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Funding Sources | Jason C.G. | Five-year follow-up of the WRAP trial was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (RP-PG-0216-20010). The WRAP trial was funded by the National Prevention Research Initiative through research grant MR/J000493. Jack M. Birch, Amy L. Ahern, Simon J. Griffin, and Stephen J. Sharp are supported by the Medical Research Council (MRC) (Grant MC_UU_00006/6). The University of Cambridge has received salary support in respect of Simon J Griffin from the National Health Service in the East of England through the Clinical Academic Reserve. This work is funded by UKRI grant MC_UU_00006/6. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any author-accepted manuscript version arising. Jason C.G. Halford is currently supported by research funding from Horizon 2020 and the American Beverage Association via the University of Liverpool. | PMC10028366 | |
Author Contributions | Jason C.G. | Jack M. Birch planned and designed the study, wrote the statistical analysis plan, conducted the analysis, and led the writing and development of the final manuscript. Julia Mueller and Stephen J. Sharp planned and designed the study, provided statistical input, reviewed the statistical analysis plan, and reviewed and edited the final manuscript. Simon J. Griffin and Amy L. Ahern planned and designed the study, reviewed the statistical analysis plan, and reviewed and edited the final manuscript. Michael P. Kelly and Jason C.G. Halford planned and designed the study and reviewed and edited the final manuscript. | PMC10028366 | |
Data Availability Statement | The data cannot be made publicly available because of ethical and legal considerations. Non-identifiable data and code can be made available to bona fide researchers on submission of a reasonable request to | PMC10028366 | ||
Supplementary Material | Supplementary dataClick here for additional data file. | PMC10028366 | ||
Acknowledgments | RECRUITMENT | We would like to thank the co-investigators on the original WRAP trial (Paul Aveyard, Jason Halford, Susan Jebb, Adrian Mander, Simon Cohn, and Marc Suhrcke) and the WRAP 5-year follow-up (Andrew Hill, Alan Brennan, Ed Wilson, Brett Doble, Carly Hughes, Jennifer Bostock, Colin Lainson, Steve Morris, and James Woodcock) who contributed to obtaining funding, the design and conduct of the trial, and follow-up, as well as the trial managers (Jennifer Woolston and Ann Thomson) and the research staff who facilitated participant recruitment and follow-up. We would like to thank the WRAP trial participants for their participation in the study. We would also like to thank Clare Boothby (University of Cambridge) for supporting with data management. | PMC10028366 | |
References | Sample characteristics by availability of data to calculate weight changeMean (SD) weight change by each exposure categoryAssociation between PROGRESS-Plus characteristics and weight change from 1-to 5-yearsA multivariable model was performed to assess the association between the exposure PROGRESS-Plus characteristic and weight change. Each model was adjusted for intervention group, baseline weight, weight change between baseline and 1 year, research centre, and source of the 5-year weight data. | PMC10028366 | ||
Objective | bleeding, myomectomy-related hemorrhage, uterine fibroids | BLEEDING, VASCULAR TUMORS, UTERINE FIBROIDS | Myomectomy is the preferred surgical approach to manage uterine fibroids. However, uterine fibroids are highly vascular tumors and, consequently, extremely susceptible to problems from myomectomy-related hemorrhage. Hence, we aim to compare oxytocin efficacy and safety profile versus tranexamic acid (TA) with ethamsylate for reducing bleeding during myomectomy. | PMC10387195 |
Methods | This randomized, double-blinded multicenter study was performed between 20 | PMC10387195 | ||
Results | INTRAOPERATIVE BLOOD LOSS | In 180 premenopausal women, oxytocin and TA with ethamsylate had no significant value in lowering intraoperative blood loss compared with the placebo for abdominal myomectomy (666.25 ± 183.03, 630.72 ± 145.83, and 646.67 ± 168.92, respectively ( | PMC10387195 | |
Conclusion | INTRAOPERATIVE BLOOD LOSS | Oxytocin and TA with ethamsylate had no significant value in lowering intraoperative blood loss compared with the placebo for abdominal myomectomy which opens a new question about the role of the use of the hemostatic drug during myomectomy especially in centers with limited resources and had higher rates. | PMC10387195 | |
Trial registration | The study was registered on Pan African Clinical Trials Registry with the following number: PACTR202008739887429 and was approved on 24/08/2020. | PMC10387195 | ||
Keywords | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10387195 | ||
Change history | 5/10/2024Editor’s Note: Readers are alerted that the reliability of data presented in this article is currently in question. Appropriate editorial action will be taken once this matter is resolved. | PMC10387195 | ||
Background | pelvic pain, blood loss, uterine fibroids, anemia, infertility, uterine leiomyomas, fibroids | POSTPARTUM HEMORRHAGE, CONTRACTIONS, BLOOD LOSS, VASCULAR TUMORS, UTERINE FIBROIDS, ANEMIA, UTERINE LEIOMYOMA, FIBROIDS, COMPLICATIONS | With about 235 million women affected globally [Clinically, uterine fibroids are frequently asymptomatic, but in 30% of cases, fibroids can be symptomatic and cause various critical complications. These complications include pelvic pain, heavy menstruation, anemia, frequent urination, bowel problems, and infertility [The current management options for fibroids include surgical, radiological, and pharmaceutical management [Regardless of the myomectomy approach, uterine leiomyomas are highly vascular tumors [Few trials have looked at the effectiveness of various perioperative pharmacologic treatments, such as oxytocin, tranexamic acid (TA), and ethamsylate, to reduce blood loss and associated morbidities during myomectomy [Oxytocin is one of the hormones that the pituitary gland is their primary source of secretion, as its primary role is to cause uterine contractions during childbirth. For preventing postpartum hemorrhage, oxytocin is the drug of preference [TA is a manufactured version of the human amino acid lysine. Its mechanism of action is reducing through its antifibrinolytic action as it inhibits plasminogen from being transformed into plasmin [ | PMC10387195 |
Methods | PMC10387195 | |||
Study design and study population | obesity, uterine fibroids, anemia, heart or lung illness, diabetes | OBESITY, ENDOCRINE OR METABOLIC DISEASE, UTERINE FIBROIDS, ANEMIA, MYOMA, HYPERTENSION, BLEEDING DISORDERS, DIABETES | We followed the CONSORT reporting guidelines in reporting our randomized, double-blinded multi-center study which was performed between 20We included premenopausal women between the ages of 30 and 50, with a minimum of five symptomatic uterine fibroids with a maximum diameter of 6 cm for the largest myoma, all intramural or subserous types, and uterine sizes smaller than 24 weeks of pregnancy. We excluded women with a history of prior surgeries, hypertension, heart or lung illness, bleeding disorders, anemia (hemoglobin (Hb) < 10 g %), chronic endocrine or metabolic diseases such as diabetes, obesity (body mass index > 30 kg/m | PMC10387195 |
Sample size calculation | The sample size was adjusted by confidence interval = 95%, margin of error = 5%, and study's power = 80%. Therefore, the minimum sample size for each group was 60. | PMC10387195 | ||
Treatment protocol | We examined all eligible patients, took full clinical history, and ordered investigations like complete blood count and ultrasound. Then, the baseline data were collected including age, body mass index, baseline HB and HCT, previous cesarean section (CS), parity, and indications for CS. Patients were separated into three simultaneous groups using simple randomization produced by a computer program. Their assignments were made using sealed opaque envelops.All patients underwent the operation by whether the Pfannenstiel or midline vertical incisions. During myomectomy, the patients received whether an injection of 30 IU of oxytocin in 500 ml of normal saline administrated during myomectomy with two ampules of distilled water which had the same color and shape of Ethamsylate and tranexamic acid before skin incision IV (group 1); received injections of 1 g of TA, 250 mg of Ethamsylate, and 110 ml of normal saline IV with an ampule of distilled water infused in 500 ml normal saline which had the same shape and color of oxytocin during myomectomy; (group 2); or received an injection of 110 ml of normal saline IV just before surgical incision with two ampules of distilled water infused in 500 ml normal saline which had the same shape and color of oxytocin; (group 3). All patients, care givers and providers and outcome assessors were blinded. | PMC10387195 | ||
Outcomes | intraoperative blood loss | SECONDARY, POSTOPERATIVE FEVER, INTRAOPERATIVE BLOOD LOSS | The primary outcome was the amount of intraoperative blood loss. The secondary outcomes included the HB, and hematocrit (HCT) values, the change in towels and suction bottle weights, the need for blood and iron transfusion, the duration of operation and hospital stay, the need for hysterectomy, and postoperative fever. | PMC10387195 |
Statistical analysis | We used SPSS version 25, IBM, USA to perform the analysis after the recording of data. We presented the qualitative variables by both number (n) and percentage (%) while the quantitative data were described by mean and standard deviation. The statistical test of one-way ANOVA was applied to evaluate quantitative outcomes while the chi-squared test was used for the qualitative outcomes. The results were considered significant when | PMC10387195 | ||
Results | PMC10387195 | |||
Primary outcome | PMC10387195 | |||
Secondary outcomes | PMC10387195 | |||
Towels and suction bottle weight | After applying a paired t-test, each drug showed a significant increase in towels' weights and suction bottle weight compared to the baseline ( | PMC10387195 | ||
Other secondary outcomes | Applying the ANOVA test, all study outcomes showed non-significant differences between all groups including operative time ( | PMC10387195 | ||
Discussion | cardiovascular morbidities, thromboembolic, postoperative blood loss, bleeding | BLEEDING, WOUND INFECTION, ADVERSE EFFECTS, POSTOPERATIVE FEVER, INTRAOPERATIVE BLOOD LOSS, EVENTS | This RCT indicated that oxytocin and TA with ethamsylate had no significant value in lowering intraoperative blood loss compared with the placebo for abdominal myomectomy. Also, the changes in both HB and HCT values showed no significant differences between the three groups. Non-significant trends were observed for a reduction in operation time, intra/postoperative blood transfusion, hospital stay, postoperative fever, and wound infection.Our results contrasted with a prior RCT conducted on the Egyptian population. They found that women assigned to get TA and ethamsylate instead of oxytocin experienced substantially less intraoperative blood loss during myomectomy [Furthermore, two recent systematic reviews and meta-analyses found that prophylactic TA was associated with considerable decreases in total, intra, and postoperative blood loss compared to the placebo for women undergoing myomectomy [Concerning HB and HCT levels, our study was in line with two previous analyses that showed that in comparison to the control group, preventive TA and oxytocin were linked to a considerable reduction in postoperative HB and HCT [Despite that, a preventative TA was associated with a considerably shorter hospital stay following myomectomy in a prior study; there was no evident difference in the operating time and blood transfusion rate between the intervention and placebo, which is consistent with our findings [All the perioperative therapies discussed above have self-limited adverse effects regarding safety outcomes. Although these events are discovered to be extremely low. TA is generally safe; however, intravenous TA is believed to raise the risk of thromboembolic and cardiovascular morbidities [Compared to GnRH analogs, the most common approach for lowering myomectomy bleeding, TA and ethamsylate, are less expensive [ | PMC10387195 |
Limitations | ethamyslate | The main limitation of this RCT is the scant number of published RCTs in this field. The amount of evidence that is now available on this topic is still insufficient to draw solid conclusions about the efficacy of the discussed therapies. Future research should compare prophylactic oxytocin against TA with ethamyslate among myomectomy patients pre- and post-operatively in additional multicenter, large-sized, and well-controlled RCTs. | PMC10387195 | |
Acknowledgements | Not available. | PMC10387195 | ||
Authors’ contributions | AAE | AMA, EE, EF, AM, DFMA, AS, ME, AMA, AGA, AAM, FA, AHB, IE, HGAE, SAA, and HM were responsible for analyzing and interpreting the patient data. MAK, HA, AAE, and MA were responsible for statistical analysis and revising the manuscript. | PMC10387195 | |
Funding | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). No funds were received. | PMC10387195 | ||
Availability of data and materials | The datasets used and/or analyzed during the current study are not publicly available due to the confidentiality of participants' data and the difficulty of organizing the raw data to be suitable for publication; however, they are available from the corresponding author on reasonable request. | PMC10387195 | ||
Declarations | PMC10387195 | |||
Ethics approval and consent to participate | The study was approved by the ethics committee of the Quality Education Assurance Unit et al. Azhar Faculty of Medicine and all patients gave informed consent before enrollment. All methods were performed in accordance with the Declaration of Helsinki. | PMC10387195 | ||
Consent for publication | Not applicable. | PMC10387195 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10387195 | ||
References | PMC10387195 | |||
1. Introduction | inflammation, OI, gingivitis, pain | ADVERSE EVENTS, INFLAMMATION, DISEASE, GINGIVITIS, DENTAL PLAQUE, OIS, PLAQUE, HYPERSENSITIVITY SYMPTOMS | These authors contributed equally to this work.Background: To evaluate the efficacy and safety of oral irrigator (OI) in controlling dental plaque and gingivitis. Methods: Ninety participants diagnosed with gingivitis were randomly assigned to two groups, given a toothbrush combined with OI (WaterPikPeriodontal disease is a common disease that may bring severe implications for oral and systemic health and negatively impact the patient’s quality of life [Compared with manual floss, oral irrigators (OIs) could be potential interdental cleaning devices. OIs, introduced to the public in the 1960s, are generally designed to remove soft debris and unattached plaque through the mechanical action of a pulsating stream of water [Except for efficacy, less attention has been given to the safety of OIs, especially those with maximum pressures of 100 Psi. Oral tissue assessments and participants’ diaries are the primary methods to assess the safety of OIs [This study aimed to investigate the efficacy and safety of OIs with broader and adjustable pressure settings in managing dental plaque and gingival inflammation for patients with gingivitis during 12 weeks of follow-up. It is hypothesized that, compared to manual toothbrushing only, this OI as an adjunct would improve plaque and gingival inflammation-related indices in patients with gingivitis without causing serious adverse events and pain and dentin hypersensitivity symptoms. | PMC9965011 |
2. Materials and Methods | PMC9965011 | |||
2.1. Study Design and Ethical Considerations | WEST | A 12-week randomized, single-blind, parallel-group clinical trial was conducted at West China Hospital of Stomatology, Sichuan University, Chengdu, China. The research program was approved by the Research Ethics Committee of West China Hospital of Stomatology, Sichuan University (WCHSIRB-D-2021-493). This study was conducted in full compliance with the Declaration of Helsinki, the related regulations of the People’s Republic of China, and Good Clinical Practice. This trial was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR, Registration number: (ChiCTR2100054254)). | PMC9965011 | |
2.2. Sample Size | OIS | The sample size was calculated using G*power 3.1.9.7 based on the mean Modified Gingival Index (MGI) of 1.18 with a standard deviation of 0.2 in the OIs group according to a previous study data [ | PMC9965011 | |
2.3. Eligible Criteria | PMC9965011 | |||
2.3.1. Inclusion Criteria | gingivitis | GINGIVAL BLEEDING, GINGIVITIS | Male and female aged 18 to 65 years old.In good general health with brushing teeth as a daily habit.Possessing at least 20 permanent teeth (excluding the third molars) and 5 evaluable teeth in each quadrant.Suffering from gingivitis and possessing at least 20 gingival bleeding on probing at the baseline examination.T-QH > 1.5 at baseline examination. | PMC9965011 |
2.3.2. Exclusion Criteria | xerostomia, periodontitis, Allergies, tumors, orthodontic | DENTAL CARIES, SYSTEMIC DISEASE, XEROSTOMIA, PERIODONTITIS, PERIODONTAL DISEASES, TUMORS, ALLERGIES | Pregnant or breastfeeding women.Cigarette smoking.Dental students, employees of the clinical research center, or product-related companies.Suffering from periodontitis or gingival recession.Using oral hygiene adjunct tools regularly (i.e., electric toothbrushes, dental floss, interdental brush, mouthwashes, etc.).Wearing orthodontic bands, orthodontic appliances, removable dentures, or gross prosthesis.Suffering from untreated dental caries, mucosal lesions, xerostomia, oral tumors, or severe systemic diseases that may affect periodontal diseases.Received professional periodontal scaling and root planning within four weeks, periodontal surgery within six months, or received oral and maxillofacial surgery within three months.Participated in another clinical trial within three months.Antibiotics, nonsteroidal anti-inflammatory drugs, Chinese medicine, or anticoagulant drugs are being taken.Allergies to the material used in the study product. | PMC9965011 |
2.4. Randomization and Allocation | After enrollment based on the eligibility criteria, the central randomization method was applied based on computer software. The enrollment and randomization process were conducted by a third party that was unrelated to the clinical examination. The participants were arranged into control or test groups in a ratio of 1:1, with 45 participants in each group. Investigators were blinded to randomization and allocation concealment until the completion of the studies. | PMC9965011 | ||
2.5. Interventions and Outcomes Measurement | OI | SECONDARY, OIS | After preliminary screening of personal medical history and oral examination at baseline, the participants were randomly assigned to one of the intervention groups: the toothbrush + oral irrigator group (test group) received an OI (WaterPikBefore every clinical examination, all participants were instructed to refrain from oral hygiene for 12 h and fast for solids and liquids for 2 h. A single trained examiner evaluated all gingival inflammation-related indices. The MGI [Participants returned to the clinical research center for dental examination at 4 weeks ± 3 days, 8 weeks ± 3 days, and 12 weeks ± 3 days after baseline examinations. The T-QH and gingival inflammation-related indices, including MGI, BI, and BOP%, were reevaluated. Furthermore, the safety indicators were also recorded. The modified Bass technique and the method of OIs use were reinforced at each visit by the same dental assistant. The primary outcomes were gingivitis-related indices after 12 weeks of using OIs. The secondary outcomes were plaque-related indices and gingivitis-related indices at 4 weeks and the safety indicators. | PMC9965011 |
2.6. Statistical Analysis | The efficacy evaluation was analyzed with full analysis set (FAS) based on the intention to treat principle and the per-protocol set (PPS), and the safety evaluation was based on the safety set (SS). The FAS comprised participants who had received at least one post-intervention assessment after randomization. The PPS included participants who completed the trial without significant protocol deviations that could have affected the outcomes. The last observation carried forward (LOCF) was adopted for imputing the missing values of results. Analyses were performed by an independent company (Vantage Marketing and Research Consultants Ltd., Guangzhou, China) using statistical software (SPSS | PMC9965011 | ||
4. Discussion | traumatic injuries, inflammation, OI, gingivitis, pain, OIs | ADVERSE EVENTS, INFLAMMATION, GINGIVAL BLEEDING, GINGIVITIS, DENTAL PLAQUE, OIS, PLAQUE, HYPERSENSITIVITY SYMPTOMS, DENTIN HYPERSENSITIVITY | This study evaluated the efficacy and safety of oral irrigators with broader range of pressures in removing plaque and relieving gingivitis. The test group showed significant improvement in plaque and gingivitis indices than the control group. Higher irrigation pressures significantly correlated with the reduction in percentage of BOP%. The OI may be associated with transient gingival bleeding without causing significantly higher of pain or dentin hypersensitivity symptoms. Both intention-to-treat-based and per-protocol analyses were performed for efficacy evaluation to obtain more accurate results. The per-protocol analysis tends to exaggerate the treatment effect, and the results obtained from the intention-to-treat-based analysis more closely represent clinical practice and actual effectiveness [At baseline, all clinical parameters were similar in both groups. After 12 weeks, dental plaque and gingival inflammation were significantly improved in the test group compared with the control group in FAS and PPS, indicating that OIs effectively controlled plaque and relieved gingival inflammation. Significantly lower gingival inflammation indices in the test group were also observed at 4 weeks and 8 weeks. Compared to manual toothbrushing alone, the OIs group was significantly more effective in controlling gingival inflammation, which is consistent with the findings of most studies [The reduction in percentage of all gingival inflammation-related indices and plaque index in the test group were also significantly higher compared with control group in FAS and PPS. During the 12 weeks follow-up, a decreasing trend of gingival inflammation-related indices was observed in both groups. However, plaque in both groups showed an upward trend after the 4 weeks visit, with gingival inflammation remaining relatively low, which may be explained by the previous study’s findings [As shown in The irrigation pressure seems to be positively correlated with the efficacy of OIs in relieving gingival inflammation. However, the traumatic injuries that may be associated with high-pressure water flow generated by the OIs have also gained attention [Regarding safety, previous research has investigated a variety of systemic and soft tissue-related indicators and showed that OIs are generally not deleterious to people in good general health [Similar adverse events were found in the two groups. Despite the fact that transient gingival bleeding was found to be likely associated with OIs, gingival bleeding is considered one of the common symptoms of gingivitis [Oral irrigation appears to be an effective adjunct in managing gingivitis. Several mechanisms may be involved. For instance, OIs may remove food deposits and interfere with plaque maturation by flushing loosely adhered plaques [In this study, we evaluated the efficacy of the OIs in gingivitis patients based on both intention-to-treat and per-protocol analysis. We also analyzed the relationship between its efficacy and irrigation pressure. In terms of safety, we analyzed the relationship between OIs and self-reported symptoms of pain and dentin hypersensitivity using the VAS scale for the first time. However, there are still limitations in this study. For instance, we did not use other interdental cleaning tools (e.g., flossing and interdental brushes) for comparison with the efficacy of OIs. The superiority trials between OIs and other interdental cleaning tools are needed in the future. | PMC9965011 |
5. Conclusions | OIs | OIS, PLAQUE | With the limitations of the study, we conclude that OIs as adjuncts to toothbrushing are significantly more effective than toothbrushing alone in controlling plaque and improving gingival health. Its efficacy was positively correlated with irrigation pressure and the amount of plaque. Furthermore, the application of OIs was safe during the 12 weeks observation period, and with its good compliance, OIs could be effective adjunct cleaning tools. | PMC9965011 |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC9965011 | ||
Author Contributions | Conceptualization, L.C. and X.R.; methodology, L.C. and X.R.; investigation, L.C., R.C., X.R., Y.X., Y.Z. and Y.C.; formal analysis, X.R., Y.X. and J.H.; resources, S.J. and J.H.; writing—original draft preparation, X.R. and J.H.; writing—review and editing, R.C., L.C. and T.H.; supervision, T.H.; project administration, J.L.; funding acquisition, L.C., T.H. and J.L. All authors have read and agreed to the published version of the manuscript. | PMC9965011 | ||
Institutional Review Board Statement | WEST | The procedures for this study were conducted under the 1964 Declaration of Helsinki, the relevant regulations of the People’s Republic of China and Good Clinical Practice. The study protocol was reviewed and approved by the Research Ethics Committee of West China Hospital of Stomatology, Sichuan University (WCHSIRB-D-2021-493). | PMC9965011 | |
Informed Consent Statement | Informed consent was obtained from all participants involved in the study. | PMC9965011 | ||
Data Availability Statement | Data for this study can be obtained by contacting the corresponding author under reasonably requested. | PMC9965011 | ||
Conflicts of Interest | The authors declare that they have no relevant financial or non-financial interest. | PMC9965011 | ||
Methods | RHD | Participants (n = 24) received between 6.9 mL to 20.7 mL (3–9 times the standard dose) of BPG as a single infusion into the abdominal subcutaneous tissues via a spring-driven syringe pump over approximately 20 minutes. Semi-structured interviews at four time points were recorded, transcribed verbatim and thematically analysed. Tolerability and specific descriptors of the experience were explored, alongside thoughts on how the intervention could be improved for future trials in children and young adults receiving monthly BPG intramuscular injections for RHD. | PMC10138475 | |
Results | bruising, pain | Participants tolerated the infusion well and were able describe their experiences throughout. Most reported minimal pain, substantiated via quantitative pain scores. Abdominal bruising at the infusion site did not concern participants nor impair normal activities. Insight into how SCIP could be improved for children included the use of topical analgesia, distractions via television or personal devices, a drawn-out infusion time with reduced delivery speed, and alternative infusion sites. Trust in the trial team was high. | PMC10138475 | |
Conclusion | RHD | Qualitative research is an important adjunct for early-phase clinical trials, particularly when adherence to the planned intervention is a key driver of success. These results will inform later-phase SCIP trials in people living with RHD and other indications. | PMC10138475 | |
Data Availability | All relevant data are within the paper and its | PMC10138475 | ||
Introduction | pain, ARF | ARF, RHD, ACUTE RHEUMATIC FEVER | Benzathine penicillin G (BPG) has been used since the 1950s for the prevention and treatment of recurrent episodes of acute rheumatic fever (ARF), caused by repeated Regular IM injections of BPG are the only proven treatment to prevent recurrent ARF and progression to RHD [Qualitative research is a useful accompaniment to clinical trials, providing insight into the impact of complex procedures beyond quantitative pain scores, pharmacokinetics, or efficacy of an intervention [ | PMC10138475 |
Methods | ARF, pain | ARF | The clinical aspects of the SCIP trial have been described elsewhere by Kado et al [For the qualitative component, all study participants were interviewed in English by one of two investigators at four timepoints–immediately prior to their infusion, during their infusion, two hours post-infusion and approximately seven days after dosing. All interviews occurred face-to-face. Interviews were between five and thirty minutes in length, with the first three taking place bedside in the clinical suite the trial was being conducted in, and the last in a private consult room. The semi-structured interviews used a standardised interview guide consisting of a series of open-ended questions regarding reasons for taking part in the study, experience of clinical procedures (including dried blood sample [DBS] collection from finger prick samples, intravenous cannula, and subcutaneous catheter insertion), experience of the infusion, tolerability of the procedure, ability to manage pain in the days post-infusion and suggestions for improvement. Participants were also asked to reflect on how this procedure might be tolerated by children, adolescents and young adults living with ARF [Interviews were audio recorded and transcribed verbatim. Transcripts were thematically analysed according to the methods detailed by Braun and Clarke [The study was approved by Bellberry Human Research Ethics Committee (2020-12-1348) and registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622000916741). All participants provided written, informed consent prior to participating. | PMC10138475 |
Results | The 24 participants recruited to the SCIP trial had a median age of 26.9 years and 20 (83.3%) were male. Nine (37.5%) were Caucasian, 8 (33.3%) Asian, 3 (12.5%) Latino, 2 (8.3%) African and 2 (8.3%) of mixed ethnicity. While English was known to be a second language for several participants these data were not captured, however English competency was a requirement for participation in the trial. All consented to their interviews being recorded. As staffing capabilities were constrained on one of the dosing days, questions asked during and two two-hours post infusion were combined and asked during a single recording for four participants. No participants missed an opportunity to be interviewed at timepoints two, three or four and data from 92 recordings were included in the final analysis. The themes discussed below are presented in a manner that aims to demonstrate the participant journey through the study experience. Pseudonyms are used in place of names with basic demographic data provided. | PMC10138475 | ||
Discussion | infection, ARF, pain | ARF, ADVERSE EVENTS, RECRUITMENT, RHD, INFECTION, STREP | Qualitative research was integrated into the methodology of this trial to better understand the recipient experience of a procedure previously not completed in a volunteer cohort. Given the previously described patient preference for BPG delivery that is less frequent and less painful [An element of phase-1 trials which is challenging to address is adequately preparing participants for what to expect, given that by their very nature, there is little prior experience to draw on. This was evident in SCIP specifically for accurate description of pain and the kinds of discomfort likely to be experienced. Concerningly, the qualitative data highlighted two participants were not expecting an extended infusion, apparently interpreting the information provided during screening and the consent process to mean the procedure was a single and quick needle. To address this unexpected gap between ‘informed consent’ and a clear understanding of the procedures involved, we will be adapting recruitment materials for similar research to include illustrative resources and a greater discussion with study investigators. This combination of verbal, written and even pictorial evidence has been shown to enable higher health literacy and engagement with trial expectations and anticipated outcomes [SCIP participants were generous in their suggestions on how to improve the study for children, with answers to these questions often the most in-depth answers to any on the guide. These ideas, specifically distractions, a slower infusion time and larger doses of lignocaine anaesthesia, are likely to be integrated into SCIP-II highlighting the importance of understanding the participant experience in early phase clinical trials. A critical question that we were unable to address in this study was how the experience of subcutaneous infusion compares with current practice for SP; i.e., IM injections of BPG every three to four-weeks. The next phase of this research is to undertake a similar study in a cohort of children, adolescents and young adults currently living with ARF (SCIP-II, to be completed in New Zealand) and these questions will be explored with participants through qualitative investigation. In addition, as most pain experienced by participants during the infusion pertained to its speed, alternate infusion methods that allow for more control of injection–including hand pushing of syringes–are under investigation for the second phase and are expected to incorporate greater provision of analgesia.Significantly more research is required before it can be determined if this nascent procedure is clinically safe and effective and offers desired penicillin concentrations above that required to protect against Strep A infection. However, as investigations progress, we as authors advocate for considerations to be made regarding culturally appropriate techniques for engagement and clear communication with the target population given the burden of ARF and RHD in Australia specifically is experienced by Aboriginal and Torres Strait Islander people. At Telethon Kids Institute–where this research was conducted–the A strength of this study is that all participants consented to be interviewed and no participant missed a timepoint where qualitative data were collected, likely due to the timepoints of interview (three on the same day) and rapport with the interviewer undertaking questioning at day-7 post interview. Additionally, the same two people conducted all interviews, with the seven-day timepoint completed by the investigator most familiar with participants (having been present at dosing day and the four follow-up appointments since). This allowed for the development of rapport and ultimately, the final interviews were the most in-depth. However, given some adverse events extended beyond 7-days post-infusion, excluding interviews at later follow-up appointments limited opportunities to explore these experiences further. To address this SCIP-II will be involving interviews with participants on infusion day and 28- and 70-days post-infusion. A further study limitation was that all interviews were completed in English which may have repressed the true expression of those for whom this was not their first or most comfortable language. Certain demographic data was not collected (i.e., parental status, preferred language) which impeded a more in-depth analysis of the transcripts and ascertainment of data limitations. Additionally, some transcripts were incomplete where background noise or accents made words unascertainable. | PMC10138475 |
Conclusion | pain | Qualitative research is a suitable method to be integrated into clinical trials, providing more in-depth information to the tolerability and acceptability of a procedure. The pharmacokinetic data from SCIP support the infusion of high-dose BPG as a possible alternative to monthly IM SP, a finding that would likely be redundant should it prove to be more painful or less tolerable than the current therapy. Our qualitative data demonstrated that the procedure under investigation was acceptable to participants with tolerable discomfort for most. It also identified a subset of participants with more extreme pain, and potential approaches that could be explored to alleviate this. Furthermore, findings from this sub-study have allowed for the development of more detailed participant information sheets for the SCIP-II trial–with suggestions provided by participants of SCIP-I to be incorporated for paediatric and adult cohorts. | PMC10138475 | |
Supporting information | PMC10138475 | |||
A summary of qualitative themes and supporting quotes. | (DOCX)Click here for additional data file. | PMC10138475 | ||
ABSTRACT | PMC9970201 | |||
Background | Carbohydrate (CHO) and carbohydrate-protein co-ingestion (CHO-P) have been shown to be equally effective for enhancing glycogen resynthesis and subsequent same-day performance when CHO intake is suboptimal (≤0.8 g/kg). Few studies have specifically examined the effect of isocaloric CHO vs CHO-P consumption on subsequent high-intensity aerobic performance with limited time to recover (≤2 hours) in masters class endurance athletes. | PMC9970201 | ||
Methods | ± | This was a randomized, double-blind between-subject design. Twenty-two male masters class endurance athletes (age 49.1 ± 6.9 years; height 175.8 ± 4.8 cm; body mass 80.7 ± 8.6 kg; body fat (%) 19.1 ± 5.8; VO | PMC9970201 | |
Results | A one-way ANCOVA indicated a significant difference among the group means for the posttest TTE (F | PMC9970201 | ||
Conclusions | Both CHO and CHO-P effectively promoted an increase in TTE performance with limited time to recover in this sample of masters class endurance athletes. Water and electrolytes alone were not effective for restoring endurance capacity during the second bout of exhaustive exercise. | PMC9970201 | ||
KEYWORDS | PMC9970201 | |||
Background | endurance exercise, endurance exercise [Exercise-induced dehydration | EVENTS | The rate of participation by masters class athletes (MCAs) in organized endurance and ultra-endurance events (>6 hours) has increased exponentially over the past 10–15 years [Two different isoenergetic options have been shown to effectively promote glycogen resynthesis post-exercise: CHO (1.2 g/kg) and CHO-P (0.8 g/kg CHO + 0.4 g/kg PRO) [Masters class endurance athletes frequently train in the evening and the next morning, on successive weekend days, or twice per day one-to-two times per week when preparing for a triathlon. A high weekly training volume combined with the demands of family and professional responsibilities is a considerable time investment [Protein intake promotes skeletal muscle remodeling and repair, adaptation to training, and replenishment of energy stores [A post-exercise and (daily) per meal intake of 0.40 g/kg of protein or approximately 30 g has been recommended by others to promote the repair and remodeling of skeletal muscle in master athletes who regularly engage in endurance exercise [Exercise-induced dehydration can impair thermoregulation and promote cardiovascular strain during a bout of prolonged endurance exercise [While there is an increased rate of participation by MCAs in endurance sports, a critical gap in the research exists related to post-exercise nutrition specific to MCAs and short-term (2 hours or less) recovery. This is problematic as slower recovery rates between subsequent bouts of exercise have been demonstrated, and higher protein needs post-exercise have been indicated to promote muscle remodeling and repair in MCAs [ | PMC9970201 |
Methods | PMC9970201 | |||
Study design | This study utilized a randomized, double-blind, placebo-controlled between-subject design to examine the effects of CHO and CHO-P supplementation on short-term recovery following aerobic interval exercise and time to exhaustion testing in male MCAs. The athletes were required to visit the laboratory on three separate occasions, with testing visits separated by a minimum of 48 hours and completed within two weeks. Timeline and exercise testing protocol. | PMC9970201 | ||
Subjects | Twenty-two male MCAs (49 ± 6 years, VOConsort flow diagram.Mean and SD values for demographic data.Cycling was the primary sport reported by 18 participants: PLA (n = 7), CHO (n = 4), CHO-P (n = 7). Body fat (%) and fat-free mass was reported for all but one participant in the CHO-P group. | PMC9970201 | ||
Results | PMC9970201 | |||
Participants | illness | FLU | Data from 22 trained male MCAs (49 ± 6 years old) were used in this research investigation. Thirty-one athletes were recruited; however, three were withdrawn from the study due to illness (i.e. COVID, flu); two discontinued participation after expressing discomfort with the mask required for metabolic testing; and one was withdrawn due to scheduling issues ( | PMC9970201 |
Blinding | Blinding results were available for 19 of 22 total participants with 31.6% (n = 6) correctly identifying which treatment beverage they consumed. | PMC9970201 | ||
Discussion | ±, nutritional beverage, MCAs | ADVERSE EFFECTS | The purpose of this investigation was to examine the effectiveness of three different beverages (CHO, CHO-P, and PLA) on short-term recovery from repeated bouts of exhaustive exercise in male endurance MCAs. The results support our hypothesis that CHO-P (0.8 g/kg bm CHO + 0.4 g/kg bm PRO) was equivalent to CHO (1.2 g/kg bm) for promoting an increase in time to exhaustion (TTE) performance following a 2-hour recovery period. Both CHO and CHO-P were superior to PLA (electrolytes and water) for supporting short-term recovery in masters class endurance athletes. The other main finding of this investigation was that both CHO and CHO-P appeared to be equally effective and significantly better than PLA in promoting HRR as assessed via the HRRi.A similar study with younger participants [On an individual level, unadjusted values indicated 63% (5 of 8) of participants in the PLA group demonstrated a decline in TTE performance averaging a − 68 sec change from the first to second bout of exercise, with a range of −16 to −185 sec. In comparison, only one of seven participants in the CHO group experienced a decrease in TTE performance (−18-sec) during the subsequent exercise bout, with the range of The MCAs who completed this study identified with a specific sport (i.e. primarily cycling but also running), and while as a group cannot be considered professional road cyclists, time-trial and exercise capacity testing are considered valid performance measurements for endurance athletes who regularly engage in prolonged high-intensity exercise that require periods of sustained power output [Three previously published studies that have examined post-exercise isocaloric CHO (1.2 g/kg bm) and CHO-P (0.8 g/kg bm CHO + 0.4 g/kg PRO) drinks and recovery from exhaustive exercise in young endurance-trained males have demonstrated that glycogen resynthesis postexercise is not necessarily the primary determinant of endurance-based performance outcomes [TTE at 90% PPO, while significantly improved during a subsequent bout of exercise relative to PLA, was not different between the CHO and CHO-P groups. CHO-P was not superior to CHO for improving acute TTE performance during a subsequent bout of high-intensity exercise; however, the addition of protein to a recovery beverage may have longer-term benefits. Doering et al. (2016) reported that a group of masters triathletes consumed 0.3 ± 0.2 g/kg bm of protein in the post-exercise recovery meal, which is slightly less than the recommended amount of 0.4 g/kg bm that has been found to maximally stimulate muscle protein synthesis in older adults [We found that adding protein to the recovery drink did not interfere with the acute performance benefits also seen in the CHO group. The inclusion of protein in the recovery drink has additional benefits, such as creating a more anabolic environment. As a result, athletes may be able to adjust more quickly to changes in their training schedules when they add protein to their diet. In support, Churchward-Venne et al. (2020) reported that whole-body net protein balance was The current investigation utilized a novel index to examine HRR relative to total work. Results indicated an improved recovery for both the CHO and CHO-P conditions at each of the three time points postexercise, with no difference between conditions. In comparison, the PLA condition was inadequate for promoting HRR at 1-, 2-, and 5-min postexercise as evidenced by a significantly higher HRRi value. The findings of an improved recovery for the CHO and CHO-P conditions are similar to the findings of Moreno and colleagues (2013) and others [Even though in the current study PLA provided similar amounts of water and electrolytes, it is possible that HRR may not be a suitable indicator for assessing recovery of parasympathetic activity either with fluid alone (i.e. water), within the first 5 min of exercise cessation, or following high-intensity exercise [There are several limitations to this study, including the rate of compliance completing the electronic 24-hour dietary assessment. In addition, dietary intake was not standardized among participants prior to the experimental protocol; however, statistical analysis revealed no significant differences in energy intake or macronutrient distribution between the three treatment groups for those athletes that did comply. We did not standardize dietary intake on the day of the experimental protocol nor was the high-intensity exercise examined in a fasted state. We also did not quantify or restrict caffeine intake 24 hours prior to testing. The goal of this investigation was to examine recovery from high-intensity exercise in an applied manner which allowed for exercise testing without a drastic change to the participant’s habitual diet or nutritional pre-exercise practice [This is the first study to examine the effect of an isocaloric CHO vs CHO-P drink on performance during a repeated bout of exhaustive exercise following a 2-hour recovery period in MCAs. The primary novel outcome of this study was that CHO-P was equally effective as CHO for enhancing performance in a subsequent bout of high-intensity exercise with a limited time to recover. In addition, the incorporation of a novel index to examine HRR relative to total work (HRRi) indicated an improved recovery for both the CHO-P and CHO conditions within the first 5 min of exercise cessation, in comparison to a water and electrolyte solution. This study found that the use of an adequate CHO-containing nutritional beverage significantly improved recovery in the group of masters class endurance athletes, while replacing a portion of the carbohydrate content with protein had no adverse effects on either recovery or performance. | PMC9970201 |
Disclosure statement | No potential conflict of interest was reported by the author(s). | PMC9970201 | ||
References | PMC9970201 | |||
1. Introduction | death, HBV-related HCC, HBV suppression, toxicity, cancer, HCC, HBV-related HCC.Hepatocellular carcinoma | HEPATITIS B, VIRUS, RECURRENCE, CANCER, HEPATOCELLULAR CARCINOMA | These authors contributed equally to this work.Hepatocellular carcinoma (HCC) usually recurs after curative surgical resection. Currently, no approved adjuvant therapy has been shown to reduce HCC recurrence rates. In this study, the in vivo effect of sequential combination treatment with recombinant mouse interferon-alpha (rmIFN-α) and an anti-mouse-PD1 antibody on hepatitis B virus (HBV) clearance in mice was evaluated. A Phase I clinical trial was then conducted to assess the safety, tolerability, and inhibitory activity of sequential therapy with ropeginterferon alfa-2b and nivolumab in patients with HCC recurrence who underwent curative surgery for HBV-related HCC. The animal modeling study showed that HBV suppression was significantly greater with the rmIFN-α and anti-PD1 sequential combination treatment in comparison with sole treatment with rmIFN-α or anti-PD1. In the Phase I study, eleven patients completed the sequential therapy with ropeginterferon alfa-2b every two weeks for six doses at 450 µg, followed by three doses of nivolumab every two weeks up to 0.75 mg/kg. A notable decrease in or clearance of HBV surface antigen was observed in two patients. The dose-limiting toxicity of grade 3 alanine transaminase and aspartate aminotransferase increases was observed in one patient. The maximum tolerated dose was then determined. To date, no HCC recurrence has been observed. The treatment modality was well tolerated. These data support the further clinical development of sequential combination therapy as a post-surgery prophylactic measure against the recurrence of HBV-related HCC.Hepatocellular carcinoma (HCC) is a common and fatal cancer worldwide [Programmed cell death 1 (PD1) is a negative costimulatory receptor expressed primarily on the surface of activated T cells [Ropeginterferon alfa-2b represents a new-generation PEGylated interferon alpha (IFN-α)-based therapy with a favorable pharmacokinetic profile. It can be injected less frequently, for example, once every two weeks [ | PMC10778875 |
2. Results | PMC10778875 | |||
2.1. Animal Modeling Data | An HBV mouse model (HBV-HDI) was generated via the intravenous injection of an HBV genotype A DNA plasmid into CBA/CaJ mice [ | PMC10778875 | ||
2.2. Phase I Clinical Study | toxicities, DLTs | CANCER RECURRENCE | A Phase I study was conducted to determine the maximum tolerated dose (MTD). A total of 12 eligible patients were enrolled in Cohorts 1 and 2 (The mean age and standard deviation of the eligible patients were 61.8 and 10.3 years, respectively (Dose-limiting toxicities (DLTs) were observed in one patient. Drug-related grade 3 ALT and AST increases were observed in one patient in Cohort 1. The patient completed the ropeginterferon alfa-2b treatment and received one dose of nivolumab. No DLTs were observed in Cohort 2. However, given that the DLTs of grade 3 ALT and AST increases were observed in Cohort 1 and that there were greater levels of grade 2 ALT and AST increases in Cohort 2, we determined that Cohort 2 reached the MTD of the study based on the overall safety assessment. Therefore, six doses of ropeginterferon alfa-2b at 450 ug followed by three doses of nivolumab at 0.75 mg/kg were determined to be the MTD for the adjuvant sequential combination therapy.To date, all patients are alive without cancer recurrence. The mean follow-up period was 716.75 days (minimum, 114 days; maximum, 1416 days). HBsAg was undetectable in one patient in Cohort 1 at follow-up week 12 and after ( | PMC10778875 |
3. Discussion | HBV-related HCC, HBV infection, HBV suppression, CHB infection, HCC, deaths | TUMOR RECURRENCE | HCC is a common cause of cancer-related deaths, and most cases are associated with HBV infection. Patients with HCC are at a high risk of tumor recurrence after surgical resection. Currently, there are no approved therapies for inhibiting tumor recurrence. In this study, our animal modeling data demonstrated that sequential combination treatment with rmIFN-α and anti-PD1 antibody led to a synergistic effect in HBV suppression and clearance. Our Phase I clinical study further suggested that sequential combination therapy with ropeginterferon alfa-2b and nivolumab was well tolerated. This combination therapy can facilitate the clearance of residual HBV infection and inhibit cancer recurrence in patients with HBV-related HCC after curative surgery.PD-L1 is often overexpressed during CHB infection [Type 1 IFNs, including IFN-α and beta (IFN-β), share the same receptor components and induce similar biological activities [ | PMC10778875 |
4. Materials and Methods | PMC10778875 | |||
4.1. HBV-HDI Mouse Model | Six- to eight-week-old male CBA/CaJ mice were bred at the National Taiwan University Laboratory Animal Center. The mice were intravenously injected with 10 μg of HBV genotype A DNA plasmid dissolved in PBS equivalent to approximately 8% of the mouse’s body weight, as previously described [ | PMC10778875 | ||
4.2. Preclinical Materials | Anti-mouse PD1 (RMP-17) is a monoclonal antibody targeting mouse PD1 generated via hybridoma screening at the PharmaEssentia Corporation Research Laboratory. rmIFN-α was produced using the | PMC10778875 | ||
4.3. Treatment of HBV-Carrying CBA/CaJ Mice | Mice were divided into eight groups to investigate the effect of rmIFN-α on sequential combination with anti-mouse PD1. The drug dosages and administration routes are described below.Group 1 (control): Six HBV-carrying CBA/CaJ mice were subcutaneously (s.c.) injected with 200 μL of PBS every other day (Q2D) × 8 (days 0–14).Group 2: Six HBV-carrying CBA/CaJ mice were s.c. injected with 800 IU/g of rmIFN-α (Q2D × 8, days 0–14).Group 3: Six HBV-carrying CBA/CaJ mice were s.c. injected with 800 IU/g of rmIFN-α (Q2D × 22, days 0–42)Group 4: Ten HBV-carrying CBA/CaJ mice were intraperitoneally (i.p.) injected with 32 μg/g of the anti-mouse PD1 antibody (Q2D × 6, days 16–26).Group 5: Ten HBV-carrying CBA/CaJ mice were i.p. injected with 32 μg/g of anti-mouse PD1 antibody (Q2D × 10, days 16–34).Group 6: Ten HBV-carrying CBA/CaJ mice were s.c. injected with 800 IU/g of rmIFN-α (Q2D × 8, days 0–14) and then i.p. injected with 32 μg/g of the anti-PD1 antibody (Q2D × 6, days 16–26).Group 7: Ten HBV-carrying CBA/CaJ mice were s.c. injected with 800 IU/g of rmIFN-α (Q2D × 22, days 0–42) and then i.p. injected with 32 μg/g of the anti-PD1 antibody (Q2D × 6, days 44–54).Group 8: Ten HBV-carrying CBA/CaJ mice were s.c. injected with 800 IU/g of rmIFN-α (Q2D × 43, days 0–84) and then i.p. injected with 32 μg/g of the anti-PD1 antibody (Q2D × 6, days 86–96). | PMC10778875 | ||
4.4. Quantification of HBsAg and HBV DNA in Mice | Serum HBsAg and HBV DNA levels were quantified using the Abbott Architect I1000 system (Abbott Diagnostics, Green Oaks, IL, USA) and the Roche Lightcycler 480 (Roche Diagnostics, GmbH, Mannheim, Germany), respectively. The sequences of HBx-specific primers used to quantify the copy numbers of HBV DNA were 5′-CCGATCCATACTGCGGAAC-3′ (forward (nt 1261–1600)) and 5′-GCAGAGGTGAAGCGAAGTGCA-3′ (reverse) [ | PMC10778875 | ||
4.5. Clinical Materials: | Ropeginterferon alfa-2b was produced by the PharmaEssentia Corporation. It was provided as a prefilled syringe of 500 µg/1.0 mL. Nivolumab (OPDIVO | PMC10778875 | ||
4.6. Study Design | hepatitis B-related HCC | This clinical study was designed as a Phase I/II trial. The Phase I study aimed to evaluate the safety and tolerability and define the MTD of the sequential administration of ropeginterferon alfa-2b and nivolumab in patients who received curative surgery for hepatitis B-related HCC. The Phase II trial was designed to further evaluate the safety and prophylactic effect of the sequential administration of ropeginterferon alfa-2b and nivolumab at the MTD. Phase I was conducted at the National Taiwan University Hospital (NTUH), Taiwan (approval number: 201710061MIPB). The Phase I study was completed, but the Phase II study has not yet started.Sequential administration of ropeginterferon alfa-2b and nivolumab was assessed using a 3 + 3 dose escalation scheme. Eligible patients were enrolled in four dose cohorts to receive six doses of ropeginterferon alfa-2b at a dose of 450 μg once every two weeks, followed by three doses of nivolumab every two weeks at a predetermined dose level based on the cohort, including 0.3 mg/kg for Cohort 1; 0.75 mg/kg for Cohort 2; 1.5 mg/kg for Cohort 3; and 3 mg/kg for Cohort 4. Ropeginterferon alfa-2b was administered via subcutaneous injection, and nivolumab was administrated through intravenous infusion over 60 min [ | PMC10778875 | |
4.7. Patients | malignancy, HBV-related HCC, HCC | ONCOLOGY, COMPENSATED LIVER DISEASE | Patients with HBV-related HCC who underwent surgical resection within eight weeks were enrolled. Other major inclusion criteria included positive results for HBsAg, undetectable HBV DNA, compensated liver disease, normal fundoscopic examination, and an Eastern Cooperative Oncology Group Performance Status score of 0 to 1. The major exclusion criteria included HCC that was not related to HBV; vascular invasion of HCC in imaging diagnosis; patients who had undergone transcatheter arterial embolization or chemoembolization, transcatheter arterial infusion, or chemolipiodolization in combination with surgery; and a concurrent active malignancy other than HCC. | PMC10778875 |
5. Conclusions | HBV suppression, HCC | Our animal data demonstrated a synergistic effect between rmIFN-α and anti-PD1 treatment for HBV suppression or even clearance. This effect was observed in patients with HCC who received sequential combination therapy with ropeginterferon alfa-2b and nivolumab in a Phase I clinical study. Most AEs were either mild or moderate. Increased liver transaminase was common but not associated with increased bilirubin levels or clinical symptoms. No unexpected AEs were observed. The MTD of sequential combination therapy with ropeginterferon alfa-2b and nivolumab was determined. Further exploration and clinical development of combination therapy are required. | PMC10778875 | |
Author Contributions | A.Q., C.-R.W., M.-C.H., C.-Y.T. and P.-J.C. contributed to the work. P.-J.C. and M.-C.H. enrolled and treated patients. All authors have read and agreed to the published version of the manuscript. | PMC10778875 | ||
Institutional Review Board Statement | The animal experiments were performed in accordance with the guidelines established by the Institutional Animal Care and Use Committee of the National Taiwan University College of Medicine. The Phase I/II clinical study was approved by the Institutional Review Board of NTUH (201710061MIPB) on 22 December 2017 and conducted according to the principles of the Declaration of Helsinki for all human experimental investigations. The Phase I/II clinical studies were registered at | PMC10778875 | ||
Informed Consent Statement | Informed consent was obtained from all participating patients. | PMC10778875 | ||
Data Availability Statement | Data will be available to external researchers upon reasonable request from the investigators and PharmaEssentia. | PMC10778875 | ||
Conflicts of Interest | ALBERT | Albert Qin and Chan-Yen Tsai work for the PharmaEssentia Corporation. Pei-Jer Chen has served as a consultant for the PharmaEssentia Corporation. The other authors have no conflicts of interest to declare. | PMC10778875 |
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