Role of central endpoint adjudication and challenges in trials on neonatal sepsis-a case of ProSPoNS trial.

Despite progress in reducing the infant mortality in India, the neonatal mortality decline has been slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming to prevent neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention includes probiotic supplementation. This article communicates the decision by the ProSPoNS trial investigators to establish a Central Endpoint Adjudication Committee (CEAC) as an addendum to the protocol published in Trials in 2021 for the purpose of clarifying the primary outcome. In the published protocol, 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." To align all the three above, the investigators meeting, held on 17th-18th August 2023, at MGIMS Sevagram, Wardha, deliberated and unanimously agreed that "physician diagnosed sepsis" is the primary study outcome which includes sepsis/PSBI. The CEAC, chaired by an external subject expert and members including trial statistician, a microbiologist, and all site principal investigators will employ four criteria to determine "physician diagnosed sepsis": (1) blood culture status, (2) sepsis screen status, (3) PSBI/non-PSBI signs and symptoms, and (4) the clinical course for each sickness event. 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. The decision to utilize the guidance of a CEAC is recommended as the gold standard in multicentric complex clinical trials to achieve consistency and accuracy in assessment of outcomes.Trial registrationClinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019.

Effect of IV ferric carboxy maltose for moderate/severe anemia: a systematic review and meta-analysis.

Introduction: Anemia remains a prevalent global health issue with varying severity. Intravenous iron supplementation, particularly with ferric carboxymaltose (FCM), has appeared as a possible therapeutic intervention for individuals with moderate to severe anemia. The study aimed to assess the efficacy and safety of ferric carboxymaltose (FCM) in reducing anemia. Methods: We searched electronic databases, registries, websites, e-libraries, reference lists of reviews, citations, etc. We included randomized control trials (RCTs), non-RCTs, and single-arm studies, while observational studies, case series, and case studies were excluded. Two reviewers independently screened the studies and extracted the data. We included studies of moderate-to-severely anemic Indians and excluded Indians with other comorbidities. We assessed the risk of bias and the overall quality of evidence (QoE) using GRADE GDT. Result: We identified 255 studies and included 14 studies (11 RCT, one non-RCT, and two single-arm studies) with 1,972 participants for qualitative analysis and 10 studies in the meta-analysis. All the included studies detailed the use of FCM for anemia. The primary outcomes assessed in the included studies were anemia, hemoglobin, and adverse events. The outcomes assessed ranged from 2 weeks to 12 weeks. The risk of bias varied across different studies with different outcomes. FCM is consistent with a fewer number of adverse events as compared to other interventions and provides "moderate" to "very low" QoE. Conclusion: A slow single infusion of 1 gram of FCM is well-tolerated, safe, and effective in treating iron deficiency anemia (IDA) and surpasses other interventions (Iron Sucrose Complex (ISC), Iron sucrose, and ferrous ascorbate) in elevating hemoglobin levels and replenishing iron stores. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=459363, CRD42023459363.

Acceptability of PrEP among MSM and transgender communities-Qualitative findings from two metropolitan cities in India.

BACKGROUND: Global evidence suggests that Pre-Exposure Prophylaxis (PrEP) plays a pivotal role in reducing new HIV-infections among key populations (KP). However, the acceptability of PrEP differs across different geographical and cultural settings and among different KP typologies. Men who have sex with men (MSM) and transgender (TG) communities in India have around 15-17 times higher prevalence of human immunodeficiency virus (HIV) than the general population. The low rates of consistent condom use and poor coverage of HIV testing and treatment among the MSM and transgender communities highlight the need for alternative HIV prevention options. METHODS: We used data from 20 in-depth interviews and 24 focused group discussions involving 143 MSM and 97 transgender individuals from the two metropolitan cities (Bengaluru and Delhi) in India to qualitatively explore their acceptability of PrEP as a HIV prevention tool. We coded data in NVivo and conducted extensive thematic content analysis. RESULTS: Awareness and use of PrEP were minimal among the MSM and transgender communities in both cities. However, on being provided with information on PrEP, both MSM and transgender communities expressed willingness to use PrEP as an additional HIV-prevention tool, to complement inability to consistently use condoms. PrEP was also perceived as a tool that could enhance the uptake of HIV-testing and counseling services. PrEP awareness, availability, accessibility and affordability were identified as determining factors that could influence its acceptability. Challenges such as stigma and discrimination, interrupted supply of drugs and non-community-friendly drug dispensing sites were identified barriers to continuing PrEP. CONCLUSIONS: Using qualitative data from two Indian settings, this study provides community perspectives and recommendations to stakeholders and policymakers for introduction of PrEP into programs as a prevention tool among MSM and transgender communities in India.

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.

BACKGROUND: Progress has been made in the reduction of under-five mortality in India; however, neonatal mortality is reducing at a slower rate. Efforts are required to bring down neonatal mortality in order to attain the Sustainable Development Goal-3. Prevention of sepsis among the high-risk, vulnerable low birth weight neonates by a newer intervention with probiotic supplementation is promising. METHODS: A phase III, multicenter, randomized, double-blind, placebo-controlled study is being conducted at six sites in India. A total of 6144 healthy low birth weight (LBW) infants fulfilling the eligibility criteria would be enrolled within the first week of life, after obtaining written informed consent from the parents of the infant. Randomization in 1:1 ratio, stratified by site, sex, and birth weight, would be done through an interactive web response system (IWRS) using a standard web browser and email service. Vivomixx®, a probiotic containing a mix of 8 strains of bacteria, in a suspension form standardized to deliver 10 billion CFU/ml, or an organoleptically similar placebo would be fed to enrolled infants in a 1-ml/day dose for 30 days. The follow-up of enrolled infants for 60 days would take place as per a pre-specified schedule for recording morbidities and outcome assessments at the six participating sites. Screening for morbidities would be conducted by trained field workers in the community, and sick infants would be referred to designated clinics/hospitals. A physician would examine the referred infants presenting with complaints and clinical signs, and blood samples would be collected from sick infants for diagnosis of neonatal sepsis by performing sepsis screen and blood culture. Appropriate treatment would be provided as per hospital protocol. The study would be implemented as per the MRC guideline for the management of Global Health Trials in accordance with ICH-GCP and Indian Regulatory guidelines. A contract research organization would be engaged for comprehensive monitoring and quality assurance. The final analysis would be conducted in a blinded manner as per the statistical analysis plan (SAP) to estimate the primary outcomes of sepsis, possible serious bacterial infection (PSBI), and secondary outcomes. The codes will be broken after DMC permission. The protocol has been reviewed by the Research Ethics Committee of the Liverpool School of Tropical Medicine (REC-LSTM), from Research Ethics Committees of the six subject recruitment participating sites. DISCUSSION: This adequately powered and well-designed trial would conclusively answer the question whether probiotics can prevent neonatal sepsis in the high-risk group of low birth weight infants as indicated by a pilot study in 1340 LBW infants, evidence from systematic reviews of hospital-based studies, and a primary study on healthy newborns in Orissa. Results of the study would be generalizable to India and other low-middle-income countries. TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197 . Registered on 16 May 2019.

Interventions for Addressing Anemia Among Children and Adolescents: An Overview of Systematic Reviews.

Context: Anemia is a public health problem that can lead to growth, cognitive, and motor impairments. Objective: To collate evidence on interventions for addressing childhood and adolescent anemia. Methods: In this overview of systematic reviews, we included Cochrane as well as non-Cochrane systematic reviews (SRs) irrespective of language and publication status. Two sets of review authors independently screened articles for eligibility and extracted data from relevant SRs. We present data in a tabular format and summarize results based on outcome reported, age of participants, and type of interventions. We also adopt a "measurement for change" approach to assess the utility of measurement for development of interventions in childhood and adolescent anemia. Results: Our search yielded 2,601 records of which 31 SRs were found eligible for inclusion. Results were favorable for fortification and supplementation with clear reduction in the risk of anemia and increase in hemoglobin levels across all age groups. Other interventions reported by the SRs were inconclusive and suggest further research. Conclusions: Current evidence suggests that fortification or supplementation with iron and micronutrients leads to better reduction in the risk of anemia and improvements in hemoglobin levels among children and adolescents. Results of this overview can help decision makers in informing selection of interventions to address childhood and adolescent anemia. Review Registration: PROSPERO CRD42016053687.