Community Access to Rectal Artesunate for Malaria
Condition: Malaria
MeSH terms: Malaria
Study type: Observational

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. 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:

      I. 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:

        1. 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.

        2. 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.

        3. 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:

        4. 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.

        5. 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:

        1. 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.

        2. 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.

        3. 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:

        1. RAS needs assessment data and orders

        2. Reports from supportive supervision of CHWs

        3. CHW monthly reports

        4. 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)
    

Observational model: Other
Time perspective: Prospective
Sampling method: Non-Probability Sample
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.
      
Keywords: Severe malaria; Mortality; Referral; Rectal artesunate; iCCM; Community based treatment