Clinical trials in settings with intermittent or non-existent internet and power connectivity, for example during humanitarian emergencies, present challenges in the synchronisation of data across different sites, in addition to accessing a centralised database in real-time. To overcome these, we designed a novel hybrid analogue/digital data management system which was deployed during the rapid implementation of a Phase III evaluation of a two-dose preventative vaccine for Ebola virus disease in Goma, Democratic Republic of the Congo, from 2019 to 2022. We provided study participants with an Enhanced Participant Record Card (EPRC) that served as eligibility for, and confirmation of, vaccination and was used in combination with Open Data Kit (ODK) electronic case report forms to create an off-grid study participant management system. To understand the utility of the EPRC, we analysed data from 15,327 study participants who received both vaccines and various types of prompts or reminders to return for dose 2, including home visits, telephone calls, or short messaging service (SMS). A total of 53% participants referred to the date on the EPRC as a prompt to return for dose 2 and 36.1% mentioned this as the only prompt. A multivariable generalised linear mixed-effects model showed that those who were not working, those aged 45–64 years or who had a chronic medical condition identified prior to receiving dose 2 were more likely to use the date on the EPRC as a prompt. Our findings demonstrate the utility of this system in the facilitation of decentralised data collection in off-grid locations that may be useful for future trials in complex humanitarian settings.
BACKGROUND
Conflict is known to impact maternal and neonatal health in Eastern Democratic Republic of the Congo (DRC), an area of longstanding insecurity. We conducted a systematic review on pregnancy and neonatal outcomes in this region to provide a comprehensive overview of maternal and neonatal outcomes over a 20-year period.
METHODS
We systematically searched databases, such as Medline, EMBASE, Global Health, ClinicalTrials.gov and the Cochrane Library, along with grey literature, for articles published between 2001 and 2021. These articles provided quantitative data on selected pregnancy and neonatal outcomes in the provinces of Ituri, Maniema and North and South Kivu, Eastern DRC. We conducted a descriptive analysis, combining results from different data sources and comparing incidence of outcomes in North Kivu with those in other provinces in Eastern DRC.
RESULTS
A total of 1,065 abstracts from peer-reviewed publications and 196 articles from the grey literature were screened, resulting in the inclusion of 14 scientific articles in the review. The most frequently reported pregnancy complications were caesarean sections (11.6%–48.3% of deliveries) and miscarriage (1.2%–30.0% of deliveries). The most common neonatal outcomes were low birth weight (3.8%–21.9% of live births), preterm birth (0.9%–74.0%) and neonatal death (0.2%–43.3%).
CONCLUSION
Our review provides data on pregnancy and neonatal outcomes in Eastern DRC, which will be valuable for future studies. Despite the area's ongoing armed conflict, the percentages of complications we noted in Eastern DRC are comparable with those observed in other countries in the region.
During the 2018–2020 Ebola virus disease outbreak in Democratic Republic of the Congo, a phase 3 trial of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine (DRC-EB-001) commenced in Goma, with participants being offered the two-dose regimen given 56 days apart. Suspension of trial activities in 2020 due to the COVID-19 pandemic led to some participants receiving a late dose 2 outside the planned interval. Blood samples were collected from adults, adolescents, and children prior to their delayed dose 2 vaccination and 21 days after, and tested for IgG binding antibodies against Ebola virus glycoprotein using the Filovirus Animal Nonclinical Group (FANG) ELISA. Results from 133 participants showed a median two-dose interval of 9.3 months. The pre-dose 2 antibody geometric mean concentration (GMC) was 217 ELISA Units (EU)/mL (95% CI 157; 301) in adults, 378 EU/mL (281; 510) in adolescents, and 558 EU/mL (471; 661) in children. At 21 days post-dose 2, the GMC increased to 22,194 EU/mL (16,726; 29,449) in adults, 37,896 EU/mL (29,985; 47,893) in adolescents, and 34,652 EU/mL (27,906; 43,028) in children. Participants receiving a delayed dose 2 had a higher GMC at 21 days post-dose 2 than those who received a standard 56-day regimen in other African trials, but similar to those who received the regimen with an extended interval.
During the 2018–2020 Ebola virus disease (EVD) outbreak, residents in Goma, Democratic Republic of the Congo, were offered a two-dose prophylactic EVD vaccine. This was the first study to evaluate the safety of this vaccine in pregnant women. Adults, including pregnant women, and children aged ≥1 year old were offered the Ad26.ZEBOV (day 0; dose 1), MVA-BN-Filo (day 56; dose 2) EVD vaccine through an open-label clinical trial. In total, 20,408 participants, including 6635 (32.5%) children, received dose 1. Fewer than 1% of non-pregnant participants experienced a serious adverse event (SAE) following dose 1; one SAE was possibly related to the Ad26.ZEBOV vaccine. Of the 1221 pregnant women, 371 (30.4%) experienced an SAE, with caesarean section being the most common event. No SAEs in pregnant women were considered related to vaccination. Of 1169 pregnancies with a known outcome, 55 (4.7%) ended in a miscarriage, and 30 (2.6%) in a stillbirth. Eleven (1.0%) live births ended in early neonatal death, and five (0.4%) had a congenital abnormality. Overall, 188/891 (21.1%) were preterm births and 79/1032 (7.6%) had low birth weight. The uptake of the two-dose regimen was high: 15,328/20,408 (75.1%). The vaccine regimen was well-tolerated among the study participants, including pregnant women, although further data, ideally from controlled trials, are needed in this crucial group.
Limited data exist to inform community management of children with moderate acute malnutrition (MAM), who are normally excluded from severe acute malnutrition (SAM) treatment programmes. This study was conducted to generate evidence of longitudinal outcomes in children aged 6-59 months with MAM (defined as mid-upper arm circumference, MUAC, 115-124mm), without interventional supplementary feeding. In this study, children in India with MAM were followed up for six months to better understand their long-term nutritional outcomes.
METHODS
We carried out a multicentre prospective longitudinal observational study, nested within a randomized trial, in Jharkhand, India. Children with MAM were enrolled over a 12-month period in 46 centres in Jharkhand state, and followed up for six months while attending government integrated child development services. Anthropometric, clinical and sociodemographic characteristics were recorded at enrolment. The primary outcome was deterioration to SAM (MUAC <115 or bilateral pitting oedema) or death within six months. Risk factors for this outcome were investigated.
ETHICS
This study was approved by the MSF Ethical Review Board and by the ethics review boards of the Rajendra Institute of Medical Sciences, Ranchi and Jawaharlal Nehru University, New Delhi, India, and London School of Hygiene & Tropical Medicine, UK. Clinical Trial Registry-India number, CTRI/2017/12/010743.
RESULTS
Of 971 children enrolled, 98 (10.0%) were lost to follow-up, mainly linked with seasonal migration; 12 were seen outside of the six-month window (three before day 168 and nine after day 210). Of 861 children included in the analysis, 595 (61.3%) were female, with a mean age of 16.0 months (standard deviation 9.7). At enrolment 333 (34.3%) had MUAC 115-119mm, 430 (44.3%) had weight-for-height z-score (WHZ) <-3 and 431 (44%) had a WHZ of -2 to-3. Within six months, 133 (15.5%) deteriorated to SAM or died (95% confidence interval, CI: 13.1-18.0%; five deaths), of whom 97 children deteriorated to poor outcome (SAM or death) by three months (11.3%, with one death; representing over two thirds of those deteriorating to poor outcome by six months). In an adjusted logistic regression model, with an interaction between MUAC at enrolment (115-119, 120-124mm) and age (6-11, 12-23, ≥24 months), significantly increased odds of deterioration to SAM or death were seen amongst those with MUAC 115-119mm in all age groups (p≤0.02) and in those under one year with MUAC<125mm. After adjustment, there was no evidence of associations with socio-demographic factors, breastfeeding or WHZ<-3.
CONCLUSION
Children aged under 1 year and children with MUAC 115-119mm should be closely monitored, considering high MAM burdens in India. Increasing the MUAC admission criterion and/or targeted interventions for MAM children at higher risk could be considered. WHZ<-3 not already MUAC<115mm does not appear to be a risk factor for deterioration.
In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea.
METHODS
In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group.
RESULTS
A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed.
CONCLUSIONS
The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).
Most interventions for community-based management of severe acute malnutrition (CM-SAM) worldwide utilise mid-upper arm circumference (MUAC) <115mm for eligibility and ≥125mm for discharge. However, this discharge criterion is based on very limited evidence, with no data from the Indian subcontinent. India, home to over one-third of malnourished children globally, provides facility-based care based on weight-for-height with no guidelines for CM-SAM. Previous observational data suggests relapse in children reaching ≥120mm is similar to that for ≥125mm, whilst duration of treatment required to achieve ≥125mm is nearly doubled, with higher default rates. This trial in the state of Jharkhand, India investigated whether discharge with MUAC ≥120mm is non-inferior to MUAC ≥125mm for risk of relapse to SAM or death.
METHODS
We conducted a multicentre randomized controlled noninferiority trial for SAM children aged between six and 59 months across 46 centres in Jharkhand, India. Over 12 months, children with MUAC<115mm and without oedema at admission were randomly allocated to be discharged either at MUAC ≥120 mm or MUAC ≥125mm. Endpoints were status at three months (primary) and six months (secondary) after reaching their allocated discharge MUAC. Non-inferiority was concluded if the upper bound (UB) of a one-sided 95% confidence interval was within a pre-defined 13% margin, based on pragmatic operational indicators.
ETHICS
This study was approved by the MSF Ethics Review Board and by the Ethical Review Boards of the Rajendra Institute of Medical Sciences, Ranchi and Jawaharlal Nehru University, New Delhi, India, and London School of Hygiene & Tropical Medicine, UK. Clinical Trials Registry – India number, CTRI/2017/12/010743.
RESULTS
Of 633 children enrolled, 316 were allocated to the standard of care arm (discharge at ≥125mm) and 317 to the ≥120mm arm. No significant clinical-epidemiological differences were detected between cohorts not reaching their allocated discharge MUAC, however there was a higher proportion of treatment non-response (17.5% vs 9%) in the 125mm arm. Of 194 and 236 children reaching discharge criteria in each arm respectively, 176 and 216 were eligible for intention-to-treat analysis. For the standard of care arm, 42% of children were male, with a mean age of 12.6 months (standard deviation, SD; 7.9); for the ≥120mm arm, 41% were male, with a mean age of 12.1 months (SD; 7.1). Overall, non-inferiority was observed within three months; unadjusted risk difference (RD) 6.4%, 95% UB=11.6%, ≥125mm: n=14 (8.0%; 14 relapse, 0 death), ≥120mm: n=31 (14.4%; 30 relapse, 1 death). In pre-specified stratified analyses, non-inferiority was observed in children with MUAC 110-114mm at enrolment (N=285, RD 2.0%, 95% UB 7.5%); however, inferiority was observed with MUAC<110mm (N=107, RD 17.5%, 95% UB 29.0%). In stratified secondary outcome analyses at six months, conclusions were similar.
CONCLUSION
Using a non-inferiority margin of 13%, results support ≥120mm as a discharge criterion in children admitted with MUAC 110-114mm, but not in those with MUAC<110mm. This margin in children discharged earlier needs to be balanced against greater capacity for programmatic coverage. Considering over two thirds of children are admitted with MUAC 110-114mm, defining discharge criteria by admission MUAC may have important implications on increasing capacity and cost-effectiveness of CM-SAM programming in India.
The long-term treatment outcome of visceral leishmaniasis (VL) patients with HIV co-infection is complicated by a high rate of relapse, especially when the CD4 count is low. Although use of secondary prophylaxis is recommended, it is not routinely practiced and data on its effectiveness and safety are limited.
METHODS:
A prospective cohort study was conducted in Northwest Ethiopia from August 2014 to August 2017 (NCT02011958). HIV-VL patients were followed for up to 12 months. Patients with CD4 cell counts below 200/μL at the end of VL treatment received pentamidine prophylaxis starting one month after parasitological cure, while those with CD4 count ≥200 cells/μL were followed without secondary prophylaxis. Compliance, safety and relapse-free survival, using Kaplan-Meier analysis methods to account for variable time at risk, were summarised. Risk factors for relapse or death were analysed.
RESULTS:
Fifty-four HIV patients were followed. The probability of relapse-free survival at one year was 50% (95% confidence interval [CI]: 35-63%): 53% (30-71%) in 22 patients with CD4 ≥200 cells/μL without pentamidine prophylaxis and 46% (26-63%) in 29 with CD4 <200 cells/μL who started pentamidine. Three patients with CD4 <200 cells/μL did not start pentamidine. Amongst those with CD4 ≥200 cells/μL, VL relapse was an independent risk factor for subsequent relapse or death (adjusted rate ratio: 5.42, 95% CI: 1.1-25.8). Except for one case of renal failure which was considered possibly related to pentamidine, there were no drug-related safety concerns.
CONCLUSION:
The relapse-free survival rate for VL patients with HIV was low. Relapse-free survival of patients with CD4 count <200cells/μL given pentamidine secondary prophylaxis appeared to be comparable to patients with a CD4 count ≥200 cells/μL not given prophylaxis. Patients with relapsed VL are at higher risk for subsequent relapse and should be considered a priority for secondary prophylaxis, irrespective of their CD4 count.