Community Access to Rectal Artesunate for Malaria

Malaria Clinical Trial

— CARAMAL  

Official title:

Community Access to Rectal Artesunate for Malaria (CARAMAL): Observational Research in Nigeria, Uganda and DR Congo

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03568344
• Other study ID #: P 001-17-1.2
• Status: Completed
• Start date: June 15, 2018
• Est. completion date: August 31, 2021

Study information

• Verified date: January 2021
• Source: Swiss Tropical & Public Health Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical 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. 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13758
• Est. completion date: August 31, 2021
• Est. primary completion date: August 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 59 Months

Eligibility

Inclusion Criteria:

• 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:

• 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

Exclusion Criteria:

• 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

• 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

Related Conditions & MeSH terms

• Malaria

Locations

Country	Name	City	State
Congo, The Democratic Republic of the	Kinshasa School of Public Health, University of Kinshasa	Kinshasa
Nigeria	Akena Associates Ltd.	Abuja
Uganda	Makerere University School of Public Health	Kampala

Sponsors (7)

Lead Sponsor	Collaborator
Swiss Tropical & Public Health Institute	Akena Associates Ltd., Clinton Health Access Initiative Inc., Kinshasa School of Public Health, Makerere University, UNICEF, UNITAID

Countries where clinical trial is conducted

Congo, The Democratic Republic of the,  Nigeria,  Uganda, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	From RAS administration up to 28 days
Secondary	Proportion of children <5 years with severe febrile illness without parasites on day 28	Rapid diagnostic test for malaria	28 days after RAS administration
Secondary	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)	Through study completion, an average of 2 years
Secondary	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)	From RAS administration up to 28 days
Secondary	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)	Through study completion, an average of 2 years
Secondary	Proportion of children <5 years with severe febrile illness managed pre-referral according to guidelines	Patient surveillance system (data collected at CHW / primary HF)	Through study completion, an average of 2 years
Secondary	Proportion of children <5 years with severe febrile illness managed post-referral according to guidelines	Patient surveillance system (data collected at referral facility)	Through study completion, an average of 2 years
Secondary	Frequency of passively reported adverse events after RAS administration	Continuous monitoring of patients medical records (referral facility) for adverse events	From RAS administration up to 28 days
Secondary	Frequency of delayed haemolytic anaemia within 28 days after RAS administration	Hemoglobin measurement	28 days after RAS administration
Secondary	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)	Through study completion, an average of 2 years
Secondary	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)	Through study completion, an average of 2 years
Secondary	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)	Through study completion, an average of 2 years
Secondary	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)	Through study completion, an average of 2 years
Secondary	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)	Through study completion, an average of 2 years
Secondary	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)	Through study completion, an average of 2 years
Secondary	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)	From RAS administration up to 28 days
Secondary	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	Through study completion, an average of 2 years

External Links

•   Community Access to Rectal Artesunate for MALaria (CARAMAL)
•   New Unitaid grants help protect women and children from malaria
•   Swiss TPH, Caramal Project Page
•   Unitaid - WHO provides first-ever approval for rectal artesunate product for severe malaria
•   WHO - Integrated community case management of malaria