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

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.

A randomized, controlled study to evaluate the safety and immunogenicity of a heterologous booster dose of an adjuvanted SARS CoV-2 recombinant spike protein vaccine in adults (preprint)

Background Due to waning immunity following primary immunization with Covid-19 vaccines, booster doses may be required. The present study assessed a heterologous booster of SII-NVX-CoV2373 (spike protein vaccine) in adults primed with viral vector and inactivated vaccines.Methods In this Phase 3, observer-blind, randomized, active controlled study, a total of 372 adults primed with ChAdOx1 nCoV-19 (n = 186) or BBV152 (n = 186) at least six months ago, were randomized to receive a booster of SII-NVX-CoV2373 or control vaccine. The control group received homologous booster of ChAdOx1 nCoV-19 or BBV152 depending upon the prime cohort. Anti-S IgG and neutralizing antibodies were assessed at baseline (day 1), day 29, day 91 and day 181 for immunogenicity assessments. Solicited reactions were collected for one week after vaccination. Unsolicited adverse events (AEs) were collected for 28 days while serious adverse events (SAE) and adverse events of special interest (AESI) were reported throughout the six-month study duration. (Identifier: CTRI/2022/04/042017)Results In both the ChAdOx1 nCoV-19 primed group and BBV152 primed group, 186 participants each received the study vaccines. In the ChAdOx1 nCoV-19 Prime cohort, at 28 days after the booster dose, there was a 3.9- to 5.1-fold-rise and 1.9- to 2.8-fold-rise in anti-S IgG and neutralizing antibody titres from the baseline in the SII-NVX-CoV2373 group and the ChAdOx1 nCoV-19 group, respectively. The same responses for the BBV152 prime cohort was 7.4- to 10.4-fold-rise and 1.5- to 2.5-fold-rise in the SII-NVX-CoV2373 group and the BBV152 group, respectively. There was 86.96% (95% CI 78.32, 93.07) to 94.57% (95% CI 87.77, 98.21) and 37.63% (95% CI 27.79, 48.28) to 79.57% (95% CI 69.95, 87.23) anti-S IgG and neutralizing antibody seroresponse (2-fold-rise from baseline) in the SII-NVX-CoV2373 group and ChAdOx1 nCoV-19 group, respectively. The same was 94.51% (95% CI 87.64, 98.19) to 98.90% (95% CI 94.03, 99.97) and 20.43% (95% CI 12.77, 30.05) to 74.19% (95% CI 64.08, 82.71) in the SII-NVX-CoV2373 group and BBV152 group, respectively. No SAE or AESI was caused by the study vaccines.Conclusion SII-NVX-CoV2373 showed a numerically higher boosting effect than homologous boosters in adults primed with ChAdOx1 nCoV-19 and BBV152. The vaccine was also safe and well tolerated.

A Phase 2/3 observer-blind, randomized, controlled study to determine the safety and immunogenicity of SARS-CoV-2 recombinant spike protein vaccine in Indian children and adolescents aged 2 to 17 years (preprint)

Background: A recombinant, adjuvanted COVID-19 vaccine, SII-NVX-CoV2373 was manufactured in India and evaluated in Indian children and adolescents to assess safety and immunogenicity. Methods: This was a Phase 2/3 observer-blind, randomized, controlled study in children and adolescents aged 2 to 17 years. Participants were randomly assigned in 3:1 ratio to receive two doses of SII-NVX-CoV2373 or placebo on day 1 and day 22. Solicited adverse events (AEs) were collected for 7 days after each vaccination. Unsolicited AEs were collected for 35 days following first dose and serious AEs (SAEs) and adverse events of special interest (AESI) were collected throughout the study. Anti S IgG and neutralizing antibodies against the SARS-CoV-2 were measured at baseline, day 22, day 36 and day 180. Variant immune responses were assessed in a subset of participants at baseline, day 36 and day 180. Primary objectives were to demonstrate non-inferiority of SII-NVX-CoV2373 in each pediatric age group (12 to 17 years and 2 to 11 years, separately) to that in adults in terms of ratio of titers of both anti-S IgG and neutralizing antibodies 14 days after the second dose (day 36). Non-inferiority was to be concluded if the lower bound of 95% CI of the ratio was >0.67. Results: A total of 920 children and adolescents (460 in each age cohort; 12 to 17 years and 2 to 11 years) were randomized and vaccinated. The demographic and baseline characteristics between the two groups were comparable in both age groups. After the second dose, there were more than 100-fold rise in anti-S IgG GMEUs and more than 84-fold rise in neutralizing antibodies GMTs from baseline in the participants who received SII-NVX-CoV2373. The GMTs in both age groups were non-inferior to those observed in Indian adults. The seroconversion rate was [≥] 98% (anti-S IgG) and [≥] 97.9% (neutralizing antibodies) in both age groups, respectively. Similar findings were seen in the baseline seronegative participants. SII-NVX-CoV2373 also showed robust responses against various variants of concern. Injection site pain, tenderness, swelling, erythema and fever, headache, malaise, fatigue, myalgia, arthralgia, nausea and vomiting were the common solicited adverse events which were transient and resolved without any sequelae. Throughout the study, only two causally unrelated SAEs and no AESI were reported. Conclusion: SII-NVX-CoV2373 has been found safe and well tolerated in children and adolescents of 2 to 17 years. The vaccine was highly immunogenic and the immune response was non-inferior to that in adults.