Ameliorating Metabolic Profiles After Kidney Transplantation: A Protocol for an Open-Label, Prospective, Randomized, 3-Arm, Controlled Trial.
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SUBMITTER: Yin S
PROVIDER: S-EPMC8733302 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:INTRODUCTION:The use of marginal or extended criteria donor livers is increasing. These organs carry a greater risk of initial dysfunction and early failure, as well as inferior long-term outcomes. As such, many are rejected due to a perceived risk of use and use varies widely between centres. Ex situ normothermic machine perfusion of the liver (NMP-L) may enable the safe transplantation of organs that meet defined objective criteria denoting their high-risk status and are currently being declined for use by all the UK transplant centres. METHODS AND ANALYSIS:Viability testing and transplantation of marginal livers is an open-label, non-randomised, prospective, single-arm trial designed to determine whether currently unused donor livers can be salvaged and safely transplanted with equivalent outcomes in terms of patient survival. The procured rejected livers must meet predefined criteria that objectively denote their marginal condition. The liver is subjected to NMP-L following a period of static cold storage. Organs metabolising lactate to ?2.5?mmol/L within 4?hours of the perfusion commencing in combination with two or more of the following parameters-bile production, metabolism of glucose, a hepatic arterial flow rate ?150?mL/min and a portal venous flow rate ?500?mL/min, a pH ?7.30?and/or maintain a homogeneous perfusion-will be considered viable and transplanted into a suitable consented recipient. The coprimary outcome measures are the success rate of NMP-L to produce a transplantable organ and 90-day patient post-transplant survival. ETHICS AND DISSEMINATION:The protocol was approved by the National Research Ethics Service (London-Dulwich Research Ethics Committee, 16/LO/1056), the Medicines and Healthcare Products Regulatory Agency and is endorsed by the National Health Service Blood and Transplant Research, Innovation and Novel Technologies Advisory Group. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER:NCT02740608; Pre-results.
| S-EPMC5719273 | biostudies-literature
Project description:BACKGROUND After liver transplantation (LT), nonadherence to immunosuppressants due to the complex regimen can lead to graft rejection and loss. This study assessed the efficacy and safety of conversion from twice-daily tacrolimus (Bid-Tac) to once-daily prolonged-release tacrolimus (OD-Tac) in living donor LT (LDLT) recipients. MATERIAL AND METHODS Among patients who underwent LDLT between November 2015 and October 2016, those who agreed to participate in this study were screened, and those with good general condition and stable liver functions were enrolled. Participants underwent a conversion from Bid-Tac to OD-Tac with a dose ratio of 1: 1 at about 10-14 weeks after LDLT and were followed-up for 24 weeks. RESULTS Thirty-one patients were enrolled. The median number of conversion days after LDLT was 12.3 weeks (range, 10.3-13.8). Adherence was evaluated during the outpatient visits at weeks 2, 4, 8, 16, and 24 after Tac conversion, and 100% adherence was observed at all time points. There were no cases of acute rejection, graft loss, or patient death after Tac conversion. Nineteen cases of adverse events occurred in 11 patients (35.5%), none of which were severe. Alopecia was the most common, affecting 3 (9.7%) patients, followed by pruritus (n=2, 6.45%). There were no changes in renal function or in liver function test, serum glucose level, and lipid profile. CONCLUSIONS Early Tac conversion from Bid-Tac to OD-Tac is safe and feasible. However, further studies are needed to elucidate its long-term effects.
| S-EPMC6248274 | biostudies-literature
Project description:Introduction: Ageing of the general population has led to an increase in the use of suboptimal kidneys from expanded criteria donation after brain death (ECD-DBD) and donation after circulatory death (DCD) donors. However, these kidneys have inferior graft outcomes and lower rates of immediate function. Normothermic machine perfusion (NMP) may improve outcomes of these suboptimal donor kidneys. Previous non-randomized studies have shown the safety of this technique and suggested its efficacy in improving the proportion of immediate functioning kidneys compared to static cold storage (SCS). However, its additional value to hypothermic machine perfusion (HMP), which has already been proved superior to SCS, has not yet been established. Methods and analysis: This single-center, open-label, randomized controlled trial aims to assess immediate kidney function after 120 minutes additional, end-ischemic NMP compared to HMP alone. Immediate kidney function is defined as no dialysis treatment in the first week after transplant. Eighty recipients on dialysis at the time of transplant who receive an ECD-DBD or DCD kidney graft are eligible for inclusion. In the NMP group, the donor kidney is taken of HMP upon arrival in the recipient hospital and thereafter put on NMP for 120 minutes at 37 degrees Celsius followed by transplantation. In the control group, donor kidneys stay on HMP until transplantation. The primary outcome is immediate kidney function. Ethics and dissemination: The protocol has been approved by the Medical Ethical Committee of Erasmus Medical Center (2020-0366). Results of this study will be submitted to peer-reviewed journals. Registration: registered in clinicaltrials.gov (NCT04882254). Highlights: This is the first RCT to compare additional NMP to HMP alone. Extensive sampling will offer in-depth analysis of kidney physiology during NMP. This RCT may help identify biomarkers to predict clinical outcomes during NMP. Biomarkers can help develop NMP as assessment tool for declined kidneys.
| S-EPMC8499718 | biostudies-literature
Project description:Background: Caffeine citrate has been approved in China for the management of apnea of prematurity. This clinical trial was conducted as a condition of regulatory approval. The aim was to confirm the efficacy of caffeine citrate in the treatment of recurrent intermittent hypoxia and bradycardia in preterm newborns with primary apnea. Objectives: The primary outcome was the change from baseline in the number of apnea events after loading dose administration of caffeine citrate. Secondary efficacy outcomes included the change from baseline in apnea events after 2 and 4 weeks of maintenance doses. Methods: This was a multicenter, prospective longitudinal open-label, single-arm study. Neonates who had experienced at least four apnea events during a 24 h period received a loading dose of caffeine citrate 20 mg/kg; those who required additional maintenance doses received 5 mg/kg/day (titrated up to 10 mg/kg/day in case of insufficient response). The number of apnea events was recorded for 6-12 h prior to the loading dose (baseline), and for 12 h post-dose, following the loading dose and at Weeks 2 and 4 (during maintenance). Results: A total of 247 neonates received the loading dose, who had a significant reduction from baseline of 3.9 events (p < 0.001) in the mean number of apnea events. The subset of neonates who required maintenance doses also had significant reductions in the number of events at all visits (p < 0.001 for all). A total of 79.4% of participants had at least one adverse event, but only one non-serious and no serious events were considered related to treatment. Conclusions: In this large, prospective, open-label study, premature infants with a history of apnea who received caffeine citrate were significantly less likely to experience further apnea events.
| S-EPMC7078308 | biostudies-literature
Project description:Objective To evaluate the efficacy and tolerability of single pulse transcranial magnetic stimulation (sTMS) for the preventive treatment of migraine. Background sTMS was originally developed for the acute treatment of migraine with aura. Open label experience has suggested a preventive benefit. The objective of this trial was to evaluate the efficacy and tolerability of sTMS for migraine prevention. Methods The eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (ESPOUSE) Study was a multicenter, prospective, open label, observational study. From December 2014 to March 2016, patients with migraine (n?=?263) were consented to complete a 1-month baseline headache diary followed by 3 months of treatment. The treatment protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment. Patients reported daily headache status, medication use, and device use with a monthly headache diary. The primary endpoint, mean reduction of headache days compared to baseline, was measured over the 28-day period during weeks 9 to 12. The primary endpoint was compared to a statistically-derived placebo estimate (performance goal). Secondary endpoints included: 50% responder rate, acute headache medication consumption, HIT-6, and mean reduction in total headache days from baseline of any intensity. Results Of a total of 263 consented subjects, 229 completed a baseline diary, and 220 were found to be eligible based on the number of headache days. The device was assigned to 217 subjects (Safety Data Set) and 132 were included in the intention to treat Full Analysis Set. For the primary endpoint, there was a -2.75?±?0.40 mean reduction of headache days from baseline (9.06 days) compared to the performance goal (-0.63 days) ( p?<?0.0001). The 50% responder rate of 46% (95% CI 37%, 56%) was also significantly higher ( p?<?0.0001) than the performance goal (20%). There was a reduction of -2.93 (5.24) days of acute medication use, headache impact measured by HIT-6, -3.1 (6.4) ( p?<?0.0001), and total headache days of any intensity -3.16 days (5.21) compared to the performance goal (-0.63 days) ( p?<?0.0001). The most common adverse events were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%). There were no serious adverse events. Conclusions This open label study suggests that sTMS may be an effective, well-tolerated treatment option for migraine prevention. Trial registration number NCT02357381.
| S-EPMC5944078 | biostudies-literature
Project description:Necrobiosis Lipoidica (NL) is a rare granulomatous disease. There are few effective treatments for NL. We sought to investigate the efficacy and safety of the JAK 1/2 inhibitor, ruxolitnib, in the treatment of NL and identify biomarkers associated with disease and treatment response. We conducted an open-label, phase 2 study of ruxolitinib in 12 patients with NL. We performed transcriptomic analysis of tissue samples pre- and post-treatment. At week 12, the mean NL lesion score decreased by 58.2% (SD 28.7%, P=0.003). Transcriptomic analysis demonstrated enrichment of type I and type II interferon pathways in baseline disease. Weighted Gene Co-expression Network Analysis (WGCNA) demonstrated post-treatment changes in interferon pathways with key hub genes IFNG and STAT1. Limitations include small sample size and a study group limited to patients with <10% BSA. In conclusion, ruxolitinib is an effective treatment for NL and targets the key pathogenic mediators of disease.
2024-02-19 | GSE255518 | GEO
Project description:Renal dysfunction is associated with poor long-term outcomes after liver transplantation. We examined the renal sparing effect of everolimus (EVR) compared to standard calcineurin inhibitor (CNI) immunosuppression with direct measurements of renal function over 24 months.MethodsThis was a prospective, randomized, open-label trial comparing EVR and mycophenolic acid (MPA) with CNI and MPA immunosuppression. An Investigational New Drug Application (IND # 113882) was obtained with the Food and Drug Administration as EVR is only approved for use with low-dose tacrolimus. Serum creatinine, 24-hour urine creatinine clearance, iothalamate clearance, Cockcroft-Gault creatinine clearance (CrCl), and Modification of Diet in Renal Disease estimated glomerular filtration rate were prospectively measured at 4 study visits. Nonparametric statistical tests were used for analyses, including the Mann-Whitney U test for continuous outcomes and Pearson's chi-square test for binary outcomes. Effect size was measured using Cohen's d. Patients also completed quality of life surveys using the FACT-Hep instrument at each study visit. Comparison between the 2 groups was performed using the Student t test.ResultsEach arm had 12 subjects; 4 patients dropped out in the EVR arm and 1 in the CNI arm by 24 months. Serum creatinine (P = 0.015), Modification of Diet in Renal Disease estimated glomerular filtration rate (P = 0.013), and 24-hour urine CrCL (P = 0.032) were significantly better at 24 months with EVR. Iothalamate clearance showed significant improvement at 12 months (P = 0.049) and a trend toward better renal function (P = 0.099) at 24 months. There was no statistical significance with Cockcroft-Gault CrCl. Adverse events were not significantly different between the 2 arms. The EVR group also showed significantly better physical, functional, and overall self-reported quality of life (P = 0.01) at 24 months.ConclusionsEVR with MPA resulted in significant long-term improvement in renal function and quality of life at 24 months after liver transplantation compared with standard CNI with MPA immunosuppression.
| S-EPMC8191692 | biostudies-literature
Project description:BackgroundThere is strong rationale for interference with T cell co-stimulation in IgG4-related disease (IgG4-RD), but the literature to evaluate this is limited to a single case report.MethodsWe conducted a ten-subject proof-of-concept trial of abatacept in active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD. Subjects received subcutaneous abatacept 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but if used had to be discontinued by week four. The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD Responder Index score of 0. Peripheral blood mononuclear cells were collected at baseline, four weeks, and 12 weeks. B and T cell subsets were quantified using a 25-parameter flow cytometry panel.FindingsThe subjects' median age was 68 years; seven subjects were male and nine were Caucasian. Baseline organ involvement was diverse with a median of 5 organs affected at the time of enrollment. The median serum IgG4 concentration was 597 mg/dL (IQR 304-913 mg/dL). Three subjects received concomitant prednisone at baseline. Six subjects (60%) had a disease response by week 12, five of whom maintained this response at week 24. Abatacept was stopped in the remaining five subjects (50%) due to flare (N = 1) or lack of response by week 12 (N = 4). Three subjects (30%) achieved the primary endpoint.Baseline proportions of unswitched memory B cells predicted responsiveness to abatacept. Reductions in serum IgE, circulating plasmablasts, and activated type 2 T follicular helper (TFH2) cells correlated with response to treatment. One adverse event (grade two thrombocytopenia) was attributed to abatacept.InterpretationAbatacept was associated with variable treatment responses in IgG4-RD. Half of the subjects achieved sustained treatment responses to abatacept alone, without glucocorticoids. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, and activated TFH2 cells. Response to abatacept was predicted by higher proportions of unswitched memory B cells at baseline.
| S-EPMC9004478 | biostudies-literature
Project description:BackgroundAlthough the bortezomib-based triple-drug therapy is considered as a front-line therapy for multiple myeloma (MM) in Chinese patients, increased level of toxicity leads to treatment dissatisfaction. Treatment with ixazomib, an oral proteasome inhibitor, has demonstrated better efficacy and safety profile without increasing the toxicity. In this study, we investigate the safety and clinical outcomes of Chinese patients with newly diagnosed MM (NDMM) who transitioned from a bortezomib-based triple-drug therapy to an ixazomib-based triple-drug therapy in a real-world clinical setting.MethodsThis will be an open-label, single-arm, multicenter, prospective, observational study will recruit Chinese patients (aged ≥ 18 years) diagnosed with NDMM using International Myeloma Working Group (IMWG) criteria and who have received a bortezomib-based triple-drug therapy for more than two cycles as initial therapy. The previous bortezomib-based triple-drug therapy may include bortezomib, cyclophosphamide, and dexamethasone or lenalidomide, bortezomib, and dexamethasone or bortezomib, doxorubicin, and dexamethasone or bortezomib, thalidomide, and dexamethasone. At the time of enrollment, patients must have achieved at least partial response as defined by IMWG criteria. Approximately 320 eligible patients at 15 top MM hospitals in China will be treated with ixazomib triple-drug therapy and followed up once every 3 months for 24 months, unless specified. The primary endpoint is to assess progression-free survival at 2 years for Chinese patients with NDMM who have transitioned from a bortezomib-based triple-drug therapy to ixazomib-based triple-drug therapy. The clinical effectiveness, safety and tolerability, patient-reported outcomes, and health economic/resource utilization will be evaluated as secondary endpoints.Planned outcomesThe results from this study may provide evidence to verify the benefits of transitioning from bortezomib-based triple-drug therapy to ixazomib-based triple-drug therapy in Chinese patients with NDMM in a real-world clinical setting.Trial registrationThe study has been registered at clinicalTrials.gov (NCT05013190).
| S-EPMC9898406 | biostudies-literature
Project description:Ruxolitinib is a Janus kinase 1/2 inhibitor (JAK1/2) that blocks signal transduction of interferon-gamma, a critical cytokine involved in the pathogenesis of cutaneous lichen planus (LP). In this prospective phase II study, we investigated the efficacy of topical ruxolitinib in cutaneous LP and performed transcriptomic analysis pre- and post-therapy. Twelve patients with cutaneous LP applied topical ruxolitinib twice daily for 8 weeks. Primary endpoints were change in total lesion count and modified Composite Assessment of Index Lesion Severity (mCAILS) score in index treated and untreated index control lesions at week 4. Total lesion count decreased by a median of 50 lesions (interquartile range 25, 723; p<0.001). mCAILS scores decreased by a mean difference of 7.6 (standard deviation 8.8, p=0.016) between index treated and control lesions. Type I and II interferon pathways were enriched in LP and responsive disease displayed downregulation of interferon-stimulated genes (ISGs). In this small pilot study, topical ruxolitinib was highly effective in the treatment of cutaneous LP. Transcriptomic analysis confirmed LP as an interferon-driven disease and downregulation of ISGs correlated with disease response.
2022-01-13 | GSE193351 | GEO