Process Evaluation of a Metformin RCT for People Living with HIV with Pre-Diabetes in Tanzania (META Trial): a study protocol

Nandakumar Ravichandran; John Broughan; Geoff McCombe; Sheila Loughman; Sokoine Kivuyo; Faith Aikaeli; Doreen Pamba; Erik Van Widenfelt; Magreth Mbena; Jeffrey V Lazarus; Sayoki Mfinanga; Kaushik Ramaiya; Shabbar Jaffar; Anupam Garrib; Walter Cullen

doi:10.12688/hrbopenres.14251.1

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Study Protocol

Process Evaluation of a Metformin RCT for People Living with HIV with Pre-Diabetes in Tanzania (META Trial): a study protocol

[version 1; peer review: awaiting peer review]

Nandakumar Ravichandran ¹, John Broughan², Geoff McCombe¹, [...] Sheila Loughman¹, Sokoine Kivuyo³, Faith Aikaeli³, Doreen Pamba³, Erik Van Widenfelt⁴, Magreth Mbena⁵, Jeffrey V Lazarus⁶, Sayoki Mfinanga³, Kaushik Ramaiya⁵, Shabbar Jaffar⁴, Anupam Garrib⁴, Walter Cullen¹

Nandakumar Ravichandran ¹, John Broughan², [...] Geoff McCombe¹, Sheila Loughman¹, Sokoine Kivuyo³, Faith Aikaeli³, Doreen Pamba³, Erik Van Widenfelt⁴, Magreth Mbena⁵, Jeffrey V Lazarus⁶, Sayoki Mfinanga³, Kaushik Ramaiya⁵, Shabbar Jaffar⁴, Anupam Garrib⁴, Walter Cullen¹

PUBLISHED 02 Oct 2025

Author details Author details

¹ University College Dublin School of Medicine, Dublin, Leinster, Ireland
² Clinical Research Centre, School of Medicine, University College Dublin, Dublin, Ireland
³ National Institute for Medical Research, Dar es Salaam, Dar es Salaam, Tanzania
⁴ University College London Institute for Global Health, London, England, UK
⁵ Shree Hindu Mandal Hospital, Dar es Salaam, Dar es Salaam, Tanzania
⁶ Barcelona Institute for Global Health, Barcelona, Catalonia, Spain

Nandakumar Ravichandran
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Software, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

John Broughan
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Software, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Geoff McCombe
Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation

Sheila Loughman
Roles: Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Sokoine Kivuyo
Roles: Data Curation, Formal Analysis, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing

Faith Aikaeli
Roles: Data Curation, Formal Analysis, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing

Doreen Pamba
Roles: Methodology, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Erik Van Widenfelt
Roles: Data Curation, Project Administration, Software, Validation, Writing – Original Draft Preparation

Magreth Mbena
Roles: Formal Analysis, Investigation, Validation, Writing – Original Draft Preparation

Jeffrey V Lazarus
Roles: Data Curation, Funding Acquisition, Resources, Supervision, Writing – Original Draft Preparation

Sayoki Mfinanga
Roles: Formal Analysis, Funding Acquisition, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

Kaushik Ramaiya
Roles: Formal Analysis, Funding Acquisition, Project Administration, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Shabbar Jaffar
Roles: Data Curation, Funding Acquisition, Investigation, Project Administration, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Anupam Garrib
Roles: Data Curation, Formal Analysis, Funding Acquisition, Project Administration, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Walter Cullen
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS AWAITING PEER REVIEW

Abstract

Background

Diabetes is a common comorbidity among people living with HIV. As the prevalence of diabetes rises across sub-Saharan Africa (SSA), there is an urgent need for effective interventions to address diabetes and pre-diabetic conditions in HIV patients. The META (Metformin Treatment in Africa) trial aims to assess the effectiveness of metformin in preventing diabetes among people living with HIV (PLHIV) on antiretroviral therapy (ART) who have pre-diabetes. This paper presents the process evaluation, which explores the feasibility, acceptability, and perceived effectiveness of the META trial and its intervention in real-world clinical settings in Dar es Salaam, Tanzania.

Methods

A mixed methods approach will be employed using a pragmatic realist theoretical framework. Qualitative data will be gathered through in-depth semi-structured interviews using stratified purposive sampling of trial participants (n=20), policymakers (n=10) and focus group discussions with associated health care providers and clinicians working in HIV and non-communicable disease care (n=20). Short cross-sectional surveys will be administered prior to interviews. Data collection will take place across five health facilities in Dar es Salaam, Tanzania. Qualitative data analysis will be complemented by Braun and Clarke’s ‘Reflexive Thematic Analysis’ technique, and survey data will be analysed using SPSS.

Discussion

The study’s pragmatic realist framework is expected to produce findings with greater depth, scope, and practical relevance. The study findings will contribute to existing knowledge regarding the experiential components of trials involving persons on ART and/or with pre-diabetes, as well as metformin-based interventions. Findings will support interpretation of trial outcomes, highlight facilitators and barriers to implementation, and provide evidence to guide future policy, scale-up, and integration of diabetes prevention strategies into HIV care in SSA.

Process evaluation registration: Clinicaltrials.gov, NCT06743698

Trial registration: ISRCTN77382043

Keywords

Pre-diabetes, HIV, Metformin, Clinical trial, Process evaluation

Corresponding author: Nandakumar Ravichandran

Competing interests: No competing interests were disclosed.

Grant information: The META Trial is funded by the EDCTP2 programme supported by the European Union Horizon 2020 research and innovation programme and funded by the European Union under Global Health EDCTP3. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or Global Health EDCTP3. Neither the European Union nor the granting authority can be held responsible for them.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2025 Ravichandran N et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Ravichandran N, Broughan J, McCombe G et al. Process Evaluation of a Metformin RCT for People Living with HIV with Pre-Diabetes in Tanzania (META Trial): a study protocol [version 1; peer review: awaiting peer review]. HRB Open Res 2025, 8:109 (https://doi.org/10.12688/hrbopenres.14251.1) First published: 02 Oct 2025, 8:109 (https://doi.org/10.12688/hrbopenres.14251.1) Latest published: 02 Oct 2025, 8:109 (https://doi.org/10.12688/hrbopenres.14251.1)

Introduction

Diabetes is a common comorbidity among people living with HIV¹. In sub-Saharan Africa (SSA), the prevalence of diabetes rose from 4 million cases in 1980 to 23·6 million cases in 2021, marking a 490% increase and is projected to increase to 54.9 million by 2045 without effective interventions². This trend is contributing to a growing syndemic of HIV and diabetes across SSA³. While the scale-up of antiretroviral therapy (ART) since 2003 has significantly reduced HIV-related morbidity and mortality, SSA now faces a parallel challenge: the rising burden of type 2 diabetes^4,5. Notably, non-AIDS-related deaths among people with HIV increased by 18% between 2010 and 2022⁶. Many individuals develop diabetes after progressing through a pre-diabetic phase, which carries a high annual conversion rate to clinical diabetes⁷. This underscores the urgent need for effective, targeted interventions for people with HIV at risk of developing diabetes.

A phase II randomized, double-blind, placebo-controlled trial (ISRCTN76157257), funded by the UK’s National Institute for Health Research (NIHR), was conducted between 2018 and 2021 to evaluate the feasibility and safety of metformin in this population⁸. Metformin is the recommended first-line drug for persons with diabetes and HIV infection in the UK, Africa, and elsewhere¹. Despite considerable disruption to the phase II trial caused by COVID-19, 277/364 (76%) of participants completed the study and had glycaemia tests as scheduled or within six days of their final appointment. A further 41/364 (11%) completed the study between seven and 30 days after their scheduled appointment. Adherence to medicines was high. At the final assessment at 12 months, close to 100% of participants who had their final glucose test within six days of their scheduled appointment date said that they had taken more than 95% of their medicines in the last 28 days. For all participants who completed, this was figure was 80%⁸.

Given the positive results of the phase II trial and the well-established safety and efficacy profile of metformin, the phase II trial led to a phase III trial (META Trial – ISRCTN77382043). Funded by the European and Developing Countries Clinical Trials Partnership (EDCTP2 and EDCTP3). This trial aims to identify a low-cost intervention to prevent or delay the onset of diabetes in people living with HIV on ART in SSA⁹. The phase III trial has completed recruitment and follow up is ongoing and expected to finish in February 2026.

Recognizing the value of understanding contextual factors in clinical trials, Van Hout et al. demonstrated that process evaluations can capture subtle but critical elements influencing trial outcomes^10,11. Building on this insight, the current study aims to conduct a mixed methods process evaluation of the META trial to explore the feasibility, acceptability and perceived effectiveness of the trial and its intervention. This paper presents the study protocol for a mixed methods process evaluation of the META trial, focusing on the implementation and impact of metformin use in HIV-positive individuals on ART with pre-diabetes in sub-Saharan Africa.

Methodology

Research design and theoretical framework

This mixed method process evaluation study aims to examine the feasibility, acceptability, and perceived effectiveness of the META trial and its intervention by conducting in-depth semi-structured qualitative interviews and brief surveys with a purposive sample of trial participants. Additionally, qualitative interviews with policy makers and focus groups with associated health care providers (HCPs) and clinicians working in HIV and non-communicable disease (NCD) care will be conducted. A pragmatic realist theoretical framework will be used. The pragmatic approach endorses the use of mixed methods approaches to capture a more complete and dynamic picture of the phenomenon under study¹². Also, to achieve a good understanding of the trial’s perceived effectiveness and factors influencing this, a realist approach will facilitate attention towards the META Trial intervention’s mechanism and its outcomes, particularly with respect to the diversity of contextual factors surrounding the intervention, namely the perspectives of stakeholders involved and the multiplicity of biological, social / structural, and psychological factors underpinning these individuals’ realities¹³. The study design and protocol were also informed by the ‘Standards for reporting qualitative research: a synthesis of recommendations’¹⁴.

Setting, participants and sampling

The META trial is being conducted in five health facilities in Dar es Salaam in Tanzania. Dar es Salaam is the largest city in Tanzania, with a population of over nine million people. This process evaluation will involve a purposive sample of trial participants (n = 20) who will complete brief surveys (see Appendix 2) and participate in semi-structured interviews (see Appendix 3). Three to four focus groups, each comprising 5-7 HCPs, including clinicians working in HIV and NCD care, will be conducted to understand their perspectives and experiences (see Appendix 4). In addition, 10 policymakers will be individually interviewed to explore policy relevance and system level factors (see Appendix 5). Research suggests these sample sizes are sufficient to achieve data saturation which will be considered when reaching the point where further data collection becomes ‘counter-productive’, and where the ‘new’ does not necessarily add anything to the overall study or theory¹⁵. Data collection will be carried out in person or online by a Social Scientist at National Institute for Medical Research, Tanzania. To assure data quality and to foster local capacity, the researcher underwent training from University College Dublin (UCD) in qualitative data collection and analysis methods. Training covered study-specific content (such as study background, aims, and procedures), small scale piloting and culturally appropriate techniques to aid communication and engagement during data collection (Table 1).

Table 1. Summary of Participant Groups, Sample Sizes, and Data Collection Methods.

Participant group	Sample size (n)	Data collection method	Purpose
META trial participants	20	Brief surveys + Semi- structured interviews	Assess feasibility, acceptability, perceived effectiveness
Healthcare providers, HIV and NCD clinicians	3–4 focus groups of 5–7 HCPs	Focus group discussions	Explore experiences of NCD burden in PLHIV and the META trial and its intervention
Policymakers	10	Semi-structured interviews	Understand system-level factors, policy relevance

Patient inclusion criteria

Participants who participated in the META Trial (see Appendix 1)
Participants who have the capacity to provide written informed consent

Participant recruitment

To minimise selection and random bias, stratified purposive sampling will be used to select participants that reflect key characteristics (such as age and gender) of the META Trial population, ensuring representation from both intervention and placebo arms. Stratified purposive sampling involves selecting specific subgroups of participants based on relevant characteristics and allocating a set number from each stratum. This approach enhances trustworthiness and rigour in qualitative research¹⁶.

A purposive list of participants for the process evaluation will be generated by the database manager from both trial arms, maintaining allocation concealment. Participants, the researcher collecting the data, and the process evaluation team will remain blinded to trial allocation until the trial concludes¹⁷.

Blinding is a well-established method for reducing bias by ensuring that participants, healthcare providers, and outcome assessors remain unaware of group allocation. It aims to avoid ascertainment bias, thereby preserving the integrity of outcome measurement and preventing knowledge of allocation from influencing care delivery or data collection¹⁷. The researcher will provide the individuals invited to participate with information about the study and ask to give their consent in writing before participation. To aid recruitment, the study team will collaborate with community leaders, participants’ families as appropriate, and policy makers to help foster buy-in and engagement.

Data collection

Training was conducted to standardise data collection, as will small-scale piloting to refine the methodology, ensure clarity, and address any practical issues with data collection delivered through online sessions. These sessions covered procedures to standardise the conduct and analysis of the qualitative interviews, touching on overview of study protocol, approaches to recruitment of participants, consent procedures, outline of semi-structured interviews, recording and transcription of interviews, analysis and data sharing. Training was tailored to account for cultural factors that may affect data collection. Furthermore, training was provided with a strong basis in qualitative and quantitative methods.

Data will be collected during September to November 2025 by the Social Scientist at National Institute for Medical Research, Tanzania. Training of the social scientist was conducted in August 2025. Data collection will be completed by January 2026 and data analysis will be completed by the UCD Research Team by May 2026. Data collection methods will explore the acceptability, feasibility, and perceived effectiveness of the trial and its intervention – both positive (e.g., improvements in health, quality of life, health behaviours, and health outcomes) and negative (e.g., side effects, cost). The qualitative interviews and focus groups will be structured based on realist principles to explore perceived effectiveness of the intervention, as well as Bowen et al.’s eight areas of focus to measure feasibility. These areas of focus will help assess the intervention’s (1) acceptability, (2) demand, (3) implementation, (4) practicality, (5) adaptation, (6) integration, (7) expansion and (8) limited efficacy testing¹⁸ (see Appendix 1 for interview guide).

Interviews and focus groups will be conducted in person or remotely via phone / online and their data will be collected using a digital audio-recording device. Participants will be asked to complete brief questionnaires prior to completing qualitative interviews¹⁹. The qualitative team will remain blinded to trial allocation. The process evaluation analysis team (GM, JB, NR, SL, WC) will not be involved in collecting data to avoid bias.

Data analysis

Once transcribed and translated where necessary by the researcher in participating sites, the audio recordings will be destroyed and pseudonymised versions of the transcripts will be stored in an encrypted database. The data will be pseudonymised by removing all personal identifiers (e.g., name, address) from the transcripts, storing any personal identifying information of participants separately from all transcripts where required.

Study data will be analysed by the research team after the trial is unblinded and debriefed. At this point, the patient IDs will be matched to the trial allocation groups (intervention or placebo) by the trial’s database manager. Subsequently, each patient in the intervention and control arm will be given a new pseudonymous identifier (p01, p02, p03, etc.) to further delink the data from their personal identifiers. The pseudonymised data will then be analysed through a pragmatic realist lens by two independent reviewers from UCD, as well as a third independent reviewer to resolve conflicts of data interpretation. Qualitative data analysis will also be complimented by Braun and Clarke’s ‘Reflexive Thematic Analysis’ technique²⁰ using an iterative approach in NVivo. Survey data will also be analysed by the UCD research team using descriptive statistical analysis methods in IBM SPSS.

To enhance the validity and richness of findings, a triangulation approach will be used to integrate qualitative and quantitative findings. Triangulation enhances the credibility and validity of the study by comparing and cross-verifying results from different methods and data sources²¹. Themes emerging from the qualitative data will be compared with the quantitative findings to identify areas where findings align, reinforcing conclusions, using qualitative data to elaborate and explain the findings of the quantitative data and highlight any divergent findings for further contextual explanation. Convergence will be guided by the realist framework, ensuring that multiple stakeholder perspectives are synthesized to understand contextual mechanisms behind intervention outcomes.

Discussion

This process evaluation is designed to provide a richer understanding of the feasibility, acceptability, and perceived effectiveness of the META trial intervention in a real-world context in Tanzania. While existing evidence suggests that metformin may be effective in controlled settings²², its efficacy in this specific population and context remains uncertain. As such, this evaluation is essential not only for assessing whether the intervention works, but also for exploring how and why it may or may not be feasible, acceptable, and effective in practice. In addition to measuring outcomes, the study will explore potential confounding factors such as participants’ socio-economic status, dietary habits and health-related behaviours that could independently affect the results. These factors may influence the intervention’s apparent effectiveness, regardless of which trial arm participants were assigned to, and are therefore critical to interpreting the findings accurately. By investigating the nuanced aspects of the META intervention with mixed research methods, Bowen et al.’s feasibility framework, and a realist perspective, the process evaluation will help explain underlying mechanisms of impact, uncover contextual and behavioural influences, and provide insights to inform future implementation and policy decisions.

Recent systematic reviews highlighted insufficient reporting of process evaluations and rare use of theoretical frameworks to guide process evaluations within RCTs^23,24. While qualitative process evaluations have been carried out in RCTs to explore the effects of interventions and barriers to implementation²⁵, this study is one of the very few to collect process evaluation data while blinding and allocation concealment are maintained in a placebo-controlled RCT. Importantly, participants from both the intervention and placebo groups will be interviewed without knowledge of their allocation. Blinding will be preserved until the trial’s conclusion, and the process evaluation will be analysed after unblinding. There is a lack of studies implementing hybrid approaches combining methodological innovation (a rigorous qualitative evaluation of a drug trial) with the ability to gain high-value insights into how participants perceive the effects of the intervention and the placebo. This study addresses this gap.

The study’s pragmatic realist framework guides this mixed methods approach employing semi-structured interviews, surveys, and focus groups that will produce findings with greater depth, scope, and practical benefits²⁶. The sample size for this study has been determined to be sufficient to achieve data saturation, as suggested by previous research¹⁵. The theoretically flexible Braun and Clarke framework has many benefits for studies such as this which are interpretive in nature, as it is a method for identifying, analysing, and reporting patterns (themes) within data.

Recognising potential challenges such as participant dropout, logistical barriers in data collection, and unforeseen delays (e.g., public health crises), the study will incorporate risk mitigation strategies. These include maintaining a robust community engagement strategy with local leaders and stakeholders to aid recruitment, leveraging digital tools for communication and data management, training in cultural sensitivity for the researcher. Proactive engagement with participants can address concerns of study participants via regular follow-up, and the engagement can also provide training in audit for researchers.

The study findings will contribute to existing knowledge regarding the experiential components of trials regarding persons on ART and/or with pre-diabetes, as well as metformin-based interventions. Further, valuable knowledge will be acquired regarding the experiences of trials conducted in SSA, particularly Tanzania. On a policy level, it is expected that the study will impact on policy in the region and the involvement of local policymakers throughout will ensure better uptake of results.

Ethical considerations

This process evaluation is listed on the ClinicalTrials.gov registry (registration number: NCT06743698). Ethical approvals for the process evaluation were obtained from the UCD Research Ethics Committee (LS-25-29-Cullen) and the National Institute for Medical Research Ethics committee in Tanzania (Certificate-7493), and the study is compliant with the Declaration of Helsinki. Written informed consent for participation in interviews will be obtained by the researcher collecting the data from all participants. During this process, all participants will be provided with written information about the research; this will also be explained verbally, and they will be informed that their participation is voluntary and that they may withdraw from participation at any time without any penalty. The META trial is listed on the International Standard Randomised Controlled Trial Number (ISRCTN) registry (registration number: ISRCTN77382043).

Data management

The data controller of the study is the National Institute for Medical Research, Dar es Salaam, Tanzania. As per signed data sharing agreements, data will be collected by the research team in Tanzania, transcribed, translated to English and anonymised prior to being shared with the UCD research team via a secure folder on a project-specific secure Google drive.

The safety of all data will be ensured by (1) applying encrypted password-protected code to all transcripts; (2) storing all data in an encrypted database for up to 5 years and only being accessible by the META Trial study research teams in Ireland, Tanzania, Spain and UK; (3) storing all personal identifying information of participants separately from all study datasets and allocating each participant with a unique participant identification number to delink the information from the personal identifiers, and (4) destroying all audio recordings on completion of transcription. The data files will be uploaded onto the encrypted database, where they will be stored for up to 10 years and thereafter destroyed by the trial team. Only anonymised participants’ data will be shared during routine updates and briefing sessions.

Data availability

The data associated with this manuscript is available in the Zenodo repository. The transcripts for this study cannot be shared in the future under any circumstance with persons not named on approved ethical review documentation (including being shared publicly in a data repository). While deidentified to the greatest possible extent, the study transcripts contain details (e.g., accounts of unique characteristics and experiences) that would have a high risk of breaching the participants’ privacy and confidentiality. Anonymous and aggregated details regarding the numbers of participants that took part in the study and their basic characteristics will be publicly shared as these details do not compromise privacy and confidentiality and were agreed to by participants that signed study consent forms.

Zenodo: UCD School of Medicine. (2025). Process Evaluation of a Metformin RCT for People Living with HIV with Pre-Diabetes in Tanzania (META Trial): a study protocol. https://doi.org/10.5281/zenodo.17106273²⁷

This project contains the following extended data:

- Appendices

- SRQR checklist

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Acknowledgments and contributions

We would like to acknowledge support from University College Dublin's (UCD) School of Medicine and College of Health and Agricultural Sciences. Additionally, we extend our gratitude for the funding support provided to study investigators (GM, JB, NR, SL, WC) received through the UCD Clinical Research Centre and the Health Research Board (grant number: CRF/C-2021-002).

Faculty Opinions recommended

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