Challenges in Trials on Neonatal Sepsis- Case of ProSPoNS Trial & Role of Central Endpoint Adjudication

Challenges in Trials on Neonatal Sepsis- Case of ProSPoNS Trial & Role of Central Endpoint Adjudication | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Challenges in Trials on Neonatal Sepsis- Case of ProSPoNS Trial & Role of Central Endpoint Adjudication Anju Pradhan Sinha, Dilip K Raja, Kamlesh S Mahajan, Subodh S Gupta, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3924417/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background: Despite progress in reducing Infant mortality in India, neonatal mortality decline is slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming prevention of neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention, including probiotic supplementation. This article communicates the decision by ProSPoNS trial investigators to establish a Central Endpoint Adjudication committee as an addendum to the published protocol in 'Trials 2021.' Methods: In the pursuit of clarity regarding the primary outcome of Sepsis/PSBI in a clinical trial, a crucial decision was reached during the investigators' meeting at MGIMS Sevagram on 17th-18th August 2023. The unanimous consensus was to explicitly define "Physician diagnosed sepsis" as the primary study outcome, encompassing Sepsis/PSBI. This alignment aimed to synchronize the primary objective and outcome with the stated hypothesis, necessitating the establishment of a Central Endpoint Adjudication (CEA) process across all six trial sites. To enact this, the CEA committee, chaired by an external Subject Expert and comprising Site Principal Investigators, a Trial Statistician, and a Microbiologist, will employ four criteria to determine 'Physician diagnosed sepsis' for each sickness event in a study participant. These criteria include Blood culture status, Sepsis screen status, PSBI/non-PSBI signs and symptoms, and the Clinical course during the event, including antibiotic usage. Importantly, this clarification maintains consistency with the approved study protocol (Protocol No.5/7/915/2012 Version 3.1 dated 14 Feb 2020), emphasizing the commitment to methodological transparency and adherence to predefined standards. Results: The challenges faced in the trial implementation, such as complex multi-centric design, heterogeneity / extreme variation across sites, inconsistency with definition of sepsis in the neonatal/young infant population, remote vs. on-site training/monitoring during the Covid-19 Pandemic have been described and potential solutions to some of the challenges in clinical trials suggested. Conclusions: The decision to utilize the guidance of a Central Endpoint Adjudication Committee has been suggested as a way forward in the ProSPoNS and other multicentre complex clinical trials. Trial registration: Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019. ProSPoNS Neonatal Sepsis Clinical trial Adjudication Figures Figure 1 Background We have previously published a protocol for the currently ongoing Phase III Multicentre randomized double-blind placebo-controlled trial (ProSPoNS trial) evaluating role of probiotics (Vivomix) in prevention of neonatal sepsis in 0-2 month old Indian infants [1]. The trial is based on our previously published study that enrolled 1340 low Birth Weight Neonates [2] showing an overall 21% non-significant reduction in the incidence of suspected sepsis diagnosed by field investigators using the possible serious bacterial infection (PSBI) definition of WHO/UNICEF to detect suspected sepsis in the trial. However, in non pre-specified sub-group analysis among infants 1.5 -2.00 kg, a 71% reduction in incidence of sepsis in the intervention arm was observed. These results formed the rationale for the current trial aiming to find the conclusive evidence of a potential benefit of the probiotic intervention. The technical advisory group (TAG) of the Indian Council of Medical Research (ICMR) suggested planning and implementing a larger trial with a sufficient sample size and a specific definition of the primary outcome (sepsis), since the PSBI definition used earlier was considered to be lacking in specificity. Subsequently, an application to the UKRI JGHT call 8 was made with success [3]. In the larger ProSPoNS trial that is ongoing, we opted for a stringent definition of the primary outcome Sepsis defined as: one or more clinical signs suggestive of sepsis with a microbial isolate on blood culture; or a neonate with sterile blood culture with at least 2 sepsis screen markers being abnormal (CRP >12 mg/L, Absolute neutrophil count<1500/mm 3 , TLC15 mm, Immature to total neutrophil ratio > 0.2. Possible serious bacterial infection (PSBI) defined by WHO UNICEF is our second primary outcome in the trial. We used data of ‘Physician Diagnosed sepsis’ from the pilot trial to calculate the sample size for the ProSPoNS trial. Secondary outcomes include: 1) Stool colonization patterns at baseline day 0, day 21 and at the end of the study (day 60) in a subsample. 2) Death and late-onset sepsis: Comparison of all-cause deaths and late-onset sepsis between the intervention and control groups. 3) Clinical severe infection: One or more clinical signs - not feeding well, fever (temperature ≥ 38°C), low body temperature (< 35.5°C), severe chest in-drawing, the movement only when stimulated as confirmed by the study physician. 4) Critical Illness: One or more of clinical signs - convulsions, unable to feed at all, no movement on stimulation, unable to cry, bulging fontanelle and cyanosis as confirmed by the study physician. 5) Cost-effectiveness/utility of the probiotics intervention vs control is being taken up as a sub-study to inform policy. The protocol [1] outlined the following: The IP administration compliance check and safety follow up/Screening for morbidities would be conducted in the community by trained field workers who are trained on IMNCI (2019) guidelines, The participant would be followed up daily in the first week of life, thrice per week during weeks 2–4 of life, and weekly once in the second month of life. Field workers will be trained to screen and detect sick infants as per PSBI protocol; in case of any complaints, the field worker will accompany the parents with their infant(s) to the site hospital for further examination by the study investigator. Sepsis screen and blood culture would be performed if considered necessary for the diagnosis of neonatal sepsis, and appropriate treatment would be provided as per hospital or study protocol. In this article, we communicate the decision of the ProSPoNS trial investigators to form an adjudication committee as an addendum to the original published protocol in ‘Trials 2021'. We explain the reasons for coming to this decision by highlighting the challenges faced in trial implementation, the problem due to the heterogeneity across sites in diagnosis of sepsis and the academic problem with the definition of sepsis in the neonatal/ young infant population. Implementation Challenges in the ProSPoNS Trial Complex Multi-centre design : The randomised controlled trial (RCT) is the gold standard experimental design for assessment of interventions [4]. The Multicentre trial design allows for faster recruitment over time, recruitment from different populations maximizes the generalizability [5]. However, the use of multiple clinical sites introduces complexity in clinical trials [6] as they differ in geographical location, setting, distances to health care facilities, socio-economic factors, morbidity patterns, and ancillary treatment practices [7]. Heterogeneity /Extreme variation across sites: The trial steering committee observed variation in the morbidity pattern (adverse events, severe adverse events) across the study sites, there being one outlier each in both directions. This could be due to the sites being systematically different from one another, e.g., due to differences in patient populations, ancillary treatment practices, or other factors [7]. Repeated quality assurance measures such as retraining of staff, review of process indicators at the sites as well as monitoring visits by the clinical trial monitors were conducted to have uniform identification and reporting of cases across all sites could not result in substantial changes in the observed morbidity pattern during trial implementation. The number of cases is being reported specifically at the JIPMER, Puduchery site is lower than the other five sites. Definition of Neonatal sepsis : Neonatal sepsis is commonly termed as an infection involving the bloodstream in newborn infants less than 28 days old. Diagnosis of sepsis in newborns is not easy due to the lack of a uniform definition of sepsis unlike in children and adults where they are labeled as either ‘culture positive sepsis’ or ‘clinical sepsis’. The newborns suspected of sepsis based on maternal or peri-natal risk factors may be administered antibiotics, but their clinical course, sepsis screen and blood cultures if not suggestive of sepsis, are then labeled as ‘no Sepsis; after 3 days. Researchers/academicians recognize the problem of defining neonatal sepsis and lay down ground rules/ SOPs [8, 9] for a working definition in studies:- have discussed cases labeled as ‘Culture Negative Sepsis’ (suspected cases where despite sample collection bacteria may not grow because of several factors such as the timing of collection, bacterial load and prior antibiotic consumption. The term ‘culture negative sepsis’ has been explained based on the following criteria given below: 1). Symptomatology suggestive of sepsis or at least two maternal risk factors; 2) Individual sepsis screen markers namely total leucocyte count (TLC) and absolute neutrophil count (Neutropenia) were considered. The ability of C-Reactive protein (CRP) as a marker of late onset sepsis (LOS) remains controversial in literature [10]. 3) The clinical course of the disease where there is no other explanation for the symptoms can then be attributed to sepsis. In the beginning of the study it was assumed that blood culture positive sepsis is the gold standard method of defining neonatal sepsis. However, completion of microbiological tests results in a yield of 30-40% cases of culture positives, therefore it is not incorrect to say that it cannot reliably rule-out sepsis. Reported rates of ‘culture-negative’ or ‘suspected’ sepsis vary widely in the literature. While some experts advocate to consider sepsis, evaluations completed after 48–72 hours of negative blood cultures, data available from two large randomized controlled trials (RCTs) in recent years [11, 12] show culture-negative sepsis rates of 56% and 46%, respectively. By reviewing all morbidity cases individually, the CEAC would take into consideration the culture negative - reports and the contaminants with a balanced view. Challenges during the conduct of PROSPONS trial : Remote Vs. On-site trainings: In the year 2020 the world was hit by the Covid 19 pandemic, first cases appeared in India in March 2020 coinciding with the launch of the preparatory phase of the trial implementation. In order not to deviate from the committed timelines, we decided to adopt the online mode of functioning for the preparatory phase activities such as trainings of staff, the site readiness/feasibility visits, the investigators meetings and the site initiation visits. Under normal circumstances and as per Good clinical practices, the above activities are expected to be conducted physically. Recruitment Challenge: We observe variability in the recruitment pattern across sites. Despite all efforts the same pattern is persisting till date. Some of the reasons for low recruitment rate in the trial observed by us are: disruption of the obstetric services due to COVID-19 priority, lower delivery rate of low birth rate infants, potential participants from out of study catchment area, competing studies at particular site, and lack of engagement are other reasons [13]. Less than optimum recruitment at the site is referred as a ‘research waste’ in view of time and money spent to build the site [14]. A review of trials funded and published by the UK’s Health Technology Assessment program has reported that recruitment patterns in multicenter randomized trials fit more closely to Price's Law (50% of participants are recruited by the square root of the total number of sites), than the Pareto Principle (80% of participants are recruited by 20% of sites,) [13]. The trialists can hope for a uniform recruitment across the sites in an ideal condition [15], however it is difficult to achieve. A few additional challenges faced during implementation, measures adopted and lessons learnt are summarized in Table 1. Table 1: Challenges, measures adopted, lessons learnt and recommendations from the implementation of the ProSPoNS trial Challenges Measures adopted Lessons learnt/Recommendations Regulatory and ethical committee approvals (study sites) Complex and time-consuming process of obtaining multi-layered administrative, regulatory, and ethical approvals for sponsor as well as participating sites. Differences in approval requirements and timelines further cause delayed study initiation/implementation. The COVID 19 pandemic affected the EC’s functioning, resulting in sparse meetings. The different site-specific EC requirements, variation between sites demanded several rounds of revisions and close coordination with the site investigators. The sponsor collaborated with a regulatory expert to mitigate the regulatory submission and approval challenges. The site readiness was assessed before initiation; the CRO team was involved in catalyzing the EC submission process by actively following up with the sites. This highlights the importance/need for streamlining and collating the EC submission documents in advance. The approval process at national and local levels should consider following practical timelines for approvals. Heterogeneity/Extreme variation across sites: The ProSPoNS trial was being implemented across geographically diverse sites (public/private/Trust) with differing levels of handling patient/neonates’ volume, variable mortality & morbidity patterns, antibiotics use, clinical and health-care utilization practices; distance to health care facilities, and socio-economic, cultural and regional differences. These factors may contribute to variations in morbidity patterns across the trial sites. To minimize differences, all sites were provided with master study document templates (SoPs/operational manuals and associated documents viz., parent information sheets (PIS) and consent forms (CF), case report forms (CRFs), and study logs) developed by the study collaborators team, to ensure consistency of recruitment and data collection across sites. All sites received study-specific training from the collaborators during site initiation visits (SIVs) on the processes for recruitment, data collection, query resolution, and biological sample/microbiology laboratory procedures. Repeated quality assurance measures such as retraining of site staff on protocol and study procedures, review of process indicators at the sites as well as central periodic data review to understand the morbidity patterns, and monitoring visits by the clinical trial monitors to sites should be implemented vigorously. Variations in recruitment rates across sites The sites have shown variability in recruiting a sufficient number of subjects, as planned due to lower delivery rate, low birth weight infants, potential subjects from out of study catchment area, competing studies at particular site The site teams were involved in weekly meetings to understand their performance. The difficulties faced for enrolment were discussed among the site teams. The possible solutions were suggested to avoid future difficulties. The CRO team was instructed to thoroughly review the consent documentation Develop realistic recruitment plans with timelines to avoid variations across sites, delays and study on schedule. The resources allocation should not be uniform across all sites. The enrolment capacity of the site should be assessed during the initial site readiness assessment and the resources should be allocated accordingly. Laboratory assessments CONS/contaminants observed in blood culture test CONS status of isolates is to be decided by the CEAC. RESULTS /POTENTIAL SOLUTIONS Central Endpoint Adjudication Committee for final/Primary outcomes : Central adjudication plays a key role in achieving consistent, accurate, independent, unbiased, and blinded evaluation of suspected clinical events reported by investigators in multicentre/large clinical trials [16]. This helps in the prevention of misclassification of outcomes in clinical trials that can lead to biased estimates of treatment effect and reduced power. Ensuring appropriate adjudication methods to minimize outcome misclassification is therefore essential [17]. The original protocol of the ProSPoNS trial did not envisage having a CEA committee because the investigators did not anticipate the outcome variations across the sites despite following uniform protocols. The adjudication committee will look at these cases in an unbiased and blinded manner. In the published protocol [1], the study hypothesis and primary objective are based on ‘Sepsis’, the primary outcome has been specified as Sepsis/PSBI, whereas the sample size estimation was performed based on the ‘Physician diagnosed sepsis’. In order to bring clarity about primary study outcome the definition needs to be documented explicitly before study completion or unmasking of the trial data to enable drafting of the study statistical analysis plan accordingly. To align all the three above, the investigators meeting, held on 17 th -18 th August 2023, at MGIMS Sevagram, Wardha, deliberated and unanimously agreed that “Physician diagnosed sepsis” is the primary study outcome which includes Sepsis/PSBI. In order to align the primary objective and outcome with the stated hypothesis, we propose a Central Endpoint Adjudication process for enumeration of the primary outcomes listed across all six sites of the trial. Physician diagnosed sepsis ’ will be decided by the Central Endpoint Adjudication (CEA) committee based on four criteria for every event of sickness in a study participant namely Blood culture status, Sepsis screen status, PSBI/non-PSBI signs and symptoms and the Clinical course during the event of sickness including use of antibiotics. The CEA committee will be chaired by one external Subject Expert and shall consist of all Site PIs, Trial statistician and Microbiologist. The CEA committee will go through every event of sickness based on these four criteria and make a decision regarding whether that event of sickness would be classified as ‘ Physician diagnosed sepsis ’ or not. The above clarification does not make any change to the approved study protocol (Protocol No.5/7/915/2012 Version 3.1 dated 14 Feb 2020). The process of Adjudication: The first step is the discussion of cases by the full bench of the adjudication committee, and the second step is the resolution of disagreements in the adjudication (if any) using a vote. The adjudication committee will discuss all disagreements with all the investigators. A data set would be created with the data of participants and all the episodes of morbidities as subfolders in chronological order, with the starting point being the start date of the event, all forms related to that particular event, especially the outcome-related variables of the data from all the required forms (AE, SAE, FUP, SPF, Conmed, and birth history) would be retrieved and linked to generate a final summary/ narrative of the cases from the frozen variables requiring adjudication using a software program in ‘R’ would be prepared for the CEAC committee. Proposed examples of 10 scenarios for the adjudication process 1. SAEs with hospitalization 2. AEs with Antibiotic administration 3. Blood culture – positive cases with no antibiotic treatment 4. Sepsis screen positives with no antibiotic treatment 5. Both blood culture and screen positives with no antibiotic treatment 6. Sepsis positive cases without SAE 7. Culture/sepsis positive but not PSBI by with/without sign/symptoms 8. Culture/sepsis negative with PSBI with antibiotic treatment 9. All death cases 10. Death cases after hospitalization Other Potential Solutions Site selection/background check Study sites of the trial were selected through a multistep objective process similar to the method quoted by [18], starting with an open call on the ICMR website, with due consideration of experience of the investigators in conduct of community based studies, publications in high impact journals composite score, competence in the measurement of morbidities as judged by publications, availability of infrastructural facilities relevant to clinical trials, regulatory (CDSCO) requirement, linkages with local hospitals, and capability to recruit LBW infants in a stipulated time frame following a transparent procedure. However, a more intensive background check with regard to the rates of morbidities /outcome of interest would have been helpful in bringing homogeneity. Currently, there are tools available to aid in the process of site selection: SiteIQ, is one such tool designed to help sponsors and CROs gain unique insight into site performance. It highlights institution expertise, offers performance metrics from completed studies, and curates customized recommendations [19]. Choosing hard Vs soft outcomes Choice of hard objectively measurable outcomes [20] such as deaths, duration of hospitalization rather than soft outcomes with subjective variability in definitions & scope of personal measurement errors /judgments should be preferred as they would help the analysis without prejudice/bias. However, death as an outcome leads to another challenging requirement of huge sample sizes, longer follow up periods etc. Substantiation of clinical findings with biological outcomes: In order to explain the heterogeneity between the sites, in the ProSPoNS trial the investigators have opted to undertake the gut-colonization study to learn the microbiome in different geographic study sites. It would help in substantiating the clinical findings with biological data. An additional metagenomic study using the microbiome data collected from stool DNA at all study sites is being added to the already ongoing gut colonization study at one site. Corroboration of clinical findings with biological data is a way of authenticating the findings. The Alpha & Beta diversity/ the findings may help in validation of the clinical outcomes. Discussion The ProSPoNS trial is a multicentre trial ongoing at six sites across India. Complexity occurs in three dimensions in clinical trials: the protocol, the operations, and the potential for unanticipated change. Trials with complexity in any of these domains need special flexibility to easily adapt to the emerging variability and change [ 21 ]. The heterogeneity observed in the trial may be a reflection of genuine differences in the rates of neonatal sepsis between southern and northern populations of India and elsewhere as mentioned in literature [ 22 – 25 ]. Review of the literature suggests considerable heterogeneity in the definitions of neonatal sepsis, [ 26 ]. A related problem in these definitions is the use of subjective criteria, absence of validation leading to inability for comparison and generalizability. Most notably, there is a focus on microbiological culture for definitive diagnosis, thereby reliance of bacteriological isolation and not sepsis per se. Adult sepsis definition relies on multi-organ impairment and not on bacterial isolation alone [ 27 ]. A systematic review [ 26 ] identified 128 definitions from 80 RCTs after searching 688 articles. The single most common definition of neonatal sepsis was defined by blood culture alone (n = 35), followed by culture and clinical signs (n = 29), and then laboratory tests/clinical signs (n = 25). Blood culture featured in 83 definitions, laboratory testing featured in 48 definitions, while clinical signs and radiology featured in 80 and 8 definitions, respectively. In another exercise, we have examined the certainty of evidence from Cochrane systematic reviews on neonatal sepsis (personal communication; presented at the Cochrane colloquium 2023). Eight out of 11 Cochrane reviews reported low to very low certainty of evidence for reasons of indirectness and inconsistency, including inconsistency in how neonatal sepsis was defined in the studies [ 14 , 28 – 32 ]. During the Covid-19 pandemic, we adopted the online mode for trainings aa well as monitoring that was in line with the International Council for Harmonization of Technical Requirements of Pharmaceuticals for Human Use integrated addendum to ICH E6(R1): Guideline for Good Clinical Practice ICH E6(R3) [ 33 ]. However, it was challenging and required a lot of efforts from participants as well as trainers to successfully conduct the session s. Conclusion In conclusion, the ProSPoNS trial, a multicenter trial being implemented across India, encountered significant challenges in its implementation and the necessity for amendment that was unforeseen. Amid the COVID-19 pandemic, adopting online modes for training and monitoring aligned with international guidelines posed additional challenges, necessitating considerable efforts from participants and trainers. Addressing these challenges and standardizing the definitions would ensure the validity of the trial and research outcomes. The real time challenges faced in the implementation of the ProSPoNS trial have led us to the decision of forming a Central Endpoint Adjudication Committee as a way forward for evaluation of the final outcomes of the study. Abbreviations AEs- Adverse Events CRP -C-Reactive protein CDSCO – Central Drug Standard Control Organization CRF- Case Report Forms CEA- Central Endpoint Adjudication CONMEDS- Concomitant Medication CF- Consent forms eCRFs- Electronic Case Record Forms FUP- Follow-up ICMR- Indian Council of Medical research JIPMER -Jawaharlal Institute of Postgraduate Medical Education and Research LOS- Late onset sepsis PIS- Parent Information Sheets RCT- Randomized Controlled Trial SAE- Serious Adverse Events SIVs- Site Initiation Visits SP- Study Physician SPF- Study Physician Form TAG- The technical advisory group TLC- Total leucocyte count WHO- World Health Organization UNICEF- United Nations International Children's Emergency Fund Declarations Ethics approval and consent to participate The ethics approval and participation consent details are already listed in the ProSPoNS study Trial protocol published in BMC Trials 2021. Consent for publication Not applicable. Availability of data and material Not Applicable. Competing interests All authors declare that they have no competing interest. Funding The study is funded by the Department of Health and Social Care, the Department for International Development, the Global Challenges Research Fund, the Medical Research Council, and Wellcome Trust. The funding body has no role in the designing of the study and collection, analysis, and interpretation of data and in writing the manuscript. Authors' contributions APS drafted the manuscript. DKR, KSM, SSG,RP, ASK and GD provided inputs to the initial drafts. SS, AB, SP,SN, AVP,AB, PD, MG, TF, RN, AK, MA, PAK and RMP provided inputs for the improvement of the manuscript. Acknowledgements We would like to thank the Indian Council of Medical Research (ICMR) for the permission to conduct the study and the UK Research and Innovation, Medical Research Council, UK, for funding the trial under the Global Health Trials [JGHT] scheme 8, jointly funded by the DFID/NIHR/MRC/Wellcome Trust. Consortia the ProSPoNS study Group Pankaj Gupta , Indian Council of Medical Research (ICMR) Headquarters, V Ramalingaswami Bhawan, Ansari Nagar, New Delhi, Delhi, 110029, India Payal Kumari, Indian Council of Medical Research (ICMR) Headquarters, V Ramalingaswami Bhawan, Ansari Nagar, New Delhi, Delhi, 110029, India References Sinha AP, Gupta SS, Poluru R, Raut A V., Arora NK, Pandey RM, et al. Evaluating the efficacy of a multistrain probiotic supplementation for prevention of neonatal sepsis in 0-2-month-old low birth weight infants in India-the “ProSPoNS” Study protocol for a phase III, multicentric, randomized, double-blind, placebo-controlled trial. Trials. 2021;22. 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Health","correspondingAuthor":false,"prefix":"","firstName":"Rashmita","middleName":"","lastName":"Nayak","suffix":""},{"id":280555781,"identity":"119e59a1-0788-40c8-b9bd-1741fbc711b6","order_by":17,"name":"Arti Kapil","email":"","orcid":"","institution":"AIIMS: All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Arti","middleName":"","lastName":"Kapil","suffix":""},{"id":280555782,"identity":"d2e96110-447a-4a6d-8864-db11c4233a4b","order_by":18,"name":"Mohd. Azam","email":"","orcid":"","institution":"Kalawati Saran Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mohd.","middleName":"","lastName":"Azam","suffix":""},{"id":280555783,"identity":"bdbf0a0c-ae77-499e-ba7c-3cbc3031defe","order_by":19,"name":"Pearlin A Khan","email":"","orcid":"","institution":"ICMR: Indian Council of Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Pearlin","middleName":"A","lastName":"Khan","suffix":""},{"id":280555784,"identity":"59a1f90d-4fb6-4a64-b18c-155ae6df5623","order_by":20,"name":"Ravindra Mohan Pandey","email":"","orcid":"","institution":"AIIMS: All India Institute of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ravindra","middleName":"Mohan","lastName":"Pandey","suffix":""},{"id":280555785,"identity":"f260e72d-b095-4ea0-b1da-54015a8b81ee","order_by":21,"name":"Narendra Kumar Arora","email":"","orcid":"","institution":"INCLEN Inc: International Clinical Epidemiology Network","correspondingAuthor":false,"prefix":"","firstName":"Narendra","middleName":"Kumar","lastName":"Arora","suffix":""}],"badges":[],"createdAt":"2024-02-03 15:19:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3924417/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3924417/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53116976,"identity":"820865e0-0662-4b88-8f35-45fe45f1b686","added_by":"auto","created_at":"2024-03-20 19:45:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":50775,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdjudication Process of ProSPoNS Trial \u003c/strong\u003e(CONMEDS- Concomitant Medication, SP- Study Physician, SAE- Serious adverse events, eCRFs- Electronic Case Record Forms, PSBI- Possible Serious Bacterial Infection, CEAC- Central Endpoint Adjudication committee)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3924417/v1/363b6e7937295ac9fd7b75a3.png"},{"id":53118153,"identity":"928c4a85-6cdc-48e4-979d-6ce0deb3f13e","added_by":"auto","created_at":"2024-03-20 19:53:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":567173,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3924417/v1/5291c19d-1a75-42eb-ac4f-edf7ca3d9252.pdf"}],"financialInterests":"","formattedTitle":"Challenges in Trials on Neonatal Sepsis- Case of ProSPoNS Trial \u0026amp; Role of Central Endpoint Adjudication","fulltext":[{"header":"Background","content":"\u003cp\u003eWe have previously published a protocol for the currently ongoing Phase III Multicentre randomized double-blind placebo-controlled trial (ProSPoNS trial) evaluating role of probiotics (Vivomix) in prevention of neonatal sepsis in 0-2 month old Indian infants [1]. The trial is based on our previously published study that enrolled 1340 low Birth Weight Neonates [2] showing an overall 21% non-significant reduction in the incidence of suspected sepsis diagnosed by field investigators using the possible serious bacterial infection (PSBI) definition of WHO/UNICEF to detect suspected sepsis in the trial. However, in non pre-specified sub-group analysis among infants 1.5 -2.00 kg, a 71% reduction in incidence of sepsis in the intervention arm was observed. These results formed the rationale for the current trial aiming to find the conclusive evidence of a potential benefit of the probiotic intervention. The technical advisory group (TAG) of the Indian Council of Medical Research (ICMR) suggested planning and implementing a larger trial with a sufficient sample size and a specific definition of the primary outcome (sepsis), since the PSBI definition used earlier was considered to be lacking in specificity. Subsequently, an application to the UKRI JGHT call 8 was made with success [3].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In the larger ProSPoNS trial that is ongoing, we opted for a stringent definition of the primary outcome Sepsis defined as:\u0026nbsp;one or more clinical signs suggestive of sepsis with a microbial isolate on blood culture; or a neonate with sterile blood culture with at least 2 sepsis screen markers being abnormal (CRP \u0026gt;12 mg/L, Absolute neutrophil count\u0026lt;1500/mm\u003csup\u003e3\u003c/sup\u003e, TLC\u0026lt;5000/mm\u003csup\u003e3\u003c/sup\u003e, ESR\u0026gt;15 mm, Immature to total neutrophil ratio \u0026gt; 0.2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePossible serious bacterial infection (PSBI) defined by WHO UNICEF is our second primary outcome in the trial. \u0026nbsp;We used data of \u0026lsquo;Physician Diagnosed sepsis\u0026rsquo; from the pilot trial to calculate the sample size for the ProSPoNS trial.\u003c/p\u003e\n\u003cp\u003eSecondary outcomes include: 1)\u0026nbsp;Stool colonization patterns at baseline day 0, day 21 and at the end of the study (day 60) in a subsample. 2) Death and late-onset sepsis: Comparison of all-cause deaths and late-onset sepsis between the intervention and control groups. 3) Clinical severe infection: One or more clinical signs - not feeding well, fever (temperature \u0026ge; 38\u0026deg;C), low body temperature (\u0026lt; 35.5\u0026deg;C), severe chest in-drawing, the movement only when stimulated as\u0026nbsp;confirmed by the study physician. 4) Critical Illness: One or more of clinical signs - convulsions, unable to feed at all, no movement on stimulation, unable to cry, bulging fontanelle and cyanosis as\u0026nbsp;confirmed by the study physician. 5) Cost-effectiveness/utility of the probiotics intervention vs control is being taken up as a sub-study to inform policy.\u003c/p\u003e\n\u003cp\u003eThe protocol [1]\u003csup\u003e\u0026nbsp;\u003c/sup\u003eoutlined the following: The IP administration compliance check and safety follow up/Screening for morbidities would be conducted in the community by trained field workers who are trained on IMNCI (2019) guidelines, The participant would be followed up daily in the first week of life, thrice per week during weeks 2\u0026ndash;4 of life, and weekly once in the second month of life. Field workers will be trained to screen and detect sick infants as per PSBI protocol; in case of any complaints, the field worker will accompany the parents with their infant(s) to the site hospital for further examination by the study investigator. Sepsis screen and blood culture would be performed if considered necessary for the diagnosis of neonatal sepsis, and appropriate treatment would be provided as per hospital or study protocol. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this article, we communicate the decision of the ProSPoNS trial investigators to form an adjudication committee as an addendum to the original published protocol in \u0026lsquo;Trials 2021\u0026apos;. \u0026nbsp;We explain the reasons for coming to this decision by highlighting the challenges faced in trial implementation, the problem due to the heterogeneity across sites in diagnosis of sepsis and the academic problem with the definition of sepsis in the neonatal/ young infant population.\u0026nbsp;\u003c/p\u003e"},{"header":"Implementation Challenges in the ProSPoNS Trial","content":"\u003cp\u003e\u003cstrong\u003eComplex Multi-centre design\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe randomised controlled trial (RCT) is the gold standard experimental design for assessment of interventions [4]. The Multicentre trial design allows for faster recruitment over time, recruitment from different populations maximizes the generalizability [5]. However, the use of multiple clinical sites introduces complexity in clinical trials [6] \u0026nbsp;as they differ in geographical location, setting, distances to health care facilities, socio-economic factors, morbidity patterns, and ancillary treatment practices [7]. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHeterogeneity /Extreme variation across sites:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial steering committee observed variation in the morbidity pattern (adverse events, severe adverse events) across the study sites, there being one outlier each in both directions. This could be due to the sites being systematically different from one another, e.g., due to differences in patient populations, ancillary treatment practices, or other factors [7]. \u0026nbsp;Repeated quality assurance measures such as retraining of staff, review of process indicators at the sites as well as monitoring visits by the clinical trial monitors were conducted to have uniform identification and reporting of cases across all sites could not result in substantial changes in the observed morbidity pattern during trial implementation. The number of cases is being reported specifically at the JIPMER, Puduchery site is lower than the other five sites. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of Neonatal sepsis\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNeonatal sepsis is commonly termed as an infection involving the bloodstream in newborn infants less than 28 days old. Diagnosis of sepsis in newborns is not easy due to the lack of a uniform definition of sepsis unlike in children and adults where they are labeled as either \u0026lsquo;culture positive sepsis\u0026rsquo; or \u0026lsquo;clinical sepsis\u0026rsquo;. The newborns suspected of sepsis based on maternal or peri-natal risk factors may be administered antibiotics, but their clinical course, sepsis screen and blood cultures if not suggestive of sepsis, are then labeled as \u0026lsquo;no Sepsis; after 3 days.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResearchers/academicians recognize the problem of defining neonatal sepsis and lay down ground rules/ SOPs [8, 9] for a working definition in studies:- have discussed cases labeled as \u0026lsquo;Culture Negative Sepsis\u0026rsquo; (suspected cases where despite sample collection bacteria may not grow because of several factors such as the timing of collection, bacterial load and prior antibiotic consumption. \u0026nbsp;The term \u0026lsquo;culture negative sepsis\u0026rsquo; has been explained based on the following criteria given below:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;1). Symptomatology suggestive of sepsis or at least two maternal risk factors; 2) Individual sepsis screen markers namely total leucocyte count (TLC) and absolute neutrophil count (Neutropenia) were considered. The ability of C-Reactive protein (CRP) as a marker of late onset sepsis (LOS) remains controversial in literature [10]. 3) The clinical course of the disease where there is no other explanation for the symptoms can then be attributed to sepsis. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the beginning of the study it was assumed that blood culture positive sepsis is the gold standard method of defining neonatal sepsis. However, completion of microbiological tests results in a yield of 30-40% cases of culture positives, therefore it is not incorrect to say that it cannot reliably rule-out sepsis. Reported rates of \u0026lsquo;culture-negative\u0026rsquo; or \u0026lsquo;suspected\u0026rsquo; sepsis vary widely in the literature. While some experts advocate to consider sepsis, evaluations completed after 48\u0026ndash;72 hours of negative blood cultures, data available from two large randomized controlled trials (RCTs) in recent years [11, 12] show culture-negative sepsis rates of 56% and 46%, respectively. By reviewing all morbidity cases individually, the CEAC would take into consideration the culture negative - reports and the contaminants with a balanced view.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChallenges during the conduct of PROSPONS trial\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eRemote Vs. On-site trainings:\u003c/p\u003e\n\u003cp\u003eIn the year 2020 the world was hit by the Covid 19 pandemic, first cases appeared in India in March 2020 coinciding with the launch of the preparatory phase of the trial implementation. \u0026nbsp;In order not to deviate from the committed timelines, we decided to adopt the online mode of functioning for the preparatory phase activities such as trainings of staff, the site readiness/feasibility visits, the investigators meetings and the site initiation visits. Under normal circumstances and as per Good clinical practices, the above activities are expected to be conducted physically.\u003c/p\u003e\n\u003cp\u003eRecruitment Challenge:\u003c/p\u003e\n\u003cp\u003eWe observe variability in the recruitment pattern across sites. Despite all efforts the same pattern is persisting till date. Some of the reasons for low recruitment rate in the trial observed by us are: disruption of the obstetric services due to COVID-19 priority, lower delivery rate of low birth rate infants, potential participants from out of study catchment area, competing studies at particular site, and lack of engagement are other reasons [13]. Less than optimum recruitment at the site is referred as a \u0026lsquo;research waste\u0026rsquo; in view of time and money spent to build the site [14]. A review of trials funded and published by the UK\u0026rsquo;s Health Technology Assessment program has reported that recruitment patterns in multicenter randomized trials fit more closely to Price\u0026apos;s Law (50% of participants are recruited by the square root of the total number of sites), than the Pareto Principle (80% of participants are recruited by 20% of sites,) [13].\u003c/p\u003e\n\u003cp\u003eThe trialists can hope for a uniform recruitment across the sites in an ideal condition [15], however it is difficult to achieve. \u0026nbsp;A few additional challenges faced during implementation, measures adopted and lessons learnt are summarized in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"3\" valign=\"top\"\u003e\u003cstrong\u003eTable 1: Challenges, measures adopted, lessons learnt and recommendations from the implementation of the ProSPoNS trial\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\u003cstrong\u003eChallenges\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"53.535353535353536%\" valign=\"top\"\u003e\u003cstrong\u003eMeasures adopted\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\u003cstrong\u003eLessons learnt/Recommendations\u0026nbsp;\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\u003cstrong\u003eRegulatory and ethical committee approvals (study sites)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"53.535353535353536%\" valign=\"top\"\u003e\n \u003cul\u003e\n \u003cli\u003eComplex and time-consuming process of obtaining multi-layered administrative, regulatory, and ethical approvals for sponsor as well as participating sites. \u0026nbsp;Differences in approval requirements and timelines further cause delayed study initiation/implementation. The COVID 19 pandemic affected the EC\u0026rsquo;s functioning, resulting in sparse meetings.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe different site-specific EC requirements, variation between sites demanded several rounds of revisions and close coordination with the site investigators.\u003cbr\u003e\u0026nbsp;The sponsor collaborated with a regulatory expert to mitigate the regulatory submission and approval challenges.\u003c/li\u003e\n \u003cli\u003eThe site readiness was assessed before initiation; the CRO team was involved in catalyzing the EC submission process by actively following up with the sites.\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003eThis highlights the importance/need for streamlining and collating the EC submission documents in advance. \u0026nbsp;The approval process at national and local levels should consider following practical timelines for approvals.\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\u003cstrong\u003eHeterogeneity/Extreme variation across sites:\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"53.535353535353536%\" valign=\"top\"\u003eThe ProSPoNS trial was being implemented across geographically diverse sites (public/private/Trust) with differing levels of handling patient/neonates\u0026rsquo; volume, variable mortality \u0026amp; morbidity patterns, antibiotics use, clinical and health-care utilization practices; distance to health care facilities, and socio-economic, cultural and regional differences. These factors may contribute to variations in morbidity patterns across the trial sites.\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003cbr\u003eTo minimize differences, all sites were provided with master study document templates (SoPs/operational manuals and associated documents viz., parent information sheets (PIS) and consent forms (CF), case report forms (CRFs), and study logs) developed by the study collaborators team, to ensure consistency of recruitment and data collection across sites. All sites received study-specific training from the collaborators during site initiation visits (SIVs) on the processes for recruitment, data collection, query resolution, and biological sample/microbiology laboratory procedures.\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003eRepeated quality assurance measures such as retraining of site staff on protocol and study procedures, review of process indicators at the sites as well as central periodic data review to understand the morbidity patterns, and monitoring visits by the clinical trial monitors to sites should be implemented vigorously.\u0026nbsp;\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\u003cstrong\u003eVariations in recruitment rates across sites\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"53.535353535353536%\" valign=\"top\"\u003e\n \u003cul\u003e\n \u003cli\u003eThe sites have shown variability in recruiting a sufficient number of subjects, as planned due to lower delivery rate, low birth weight infants, potential subjects from out of study catchment area, competing studies at particular site\u003c/li\u003e\n \u003cli\u003eThe site teams were involved in weekly meetings to understand their performance. The difficulties faced for enrolment were discussed among the site teams. The possible solutions were suggested to avoid future difficulties. The CRO team was instructed to thoroughly review the consent documentation\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003eDevelop realistic recruitment plans with timelines to avoid variations across sites, delays and study on schedule. The resources allocation should not be uniform across all sites. The enrolment capacity of the site should be assessed during the initial site readiness assessment and the resources should be allocated accordingly.\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\u003cstrong\u003eLaboratory assessments\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"53.535353535353536%\" valign=\"top\"\u003eCONS/contaminants observed in blood culture test\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003eCONS status of isolates is to be decided by the CEAC.\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"RESULTS /POTENTIAL SOLUTIONS","content":"\u003cp\u003e\u003cstrong\u003eCentral Endpoint Adjudication Committee for final/Primary outcomes\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eCentral adjudication plays a key role in achieving consistent, accurate, independent, unbiased, and blinded evaluation of suspected clinical events reported by investigators in multicentre/large clinical trials [16]. This helps in the prevention of misclassification of outcomes in clinical trials that can lead to biased estimates of treatment effect and reduced power. Ensuring appropriate adjudication methods to minimize outcome misclassification is therefore essential [17]. The original protocol of the ProSPoNS trial did not envisage having a CEA committee because the investigators did not anticipate the outcome variations across the sites despite following uniform protocols. The adjudication committee will look at these cases in an unbiased and blinded manner. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the published protocol [1], the study hypothesis and primary objective are based on \u0026lsquo;Sepsis\u0026rsquo;, the primary outcome has been specified as Sepsis/PSBI, whereas the sample size estimation was performed based on the \u0026lsquo;Physician diagnosed sepsis\u0026rsquo;. \u0026nbsp;In order to bring clarity about primary study outcome the definition needs to be documented explicitly before study completion or unmasking of the trial data to enable drafting of the study statistical analysis plan accordingly. To align all the three above, the investigators meeting, held on 17\u003csup\u003eth\u003c/sup\u003e-18\u003csup\u003eth\u003c/sup\u003e August 2023, at MGIMS Sevagram, Wardha, deliberated and unanimously agreed that \u003cem\u003e\u0026ldquo;Physician diagnosed sepsis\u0026rdquo;\u0026nbsp;\u003c/em\u003eis the primary study outcome which includes Sepsis/PSBI. In order to align the primary objective and outcome with the stated hypothesis, we propose a Central Endpoint Adjudication process for enumeration of the primary outcomes listed across all six sites of the trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePhysician diagnosed sepsis\u003c/em\u003e\u0026rsquo; will be decided by the Central Endpoint Adjudication (CEA) committee based on four criteria for every event of sickness in a study participant namely Blood culture status, Sepsis screen status, PSBI/non-PSBI signs and symptoms and the Clinical course during the event of sickness including use of antibiotics.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe CEA committee will be chaired by one external Subject Expert and shall consist of all Site PIs, Trial statistician and Microbiologist. The CEA committee will go through every event of sickness based on these four criteria and make a decision regarding whether that event of sickness would be classified as \u0026lsquo;\u003cem\u003ePhysician diagnosed sepsis\u003c/em\u003e\u0026rsquo; or not.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe above clarification does not make any change to the approved study protocol (Protocol No.5/7/915/2012 Version 3.1 dated 14 Feb 2020). \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe process of Adjudication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe first step is the discussion of cases by the full bench of the adjudication committee, and the second step is the resolution of disagreements in the adjudication (if any) using a vote. The adjudication committee will discuss all disagreements with all the investigators. \u0026nbsp;A data set would be created with the data of participants and all the episodes of morbidities as subfolders in chronological order, with the starting point being the start date of the event, all forms related to that particular event, especially the outcome-related variables of the data from all the required forms (AE, SAE, FUP, SPF, Conmed, and birth history) would be retrieved and linked to generate a \u0026nbsp; final summary/ narrative of the cases from the frozen variables requiring adjudication using a software program in \u0026lsquo;R\u0026rsquo; would be prepared for the CEAC committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProposed examples of 10 scenarios for the adjudication process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. SAEs with hospitalization\u003c/p\u003e\n\u003cp\u003e2. AEs with Antibiotic administration\u003c/p\u003e\n\u003cp\u003e3. Blood culture \u0026ndash; positive cases with no antibiotic treatment\u003c/p\u003e\n\u003cp\u003e4. Sepsis screen positives with no antibiotic treatment\u003c/p\u003e\n\u003cp\u003e5. Both blood culture and screen positives with no antibiotic treatment\u003c/p\u003e\n\u003cp\u003e6. Sepsis positive cases without SAE\u003c/p\u003e\n\u003cp\u003e7. Culture/sepsis positive but not PSBI by with/without sign/symptoms\u003c/p\u003e\n\u003cp\u003e8. Culture/sepsis negative with PSBI with antibiotic treatment\u003c/p\u003e\n\u003cp\u003e9. All death cases\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e10. Death cases after hospitalization \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOther Potential Solutions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSite selection/background check\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy sites of the trial were selected through a multistep objective process similar to the method quoted by [18], starting with an open call on the ICMR website, with due consideration of experience of the investigators in conduct of community based studies, publications in high impact journals composite score, competence in the measurement of morbidities as judged by publications, availability of infrastructural facilities \u0026nbsp;relevant to clinical trials, regulatory (CDSCO) requirement, linkages with local hospitals, \u0026nbsp;and capability to recruit LBW infants \u0026nbsp;in a stipulated time frame following a transparent procedure. However, a more intensive background check with regard to the rates of morbidities /outcome of interest would have been helpful in bringing homogeneity. Currently, there are tools available to aid in the process of site selection: SiteIQ, is one such tool designed to help sponsors and CROs gain unique insight into site performance. It highlights institution expertise, offers performance metrics from completed studies, and curates customized recommendations [19].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChoosing hard Vs soft outcomes \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChoice of hard objectively measurable outcomes [20] such as deaths, duration of hospitalization rather than soft outcomes with subjective variability in definitions \u0026amp; scope of personal measurement errors /judgments should be preferred as they would help the analysis without prejudice/bias. \u0026nbsp;However, death as an outcome leads to another challenging requirement of huge sample sizes, longer follow up periods etc.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubstantiation of clinical findings with biological outcomes:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn order to explain the heterogeneity between the sites, in the ProSPoNS trial the investigators have opted to undertake the gut-colonization study to learn the microbiome in different geographic study sites. It would help in substantiating the clinical findings with biological data. An additional metagenomic study using the microbiome data collected from stool DNA at all study sites is being added to the already ongoing gut colonization study at one site. Corroboration of clinical findings with biological data is a way of authenticating the findings. The Alpha \u0026amp; Beta diversity/ the findings may help in validation of the clinical outcomes.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe ProSPoNS trial is a multicentre trial ongoing at six sites across India. Complexity occurs in three dimensions in clinical trials: the protocol, the operations, and the potential for unanticipated change. Trials with complexity in any of these domains need special flexibility to easily adapt to the emerging variability and change [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The heterogeneity observed in the trial may be a reflection of genuine differences in the rates of neonatal sepsis between southern and northern populations of India and elsewhere as mentioned in literature [\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eReview of the literature suggests considerable heterogeneity in the definitions of neonatal sepsis, [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. A related problem in these definitions is the use of subjective criteria, absence of validation leading to inability for comparison and generalizability. Most notably, there is a focus on microbiological culture for definitive diagnosis, thereby reliance of bacteriological isolation and not sepsis per se. Adult sepsis definition relies on multi-organ impairment and not on bacterial isolation alone [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. A systematic review [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] identified 128 definitions from 80 RCTs after searching 688 articles. The single most common definition of neonatal sepsis was defined by blood culture alone (n\u0026thinsp;=\u0026thinsp;35), followed by culture and clinical signs (n\u0026thinsp;=\u0026thinsp;29), and then laboratory tests/clinical signs (n\u0026thinsp;=\u0026thinsp;25). Blood culture featured in 83 definitions, laboratory testing featured in 48 definitions, while clinical signs and radiology featured in 80 and 8 definitions, respectively.\u003c/p\u003e \u003cp\u003eIn another exercise, we have examined the certainty of evidence from Cochrane systematic reviews on neonatal sepsis (personal communication; presented at the Cochrane colloquium 2023). Eight out of 11 Cochrane reviews reported low to very low certainty of evidence for reasons of indirectness and inconsistency, including inconsistency in how neonatal sepsis was defined in the studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30 CR31\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDuring the Covid-19 pandemic, we adopted the online mode for trainings aa well as monitoring that was in line with the International Council for Harmonization of Technical Requirements of Pharmaceuticals for Human Use integrated addendum to ICH E6(R1): Guideline for Good Clinical Practice ICH E6(R3) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, it was challenging and required a lot of efforts from participants as well as trainers to successfully conduct the session\u003cb\u003es.\u003c/b\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, the ProSPoNS trial, a multicenter trial being implemented across India, encountered significant challenges in its implementation and the necessity for amendment that was unforeseen. Amid the COVID-19 pandemic, adopting online modes for training and monitoring aligned with international guidelines posed additional challenges, necessitating considerable efforts from participants and trainers. Addressing these challenges and standardizing the definitions would ensure the validity of the trial and research outcomes. The real time challenges faced in the implementation of the ProSPoNS trial have led us to the decision of forming a Central Endpoint Adjudication Committee as a way forward for evaluation of the final outcomes of the study.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAEs- Adverse Events\u003c/p\u003e\n\u003cp\u003eCRP -C-Reactive protein\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCDSCO \u0026ndash; Central Drug Standard Control Organization\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCRF- Case Report Forms\u003c/p\u003e\n\u003cp\u003eCEA- Central Endpoint Adjudication\u003c/p\u003e\n\u003cp\u003eCONMEDS- Concomitant Medication\u003c/p\u003e\n\u003cp\u003eCF- Consent forms\u003c/p\u003e\n\u003cp\u003eeCRFs- Electronic Case Record Forms\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFUP- \u0026nbsp;Follow-up\u003c/p\u003e\n\u003cp\u003eICMR- Indian Council of Medical research\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJIPMER -Jawaharlal Institute of Postgraduate Medical Education and Research\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLOS- Late onset sepsis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePIS- Parent Information Sheets\u003c/p\u003e\n\u003cp\u003eRCT- Randomized Controlled Trial\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSAE- Serious Adverse Events\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSIVs- Site Initiation Visits\u003c/p\u003e\n\u003cp\u003eSP- Study Physician\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSPF- Study Physician Form\u003c/p\u003e\n\u003cp\u003eTAG- The technical advisory group\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTLC- Total leucocyte count\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWHO- World Health Organization\u003c/p\u003e\n\u003cp\u003eUNICEF- United Nations International Children\u0026apos;s Emergency Fund\u003c/p\u003e"},{"header":"Declarations","content":"\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe ethics approval and participation consent details are already listed in the ProSPoNS study Trial protocol published in BMC Trials 2021. \u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eNot applicable.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eAvailability of data and material\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eNot Applicable.\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAll authors declare that they have no competing interest.\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe study is funded by the Department of Health and Social Care, the Department for International Development, the Global Challenges Research Fund, the Medical Research Council, and Wellcome Trust. The funding body has no role in the designing of the study and collection, analysis, and interpretation of data and in writing the manuscript.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAPS drafted the manuscript. DKR, KSM, SSG,RP, ASK and \u0026nbsp;GD provided inputs to the initial drafts. \u0026nbsp;SS, AB, SP,SN, AVP,AB, PD, MG, TF, RN, AK, MA, PAK and RMP provided inputs for the improvement of the manuscript.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eWe would like to thank the Indian Council of Medical Research (ICMR) for the permission to conduct the study and the UK Research and Innovation, Medical Research Council, UK, for funding the trial under the Global Health Trials [JGHT] scheme 8, jointly funded by the DFID/NIHR/MRC/Wellcome Trust.\u003c/p\u003e\n\u003ch3\u003eConsortia\u003c/h3\u003e\n\u003ch3\u003ethe ProSPoNS study Group\u003c/h3\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003ePankaj Gupta , Indian Council of Medical Research (ICMR) Headquarters, V Ramalingaswami Bhawan, Ansari Nagar, New Delhi, Delhi, 110029, India\u003c/li\u003e\n \u003cli\u003ePayal Kumari, Indian Council of Medical Research (ICMR) Headquarters, V Ramalingaswami Bhawan, Ansari Nagar, New Delhi, Delhi, 110029, India\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSinha AP, Gupta SS, Poluru R, Raut A V., Arora NK, Pandey RM, et al. 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Trials. 2018;19:1\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eA framework to identify complex clinical trials | Drug Discovery. https://www.drugdiscoverytrends.com/defining-complexity-a-framework-to-identify-complex-clinical-trials-and-set-them-up-for-success/. Accessed 6 Dec 2023.\u003c/li\u003e\n\u003cli\u003eBang A, Baitule S, Deshmukh M, Bang A, Duby J. Home-based management of neonatal sepsis: 23 years of sustained implementation and effectiveness in rural Gadchiroli, India, 1996\u0026ndash;2019. BMJ Glob Health. 2022;7:8469.\u003c/li\u003e\n\u003cli\u003eMukhopadhyay R, Arora NK, Sharma PK, Dalpath S, Limbu P, Kataria G, et al. Lessons from implementation research on community management of Possible Serious Bacterial Infection (PSBI) in young infants (0-59 days), when the referral is not feasible in Palwal district of Haryana, India. PLoS One. 2021;16.\u003c/li\u003e\n\u003cli\u003eWang ME, Patel AB, Hansen NI, Arlington L, Prakash A, Hibberd PL. Risk factors for possible serious bacterial infection in a rural cohort of young infants in central India. BMC Public Health. 2016;16:1\u0026ndash;10.\u003c/li\u003e\n\u003cli\u003eSaha SK, Schrag SJ, El Arifeen S, Mullany LC, Shahidul Islam M, Shang N, et al. Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study. The Lancet. 2018;392:145\u0026ndash;59.\u003c/li\u003e\n\u003cli\u003eHayes R, Hartnett J, Semova G, Murray C, Murphy K, Carroll L, et al. Neonatal sepsis definitions from randomised clinical trials. Pediatr Res. 2023;93:1141\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eRello J, Valenzuela-S\u0026aacute;nchez F, Ruiz-Rodriguez M, Moyano S. Sepsis: A Review of Advances in Management. Adv Ther. 2017;34:2393\u0026ndash;411.\u003c/li\u003e\n\u003cli\u003eKorang SK, Safi S, Nava C, Gordon A, Gupta M, Greisen G, et al. Antibiotic regimens for early-onset neonatal sepsis. Cochrane Database of Systematic Reviews. 2021;2021.\u003c/li\u003e\n\u003cli\u003eGao Y, Hou L, Lu C, Wang Q, Pan B, Wang Q, et al. Enteral Lactoferrin Supplementation for Preventing Sepsis and Necrotizing Enterocolitis in Preterm Infants: A Meta‑Analysis With Trial Sequential Analysis of Randomized Controlled Trials. Front Pharmacol. 2020;11.\u003c/li\u003e\n\u003cli\u003eStaub E, Evers K, Askie LM. Enteral zinc supplementation for prevention of morbidity and mortality in preterm neonates. Cochrane Database of Systematic Reviews. 2021;2021.\u003c/li\u003e\n\u003cli\u003eLassi ZS, Kurji J, Oliveira CS de, Moin A, Bhutta ZA. Zinc supplementation for the promotion of growth and prevention of infections in infants less than six months of age. Cochrane Database of Systematic Reviews. 2020;2020.\u003c/li\u003e\n\u003cli\u003eMitra S, Gardner CE, MacLellan A, Disher T, Styranko DM, Campbell-Yeo M, et al. Prophylactic cyclo-oxygenase inhibitor drugs for the prevention of morbidity and mortality in preterm infants: a network meta-analysis. Cochrane Database of Systematic Reviews. 2022;2022.\u003c/li\u003e\n\u003cli\u003eINTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE (ICH) ICH HARMONISED GUIDELINE INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2). 2016.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ProSPoNS, Neonatal, Sepsis, Clinical trial, Adjudication","lastPublishedDoi":"10.21203/rs.3.rs-3924417/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3924417/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Despite progress in reducing Infant mortality in India, neonatal mortality decline is slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming prevention of neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention, including probiotic supplementation. This article communicates the decision by ProSPoNS trial investigators to establish a Central Endpoint Adjudication committee as an addendum to the published protocol in 'Trials 2021.'\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e \u0026nbsp;In the pursuit of clarity regarding the primary outcome of Sepsis/PSBI in a clinical trial, a crucial decision was reached during the investigators' meeting at MGIMS Sevagram on 17th-18th August 2023. The unanimous consensus was to explicitly define \"Physician diagnosed sepsis\" as the primary study outcome, encompassing Sepsis/PSBI. This alignment aimed to synchronize the primary objective and outcome with the stated hypothesis, necessitating the establishment of a Central Endpoint Adjudication (CEA) process across all six trial sites.\u003c/p\u003e\n\u003cp\u003eTo enact this, the CEA committee, chaired by an external Subject Expert and comprising Site Principal Investigators, a Trial Statistician, and a Microbiologist, will employ four criteria to determine 'Physician diagnosed sepsis' for each sickness event in a study participant. These criteria include Blood culture status, Sepsis screen status, PSBI/non-PSBI signs and symptoms, and the Clinical course during the event, including antibiotic usage. Importantly, this clarification maintains consistency with the approved study protocol (Protocol No.5/7/915/2012 Version 3.1 dated 14 Feb 2020), emphasizing the commitment to methodological transparency and adherence to predefined standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e \u0026nbsp;The challenges faced in the trial implementation, such as complex multi-centric design, heterogeneity / extreme variation across sites, inconsistency with definition of sepsis in the neonatal/young infant population, remote vs. on-site training/monitoring during the Covid-19 Pandemic have been described and potential solutions to some of the challenges in clinical trials suggested.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e The decision to utilize the guidance of a Central Endpoint Adjudication Committee has been suggested as a way forward in the ProSPoNS and other multicentre complex clinical trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eon 16 May 2019.\u003c/strong\u003e\u003c/p\u003e","manuscriptTitle":"Challenges in Trials on Neonatal Sepsis- Case of ProSPoNS Trial \u0026amp; Role of Central Endpoint Adjudication","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-20 19:45:49","doi":"10.21203/rs.3.rs-3924417/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-04-11T21:51:20+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-03-27T04:40:13+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-17T16:20:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-15T12:13:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-02-02T07:27:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c0f29c7f-6119-47fb-bdd0-d03236313a7a","owner":[],"postedDate":"March 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-27T06:36:36+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-20 19:45:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3924417","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3924417","identity":"rs-3924417","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}