Ignite Creation Date:
2024-10-26 @ 3:40 PM
Last Modification Date:
2024-10-26 @ 3:40 PM
Study NCT ID:
NCT06601712
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-08-13
Brief Title:
Post-discharge Malaria Chemoprevention Implementation Trial in Benin
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Delivery Strategies for Malaria Chemoprevention in the Post-discharge Management of Children Hospitalised with Severe Anaemia or Severe Malaria a Cluster Randomised Controlled Implementation Trial in Benin
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PDMC-SL
Brief Summary:
The proposed research aims to conduct implementation trials in Benin co-designed with national stakeholders to evaluate different delivery strategies for optimizing health system delivery of post-discharge malaria chemoprevention PDMC drugs and adherence to PDMC This chemoprevention strategy is effective in reducing hospital readmissions and deaths after discharge However there is no clear delivery platform for PDMC and adherence to the 3-day dosing regimen provided monthly three times after discharge is a potential limitation The current trial will provide evidence-based data on acceptability feasibility and cost-effectiveness to aid decision-makers The evidence generated will be used to support the effective implementation and scale-up of PDMC in high malaria-endemic areas such as Benin
Detailed Description:
Introduction Severe anaemia is a major cause of morbidity and mortality in children in malaria-endemic areas of sub-Saharan Africa accounting for a large fraction of paediatric hospitalisations and in-hospital mortality 1 However these children also remain at high risk of dying or being readmitted after discharge from hospital due to a wide range of clinical epidemiological behavioural and nutritional factors 23 A recent trial in East Africa showed that about a third of discharged children after recovery from severe anaemia were readmitted or died in the first 6 months post-discharge 4 In highly endemic settings malaria is a major cause of this post-discharge morbidity and mortality 56
In June 2022 the World Health Organization WHO recommended PDMC for the post-discharge management of children with severe anaemia in settings with moderate to high perennial malaria transmission to reduce hospital readmissions and deaths after discharge 78 However there is no obvious delivery platform for PDMC unlike for intermittent preventive treatment in infants IPTi or pregnant women IPTp Furthermore a potential limitation of PDMC is adherence to the 3-day dosing regimen which is provided monthly three times after discharge Therefore implementation research is urgently needed to support the introduction and scale-up of PDMC We propose to conduct two implementation trials to evaluate delivery strategies to optimise adherence to PDMC in different contexts one in East Africa Kenya and one in West Africa Benin The current protocol presents the trial description in Benin
Rationale of the trial The WHO recommendation highlighted the need for implementation research on optimal delivery strategies for PDMC to help guide decision-making The WHO recommendation stopped short of recommending which antimalarial drug should be used and how best to deliver PDMC indicating that these decisions are to be made at the national level and adapted to suit local contexts Importantly the recommendation does not recommend any one specific drug or regimen to be used for PDMC stating SP AL and DP were used in three trials and all regimens were found to be effective for PDMC and the medicines used for PDMC can be the same as the first-line malaria treatment but an alternative medicine is preferred Neither does the recommendation provide guidance on the optimal delivery mechanisms for giving the post-discharge chemoprevention regimen to caregivers in a way that promotes adherence and public health impact A major challenge with implementing PDMC is that there is no pre-existing platform that could be utilised for its delivery This is in contrast to other malaria prevention strategies such as seasonal malaria chemoprevention SMC intermittent preventive treatment in pregnant women IPTp and perennial malaria chemoprevention PMC previously known as IPTi and the recently recommended RTSS malaria vaccine Currently the evidence on how to implement PDMC is limited to a single implementation trial in Malawi 8 Furthermore it must be appreciated that health systems particularly in the community vary from country to country The adherence to monthly 3-day courses of PDMC after discharge under real-life conditions is unknown
Study objectives
The primary objective is to determine the effectiveness of different community delivery mechanisms and adherence support strategies to optimise end-user adherence to PDMC Secondary objectives are to i determine the clinical effectiveness of the different PDMC delivery strategies all-cause and malaria-specific readmissions and sick-child clinic visits all-cause mortality ii evaluate the effectiveness of the linkage mechanisms between the various health facility levels along the PDMC delivery continuum iii determine the acceptability and feasibility of the different PDMC delivery and adherence support strategies iv determine the incremental cost-effectiveness cost per DALY averted of the different PDMC delivery and adherence support strategies
Study design The trial is a cluster randomized implementation trial with three arms at health facilities and their catchment communities clusters to enhance end-user adherence to the three PDMC courses compared to a control arm of PDMC without specific adherence support strategies Its goal is to translate PDMC research findings into national policy guidelines and encourage their adoption in clinical practice ensuring that caregivers of vulnerable children in Benin and more broadly across sub-Saharan Africa gain access to life-saving proven medicines that help prevent or reduce hospital readmissions and deaths
Study sites Two health facilities with blood transfusion services will include in the trial in Benin The recruitment will be competitive between the two selected hospitals over approximately 14 months to reach the study sample size The first site CHU-MEL has a higher annual incidence of severe anaemia approximately 800-1000 cases per year than the second site Goho departmental hospital centre Therefore the proportion of participants enrolled at CHU-MEL could be slightly higher than in Goho
Study population
Inclusion criteria convalescent children aged below 10 years weighing above or equal to 5 kg admitted with severe anaemia haemoglobin below 5gdL or severe malaria clinically stable able to take or switch to oral medication post-transfusion Hb below 5gdL
Exclusion criteria blood loss due to trauma malignancy known bleeding disorders or sickle cell disease known hypersensitivity to study drug known heart conditions non-resident in the study area previous participation in the study known need at enrolment for prohibited medication and scheduled surgery during the 6-month course of the study HIV infection and cotrimoxazole prophylaxis are not exclusion criteria
Study intervention The final choice of drug the delivery strategy and the adherence support mechanisms to be evaluated have been co-designed with MoH and key national public health stakeholders through formative research conducted under a separate standalone protocol and through a stakeholder co-design workshop In Benin PDMC will comprise of 3-day treatment courses either dihydroartemisinin-piperaquine given at the end of weeks 2 6 and 10 after discharge PDMC will consist of three courses of dihydroartemisinin-piperaquine at the end of weeks 2 6 and 10 after discharge
Two community delivery strategies combined with adherence supports will be assessed during the trial i all the drugs given at discharge to the caregivers strategy A ii all the drugs will be given by the community health workers CHWs to the caregivers at home supervised by the qualified community health officers ASCQ strategy B Clusters will be randomly allocated in a 111 ratio to intervention a b and the control c arms The unit of randomization will be health facilitiess catchment villages to avoid contamination related to adherence supports in community Each health facility and its respective community will form a cluster In arm a all PDMC drugs will be given to the caregivers at discharge with the CHW support through monthly home visits to remind the caregiver to administrate the PDMC drugs and in arm b all PDMC drugs will be given by the community health workers CHWs to the caregivers at home with a SMSphone reminder from the qualified community health officers ASCQ Arm c represents the control arm no reminder in which all PDMC drug given to the caregivers at discharge with no other adherence support approaches
All participating children will receive standard in-hospital care for severe anaemia or severe malaria blood transfusion often combined parenteral artesunate followed by a 3-day course of artemether-lumefantrin whether they initially had malaria or not which will be started in-hospital as soon as they are able to take oral medication Many children are likely to receive parenteral antibiotics as well as part of the standard of care
Economic evaluation The cost of delivering the intervention from the providers perspective and the cost of receiving the intervention from the beneficiarys perspective will be assessed through an economic evaluation cost-effectiveness analysis involving all children and their caregivers participating in the trials in both countries The same participant groups included in the acceptability and feasibility study as well as hospital and peripheral facility managers health workers responsible for the delivery of PDMC interventions including community health workers will be requested to support the provider costing Malaria control programme managers other regional national and international stakeholders will be requested to provide perspectives on how PDMC could integrate with existing general health and malaria budget structures and the size and flexibility of relevant budgets This information will be used to inform a budget impact assessment of scaling up PDMC
Acceptability and feasibility A health services qualitative study will be conducted on a subset of participants in the trial who will be enrolled towards the end in order to assess the level of acceptability of PDMC adaptations to health workers working practices to implement the intervention perceptions of the feasibility of implementing PDMC through different delivery mechanisms and generate recommendations for effective implementation and job aides to support scale-up
Effectiveness evaluation endpoints
The primary endpoint is the proportion of children with incomplete adherence to the 9 doses of PDMC three courses of 3-day treatments 3x39 Secondary endpoints include i incidence of all-cause and malaria-specific readmissions by the end of week 14 after discharge ii incidence of all-cause and malaria-specific sick-child clinic visits by 14 weeks after discharge iii incidence of all-cause mortality by 14 weeks after discharge
Economic evaluation endpoints
The primary endpoint is the incremental cost per DALY averted of alternative PDMC adherence support strategies adherence support option A Aa adherence support option B Ab with no adherence support Ac and with each other Secondary endpoints include cost per additional child receiving a complete dose of PDMC cost per hospital readmission averted cost per child receiving a complete dose cost per readmission event cost per hospital and cost per child and cost per child death percentage change in budget required to deliver the intervention
Acceptability and feasibility evaluation endpoints i health provider manager and policy stakeholder acceptability of the regimen and perceptions of caregiver acceptability and adherence ii health provider manager and policy stakeholder perceptions of the feasibility of each delivery strategy when implemented at scale and adaptations to their working practices required to ensure effective implementation and iii caregiver and community health worker acceptability of the regimen and the alternative delivery strategies in each trial
Follow-up procedures Caregivers of eligible children will be approached for potential participation during hospitalization by dedicated study staff and a consent form will be administrated near or on the day of discharge Two nurses will be assigned to each site to oversee recruitment Under the supervision of the study coordinator they will schedule follow-up visits after randomisation After consent is obtained and before discharge household addresses will be collected including caregivers phone contacts The study staff will conduct a household visit to accurately identify the homes location for future visits including GPS coordinates to facilitate future identification of households A household questionnaire will be administered at this time including data to assess socioeconomic status Before and during the trial several sensitization activities will be conducted with on-site health workers community health workers and local community leaders heads of villages and sub-districts to explain the purpose of the study Meetings with on-site health workers will also be held periodically to maintain their commitment to the trial and identify eligible children An annual stakeholder meeting will also be held to maintain national engagement and support
Children will be followed for 14 weeks ie four weeks after the last PDMC course through passive surveillance of clinic visits and hospitalisations Each child will then be seen for an end-of-study visit towards the end of week 14 Children will also be visited at home for unannounced home visits one to three days from the last day of the last dose of each 3-day course of PDMC medication to assess adherence
Sample size A sample size of 180 participants in the control arm c and 180 in each of the two intervention arms a and b totaling 540 participants would provide 90 power to detect a 50 reduction in the primary endpoint proportion of children with incomplete adherence to the 9 doses of PDMC from 368 in the control arm to 184 RR050 in any of the two intervention arms using a 111 allocation after accounting for the multiple comparisons α 0025 and the correlation between participants from the same village followed by the same CHW using the very small intra-cluster correlation coefficient ICC value of 756e-0614 A total of 648 participants 216 per arm will be recruited from the two health facilities to allow for a 15 loss to follow-up with an average of 6 participants per cluster with 36 clusters per arm selected
Trial effectiveness analysis Risk ratios and corresponding 95 confidence intervals will be computed to compare treatment effects using generalised linear mixed model GLMM Covariate-adjusted analyses for the primary endpoint will also be conducted by adding pre-specified covariates into the above unadjusted GLMM analysis to derive the adjusted RR 95 CI The random effect for cluster will be removed if the model cannot converge Small-sample correction will be considered given the relatively low number of clusters recruited using adjusted degrees of freedom to follow the t-distribution rather than the normal distribution or bootstrapping method to get valid variance estimates A detailed study statistical analytical plan for the final analysis that will supersede the study protocol will be drawn up during the study at database lock
Economic acceptability and feasibility evaluation analysis Framework analysis will be used to identify factors influencing the effectiveness and scalability of each intervention delivery strategy We will draw on multiple frameworks whereby initial coding will be based on key elements using a pre-defined PDMC implementation framework 9 and the building blocks of the health system as defined by the World Health Organization 10 Acceptability theory will draw on Sekhons constructs of acceptability 11 - affective attitude general feelings about the intervention burden perceptions of effort needed to take part ethicality fit with their value system intervention coherence understanding of the intervention and how it works opportunity costs what must be given up in order to participate perceived effectiveness perceptions of the interventions ability to achieve its aim and self-efficacy feeling that they can do what they need to do to take part and unintended consequences
Adverse events analysis AE data will be collected but will be presented mainly in a descriptive way The frequency and percentages of each event will be indicated by the intervention arm Treatment-emergent adverse events are defined as adverse events that had an onset on or after the day of the first dose of study medication Adverse events that have missing onset dates will be considered to be treatment-emergent No formal statistical testing will be undertaken
Timeframe and duration of the study The total duration of the study is 36 months January 2024-December 2026 including 9-12 months of study preparation January -September 2024 protocol preparation and approvals October -December 2024 study preparation and set-up approximately 16-18 months of recruitment and follow-up January 2025-June 2026 and 6-8 months of data analysis and report writing July 2026 - December 2026
Ethical committee and national regulatory authorities approvals will be obtained before the trial starts
References
1 Kwambai TK Mori AT Nevitt S et al Post-discharge morbidity and mortality in children admitted with severe anaemia and other health conditions in malaria-endemic settings in Africa a systematic review and meta-analysis Lancet Child Adolesc Health 2022
2 Opoka RO Hamre KES Brand N Bangirana P Idro R John CC High Postdischarge Morbidity in Ugandan Children With Severe Malarial Anemia or Cerebral Malaria J Pediatric Infect Dis Soc 2017 63 e41-e8
3 van Hensbroek MB Jonker F Bates I Severe acquired anaemia in Africa new concepts Br J Haematol 2011 1546 690-5
4 Kwambai TK Dhabangi A Idro R et al Malaria Chemoprevention in the Postdischarge Management of Severe Anemia N Engl J Med 2020 38323 2242-54
5 Bojang KA Milligan PJ Conway DJ et al Prevention of the recurrence of anaemia in Gambian children following discharge from hospital PloS one 2010 56 e11227
6 Phiri K Esan M van Hensbroek MB Khairallah C Faragher B ter Kuile FO Intermittent preventive therapy for malaria with monthly artemether-lumefantrine for the post-discharge management of severe anaemia in children aged 4-59 months in southern Malawi a multicentre randomised placebo-controlled trial The Lancet Infectious diseases 2012 123 191-200
7 World Health Organisation Global Malaria Programme WHO Guidelines for malaria - 3 June 2022 httpsappswhointirisrestbitstreams1427681retrieve Geneva 2022
8 Nkosi-Gondwe T Robberstad B Mukaka M et al Adherence to community versus facility-based delivery of monthly malaria chemoprevention with dihydroartemisinin-piperaquine for the post-discharge management of severe anemia in Malawian children A cluster randomized trial PloS one 2021 169 e0255769
9 Damschroder LJ Aron DC Keith RE Kirsh SR Alexander JA Lowery JC Fostering implementation of health services research findings into practice a consolidated framework for advancing implementation science Implement Sci 2009 4 50
10 World Health Organisation Everybodys Business Strengthening Health Systems to Improve Health Outcomes Framework for Action Geneva WHO ISBN 978 92 4 159607 7 httpwwwwhointhealthsystemsstrategyeverybodys_businesspdf accessed 7 June 2014 2007
11 Sekhon M Cartwright M Francis JJ Acceptability of healthcare interventions an overview of reviews and development of a theoretical framework BMC Health Serv Res 2017 171 88
In June 2022 the World Health Organization WHO recommended PDMC for the post-discharge management of children with severe anaemia in settings with moderate to high perennial malaria transmission to reduce hospital readmissions and deaths after discharge 78 However there is no obvious delivery platform for PDMC unlike for intermittent preventive treatment in infants IPTi or pregnant women IPTp Furthermore a potential limitation of PDMC is adherence to the 3-day dosing regimen which is provided monthly three times after discharge Therefore implementation research is urgently needed to support the introduction and scale-up of PDMC We propose to conduct two implementation trials to evaluate delivery strategies to optimise adherence to PDMC in different contexts one in East Africa Kenya and one in West Africa Benin The current protocol presents the trial description in Benin
Rationale of the trial The WHO recommendation highlighted the need for implementation research on optimal delivery strategies for PDMC to help guide decision-making The WHO recommendation stopped short of recommending which antimalarial drug should be used and how best to deliver PDMC indicating that these decisions are to be made at the national level and adapted to suit local contexts Importantly the recommendation does not recommend any one specific drug or regimen to be used for PDMC stating SP AL and DP were used in three trials and all regimens were found to be effective for PDMC and the medicines used for PDMC can be the same as the first-line malaria treatment but an alternative medicine is preferred Neither does the recommendation provide guidance on the optimal delivery mechanisms for giving the post-discharge chemoprevention regimen to caregivers in a way that promotes adherence and public health impact A major challenge with implementing PDMC is that there is no pre-existing platform that could be utilised for its delivery This is in contrast to other malaria prevention strategies such as seasonal malaria chemoprevention SMC intermittent preventive treatment in pregnant women IPTp and perennial malaria chemoprevention PMC previously known as IPTi and the recently recommended RTSS malaria vaccine Currently the evidence on how to implement PDMC is limited to a single implementation trial in Malawi 8 Furthermore it must be appreciated that health systems particularly in the community vary from country to country The adherence to monthly 3-day courses of PDMC after discharge under real-life conditions is unknown
Study objectives
The primary objective is to determine the effectiveness of different community delivery mechanisms and adherence support strategies to optimise end-user adherence to PDMC Secondary objectives are to i determine the clinical effectiveness of the different PDMC delivery strategies all-cause and malaria-specific readmissions and sick-child clinic visits all-cause mortality ii evaluate the effectiveness of the linkage mechanisms between the various health facility levels along the PDMC delivery continuum iii determine the acceptability and feasibility of the different PDMC delivery and adherence support strategies iv determine the incremental cost-effectiveness cost per DALY averted of the different PDMC delivery and adherence support strategies
Study design The trial is a cluster randomized implementation trial with three arms at health facilities and their catchment communities clusters to enhance end-user adherence to the three PDMC courses compared to a control arm of PDMC without specific adherence support strategies Its goal is to translate PDMC research findings into national policy guidelines and encourage their adoption in clinical practice ensuring that caregivers of vulnerable children in Benin and more broadly across sub-Saharan Africa gain access to life-saving proven medicines that help prevent or reduce hospital readmissions and deaths
Study sites Two health facilities with blood transfusion services will include in the trial in Benin The recruitment will be competitive between the two selected hospitals over approximately 14 months to reach the study sample size The first site CHU-MEL has a higher annual incidence of severe anaemia approximately 800-1000 cases per year than the second site Goho departmental hospital centre Therefore the proportion of participants enrolled at CHU-MEL could be slightly higher than in Goho
Study population
Inclusion criteria convalescent children aged below 10 years weighing above or equal to 5 kg admitted with severe anaemia haemoglobin below 5gdL or severe malaria clinically stable able to take or switch to oral medication post-transfusion Hb below 5gdL
Exclusion criteria blood loss due to trauma malignancy known bleeding disorders or sickle cell disease known hypersensitivity to study drug known heart conditions non-resident in the study area previous participation in the study known need at enrolment for prohibited medication and scheduled surgery during the 6-month course of the study HIV infection and cotrimoxazole prophylaxis are not exclusion criteria
Study intervention The final choice of drug the delivery strategy and the adherence support mechanisms to be evaluated have been co-designed with MoH and key national public health stakeholders through formative research conducted under a separate standalone protocol and through a stakeholder co-design workshop In Benin PDMC will comprise of 3-day treatment courses either dihydroartemisinin-piperaquine given at the end of weeks 2 6 and 10 after discharge PDMC will consist of three courses of dihydroartemisinin-piperaquine at the end of weeks 2 6 and 10 after discharge
Two community delivery strategies combined with adherence supports will be assessed during the trial i all the drugs given at discharge to the caregivers strategy A ii all the drugs will be given by the community health workers CHWs to the caregivers at home supervised by the qualified community health officers ASCQ strategy B Clusters will be randomly allocated in a 111 ratio to intervention a b and the control c arms The unit of randomization will be health facilitiess catchment villages to avoid contamination related to adherence supports in community Each health facility and its respective community will form a cluster In arm a all PDMC drugs will be given to the caregivers at discharge with the CHW support through monthly home visits to remind the caregiver to administrate the PDMC drugs and in arm b all PDMC drugs will be given by the community health workers CHWs to the caregivers at home with a SMSphone reminder from the qualified community health officers ASCQ Arm c represents the control arm no reminder in which all PDMC drug given to the caregivers at discharge with no other adherence support approaches
All participating children will receive standard in-hospital care for severe anaemia or severe malaria blood transfusion often combined parenteral artesunate followed by a 3-day course of artemether-lumefantrin whether they initially had malaria or not which will be started in-hospital as soon as they are able to take oral medication Many children are likely to receive parenteral antibiotics as well as part of the standard of care
Economic evaluation The cost of delivering the intervention from the providers perspective and the cost of receiving the intervention from the beneficiarys perspective will be assessed through an economic evaluation cost-effectiveness analysis involving all children and their caregivers participating in the trials in both countries The same participant groups included in the acceptability and feasibility study as well as hospital and peripheral facility managers health workers responsible for the delivery of PDMC interventions including community health workers will be requested to support the provider costing Malaria control programme managers other regional national and international stakeholders will be requested to provide perspectives on how PDMC could integrate with existing general health and malaria budget structures and the size and flexibility of relevant budgets This information will be used to inform a budget impact assessment of scaling up PDMC
Acceptability and feasibility A health services qualitative study will be conducted on a subset of participants in the trial who will be enrolled towards the end in order to assess the level of acceptability of PDMC adaptations to health workers working practices to implement the intervention perceptions of the feasibility of implementing PDMC through different delivery mechanisms and generate recommendations for effective implementation and job aides to support scale-up
Effectiveness evaluation endpoints
The primary endpoint is the proportion of children with incomplete adherence to the 9 doses of PDMC three courses of 3-day treatments 3x39 Secondary endpoints include i incidence of all-cause and malaria-specific readmissions by the end of week 14 after discharge ii incidence of all-cause and malaria-specific sick-child clinic visits by 14 weeks after discharge iii incidence of all-cause mortality by 14 weeks after discharge
Economic evaluation endpoints
The primary endpoint is the incremental cost per DALY averted of alternative PDMC adherence support strategies adherence support option A Aa adherence support option B Ab with no adherence support Ac and with each other Secondary endpoints include cost per additional child receiving a complete dose of PDMC cost per hospital readmission averted cost per child receiving a complete dose cost per readmission event cost per hospital and cost per child and cost per child death percentage change in budget required to deliver the intervention
Acceptability and feasibility evaluation endpoints i health provider manager and policy stakeholder acceptability of the regimen and perceptions of caregiver acceptability and adherence ii health provider manager and policy stakeholder perceptions of the feasibility of each delivery strategy when implemented at scale and adaptations to their working practices required to ensure effective implementation and iii caregiver and community health worker acceptability of the regimen and the alternative delivery strategies in each trial
Follow-up procedures Caregivers of eligible children will be approached for potential participation during hospitalization by dedicated study staff and a consent form will be administrated near or on the day of discharge Two nurses will be assigned to each site to oversee recruitment Under the supervision of the study coordinator they will schedule follow-up visits after randomisation After consent is obtained and before discharge household addresses will be collected including caregivers phone contacts The study staff will conduct a household visit to accurately identify the homes location for future visits including GPS coordinates to facilitate future identification of households A household questionnaire will be administered at this time including data to assess socioeconomic status Before and during the trial several sensitization activities will be conducted with on-site health workers community health workers and local community leaders heads of villages and sub-districts to explain the purpose of the study Meetings with on-site health workers will also be held periodically to maintain their commitment to the trial and identify eligible children An annual stakeholder meeting will also be held to maintain national engagement and support
Children will be followed for 14 weeks ie four weeks after the last PDMC course through passive surveillance of clinic visits and hospitalisations Each child will then be seen for an end-of-study visit towards the end of week 14 Children will also be visited at home for unannounced home visits one to three days from the last day of the last dose of each 3-day course of PDMC medication to assess adherence
Sample size A sample size of 180 participants in the control arm c and 180 in each of the two intervention arms a and b totaling 540 participants would provide 90 power to detect a 50 reduction in the primary endpoint proportion of children with incomplete adherence to the 9 doses of PDMC from 368 in the control arm to 184 RR050 in any of the two intervention arms using a 111 allocation after accounting for the multiple comparisons α 0025 and the correlation between participants from the same village followed by the same CHW using the very small intra-cluster correlation coefficient ICC value of 756e-0614 A total of 648 participants 216 per arm will be recruited from the two health facilities to allow for a 15 loss to follow-up with an average of 6 participants per cluster with 36 clusters per arm selected
Trial effectiveness analysis Risk ratios and corresponding 95 confidence intervals will be computed to compare treatment effects using generalised linear mixed model GLMM Covariate-adjusted analyses for the primary endpoint will also be conducted by adding pre-specified covariates into the above unadjusted GLMM analysis to derive the adjusted RR 95 CI The random effect for cluster will be removed if the model cannot converge Small-sample correction will be considered given the relatively low number of clusters recruited using adjusted degrees of freedom to follow the t-distribution rather than the normal distribution or bootstrapping method to get valid variance estimates A detailed study statistical analytical plan for the final analysis that will supersede the study protocol will be drawn up during the study at database lock
Economic acceptability and feasibility evaluation analysis Framework analysis will be used to identify factors influencing the effectiveness and scalability of each intervention delivery strategy We will draw on multiple frameworks whereby initial coding will be based on key elements using a pre-defined PDMC implementation framework 9 and the building blocks of the health system as defined by the World Health Organization 10 Acceptability theory will draw on Sekhons constructs of acceptability 11 - affective attitude general feelings about the intervention burden perceptions of effort needed to take part ethicality fit with their value system intervention coherence understanding of the intervention and how it works opportunity costs what must be given up in order to participate perceived effectiveness perceptions of the interventions ability to achieve its aim and self-efficacy feeling that they can do what they need to do to take part and unintended consequences
Adverse events analysis AE data will be collected but will be presented mainly in a descriptive way The frequency and percentages of each event will be indicated by the intervention arm Treatment-emergent adverse events are defined as adverse events that had an onset on or after the day of the first dose of study medication Adverse events that have missing onset dates will be considered to be treatment-emergent No formal statistical testing will be undertaken
Timeframe and duration of the study The total duration of the study is 36 months January 2024-December 2026 including 9-12 months of study preparation January -September 2024 protocol preparation and approvals October -December 2024 study preparation and set-up approximately 16-18 months of recruitment and follow-up January 2025-June 2026 and 6-8 months of data analysis and report writing July 2026 - December 2026
Ethical committee and national regulatory authorities approvals will be obtained before the trial starts
References
1 Kwambai TK Mori AT Nevitt S et al Post-discharge morbidity and mortality in children admitted with severe anaemia and other health conditions in malaria-endemic settings in Africa a systematic review and meta-analysis Lancet Child Adolesc Health 2022
2 Opoka RO Hamre KES Brand N Bangirana P Idro R John CC High Postdischarge Morbidity in Ugandan Children With Severe Malarial Anemia or Cerebral Malaria J Pediatric Infect Dis Soc 2017 63 e41-e8
3 van Hensbroek MB Jonker F Bates I Severe acquired anaemia in Africa new concepts Br J Haematol 2011 1546 690-5
4 Kwambai TK Dhabangi A Idro R et al Malaria Chemoprevention in the Postdischarge Management of Severe Anemia N Engl J Med 2020 38323 2242-54
5 Bojang KA Milligan PJ Conway DJ et al Prevention of the recurrence of anaemia in Gambian children following discharge from hospital PloS one 2010 56 e11227
6 Phiri K Esan M van Hensbroek MB Khairallah C Faragher B ter Kuile FO Intermittent preventive therapy for malaria with monthly artemether-lumefantrine for the post-discharge management of severe anaemia in children aged 4-59 months in southern Malawi a multicentre randomised placebo-controlled trial The Lancet Infectious diseases 2012 123 191-200
7 World Health Organisation Global Malaria Programme WHO Guidelines for malaria - 3 June 2022 httpsappswhointirisrestbitstreams1427681retrieve Geneva 2022
8 Nkosi-Gondwe T Robberstad B Mukaka M et al Adherence to community versus facility-based delivery of monthly malaria chemoprevention with dihydroartemisinin-piperaquine for the post-discharge management of severe anemia in Malawian children A cluster randomized trial PloS one 2021 169 e0255769
9 Damschroder LJ Aron DC Keith RE Kirsh SR Alexander JA Lowery JC Fostering implementation of health services research findings into practice a consolidated framework for advancing implementation science Implement Sci 2009 4 50
10 World Health Organisation Everybodys Business Strengthening Health Systems to Improve Health Outcomes Framework for Action Geneva WHO ISBN 978 92 4 159607 7 httpwwwwhointhealthsystemsstrategyeverybodys_businesspdf accessed 7 June 2014 2007
11 Sekhon M Cartwright M Francis JJ Acceptability of healthcare interventions an overview of reviews and development of a theoretical framework BMC Health Serv Res 2017 171 88
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None