MalariaCARAMALNCT03568344
Community Access to Rectal Artesunate for Malaria
An observational study of Malaria, run by Swiss Tropical & Public Health Institute at 3 sites in 3 countries.
Trial summary
Many malaria deaths occur in places where people have poor access to preventive and curative health services. Prompt access to quality health services is critical in the case of severe childhood diseases, among which severe malaria is particularly frequent in endemic areas. Read more about this study
- Who is it for?
- Ages 6 to 59 months
- Conditions the study is for
- Malaria
- How many people
- 13,758 participants
- Where
- 3 sitesin 3 countries
- Study dates
- 15 Jun 2018to 31 Aug 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 59 months
- All sexes
- No healthy volunteers
- Child
Study population: The PSS will include all children <5 years of age seeking care for a current/recent febrile illness episode at the level of community based care providers in the study areas, including CHWs and primary health facilities. In addition, all children <5 years of age seeking care for a severe febrile illness episode directly at the referral facility will be enrolled to evaluate treatment seeking, diagnosis, treatment and disease outcome. These children will be excluded from the case fatality ratio analysis. During baseline, RAS is expected not to be available at community level in the study area, and the PSS will enroll primarily children not treated with pre-referral RAS, whereas after RAS roll-out, RAS is expected to be administered at the level of community based health care providers.
Who may be able to join
- Patient surveillance system:
- Children < 5 years
- History of fever plus danger signs indicative of severe febrile illness / suspected severe malaria, according to local iCCM guidelines
- Child referred to higher level facility by CHW/primary health facility, or, child directly attending a referral facility.
- Signed full consent form from parent / guardian
- Health care provider interview:
Show all 13Show fewer
- CHW or health worker at peripheral health facility enrolled in the iCCM referral system who treats children < 5 years OR
- Health care provider at referral hospitals treating children < 5 years OR
- Any other health care provider in project area treating children < 5 years
- Signed consent form
- Household survey:
- Household head and parent / caregiver of children < 5 years
- Signed consent form from parent / guardian
Who cannot join
- Patient surveillance system:
- Children ≥ 5 years
- Children with no permanent residence in project area
- Health care provider interview:
- Health workers not treating children < 5 years
- Health workers outside project area
Show all 12Show fewer
- Health workers who do not speak any of the local languages
- Health workers employed since < 1 month
- Household survey:
- Parents / guardians with no children < 5 years
- Parents / guardians with no permanent residence in project area
- Parents / guardians who do not speak any of the local languages
Trial locations and contacts
3 sites in 3 countries.
3 sites in 3 countries
Democratic Republic of the Congo1 site
Kinshasa School of Public Health, University of Kinshasa
Kinshasa
About this study
Official title: Community Access to Rectal Artesunate for Malaria (CARAMAL): Observational Research in Nigeria, Uganda and DR Congo
Many malaria deaths occur in places where people have poor access to preventive and curative health services. Prompt access to quality health services is critical in the case of severe childhood diseases, among which severe malaria is particularly frequent in endemic areas. In communities where parenteral treatment of severe malaria is not available, the World Health Organization (WHO) recommends administration of a single rectal dose of artesunate (RAS) to children less than 6 years, followed by immediate referral to an appropriate facility where the full package of care for severe malaria can be provided.
Many African countries have already endorsed the use of pre-referral RAS. But treatment guidelines vary widely across these countries and often do not align with the WHO recommendation. With the impending availability of quality-assured rectal artesunate (QA RAS) and countries poised to scale-up this intervention, it is critical to investigate the safe and effective implementation of RAS as part of a continuum of care for severe malaria patients. To ensure that RAS is well targeted, it is equally urgent to learn more about frequency, treatment seeking and risk factors for severe malaria at community level. The CARAMAL project has two major components: the pilot implementation of QA RAS in selected areas of the Democratic Republic of the Congo (DRC), Nigeria and Uganda, and operational research on the introduction of QA RAS into established integrated community case management (iCCM) platforms. The CARAMAL project is funded by Unitaid and coordinated by the Clinton Health Access Initiative, Inc. (CHAI). UNICEF is responsible for QA RAS implementation. Swiss TPH in partnership with the local research organizations Akena Associates Ltd. in Nigeria, Kinshasa School of Public Health in DRC and Makerere University School of Public Health in Uganda carries out the operational research component to generate evidence for the responsible implementation of RAS. Finally, the CARAMAL project will generate a better understanding of severe febrile illness, its management at all levels and key determinants of health outcomes.
Read the detailed description
Objective(s):
The overall goal of the CARAMAL project is to contribute to reducing malaria mortality in children globally by improving the community management of suspected severe malaria cases. The project will contribute to this goal by advancing the development of operational guidance to catalyse effective and appropriate scale-up of QA RAS as pre-referral treatment of severe malaria.
Accompanying the pilot roll-out of QA RAS by UNICEF, the CARAMAL project will test whether it is feasible to introduce QA RAS into established integrated community case management (iCCM) platforms with only minimal additional supportive interventions and with minimal unintended consequences such as inappropriate use as artemisinin monotherapy.
Through the research activities described in detail below, the CARAMAL project aims to answer the following research questions:
- What are the minimal requirements of a community case management system to ensure that RAS is an effective part of the continuum of care from the community to a referral facility (defined as a health care facility equipped for inpatient care of severe malaria)?
II. What are the unintended consequences of scaled implementation, such as adverse drug reactions, unforeseen costs [5], or unforeseen issues in treatment of malaria at all levels of care, and how can they be addressed?
III. Is there any use of RAS beyond the recommended guidelines, including full treatment of severe cases with RAS at community level, and the treatment of uncomplicated malaria with RAS?
IV. Can the introduction of pre-referral QA RAS reduce severe malaria case fatality ratio over time under real-world operational circumstances in three distinct settings?
What are the costs and cost-effectiveness of community and peripheral health facility based RAS?
Study Design:
The CARAMAL project has been designed as a multi-country operational research study implemented in three highly malaria-endemic countries. It will be based on a before-and-after plausibility design aligned with the roll-out of QA RAS through established community-based health care provider systems.
Activity 1: A patient surveillance system (PSS) to assess severe febrile illness/suspected severe malaria incidence, case fatality rate, and related clinical patterns, diagnoses, treatment and treatment outcomes from first contact to the point of recovery or death (baseline and after RAS roll-out) Activity 2: Health care provider surveys (HCPS) to establish the availability and uptake of QA RAS at all levels, and health providers' knowledge, attitudes and practices towards RAS (baseline and after RAS roll-out) Activity 3: Household surveys (HHS) to assess treatment seeking, caretakers' knowledge and attitudes towards RAS, and malaria intervention coverage at community level (baseline and after RAS roll-out) Activity 4: An economic evaluation to assess the costs and incremental cost-effectiveness of implementing RAS at community level compared to the current standard of care Activity 5: Routine monitoring of process indicators along the entire case management chain to continuously assess implementation progress of RAS as contextual information for other outcome indicators
Study Population:
Activity 1, Patient surveillance system:
The PSS will include all children <5 years of age seeking care for a current/recent febrile illness episode at the level of community based care providers in the study areas, including Community Health Workers (CHWs) and primary health facilities (HF). All children diagnosed at that level with severe febrile illness / suspected severe malaria will then be enrolled in the PSS and tracked at the referral health facility and at the child's home 28 days after initial diagnosis. In addition, all children <5 years of age seeking care for a severe febrile illness episode directly at the referral facility will be enrolled to evaluate treatment seeking, diagnosis, treatment and disease outcome. These children will be excluded from the case fatality ratio analysis.
Activity 2, Health care provider surveys:
The sampling frame will include all registered providers at all levels operating in the study areas, including public and private providers. A simple random sampling approach stratified by provider level (CHW, primary health facility, etc.) will be used to select providers for the survey.
Activity 3, Household surveys:
Household surveys will include randomly sampled households in the study areas. Households will be selected using a two-stage random sampling approach (village-household) whereas the sampling frames will consist of all villages in the study area and all households in the village, respectively.
In each household, the household heads and parents/caretakers of children < 5 years of age will be eligible to participate.
Measurements and Procedures:
Activity 1, patient surveillance system:
- CHW / primary health facility (first contact) According to established routine practice, the following procedures are performed: children attending a CHW or primary health facility undergo examination, treatment and referral procedures as per local guidelines. A rapid malaria test (mRDT) is performed on all children with a history of or acute fever, including children with symptoms of severe febrile illness / children with danger signs. The children are then treated as per the applicable national guidelines. Enrolled children will be assigned a unique study ID.
- Referral facility Children with severe febrile illness / suspected severe malaria and either referred to or directly reporting to a referral facility in the study area will be registered upon arrival in the facility. The study nurse will monitor the case management of each registered patient and continuously enter study-specific details on diagnosis and treatment provided throughout the patient's admission into an electronic case report form.
- At home (day 28) All children with severe febrile illness / suspected severe malaria and enrolled into the patient surveillance system (PSS) by a CHW / primary health facility or at the referral health facility will be followed up at their home by a member of the research team. The primary purpose of this visit is to establish the health status of the child using a structured questionnaire. It will also include a section on the parent's/caretaker's experience and attitude towards the use of RAS. During the home follow-up a finger-prick blood sample will be collected from all of children for:
- mRDT
- Microcuvette sample for measuring haemoglobin (Hb) concentration In case of the death of an enrolled child, the research team will attempt to conduct a verbal autopsy at a later stage. Activity 2, Health care provider surveys:
- Health Care Provider Checklist A structured checklist completed to assess the availability of essential medical supplies (incl. RAS) and equipment, human resource capacity, infrastructure and documentation.
- Health Care Provider Questionnaire An interviewer administered questionnaire with questions pertaining to the health worker's demographics, education and training, work experience and supervision, type and utility of any work-related training received, knowledge, attitudes and practices relevant to febrile case management (incl. diagnostic algorithm and (RAS) treatment guidelines) and intermittent preventive treatment in infants and pregnancy (IPTi, IPTp), experiences implementing malaria/febrile case management and prevention guidelines. More in-depth questions will be asked to health care workers administering RAS as well as different cadres of health workers providing post-referral treatment, focusing on aspects relevant to the implementation of pre-referral RAS and post-referral treatment of severe febrile illness.
Activity 3, Household surveys:
Three survey instruments will be completed with participating household heads and/or household members:
- Household Questionnaire A structured interviewer administered questionnaire to collect information about coverage and uptake of mosquito nets behaviour change campaigns and other malaria control interventions, alongside background demographic information on each household member as well as indicators of the household's socio-economic status.
- Treatment Seeking Questionnaire A semi-structured interviewer administered questionnaire completed with randomly selected household members who are parents or caretakers of a child <5 years of age. Parents/caretakers of children who reported a febrile illness (irrespective of severity) in the two weeks prior to the survey will be interviewed about that specific illness episode. The form collects information about the signs and symptoms of the illness and subsequent treatment seeking behaviours, including sources of treatment and types (if any) of drugs administered. Parents/caretakers of children who did not experience a recent febrile illness will be asked about hypothetical care seeking behaviour based on specific vignettes (one scenario of mild and one scenario of severe febrile illness). The form furthermore collects information on the knowledge and attitudes of the parents/caretakers towards RAS. The parent/caretaker will be asked about previous experiences with RAS. Parents/caretakers without any previous experience with RAS will be asked about their attitudes based on a vignette.
- Prevalence Form / blood sample collection A finger prick blood sample will be taken from every household member below 5 years of age to assess changes in malaria prevalence and anaemia over time in the study areas. A short form will accompany each finger-prick blood sample, recording the individuals' demographic details, recent travel history, intake of any medicine, the mRDT and Hb measurement result, and any treatment administered.
Activity 4, Economic evaluation:
Financial and non-financial economic costs will be collected as part of routine project records over the duration of the study. The evaluation will reflect multiple perspectives including individual (i.e. patient), societal, and health systems-level (i.e. government).
Activity 5, Routine monitoring of process indicators:
Programmatic records of the implementation of QA RAS by UNICEF will be continuously assessed, including:
- RAS needs assessment data and orders
- Reports from supportive supervision of CHWs
- CHW monthly reports
- CHW, health facility registers
Number of Participants:
Activity 1, Patient surveillance system:
The minimum sample size of 6,032 cases of severe malaria in children < 5 years over 24 months
Activity 2: Health care provider surveys:
- All referral health facilities in the project areas
- All non-referral health facilities in the study area (Uganda and DRC), while in Nigeria, a random sample of 40 facilities will be included.
- 40 community health workers (Nigeria and Uganda).
Activity 3: Household surveys 906 household survey responses on treatment-seeking for severe febrile illness will be required per country and individual survey round.
Study Sites:
- Three health zones in DRC (Kenge, Kingandu and Ipamu),
- A subset of local government areas (LGAs) in one state in Nigeria (Adamawa) , and
- Three districts in Uganda (Apac, Kole and Oyam)
- Conditions
- Malaria
- Keywords
- Severe malaria, Mortality, Referral, Rectal artesunate, iCCM, Community based treatment
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Community based tx seeking: baseline | Children <5 years of age seeking care for a current/recent febrile illness episode at the level of community based care providers in the study areas, including CHWs and primary health facilities during baseline period (no QA RAS administration). | |
| tx seeking @ referral facility: baseline | Children <5 years of age seeking care for a severe febrile illness episode directly at the referral facility during baseline period (no QA RAS administration). | |
| Community based tx seeking: Post RAS | Children <5 years of age seeking care for a current/recent febrile illness episode at the level of community based care providers in the study areas, including CHWs and primary health facilities after QA RAS roll-out (after pre-referral QA RAS administration). | |
| tx seeking @ referral facility: Post RAS | Children <5 years of age seeking care for a severe febrile illness episode directly at the referral facility after QA RAS roll-out ( no QA RAS administration). |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of children <5 years with severe febrile illness seen by CHW/primary HF that resulted in death within 28 days
Patient surveillance system (data collected at referral facility at 28 days visit including verbal autopsy)
Measured: From RAS administration up to 28 days
Secondary outcomes (16)
Proportion of children <5 years with severe febrile illness without parasites on day 28
Rapid diagnostic test for malaria
Measured: 28 days after RAS administration
Proportion of children <5 years with a recent history of fever (mild or severe) who attend CHW/primary HF
Data obtained through Household surveys (semi-structured interviewer administered Treatment Seeking Questionnaire)
Measured: Through study completion, an average of 2 years
Proportion of children <5 years with severe febrile illness seen by CHW/primary HF who completed referral
Patient surveillance system (track patients from first point of contact at CHW or primary health facility until referral health facility)
Measured: From RAS administration up to 28 days
Number of children <5 years with severe febrile illness who report directly to referral health facility
Patient surveillance system (patients with severe febrile illness reporting directly to referral health facility)
Measured: Through study completion, an average of 2 years
Proportion of children <5 years with severe febrile illness managed pre-referral according to guidelines
Patient surveillance system (data collected at CHW / primary HF)
Measured: Through study completion, an average of 2 years
Proportion of children <5 years with severe febrile illness managed post-referral according to guidelines
Patient surveillance system (data collected at referral facility)
Measured: Through study completion, an average of 2 years
Frequency of passively reported adverse events after RAS administration
Continuous monitoring of patients medical records (referral facility) for adverse events
Measured: From RAS administration up to 28 days
Frequency of delayed haemolytic anaemia within 28 days after RAS administration
Hemoglobin measurement
Measured: 28 days after RAS administration
Proportion of trained and functional CHW and primary HF who provide QA RAS
Data obtained through routine monitoring of process indicators along the entire case management chain to continuously assess implementation progress of RAS (Programmatic records)
Measured: Through study completion, an average of 2 years
Proportion of CHW/primary HF with RAS in stock
Data obtained through routine monitoring of process indicators (Programmatic records) and Health care provider surveys (structured checklist to assess the availability of essential medical supplies (incl. RAS) and equipment, human resource capacity, infrastructure and documentation)
Measured: Through study completion, an average of 2 years
Proportion of referral health facilities that have the capacity to manage severe malaria in children in line with global guidance
Data obtained through routine monitoring of process indicators (Programmatic records) and Health care provider surveys (structured checklist to assess the availability of essential medical supplies (incl. RAS) and equipment, human resource capacity, infrastructure and documentation and interviewer administered questionnaires to assess the health worker's demographics, education and training, work experience and supervision, type and utility of any work-related training received, knowledge, attitudes and practices relevant to febrile case management (incl. diagnostic algorithm and (RAS) treatment guidelines) and intermittent preventive treatment in infants and pregnancy (IPTi, IPTp), experiences implementing malaria/febrile case management and prevention guidelines)
Measured: Through study completion, an average of 2 years
Proportion of CHW/primary HF that received at least one supervisory visit in the past 3 months
Data obtained through routine monitoring of process indicators (Programmatic records)
Measured: Through study completion, an average of 2 years
Acceptability of pre-referral RAS among health workers
Qualitative data obtained through Health care provider surveys (interviewer administered questionnaires to assess the health worker's demographics, education and training, work experience and supervision, type and utility of any work-related training received, knowledge, attitudes and practices relevant to febrile case management (incl. diagnostic algorithm and (RAS) treatment guidelines) and intermittent preventive treatment in infants and pregnancy (IPTi, IPTp), experiences implementing malaria/febrile case management and prevention guidelines)
Measured: Through study completion, an average of 2 years
Acceptability of pre-referral RAS among caretakers
Qualitative data obtained through Household surveys (semi-structured interviewer administered Treatment Seeking Questionnaire including attitude towards RAS use)
Measured: Through study completion, an average of 2 years
Total financial cost of managing severe case at community level. Marginal financial cost of adding RAS to the management
Costs extracted from the routine accounting documents of the iCCM projects in the three countries, Health care providers surveys and costs incurred by caretakers during referral (PSS Day 28 assessment)
Measured: From RAS administration up to 28 days
Financial cost of RAS interventions per death averted
Incremental cost-effectiveness of QA RAS introduction over current standard of care for management of severe malaria
Measured: Through study completion, an average of 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jun 2018
- Study start15 Jun 2018
- Primary completion31 Aug 2020
- Study completion31 Aug 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Prospective
- Enrolment
- 13,758 participants (actual)
Sponsor and investigators
- Lead sponsor
- Swiss Tropical & Public Health Institute
- Sponsor type
- University, hospital or other
- Collaborators
- UNITAID, UNICEF, Kinshasa School of Public Health, Akena Associates Ltd., Clinton Health Access Initiative Inc., Makerere University
- Responsible party
- Sponsor
- Investigators
- Christian Burri, Prof, Principal investigator, Swiss Tropical & Public Health InstituteChristian Lengeler, Prof, Principal investigator, Swiss Tropical & Public Health Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03568344
- Sponsor's protocol ID
- P 001-17-1.2
- Acronym
- CARAMAL
- Status last verified
- Jan 2021
- First submitted
- 16 May 2018
- Last updated
- 17 Feb 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Gomes MF, Faiz MA, Gyapong JO, Warsame M, Agbenyega T, Babiker A, Baiden F, Yunus EB, Binka F, Clerk C, Folb P, Hassan R, Hossain MA, Kimbute O, Kitua A, Krishna S, Makasi C, Mensah N, Mrango Z, Olliaro P, Peto R, Peto TJ, Rahman MR, Ribeiro I, Samad R, White NJ; Study 13 Research Group. Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial. Lancet. 2009 Feb 14;373(9663):557-66. doi: 10.1016/S0140-6736(08)61734-1. Epub 2008 Dec 6.
PubMed 19059639Lengeler C, Burri C, Awor P, Athieno P, Kimera J, Tumukunde G, Angiro I, Tshefu A, Okitawutshu J, Kalenga JC, Omoluabi E, Akano B, Ayodeji K, Okon C, Yusuf O, Brunner NC, Delvento G, Lee T, Lambiris M, Visser T, Napier HG, Cohen JM, Buj V, Signorell A, Hetzel MW; CARAMAL Consortium. Community access to rectal artesunate for malaria (CARAMAL): A large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda. PLOS Glob Public Health. 2022 Sep 6;2(9):e0000464. doi: 10.1371/journal.pgph.0000464. eCollection 2022.
PubMed 36962706Signorell A, Awor P, Okitawutshu J, Tshefu A, Omoluabi E, Hetzel MW, Athieno P, Kimera J, Tumukunde G, Angiro I, Kalenga JC, Akano BK, Ayodeji K, Okon C, Yusuf O, Delvento G, Lee TT, Brunner NC, Lambiris MJ, Okuma J, Cereghetti N, Buj V, Visser T, Napier HG, Lengeler C, Burri C. Health worker compliance with severe malaria treatment guidelines in the context of implementing pre-referral rectal artesunate in the Democratic Republic of the Congo, Nigeria, and Uganda: An operational study. PLoS Med. 2023 Feb 21;20(2):e1004189. doi: 10.1371/journal.pmed.1004189. eCollection 2023 Feb.
PubMed 36809247Hetzel MW, Okitawutshu J, Tshefu A, Omoluabi E, Awor P, Signorell A, Brunner NC, Kalenga JC, Akano BK, Ayodeji K, Okon C, Yusuf O, Athieno P, Kimera J, Tumukunde G, Angiro I, Delvento G, Lee TT, Lambiris MJ, Kwiatkowski M, Cereghetti N, Visser T, Napier HG, Cohen JM, Buj V, Burri C, Lengeler C. Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study. BMC Med. 2022 Oct 11;20(1):343. doi: 10.1186/s12916-022-02541-8.
PubMed 36217159Brunner NC, Omoluabi E, Awor P, Okitawutshu J, Tshefu Kitoto A, Signorell A, Akano B, Ayodeji K, Okon C, Yusuf O, Athieno P, Kimera J, Tumukunde G, Angiro I, Kalenga JC, Delvento G, Lee TT, Lambiris MJ, Ross A, Cereghetti N, Visser T, Napier HG, Buj V, Burri C, Lengeler C, Hetzel MW. Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda. BMJ Glob Health. 2022 May;7(5):e008346. doi: 10.1136/bmjgh-2021-008346.
PubMed 35580913
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Community Access to Rectal Artesunate for Malaria (CARAMAL): Observational Research in Nigeria, Uganda and DR Congo
- ClinicalTrials.gov ID
- NCT03568344
- Acronym / sponsor ID
- CARAMAL / P 001-17-1.2
- Conditions
- Malaria
- Keywords
- Severe malaria, Mortality, Referral, Rectal artesunate, iCCM, Community based treatment
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 13,758 participants (actual)
- Lead sponsor
- Swiss Tropical & Public Health InstituteUniversity, hospital or other
- Collaborators
- UNITAID, UNICEF, Kinshasa School of Public Health, Akena Associates Ltd., Clinton Health Access Initiative Inc., Makerere University
- Study start
- 15 Jun 2018 (actual)
- Primary completion
- 31 Aug 2020 (actual)
- Study completion
- 31 Aug 2021 (actual)
- First posted
- 26 Jun 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Many malaria deaths occur in places where people have poor access to preventive and curative health services. Prompt access to quality health services is critical in the case of severe childhood diseases, among which severe malaria is particularly frequent in endemic areas. In communities where parenteral treatment of severe malaria is not available, the World Health Organization (WHO) recommends administration of a single rectal dose of artesunate (RAS) to children less than 6 years, followed by immediate referral to an appropriate facility where the full package of care for severe malaria can be provided.
Many African countries have already endorsed the use of pre-referral RAS. But treatment guidelines vary widely across these countries and often do not align with the WHO recommendation. With the impending availability of quality-assured rectal artesunate (QA RAS) and countries poised to scale-up this intervention, it is critical to investigate the safe and effective implementation of RAS as part of a continuum of care for severe malaria patients. To ensure that RAS is well targeted, it is equally urgent to learn more about frequency, treatment seeking and risk factors for severe malaria at community level. The CARAMAL project has two major components: the pilot implementation of QA RAS in selected areas of the Democratic Republic of the Congo (DRC), Nigeria and Uganda, and operational research on the introduction of QA RAS into established integrated community case management (iCCM) platforms. The CARAMAL project is funded by Unitaid and coordinated by the Clinton Health Access Initiative, Inc. (CHAI). UNICEF is responsible for QA RAS implementation. Swiss TPH in partnership with the local research organizations Akena Associates Ltd. in Nigeria, Kinshasa School of Public Health in DRC and Makerere University School of Public Health in Uganda carries out the operational research component to generate evidence for the responsible implementation of RAS. Finally, the CARAMAL project will generate a better understanding of severe febrile illness, its management at all levels and key determinants of health outcomes.
Detailed description
Objective(s):
The overall goal of the CARAMAL project is to contribute to reducing malaria mortality in children globally by improving the community management of suspected severe malaria cases. The project will contribute to this goal by advancing the development of operational guidance to catalyse effective and appropriate scale-up of QA RAS as pre-referral treatment of severe malaria.
Accompanying the pilot roll-out of QA RAS by UNICEF, the CARAMAL project will test whether it is feasible to introduce QA RAS into established integrated community case management (iCCM) platforms with only minimal additional supportive interventions and with minimal unintended consequences such as inappropriate use as artemisinin monotherapy.
Through the research activities described in detail below, the CARAMAL project aims to answer the following research questions:
- What are the minimal requirements of a community case management system to ensure that RAS is an effective part of the continuum of care from the community to a referral facility (defined as a health care facility equipped for inpatient care of severe malaria)?
II. What are the unintended consequences of scaled implementation, such as adverse drug reactions, unforeseen costs [5], or unforeseen issues in treatment of malaria at all levels of care, and how can they be addressed?
III. Is there any use of RAS beyond the recommended guidelines, including full treatment of severe cases with RAS at community level, and the treatment of uncomplicated malaria with RAS?
IV. Can the introduction of pre-referral QA RAS reduce severe malaria case fatality ratio over time under real-world operational circumstances in three distinct settings?
What are the costs and cost-effectiveness of community and peripheral health facility based RAS?
Study Design:
The CARAMAL project has been designed as a multi-country operational research study implemented in three highly malaria-endemic countries. It will be based on a before-and-after plausibility design aligned with the roll-out of QA RAS through established community-based health care provider systems.
Activity 1: A patient surveillance system (PSS) to assess severe febrile illness/suspected severe malaria incidence, case fatality rate, and related clinical patterns, diagnoses, treatment and treatment outcomes from first contact to the point of recovery or death (baseline and after RAS roll-out) Activity 2: Health care provider surveys (HCPS) to establish the availability and uptake of QA RAS at all levels, and health providers' knowledge, attitudes and practices towards RAS (baseline and after RAS roll-out) Activity 3: Household surveys (HHS) to assess treatment seeking, caretakers' knowledge and attitudes towards RAS, and malaria intervention coverage at community level (baseline and after RAS roll-out) Activity 4: An economic evaluation to assess the costs and incremental cost-effectiveness of implementing RAS at community level compared to the current standard of care Activity 5: Routine monitoring of process indicators along the entire case management chain to continuously assess implementation progress of RAS as contextual information for other outcome indicators
Study Population:
Activity 1, Patient surveillance system:
The PSS will include all children <5 years of age seeking care for a current/recent febrile illness episode at the level of community based care providers in the study areas, including Community Health Workers (CHWs) and primary health facilities (HF). All children diagnosed at that level with severe febrile illness / suspected severe malaria will then be enrolled in the PSS and tracked at the referral health facility and at the child's home 28 days after initial diagnosis. In addition, all children <5 years of age seeking care for a severe febrile illness episode directly at the referral facility will be enrolled to evaluate treatment seeking, diagnosis, treatment and disease outcome. These children will be excluded from the case fatality ratio analysis.
Activity 2, Health care provider surveys:
The sampling frame will include all registered providers at all levels operating in the study areas, including public and private providers. A simple random sampling approach stratified by provider level (CHW, primary health facility, etc.) will be used to select providers for the survey.
Activity 3, Household surveys:
Household surveys will include randomly sampled households in the study areas. Households will be selected using a two-stage random sampling approach (village-household) whereas the sampling frames will consist of all villages in the study area and all households in the village, respectively.
In each household, the household heads and parents/caretakers of children < 5 years of age will be eligible to participate.
Measurements and Procedures:
Activity 1, patient surveillance system:
- CHW / primary health facility (first contact) According to established routine practice, the following procedures are performed: children attending a CHW or primary health facility undergo examination, treatment and referral procedures as per local guidelines. A rapid malaria test (mRDT) is performed on all children with a history of or acute fever, including children with symptoms of severe febrile illness / children with danger signs. The children are then treated as per the applicable national guidelines. Enrolled children will be assigned a unique study ID.
- Referral facility Children with severe febrile illness / suspected severe malaria and either referred to or directly reporting to a referral facility in the study area will be registered upon arrival in the facility. The study nurse will monitor the case management of each registered patient and continuously enter study-specific details on diagnosis and treatment provided throughout the patient's admission into an electronic case report form.
- At home (day 28) All children with severe febrile illness / suspected severe malaria and enrolled into the patient surveillance system (PSS) by a CHW / primary health facility or at the referral health facility will be followed up at their home by a member of the research team. The primary purpose of this visit is to establish the health status of the child using a structured questionnaire. It will also include a section on the parent's/caretaker's experience and attitude towards the use of RAS. During the home follow-up a finger-prick blood sample will be collected from all of children for:
- mRDT
- Microcuvette sample for measuring haemoglobin (Hb) concentration In case of the death of an enrolled child, the research team will attempt to conduct a verbal autopsy at a later stage. Activity 2, Health care provider surveys:
- Health Care Provider Checklist A structured checklist completed to assess the availability of essential medical supplies (incl. RAS) and equipment, human resource capacity, infrastructure and documentation.
- Health Care Provider Questionnaire An interviewer administered questionnaire with questions pertaining to the health worker's demographics, education and training, work experience and supervision, type and utility of any work-related training received, knowledge, attitudes and practices relevant to febrile case management (incl. diagnostic algorithm and (RAS) treatment guidelines) and intermittent preventive treatment in infants and pregnancy (IPTi, IPTp), experiences implementing malaria/febrile case management and prevention guidelines. More in-depth questions will be asked to health care workers administering RAS as well as different cadres of health workers providing post-referral treatment, focusing on aspects relevant to the implementation of pre-referral RAS and post-referral treatment of severe febrile illness.
Activity 3, Household surveys:
Three survey instruments will be completed with participating household heads and/or household members:
- Household Questionnaire A structured interviewer administered questionnaire to collect information about coverage and uptake of mosquito nets behaviour change campaigns and other malaria control interventions, alongside background demographic information on each household member as well as indicators of the household's socio-economic status.
- Treatment Seeking Questionnaire A semi-structured interviewer administered questionnaire completed with randomly selected household members who are parents or caretakers of a child <5 years of age. Parents/caretakers of children who reported a febrile illness (irrespective of severity) in the two weeks prior to the survey will be interviewed about that specific illness episode. The form collects information about the signs and symptoms of the illness and subsequent treatment seeking behaviours, including sources of treatment and types (if any) of drugs administered. Parents/caretakers of children who did not experience a recent febrile illness will be asked about hypothetical care seeking behaviour based on specific vignettes (one scenario of mild and one scenario of severe febrile illness). The form furthermore collects information on the knowledge and attitudes of the parents/caretakers towards RAS. The parent/caretaker will be asked about previous experiences with RAS. Parents/caretakers without any previous experience with RAS will be asked about their attitudes based on a vignette.
- Prevalence Form / blood sample collection A finger prick blood sample will be taken from every household member below 5 years of age to assess changes in malaria prevalence and anaemia over time in the study areas. A short form will accompany each finger-prick blood sample, recording the individuals' demographic details, recent travel history, intake of any medicine, the mRDT and Hb measurement result, and any treatment administered.
Activity 4, Economic evaluation:
Financial and non-financial economic costs will be collected as part of routine project records over the duration of the study. The evaluation will reflect multiple perspectives including individual (i.e. patient), societal, and health systems-level (i.e. government).
Activity 5, Routine monitoring of process indicators:
Programmatic records of the implementation of QA RAS by UNICEF will be continuously assessed, including:
- RAS needs assessment data and orders
- Reports from supportive supervision of CHWs
- CHW monthly reports
- CHW, health facility registers
Number of Participants:
Activity 1, Patient surveillance system:
The minimum sample size of 6,032 cases of severe malaria in children < 5 years over 24 months
Activity 2: Health care provider surveys:
- All referral health facilities in the project areas
- All non-referral health facilities in the study area (Uganda and DRC), while in Nigeria, a random sample of 40 facilities will be included.
- 40 community health workers (Nigeria and Uganda).
Activity 3: Household surveys 906 household survey responses on treatment-seeking for severe febrile illness will be required per country and individual survey round.
Study Sites:
- Three health zones in DRC (Kenge, Kingandu and Ipamu),
- A subset of local government areas (LGAs) in one state in Nigeria (Adamawa) , and
- Three districts in Uganda (Apac, Kole and Oyam)
Study design
- Observational model
- Other
- Time perspective
- Prospective
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Community based tx seeking: baseline | – | –Children <5 years of age seeking care for a current/recent febrile illness episode at the level of community based care providers in the study areas, including CHWs and primary health facilities during baseline period (no QA RAS administration). |
| tx seeking @ referral facility: baseline | – | –Children <5 years of age seeking care for a severe febrile illness episode directly at the referral facility during baseline period (no QA RAS administration). |
| Community based tx seeking: Post RAS | – | –Children <5 years of age seeking care for a current/recent febrile illness episode at the level of community based care providers in the study areas, including CHWs and primary health facilities after QA RAS roll-out (after pre-referral QA RAS administration). |
| tx seeking @ referral facility: Post RAS | – | –Children <5 years of age seeking care for a severe febrile illness episode directly at the referral facility after QA RAS roll-out ( no QA RAS administration). |
Who may qualify
- Ages
- 6 to 59 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
- Study population
- The PSS will include all children <5 years of age seeking care for a current/recent febrile illness episode at the level of community based care providers in the study areas, including CHWs and primary health facilities. In addition, all children <5 years of age seeking care for a severe febrile illness episode directly at the referral facility will be enrolled to evaluate treatment seeking, diagnosis, treatment and disease outcome. These children will be excluded from the case fatality ratio analysis. During baseline, RAS is expected not to be available at community level in the study area, and the PSS will enroll primarily children not treated with pre-referral RAS, whereas after RAS roll-out, RAS is expected to be administered at the level of community based health care providers.
Key inclusion criteria (13 listed)
- Patient surveillance system:
- Children < 5 years
- History of fever plus danger signs indicative of severe febrile illness / suspected severe malaria, according to local iCCM guidelines
- Child referred to higher level facility by CHW/primary health facility, or, child directly attending a referral facility.
- Signed full consent form from parent / guardian
Key exclusion criteria (12 listed)
- Patient surveillance system:
- Children ≥ 5 years
- Children with no permanent residence in project area
- Health workers not treating children < 5 years
- Health workers outside project area
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Proportion of children <5 years with severe febrile illness seen by CHW/primary HF that resulted in death within 28 days
Time frame: From RAS administration up to 28 days
Patient surveillance system (data collected at referral facility at 28 days visit including verbal autopsy)
16 secondary outcomes
Proportion of children <5 years with severe febrile illness without parasites on day 28
Time frame: 28 days after RAS administration
Proportion of children <5 years with a recent history of fever (mild or severe) who attend CHW/primary HF
Time frame: Through study completion, an average of 2 years
Proportion of children <5 years with severe febrile illness seen by CHW/primary HF who completed referral
Time frame: From RAS administration up to 28 days
Number of children <5 years with severe febrile illness who report directly to referral health facility
Time frame: Through study completion, an average of 2 years
Proportion of children <5 years with severe febrile illness managed pre-referral according to guidelines
Time frame: Through study completion, an average of 2 years
Proportion of children <5 years with severe febrile illness managed post-referral according to guidelines
Time frame: Through study completion, an average of 2 years
Frequency of passively reported adverse events after RAS administration
Time frame: From RAS administration up to 28 days
Frequency of delayed haemolytic anaemia within 28 days after RAS administration
Time frame: 28 days after RAS administration
Proportion of trained and functional CHW and primary HF who provide QA RAS
Time frame: Through study completion, an average of 2 years
Proportion of CHW/primary HF with RAS in stock
Time frame: Through study completion, an average of 2 years
Proportion of referral health facilities that have the capacity to manage severe malaria in children in line with global guidance
Time frame: Through study completion, an average of 2 years
Proportion of CHW/primary HF that received at least one supervisory visit in the past 3 months
Time frame: Through study completion, an average of 2 years
Acceptability of pre-referral RAS among health workers
Time frame: Through study completion, an average of 2 years
Acceptability of pre-referral RAS among caretakers
Time frame: Through study completion, an average of 2 years
Total financial cost of managing severe case at community level. Marginal financial cost of adding RAS to the management
Time frame: From RAS administration up to 28 days
Financial cost of RAS interventions per death averted
Time frame: Through study completion, an average of 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2022.
- Background: PubMed 19059639Gomes MF, Faiz MA, Gyapong JO, Warsame M, Agbenyega T, Babiker A, Baiden F, Yunus EB, Binka F, Clerk C, Folb P, Hassan R, Hossain MA, Kimbute O, Kitua A, Krishna S, Makasi C, Mensah N, Mrango Z, Olliaro P, Peto R, Peto TJ, Rahman MR, Ribeiro I, Samad R, White NJ; Study 13 Research Group. Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial. Lancet. 2009 Feb 14;373(9663):557-66. doi: 10.1016/S0140-6736(08)61734-1. Epub 2008 Dec 6.
- Derived from this study: PubMed 36962706Lengeler C, Burri C, Awor P, Athieno P, Kimera J, Tumukunde G, Angiro I, Tshefu A, Okitawutshu J, Kalenga JC, Omoluabi E, Akano B, Ayodeji K, Okon C, Yusuf O, Brunner NC, Delvento G, Lee T, Lambiris M, Visser T, Napier HG, Cohen JM, Buj V, Signorell A, Hetzel MW; CARAMAL Consortium. Community access to rectal artesunate for malaria (CARAMAL): A large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda. PLOS Glob Public Health. 2022 Sep 6;2(9):e0000464. doi: 10.1371/journal.pgph.0000464. eCollection 2022.
- Derived from this study: PubMed 36809247Signorell A, Awor P, Okitawutshu J, Tshefu A, Omoluabi E, Hetzel MW, Athieno P, Kimera J, Tumukunde G, Angiro I, Kalenga JC, Akano BK, Ayodeji K, Okon C, Yusuf O, Delvento G, Lee TT, Brunner NC, Lambiris MJ, Okuma J, Cereghetti N, Buj V, Visser T, Napier HG, Lengeler C, Burri C. Health worker compliance with severe malaria treatment guidelines in the context of implementing pre-referral rectal artesunate in the Democratic Republic of the Congo, Nigeria, and Uganda: An operational study. PLoS Med. 2023 Feb 21;20(2):e1004189. doi: 10.1371/journal.pmed.1004189. eCollection 2023 Feb.
- Derived from this study: PubMed 36217159Hetzel MW, Okitawutshu J, Tshefu A, Omoluabi E, Awor P, Signorell A, Brunner NC, Kalenga JC, Akano BK, Ayodeji K, Okon C, Yusuf O, Athieno P, Kimera J, Tumukunde G, Angiro I, Delvento G, Lee TT, Lambiris MJ, Kwiatkowski M, Cereghetti N, Visser T, Napier HG, Cohen JM, Buj V, Burri C, Lengeler C. Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study. BMC Med. 2022 Oct 11;20(1):343. doi: 10.1186/s12916-022-02541-8.
- Derived from this study: PubMed 35580913Brunner NC, Omoluabi E, Awor P, Okitawutshu J, Tshefu Kitoto A, Signorell A, Akano B, Ayodeji K, Okon C, Yusuf O, Athieno P, Kimera J, Tumukunde G, Angiro I, Kalenga JC, Delvento G, Lee TT, Lambiris MJ, Ross A, Cereghetti N, Visser T, Napier HG, Buj V, Burri C, Lengeler C, Hetzel MW. Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda. BMJ Glob Health. 2022 May;7(5):e008346. doi: 10.1136/bmjgh-2021-008346.
- WHO - Integrated community case management of malariaLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Christian Burri, Prof principal investigator
Swiss Tropical & Public Health Institute
Christian Lengeler, Prof principal investigator
Swiss Tropical & Public Health Institute
3 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Malaria, run by Swiss Tropical & Public Health Institute at 3 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Democratic Republic of the Congo, Nigeria, Uganda. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of children <5 years with severe febrile illness seen by CHW/primary HF that resulted in death within 28 days (time frame: From RAS administration up to 28 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03568344, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2022.