DON in pediatric cerebral malaria, a phase I/IIA dose-escalation safety study: study protocol for a clinical trial.

BACKGROUND: Despite treatment with highly effective antimalarial drugs, malaria annually claims the lives of over half a million children under 5-years of age in sub-Saharan Africa. Cerebral malaria (CM), defined as Plasmodium falciparum infection with coma, is the severe malaria syndrome with the highest mortality. Studies in the CM mouse model suggest that a T cell-mediated response underlies CM pathology, opening a new target for therapy in humans. This trial aims to establish the preliminary safety of one such novel therapy, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). METHODS: In this phase I/IIa dose-escalation clinical trial, a single dose of intravenous (IV) DON is administered to three participants groups-healthy adults and adults with uncomplicated malaria, then pediatric participants with CM-to primarily assess safety. The secondary objective of this trial is to assess pharmacokinetics of DON over a range of doses. The open-label adult portion of the trial enrolls 40 healthy adults concurrently with 40 adults with uncomplicated malaria. Cohorts of 10 participants receive a single IV dose of DON with doses escalating between cohorts from 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, to 10 mg/kg. Following subsequent safety review, a randomized, double-blind, and placebo-controlled pediatric study enrolls 72 participants aged 6 months to 14 years with CM. The pediatric portion of the study minimally spans three malaria seasons including a planned interim analysis after 50% of pediatric enrollments. The first half of pediatric participants receive DON 0.1 mg/kg, 1.0 mg/kg, or placebo. Dosing for the second half of pediatric participants is informed by the safety and preliminary efficacy results of those previously enrolled. The pediatric portion of the study has an exploratory outcome evaluating the preliminary efficacy of DON. Efficacy is assessed by diagnostics predictive of CM outcome: electroencephalography (EEG), magnetic resonance imaging (MRI), and transcranial doppler (TCD), measured before and after DON administration. All participants with malaria receive standard of care antimalarials in accordance with local guidelines, regardless of study drug dose group. DISCUSSION: This preliminary safety and efficacy study evaluates DON, a candidate adjunctive therapy for pediatric CM. If results support DON preliminary safety and efficacy, follow-up phase II and III clinical trials will be indicated. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on 28 July 2022 (NCT05478720).

A Malawian pharmaceutical response to the COVID-19 Pandemic.

The COVID-19 pandemic has elicited swift and innovative responses due to the severity of the outbreak. Higher education institutions worldwide with pharmacy programs have identified vital gaps in COVID-19 care and has undertaken proactive steps to aid in the fight against the coronavirus. In Malawi, the Kamuzu University of Health Science's Department of Pharmacy initiated the production of a modified formulation of the World Health Organization's (WHO) recommended hand sanitizer. This manufacturing venture involved mobilizing the pharmacy faculty, identifying gaps in supplies and equipment, and utilizing evidenced-based information to create a high-quality sanitation product, which passed the requirements as tested by the Malawi Bureau of Standards. The department of pharmacy is expanding their distribution of the product to meet the needs of frontline healthcare workers and vulnerable populations. With historical issues of accessing care in Malawi and with COVID-19's spread among healthcare workers, this hand sanitizer venture is vital in the public healthcare's system response. The department of pharmacy will continue to lead the pharmacy profession in Malawi to provide targeted interventions in this unprecedented time.

Assessing the Impact of an Intervention Project by the Young women's Christian Association of Malawi on Psychosocial Well-Being of Adolescent Mothers and Their Children in Malawi.

Adolescent mothers in Malawi face psychosocial challenges such as low resilience level, low self-esteem, poor maternal-infant interaction, and exposure to intimate partner violence (IPV). Children of adolescent mothers often face numerous risks such as low birth-weight, stunted growth, infant death, low school enrolment, increased grade repetition, and dropouts that put them at greater risk of poor developmental outcomes and socio-emotional problems. This study assessed the impact of components of a community project conducted by the Young Women's Christian association of Malawi in providing psychosocial support to adolescent mothers and their children. The goals of the project were; (1) to improve early childhood development in babies born to adolescent mothers; and (2) to enhance the psychosocial well-being of adolescent mothers (self-esteem, resilience stress, and parenting skills). This descriptive mixed methods evaluation study comprised an intervention and control groups of adolescent mothers respectively. The project had 3 centers in southern region districts of Malawi. Target population was adolescent mothers 18 years of age and below. At baseline we enrolled 267 mothers and at the end of the project we had 211 mothers. The project involved monthly meetings with adolescent mothers imparting knowledge and skills and early childhood education activities. From July 2017 to June 2019, 58 sessions were conducted. In the first year the control group had no meetings, however they received the intervention in the second year. Overall results in the intervention group showed statistically significant increase in knowledge on parenting skills (p < 0.01), nutritional practice (p < 0.01), motor skills and cognitive functions in children (p < 0.01) as well as expressive language and socio-emotional capacities in children (p < 0.01), while the change in confidence and psychosocial well-being was not statistically significant (p = 0.8823). Community projects such as these enhance parenting skills and improve development of children born to adolescent mothers. Improving psychosocial support is complex and requires further research and a more holistic approach.

Using Evidence and Data to Design an Intervention in the Project Community Model for Fostering Health and Wellbeing Among Adolescent Mothers and Their Children.

In this paper, quantitative and qualitative measurements of maternal psychosocial wellbeing were utilized in three districts in Malawi that guided decision-making to increase the wellbeing of adolescent mothers and promote the healthy upbringing of their children. The 1-year design stage of the study relied on several sources of information: literature search, prior project implementation of similar projects, discussions with officials at the Malawi Department of Social Welfare, and observation visits in the targeted districts. The approaches for collecting data mentioned were triangulated for the development of a baseline survey. The baseline survey generated systematically collected data of the experiences and recalls as well as the missing data from the preliminary evaluation of the existing data. The baseline data gave the Young Women's Christian Association (YWCA) insight on the type of intervention required in order to give a greater and more holistic effect on the beneficiaries. We also discuss the lessons we learned as to whether the assumptions we had made at the onset were correct. If they were not correct, we explained the measures we took to correct the design or implementation of the project. Finally, the data provided benchmarks for project monitoring and evaluation.

Human-centred design of a new microneedle-based hormonal contraceptive delivery system.

Background: It is estimated that 225 million women worldwide have an unmet need for family planning, and more than half live in low- and middle-income countries. Increasing the choice of contraceptive methods available can reduce this unmet need. Microneedle drug delivery systems represent a new technology for minimally invasive self-administration of contraceptives. We explored stakeholders' views on different aspects of a proposed microneedle-based hormonal contraceptive delivery system. The feedback was used to iteratively develop this delivery system. Methods: Focus group discussions and semi-structured interviews were conducted with potential stakeholders (women and trans males of childbearing age, their partners, and health professionals and organisations that provide family planning advice and contraception services) in Uganda, The Gambia, Malawi, and the UK, exploring concept acceptability and gathering feedback on different aspects of design and usability of the proposed delivery system. Results: Participants viewed the concept of a new, microneedle-based contraceptive favourably. In Uganda, participants were presented with 7 different prototype applicators and identified desirable features of a preferred delivery device; their input reducing the number of prototypes that were subsequently evaluated by stakeholders in The Gambia and the UK. Participants in these countries helped to identify and/or confirm the most desirable characteristics of the applicator, resulting in design consolidation into a refined concept applicator. The final, optimised applicator prototype was validated during user research in Malawi. This human-centred design approach was also used to iteratively develop an information leaflet for the device. During these user studies, other preferred aspects of a contraceptive delivery system were also evaluated, such as anatomical site of application, duration of action, and return to fertility. Conclusions: A new microneedle-based contraceptive delivery system was iteratively developed using a human-centred design approach and was favourably received by potential stakeholders. The product is now being refined for testing in pre-clinical studies.

Enhancing Pharmacovigilance in Sub-Saharan Africa Through Training and Mentoring: A GSK Pilot Initiative in Malawi.

INTRODUCTION: Pharmacovigilance (PV) systems to monitor drug and vaccine safety are often inadequate in sub-Saharan Africa. In Malawi, a PV enhancement initiative was introduced to address major barriers to PV. OBJECTIVE: The objective of this initiative was to improve reporting of adverse events (AEs) by strengthening passive safety surveillance via PV training and mentoring of local PV stakeholders and healthcare providers (HCPs) at their own healthcare facilities (HCFs). METHODS: An 18-month PV training and mentoring programme was implemented in collaboration with national stakeholders, and in partnership with the Ministry of Health, GSK and PATH. Two-day training was provided to Expanded Programme on Immunisation coordinators, identified as responsible for AE reporting, and four National Regulatory Authority representatives. Abridged PV training and mentoring were provided regularly to HCPs. Support was given in upgrading the national PV system. Key performance indicators included the number of AEs reported, transmission of AE forms, completeness of reports, serious AEs reported and timeliness of recording into VigiFlow. RESULTS: In 18 months, 443 HCPs at 61 HCFs were trained. The number of reported AEs increased from 22 (January 2000 to October 2016) to 228 (November 2016 to May 2018), enabling Malawi to become a member of the World Health Organization Programme for International Drug Monitoring. Most (98%) AE report forms contained mandatory information on reporter, event, patient and product, but under 1% were transmitted to the national PV office within 48 h. CONCLUSION: Regular PV training and mentoring of HCPs were effective in enhancing passive safety surveillance in Malawi, but the transmission of reports to the national PV centre requires further improvement.

When a medicine or vaccine is made available for use, healthcare organisations maintain regular surveillance to confirm that the medicinal product is safe and effective. The efficiency of this surveillance depends mainly on the healthcare system and medical practices in place in each country. An important element is an effective procedure for identifying and reporting any unwanted medical occurrences (adverse events) after taking a medicinal product. In countries where regular safety surveillance has not been maintained, it is important to train and mentor healthcare providers on the need to be aware of adverse events and the importance of adhering to safety reporting procedures. GSK and partners conducted a pilot project in Malawi with the aim of improving adverse event reporting by training and mentoring healthcare providers. Training sessions and continuous mentoring were conducted over 18 months, involving 443 healthcare providers at 61 healthcare facilities. There was a large increase in the number of adverse events reported: from 22 in the 16-year period before the project started to 228 during the 18-month project period. This project showed that the training and mentoring programme for healthcare providers was effective in increasing the number of adverse events reported. This enabled Malawi to join the World Health Organization's international safety reporting scheme. Other countries facing similar challenges in safety surveillance systems could benefit from a similar approach.