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Patient characteristics | We enrolled patients with a current episode of AF lasting 7 days or less and randomized them to receive an intravenous infusion of 3 or 5 mg kg | PMC10803288 | ||
Efficacy endpoints | The primary endpoint of cardioversion within 90 min occurred in 42% (5 of 12) and 55% (12 of 22) of patients receiving AP30663 at 3 mg kg | PMC10803288 | ||
Safety endpoints | ADVERSE EVENTS, ADVERSE EVENT, EVENTS | Adverse events were reported in 50% (13 of 26) of patients for the AP30663 5 mg kgAdverse events in the safety analysis setAll data are based on investigator-reported adverse events. Data reported are the number of patients (%) and number of events (A mean decrease in heart rate was seen for all groups. This occurred earlier for the active groups compared to the placebo group, coinciding with the timing of conversions from AF to sinus rhythm (Extended Data Fig. A transient difference in change in QTcF was observed (Fig. | PMC10803288 | |
Change in QTcF from baseline in the safety analysis set. | NONSUSTAINED VENTRICULAR TACHYCARDIA | Plot showing the least squares mean and 90% CIs based on a linear mixed-effects model at the indicated time points. AP30663 3 mg kgWith Holter monitoring, the most important ventricular finding was episodes of nonsustained ventricular tachycardia seen in both the active and placebo groups with the longest episodes being four beats (Extended Data Table No apparent effect of AP30663 was observed on laboratory parameters (Extended Data Table | PMC10803288 | |
Pharmacokinetic endpoint | The plasma concentration over time is shown in Extended Data Fig. | PMC10803288 | ||
Discussion | In this phase 2 clinical trial, AP30663, a new KAmong currently existing drugs for pharmacological AF cardioversion, vernakalant and flecainide are the most efficaciousThe clinical efficacy of AP30663 aligns with the effects observed in animal models, where AP30663 showed a pronounced effect on the atrial effective refractory period in one pig model, and successfully cardioverted AF and prevented its reinduction in another pig model where vernakalant did not cardiovert any longerAP30663 inhibits the KThe safety profile of AP30663 was consistent with results from the phase 1 trial, with the exception that infusion site reactions were reported in the phase 1 trial whereas none were reported in the current trialExisting drugs with different mechanisms of action, when effective in AF cardioversion, also show efficacy in sinus rhythm maintenance (prevention of AF recurrence)This trial has some limitations. We enrolled patients with an AF episode lasting less than 7 days. Other drugs have shown decreased efficacy with longer AF durationsIn conclusion, the K | PMC10803288 | ||
Methods | PMC10803288 | |||
Trial design | arrhythmias, coronavirus disease 2019 | ARRHYTHMIAS, CORONAVIRUS DISEASE 2019 | We conducted a phase 2 randomized, double-blind, placebo-controlled, parallel-group trial with an adaptive design with the potential to test doses between 2 and 6 mg kgThe maximum number of individuals that could be enrolled based on the adaptive design was 108. Patients wore 12-lead Holter monitors to assess both efficacy and safety for at least 8 h after the infusion; the collected data were analyzed by a core laboratory for arrhythmias and semiautomated measurement of ECG intervals based on triplicate ECG extracts at prespecified time points. Patients were followed until day 30 after receiving the infusion. Please refer to the protocol in Supplementary Note In December 2022, the sponsor decided to stop the trial early because of slow enrollment, mainly due to the coronavirus disease 2019 pandemic, at a time when the sample size in the 5 mg kgThe trial protocol was approved by the following ethics committees: Den Videnskabsetiske Komité, Region Sjælland, Denmark and Egészségügyi Tudományos Tanács Klinikai Farmakológiai Etikai Bizottsága, Budapest, Hungary.All participants provided written informed consent. The trial was sponsored and funded by Acesion Pharma.ClinicalTrials.gov registration: | PMC10803288 |
Trial population | heart failure, ischemic heart disease | TORSADE DE POINTES, HEART FAILURE, ISCHEMIC HEART DISEASE, HEART | Male and female patients aged 18–80 years with a body weight of 50–110 kg and a current episode of symptomatic AF lasting between 3 h and 7 days were deemed eligible. Patients were required to be treated with anticoagulation according to current guidelines. Patients were allowed to have stable ischemic heart disease and heart failure (New York Heart Association classes I and II, left ventricular ejection fraction 40% or higher). Exclusion criteria included recent cardioversion, current or recent use of antiarrhythmic drug classes I or III (including amiodarone), QTcF greater than 450 ms or previous torsade de pointes episodes. The complete list of inclusion and exclusion criteria can be found in the next sections. | PMC10803288 |
Inclusion criteria | The inclusion criteria were: provision of written informed consent; clinical indication for cardioversion of AF; current episode of symptomatic AF lasting between 3 h and 7 days inclusive at randomization; adequate anticoagulation according to international or national guidelines; body weight 50–110 kg inclusive (with clothes, without shoes); and male patients and postmenopausal women aged 18–80 years inclusive. | PMC10803288 | ||
Exclusion criteria | renal dysfunction | The exclusion criteria were: significant clinical illness or surgical procedure within 4 weeks before the screening visit; present renal dysfunction (estimated glomerular filtration rate less than 30 ml minThe trial was conducted at ten sites in Hungary and Denmark. | PMC10803288 | |
Trial intervention | The trial ended up testing 3 mg kgIf patients did not cardiovert within the 90 min after the start of the infusion, they were to undergo an electrical (direct current) cardioversion. | PMC10803288 | ||
Trial endpoints | ADVERSE EVENTS, SECONDARY, RECURRENCE | The primary endpoint was the proportion of patients converting from AF to sinus rhythm within 90 min from the start of the infusion and who subsequently had no AF recurrence within 1 min of conversion. Key secondary efficacy endpoints included time to conversion from AF, the proportion of patients with relapse of AF within 5 min after pharmacological (AP30663) or direct current cardioversion and the proportion of patients in sinus rhythm at 3 and 24 h after the start of the infusion. Key secondary safety endpoints included adverse events and change in QT interval corrected using the Fridericia formula (QTcF). Pharmacokinetics were also assessed as a secondary endpoint.Exploratory endpoints addressing the potential for treatment effect interactions with baseline variables and pharmacokinetic parameters were specified in the protocol; however, due to the limited sample size, these analyses were severely underpowered and are not reported in this article. | PMC10803288 | |
Statistical analyses | To ensure an efficient adaptive trial design, Bayesian statistics were used. In part 1 of the trial, a dose of 3 mg kgECG parameters were analyzed based on a linear mixed-effects model; a least squares mean with 90% CIs was reported for these.The safety analysis set was prespecified to be used for all safety analyses and consisted of all randomized participants who were administered double-blind trial treatment. The full analysis set was prespecified to be the primary one for all efficacy analyses and consisted of all randomized participants who were administered double-blind trial treatment and had an evaluable AF conversion status within 90 min from the start of the infusion.The sample size was selected based on a similar previous trialData analyses were done by the contract research organization Syneos Health and by the sponsor. All authors had access to the data. SAS v.9.4 or higher and R v.3.5.2 or higher were used for the analyses. Data were collected through the electronic data capture system Medidata Classic Rave (2019–2023). | PMC10803288 | ||
Reporting summary | Further information on research design is available in the | PMC10803288 | ||
Online content | Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02679-9. | PMC10803288 | ||
Supplementary information |
Supplementary Notes 1–3. Supplementary Note Reporting Summary | PMC10803288 | ||
Extended data | PMC10803288 | |||
AP30663 chemical structure. | AP30663 chemical name: (3
| PMC10803288 | ||
Changes in heart rate in the safety analysis set. | The plots show least squares mean and 90% CI based on a linear mixed-effects model. AP30663 3 mg/kg n = 15 patients, AP30663 5 mg/kg n = 22 patients, Placebo n = 26 patients.
| PMC10803288 | ||
Extended data | is available for this paper at 10.1038/s41591-023-02679-9. | PMC10803288 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02679-9. | PMC10803288 | ||
Acknowledgements | We thank the patients who participated in the trial and the site investigators and staff. Grant funding for the present study was received from Wellcome Trust (Translational Award, 200450/Z/16/Z) and Innovation Fund Denmark (8064-00074B). | PMC10803288 | ||
Author contributions | N.E., M.G., U.S.S., J.G.D. and B.H.B. designed the trial. B.V. and A.G.H. amended the trial design based on input from J.T., among others. P.D., S.H.H. and D.L.B. served on the data monitoring committee. A.G.H. and B.V. monitored the trial for the sponsor while in the conduct phase. A.G.H. performed the supplementary statistical analyses. A.G.H. wrote the first draft of the paper and all authors revised it. All authors vouch for the accuracy and completeness of the reported data. | PMC10803288 | ||
Peer review | PMC10803288 | |||
Data availability | Data originating from the trial are considered commercially sensitive; as such, they are not publicly available. To the extent that current legislation allows it, the authors will provide access to individual deidentified participant-level data that underlie the data presented in this article to researchers who provide a methodologically sound proposal for academic purposes to interpret, verify and extend research in the article that does not violate intellectual property or confidentiality obligations, beginning 12 months after article publication. Researchers should contact the corresponding author when applying for data access. Use of data will be restricted to the agreed purpose. | PMC10803288 | ||
Competing interests | Nordisk, MyoKardia | HEART, HEART DISEASE, EDWARDS | A.G.H., B.V., U.S.S., J.G.D., M.G. and B.H.B. are employees of Acesion Pharma and hold shares or warrants in the company. N.E. is a consultant to Acesion Pharma. P.D. received consulting fees and honoraria from Acesion Pharma. D.L.B. has served on the Advisory Boards of Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences and Stasys. He has served on the Board of Directors of Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), the Society of Cardiovascular Patient Care and TobeSoft. He has been the Inaugural Chair of the American Heart Association Quality Oversight Committee. He has been a consultant for Broadview Ventures and Hims. He has served on the Data Monitoring Committees of Acesion Pharma, Assistance Publique-Hôpitaux de Paris, the Baim Institute for Clinical Research (formerly the Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), the Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), the Duke Clinical Research Institute, the Mayo Clinic, the Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo, and for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute and Rutgers University (for the National Institutes of Health-funded MINT trial). He has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi and Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly the Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committee), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary and Treasurer), WebMD (CME steering committee), Wiley (steering committee), Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair) and VA CART Research and Publications Committee (Chair). He is named on a patent for sotagliflozin (assigned to the Brigham and Women’s Hospital who assigned it to Lexicon; neither P.D. nor the Brigham and Women’s Hospital receive any income from this patent). He has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, the Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene and 89Bio. He has received royalties from Elsevier (Editor, Braunwald’s Heart Disease). He has been a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte and Vascular Solutions. He is a trustee of the American College of Cardiology. He has carried out unfunded research for FlowCo. S.H.H. and J.T. declare no competing interests. | PMC10803288 |
References | PMC10803288 | |||
Background | PATHOLOGY | This study focused on the impact of therapeutic alliance on therapy dropout in a naturalistic sample of patients with borderline pathology receiving dialectical behavior therapy (DBT) in a residential setting. We assumed that low therapeutic alliance shortly after admission would be associated with elevated dropout. | PMC10439653 | |
Methods | DSM-5 borderline personality disorder | REGRESSION, PATHOLOGY | 44 participants with borderline pathology (≥ 3 DSM-5 borderline personality disorder criteria) in a residential DBT program completed a quality assurance questionnaire set assessing demographic information, pretreatment psychopathology and therapeutic alliance during the first seven days of their residential stay. Predictors of dropout were investigated using binary logistic regression analyses. | PMC10439653 |
Results | The dropout rate was 34.1% ( | PMC10439653 | ||
Conclusions | PATHOLOGY | This study supports the importance of therapy process variables, here the therapeutic alliance at the beginning of treatment, as predictors of therapy dropout in borderline pathology. If this finding is replicated, it shows the potential importance of monitoring the therapeutic relationship throughout the therapeutic process. ClinicalTrials.gov Identifier: NCT05289583, retrospectively registered on March 11, 2022. | PMC10439653 | |
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10439653 | ||
Methods | PMC10439653 | |||
Recruitment | BPD | DISORDER | We approached all patients from age 18 to 65 that were discharged from our residential personality disorder unit between January 2019 and December 2021, and who fulfilled three or more criteria for BPD (Borderline Personality characteristics; BPC) as defined by DSM-5 ( | PMC10439653 |
Procedure | Within the first week of their residential stay, all participants who met the inclusion criteria were informed about the objectives and conditions of the study. They gave their written informed consent to participate in the study and to publish the results. The ethical standards were in line with the Declaration of Helsinki. Subsequently, each participant completed a set of questionnaires. Dropout status was documented at discharge (see definition of dropout). | PMC10439653 | ||
Measures | PMC10439653 | |||
Clinical measures | Depression, Trauma, depressive symptoms | Borderline symptom severity was assessed using the Borderline Symptom List [BSL; The Beck Depression Inventory – Second Edition (BDI-II) was used to assess current depressive symptoms [The Childhood Trauma Questionnaire [CTQ; The Posttraumatic Diagnostic Scale [PDS; To assess the severity of general psychopathology, we administered the Symptom Checklist in the 90-items revised version [SCL-90-R; Dissociation was assessed using the Dissociative Experiences Scale [DES; The World Health Organization Quality of Life Questionnaire in its brief version [WHOQOL-BREF; | PMC10439653 | |
Working alliance | The patient-rated therapeutic alliance was assessed via the short (12-item) version of the Working Alliance Inventory [WAI-SR; 24]. It consists of three subscales with four items each rated using a 5-point response scale: (1) agreement on the tasks of treatment, (2) agreement on the goals of treatment and (3) development of an affective bond. The WAI-SR is widely used and has been proven to show good psychometric properties in international as well as German inpatient and outpatient samples [ | PMC10439653 | ||
Treatment | personality disorder | The residential treatment in our personality disorder unit is certified by the German DBT Board of Certification (DDBT). As common in DBT settings, patients were seen in outpatient counseling sessions before starting DBT (DBT briefing). The briefing, which lasts one hour, includes examination of the patient, assessment of treatment history, indication for treatment, and assessment of both inclusion and exclusion criteria for treatment. As often as possible, the therapist who provided the briefing also provided the treatment, usually two to three months later. However, due to organizational reasons, this was not always possible; in these cases, another therapist took over after the DBT briefing (documented as a change of therapist). A change of therapist did not occur due to clinical considerations in any case. There were no further contacts after DBT briefing and DBT treatment. Patients were admitted to our ward approximately three months after the DBT briefing and were treated with DBT integrated in a standard residential setting for a total of eight to ten weeks. There was no change of therapist during treatment for any reason (organizational or clinical). Within the sixth week, the discharge date was determined depending on the patient’s progress, goals, and needs. | PMC10439653 | |
Dialectical behavior therapy | BPD | DBT is a cognitive-behavioral treatment program that was developed to treat suicidal patients with BPD [ | PMC10439653 | |
Therapeutic alliance in DBT | The therapeutic alliance in DBT is enforced by three dialectical principles. The patient-therapist relationship is seen as a “real” relationship, patient and therapist are equally affected by behavioral principles. Beyond that, DBT comprehends this relationship as a dynamic interaction that needs conflicts and conflict resolution as a process of change by constantly interweaving acceptance and change. The relationship in DBT is continuously both a tool to make the treatment work as well as itself having a therapeutic effect [ | PMC10439653 | ||
Standard inpatient care | Standard Inpatient Care (SIC) included all non-specific therapeutic elements. Over an eight- to ten-week period, participants received 30-minute supportive conversations with the primary nurse twice a week, art or music therapy twice a week, and weekly body therapy. In addition, all patients received morning rounds, movement therapy and learned relaxation techniques. Patients also received standard psychopharmacological treatment, which was documented. | PMC10439653 | ||
Definition of dropout | dysfunctional behavior, therapy-disrupting behaviors, Dysfunctional behaviors, non-suicidal self-injuries, maladaptive behavior, dysfunctional behaviors, BPD | To assess treatment discontinuation, we recorded whether the participant was discharged from our unit before week eight or before the final discharge date set at week six. The reasons for discontinuation were documented (by the patient or by the ward). In all cases, contingency management was the reason for discharge on part of the ward. It includes positive consequences for functional behaviors to reinforce these and increase the likelihood of their occurrence, as well as negative consequences for dysfunctional behaviors to extinguish these. Although dysfunctional behavior patterns are part of the clinical picture of BPD, reducing them is necessary in order to reduce negative consequences for the patients themselves and others on the ward, and furthermore to enable the use of adaptive strategies in the first place. Dysfunctional behaviors, on the one hand, depend on the goals of the patients. On the other hand, some dysfunctional behaviors are defined according to the DBT hierarchy: suicidal behaviors, severe non-suicidal self-injuries, drug use, and therapy-disrupting behaviors (missing sessions, violating general ward rules). When dysfunctional behavior occurs repeatedly (usually four times), a patient is discharged from treatment. If maladaptive behavior occurs, intensive work is done to build up adaptive problem-solving strategies. If maladaptive strategies repeatedly occur despite intensive coaching, treatment is discontinued (assuming that the therapy in its current form or at the current time is not helpful). The more a behavior is harmful to other patients on the ward, the sooner a patient will be discharged (e.g., assaulting a fellow patient leads to immediate discharge). | PMC10439653 | |
Data analyses | The initial analyses included group comparisons with Mann-Whitney-U-tests and χ² statistics as well as exploratory correlation analyses. These statistics were obtained using SPSS 25 [ | PMC10439653 | ||
Results | PMC10439653 | |||
Discussion | BPD, PTSD, substance abuse | PATHOLOGY | The purpose of this study was to investigate whether early patient-rated therapeutic alliance is related to dropout in a residential DBT treatment. It is a follow-up to a previous study which showed that a change of therapist between DBT-briefing and -treatment increased the dropout rate of DBT [Our results support the importance of therapy process variables, and therapeutic alliance in particular, as predictors of therapy dropout in borderline pathology. Patients who demonstrated a stronger therapeutic relationship at baseline had a lower risk of dropout over the course of treatment. This finding extends the existing literature finding that a poor therapeutic alliance predicts dropout in DBT [In order to [DBT claims to have a specific influence on the therapeutic alliance, that is, to particularly enhance the state-like alliance. In a study by Bedics et al. [Furthermore, regular monitoring of the therapeutic alliance may be useful to improve treatment. In a multilevel meta-analysis, feedback on patients’ progress (including the therapeutic alliance in some of the studies reviewed) to the therapists has been found to improve treatment and decrease dropout rates [Different from what we expected, the strength of the therapeutic relationship was not significantly related to a change of therapist in our study. This result could mean that the change of therapist puts less strain on the therapeutic relationship than primarily assumed. However, the proportion of patients for whom change of therapist was necessary due to organizational reasons on our ward was higher in the present study (75%) than in our previous study [Comparable to previous studies, dropout rate was not associated with socio-demographic variables [A strength of this study is that we captured reasons for treatment discontinuation. Dropout on part of the patient and on part of the therapeutic team is relatively equally distributed. This result is comparable to our previous study [The study has several limitations, some of which are associated with the naturalistic setting of the study. First, only clinical diagnoses were made; no detailed diagnostics were performed using diagnostic interviews and independent raters. Therefore, previously known predictors such as PTSD, substance abuse and the number of BPD symptoms may not have been picked up. The sample is naturally very heterogeneous. We only used self-report measures, also for capturing the therapeutic relationship. This makes missing values more likely.Moreover, the therapeutic relationship was recorded one-sidedly by the patients. However, in psychotherapy research, the patient’s (not the therapist’s) judgment of the therapeutic alliance is particularly important. Not all patients chose to participate in the study and complete the questionnaires. Patients who chose not to participate may have special characteristics that affect the generalizability of the results. Furthermore, the sample size is very small; the results require replication. In addition, an impact of the COVID pandemic on dropout rates and reasons for dropout cannot be ruled out.Future research should replicate and further examine the effects of the therapeutic relationship rated by both patients and therapists on dropout and also treatment outcome in a larger sample. In addition, the improvement of the therapeutic relationship in general or certain aspects of it (e.g., subscale of the WAI) through feedback of the patient-rated therapeutic relationship to the therapists in DBT should be examined. Beyond that, other treatment process variables, such as expectations of treatment, should be included. | PMC10439653 |
Acknowledgements | We acknowledge support for the publication costs by the Open Access Publication Fund of Bielefeld University and the Deutsche Forschungsgemeinschaft (DFG). | PMC10439653 | ||
Authors’ contributions | TB | CS recruited patients, conducted therapies, organized and supervised the assessments, performed the statistical analysis and drafted the manuscript. MB participated in the study design and supervised therapies. MD participated in the study design and manuscript preparation. TB participated in the study design and manuscript preparation. All authors read and approved the final manuscript. | PMC10439653 | |
Funding | Open Access funding enabled and organized by Projekt DEAL. | PMC10439653 | ||
Data availability | The dataset supporting the conclusions of this article is shared upon request directed to Carolin Steuwe (carolin.steuwe@evkb.de). | PMC10439653 | ||
Declarations | PMC10439653 | |||
Competing interests | The authors declare no competing interests. | PMC10439653 | ||
Ethics approval and consent to participate | 48147 | DER | All participants gave their written informed consent to study participation and ethical standards were in accordance with the declaration of Helsinki. The requirement for ethical approval was waived by the Ethics Committee Münster (Ethikkommission der Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Universität Münster, Gartenstraße 210–214, 48147 Münster) because of the retrospective nature of the study. | PMC10439653 |
Consent for publication | of clinical data and information was obtained. | PMC10439653 | ||
Abbreviations | Depression, Trauma | Beck Depression Inventory 2nd EditionBorderline Personality CharacteristicsBorderline Personality DisorderChildhood Trauma QuestionnaireDialectical Behavior TherapyDBT Board of CertificationDissociative Experiences ScaleDiagnostic and Statistical Manual of Mental DisordersGlobal Severity Index (SCL-90-R)Posttraumatic Stress Diagnostic ScalePosttraumatic Stress DisorderSymptom-Checklist 90 items, revised versionStandard Inpatient CareWorking Alliance Inventory-Short RevisedWorld Health Quality of Life Questionnaire | PMC10439653 | |
References | PMC10439653 | |||
Objective | This study aims to investigate the topical steroid regimen after small incision lenticule extraction (SMILE) for its effect on very early restoration of visual quality. | PMC10520117 | ||
Methods | A total of 180 patients (360 eyes) who underwent SMILE were enrolled. These patients were randomly assigned to three groups, with 60 patients in each group. The only difference among these three groups was the administration of 0.1% fluorometholone (FML) eye drops within two hours after SMILE: no FML in group A, 0.1% FML once every hour in group B and 0.1% FML once every half hour in group C. The corrected distance visual acuity (CDVA), objective scattering index (OSI), modulation transfer function (MTF) cut-off, Strehl ratio (SR) and incidence of subjective symptoms were evaluated preoperatively, at 2, 4 and 24 h and one week after SMILE. | PMC10520117 | ||
Results | The CDVA, MTF cut-off and SR values were significantly higher in group C, when compared to the other two groups, at 2 and 4 h after SMILE ( | PMC10520117 | ||
Conclusion | The administration of 0.1% FML eye drops every half hour within two hours after SMILE accelerates the restoration of visual and optical quality, and reduces the incidence of subjective symptoms during the very early phase after surgery. | PMC10520117 | ||
Keywords | PMC10520117 | |||
Introduction | myopia | MYOPIA | Small incision lenticule extraction (SMILE) and femtosecond laser-assisted in situ keratomileusis (FS-LASIK) are presently the two popular techniques for myopia treatment [The postoperative treatment regimens for SMILE and FS-LASIK are usually similar, which include the administration of antibiotics and steroid eye drops for four times a day after surgery [ | PMC10520117 |
Patients and methods | PMC10520117 | |||
Ethics statement | The present prospective study was approved by the Ethics Committee of Fujian Medical University (Fuzhou, China) and was conducted in compliance with the principles of the Declaration of Helsinki. A written informed consent was obtained from all patients. | PMC10520117 | ||
Participants and treatment procedures | EYE | In the present study, 180 patients (360 eyes), who underwent SMILE at the Eye Center of Fujian Medical University between July and November 2019, were randomly divided into three groups using a random number table, with 60 patients (120 eyes) in each group. The protocol for the SMILE procedure was the same as the protocol described by Liu et al. [All patients received 0.5% levofloxacin eye drops (Santen Pharmaceutical Co., Ltd., Osaka, Japan) for four times a day, which was immediately administered after the SMILE procedure, and 0.1% fluorometholone (FML) eye drops (Santen Pharmaceutical Co., Ltd., Osaka, Japan), which were administered within two hours after the SMILE procedure (except for group A), and for four times a day starting from the second day after the SMILE procedure. According to the regimen for FML administration after SMILE, the patients were divided into three groups: no FML in group A, 0.1% FML once every hour (twice in total) in group B and 0.1% FML once every half hour (four times in total) in group C. | PMC10520117 | |
Examination and measurements | blurred vision, dryness | INTRAOCULAR PRESSURE | The corrected distance visual acuity (CDVA), mean spherical equivalent (MSE) and intraocular pressure (IOP) were measured before SMILE, at 2, 4 and 24 h, one week after SMILE, and at each follow-up visit thereafter. The CDVA was examined using a standard Landolt visual acuity chart, and the values were converted to the logarithm of the minimal angle resolution (logMAR) of visual acuity for the statistical analysis. The MSE was measured using an open-field autorefractor (Grand Seiko WR-5100 K; RyuSyo Industrial Co., Ltd., Kagawa, Japan), and the IOP was measured using a non-contact tonometer (TX-20; Canon, Tokyo, Japan).The optical quality was measured with the Optical Quality Analysis System II (OQAS; Visiometrics, Terrassa, Spain) using the dual-channel technique [The incidence of subjective symptoms after SMILE was collected from all patients, which included foreign body sensation, eye soreness, eye dryness and blurred vision, at 2, 4 and 24 h and one week after SMILE. | PMC10520117 |
Statistical analysis | SPSS 18.0 (SPSS Inc., Chicago, Illinois, USA) was used for the statistical analysis. The variables used for the present study comprised the parametric data, and these were tested as normal distribution. All measurements were repeated for three times, and the mean values were used for the analysis. Two-way ANOVA was used to compare the differences in measurements between groups. A | PMC10520117 | ||
Results | PMC10520117 | |||
Study participants | The demographics of the study participants are summarized in Table Demographic information of patients at pre-operation* | PMC10520117 | ||
CDVA, MTF, SR and OSI after SMILE | In groups A, B and C, in which different 0.1% FML regimens were administered, CDVA was examined at 2, 4 and 24 h and one week after SMILE. The number of eyes in each group, with a CDVA higher than 1.0 (logMAR, 0.00), is presented in Fig. The number of eyes in each group that had a visual acuity of higher than 1.0 (logMAR, 0.00) at 2, 4 and 24 h after small incision lenticule extraction (SMILE), *Measurements at postoperative two hours*Measurements at postoperative four hours*Measurements at postoperative 24 h*Measurements at postoperative one week*The MTF cut-off, SR and OSI at 2, 4 and 24 h and one week after SMILE are presented in Tables The incidence of subjective symptoms after SMILE was recorded (Table The incidence of subjective symptoms in the different groups (%)* | PMC10520117 | ||
Authors’ contributions | QL was involved in data curation, formal analysis, investigation, methodology, resources, software, supervision, validation, visualization, writing of the original draft and review and editing of the manuscript. ZS was involved in project administration and review and editing of the manuscript. XZ was involved in validation, visualization and review and editing of the manuscript. All authors read and approved the final manuscript. | PMC10520117 | ||
Funding | The authors have not disclosed any funding. | PMC10520117 | ||
Data availability | The authors confirm that the data that support the findings of the study are available within the article. | PMC10520117 | ||
Declarations | PMC10520117 | |||
Conflicts of interest | The authors declare that they have no conflicts of interest related to the publication of this manuscript. | PMC10520117 | ||
Ethical approval | The prospective study was approved by the Ethics Committee of Fujian Medical University (Fuzhou, China). All procedures performed in studies that involved human participants were in accordance with the ethical standards of the institutional and/or national research committee, and the 1964 Helsinki Declaration and its later amendments, or comparable ethical standards. | PMC10520117 | ||
Informed consent | Written informed consent was obtained from all participants included in the study. | PMC10520117 | ||
References | PMC10520117 | |||
Background | CIPN | CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY, ADVERSE EFFECT | Chemotherapy-induced peripheral neuropathy (CIPN) is a painful, dose-limiting adverse effect of commonly used chemotherapeutic agents. The purpose of this exploratory study was to evaluate the efficacy and safety of mirogabalin in patients with moderate to severe CIPN during chemotherapy and the effects of 12 weeks’ intervention on chemotherapy completion and CIPN severity. | PMC10640752 |
Methods | CIPN, NRS, pain | ADVERSE EVENTS | Patients experiencing moderate to severe CIPN while undergoing oxaliplatin- or taxane-containing chemotherapy for colorectal, gastric, non-small-cell lung, or breast cancer received mirogabalin at between 5 and 15 mg twice daily. The primary endpoint was change in numeric rating scale (NRS) score for pain from baseline to week 12. Secondary endpoints included NRS scores for tingling and sleep, completion of chemotherapy, severity of CIPN, and quality of life (QOL) scores. The safety endpoint was incidence of adverse events. | PMC10640752 |
Results | NRS | Of 58 patients who consented to participation, 52 were eligible and constituted the full analysis set and safety analysis set. From baseline to week 12 (last observation carried forward [LOCF]), NRS score decreased by 30.9%: mean change (95% confidence interval [CI]), − 1.7 (− 2.4 to − 1.0) ( | PMC10640752 | |
Conclusions | cancer, CIPN | CANCER | Intervention with mirogabalin during chemotherapy may be effective and safe for cancer patients with moderate to severe CIPN. It can contribute to completion of chemotherapy without worsening of CIPN. | PMC10640752 |
Trial registration | Japan Registry of Clinical Trials (jRCTs031210101, registered 20/5/2021). | PMC10640752 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12885-023-11560-4. | PMC10640752 | ||
Keywords | PMC10640752 | |||
Background | cancers, neuropathic pain, CIPN, pain, chronic CIPN, neurotoxic | CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY, CANCERS, ADVERSE EVENT, ONCOLOGY | Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse event affecting patients receiving treatment with neurotoxic chemotherapeutic agents including platinum, taxanes, and vinca alkaloids [Many clinical trials relating to pain treatment of CIPN have been reported. Most of these previous studies were conducted in patients with chronic CIPN after completion of chemotherapy, and only a few studies evaluated patients with CIPN during or immediately after chemotherapy. Therefore, although the management of pain caused by CIPN during the course of chemotherapy is a common problem in real-world clinical practice, there is no consensus about the management of CIPN during chemotherapy. In daily practice, chemotherapy is reduced or discontinued based on the patient’s subjective pain intensity, resulting in negative consequences for patient outcomes [When neuropathic pain medications are used during chemotherapy, the severity of CIPN specifically should be appropriately assessed in parallel with the assessment of neuropathic pain, according to the American Society of Clinical Oncology (ASCO) guideline [Several treatment options are currently available for CIPN, including selective serotonin–norepinephrine reuptake inhibitors (e.g. duloxetine), gabapentinoids (pregabalin, gabapentin), and tricyclic antidepressants (e.g. amitriptyline) [Mirogabalin besilate (henceforth referred to as mirogabalin) is an oral gabapentinoid drug with analgesic effects resulting from its ability to bind to the αIn the present study, from the perspective of real-world medical practice, we evaluated the efficacy of mirogabalin for the treatment of pain in patients who developed moderate to severe CIPN during chemotherapy with oxaliplatin or taxane for four types of solid cancers (colorectal, gastric, non-small-cell lung, and breast cancers). We also examined its influence on the completion of chemotherapy and the risk of worsening of CIPN due to underestimation of pain under mirogabalin treatment. | PMC10640752 |
Methods | PMC10640752 | |||
Study design | CIPN, Same-type cancer | MAY | The present study was conducted as part of the MiroCIP study, carried out in Japan. MiroCIP study comprised two parts: a multicenter prospective ongoing registrational study that started in May 2021, and this exploratory, interventional, open-label, single-arm study carried out between May 2021 and September 2022 (Fig. Design of the MiroCIP study, which comprised a registrational study and an interventional study. Same-type cancer patients with chemotherapy-induced peripheral neuropathy (CIPN) and receiving oxaliplatin or taxanes outside the registration study part did not participate in the 1-year follow-up registration part of the MiroCIP study. | PMC10640752 |
Trial registration | The MiroCIP study is registered in the Japan Registry of Clinical Trials under the identifier jRCTs031210101 (date of registration, 20/5/2021). | PMC10640752 | ||
Participating institutions | The present interventional part of MiroCIP study was carried out at 12 institutions across Japan (Supplementary Table | PMC10640752 | ||
Patients | allergy, CIPN, pain | ADVERSE EVENT, ALLERGY, COMPLICATIONS | Key eligibility criteria included age ≥ 20 years, a diagnosis of CIPN grade ≥ 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and a pain numerical rating scale (NRS) score ≥ 4; patients had colorectal, gastric, non-small-cell lung, or breast cancer and were undergoing chemotherapy with a regimen including oxaliplatin or taxane. Patients with pain due to causes other than CIPN (as carefully judged by the attending physician), with allergy to mirogabalin, and with major organ complications were excluded. Full eligibility criteria are provided in the Of the patients enrolled in the registrational study or from outside the registrational study, those who provided written informed consent to participate in and met the eligibility criteria for this interventional study were enrolled. Most patients were enrolled from the MiroCIP registrational study, but 16 patients were enrolled from outside the MiroCIP registrational study to ensure the pre-specified target sample size. | PMC10640752 |
Treatment | renal impairment | RENAL IMPAIRMENT | The treatment period was 12 weeks. Mirogabalin was administered orally at 5 mg twice daily during the first week of the titration period and was titrated up to 10–15 mg twice daily in the following weeks based on age, symptoms, and renal function. For patients with moderate renal impairment (i.e. creatinine clearance 30 to < 60 mL/min), the maintenance dose was 5–7.5 mg twice daily according to the package insert [Prohibited medications included pregabalin, gabapentin, carbamazepine, duloxetine, and lorazepam. The use of compression therapy, cryotherapy, or acupuncture was also prohibited. Co-administration of opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen was permitted if they were administered prior to enrollment and no changes in dosage or administration were made during the study period. | PMC10640752 |
Endpoints | sleep disturbance, CIPN, pain, NRS pain, Neurotoxicity, Cancer | ONCOLOGY, ADVERSE EVENTS, CANCER | The primary efficacy endpoint was the change in NRS pain score from baseline to week 12 [Secondary efficacy endpoints included changes from baseline to weeks 4 and 12 in NRS scores in the last 7 days for tingling (0 = “no tingling” to 10 = “worst tingling possible”) and sleep disturbance (0 = “no sleep disturbance” to 10 = “sleep completely disturbed by pain”); cases of dose reduction, suspension, and discontinuation of chemotherapy during the study period; sensory CIPN severity as assessed by CTCAE version 5.0 at baseline, week 4, and week 12, the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-NTX) [The permissions for the FACT/GOG-NTX and Modified TNSr were obtained in advance as follows. For FACT/GOG-NTX, the FACIT and all related works are owned and copyrighted by and the intellectual property of David Cella, Ph.D; permission for use of the FACT/GOG-NTX is obtained by contacting Dr. Cella at information@facit.org. For the Modified TNSr, all licensed works and derivative works shall be marked as appropriate with the following: “Copyright Johns Hopkins University (2023). All rights reserved.”The safety endpoint was the incidence of adverse events (AEs). AEs were coded using the Japanese version of the Medical Dictionary for Regulatory Activities, version 25.0. | PMC10640752 |
Sample size | The target sample size was set at 55 patients for feasibility reasons, as this was an exploratory interventional study. In previous clinical trials on the efficacy of mirogabalin, the standard deviations (SDs) for the change in NRS score from baseline to 12 weeks were 1.5 [ | PMC10640752 | ||
Statistical analyses | Efficacy analyses were carried out using data for the full analysis set (FAS), defined as all eligible patients who had received at least one dose of the study drug and for whom baseline data were available. Supplementary analyses for efficacy endpoints were conducted using data for the per protocol set (PPS), defined as all patients in the FAS whose treatment was provided in compliance with the study protocol and the Japanese package insert of mirogabalin [For the primary endpoint, the primary analysis was performed by calculating summary statistics, 95% CIs and Statistical analysis was carried out using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). The significance level for hypothesis testing was set at 5% (two-sided), and the CI for both sides was 95%. Because the study was exploratory, no adjustments were made for multiple comparisons. | PMC10640752 | ||
Results | PMC10640752 | |||
Patients | chemotherapy-induced peripheral neuropathy | CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY | Fifty-eight patients were screened, 57 were enrolled, and 52 received at least one dose of study drug (FAS) (Fig. Patient disposition. The per protocol set (PPS) comprised 30 patients, after exclusion of 22 patients from the full analysis set (FAS) for violations of protocol (study drug not administered in compliance with the Japanese package insert of mirogabalin, such as not at twice-daily dosage and not at an effective dosage, Patient baseline characteristics are summarized in Table Baseline demographic and clinical characteristics of patients with chemotherapy-induced peripheral neuropathy in the MiroCIP interventional study (full analysis set)
| PMC10640752 |
Changes in NRS score for pain | Pain | Results for the primary efficacy endpoint (Fig. Pain (including tingling) assessed by numeric rating scale score over 12 weeks of mirogabalin treatment: in the total (full analysis set) (The trend in reduction in NRS score from baseline was not clinically meaningful different irrespective to presence or absence of dose reduction, suspension, or discontinuation of chemotherapy due to all causes. The change in NRS score from baseline to week 12 was − 1.4 [− 2.3 to − 0.6]; Similar results were obtained using PPS data (mean change [95% CI], − 1.5 [− 2.2 to − 0.8]; | PMC10640752 | |
Changes in NRS scores for tingling and sleep disturbance | Supplementary Table | PMC10640752 |
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