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Graphical Abstract | PMC10636255 | |||
Statement of Significance | Narcolepsy, narcolepsy, daytime sleepiness | NARCOLEPSY, NARCOLEPSY WITHOUT CATAPLEXY, NARCOLEPSY, NARCOLEPSY AND CATAPLEXY, NARCOLEPSY TYPE 1, NARCOLEPSY WITH CATAPLEXY | Narcolepsy is classified into two subtypes: narcolepsy type 1 (NT1), or narcolepsy with cataplexy, and narcolepsy type 2 (NT2), or narcolepsy without cataplexy. The etiology of NT2 is not well understood, and limited published data are available on the benefits of treatment specific to NT2, as trials have historically enrolled patients with narcolepsy with cataplexy or unspecified narcolepsy. A recently approved extended-release once-nightly sodium oxybate (ON-SXB) demonstrated effectiveness for treating excessive daytime sleepiness in adults with narcolepsy and cataplexy in patients with NT1. Results from post hoc analyses of the phase 3 REST-ON trial demonstrated consistent efficacy of ON-SXB in patients regardless of narcolepsy type. ON-SXB is the only once-at-bedtime oxybate treatment option for people with either narcolepsy type. | PMC10636255 |
Introduction | Narcolepsy, cataplexy, narcolepsy, EDS, loss of hypothalamic hypocretin, NT2 [ | NARCOLEPSY, NARCOLEPSY WITHOUT CATAPLEXY, CATAPLEXY, NARCOLEPSY, NARCOLEPSY TYPE 1, NARCOLEPSY WITH CATAPLEXY | Narcolepsy is classified into two subtypes: narcolepsy type 1 (NT1), or narcolepsy with cataplexy, and narcolepsy type 2 (NT2), known as narcolepsy without cataplexy [The etiology of NT1 is recognized to be due to severe loss of hypothalamic hypocretin (orexin) neurons resulting in low or undetectable cerebrospinal fluid (CSF) orexin levels [Guidelines in both the US and Europe recommend sodium oxybate (SXB, sodium salt of ɣ-hydroxybutyrate) for the treatment of adults with either NT1 or NT2 [The first once-at-bedtime oxybate (LUMRYZ, sodium oxybate for extended-release oral suspension [FT218; once-nightly sodium oxybate (ON-SXB)], Avadel Pharmaceuticals, Chesterfield, MO) was recently approved by the US Food & Drug Administration (FDA) for treatment of cataplexy or EDS in adults with narcolepsy [There are limited published data on treatment efficacy in people with NT2 [ | PMC10636255 |
Methods | PMC10636255 | |||
Study Design | narcolepsy | NARCOLEPSY | REST-ON was a multicenter phase 3, randomized, double-blind, placebo-controlled clinical trial (NCT02720744). The trial was designed to evaluate the efficacy and safety of ON-SXB for the treatment of narcolepsy. Full details on the trial design were previously published [REST-ON was approved by institutional review boards at participating centers and conducted in compliance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, International Council for Harmonisation guidelines, and applicable national and local laws and regulatory requirements. Before participation in the study, participants provided written informed consent. For patients aged 16 or 17 years, consent was obtained from both the patient and their legal, authorized guardian [ | PMC10636255 |
Participants | Full details on participants’ inclusion criteria were previously published [ | PMC10636255 | ||
Assessment | sleep stage, cataplexy, g).On | SECONDARY, CATAPLEXY | This post hoc analysis evaluated primary and secondary endpoints from the REST-ON study in 2 separate subgroups: participants with NT1 and those with NT2. Coprimary efficacy endpoints were the change from baseline in MWT, CGI-I, and weekly cataplexy attacks (not applicable for this analysis). Secondary endpoints included change from baseline in the (1) number of sleep stage shifts, (2) number of nocturnal arousals, (3) patient-reported quality of sleep, (4) patient-reported refreshing nature of sleep, and (5) patient-reported ESS score. Both primary and secondary efficacy assessments were recorded at baseline and weeks 3 (6 g), 8 (7.5 g), and 13 (9 g).On the test day, mean sleep latency on the MWT was averaged over five 30-minute trials. Each trial was terminated immediately after sleep onset or after 30 minutes if no sleep onset occurred [ | PMC10636255 |
Statistical Analyses | sleep stage, cataplexy | SECONDARY, CATAPLEXY | This post hoc analysis assessed the primary and secondary efficacy endpoints in the NT1 and NT2 cohorts separately and was conducted on the modified intent-to-treat population (mITT). The mITT population was composed of all participants with at least 1 efficacy measurement after receiving either 6 g of ON-SXB or placebo. Notably, the trial was not powered for subgroup analyses and enrollment of participants with NT2 was limited by the sample size of the NT1 population required for the cataplexy endpoint.The change from baseline for mean sleep latency on the MWT with ON-SXB vs placebo at weeks 3 (6 g), 8 (7.5 g), and 13 (9 g) was analyzed using a mixed-effects model for repeated measures (MMRM). An MMRM model was also used to analyze changes from baseline with ON-SXB vs placebo at weeks 3 (6 g), 8 (7.5 g), and 13 (9 g) in (1) sleep stage shifts, (2) nocturnal arousals, (3) sleep quality, (4) refreshing nature of sleep, and (5) ESS score. In the model, treatment, visit, treatment by visit, time and treatment by time (ESS only), US or non-US study site, and baseline score were fixed effects; participants were random effects. The MMRM model also included covariate of baseline values and unstructured variance-covariance structure. GLIMMIX model for binomial data was used to analyze CGI-I categorized responses (ie, the proportion of participants who were very much or much improved), and the response variable was the observed values for each CGI-I categorized response [ | PMC10636255 |
Results | PMC10636255 | |||
Participant Disposition and Demographics | narcolepsy | NARCOLEPSY, NARCOLEPSY TYPE 1, DISEASE CHARACTERISTIC | As described previously, 222 participants were enrolled and randomly assigned to either ON-SXB or placebo (Baseline demographics and disease characteristics (safety population)BMI, body mass index; NT1, narcolepsy type 1; NT2, narcolepsy type 2; ON-SXB, once-nightly sodium oxybate (FT218).Baseline measurements (mITT population)ESS, Epworth Sleepiness Scale; mITT, modified intent-to-treat; NT1, narcolepsy type 1; NT2, narcolepsy type 2; ON-SXB, once-nightly sodium oxybate (FT218); VAS, visual analog scale. | PMC10636255 |
Efficacy | PMC10636255 | |||
Coprimary Endpoints | PMC10636255 | |||
MWT | narcolepsy | NARCOLEPSY | At baseline, the mean (SD) sleep latency on the MWT was similar between the ON-SXB and placebo arms for both the NT1 and NT2 subgroups (Improvement from baseline for the 2 coprimary endpoints by narcolepsy type (mITT population). (A) MWT (LSM change from baseline [MMRM analysis]) and (B) CGI-I (OR for “much” or “very much improved” [GLIMMIX model]). * | PMC10636255 |
CGI-I | The mean (SD) baseline CGI-Severity scores were similar between the ON-SXB and placebo arms for the NT1 and NT2 subgroups ( | PMC10636255 | ||
Secondary Endpoints | PMC10636255 | |||
Sleep Stage Shifts | narcolepsy, sleep stage | NARCOLEPSY, SECONDARY | At baseline, the total mean (SD) number of shifts from stages N1, N2, N3, and REM sleep to wake or from N2, N3, and REM sleep to N1 was similar between ON-SXB and placebo for the NT1 and NT2 subgroups (Change from baseline for the 5 secondary endpoints by narcolepsy type (mITT population [MMRM analysis]). (A) sleep stage shifts, (B) nocturnal arousals, (C) sleep quality, (D) refreshing nature of sleep, and (E) Epworth Sleepiness Scale. * | PMC10636255 |
Nocturnal Arousals | arousals, SD | At baseline, the mean number (SD) of nocturnal arousals was similar between ON-SXB and placebo arm in participants with NT1 and NT2 ( | PMC10636255 | |
Sleep Quality | At baseline, patient-reported mean (SD) sleep quality was similar between ON-SXB and placebo for both the NT1 and NT2 subgroups ( | PMC10636255 | ||
Refreshing Nature of Sleep | Patient-reported mean (SD) rating on refreshing nature of sleep was similar at baseline between ON-SXB vs placebo in the NT1 and NT2 subgroups ( | PMC10636255 | ||
ESS | At baseline, mean (SD) ESS scores were similar between ON-SXB and placebo for participants with NT1 and NT2 ( | PMC10636255 | ||
Discussion | cataplexy, narcolepsy, EDS, sleepiness, Adverse drug reactions | NARCOLEPSY, SECONDARY, CATAPLEXY, ADVERSE DRUG REACTION | This post hoc analysis of data from REST-ON assessed efficacy endpoints in NT1 and NT2 subgroups separately and provides further insight into baseline measures of EDS and DNS in each narcolepsy type. Although patients with either NT1 or NT2 experience pathologic sleepiness [A diagnosis of NT1 can be made based on findings from CSF, however, lumbar puncture is rarely performed in the United States [When immediate-release SXB was initially approved by the FDA in 2002, the indication was limited to the treatment of cataplexy in narcolepsy. In 2005, the indication was expanded to include EDS in narcolepsy. In practice, some clinicians may reserve the use of oxybates for NT1, despite the approved indication [Overall, efficacy benefits with ON-SXB vs placebo were consistent between patients with NT1 and NT2. Although not all endpoints in the NT2 subgroup reached statistical significance, the magnitude of change was clinically significant. The lack of statistical significance in some of the secondary endpoints (ie, refreshing nature of sleep and ESS score) was likely a result of the small sample size of the NT2 subgroup and insufficient power; enrollment of participants with NT2 was limited by the oversampling of the NT1 group in REST-ON [ON-SXB was well tolerated in REST-ON. Adverse drug reactions during treatment with ON-SXB were consistent with the known safety profile of twice-nightly SXB and were generally mild or moderate [ | PMC10636255 |
Conclusions | The single bedtime dose of ON-SXB demonstrated clinically meaningful improvements in measures of EDS and DNS as well as overall condition compared to placebo in both the NT1 and NT2 subgroups across all doses evaluated (6, 7.5, and 9 g) in this post hoc analysis. In contrast to the twice-nightly oxybate formulations, ON-SXB does not disrupt or fragment sleep, and is less burdensome for patients as they can avoid the middle-of-the-night dose, which is particularly relevant given the potential chronic need for pharmacotherapy. | PMC10636255 | ||
Acknowledgments | David Seiden, MD, participated in conduct of the study and publication planning during his employment at Avadel Pharmaceuticals (Chesterfield, MO). Medical writing support was provided by Sejal Gunness, PhD, of The Curry Rockefeller Group, LLC (Tarrytown, NY), and was funded by Avadel Pharmaceuticals (Chesterfield, MO).
| PMC10636255 | ||
Funding | This study was funded by Avadel Pharmaceuticals (Chesterfield, MO). Avadel was involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. | PMC10636255 | ||
Financial Disclosure Statement | PMC10636255 | |||
Nonfinancial Disclosure Statement | PMC10636255 | |||
Authors’ Contributions | PMC10636255 | |||
Data Availability | The data underlying this article will be shared upon reasonable request to the corresponding author. | PMC10636255 | ||
References | PMC10636255 | |||
Aim | melanoma, cancer testis antigen NY-ESO-1 | MELANOMA | We have previously reported that polyfunctional T cell responses can be induced to the cancer testis antigen NY-ESO-1 in melanoma patients injected with mature autologous monocyte-derived dendritic cells (DCs) loaded with long NY-ESO-1-derived peptides together with | PMC10264280 |
Objective | To assess whether inclusion of | PMC10264280 | ||
Design, setting and participants | Cancer | BLOOD, MALIGNANT CUTANEOUS MELANOMA, CANCER | Single-centre blinded randomised controlled trial in patients ≥ 18 years old with histologically confirmed, fully resected stage II–IV malignant cutaneous melanoma, conducted between July 2015 and June 2018 at the Wellington Blood and Cancer Centre of the Capital and Coast District Health Board. | PMC10264280 |
Results | DISEASE | Thirty-eight patients gave written informed consent; 5 were excluded before randomisation due to progressive disease or incomplete leukapheresis, 17 were assigned to DCV, and 16 to DCV + | PMC10264280 | |
Conclusions | A high population coverage of NY-ESO-1-specific T cell responses was achieved with a good safety profile, but we failed to demonstrate that loading with | PMC10264280 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00262-023-03400-y. | PMC10264280 | ||
Keywords | Open Access funding enabled and organized by CAUL and its Member Institutions | PMC10264280 | ||
Introduction | death, melanoma | DISEASE, MELANOMA | Surgical treatment is effective for early-stage melanoma, but patients with resected advanced disease have a high risk of relapse. Recent clinical evaluation of immune checkpoint blockade in this adjuvant setting has shown a significant reduction of the relative risk of death [We recently tested the feasibility and safety of dendritic cell (DC)-based vaccines in high-risk melanoma patients, where the cells were loaded with long NY-ESO-1 peptides designed to give good population coverage on the diverse HLA polymorphism of the human population [ | PMC10264280 |
Materials and methods | PMC10264280 | |||
Trial design | This was a two-stage study (Fig. Consort flow diagram. Numbers of patients allocated through pre-screening, consent, leukapheresis and Stage I and II of the study. In Stage I, patients were randomised to receive two cycles of DCV (Arm 1) or two cycles of DCV + | PMC10264280 | ||
Patient population | AJCC) Stage II, malignancy, malignant cutaneous melanoma, organ dysfunction, infection, skin cancer, Hepatitis B, Cancer | ADVERSE EVENT, OCULAR MELANOMA, BLOOD, ADVERSE EVENT, MALIGNANT CUTANEOUS MELANOMA, RECRUITMENT, INFECTION, SKIN CANCER, ONCOLOGY, HEPATITIS B, CANCER OF THE CERVIX, CANCER | Patients with histologically confirmed, fully resected American Joint Committee on Cancer (AJCC) Stage II, III or IV malignant cutaneous melanoma who were: ≥ 18 years old; no more than 12 months post-surgery; at least two weeks since most recent surgery; Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; and had normal full blood counts and renal and liver function biochemistry. Patients were excluded if they had: mucosal or ocular melanoma; received prior chemotherapy or radiotherapy within 6 weeks of recruitment; received prior immunotherapy, been diagnosed with another malignancy in the past 3 years (except non-melanoma skin cancer or in situ cancer of the cervix); active infection with Hepatitis B, C or Human immunodeficiency virus (HIV); uncontrolled or unstable autoimmune disease; previous use of long-term immunosuppressive therapy before leukapheresis; co-morbid conditions that would require long-term use (> 1 month) of systemic corticosteroids during study treatment; concurrent major organ dysfunction or other unstable medical condition; or were pregnant or breastfeeding. Patients were recruited by the Wellington Blood and Cancer Centre (WBCC) or Auckland City Hospital.Eligible patients who gave written informed consent underwent leukapheresis to provide peripheral blood mononuclear cells (PBMCs) from which monocyte-derived DCs were generated, with a maximum of 12 weeks to prepare the vaccine and start study treatment. Both DCV and DCV + All clinical procedures and assessments were carried out at WBCC, except for day 1 and day 15 blood draws for Auckland-based patients. Clinical assessments were undertaken at screening and with each vaccine visit until the end of study (28 days after the last vaccination). Adverse events were recorded from the date of consent until end of the study treatment and coded according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). For analysis of T cells and NKT cells, blood was collected 1–6 days before treatment was initiated, immediately before each vaccination, 24 h after vaccination, and 2 and 4 weeks after vaccination. Blood was collected for analysis of serum cytokines 2 days before treatment was initiated, immediately before each vaccination, and 6 h and 24 h after vaccination. Blood samples were enriched for PBMCs within 6 h of collection and immediately cryopreserved for later analysis. Methodology for vaccine manufacture and immune analysis are provided in Supplementary Materials and Methods. | PMC10264280 |
Treatment | Each cycle of vaccination consisted of a single intravenous dose of 10 × 10 | PMC10264280 | ||
Outcome measures | SECONDARY | The primary outcome measure was the area under the curve (AUC) of the total count of NY-ESO-1The protocol-specified secondary efficacy outcome measures were: (i) NY-ESO-1-specific T cell response over the first two cycles (Yes/No) as measured by ICS of PBMCs following in vitro restimulation on peptide for 10 days, (ii) CD4 | PMC10264280 | |
Statistical analysis | PMC10264280 | |||
Primary analysis | The primary analysis compared the AUC across the first two cycles of the log | PMC10264280 | ||
Secondary analyses | SECONDARY | For secondary analyses comparing T cell responses measured by ICS, the outcome for each patient was classified as to whether IFN-γ-producing T cells were detected over the first two cycles. Responses were determined using the distribution free sampling approach developed by Moodie et al. [For the Stage II analyses of objective (iii), the outcomes over cycles 3 and 4 in the Stage I DCV + | PMC10264280 | |
Sample size justification | Our murine studies suggested a four- to fivefold increase in T cell response using vaccines with the addition of | PMC10264280 | ||
Interim analyses | Formal interim analyses were carried out at two time points, the first when 6 patients had completed two cycles to determine final dose (a threefold increase on safe dose established in our earlier dose escalation study), and the second when 20 patients had completed 2 cycles to consider safety and futility. | PMC10264280 | ||
Results | PMC10264280 | |||
Stage I | PMC10264280 | |||
Patient characteristics and treatment | A summary of the allocation of all enrolled patients is shown in Fig. Baseline demographics and medical history by treatment group (Stage I)All patients started treatment within two days of the randomisation, and all except one received the planned dose of 10 × 10 | PMC10264280 | ||
Primary outcome measure: NY-ESO-1 peptide-specific T cell response | To assess the impact of including Analysis of NY-ESO-1-specific T cell responses by ex vivo IFN-γ ELISpot at Stage I. Heatmaps in Fig. | PMC10264280 | ||
Secondary efficacy measures | PMC10264280 | |||
NKT cell response | To evaluate the cellular response to α-GalCer, NKT cell counts were measured in PBMCs by flow cytometry using fluorescent α-GalCer-loaded human CD1d tetramers. The gating strategy is provided in Supplementary Fig. 3. Data are expressed as number of NKT cells per 100 CD3Analysis of NKT cell responses at Stage I. Comparison of cytokine levels for DCV + | PMC10264280 | ||
Serum cytokine levels | To evaluate serum cytokine responses to the vaccines in the two treatment arms, levels of 11 cytokines that were specified a priori (based on association with in vivo NKT cell responses in earlier trials) were compared using multiplex immunoassays. Median cytokine levels based on fluorescence intensity are provided in Supplementary Table 3, and changes over time for each patient are presented as heatmaps in Supplementary Fig. 4. The comparisons of the AUCs of the median fluorescence intensity (after subtraction of background fluorescence) are shown in Table | PMC10264280 | ||
Safety outcomes at Stage I | syncope, back pain, pain, infection, vasovagal reaction, depressed, backpain | ADVERSE EVENTS, ADVERSE EVENT, EVENT, INFECTION, OSTEOMYELITIS, VASOVAGAL REACTION, EVENTS, SEQUELAE | During leukapheresis procedures to harvest cells for DC generation, which were conducted before randomisation, there were six grade 3 adverse events (AE) reported: infection (1 event); backpain (1); syncope (2); depressed level of consciousness (1) and vasovagal reaction (1). One of the patients, who experienced three of these events, did not complete leukapheresis and withdrew before randomisation. The patient had osteomyelitis, back pain (managed with pain medication) and depressed level of consciousness. Once the SAE sequelae had resolved, the patient re-entered screening and ultimately completed all cycles of treatment without any further AEs. Adverse events experienced in Stage I of the treatment schedule are presented in Supplementary Table 4. No patients experienced a grade 3 or higher AE over the first two cycles of vaccination after randomisation in Stage I of the study. | PMC10264280 |
Stage II | PMC10264280 | |||
Capacity of repeated DCV + | To assess whether DCV + Capacity of repeated DCV + | PMC10264280 | ||
Capacity of DCV + | To assess whether vaccines with Capacity of DCV + | PMC10264280 | ||
Safety outcomes at Stage II | ADVERSE EVENT, ADVERSE EVENT | Adverse events experienced in Stage II of the treatment schedule are presented in Supplementary Table 6. No patients experienced a grade 3 or higher adverse event over the 3rd and 4th cycles of vaccination. | PMC10264280 | |
Clinical course and subsequent therapy | A swimmer plot in Fig. Patient treatment, clinical course and survival. | PMC10264280 | ||
Discussion | NKT cell dysfunction, cancer, death, melanoma | RECURRENCE, MELANOMA, PROLIFERATION, CANCER, STAGE III MELANOMA | In this randomised study, fully resected high-risk melanoma patients were assigned to receive autologous DC-based vaccines loaded with long peptides from NY-ESO-1 alone, or the peptides loaded together with the NKT cell agonist The vaccine-induced T cell responses observed could be detected in PBMCs evaluated directly ex vivo by IFN-γ ELISpot, using the long NY-ESO-1-derived peptides as recall agents. There are only a few other reports where NY-ESO-1-specific T cell responses have been detected so readily without requiring several days of in vitro restimulation with antigen [The lack of significant effect of including A likely explanation for the lack of T cell enhancement with It is possible that NKT cell function was impaired in the patient cohort. There have been previous reports of NKT cell dysfunction in cancer patients [It should be noted that the modest levels of NKT cell proliferation observed in this trial are in contrast to a comparable study conducted by Chang et al., with Given that effective NKT cell helper function in animals is typically associated with extensive NKT cell proliferation, the weak proliferation observed in vivo here was perhaps insufficient to meet the threshold required for adjuvant activity. The dose of The NY-ESO-1 antigen used in this study has been targeted by vaccines in several previous clinical studies. In a retrospective analysis of early phase clinical trials of adjuvant NY-ESO-1-based vaccine immunotherapy (using DCs, peptide in adjuvant, or peptides with toll-like receptor agonists), Lattanzi et al. compared 67 vaccinated patients with resected stage III melanoma to 123 historical control patients who received no adjuvant therapy and found that the vaccine was associated with decreased risk of recurrence and death [Overall, this study failed to demonstrate a significant advantage to loading peptide-pulsed MoDCs with | PMC10264280 |
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (PDF 3362 KB) | PMC10264280 | ||
Acknowledgements | The authors wish to thank the patients involved for contributing to the study and also the Hugh Green Cytometry Core for flow cytometry support. | PMC10264280 | ||
Author contributions | JJ | RECRUITMENT | ND and OG developed the cellular methodology and performed the immunogenicity analyses. KS prepared the statistical plan and performed the statistical analysis with YH. CB chaired the trial management committee, oversaw patient recruitment and treated patients. EB and BM developed the methodology and manufactured the cellular vaccine to GMP standards. GMW, PRD and MAB developed the synthetic methodology and manufactured GMP grade peptides. GC, JJ, STSC and GFP developed the synthetic methodology and manufactured GMP grade α-GalCer, and conducted analytical and stability studies on the peptides and α-GalCer. CEW, TO, JL, AM, MD and RW provided local clinical support. CB, KS, VAH, JM, MMcC, CEW, MD, and MPF undertook clinical project development and management, analysis and reporting. ND, OG, KS, YH, BM, AA-H, OKB and IFH analysed the immunological data. ND, OG, KS, CB and IFH wrote the manuscript, with input from the other authors. CB, KS, MPF, GFP, RK, PRD and IFH conceived and designed the study. | PMC10264280 |
Funding | Open Access funding enabled and organized by CAUL and its Member Institutions. This work was funded by Health Research Council Programme Grant 10/667 and the Health Research Council of New Zealand IROF fund 14/1003. | PMC10264280 | ||
Declarations | PMC10264280 | |||
Conflict of interest | The Ferrier Research Institute and GlycoSyn are commercial suppliers of clinical grade alpha-galactosylceramide. | PMC10264280 | ||
References | PMC10264280 | |||
Introduction | PAD, peripheral artery disease | PAD, EVENTS, PERIPHERAL ARTERY DISEASE | Globally, more than 200 million people suffer from peripheral artery disease (PAD), and its prevalence is rising with the increasing aging populationThe role of medical therapy after revascularization is especially essential for symptomatic PAD patients who have undergone revascularization either by endovascular intervention or open surgery. According to a recent analysis of administrative data from the United States, there has been a rapid increase in major adverse limb events (MALE) during the first year after PAD revascularization, with 12.9% of patients readministered for MALE at a median of 4 months post-procedureSarpogrelate is a selective 5-hydroxytryptamine (5-HT) 2A receptor antagonist that inhibits 5-HT-induced platelet aggregationTherefore, in the current SAFE (Sarpogrelate Anplone in Femoropopliteal artery intervention Efficacy) study we performed a clinical trial to assess the efficacy and safety of dual antiplatlet therapy (DAPT) with sarpogrelate and aspirin compared to clopidogrel and aspirin in PAD patients during the early periods following endovascular revascularization. | PMC9925771 |
Methods | PMC9925771 | |||
Study design | The detailed design of this trial has been published previously | PMC9925771 | ||
Study population | atherosclerotic steno-occlusive, stenosis | BLEEDING TENDENCY, LIMB ISCHEMIA, ARTERIAL DISEASE, STENOSIS | Eligible patients were adults with a significant atherosclerotic steno-occlusive lesion (≥ 50% diameter stenosis on angiography) of the FP artery. Patients were eligible for randomization after successful endovascular FP intervention (defined as < 30% residual stenosis on completion angiography) with adequate inflow and patent outflow. To achieve an adequate inflow and at least one patent below-the-knee (BTK) outflow, concomitant iliac procedures, and BTK procedures were permitted. Key exclusion criteria were known bleeding tendency, acute limb ischemia, inflammatory arterial disease, previous FP bypass or intervention on the same leg, or ongoing anticoagulation therapy. The inclusion and exclusion criteria are listed in the study protocol | PMC9925771 |
Randomization and study treatment | The study scheme is shown in Fig. Consort diagram of the SAFE trial.Randomization was conducted by an centralized, independent statistical core at the Medical Research Collaborating Center (MRCC, | PMC9925771 | ||
End points | above-knee, major amputation, death, bleeding, restenosis | ADVERSE EVENTS, BLEEDING, RESTENOSIS | The primary endpoint was the binary restenosis rate, defined as > 50% luminal reduction of the initially treated FP lesion on CTA or catheter angiography at six months post-intervention. Secondary endpoints were target lesion revascularization, major amputation (unplanned ipsilateral below-knee or above-knee amputation), major bleeding (bleeding requiring ≥ 2 units of blood transfusion, surgical intervention, or inotropic support), death from any cause, and serious adverse events during the study period | PMC9925771 |
Sample size calculation | restenosis | RESTENOSIS | The sample size calculation was based on an assumed incidence of the primary endpoint (binary restenosis) of 11% in the clopidogrel group and 6% in the sarpogrelate group, according to the previous literature | PMC9925771 |
Statistical analysis | bleeding | BLEEDING, MINOR, SECONDARY, REGRESSION, EVENTS | The main analysis of the primary endpoint was performed on the per-protocol set (PPS), consisting of all subjects that finished 6 months of follow-up and underwent a final 6-month assessment of ankle brachial index (ABI), CTA or angiography and showing > 80% of medication adherence. The non-inferiority hypothesis for the primary outcome was tested through a one-sided 97.5% confidence interval (CI) approach. The weighted difference of proportion of primary endpoint and the 95% CI around the difference between study treatments was calculated using a Wald test with continuity correction. The ZFor other secondary outcomes, the proportion of subjects meeting the definition of endpoints was summarized using descriptive statistics in both FAS and PPS. The rates of major and minor bleeding and cardiovascular events were compared using the Chi-square test or Fisher exact test as appropriate. The rates of target lesion revascularization, all-cause mortality, and major amputation were compared between groups using log-rank tests and presented as survival curves constructed using Kaplan–Meier methods. Risk factors for the primary outcome were assessed using logistic regression models. Significance tests were two-sided for all analyses unless specified otherwise. A p-value of < 0.05 was considered a statistically significant difference between the groups. Statistical analysis was performed with SAS 9.4 (SAS institute Inc., Cary, NC, USA). | PMC9925771 |
Results | PMC9925771 | |||
Study participants | A total of 272 patients were enrolled and randomly assigned to receive aspirin plus sarpogrelate (n = 134, sarpogrelate group) or aspirin plus clopidogrel (n = 137, clopidogrel group) after successful endovascular therapy (EVT) for target FP lesion (Fig. | PMC9925771 | ||
Baseline characteristics of patients | Baseline characteristics of the intention-to-treat population (i.e. the FAS) are shown in Table Baseline patient characteristics. Data were compared using Chi-square test or t-test. SD, standard deviation; Hb A1c, hemoglobin A1C; eGFR, estimated glomerular filtration rate; ABI, ankle brachial index. | PMC9925771 | ||
Characteristics of endovascular therapy | restenosis | RESTENOSIS | Table Characteristics of the target lesions and endovascular therapy. Data were compared using Chi-square test, t-test or Fisher's exact test. * percentages calculated from patients with stent insertion. † percentage calculated from patients with balloon angioplasty. BMS, bare metal stent; BTK, below-the-knee; DCB, drug-coated balloon; DES, drug-eluting stent; EVT, endovascular therapy; FP, femoropopliteal; SD, standard deviation; TASC, trans-atlantic inter-society consensus.The primary outcome of target lesion restenosis at 6 months was found in 19.1% (21/110) of the clopidogrel group and in 13% (13/100) of the sarpogrelate group (absolute risk difference 6.1%, 95% CI − 4.7 − 16.9% by Wald test with continuity correction). The non-inferiority of sarpogrelate compared to the clopidogrel was established, as the lower limit of the 95% CI was within the predefined margin of 0.05 (p-value for non-inferiority, 0.02; Fig. Noninferiority test for the primary outcome of target lesion restenosis.Prespecified subgroup analysis revealed that risk of target lesion restenosis between the two intervention arms was similar across most major subgroups (Fig. Subgroup analysis for the risk of target lesion restenosis. | PMC9925771 |
Secondary outcomes | bleeding, death, ischemic stroke, petechiae, septic shock, epistaxis, embolism, heart failure | CEREBRAL HEMORRHAGE, BLEEDING, MYOCARDIAL INFARCTION, BOWEL PERFORATION, TRANSIENT ISCHEMIC ATTACK, THROMBOTIC OCCLUSION, ISCHEMIC STROKE, EMBOLISM, PETECHIAE, SECONDARY, ADVERSE EVENT, ACUTE CORONARY SYNDROME, SEPTIC SHOCK, EPISTAXIS, EVENTS, HEART FAILURE | The occurrence of secondary outcome events of target lesion revascularization, major amputation, serious adverse event, major bleeding, mortality were overall rare, with no difference between the two groups (Table Primary and secondary outcome events. Data were compared using Chi-square test or Fisher's exact test. *1 cerebral hemorrhage, 1 hemoglobin drop needing transfusion in the clopidogrel group. †2 epistaxis, 1 upperarm petechiae in the clopidogrel group, 1 vitreous hemorrahge in the sarpogrelate group. ‡Causes of death were septic shock (n = 1), heart failure (n = 1), unknown (n = 1) in clopidogrel group, and myocardial infarction (n = 1), bowel perforation (n = 1) in the sarpogrelate group. § Any serious adverse event defined as all-cause death, ischemic stroke, transient ischemic attack, systemic embolism, acute coronary syndrome, early thrombotic occlusion, major bleeding, and major amputation.Kaplan–Meier analysis of the ( | PMC9925771 |
Factors associated with target lesion restenosis | restenosis | RESTENOSIS | The treatment group was not associated with target lesion restenosis (Table | PMC9925771 |
Discussion | thrombosis, PAD, CAD, thrombus, restenosis | THROMBOSIS, PROLIFERATION, DISEASE, PAD, THROMBUS, EVENTS, RESTENOSIS, CAD | The current trial involving patients who had undergone successful FP EVT showed that the sarpogrelate plus aspirin (sarpogrelate group) is non-inferior to the clopidogrel plus aspirin (clopidogrel group) in terms of 6-month target lesion restenosis. The limb-related events and cardiovascular events of the two groups were also comparable.After EVT for PAD, antiplatelet agents are used for three purposes, including prevention of early thrombosis, maintenance of long-term patency, and prevention of cardiovascular events. While aspirin- or clopidogrel-based monotherapy or DAPT is commonly used for these purposesThe best antithrombotic treatment for FP intervention remains a matter of debate. The ACC/AHASarpogrelate is an attractive drug choice for PAD considering its inhibitory effects on antiplatelet aggregation and vasoconstriction that prevent early thrombus and anti-vascular smooth muscle proliferation properties that prevent intimal hyperplasiaTo the best of our knowledge, this study was the first to show the efficacy of SR sarpogrelate after PAD EVT. We enrolled 272 patients at 10 tertiary centers in Korea, which represents the current trend of EVT for FP disease in Korea. Further comparison with data from the Western population would highlight racial or ethnic differences in EVT for PAD. The sarpogrelate group showed a tendency of less restenosis at 6 months than the clopidogrel group (13% vs 19%) without statistically significant difference. Secondary endpoints of safety outcomes were very rare in both groups, showing that both DAPT regimens are safe after FP EVT.Interestingly, in subgroup analysis, clopidogrel and aspirin showed better efficacy for reducing restenosis in CAD patients than sarpogrelate and aspirin together. A larger-scale study is needed to prove this concept. Multivariate analysis revealed TASC C/D lesions (vs A/B lesions) and only balloon angioplasty (vs stenting) were significant risk factors for restenosis at 6 months.Another noteworthy point is that a sarpogrelate SR formulation requiring once-daily dosing rather than thrice-daily was used in our study. Multiple dosing is a well-known risk factor for medication nonadherence, especially in chronic diseasesThis study has limitations. First, although a reasonable number of participants proved the non-inferiority of SR sarpogrelate to clopidogrel, this study was performed on a limited population in Korea. For generalization, multinational studies in a large population are needed. Second, the primary endpoint was restenosis at 6 months, and thus, only short-term follow-up data were available for this study. Post hoc data collection and 2-year analysis is anticipated and may reveal additional information. Third, the method of EVT was chosen at the discretion of the physician, and the study was not powered to compare the effectiveness of sarpogrelate and clopidogrel within each type of EVT (i.e. drug-coated balloons, drug-eluting stents, bare-metal stents, and plain balloon angioplasty). As in coronary beds, different medication regimens may prove more beneficial after different types of EVT. Fourth, although we had planned for a 10% dropout rate, only 78% of the randomized patients completed the six months intervention. This may have contributed to the insignificant results of the sensitivity analysis in the FAS analysis. In addition, a higher dropout rate in the per-protocol analysis could have resulted in a larger type I error than we expected, diluting the actual difference between the two intervention groups. Thus, larger-scale trials are warranted to confirm our results. Lastly, the noninferiority margin of our study was based on an expert panel discussion on the clinically meaningful difference in restenosis rate in FP lesions. While the selection of noninferiority margin needs to consider the standard treatment's effect estimate by pooling the relevant placebo-controlled randomized trial results, this was not possible as there was only one trial with inadequate sample sizeIn conclusion, results from the current trial suggest that sarpogrelate plus aspirin is non-inferior in preventing early restenosis after FP EVT compared to clopidogrel plus aspirin. Additional clinical trials in larger multinational, multiethnicity trial populations are warranted to generalize these findings. | PMC9925771 |
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-29006-z. | PMC9925771 | ||
Acknowledgements | This is an investigator-initiated study supported by a grant from Daewoong Pharmaceutical Co., Ltd., South Korea. The funder provided SR sarpogrelate (Anplone®) for this study but had no role in study design, data collection, analysis, interpretation, or writing of the report. We thank doctors Mi-Sook Kim and So-Hyun Choi for their independent statistical analyses and all the patients and staff who participated in this trial. The current addresses of the two authors were changed to Kyungpook National University School of Medicine (W.S.Y.) and Asan Medical Center (J.G.G.). | PMC9925771 | ||
Author contributions | Authors S.K.M., A.H., T.S., Y.J.P., H.K. and J.L. conceived and designed the study, participated in the conduction of the trial and interpretation of data as well as drafting the manuscript. Authors S.W.S., S.S.L., I.M.J., J.M.K., J.G.G., W.S.Y., and Y.P.C. contributed in the study design, conduction of the trial, data collection and critical review of the manuscript. All authors read and approved the final manuscript. | PMC9925771 | ||
Data availability | Individual data for the paper are available from the corresponding author on reasonable request. | PMC9925771 | ||
Competing interests | The authors declare no competing interests. | PMC9925771 | ||
References | PMC9925771 | |||
Objective | T2DM | ALBERT, TYPE 2 DIABETES MELLITUS | Edited by: Gaetano Santulli, Albert Einstein College of Medicine, United StatesReviewed by: Dilip Sharma, Rutgers, The State University of New Jersey, United States; Sudhanshu Kumar Bharti, Patna University, India; Seok-Yeong Yu, University of Nebraska Medical Center, United States†These authors have contributed equally to this workWe aimed to investigate the effect of Cyclocarya paliurus leaves extracts (CP) on glucose and blood lipid metabolism and its relationship with intestinal flora in type 2 diabetes mellitus (T2DM) patients. | PMC10246770 |
Methods | T2DM-associated, T2DM | In this open-label, 84-day randomized controlled trial, a total of 38 T2DM patients were randomly assigned to the CP group or the Glipizide group (G group) in a 2:1 ratio. T2DM-associated metabolic phenotypes, gut microbiota and metabolites including short-chain fatty acids (SCFAs) and bile acids (BAs) were detected. | PMC10246770 | |
Results | TG, post-meal blood glucose | At the end of intervention, CP, like Glipizide, significantly improved HbA1c level and other glucose metabolism parameters (fasting plasma glucose (FBG), 2-hour post-meal blood glucose (2hPBG), the area under curve of oral glucose tolerance test glucose (OGTT glucose AUC)). Moreover, CP also resulted in the significant improvement in the levels of blood lipid and blood pressure. Notably, the improvement in blood lipid(triglycerides (TG) and high-density lipoprotein cholesterol (HDL-c)) and blood pressure (diastolic blood pressure (DBP)) was significantly greater in the CP group compared with the G group. Furthermore, the liver and kidney function parameters did not significantly change in both CP group and the G group over the 84-day period. Additionally, the enrichment of potentially beneficial bacteria (Faecalibacterium and Akkermansia), SCFAs and unconjugated BAs and the depletion of potential pathogenic bacteria (Prevotella_9) and conjugated BAs were observed in the CP group, while the abundances of the gut microbial were kept stable in the G group after intervention. | PMC10246770 | |
Conclusion | T2DM-associated metabolic, T2DM | CP displays a more beneficial effect in the alleviation of T2DM-associated metabolic phenotypes than glipizide by regulating gut microbiota and metabolites in T2DM patients, with no significant effects on liver and kidney function. | PMC10246770 | |
Introduction | T2DM, dysbiosis | TYPE 2 DIABETES MELLITUS | Type 2 diabetes mellitus (T2DM), whose prevalence has been estimated to raise from 536.6 million people in 2021 to 783.2 million by 2045 (Cyclocarya paliurus (C. paliurus) (Batal) IIjinskajia, an endemic plant belonging to Cyclocarya genus of the Juglandaceae family, is also known as the money tree, and it is distributed in 420–2500 m mountainous regions of Jiangxi, Hubei, Hunan, Guizhou and other provinces in China (Gut microbiota plays an important role in T2DM. Moderate dysbiosis with a decrease in butyric-producing bacteria and an increase in opportunistic pathogens was found in T2DM patients in China (As above mentioned, C. paliurus seems to have the potential to be a new treatment medication for T2DM. However, to our knowledge, no existing literature or research is available to address the question concerning whether C. paliurus can improve glucose and lipid metabolism in T2DM patients. Thus, we conducted a pilot clinical randomized controlled study to compare the effect of C. paliurus leaves extracts (CP) and an antidiabetic drug Glipizide on metabolic phenotypes, including the intestinal microbiota and their metabolites (SCFAs and bile acids) in T2DM patients. | PMC10246770 |
Method | PMC10246770 | |||
Study design and subjects | A randomized and open-label, controlled clinical trial was designed and conducted according to Consolidated Standards of Reporting Trials guidelines ( | PMC10246770 | ||
Sample sizes calculation | According to Movahed et al., the HbA1c difference between intervention group and control group was expected to be 1.2% at the end of the intervention ( | PMC10246770 | ||
The medication intervention | T2DM | Before starting the clinical trial, all the enrolled participants underwent a 2-week run-in period and received a diet and exercise education about the daily management of T2DM. Once the 2-week run-in period completed, participants entered the intervention study immediately. In the CP group, the participants received CP powder (2g/time, 3 times/day orally before meals) (CP were provided by Chenzhou Mingrun biological products Co. LTD, Hunan, China) ( | PMC10246770 | |
Preparation of Cyclocarya paliurus leaves extracts and phytochemical analysis | Cyclocarya paliurus leaves extracts (CP)were provided by Chenzhou Ming run biological products Co. LTD Hunan, China. The license number of this product is QS431006011417.The leaves of C. paliurus has long been used as a bitter Traditional Chinese Medicine which has also been historically used as an herbal tea in the folk. Nowadays, the products derived from the leaves of C. paliurus have become a very popular health product in China (The composition of the C. paliurus leaves extracts was determined by high performance liquid chromatography (HPLC, Agilent 1200, USA) equipped with Agilent 5 TC-C18 (4.6 mm ×250 mm, 5μm). The system parameters were set as follows: injection volume, 5μL; the column temperature, 30°C; and the mobile phase flow rate, 0.8mL/min. The mobile phase consisted of two solvents: (A) 0.2% aqueous acetic acid and (B) acetonitrile. The elution conditions were as follows: 0–5min, gradient 5% B; 5–10 min, linear gradient 5–10% B; 10–15 min, linear gradient 10–25% B; 15–25 min, linear gradient 25–40% B; 25–30min, linear gradient 40–90% B. Peaks were detected at 254 nm. The quantification of different component monomers was based on the peak areas and calculated as equivalents of the standard compounds; all contents were expressed as mg/g component dry weight. The temperature of the column oven was set at 40 °C, the flow rate was set at 0.6 mL/ min and the injection volume was 5 µL. | PMC10246770 | ||
Clinical assessment | Participants were asked not to make any change to their daily physical activity and to maintain body weight. On Day 0, Day 42, and Day 84, the 7-day recall method was used to measure physical activity energy expenditure through an interview-administered survey instrument modified from the Cross-Cultural Activity Participation Study ( | PMC10246770 |
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