Malaria persists as a formidable global health challenge, exacting a heavy toll on both morbidity and mortality rates worldwide [1-3]. Africa, in particular, bears a disproportionate burden, with 94% of malaria cases (246 million) and 95% (n=569,000) of malaria deaths recorded by the World Health Organization (WHO) in 2023 [2]. Children younger than 5 years constituted approximately 76% of malaria-related fatalities, making malaria a leading cause of childhood illness and death in the region [2,4]. Beyond its impact on children, malaria significantly influences maternal outcomes directly and neonatal outcomes indirectly because it heightens the risks of abortion, low birth weight, preterm delivery, stillbirth, and neonatal death [5-7].

The pursuit of improved malaria treatment remains an ongoing endeavor, particularly for severe disease [8,9]. However, a significant impediment arises from the lack of consensus on appropriate outcomes for use in clinical trials, thereby posing a challenge to measuring and evaluating the efficacy of antimalarial and/or adjunctive treatments. A systematic review has highlighted the considerable heterogeneity, with 101 diverse outcome measures reported in 27 trials spanning from 2010 to 2020 [10]. This disparity has led to the measurement of diverse outcomes and the use of various instruments for assessing the same outcome, resulting in inconsistencies in reported results and complicating the comparison of outcomes in systematic reviews and meta-analyses [10]. Creating a core outcome set (COS) for severe malaria treatment in trials could help mitigate the current deficiencies in addressing reporting challenges.

A COS is defined by the Core Outcome Measures in Effectiveness Trials (COMET) as “an agreed standardized set of outcomes that should be measured and reported, as a minimum, in all clinical trials in specific areas of health or health care” [11]. While a previous study has developed COS for malaria in the context of vaccine trials [12], a notable gap exists concerning the treatment of severe malaria, especially with the inclusion of adjunctive therapies [10]. This void is a critical concern for global health, given the severe and widespread impact of severe malaria. Urgent attention is warranted to address this gap.

The scope of the COS specifies the particular health care domain or condition it addresses, detailing its target population, interventions, and settings. This clarity ensures its appropriate and consistent use, thereby avoiding any ambiguity [13-15]. For this COS, the scope encompasses severe malaria, characterized by complications such as impaired consciousness, acidosis, and severe anemia. The target population includes all groups affected by severe malaria, including children under five, adults, pregnant women, and travelers who reside in endemic and nonendemic regions. The interventions involve antimalarial treatments and adjunctive therapies to manage complications. The setting is within clinical trials to standardize outcome selection and reporting, ensuring relevance and consistency across studies. The aim of the study is to develop a COS for trials in the treatment of severe malaria.

We conducted a search for an existing COS for severe malaria treatment trials, adhering to the COMET guidelines’ recommendation to prevent duplication of ongoing or preexisting studies. No such study was found.

We will develop the COS through the following phases:

This study protocol will adhere to the guidelines outlined in the Core Outcome Set–Standardised Protocol Items (COS-STAP) statement checklist [16] (Checklist 1). The study has been registered on the COMET Initiative website [17]. The study will follow the COMET Initiative guidelines for developing a COS to produce a reliable, valid, and responsive minimum set of outcomes to be measured and reported in all clinical trials considering the treatment of severe malaria [13]. The schematic overall flow and link between the different phases of the study are presented in Figure 1.

The systematic review of the study sought to build upon an earlier systematic review that examined outcomes reported in trials for severe malaria treatment conducted between January 1, 2010, and June 30, 2020 [10]. The objective of the update was to capture and integrate any newly published or registered trials focusing on severe malaria treatment conducted from July 1, 2020, to July 26, 2024. The updated systematic review followed the guidelines outlined in the “Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions” checklist (Checklist 2) [18].

The eligibility criteria for this systematic review were established to ensure the inclusion of studies directly addressing the research objectives.

The search strategy for this study was carefully designed to capture all relevant studies about severe malaria treatment within the defined scope. The search terms focused on 4 critical concepts: severe malaria, treatment, hospital, and RCTs. The search was restricted to English-language publications to ensure clarity and accessibility of the content. The time frame was deliberately chosen to provide an updated and comprehensive overview of outcomes from RCTs published between July 2020 and the search date. This time frame bridges the gap left by a prior systematic review [10], whose last search concluded in June 2020. The final search was conducted on July 26, 2024, covering publications up to that date. A complete list of the search terms and the detailed construction of the search strategy for MEDLINE, Literatura Latino-Americana em Ciências da Saúde (LILACS), and ClinicalTrials.gov are provided in Multimedia Appendix 1.

Searches were conducted across key databases and clinical trial registries, including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, and LILACS, to ensure comprehensive geographical coverage. The search also extended to registries such as the International Standard Randomized Controlled Trial Number (ISRCTN), ClinicalTrials.gov, and the Pan-African Clinical Trial Registry (PACTR) to identify ongoing and unpublished trials, addressing potential publication bias. To enhance robustness, citation lists of retrieved trials were reviewed for additional records, ensuring no relevant studies were overlooked [20,21].

The search results were organized using EndNote X9 (Clarivate) reference management software. Duplicate entries were removed, followed by a double-screening of records. Titles and abstracts were initially reviewed to identify relevant trials, with eligible trials undergoing a detailed full-text review to ensure they met the inclusion criteria. For trials from registries without published results, entries were cross-referenced using key identifiers. We discussed and resolved any eligibility concerns by consensus. Trials not meeting the criteria were excluded, with explanations documented. The screening and selection process is detailed in a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram (Figure 2).

To systematically organize and analyze information, a data charting form was developed in Microsoft Excel (Multimedia Appendix 2). This form outlined specific variables to be collected, aligning with the study’s aim. The variables captured essential trial details, ensuring thorough data collection. The extracted data included trial characteristics such as study title, publication year, participant demographics, study design and phase, intervention type, and outcome measures. Outcome measures were described verbatim from study protocols or trial registry entries to maintain accuracy. Details about the instruments or methods used to measure these outcomes were also included, providing context for how the outcomes were quantified.

The study aims to use qualitative research methods to explore and identify the outcomes of severe malaria that parents, guardians, and carers consider important to measure in treatment trials.

A descriptive qualitative research design was used in this study to identify outcomes reported by parents, guardians, and caregivers of children affected by severe malaria. Descriptive qualitative research aims to provide a detailed and comprehensive account of a phenomenon by focusing on the “who, what, where, and when” aspects, without delving into theoretical interpretations or complex explanations [26-28].

Without patient involvement in the COS development process, there is a risk that important outcomes will be overlooked, which could hinder the ability to assess treatment effectiveness. Several studies have used qualitative research in COS development to identify relevant outcomes, capture stakeholders’ perspectives, and ensure that the outcomes included in clinical trials reflect the priorities of patients, caregivers, and health care professionals [22,29-31]. Incorporating qualitative methods into the outcome identification process offers several benefits, particularly in providing a deeper understanding of why certain outcomes are important to patients, parents, and caregivers [22,32]. This helps ensure that the outcomes presented in the COS reflect the true priorities and needs of those most affected by severe malaria.

Participants for this study were recruited from Ghana, a country in sub-Saharan Africa, which is one of the regions that bears a disproportionately high burden of malaria [33-35]. Targeting recruitment in these settings allowed for the inclusion of populations facing significant challenges with severe malaria, enriching our understanding of its impact. This study was conducted in Kumasi, the capital of Ghana’s Ashanti Region, a malaria hotspot with an increase in cases in recent years [36,37], with clinical malaria prevalence rates ranging from 3.4% to 16.9% [38]. The study was conducted at the Komfo Anokye Teaching Hospital (KATH) in Kumasi, within its Child Health Directorate. KATH was chosen for its role as the principal referral center for the region, providing specialized care for severe and complex conditions, including severe malaria, and offering access to a diverse patient population. The Child Health Directorate’s expertise in pediatric care enabled engagement with a broad range of stakeholders and grounded the research in a context reflecting the challenges and priorities of populations at the epicenter of the malaria burden.

Participants were recruited from the Severe Malaria Africa: A Research and Trials Consortium (SMAART) observational study, which aims to describe the treatment for children with severe malaria from hospital presentation to 6 months after discharge. The study enrolled 2 cohorts: hospitalized children with severe malaria and time-matched controls with nonsevere malaria, with follow-up over 6 months to assess outcomes. Children aged 3 months to 15 years were included to generate insights into severe malaria management.

In total, 3 supervisors involved in this study are members of the SMAART Consortium. They facilitated contact with the local principal investigator at KATH, enabling the identification of key gatekeepers. These gatekeepers reviewed patient records to identify eligible participants, whose parents, guardians, or caregivers were then informed about the study and invited to participate.

We initially planned to recruit parents, guardians, or caregivers of children currently receiving treatment for severe malaria at KATH. However, we revised our protocol to include those whose children had been treated for severe malaria within the past year. This change was made after observing that the severity of the children’s conditions often left their caregivers too distracted to engage fully in interviews. The 1-year time frame aimed to reduce recall bias [39,40]. Participants were purposefully sampled based on the following criteria: (1) aged ≥18 years; (2) parent and guardian or caregiver caring for an infant, diagnosed with and treated for severe malaria within a year at the time of recruitment; and (3) those admitted to and treated at the KATH during the time of recruitment.

Experienced qualitative researchers, GDA and 2 SMAART study team members, conducted face-to-face semistructured interviews with parents, guardians, or caregivers. Semistructured interviews were chosen for their flexibility and ability to explore experiences, attitudes, and perceptions in depth [41,42]. This method allows researchers to guide discussions while adapting to participant responses, making it effective for collecting open-ended data and delving into personal and sensitive issues. The interviews were guided by a topic guide based on predefined themes from previous research, ensuring a thorough exploration of participant responses (Multimedia Appendix 3) [22,43,44].

Interviews were conducted in the local language to ensure participants felt comfortable. Consent was obtained before recording, respecting participants’ autonomy and privacy. The interviews took place in a private office within the Child Health Directorate, providing a confidential environment. During the interviews, demographic information of participants was collected, and a “concept-elicitation” approach encouraged open dialogue. Topics included understanding of severe malaria, important outcomes, hospital-based treatment experiences, and the broader impact of severe malaria on their lives. This approach ensured participants’ voices were central to the study’s findings.

The research team provided detailed explanations of the study procedures to potential participants, ensuring they had sufficient time to review the participant information sheet (PIS) and informed consent form (ICF) thoroughly. Participants were encouraged to ask questions and seek clarifications to ensure they fully understood the study’s purpose, requirements, and role. The research staff, all trained in ethical research practices, carefully assessed participants’ comprehension of the study procedures. Participants were informed that their participation was voluntary, with the right to withdraw at any time without affecting their medical care. A distress protocol adopted from a previous study (Multimedia Appendix 4) [22] was in place to support participants during potentially distressing interviews. If participants appeared uncomfortable, interviews were paused or stopped, and support options, such as referrals to health care professionals, were offered.

All participants who complete the Delphi process will be invited to participate in an online consensus meeting conducted via Zoom. To ensure that discussions reflect a range of perspectives while remaining manageable, each stakeholder group will be represented by a minimum of 2 participants. This approach is intended to balance inclusivity with feasibility and to ensure that all stakeholder voices are adequately represented during the outcome agreement. If an invited participant cannot attend, efforts will be made to find a suitable replacement from the same stakeholder group. To facilitate broad international participation, meetings will be scheduled to accommodate different time zones and participant availability.

Before the meetings, all necessary materials (outcomes rated through the Delphi process and voting patterns from different stakeholder groups) will be circulated to ensure participants are well prepared. To enhance engagement and decision-making, participants will be provided with a secure weblink to cast their votes remotely during the meeting.

The primary objective of the consensus meeting is to finalize the COS through structured discussions involving a diverse international panel. Outcomes identified through the Delphi process will be reviewed alongside voting patterns from different stakeholder groups. Discussions will be chaired by experienced, nonvoting facilitators to ensure neutrality. Following these discussions, participants will engage in anonymous, computerized voting. An outcome will be included in the final COS if it receives at least 70% approval from participants, with representation from all stakeholder groups.

Following agreement on the final COS, outcome measurement instruments for each outcome will be identified and evaluated in accordance with COSMIN guidelines[56]. This process will ensure that recommended instruments are valid, reliable, and appropriate for use in severe malaria treatment trials.

Systematic literature searches will be conducted to identify existing instruments used to measure the outcomes included in the COS. Sources will include published clinical trials and methodological studies relevant to severe malaria and related conditions. Identified instruments will then be assessed for methodological quality using the COSMIN Risk of Bias checklist, with the evaluation of key measurement properties such as validity, reliability, and responsiveness. Where evidence is insufficient or no appropriate instrument exists, gaps in outcome measurement will be highlighted, with recommendations for future research or instrument development.

The results of this research will be written as part of a PhD dissertation and publications and will be disseminated at conferences, on the project webpage, featured in network newsletters, presented at seminars, as well as distribution of leaflets to all expert networks associated with the treatment of severe malaria in trials. To enhance accessibility, a plain English summary will be provided in infographics and on social media to facilitate broader engagement. The study protocol and results will be publicly available on the Open Science Framework to facilitate free and widespread sharing of the research. Participants will receive the findings of this research if they consent to it.

At the interview venue, participants were provided with a written ICF (Multimedia Appendix 5) after being guided through the PIS (Multimedia Appendix 6) to ensure they fully understood the study’s purpose and procedures. For participants unable to read or write, the PIS and ICFs were read aloud and translated into the local language to facilitate comprehension. Local gatekeepers played a crucial role in assisting participants by printing and signing the forms when necessary.

Participants unable to sign the consent form had the option to provide a thumbprint, ensuring inclusivity and respect for diverse literacy levels. All signed consent forms were securely stored in a locked filing cabinet at the local co-investigator’s office, safeguarding participants’ confidentiality and adhering to ethical research practices. All data were managed according to the University College London (UCL) Research Ethics Committee and the Komfo Anokye Teaching Hospital Institutional Review Board (KATH-IRB) guidelines.

Ethical approval for the qualitative interview phase of this study was obtained from the UCL Research Ethics Committee (project ID 27289/001) and the KATH-IRB, Ghana (reference KATH IRB/AP/087/24). All interview participants received written study information and provided written informed consent before participation. Data were treated with strict confidentiality, with participants assigned system-generated study identification numbers, and all personally identifiable information anonymized. No names or identifiable details appear in the thesis or resulting publications. Audio recordings and transcripts were securely stored on UCL OneDrive and accessible only to authorized members of the research team, with anonymized data retained for thesis write-up and repository deposit. Interview participants received GH¢50 (US $4.5) airtime to compensate for time, inconvenience, and transport costs.

The subsequent Delphi surveys and consensus meeting phases will be conducted under the same ethical approvals. Participants will be provided with written study information and will give informed consent before participation. Survey participants will be able to pause, save, and return to the survey, and participation will be voluntary with the option to withdraw at any time. Where applicable, names will be collected solely for acknowledgment and email addresses for survey administration and dissemination of study results; participants will be able to opt out of both. All data will be anonymized using study IDs, stored securely, and accessible only to authorized researchers. Email addresses will be retained until completion of the PhD project (anticipated September 30, 2026) and then deleted. No financial compensation is planned for participation in the survey or consensus meeting phases.

The study involved 26 participants, the majority of whom were female (n=20, 76.9%), aged 21 to 70 years. The largest age group was 40 to 49 years (n=9, 34.6%), followed by 30 to 39 years (n=8, 30.8%).

Educational backgrounds varied: 50% (n=13) completed junior high school, and 7.7% (n=2) had no formal education.

Most participants were married (n=15, 57.7%) and mothers (n=16, 61.5%). Occupations included trading (n=16, 61.5%), skilled work (n=5, 19.2%), farming (n=3, 11.5%), professionals, and retired (n=1, 3.8% each). The patients were mostly male (n=16, 61.5%), aged 2 to 14 years, and older than 5 years (n=17, 65.4%), with the majority in primary school (n=14, 53.8%).