enrolled to the first expansion cohort, and 36 were enrolled to the second expansion cohort. By data cut-off, treatment had been discontinued in all 124 patients. Patient disposition is summarized in | PMC9882996 |
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Patient disposition flow diagram. | lymphoma, DLBCL | LYMPHOMA, DISEASE CHARACTERISTIC | Patient baseline demographics and disease characteristics for all lymphoma patients and all DLBCL patients are shown in | PMC9882996 |
Efficacy | BEST | Best overall responses to mivavotinib are shown in | PMC9882996 |
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Best overall response | DISEASE | Percentages are based on the total number of patients in the response-evaluable population in each column. 2-sided 95% exact binomial CIs were used. Abbreviation: SD: stable disease. | PMC9882996 |
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Kaplan–Meier curve for estimated median DOR in the DLBCL combined cohort (response-evaluable population). | lymphoma, PD, death, DLBCL | LYMPHOMA, EVENTS, EVENT, DISEASE PROGRESSION | DOR was defined as the time from the date of first documentation of PR or better to the date of first documentation of PD or relapse. Among patients with CR, no patients had a PD/relapse event, and data were censored with a range of less than one month (1 day) to 63.0 months with responses ongoing for all 14 patients at the time of data cut. Among patients with PR, 4 patients had a PD/relapse event, and data were censored for the remaining 8 patients.Within the subgroup of patients with DLBCL (excluding those enrolled in dose escalation), 33 patients in the first expansion cohort were evaluable for response and 25 in the second cohort were evaluable for response. The ORR was 24% (95% CI, 11.1–42.3) in the first DLBCL cohort (18% with CR and 6% with PR) and 56% (95% CI, 34.9–75.6) in the second DLBCL cohort (20% with CR and 36% with PR). Considering all response-evaluable patients with DLBCL enrolled in the study (The median progression-free survival (PFS) in all patients with lymphoma was 2.0 months (95% CI, 1.6–3.3); 86 patients (69%) experienced PFS events, of which 53 (62%) were due to progression and 33 (38%) were due to death. In patients with DLBCL, the median PFS was 1.6 months (95% CI, 1.5–1.9), and 67 patients (75%) experienced PFS events; 41 (61%) were due to disease progression and 26 (39%) were due to death ( | PMC9882996 |
Kaplan–Meier curve for estimated median PFS in the DLBCL combined cohort (safety population). | lymphoma, death, DLBCL | LYMPHOMA, DISEASE | PFS is defined as the time from the date of the first study treatment administration to the date of the first documentation of progressive disease or death.The median overall survival (OS) was 8.3 months (95% CI, 3.7–NE) in patients with lymphoma and 3.9 months (95% CI, 2.1–NE) in patients with DLBCL. Overall, 52 patients with lymphoma (42%), including 42 patients in the DLBCL cohorts (47%), died within the time period between the first dose and the last follow-up.Within the DLBCL response-evaluable population ( | PMC9882996 |
Safety | lymphoma, DLBCL | LYMPHOMA | All patients received at least one dose of mivavotinib and were evaluable for safety. Patients received a median of 2 treatment cycles (range 1–68), and the median treatment duration was 6.8 weeks for all patients with lymphoma and 6.0 weeks for patients with DLBCL. Safety is summarized in | PMC9882996 |
Overview of TEAEs (safety population) | Deaths | ADVERSE EVENT | TEAEs are defined as any adverse event that occurs after administration of the first dose of study treatment through 28 days after last dose of study treatment, or until the start of subsequent antineoplastic therapy. Deaths occurred within 28 days of last treatment dose. Percentages are based on the number of patients in each treatment group for the designated population of this table. | PMC9882996 |
Most frequent TEAEs occurring in ≥10% of patients by preferred term (safety population) | ADVERSE EVENT | TEAEs are defined as any adverse event that occurs after administration of the first dose of study treatment through 28 days after the last dose of study treatment, or until the start of subsequent antineoplastic therapy. Abbreviations: ALT: alanine aminotransferase; CPK: creatine phosphokinase. | PMC9882996 |
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Most common grade ≥3 TEAEs occurring in ≥10% of patients by preferred term (safety population) | lymphoma, TEAE | LYMPHOMA, ADVERSE EVENT | TEAEs are defined as any adverse event that occurs after administration of the first dose of study treatment through 28 days after the last dose of study treatment, or until the start of subsequent antineoplastic therapy.All patients with lymphoma experienced at least one TEAE; 96% experienced a grade ≥3 TEAE, and 76% experienced a grade ≥3 TEAE considered by the investigator to be related to mivavotinib ( | PMC9882996 |
DISCUSSION | deaths, pneumonitis, hypophosphatemia, pneumonia, neutropenia, metabolic disorder, toxicity, respiratory failure, thrombocytopenia, anemia, DLBCL, GCB and non-GCB DLBCL, lymphoma, lymphoma malignancies | PNEUMOCYSTIS PNEUMONIA, PNEUMONITIS, HYPOPHOSPHATEMIA, PNEUMONIA, NEUTROPENIA, METABOLIC DISORDER, RESPIRATORY FAILURE, DISEASE, THROMBOCYTOPENIA, SOLID TUMORS, OPPORTUNISTIC INFECTION, ANEMIA, MULTIORGAN FAILURE, LYMPHOMA, COMPLICATIONS | Primary data from this phase I, first-in-human study investigating the safety, tolerability, and preliminary efficacy of SYK/FLT3 inhibitor mivavotinib, conducted in patients with advanced solid tumors or lymphoma malignancies, were previously reported [The ORR and CR rates reported here for all patients with lymphoma including those with DLBCL are clinically meaningful, given the limited treatment options and poor outcomes for these patients with relapsed or refractory disease [Meaningful response rates were observed in both GCB and non-GCB DLBCL subtypes, consistent with the findings of our initial report [Although population-level outcomes data are limited for patients with relapsed or refractory DLBCL, in the large retrospective SCHOLAR study of 636 patients, estimated objective response rates were 26% with a CR rate of 7% and a median OS of 6.3 months [CAR T-cell therapy is expected to become the new standard of care for relapsed or refractory DLBCL [Overall, safety findings were consistent with the primary analysis and toxicity was manageable despite a high proportion of patients experiencing grade ≥3 TEAEs (96% all cause, and 76% determined by the investigator as being related to mivavotinib). The most common grade ≥3 TEAEs were increased amylase, neutropenia and hypophosphatemia; other common grade ≥3 TEAEs included elevations in clinical laboratory investigations, including AST, amylase, lipase and blood creatine phosphokinase, which were largely asymptomatic and reversible upon dose reduction or discontinuation of the study drug, consistent with the initial analysis. The most common hematologic grade ≥3 TEAE was neutropenia (27%), with most of these patients receiving G-CSF support to manage it; this was largely expected due to the number of patients with bone marrow involvement at study entry. Other hematologic grade ≥3 TEAEs including anemia and thrombocytopenia occurred in 19% and 15% of patients, respectively. The most common metabolic disorder of grade ≥3 was hypophosphatemia (26%). Serious TEAEs were reported in 76% of patients; however, only 27% of patients had serious TEAEs determined by the investigator as being related to mivavotinib, and only 26% of patients had serious TEAEs that led to discontinuation. There were 39 on-study deaths among patients with lymphoma, 4 of which were considered related to mivavotinib and were due to complications from pneumocystis pneumonia, multiorgan failure, respiratory failure and disseminated varicella. The most common reasons for discontinuation were pneumonia and pneumonitis; further intervention to reduce the risk of opportunistic infection (e.g., In conclusion, the anti-tumor efficacy of mivavotinib monotherapy observed in the primary analysis of this study was confirmed in our analysis of patients with lymphoma, including an expanded cohort of patients with relapsed or refractory DLBCL, with responses that were deep and durable. These findings support SYK as a potential therapeutic target for the treatment of this population of patients. Further investigation of markers to predict response to SYK inhibition, and research into possible mivavotinib treatment combinations, are needed to develop mivavotinib further, and to provide more extensive therapy options for patients with relapsed or refractory DLBCL who have limited treatment options. | PMC9882996 |
MATERIALS AND METHODS | PMC9882996 |
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Study design | lymphoma, toxicity, lymphoid malignancies, DLBCL | LYMPHOMA, DISEASE PROGRESSION, CLL, SOLID TUMORS | This was an open-label, multicenter, phase I, dose escalation and expansion study of QD, oral, single-agent mivavotinib in patients with advanced solid tumors or lymphoid malignancies. The full study design and methods have previously been reported [Briefly, in the dose escalation phase, adults with a confirmed diagnosis of lymphoma for which no standard treatment was available were enrolled to receive escalating doses of oral mivavotinib (60 mg, 80 mg, 100 mg or 120 mg QD) in an accelerated 3+3 dose escalation design. In the expansion phase, patients with lymphoid malignancies received mivavotinib 100 mg QD (the MTD from the dose escalation phase) in one of six disease-specific cohorts: CLL, iNHL, MCL, EBV+PTLD and two separate DLBCL expansion cohorts. All patients in the escalation and expansion phases received oral mivavotinib at their assigned dosage in continuous 28-day cycles until disease progression or unacceptable toxicity. | PMC9882996 |
Patients | malignant lymphoma, DLBCL, Lymphoma | LYMPHOMA, DISEASE, MALIGNANT LYMPHOMA, LYMPHOMA | Lymphoma patients enrolled in both the escalation and expansion phases had histologically or cytologically confirmed lymphoma, according to the modified International Working Group (IWG) 2007 criteria for malignant lymphoma [Patients enrolled in the first DLBCL expansion cohort had pathologically confirmed DLBCL with at least one site of measurable disease based on IWG criteria for malignant lymphoma [ | PMC9882996 |
Assessments | death, toxicity, TTP, DLBCL, PD, lymphoma, Cancer | DISEASE PROGRESSION, ADVERSE EVENT, ADVERSE EVENT, DISEASE, LYMPHOMA, TTP, CANCER | Efficacy endpoints including ORR, DOR, PFS, TTP and OS were analyzed for all patients with lymphoma, including the additional DLBCL expansion cohort, and for the full DLBCL subgroup (both expansion cohorts and the escalation cohort combined), based on data collected up to June 29, 2021. This report includes extended follow-up data for patients included in the initial analysis, as well as data for additional DLBCL patients. DOR was also analyzed among the separate DLBCL cohorts, and assessments of ORR were made in the GCB, non-GCB, or unknown GCB classified DLBCL subgroups.Responses were assessed in patients who received at least one dose of study drug and had at least one post-baseline disease assessment (response-evaluable population). Assessments were performed at cycles 2, 4, 6, then every 3 cycles through cycle 24, and thereafter every 6 cycles (until disease progression or the start of alternative therapies). PFS, TTP and OS were evaluated in the ITT population, based on the time from the date of first study drug administration to the date of first documentation of PD (PFS/TTP) or death (PFS/OS).The safety population was defined as all patients in any lymphoma cohort receiving at least one dose of study drug. Adverse events and toxicity were assessed continually during treatment and were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.Statistical analyses were primarily descriptive without formal hypothesis testing. Median DOR, PFS and OS were estimated using the Kaplan–Meier method. | PMC9882996 |
Data sharing statement | Requests for de-identified datasets for the results reported in this publication will be made available to qualified researchers following submission of a methodologically sound proposal. Data will be made available for such requests following online publication of this article and for 1 year thereafter in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. Calithera does not share identified participant data or a data dictionary. | PMC9882996 |
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SUPPLEMENTARY MATERIALS | PMC9882996 |
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ACKNOWLEDGMENTS | RP, TG | ONCOLOGY, EMD | This study was sponsored by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. We thank all of the patients and their families, and the investigators and staff at all clinical sites, for their participation in the trial. The authors acknowledge Tori Gordon, BSc, of Ashfield MedComms, an Inizio Company, for medical writing support for the development of this manuscript under the direction of the authors, which was funded by Takeda Pharmaceuticals U.S.A., Inc., and complied with the Good Publication Practice 3 ethical guidelines (Battisti WP, et al. Ann Intern Med 2015. 163: 461–4). R. Popat and W. Townsend acknowledge support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
LIG, SM, IP, YS and FB were involved in the conception and design of the study. LIG, RK, JBK, RP, HAB, SF, MRP, GG, DES, FIC, JR, JPO, PLZ, SPI, WT, HM, IP, SW, SK, YY, JZ, KS, YS, CC, and FB made substantial contributions to the acquisition, analysis and interpretation of data. All authors drafted the work or revised it critically for important intellectual content. All authors approved of the final version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
LIG is on the Data Safety and Monitoring Board (DSMB) for Janssen and is a consultant for Ono Pharmaceuticals. RK received research support from Takeda. RP received honoraria and consultancy fees from Takeda, Janssen, BMS, GSK and Roche. HAB is employed by Sarah Cannon and HCA Healthcare; owns stocks/shares at HCA Healthcare; holds a non-compensated consulting position for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, GRAIL, Incyte, Novartis, TG Therapeutics, Vincerx Pharma; and reports grants or funds paid to their institution from AbbVie, Agios, ARMO Biosciences, Array BioPharma, AstraZeneca, Bayer, BeiGene, BioAtla, BioMed Valley Discoveries, Boehringer Ingelheim, Bristol-Myers Squibb, CALGB, CicloMed, eFFECTOR Therapeutics, Lilly, EMD Serono, Roche/Genentech, GlaxoSmithKline, Harpoon Therapeutics, Hengrui Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, Macrogenics, MedImmune, Merck, Millennium, Moderna, Pfizer, Revolution Medicine, Foundation Medicine, SeaGen, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals, Xbiotech, Zymeworks, Arch Oncology, Arvinas, Coordination Pharmaceuticals, NGM Biopharmaceuticals, Gossamer Bio, Ryvu Therapeutics, and BioTheryX. SM received honoraria from Karyopharm, GSK, BMS, Janssen and Oncopeptides. MRP reports leadership at ION Pharma; honoraria from Pfizer, Pharmacyclics, Bayer, Janssen, Genentech, and Adaptive Biotechnologies; consulting/advisory role at Pharmacyclics, Janssen, Pfizer, and EMD Serono; and speakers’ bureaus at Exelixis, Genentech, Roche, Taiho Pharmaceutical, and Celgene. GG reports participation in advisory boards for Roche, IQVIA, Kite-Gilead, Italfarmaco, Takeda, Ideogen, and Genmab; support for attending meetings from Roche, and Sandoz; and training activities for Roche, Takeda, Clinigen, Ideogen, Beigene, and Incyte; and individual scientific consultancy for Takeda. DES reports honoraria from AbbVie, AstraZeneca, Beigene, Janssen, Lily, Roche, and Takeda; consulting fees from AbbVie, ASTEX, AstraZeneca, Beigene, Janssen, and Kyowa Kirin; and financial support for conference/travel from AbbVie, Novartis, and Roche. FIC reports participation in advisory council/committees for Eli-Lilly, Bristol Meyers Squibb, MSD, Roche, Merck-Serono, Astra-Zeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astella, GSK, Sotio, Eisai, Daiichi-Sankyo, Taiho, Servier; honoraria from Eli-Lilly, Eisai, Servier, Roche; and grants or funds from Eli-Lilly, Janssen-Cilag. JPO reports participation in advisory council/committees for Janssen, Takeda, and Roche; and grants/funds from Takeda. PLZ reports participation in advisory council/committees for Takeda, MSD, AbbVie, BMS, and ADC Therapeutics; and honoraria from Takeda, MSD, BMS, Gilead, Novartis, Kyowa Kirin, Sanofi, Incyte, Roche, Eusapharma, Janssen, Incyte, and AstraZeneca. SPI reports honoraria from Curebio, MD Education, and Target Oncology; consulting fees from Seagen, Yingli, Legend, and Securabio; and grants/funds from Merck, Seagen, CRISPRx, Legend, Myeloid, Innate, Rhizen, Spectrum, Affimed, Takeda, Yingli, and Ono. WT reports participation in advisory council/committees for Roche, Incyte, and Takeda; honoraria and consulting fees from Roche, Incyte, Takeda, Gilead, and BMS. SK reports employment and ownership of stocks/shares at Labcorp Drug Development. KS reports ownership of stock at AstraZeneca and Teva Pharmaceuticals. HM, IP, SW, SK, YY, JZ, KS and YS are all employees of Takeda; IP and SW also report the ownership of stocks/shares at Takeda. CC reports honoraria and consulting fees from Takeda and Regeneron; and honoraria from BMS, AstraZeneca, Gilead, and Novartis. FB reports participation in advisory council/committees, honoraria, consulting fees, and grants or funds from Roche, Genentech, AbbVie, Janssen, Lilly, AstraZeneca, Novartis, Kite, BMS, Takeda, TG therapeutics, BeiGene, Advantage, Allogene, LAVA therapeutics, Enterome. SF, JBK, and JR report no conflicts of interest.
All patients provided written informed consent. The study was conducted in accordance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, in accordance with the International Conference on Harmonization Good Clinical Practice standards, and applicable regulatory requirements. Relevant institutional review boards or ethics committees approved all aspects of the study, and all authors had access to primary clinical trial data. This trial is registered at ClinicalTrials.gov (NCT02000934).
This study was funded by Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA. | PMC9882996 |
Abbreviations | alanine aminotransferaseautologous stem-cell transplantaspartate aminotransferaseB-cell receptorCD19-targeted chimeric antigen receptorconfidence intervalchronic lymphocytic leukemiacreatine phosphokinasecomplete responsediffuse large B-cell lymphomaduration of responseEpstein Barr Virus-positive post-transplant lymphoproliferative disorderFMS-like tyrosine kinase 3germinal center B-cellgranulocyte colony stimulating factorindolent non-Hodgkin’s lymphomaintention-to-treatInternational Working Groupmantle cell lymphomamaximum tolerated dosenot estimableoverall response rateoverall survivalprogressive diseaseprogression-free survivalpartial responseonce dailyrituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisonestable diseasespleen tyrosine kinasetreatment-emergent adverse eventstime to progression | PMC9882996 |
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REFERENCES | PMC9882996 |
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Objectives | stroke, acute ischemic stroke, AIS | STROKE, RECURRENCE | We investigated the efficacy of intensive rosuvastatin therapy plus 7-day dual antiplatelet therapy (DAPT) in reducing stroke recurrence for patients with acute ischemic stroke (AIS) and compared subgroups of patients. | PMC9941271 |
Methods | bleeding, stroke, liver injury, statin-associated myopathy, SAPT | STROKE, BLEEDING, RECURRENCE, ISCHEMIC STROKE | We enrolled patients with AIS whose time of onset to medication was ≤ 72 h, and the baseline scores of NIHSS (bNIHSS) were 0–10. The patients received intensive rosuvastatin therapy plus 7-day DAPT with aspirin and clopidogrel (study group) or rosuvastatin plus single antiplatelet therapy (SAPT, control group). The primary outcomes were recurrence of ischemic stroke, bleeding, statin-induced liver injury, and statin-associated myopathy (SAM) within 90 days. We also performed a subgroup analysis to assess the heterogeneity of the two therapy regimens in reducing recurrent stroke. | PMC9941271 |
Results | RECURRENT STROKE | Recurrent stroke occurred in 10 patients in the study group and 42 patients in the control group (hazard ratio [HR], 0.373, 95% confidence interval [CI], 0.178–0.780; | PMC9941271 |
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Conclusions | stroke, bleeding, statin-associated | ADVERSE EVENTS, STROKE, BLEEDING | Without increasing bleeding and statin-associated adverse events, intensive rosuvastatin therapy plus 7-day DAPT significantly reduced the risk of recurrent stroke, especially for subgroups with high-risk factors. | PMC9941271 |
Supplementary Information | The online version contains supplementary material available at 10.1007/s00228-022-03442-8. | PMC9941271 |
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Keywords | PMC9941271 |
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Introduction | DISORDER OF LIPID METABOLISM, DYSFUNCTION, ARTERIAL THROMBOSIS | Disorder of lipid metabolism, dysfunction of endothelial cells, and aggregation of many inflammatory factors are the external conditions of arterial thrombosis [Intensive statin therapy is commonly combined with dual antiplatelet therapy (DAPT) in patients with ACS after percutaneous coronary intervention, stent implantation [ | PMC9941271 |
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Materials and methods | PMC9941271 |
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Patients | infarction lesions, Stroke | EMERGENCY, STROKE | We recruited patients aged 18 years or older who were admitted to the Emergency Department of our hospital from October 2016 to December 2019. Computed tomography (CT) and magnetic resonance imaging (MRI) of the head was used to confirm the new focal infarction lesions within 72 h after the onset. Their National Institutes of Health Stroke Scale (NIHSS) scores at registration were 0–10. We excluded patients with intravenous thrombolysis/arterial thrombectomy or anticoagulation treatments, patients undergoing menstruation or pregnancy, and patients preparing for pregnancy within 3 months. In total, 331 patients with AIS met the above criteria, including 204 patients in the control group and 127 patients in the study group according to the therapy regimens. The Medical Ethics Committee of the China Rehabilitation Research Center approved this study (Ethics approval number: 2018–022-1). All patients provided written | PMC9941271 |
Therapy regimens | reduced recurrent vascular events | Patients in the study group received DAPT + intensive rosuvastatin therapy: aspirin (Bayer, 100 mg per tablet) 100 mg/d with an initial dose of 300 mg for 90 days, clopidogrel (Sanofi, 75 mg per tablet) 75 mg/d with an initial dose of 75–300 mg determined based on the clinical symptoms for 7 days, plus rosuvastatin (Nanjing Chia Tai-Tianqing Pharmaceutical Co., Ltd, 10 mg per tablet), 20 mg/d for 21 days, and then 10 mg/d for 90 days in total. Patients in the control group received SAPT + rosuvastatin: aspirin (Bayer, 100 mg per tablet) 100 mg/d or clopidogrel (Sanofi, 75 mg per tablet) 75 mg/d for 90 days, plus rosuvastatin (Nanjing Chia Tai-Tianqing Pharmaceutical Co., Ltd, 10 mg per tablet) 10 mg/d for 90 days.According to previous studies, aspirin and clopidogrel consistently reduced recurrent vascular events [ | PMC9941271 |
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Assessment criteria | fecal occult blood, Bleeding, GUSTO, coronary occlusion, neurological deficits, neurological deficit symptoms | BLEEDING, EVENTS, CORONARY OCCLUSION, ISCHEMIC STROKE | We assessed focal neurological deficits by assessing the bNIHSS, which ranges from 0 to 43, with higher scores indicating worse deficits [Recurrent ischemic stroke—the aggravation of existing clinical symptoms or the emergence of new focal neurological deficit symptoms within 90 days after the first treatment—was confirmed by CT and MRI scans of the head, which showed obviously enlarged original lesions or new ischemic lesions. Bleeding events included intracranial and gastrointestinal mucosal hemorrhage, which were confirmed by head CT and gastric contents analysis or fecal occult blood test, respectively, within 90 days after treatment. According to the global use of streptokinase and tissue plasminogen activator to treat coronary occlusion (GUSTO) [ | PMC9941271 |
Statistical analysis | This study adopted an incomplete randomized controlled trial design, with Type I Error α = 0.05 and power of test (1 − β) = 0.85. The PASS 15.0 software (NCSS, LLC, Kaysville, UT, USA) was used to estimate the sample size. According to a meta-analysis by Kwok et al. [SPSS 25.0 statistical software (IBM Corporation, Armonk, NY, USA) was used for data analysis. We expressed measurement data as the median (M) and inter-quartile range (IQR) from the rank-sum test results and expressed count data as % from the χ | PMC9941271 |
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Results | PMC9941271 |
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Recurrent ischemic stroke | GUSTO, bleeding, ischemic stroke | BLEEDING, ISCHEMIC STROKE | Within 90 days, 52 patients underwent recurrent ischemic stroke: 10 (7.87%) in the study group and 42 (20.60%) in the control group. The study group had a 62% lower risk of recurrent ischemic stroke than the control group (hazard ratio [HR] for the study group The primary outcome within 90 days*The bleeding was divided into mild, moderate, and severe bleeding according to GUSTO criteria [Probability of survival free of recurrent ischemic stroke within 90 days | PMC9941271 |
Bleeding events | bleeding | EVENTS, BLEEDING | A total of 9 patients (7.09%) in the study group and 14 patients (6.86%) in the control group reported bleeding events. A Cox proportional hazards model revealed no significant difference between the two groups (HR, 1.019; 95% CI, 0.441–2.353; | PMC9941271 |
Statin-induced liver injury or SAM | None of the patients showed an increase superior to three-fold in the levels of ALT, AST, or CK. The ALT, AST, LDH, and CK levels remained stable before therapy and after 2 weeks (14 ± 3 days) among the groups (Comparison of various enzymology before and 2 weeks after medication (comparison of the levels of transaminase and muscle enzymes before and 2 weeks (14 ± 3 days) after treatment intra each group) | PMC9941271 |
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Heterogeneity in reducing recurrent ischemic stroke among subgroups | atrial fibrillation, diabetes, AIS, ischemic stroke | RECURRENT CEREBRAL INFARCTION, HYPERLIPIDEMIA, ISCHEMIC STROKE, ATRIAL FIBRILLATION, HYPERTENSION, DIABETES | To explore the heterogeneity of the two different therapy regimens in reducing the risk of recurrent ischemic stroke for AIS patients within 90 days, we performed a subgroup analysis according to the aforementioned stratification. The intensive rosuvastatin therapy plus 7-day DAPT always effectively reduced the risk of recurrent ischemic stroke, with the HR value of each subgroup located on the left side of the invalid line, except the subgroup with bNIHSS ≤ 2. It was particularly efficient in these subgroups with high-risk factors such as the elderly, hypertension, diabetes, hyperlipidemia, or prior-stroke, non-antiplatelet treatment, and high-bNIHSS (3–10 points), while it was less efficient in female, OMT > 48 h, and prior atrial fibrillation subgroups (Fig. Hazard ratio for the recurrent cerebral infarction in subgroups at 90 days | PMC9941271 |
Discussion | thrombosis, bleeding, stroke, liver injury, neurological deficit, rupture, atrial fibrillation, platelet aggregation, diabetes | THROMBOSIS, BLEEDING, RECURRENCE, HYPERLIPIDEMIA, ADVERSE EVENTS, STROKE, PLAQUE, ATRIAL FIBRILLATION, HYPERTENSION, CEREBRAL INFARCTION, DIABETES | In this study, compared with rosuvastatin plus SAPT, the intensive rosuvastatin therapy plus 7-day DAPT significantly reduced the risk of recurrent stroke within 90 days for patients with mild to moderate AIS, without increasing adverse events, such as bleeding, statin-induced liver injury, or SAM. The reduction was particularly significant in the subgroups with high-risk factors (the elderly [> 68 years old], hypertension, diabetes, hyperlipidemia, prior-stroke, non-antiplatelet treatment, and high bNIHSS [3–10 points]), but not significant in female, OMT > 48 h, and prior atrial fibrillation subgroups. These results should be interpreted by considering the characteristics of the therapy regimens in this study, namely, the strong inhibition of platelet aggregation and reduction of thrombosis by DAPT and the multiple effects of intensive statin therapy.Previous study showed that statins, especially fat-soluble statins, commonly caused statin-induced liver injury and SAM, along with a three-fold or more increase in ALT, AST, or CK levels [In the elderly subgroup (> 68 years old), the study therapy reduced the risk of stroke recurrence more than the control therapy did, which may be related to elderly patients’ high risk of stroke [At the early stage of cerebral infarction, a large part of the brain tissue is still in the ischemic penumbra due to the incomplete rupture of the lipid plaque and relatively mild inflammatory storm [The NIHSS can not only quantify the symptoms and signs of focal neurological deficit [Many studies have shown that AIS patients with high-risk factors [Aspirin and clopidogrel are the most common antiplatelet drugs. Aspirin has an irreversible inhibitory effect on platelet aggregation through acetylated platelet cyclooxygenase, while clopidogrel, as an adenosine diphosphate receptor inhibitor, inhibits platelet aggregation. For patients who took antiplatelet agents regularly and still had AIS, the possible cause was aspirin resistance [ | PMC9941271 |
Limitations | This study was a single-center study with small sample size and incomplete randomized controlled design. These characteristics inevitably led to some weaknesses in the research results, which need to be confirmed by future large sample size and multi-center clinical studies. | PMC9941271 |
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Conclusion | liver injury, diabetes, bleeding, ischemic stroke | BLEEDING, HYPERLIPIDEMIA, ISCHEMIC STROKE, HYPERTENSION, DIABETES | Compared with rosuvastatin plus SAPT, the intensive rosuvastatin therapy plus 7-day DAPT with aspirin and clopidogrel significantly reduced the risk of recurrent ischemic stroke within 90 days for patients with mild to moderate AIS, without increasing bleeding, statin-induced liver injury, or SAM. These effects were particularly significant in the subgroups with high-risk factors such as elderly patients (> 68 years old), patients with hypertension, diabetes, hyperlipidemia, prior-stroke, non-antiplatelet treatment, and high bNHISS scores (3–10). | PMC9941271 |
Acknowledgements | We thank Ph.D Yunlei Wang for careful reading of the manuscript. | PMC9941271 |
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Author contribution | Study conception or design: TZ and HTL. Acquisition of the data: TD, XML, JMC, XHY. Analysis and interpretation of the data: TD, WH, XML. Drafting and revising the article: TZ and HTL. All authors read and approved the final manuscript. | PMC9941271 |
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Funding | This study was funded by Beijing Municipal Commission of Science and Technology (Grand Numbers: Z181100001718066). | PMC9941271 |
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Data availability | All the required data about the study are present in the manuscript. We are happy to provide additional data if the reviewer or the editor requires further data. | PMC9941271 |
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Declarations | PMC9941271 |
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Ethical approval | The Medical Ethics Committee of China Rehabilitation Research Center has approved the study (Ethics approval number: 2018–022-1). Written informed consents were obtained from all participants. | PMC9941271 |
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Conflict of interest | The authors declare no competing interests. | PMC9941271 |
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References | PMC9941271 |
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Methods | PMC10684334 |
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Study design | This was a large, multinational case series of the performance of a single-use duodenoscope for ERCP. Institutional Review Board and Ethics Committee approvals for the study were obtained at all study sites. All enrolled patients provided written informed consent for study participation before they contributed data. Single-use duodenoscopes were provided without charge to the investigational sites for use in the study procedures.
Boston Scientific Corporation (Marlborough, Massachusetts, USA) sponsored and funded the study. Sixteen endoscopists participated in published research during development of the single-use duodenoscope
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Single-use duodenoscope | STERILE |
The device used in this study was the EXALT Model D single-use duodenoscope (Boston Scientific Corporation), a sterile, single-use duodenoscope designed to function similarly to currently marketed reusable duodenoscopes, and to be discarded after use in a single procedure. The single-use duodenoscope received US FDA clearance in December 2019 and gained a CE mark in January 2020
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Patient population | RECRUITMENT |
The study protocol allowed for recruitment of adult patients scheduled for ERCP per the standard of care at up to 40 participating healthcare centers. Eligible patients were recruited for the study on selected weekdays when participating endoscopists were performing ERCPs. Patients were eligible for inclusion if they were aged ≥ 18 years, willing and able to comply with the study procedures and to provide written informed consent to participate in the study, and were scheduled for a clinically indicated ERCP or other duodenoscope-based procedure. Excluded from the study were potentially vulnerable patients including, but not limited to: pregnant women, patients for whom endoscopic techniques were contraindicated, patients enrolled in another investigational study that would directly interfere with the current study, and patients excluded at investigator discretion. Unlike previous studies of the single-use duodenoscope, the current study included patients with “altered pancreaticobiliary anatomy” because this was not a contraindication in the Directions for Use approved in 2020
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Study procedures | PMC10684334 |
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Patient assessments | ADVERSE EVENTS | All enrolled participants had a preprocedural study visit for assessment of their demographics and relevant medical history. After the index procedure, participants were evaluated in person or by telephone at 72 hours (−1 day to + 2 days) and again at 30 days (± 3 days) to screen for post-procedure adverse events (AEs) or resolution of any previously reported issues. If the last follow-up visit was not completed, the reason was noted on the study completion form. Participants were considered lost to follow-up if they failed to return for their scheduled follow-up visits and were unable to be contacted by the study site staff after at least three documented attempts. | PMC10684334 |
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ERCP procedures | Participating endoscopists agreed to use the single-use duodenoscope in place of other brands of duodenoscope(s) used in the endoscopy unit for ERCP. Endoscopists’ level of experience was categorized as “expert” (> 2000 lifetime ERCPs) and “less expert” (≤ 2000 lifetime ERCPs). Start and stop times of the procedure, post-procedure subjective feedback on performance-related attributes, American Society for Gastrointestinal Endoscopy (ASGE) grade for complexity of the ERCP procedure, and all attempted or completed maneuvers during the ERCP were documented. Device deficiencies were recorded and reported, regardless of whether they led to an AE or inability to complete the ERCP. If the necessary maneuvers could not be completed with the single-use device and the endoscopist crossed over to use a reusable duodenoscope, the reason for noncompletion with the single-use device was recorded, and the ability to complete the ERCP maneuvers with a reusable duodenoscope was documented.
Difficult common bile duct (CBD) cannulation was defined by a modification of the European Society of Gastrointestinal Endoscopy (ESGE) definition
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Outcomes | SECONDARY | The primary end point was the ability to complete the ERCP procedures for the intended indication(s). The secondary end points were: (i) the incidence of crossover from the single-use duodenoscope to a reusable duodenoscope; (ii) comparison of outcomes by ASGE grade, endoscopist level of experience, or prior sphincterotomy; (iii) endoscopist ratings of overall satisfaction with the single-use duodenoscope on a scale of 1 (worst) to 10 (best); (iv) serious AEs (SAEs) related to the device and/or procedure, assessed through to 30 days after the ERCP or other duodenoscope-based procedure. | PMC10684334 |
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Statistical analysis | Descriptive statistics included: frequency statistics for patient and procedural characteristics and procedure completion rates (completion rates reported separately for cases with and without crossover to a reusable duodenoscope); median and range for overall satisfaction and procedure duration; and mean (SD) and range for age and mean number of cannulation attempts. Endoscopist experience and ASGE complexity grades were assessed for completion time and performance ratings using Wilcoxon rank-sum tests, and for number of cannulation attempts using a negative binomial model. Fisher’s exact test was used to compare the occurrence of crossover to a reusable duodenoscope by level of experience or by ASGE case complexity level. For binary data, 95 %CIs were calculated using the Clopper–Pearson exact methods. Statistical analyses were performed using SAS 9.4 software (SAS Institute Inc., Cary, North Carolina, USA). | PMC10684334 |
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Results | PMC10684334 |
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Enrollment and patient characteristics |
Of 809 patients who were screened, 551 (68.1 %) were enrolled after providing written informed consent to participate in the study. Reasons for nonparticipation are summarized in
Patient flow through the study.
Of the 551 patients (mean age 59.9 years) who had a procedure, 281 (51.0 %) were male and 332 (60.3 %) had a prior ERCP (
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Characteristics of the 551 patients who were entered into the study and underwent an ERCP procedure that began with a single-use duodenoscope. | cancer | CANCER, STRICTURE, BACTERIAL INFECTION | Older than 65 yearsIIIIIIIVVNot assessedBile duct stones/gallstones(current)Documented biliary or pancreatic stricture, unresolvedCurrent immunosuppression (any cause)Pharmacologically inducedPost-transplantPost-chemotherapy for cancer other than bile ductPost-chemotherapy for bile duct cancerDisease inducedIn preparation for bone marrow or other transplantationOtherChronic pancreatitisPancreatic tumorAbnormal image findingCholangitis (current)CholangiocarcinomaPrimary sclerosing cholangitisOther gastrointestinal cancerPancreatic stones (current)Recurrent cholangitisHepatic tumorHepatitisPancreatic pseudocystKnown history of MDRO colonizationKnown current MDRO colonizationCurrent documented bacterial infection, other than cholangitisOtherERCP, endoscopic retrograde cholangiopancreatography; MDRO, multidrug-resistant organism.Of the 332 patients for whom the referral source was documented, 102 (30.7 %) presented directly to the participating study site, 154 (46.4 %) were referred from an academic medical center, and 76 (22.9 %) from a community medical center. | PMC10684334 |
General ERCP characteristics |
A total of 61 endoscopists (46 expert, 15 less expert) at 22 academic centers in 11 countries (1–6 endoscopists per center) performed 551 procedures: 25 cases at 21 of the study sites and 26 cases in the other. The median number of procedures performed by each endoscopist was seven (range 1–25). All procedures were performed in endoscopy suites, almost all (99.6 %; 549/551) during normal working hours, and most with endoscopy processing staff present (79.1 %; 436 /551) (
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Characteristics of the 551 endoscopic procedures carried out. | sphincter of Oddi dysfunction, biliary stone, biliary leaks, divisum, pseudocyst, pancreatic stones, intrahepatic stones, tumors, pancreatic strictures, biliary strictures | RECURRENT PANCREATITIS, MINOR, SPHINCTER OF ODDI DYSFUNCTION, STRICTURES, TUMORS | PropofolOpioidNeuromuscular blockerInhalation agentEtomidateOtherPropofolOpioidSevofluraneBenzodiazepineNeuromuscular blockerOtherProneSupineLeft lateral decubitusEndoscopy suite
Difficult cannulation without failed ERCP
Failed ERCP without difficult cannulationFailed ERCP with difficult cannulationCompleted, no crossoverCompleted with crossoverNot completed, without crossoverNot completed, with crossoverGrade 1Grade 2Grade 3Grade 4Procedures not included in ASGE grading systemERCP, endoscopic retrograde cholangiopancreatography; NSAID, nonsteroidal anti-inflammatory drug; ASGE, American Society for Gastrointestinal Endoscopy.One case was aborted (because patient had food in the stomach) so the procedure time was 0 and was not included in the “total procedure time” calculation.Denominator = 514 procedures.ASGE grade for complexity of ERCPs: grade 1, deep cannulation of duct of interest, main papilla, sampling; grade 2, biliary stone extraction < 10 mm, treat biliary leaks, treat extrahepatic benign and malignant strictures, placed prophylactic stents; grade 3, biliary stone extraction ≥ 10 mm, minor papilla cannulation in divisum and therapy, removal of internally migrated biliary stents, intraductal imaging/biopsy/fine needle aspiration, management of acute or recurrent pancreatitis, treat pancreatic strictures, remove pancreatic stones mobile and < 5 mm, treat hilar tumors, treat benign biliary strictures hilum and above, manage suspected sphincter of Oddi dysfunction (with or without manometry); grade 4, remove internally migrated pancreatic stents, intraductal image-guided therapy (e. g. photodynamic therapy, electrohydraulic lithotripsy), pancreatic stones impacted and/or ≥ 5 mm, intrahepatic stones, pseudocyst drainage/necrosectomy, ampullectomy, ERCP after Whipple or Roux-en-Y bariatric surgery.Investigators reported that after the study procedures, most of the single-use duodenoscopes were discarded in standard medical waste (35.4 %; 195 /551), or medical grade recycling (29.9 %; 165/551), regulated medical waste (24.9 %; 137/551), a sharps disposal container (4.9 %; 27/551), or other (4.9 %; 27/551). A high proportion of patients completed the 72-hour (92.9 %; 512/551) and 30-day (89.8 %; 495/551) study follow-up. | PMC10684334 |
Cannulation details | Difficult CBD cannulation was reported for 150 /514 cases (29.2 %) using the single-use duodenoscope (10 of which were failed ERCPs), and in 15 cases in which a reusable duodenoscope was used after crossover.Advanced cannulation techniques performed included: precut (access) papillotomy (n = 42; 7.6 %), double wire (n = 31; 5.6 %), pancreatic duct plastic stent (n = 24; 4.4 %), rendezvous with EUS (n = 3; one also had precut but ERCP still failed and went to rendezvous), cholangioscopy (n = 2), papillectomy (n = 1), transpancreatic sphincterotomy (n = 1), clip used to bring hidden papilla out from fold (n = 1), and accessory papilla cannulation (n = 1). | PMC10684334 |
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Ability to complete ERCP for intended indication | DILATION |
Among the 551 study cases, 529 (96.0 %, 95 %CI 94.0 %–97.5 %) were completed for the intended indication, including 503 (91.3 %, 95 %CI 88.6 %–93.5 %) using only the single-use duodenoscope, and 26 (4.7 %, 95 %CI 3.1 %–6.8 %) including crossover from the single-use to a reusable duodenoscope. Of the 22 cases that were not completed, 11 included crossover to a reusable duodenoscope (
A total of 514 patients (93.3 %) underwent an ERCP procedure that used the single-use duodenoscope only (
For 524 patients (95.1 %), all of the intended maneuvers were completed. Over 20 different types of maneuvers were performed using the single-use duodenoscope, including sphincterotomy, papillectomy/ampullectomy, cannulation, mechanical lithotripsy, clearance of bile duct or pancreatic duct stones, biliary or pancreatic stent placement or removal, balloon dilation, cholangioscopy (n = 24), pancreatoscopy (n = 9), cytology brushing, biopsy, and others. Pancreatic maneuvers were performed in 128 patients (23.2 %). | PMC10684334 |
Subsets and Splits