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Ethics statement | The studies involving humans were approved by the local Ethical Committee with Authorization Number AOU 0010923/19 on 12/04/2019 and AIFA Authorization Number AIFA/SC/P/33830 on 25/03/2019. EudraCT Number 2018-003458-26. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. | PMC10613634 |
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Author contributions | GN, MMe, CM | AC: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. AC-L: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. MMa: Data curation, Investigation, Methodology, Software, Writing – original draft. AP: Data curation, Investigation, Methodology, Writing – original draft. AN: Data curation, Investigation, Methodology, Writing – original draft. SB: Data curation, Investigation, Methodology, Writing – original draft. DL: Data curation, Investigation, Methodology, Writing – original draft. RB: Data curation, Investigation, Methodology, Writing – original draft. LF: Data curation, Investigation, Methodology, Writing – original draft. LG: Data curation, Investigation, Methodology, Supervision, Writing – review & editing. BB: Methodology, Project administration, Resources, Writing – original draft. ER: Methodology, Project administration, Resources, Writing – original draft. GN: Methodology, Project administration, Resources, Writing – original draft. JM: Writing – review & editing, Writing – original draft. MMe: Data curation, Investigation, Writing – original draft. GC: Data curation, Investigation, Writing – original draft. MG: Data curation, Investigation, Writing – original draft. GO: Data curation, Investigation, Writing – original draft. VB: Data curation, Investigation, Writing – original draft. GG: Conceptualization, Investigation, Methodology, Supervision, Writing – review & editing. CM: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing. | PMC10613634 |
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Conflict of interest | CM | GG and CM received a research grant and a speaker honorarium from Gilead, ViiV, MERCK, and Jansen. GG and CM are on the advisory boards of Gilead, ViiV, and MERCK. JM received a speaker honorarium from Gilead and ViiV.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10613634 |
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Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10613634 |
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Supplementary material | The Supplementary Material for this article can be found online at: Click here for additional data file.Box-plots of primary endpoint CD4, CD8 count and CD4/CD8 ratio and adjusted prediction with 95% CI from fitting the mixed linear model.Click here for additional data file.Box-plots of monocytes and IL-6 and adjusted prediction with 95% CI from fitting the mixed linear model.Click here for additional data file. | PMC10613634 |
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References | PMC10613634 |
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Subject terms | T1D, Diabetes | TYPE 1 DIABETES, DIABETES | Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6–15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (Results from the DiViD Intervention, a phase 2 randomized, placebo-controlled trial, showed that antiviral treatment with pleconaril and ribavirin for 6 months resulted in higher endogenous insulin production in children and adolescents with new-onset type 1 diabetes. | PMC10667091 |
Main | T1D, enteroviral infection, Diabetes | ENTEROVIRAL INFECTION, AUTOIMMUNE RESPONSE, ENTEROVIRUS, DISEASE, TYPE 1 DIABETES, DIABETES | Type 1 diabetes (T1D) is characterized by progressive loss of pancreatic β cell function that leads to lifelong dependence on insulin therapyThe disease is the result of a complex interplay between genetic predisposition, the immune system and environmental factorsIn the Diabetes Virus Detection study (DiViD), pancreatic tissue was collected from six adult patients with newly diagnosed T1DPleconaril, developed against enteroviruses, clears viruses in β cell models of persistent enterovirus infectionDespite existing evidence for enteroviral infection initiating the autoimmune response and subsequent β cell destruction in genetically predisposed individuals, it is unclear if the main effect of the viruses is to initiate or drive the disease process, or both | PMC10667091 |
Results | PMC10667091 |
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Participants | The trial included a screening period from the day of diagnosis until baseline (up to 3 weeks), a 26-week treatment period and a 26-week off-therapy follow-up period, and an ongoing extended follow-up of 2 additional years (to be reported). Out of 96 randomized participants, 47 (19 females and 28 males) were randomized to pleconaril and ribavirin and 49 (21 females and 28 males) to placebo. Participants were recruited between 20 August 2018 and 20 October 20. Details of the screening, randomization and follow-up of participants are provided in the CONSORT diagram (Fig. | PMC10667091 |
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Primary endpoint | The primary endpoint was endogenous insulin production at 12 months, as assessed by the 2-h serum C-peptide rea under the curve (AUC) during a mixed meal tolerance test (MMTT). Endogenous insulin production was measured at baseline, and then at 3, 6 and 12 months. The primary endpoint was analyzed using a linear mixed model for repeated measures. At 12 months, the serum C-peptide AUC was higher in the pleconaril and ribavirin treatment group compared to the placebo group (average marginal effect (AME) = 0.057 at 12 months in the linear mixed model; 95% confidence interval (CI) = 0.004–0.11, | PMC10667091 |
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Discussion | T1D, hemolysis, autoimmunity, hypoglycemia | DISEASE PROGRESSION, VIRUS, SIDE EFFECT, PERSISTENT INFECTION, AUTOIMMUNE RESPONSE, INFLAMMATION, HEMOLYSIS, DYSFUNCTION, HYPOGLYCEMIA, SECONDARY, AUTOIMMUNITY, PATHOGENESIS | In this phase 2 trial involving children and adolescents with newly diagnosed T1D, combination therapy with the antiviral drugs pleconaril and ribavirin for 6 months resulted in a higher endogenous insulin production than placebo 12 months from baseline. The treatment was safe and tolerable.Viruses contribute to the pathogenesis of T1D, both by damaging β cells or triggering the autoimmune response. Establishment of a low-grade persistent infection in β cells maintains inflammation, leading to the breakdown of tolerance to β cell antigens, β cell dysfunction and stress, each of which might then contribute to autoimmunity as part of a vicious circleBeneficial effects of antiviral treatment on β cell function have been observed in the present study at the onset of clinical stage 3 T1D, in a situation where disease progression had been ongoing for months or years. At this late stage of pathogenesis, patients might still have considerable numbers of β cells but they may not function normallyThis trial was not designed to distinguish the individual effects of the two study drugs included in this treatment. The main reason for including ribavirin was to prevent the development of viral drug resistance. Ribavirin has a broader antiviral effect both on enteroviruses and several other viruses, and may also have immunomodulatory effectsThe scale of the observed difference in C-peptide secretion between the pleconaril and ribavirin group and the placebo group after 12 months is comparable to the scale of improvement reported for anti-inflammatory medications and lately verapamil, which have been evaluated for newly diagnosed T1D in randomized control trialsThe observed difference in C-peptide AUC at baseline was not significant (The observed moderate effect of pleconaril and ribavirin may have clinical implications. In general, even a limited preservation of C-peptide levels is associated with improved metabolic control, reduced hypoglycemia and lower long-term microvascular complicationsLower HbA1c was observed in the pleconaril and ribavirin group during the antiviral treatment period (3 and 6 months from baseline) than in the placebo group; at the later time point, 6 months after the end of treatment, the difference in HbA1c between the groups was less pronounced. A known side effect of ribavirin is that it can induce hemolysis, leading to reduced lifespan of erythrocytes and lowering of HbA1c (ref. The trial has some limitations. First, the study included a small number of participants. The statistical power calculation for this trial was aimed at the primary endpoint and was not designed to estimate the power to detect secondary endpoints, which have greater between-person variation and laboratory analytical variation. Effects beyond those in the population studied, that is, centers, age, sex and potential role of COVID-19, could not be credibly examined. Second, the observed significant difference between the treatment and placebo group should be replicated using a higher number of participants of different ages and living in different countries, thus representing different microbiological environments. Third, information regarding continuous glucose monitoring was not available for all participants. Possible persisting low-grade enterovirus infection in the pancreas is difficult to detect from serum or samples taken from the periphery, even if the virus is detected in the pancreatic isletsIn conclusion, this study shows that among children and adolescents with newly diagnosed T1D, the combination therapy of two antiviral drugs, pleconaril and ribavirin, resulted in higher residual endogenous insulin production than placebo. These results provide a rationale for future studies to evaluate the efficacy of antiviral drugs in the prevention and treatment of T1D. | PMC10667091 |
Methods | PMC10667091 |
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Trial design | T1D, Diabetes | DIABETES | We conducted this phase 2, randomized, placebo-controlled, double-blind, parallel-group clinical trial at two sites: Oslo University Hospital, Norway and Steno Diabetes Center Copenhagen/Herlev University Hospital, Copenhagen, Denmark. Participants were children and adolescents aged 6–15 years with newly diagnosed T1D, randomly assigned in a 1:1 ratio to receive either a combination of pleconaril and ribavirin or placebo. We used block randomization, stratified according to site. The trial included a screening period from the day of diagnosis until baseline (up to 3 weeks), a 26-week treatment period and a 26-week off-therapy follow-up period, as well as an ongoing extended follow-up of two additional years (to be reported). The trial was conducted in accordance with the principles of the Declaration of Helsinki 2013, the International Conference on Harmonization Good Clinical Practice guidelines and applicable regulatory requirements. Approvals were obtained from the governmental and regional research ethics committees in Oslo and Copenhagen. Written informed consent was obtained from the participant’s caregiver and participants gave their verbal consent after receiving age-adjusted information. For the complete study protocol, see the | PMC10667091 |
Participants and randomization | T1D, hemolytic anemia, cardiac disease, Diabetes | DISEASES, HEMOLYTIC ANEMIA, DISEASE, CARDIAC DISEASE, DIABETES, IMPAIRED RENAL FUNCTION | Participants were aged between 6 and 15 years, had received a diagnosis of stage 3 T1D according to the American Diabetes Association criteriaThe main inclusion criteria, which had to be fulfilled at screening before receiving the study agent, were: (1) diagnosed with T1D (International Statistical Classification of Diseases and Related Health Problems, 10th Revision code E10.9) with the first injection of insulin 3 weeks before inclusion; (2) willing and capable of taking the study drugs and meeting for tests and follow-up as described; (3) providing signed informed consent and expected to cooperate for the treatment and follow-up obtained and documented according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use GCP, as well as national and local regulations; and (4) aged from 6.00 to 15.99 years at inclusion.The main exclusion criteria were: (1) treatment with any oral or injected antidiabetic medication other than insulin; (2) a history of hemolytic anemia or significantly abnormal hematology results at screening; (3) history of severe cardiac disease in the previous 6 months; (4) impaired renal function; (5) participation in other clinical trials with a new chemical entity within the previous 3 months; (6) inability or unwillingness to comply with the provisions of the study protocol; (7) females who were lactating or pregnant; (8) males or females (after menarche) not willing to use highly effective contraception (progesterone-only hormonal anticonception with inhibition of ovulation or sexual abstinence) and barrier contraception (condoms), if sexually active during the treatment period and in the following 7 months; (9) presence of a serious disease or condition, which in the opinion of the investigators made the patient ineligible for the study. | PMC10667091 |
Treatment | VIRUS, CHRONIC VIRAL INFECTIONS | Pleconaril and ribavirin were administered as oral solutions (to enable weight-based dosing) at home as separate mixtures for 26 weeks. Combination treatment was chosen to increase and broaden the antiviral effect and to reduce the risk of emergence of drug-resistant virus variants. A 6-month treatment was chosen based on clinical experience from treating other chronic viral infections. In cell models, pleconaril eradicated persistent enterovirus infection in 5–6 weeks | PMC10667091 |
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Endpoints | The primary endpoint was endogenous insulin production, as assessed according to the 2-h serum C-peptide AUC during an MMTT at 12 months. The AUC was calculated at each visit using the trapezoidal rule on five measurements collected during the 2-h test (at 0, 15, 30, 60 and 90 min, respectively). Secondary endpoints included a preserved peak C-peptide level greater than 0.2 pmol ml | PMC10667091 |
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Laboratory methods | Enterovirus | ENTEROVIRUS | All laboratory analyses were performed with the same methods throughout the trial for all participants. All sampling and biobanking followed the INNODIA Master Protocol and Standard of ProceduresHbA1c was analyzed using international standard methods (coefficient of variantion (CV) 2%). Glycated albumin (%) was determined with liquid chromatography–tandem mass spectrometry (CV 2–6%) (ref. Enterovirus RT–PCR was performed using nasal swab, nasopharyngeal aspirates, saliva, stool and serum samples as described previously | PMC10667091 |
Statistical analysis | ADVERSE EVENTS, SECONDARY, RECRUITMENT, SENSITIVITY | The sample size calculation is based on the efficacy continuous variable ‘2-h AUC C-peptide’. Because this variable is strongly skewed to the right, a logarithmic transformation (log(Both efficacy and safety analyses included all participants who had received at least one dose of pleconaril and ribavirin or placebo.The primary null hypothesis was evaluated in the full analysis set (FAS), defined as all participants fulfilling the entry criteria who were randomly assigned to a treatment group. Sensitivity analysis was performed in the per protocol analysis set, which included all participants in the FAS who met the study eligibility criteria, with no major protocol deviations affecting treatment efficacy, and who complied with the prescribed treatment. Safety data were analyzed for all participants having taken the study medication. Individuals who withdrew from the study were included in the safety analysis. The primary endpoint was analyzed using a linear mixed model for repeated measures that was fitted on the log-transformed C-peptide AUC data. The model used the longitudinal log-transformed serum C-peptide AUCs at baseline, 3 months, 6 months and 1 year as the response variable and included categorical effects of site, treatment, time and treatment-by-time interaction, as well as a random effect for the patient ID to account for repeated measurements. The linear mixed model included all repeated measurements of C-peptide AUCs, which were available for 89 participants (42 in the pleconaril and ribavirin group and 47 in the placebo group, of which 87 had the 12-month measurement and the remaining 2 only had the previous measurements). The treatment effect was defined as the AME; the primary estimate of treatment effect was obtained as the AME at 12 monthsThe detailed statistical analysis plan (SAP) was produced before the final database lock, before extracting files from the INNODIA clinical database and before unblinding of treatment allocation. The SAP was signed by the authorized chief statistician of Oslo University Hospitals.We fitted a linear mixed model on the mean residual insulin secretion, using the values collected at baseline, 3 months, 6 months and 12 months as a longitudinal outcome variable, and including a random effect for patient ID to account for dependency among measurements taken for the same individual. We included categorical effects for the study site, treatment, time and an interaction term between treatment and time. Because baseline values were collected before randomization, the treatment effect was set to 0 at baseline. Including the baseline value as one of the repeated measurements and forcing the treatment effect to be null at baseline is not only equivalent to adjusting for baseline, but is also the preferred alternative to analyze longitudinal endpointsThe strength of the model we used lies in the fact that we also included the measurements taken at 3 and 6 months, which provides additional power for the analysis. Using exclusively the change from baseline to 12 months would have resulted in less power. The present study had 96 participants; only 87 had records at 12 months. Eighty-nine patients had records at 3 or 6 months; such information can be used to strengthen the conclusion of the analyses. The measurements at 3 and 6 months were listed in the protocol as secondary endpoints; we analyzed them simultaneously in the proposed model. To ensure that we did not incur issues of multiplicity, we defined the primary treatment effect as the treatment effect at 12 months, which is consistent with the protocol. Including the interaction between time and treatment in the model allows us to do so by defining the treatment effect at 12 months as the AME at 12 months.The use of multiple measurements reduces the uncertainty and increases the power of the findings, thus resulting in a statistically significant (To investigate the robustness of the results, we also ran a Wilcoxon The secondary endpoints of mean insulin dosage per body weight, HbA1c, glycated albumin and insulin dose-adjusted HbA1c, were analyzed using a linear mixed model for repeated measures with the same structure and covariates as for the primary endpoint.The dichotomous secondary endpoint corresponding to the proportion of patients with peak C-peptide above 0.2 pmol mlResults are reported as the mean (s.d.) for continuous outcomes and A safety and data monitoring committee was established before starting participant recruitment (committees members are listed in the ‘Acknowledgements’).The trial was monitored closely with regard to safety. The data monitoring committee assessed the safety data and adverse events through the course of the trial. Efficacy data (primary endpoint) were not analyzed before unblinding. Therefore, no interim analysis was performed on the primary endpoint and no adaptive design or error rate control was needed. | PMC10667091 |
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Reporting summary | Further information on research design is available in the | PMC10667091 |
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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/s41591-023-02576-1. | PMC10667091 |
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Supplementary information |
Supplementary treatment description, Tables 1 and 2 and legend to Extended Data Fig. 1.Reporting Summary | PMC10667091 |
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Extended data | PMC10667091 |
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Extended data | is available for this paper at 10.1038/s41591-023-02576-1. | PMC10667091 |
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Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02576-1. | PMC10667091 |
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Acknowledgements | P. | LARSEN, SONNE, JUVENILE DIABETES | We thank the participants and their families for their tremendous efforts during the COVID-19 pandemic lockdowns. We thank our colleagues at the local pediatric departments in Norway for their help recruiting the participants for the trial. We thank the study nurses T. Roald and C. Steinhovden, Oslo University Hospital, and A. Hillersborg, Herlev University Hospital. We thank L. Sandvik who performed the statistical power calculations. This trial is associated with the INNODIA Consortium: we thank C. Matthieu and the late D. Dunger for their support; P. Jaroslaw Chmura and S. Brunak, University of Copenhagen for managing the INNODIA database and electronic case record forms (CRFs) used in the trial; S. Bruggraber, University of Cambridge for practical support and advice regarding the shipment of samples and biobanking; M. Knip, University of Helsinki for performing the autoantibody analysis; C. Brede and Ø. Skaberg, Stavanger University Hospital, for performing the analysis of the glycated albumin; J. P. Berg, University of Oslo for mentoring I.M.M.; the Data Safety Monitoring Committee (T. J. Berg (leader), University of Oslo, R. Hanås, Uddevalla Hospital, Sweden, M. LeBlanc, Statistician, Oslo University Hospital and M. Lagging, University of Gothenburg); J. R. Larsen, Oslo University Hospital for support with study planning; the Clinical Trial Support Unit, Oslo University Hospital (M. Colban for assisting with the applications to the Norwegian Medicines Agency, B. L. Adamsen for the GCP monitoring of the trial, and I. Christoffer Olsen and M. Valberg for supervising the statistical analysis); B. Sonne Rasmussen for GCP monitoring in Copenhagen; and A. Mander, University of Cardiff for advice regarding the SAP. This study was funded by the Health Region South East, Norway (grant no. 2016119); the Juvenile Diabetes Research Foundation (grant no. 2-SRA-2019-810-M-B); and European Union supported by IMI2-JU under grant agreement no. 115797 (INNODIA) and no. 948268 (INNODIA HARVEST). This joint undertaking received support from the Union’s Horizon 2020 research and innovation program and through the EFPIA, JDRF and The Leona M. and Harry B. Helmsley Charitable Trust. All grants were provided to the principal investigator K.D.-J. The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the manuscript. | PMC10667091 |
Author contributions | CRF | VIRUS, CRF | K.D.-J. is the principal investigator of the DiViD studies, including this intervention trial. He conceived the project, drafted the protocol, organized the staff and collaborations with partners, partnered with Apodemus/Curovir AB for the trial, organized the applications to the medicine agencies and ethics committees, organized the funding and the collaboration with INNODIA and related laboratories, planned and organized the statistical analysis and wrote the first and final drafts of this manuscript. L.K. managed the trial together with K.D.-J. and supervised the staff. He actively participated in writing the protocols, the applications to the medicines agencies, ethics committees and funding agencies, organized the collaboration with INNODIA database staff and the development of the INNODIA electronic CRF system. He participated in writing the SAP, analyzed the data and wrote all the drafts of the manuscript. I.M.M. was a PhD candidate and physician and performed all the study visits for the participants in Oslo, entered clinical data into the CRF system, collected and prepared all the samples together with T.R. and managed the biobank. She ensured the quality of the database, participated in writing the SAP, analyzed the data and wrote the manuscript. E.P. was a statistician. She participated in writing the SAP, analyzed the data and wrote the first and final drafts of the manuscript. F.B.M. and T.W.H. were PhD candidates and physicians and performed all the study visits in Copenhagen. They entered clinical data into the CRF system, and collected and prepared all the samples for storing and shipping. T.R. was a study nurse and performed all the study visits of participants in Oslo, entered clinical data into the CRF system and collected and prepared all the samples together with I.M.M. She organized the biobank and the shipping of samples to the international laboratories. J.W. was responsible for managing the GMP production of pleconaril and ribavirin at Anthem BioSciences in Bangalor and the GMP production of the investigational medicinal product at Unimedic in Matfors, Sweden. He also prepared the investigator’s brochure and investigational medicinal product dossier and arranged the logistics and distribution of the drugs with Birka BioStorages. N.L. participated in planning the trial. She actively participated in writing the protocol, the applications to the medicines agencies and ethics committees and helped writing the final manuscript. P.B. and the National Institute for Health and Care Research Cambridge Biomedical Research Centre, Core Biochemistry Assay Laboratory, Cambridge University Hospitals NHS Foundation Trust analyzed the serum C-peptide samples. H.H. participated in the planning of the trial, tested the potential antiviral drugs, analyzed all virus data for the trial and assisted with preparing the final manuscript. J.L. participated in planning the trial, contributed to the C-peptide data with the statistical power calculation and contributed to writing the final manuscript. K.F.H. participated in trial planning and in writing the final manuscript. J.J. was the trial manager in Copenhagen and supervised the staff. He applied to the Danish ethics committee and the Danish medicines agency. He participated in the interpretation of the results and helped with preparing the final manuscript. All authors collected the data, contributed intellectually and critically reviewed the scientific content of the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work. L.K. and K.D.-J. are the guarantors of this work and, as such, had full access to all the data in the study, verified the data and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. | PMC10667091 |
Peer review | PMC10667091 |
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Data availability | Data collected for the study and presented herein will be made available to others when the end-of-trial reports, after 3 years of follow-up, have been published. Anonymized participant data can be obtained upon reasonable request from the corresponding author. Proposals will be reviewed on the basis of scientific merit, ethical review, available resources and regulatory requirements. After approval of a proposal, anonymized data will be made available for reuse. The corresponding author has the right to review and comment on any draft papers based on these data before publication. Availability will follow General Data Protection Regulations. Data will be organized in a data dictionary and participant data will be de-identified. Related study documents, including the informed consent forms (in Norwegian) will also be available. The study protocols and the SAP are found in the | PMC10667091 |
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Code availability | All the code used for the descriptive tables and the analysis of the primary and safety endpoints is publicly available at | PMC10667091 |
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Competing interests | enterovirus-induced | DISEASES | H.H. is a shareholder and member of the board of Vactech Ltd, which develops vaccines against picornaviruses. N.L. and J.W. are employees of Apodemus/Curovir AB, which own the rights to the commercialization of the results of this trial. Curovir AB is developing antiviral drugs for enterovirus-induced diseases. The other authors declare no competing interests. | PMC10667091 |
References | PMC10667091 |
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Keywords | HYPOPLASTIC LEFT HEART SYNDROME | The Single Ventricle Reconstruction (SVR) Trial was a randomized prospective trial designed to determine survival advantage of the modified Blalock-Taussig-Thomas shunt (BTTS) vs the right ventricle to pulmonary artery conduit (RVPAS) for patients with hypoplastic left heart syndrome. The primary aim of the long-term follow-up (SVRIII) was to determine the impact of shunt type on RV function. In this work, we describe the use of CMR in a large cohort follow up from the SVR Trial as a focused study of single ventricle function. The SVRIII protocol included short axis steady-state free precession imaging to assess single ventricle systolic function and flow quantification. There were 313 eligible SVRIII participants and 237 enrolled, ages ranging from 10 to 12.5 years. 177/237 (75%) participants underwent CMR. The most common reasons for not undergoing CMR exam were requirement for anesthesia (Open access funding provided by SCELC, Statewide California Electronic Library Consortium | PMC10435402 |
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Introduction | hypoplastic left heart syndrome, valve regurgitation, congenital heart disease | HYPOPLASTIC LEFT HEART SYNDROME | The Single Ventricle Reconstruction (SVR) Trial was the first of its kind—a prospective randomized trial in congenital heart surgery designed to evaluate the effect of systemic to pulmonary shunt type on short-term survival [Cardiac magnetic resonance imaging (CMR) is the gold standard for the assessment of right and left ventricular function and myocardial viability in congenital heart disease due to its superior blood-tissue contrast, 3-dimensional imaging, and quantification of blood flow, valve regurgitation, and chamber volumes [Given the inherent advantages of CMR for assessment of RV function, the SVR III trial was designed with right ventricular ejection fraction (RVEF) by CMR as the primary outcome measure. Taking into account the improvements over time in the use of CMR in younger children, this specific protocol was designed to overcome concerns regarding the feasibility of using CMR data as the prospective outcome of a clinical trial in 10–12-year-olds with hypoplastic left heart syndrome who have undergone Fontan operations. The objective of this report is to provide a detailed, modern assessment of the use and limitations of CMR in this prospective research setting. | PMC10435402 |
Materials and Methods | inferior vena cava (IVC)/Fontan, PHN, expiratory breath, inspiratory breath | MINOR, PHN | This study is a descriptive design to evaluate the use of CMR in the SVR long-term follow-up cohort using standard CMR methods [As a part of the SVR III cohort study, participants were asked to undergo a non-contrast, non-sedated CMR exam to assess single ventricle function, blood flow in the major venous and arterial vessels including the superior vena cava (SVC), inferior vena cava (IVC)/Fontan conduit, right pulmonary artery (RPA), left pulmonary artery (LPA), neo-ascending aorta, descending aorta, pulmonary veins and tricuspid inflow. Exclusion criteria from CMR exam were the presence of an implantable device, including pacemakers and implantable defibrillators, or the need for anesthesia or sedation. Patients would still be enrolled in the SVR III study regardless of CMR study participation. If the participants underwent a clinically indicated CMR exam requiring contrast or sedation for clinical diagnostic purposes, and it included SVR III protocol components, it was used for analysis. The trial design, methodology, and complete SVR III protocol was published elsewhere. [MRI protocol: The CMR protocol was designed by a small committee of representatives from participating PHN sites. All studies were performed on 1.5 T scanners (Phillips, General Electric, or Siemens). Participants were studied while freely breathing except as otherwise indicated. Scans were acquired with retrospective ECG gating, maximum parallel imaging acceleration factor of 2, and 3 signal averages. The use of a spoiled gradient recalled echo was encouraged in the setting of prominent susceptibility artifact. The CMR protocol was performed in a stepwise fashion, prioritizing SSFP cine data for measurement of RVEF, and included:ECG gated 3 plane localizersECG gated balanced steady-state free precession (SSFP) cines: RV 2-chamber (vertical long axis), RV “4-chamber” (horizontal long axis), short axis stack through entire RV, and 3-chamber (outflow tract). Slice thickness 5–7 mm, pixel dimensions < 1.5 × 1.5 mm^2, TR < 4 ms, and TE ~ 2 ms.Non-contrast MRA: 3D respiratory navigator and ECG gated SSFP acquisition from the mid-liver to top of the aortic arch with acquired resolution 1.5 mm^3. The trigger delay was optimized for the heart rate and the shot duration was maintained < 130 ms.Phase contrast velocity acquisitions: SVC, IVC/Fontan, RPA, LPA, Neo ascending aorta, pulmonary veins, and tricuspid valve inflowIf CMR were performed as a clinically indicated exam and intravenous gadolinium contrast agent were used, additional data could include:Contrast enhanced magnetic resonance angiography (MRA) from the liver to top of the aortic arch during an inspiratory breath hold.Gradient echo inversion recovery late gadolinium enhancement (LGE) in the short axis stack, 2-chamber (VLA), 4-chamber (HLA), and 3-chamber (outflow tract) planes. LGE images were acquired with an expiratory breath hold if possible.Flow analysis in other vessels not included in the standard research protocol above could also be included.The anonymized CMR studies were transferred to the core laboratory via a commercial medical image cloud service (Ambra Health, New York). Before quantitative analysis study image quality was graded by the core laboratory on a 0–4 scale.0-uninterpretable1-poor: major artifacts compromising all data2-fair: major artifacts compromising some data3-good: minor artifacts without data compromise4-excellent: no or minimal artifacts.Study artifacts included missing slices, incomplete anatomical coverage, velocity aliasing, susceptibility effects due to intravascular devices and coils, patient motion, and ineffective cardiac gating. Images were determined to be adequate for analysis by two reviewers, and images had to be of a quality that allowed for endocardial and epicardial border identification over the entire ventricular mass and volume. Images were analyzed with CVI42 (Circle Cardiovascular Imaging, Calgary, Alberta). Image analysis included standard planimetry for ventricular volumes and ejection fraction and phase contrast velocity measurement. RV ejection fraction was the study primary outcome variable. If available, vessel diameter measurements were made on the non-contrast 3D SSFP MRA. DICOM header information was used to calculate the total scan, short axis function, and phase contrast velocity imaging times. Image time could not be calculated for some datasets due to the DICOM header information being removed during anonymization. | PMC10435402 |
Results | SECONDARY | At the start of SVRIII, 313 patients were eligible for enrollment, and 237 patients enrolled with a median age of 10.76 years [IQR 10.28, 11.35] at the time of consent, Fig. This is a flow chart demonstrating the breakdown of eligible patients enrolled in SVR III and the total number of CMR exams with adequate imaging for measurement of right ventricular ejection fractionprovides reasons enrolled participants did not undergo a CMR examThe 177 CMR studies were performed at sites with scanners from three vendors: GE (18 exams), Philips (87 exams), and Siemens (72 exams). 135/177 (76%) studies were performed for the purpose of research only, without sedation or contrast. There were 42/177 (24%) studies performed for a clinical indication. There were 29/177 (16%) total studies performed using a gadolinium contrast agent. There were 10/177 (6%) total studies performed under generalized endotracheal tube anesthesia (This figure demonstrates the distribution of study quality for all CMR exams performed in the SVR III studydemonstrates the study quality grade and the type of artifacts noted in studies with that grade. The number in parentheses indicates the number of studies noted to have that artifactThe median total exam time was 54 min [IQR 40, 74]. There was high variability in the total exam time—minimum 8 min and maximum 154 min. The variability was secondary to sites adding LGE imaging or other pulse sequences to the base required exam, which is expected with the addition of imaging and contrast injection. Short exam times were from aborted studies or limited studies due to artifact. The median time to acquire adequate SSFP cine images for the primary outcome measure was 20 min [IQR 14, 27]. Similarly, the time for phase contrast image acquisition was 18 min [IQR 12, 25]. | PMC10435402 |
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Discussion | congenital heart disease, paralysis | GENETIC SYNDROMES | In the long-term follow-up of the Single Ventricle Reconstruction Trial [Earlier data from the SVR Trial suggested that RV function as measured by echocardiography was impaired prior to Fontan surgery in patients who were palliated with a RVPAS versus those who received a mBTTS [While 75% of the patients in this study were able to undergo CMR and nearly all of those had interpretable RV function data, 25% of the patients were unable to undergo CMR. The two most common reasons were MRI-unsafe implanted devices and need for sedation or anesthesia. Over time, the number of patients excluded from CMR studies for both of these reasons can be decreased with advances in device technology, CMR technique and the MRI environment.Implanted devices are relative contraindications to CMR due to safety concerns and imaging artifacts. The presence of a cardiac implantable electronic device (CIED) was previously considered an absolute contraindication to MRI, but that has changed more recently. A growing body of literature in adults has demonstrated safety in scanning patients with non-MRI compatible devices [A recent single center review documented 20% anesthesia use in patients undergoing CMR exam for any reason at age 10 years [CMR in younger children without anesthesia may require free breathing techniques, as many children are unable to comply with breath holding through the entire scan. Furthermore, children undergoing CMR under general anesthesia often require similar free breathing techniques to minimize the use of paralysis and ventilator pauses during an exam. While CMR more frequently required a breath hold for adequate imaging in the past, there are free breathing techniques in standard clinical use including multiple signal averaging and accelerated acquisition using parallel imaging, as well as emerging techniques such as real time CMR [Study quality was adequate for measuring RVEF as the primary outcome using a free breathing CMR exam technique. Common artifacts experienced during the study included metallic susceptibility artifact, motion artifact, artifact from the MR environment (radiofrequency artifact) and phase contrast velocity encoding that was too low for the velocity of blood flow (aliasing). Older stainless steel coils and other implanted devices cause large susceptibility or “blooming” artifacts that obliterate much of the chest anatomy and were the most common reason for the inability to measure ejection fraction [Our study is limited by potential selection bias in our long-term follow up of this specific cohort. Patients who were eligible but not enrolled may have been sicker, had developmental delays, genetic syndromes or had known implantable devices that resulted in the patients and families declining participation. There is also a survival bias in our follow up cohort, and it is possible that the patients who were transplanted or died could have had more difficult, lengthy, or poor-quality studies. This research protocol was designed for efficient CMR exams and not for evaluating accuracy or reproducibility of the volumetric analysis; however, it is important to note the protocol follows current guidelines for CMR use in children and adults with congenital heart disease | PMC10435402 |
Funding | HEART | Open access funding provided by SCELC, Statewide California Electronic Library Consortium. This study was funded by NIH 1 U10 HL068270, Pediatric Heart Network - NHLBI (Goldberg). | PMC10435402 |
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Declarations | PMC10435402 |
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Conflict of interest | MC Consultant for Longeveron, JD Scientific Advisory Board for Alcor Scientific. | PMC10435402 |
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References | PMC10435402 |
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Summary | Contributed equally. | PMC10275696 |
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Background | The efficacy of on-demand HIV pre-exposure prophylaxis (PrEP) for men in sub-Saharan Africa has not been evaluated, and the on-demand PrEP dosing requirement for insertive sex remains unknown. | PMC10275696 |
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Methods | HIV-negative males 13–24 years, requesting voluntary medical male circumcision (VMMC), were enrolled into an open-label randomised controlled trial (NCT03986970), and randomised 1:1:1:1:1:1:1:1:1 to control arm or one of eight arms receiving emtricitabine-tenofovir disoproxil fumarate (F/TDF) or emtricitabine-tenofovir alafenamide (F/TAF) over one or two days, and circumcised 5 or 21 h thereafter. The primary outcome was foreskin p24 concentrations following | PMC10275696 |
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Findings | 144 participants were analysed. PrEP with F/TDF or F/TAF prevented | PMC10275696 |
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Interpretation | A double dose of either F/TDF or F/TAF given once either 5 or 21 h before | PMC10275696 |
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Keywords | PMC10275696 |
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Research in context | PMC10275696 |
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Evidence before this study | We searched PubMed and | PMC10275696 |
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Added value of this study | TAF-FTC | This clinical trial uses Both drugs showed significant PEP activity in foreskin explants however, protection was limited after 48 h, with TAF-FTC providing more durable protection compared to TFV-FTC. | PMC10275696 |
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Implications of all the available evidence | Understanding dosing requirements for insertive sex is necessary to provide guidance for optimal use. The high concentration of protection found in this study of foreskins from men in Uganda and South Africa provides for the data for insertive sex in men from SSA. Our data suggest that on-demand PrEP could be simplified to a double dose of F/TDF or F/TAF given 5–21 h prior to intercourse. The limited efficacy of TFV-FTC or TAF-FTC as PEP when initiated 48 h after HIV exposure supports evidence from rectal tissue that PEP initiation should be within 48 h of potential exposure to HIV. | PMC10275696 |
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Methods | PMC10275696 |
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Study design and participants | HIV negative males aged 13–24 years were recruited from VMMC clinics at Chris Hani Baragwanath Academic Hospital, Soweto, South Africa or Entebbe General Hospital, Entebbe, Uganda. Eligibility criteria included being clinically eligible for VMMC, weighing >35 kg, and being able to give written informed consent. Full eligibility criteria are described in the protocol (appendix: study protocol). This was a randomised controlled trial with nine trial arms: one control arm and eight treated arms that received PrEP prior to VMMC (Drug: F/TDF or F/TAF (Gilead, Foster City, CA, USA)Dose: double dose on day one, or double dose on day one and single dose on day 2 (2 + 1).Time from last PrEP dose to VMMC: 5 h or 21 h | PMC10275696 |
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Randomization and masking | Participants were randomised in a 1:1:1:1:1:1:1:1:1 ratio to control arm or one of the eight treated arms. Random allocation sequence was generated by an independent statistician using Stata, stratified by country and using block size 9. Participants who were not circumcised following randomisation were excluded according to protocol, and an additional set of randomisation codes generated using the same approach, to ensure a target sample size of 16 evaluable participants per trial arm was attained. Sequentially numbered opaque envelopes labelled with unique randomisation identifier and containing the allocated intervention arm were prepared by two administrators otherwise uninvolved in the study. At time of randomisation, clinical staff opened the sequential envelope and scheduled the participant to receive PrEP (if applicable) and VMMC, as per randomisation arm. Participants and care providers were not blinded to trial arm. Laboratory outcome assessors were blinded until all measurements were completed. | PMC10275696 |
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Ethical approvals | RECRUITMENT | Written informed consent was obtained from all participants aged ≥18 years and emancipated minors (in Uganda); for those <18 years and not emancipated minors, assent with parental consent was obtained. The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice and approved in the South African Health Products Regulatory Authority (20181004). Ethical approval was granted from University of Cape Town (290/2018), University of the Witwatersrand (180906 B, M1811148, 180108), Uganda Virus Research Institute research ethics committee (GC/127/18/12/680), Uganda National Council of Science and Technology (HS2534), Uganda National Drug Authority (618/NDA/DPS/09/2019), and London School of Hygiene and Tropical Medicine research ethics committee (17403). An independent Data Safety and Monitoring Board evaluated trial progress and safety data twice during recruitment; no interim analyses were done. | PMC10275696 |
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Outcomes | SECONDARY | The primary outcome was HIV-1 p24 concentration in participants' foreskin tissue up to day 15 following The secondary outcomes included p24 concentrations in PBMCs; drug concentration in foreskin tissue, foreskin CD4+/CD4-cells, blood (plasma and PBMCs); additional effect of | PMC10275696 |
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Sampling | BLOOD, COLD | Study samples were collected during VMMC visit 5 h or 21 h ± 40 min after the last PrEP dosing. Blood and foreskin tissue, including inner and outer, were collected. VMMC was performed using the dorsal slit method according to local guidelines. Tissue was placed immediately in cold culture media DMEM. Samples were immediately transported to the laboratory on ice (median transit time 30 min). Processing of samples was performed immediately upon arrival to the laboratory. | PMC10275696 |
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Isolation of peripheral blood mononuclear cells | PD | LYSIS | PBMC were isolated by density-gradient centrifugation using Lymphoprep™ (Stem Cell Technologies, Vancouver, Canada) followed by erythrocyte lysis (ACK Lysing buffer, Gibco, Waltham, MA, USA). For pharmacodynamic (PD) analysis, cells were resuspended in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 2 mM | PMC10275696 |
Ex vivo challenge of foreskin tissue and PBMCs | infection | INFECTION | Foreskin was cut into 2 mmExplants from the control arm were used as baseline of infection. Additional explants from the control arm were dosed | PMC10275696 |
Isolation of CD4+ and CD4-cells from foreskin | Foreskin tissue was cut into 4 mm | PMC10275696 |
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Bioanalytical methods | Concentrations (denoted as [drug or metabolite]) of TFV, FTC, and the pro-drug TAF, were measured in plasma and foreskin tissue. Concentrations of the active phosphorylated intracellular metabolites – tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) were determined in PBMCs, foreskin tissue, and isolated foreskin CD4+ and CD4-cells. Analyte quantification was performed using a SCIEX 4500 or 5500 triple quadrupole mass spectrometer (AB Sciex UK Limited; Warrington, UK). Data acquisition and processing were performed using FDA CFR Part 11 compliant SCIEX Analyst and Multiquant software platforms. LC-MS assays were validated in accordance with FDA Bioanalytical Method Validation Guidelines. | PMC10275696 |
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Statistical analysis | The planned sample size of 144 participants was based on feasibility of conducting this number of experiments based on previous | PMC10275696 |
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Role of the funding source | Funders had no role in the data collection, data analysis or data interpretation. In addition, EDCTP2 and Vetenskapsrådet had no role in study design or writing of the report. All authors had full access to all study data and had final responsibility for the decision to submit for publication. | PMC10275696 |
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Discussion | TAF | HIV INFECTIONS | CHAPS is a trial of on-demand PrEP in young men in Uganda and South Africa, evaluating F/TAF for PrEP and PEP timing and dosing to prevent HIV acquisition after The aim of the study was to provide guidance for dosing requirements and time to protection following starting PrEP. Our primary outcome demonstrated that an on-demand double dose regimen of F/TDF or F/TAF, given on a single occasion, is protective between 5 and 21 h prior to insertive intercourse, and that post-coital dosing conferred additional protection in PBMCs but not tissue. Our data did not show clear superiority of TAF to TDF in protecting foreskins against HIV infections, however the higher TFV-DP intracellular concentrations we report in those who received TAF suggest that protection may be of longer duration, or that the dosing requirements for on-demand F/TAF are somewhat lower than for F/TDF. The results of this study align with findings from the social science arm of CHAPS, which clearly showed that young men in Uganda, Zimbabwe and South Africa favoured on-demand PrEP and if possible, a pre-coital only PrEP regime.Both F/TDF and F/TAF were well tolerated and highly effective against PBMC metabolite exposures achieved in the F/TDF arms were comparable to those reported in the IPERGAY single dose pharmacokinetic study.Intracellular TFV-DP accumulated in foreskin, which is potentially attributed to its long intracellular half-life in mucosal tissues (34–53 h in cervicovaginal tissuesThis study has successfully measured phosphorylated antiretroviral nucleosides in CD4± cells isolated from foreskin tissue. Data from this small sub-study revealed that, unlike the PBMCs compartment, dosing with TAF did not confer preferential distribution of TFV-DP into foreskin HIV target cells. The lack of correlation between PBMCs and foreskin CD4+ fractions, further supports the notion that CD4+ cells are a distinct cellular sub-population. However, the small sample size, low detection rate, and high inter-subject variation mean that these preliminary data should be interpreted with caution.A key strength of the trial design is the ability to assess several important PrEP variables including PrEP drug, PrEP dose and timing, and link tissue and cellular pharmacokinetics to pharmacodynamics. Unlike studies with HIV incidence as an outcome, no participants were exposed to additional risk of HIV due to group allocation.Our study had some limitations. Firstly, this was an open-label study with blinding of arm allocation to laboratory staff but not participants or clinical personnel. Second, one foreskin specimen and two PBMC specimens from the control arm were not infected following In an era when efficacy studies for HIV protection are large and prohibitively expensive, evidence from phase II studies of this nature will maximise the chance of identifying the most efficacious dosing strategy and filling data gaps around onset and offset of protection. This factorial design using the p24 protein as a surrogate endpoint can be used to efficiently select drug combinations and dosing regimens for testing in phase III, while obviating the unnecessary costs of futile regimens. The results from this study and future | PMC10275696 |
Contributors | CH and JS contributed equally to conceptualisation, formal analysis, investigation, methodology, resources, supervision, validation, writing – original draft; LE: conceptualisation, formal analysis, investigation, methodology, resources, supervision, validation, writing – original draft; LL: project administration, resources, supervision; DO, PS and RM: resources; ASS: project administration, resources; ADP, PN, TBS, GO, SM, AA, SDP and SP: investigation; BA: project administration, resources; KOH and CC: methodology; JS and HW: conceptualisation; SK: conceptualisation, supervision, validation, writing – original draft; FC: conceptualisation, resources, supervision, validation, writing – original draft; CMG: conceptualisation, resources, supervision; PK: conceptualisation, supervision; ELW: data curation, formal analysis, supervision, validation, writing – original draft; NM and JF contributed equally to conceptualisation, funding acquisition, resources, supervision, writing – original draft. All authors contributed to the writing– review & editing. All authors read and approved the final version of the manuscript. Participants enrolled in the CHAPS cohort provided their time and consented for the donation of resected foreskin to the study.` | PMC10275696 |
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Data sharing statement | Deidentified participant data and a corresponding data dictionary will be available together with the study protocol, with publication and upon request to the corresponding author. This will be made available on LSHTM Data Compass repository. The Trial Management Group will approve data sharing requests. | PMC10275696 |
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Declaration of interests | CH has received research grants from EDCTP, Vetenskapsrådet and Gilead Sciences. LE has received research grants from EDCTP, and Gilead Sciences. LL has received research grants from EDCTP, Gilead Sciences, Roche Diagnostic, DO has received research grants from EDCTP, AS has received research grants from EDCTP, AP has received research grants from EDCTP, PN has received research grants from EDCTP, PS has received research grants from EDCTP, DS has received research grants from EDCTP, RM has received research grants from EDCTP, BA has received research grants from EDCTP, SP has received research grants from EDCTP, CC is an employee of Gilead Sciences, JS has received research grants from EDCTP, HW has received research grants from EDCTP, SK has received research funding, speaker honoraria and consulting fees from EDCTP, Gilead Sciences, ViiV, Merck, GSK, and Ridgeback. FC has received research grants from EDCTP and Vetenskapsrådet. ELW has received grants from EDCTP, MRC, and NIH. CG has received research grants from EDCTP. PK has received research grants from EDCTP. EW has received research grants from EDCTP, NIH and MRC. NM has received research grants from EDCTP, and Gilead Sciences and provided unpaid advice and leadership in the DSMB and Setshaba boards. CC is a full-time employee of Gilead Sciences. All other authors declare no competing interests aside from the research grant received for this study by EDCTP. | PMC10275696 |
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References | PMC10275696 |
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Supplementary data | PMC10275696 |
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Supplementary material | PMC10275696 |
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Protocol The CHAPS Trial Version 1.2 | PMC10275696 |
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CHAPS Study Team list | PMC10275696 |
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Acknowledgements | We would like to acknowledge all study participants and their parents for their involvement in this study. This study was funded by EDCTP2 programme from the Supplementary data related to this article can be found at | PMC10275696 |
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Background | Ankle sprains | Ankle sprains are frequent injuries in general practice. However, no effective treatment is available yet. | PMC10755994 |
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Aim | lateral ankle sprains | To examine the effectiveness of an unsupervised e-health-supported neuromuscular training programme in combination with usual care compared with usual care alone in patients with acute lateral ankle sprains in general practice. | PMC10755994 |
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Design and setting | lateral ankle sprain | Randomised controlled trial with 1-year follow-up among patients (14–65 years) who visited the GP with an acute lateral ankle sprain within 3 weeks of injury. | PMC10755994 |
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Method | pain | The intervention group received, in addition to usual care, an unsupervised e-health-supported neuromuscular training programme and the control group received usual care alone. The primary outcome was self-reported re-sprains during 52 weeks of follow-up. Secondary outcomes were ankle function, pain in rest and during activity, subjective recovery, and return to the same type and level of sport. | PMC10755994 |
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Results | SECONDARY | In total, 165 participants (mean age 38.3 years and 69 [41.8%] male) were included. No statistically significant difference in the occurrence of a re-sprain were found between the intervention 20.7% (17/82) and control group 24.1% (20/83) (hazard ratio 1.14, 95% confidence interval = 0.59 to 2.21). Also, no statistically significant differences in secondary outcomes were found between groups. The adherence rate to the programme was low (6.1%, 5/82). | PMC10755994 |
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Conclusion | re-sprains | The rate of re-sprains was relatively high and an unsupervised e-health-supported neuromuscular training programme does not yield meaningful effects and does not encourage adherence in preventing re-sprains in patients in general practice. More research is necessary to indicate the best treatment modality and way of delivery for these patients. | PMC10755994 |
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Introduction | injuries of the musculoskeletal, lateral ankle sprains, re-sprains, ankle sprains | RECURRENCE | Acute lateral ankle sprains (LASs) are one of the most common injuries of the musculoskeletal system. The incidence rate in the general population is 2.15 per 1000 person-years in the US, with the highest incidence seen in patients aged between 15 and 24.Given the relatively high risk of re-sprains, effective treatment of LASs is important to prevent long-term complaints and re-sprains. Acute LASs that require medical treatment are often seen by the GP. The Dutch College of General Practitioners’ guideline for ankle sprains recommends different treatment options, such as Rest, Ice, Compression, Elevation (RICE), bracing, or exercises.An 8-week unsupervised neuromuscular training programme examined in a Dutch trial among athletes was effective with a relative recurrence risk reduction of 35%.The current study therefore aimed to examine the effectiveness of an app-based unsupervised neuromuscular training programme, in addition to GP-led usual care, compared with GP-led usual care alone in patients with an acute LAS in general practice, in reducing the number of recurrent LASs. | PMC10755994 |
Method | PMC10755994 |
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Trial design | fits | The trAPP-study was undertaken according to a previously published protocol.How this fits in | PMC10755994 |
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Participants | fracture | EVENTS | Patients with an acute LAS (14–65 years) who visited a GP within the 3 weeks after the injury were eligible for inclusion. Exclusion criteria were a LAS during the previous year, a fracture, or no understanding of the Dutch language. Interested patients were referred to the research team by the GP. Additionally, participants were recruited through social media channels (for example, Facebook, Twitter [now known as X]) and advertisements at sports centres and events. All potential participants were screened for eligibility by the research assistant by telephone and provided written informed consent. | PMC10755994 |
Randomisation procedure | Participants were randomised by a computer-generated randomisation list (block sizes two, four, and six) with a 1:1 allocation ratio, to receive either the app-based programme, in addition to GP-led usual care (intervention group) or GP-led usual care alone (control group). An independent data manager created the randomisation list and this was concealed for other involved researchers. | PMC10755994 |
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Interventions | The control group only received GP-led usual care. The content of usual care was based on the Dutch Guideline for GPs and best practice.The intervention group received, in addition to GP-led usual care, an 8-week standardised neuromuscular training programme. The free application ‘Versterk je enkel’ (‘Strengthen your ankle’) guided participants through the programme. Participants were instructed to perform three training sessions per week. Every session consisted of six exercises, which became more difficult in time and were performed in different conditions (with eyes open or shut, with or without a handhold, on an even or uneven surface) (Supplementary Information S1 [in Dutch]). | PMC10755994 |
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Outcomes | Ankle Disability, pain | Participants completed, after baseline, online questionnaires at 4, 8, 12, 16, 21, 26, 31, 35, 39, 43, 47, and 52 weeks’ follow-up. The baseline questionnaire included questions on demographics, educational level (‘low’, ‘middle’, or ‘high’), comorbidities, paid job (‘yes, <16 hours’, ‘yes, >16 hours’, or ‘no’), sports participation (‘yes’ or ‘no’), minutes of sport participation per week, previous LASs, Ankle Function Score (AFS) (0–100) and Foot and Ankle Disability Index (FADI) (0–100),All follow-up questionnaires collected information about the previous month and included the occurrence of a recurrent LAS of the index LAS, subjective recovery (measured on a 7-point Likert scale ranging from 1 ‘completely recovered’ to 7 ‘worse than ever’; patients are deemed to be recovered if they rate themselves as ‘completely recovered’ [ = 1] or ‘strongly recovered’ [ = 2] on the Likert scale, whereas those who rate themselves as ‘3, slightly recovered’ to ‘7, worse than ever’ are deemed to be not recovered), AFS (0–100),The primary outcome was the difference in self-reported recurrent LAS between the intervention and control group during 1-year follow-up. A recurrent LAS was defined as a re-sprain of the index LAS.Secondary outcomes were differences in ankle function, pain at rest and during activity, subjective recovery, and sport participation (type and level) at 12, 26, and 52 weeks. | PMC10755994 |
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Use of co-intervention | pain | AIDS | The use of co-interventions was monitored during follow-up by monthly questionnaires and included information on visits to a healthcare professional (for example, GP, sports physician, specialist) and on self-initiated aids and treatment (for example, pain medication, brace, or taping). | PMC10755994 |
Adherence | The intervention group completed an extra weekly questionnaire on the number of exercises performed. Adherence was determined by the total number of exercises performed per week during the programme and it was defined by completing ≥75% of the total number of exercises in the programme. | PMC10755994 |
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Sample size | A difference of 19% in the incidence of recurrent LASs between the two groups after 1-year follow-up was considered as clinically relevant. | PMC10755994 |
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Statistical analysis | ankle sprain, pain | REGRESSION, EVENT, RECURRENCE, SECONDARY | Differences between the two groups were analysed following the intention-to-treat principle. Cox regression analysis, with adjustment for sex, was performed for comparing recurrence risk between groups and presented as a hazard ratio (HR) with a 95% confidence interval (CI). The first self-reported recurrent LAS was used as the event. Differences between continuous secondary outcomes were examined with linear mixed models using regression techniques for repeated measures and adjusted for age, sex, body mass index (BMI), educational level, and treatment of ankle sprain by GP at baseline. The covariance structure ‘Unstructured’, with the lowest Akaike’s information criterion, was chosen as a data structure in the analyses to model the covariance of repeated measures. The time-point of follow-up were fixed effects. All outcomes measured at the time points before the time-point of interest (including baseline values) were included in the analyses. The intervention effect on continuous secondary outcomes was quantified as the mean difference between trial arms. Mixed-multilevel models, estimated using restricted maximum likelihood, were fitted to analyse repeated measures data as they allow inclusion of participants that provide outcome data in at least one study wave.Logistic regression models, adjusted for sex, BMI, treatment of ankle sprain by GP at baseline, pain at rest, pain during exercise, FADI, and AFS, were fitted to compare binary outcomes between the trial groups. Differences in subjective recovery and return to the same sport and the same level of sport between the groups were presented as odds ratios (ORs) with their 95% CI. In case of statistically significant differences in the categorical secondary outcomes between the groups, the number needed to treat was calculated (defined as 1 divided by the risk difference between the groups). All analyses were performed in SPSS Statistics (version 25) and | PMC10755994 |
Not in line with published protocol | In contrast to what is stated in the previously published study protocol, the cost-effectiveness analysis has not yet been performed, and therefore it is not reported in this manuscript. | PMC10755994 |
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Results | From November 2014 until January 2018, 386 patients were interested in the study (Flowchart of the inclusion of patients in the trAPP-study.
Mixed-multilevel model analyses allowed inclusion of all participants who provided outcome data in at least one follow-up measurement.
Baseline characteristics of the trAPP-study participants (
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Primary outcome | re-sprains | Overall, 22.4% (37/165) of the participants reported one or more re-sprains during follow-up: 24.1% (20/83) in the control group and 20.7% (17/82) in the intervention group. A total of 51 re-sprains were reported by these 37 participants (26 in the intervention and 25 in the control group). There was no statistically significant difference in the occurrence of re-sprains between the two groups (HR 1.14, 95% CI = 0.59 to 2.21, adjusted for sex; unadjusted HR 1.02). | PMC10755994 |
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Secondary outcomes | SECONDARY | No differences were observed in any of the secondary outcome measures between the two groups at 12, 26, and 52 weeks (Secondary study outcomes during 1-year follow-up
| PMC10755994 |
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Adherence | The number of responses to the specific intervention questionnaires ranged from 74.4% (61/82; week 2) to 51.2% (42/82; weeks 4 and 5). Twenty participants (20/82; 24.4%) were adherent with the intervention programme (that is, performed ≥75% of total prescribed exercises) and only five participants (5/82; 6.1%) were completely adherent (that is, three sets of six exercises per week over 8 weeks). | PMC10755994 |
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Discussion | PMC10755994 |
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Summary | In this trial, the effectiveness of an unsupervised e-health-supported training programme, in addition to GP-led usual care, was examined among 165 participants with a LAS in general practice. In contrast with Hupperets | PMC10755994 |
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Strengths and limitations | RECURRENCE | The current study is a high-quality pragmatic RCT evaluating an e-health intervention in addition to usual care about the recurrence rate of LASs in general practice. Nevertheless, some limitations need to be addressed. First, the number of included participants was lower than anticipated and the loss to follow-up was 25.5%, which was higher than expected and therefore had an impact on the power of the analyses. | PMC10755994 |
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Comparison with existing literature | ankle sprain, ankle injuries, pain | To the authors’ knowledge, this is the first RCT to evaluate an unsupervised e-health-supported training programme for patients with an acute LAS in general practice. Rehabilitation programmes for ankle injuries, such as proprioceptive training programmes, have been studied previously in both general and sport populations,One of the reasons that the current study found no effect of the training programme could be the study population. Hupperets The low adherence rate may have been affected by the fact that there was no contact with the research team about the performance and progress of the intervention programme. Inherent to the adherence, the unsupervised component of the programme could be a limitation. The absence of supervision for motivation, and especially quality control of exercises, could be another reason for the low adherence and contribute to the ineffectiveness of the intervention. This is strengthened by the fact that previous studies have shown that supervised rehabilitation, compared with home exercises, seems to be more effective in reducing pain, subjective instability, and function after an ankle sprain. | PMC10755994 |
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Implications for research and practice | sprain | An unsupervised e-health supported neuromuscular training programme, in addition to GP-led usual care, in its current form is not effective and does not encourage adherence in the prevention of a recurrent sprain during 1 year of follow-up in patients with an acute LAS in general practice. More research is needed to determine the best treatment modality and way of delivery for this group of patients.The authors thank all GPs that recruited participants in their practices and all included participants who volunteered to participate in the trial. | PMC10755994 |
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