Radical CUREfor MAlaria Among Highly Mobile and Hard-to-reach Populations in the Guyanese Shield

Study Overview
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Brief Summary
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The investigators are proposing a new malaria control strategy to reach the group of garimpeiros not reached by the usual actions of the health services. As it is a complex strategy, several evaluation mechanisms have been designed. The main characteristics of the research are: Access to the target population: our target population is represented by miners active and mobile in the south of the Guiana Shield, between Amapá (Brazil), French Guiana (France) and Suriname. To overcome the obstacles posed by the remoteness and clandestinity of the communities of interest, our intervention will take place in the logistical and support hubs (staging areas) of the miners, located in the border regions between the above territories. Thus, it will take advantage of their periodic mobility between these bases and the gold mining sites, and reach the target population where it can be easily accessed. The intervention will be combined and will include a common core (malaria health education activity) and two modules that will be offered to participants. Each participant (meeting the inclusion criteria) will be able to choose between participating to one or both modules. The common core of health education will focus on malaria: its causes, means of prevention, the main differences between P. falciparum and P. vivax disease, the importance of a complete treatment against any form of Plasmodium spp. Module A of the intervention will be treatment targeting asymptomatic individuals at risk of carrying P. vivax. The aim of this module is to prevent relapses and reduce the number of human hosts able to transmitthe parasite. Module B of the intervention will correspond to the provision, after appropriate training, of a Malakit self-test and self-treatment kit. The aim of this module is to provide access to quality diagnosis and treatment for episodes of symptoms consistent with malaria that occur in situations of extreme remoteness from health services. The purpose of this study is to evaluate a strategy that, if appropriate, can be implemented by health authorities in countries with residual malaria transmission in populations with characteristics similar to our study population. The investigators will therefore use a pragmatic approach so that the conclusions drawn can be transposed as easily as possible to real life, while at the same time putting great effort into the safety of the intervention. Thus, the study field workers who will administer the intervention will have a similar profile to health workers recruited by a large number of malaria control programmes, particularly in remote areas. In addition, monitoring will be simplified and monitoring data can be collected both through face-to-face visits and remotely administered questionnaires. The investigators chose to design many of the components of the intervention and study with a participatory approach. In order to generate the data necessary for health authorities to potentially take ownership of the intervention in the future, the study will evaluate two aspects of the intervention: effectiveness and implementation. First, the investigators want to evaluate the population-scale effectiveness ofthe intervention to reduce malaria transmission with a quasi-experimental approach. Secondly, the investigators will analyse the implementation of theintervention, and generate valuable knowledge for further implementation within local health services. This evaluation will be carried out through the components of the CUREMA study: the intervention itself, pre/post-intervention cross-sectional surveys, a nested cohort, the qualitative component and the modelling of epidemiological surveillance data. • The implementation of these components will have an expected duration of approximately 27 months, the start of inclusions is scheduled for September 2022.

Official Title
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Radical CUREfor MAlaria Among Highly Mobile and Hard-to-reach Populations in the Guyanese Shield

Conditions
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Malaria, Vivax

Intervention / Treatment
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* Drug: PART
* Drug: Malakit
* Other: CROSS-SECTIONAL PRE- AND POST-INTERVENTION SURVEYS
* Other: QUALITATIVE STUDY


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for PART and Malakit: Be 18 years of age or older Agree to participate in the study Have an actual involvement in gold mining activities (having been to the garimpo in the last year or planning to enter the garimpo in the following two weeks), regardless of country No symptoms of malaria at the time of the inclusion visit Weigh over 35 Kg Eligibility Criteria for PART - Module A Wish to take part in module A Epidemiological and/or biological criteria in favour of a current asymptomatic carriage of P. vivax (blood stage or liver stage). At least one of the following conditions: have a history of clinical malaria during the past 12 months AND/OR have stayed for at least 1 month during the last 12 months in an area with extensive P. vivax transmission AND/OR have a positive P.vivax rapid serological test Eligibility Criteria for Malakit - Module B: Wish to take part in module B Plan to enter agarimpo located in French Guiana the following month Exclusion Criteria for PART - Module A: Refuse to participate in an active follow-up during the 14 days following the start of treatment Current pregnancy (declared or rapid urine test positive) or breastfeeding Haemoglobinemia below 9 g/dL G6PD activity below 70%. Have received a full course of tafenoquine within the last 3 months Hypersensitivity or known contraindication to primaquine or tafenoquine Exclusion Criteria for Malakit - Module B: Inability to self-test (perform and interpret an RDT) during training Inability to understand and explain correctly what to do in case of malaria symptoms (tests and ACT posology) Inclusion criteria for Pre/post intervention surveys Be 18 years of age or older Agree to participate in the research Having left a garimpolocated in French Guiana since maximum two weeks. Weigh over 35 Kg

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an intervention study, multicentre and international using mixed methods and quasi-experimental designthat associates an effectiveness evaluation and an implementation research approach, thus characterising a hybrid design (142). We intend to combine several components that will contribute to achieve the primary and secondary objectives: The intervention per se, which is the core of the study, and combines delivery of the intervention (Module A, Module B or Module A and B) with data collection at inclusion and during a 14-day follow-up. Pre- and post-intervention research (cross-sectional studies), being preponderant for the evaluation of primary objectives (with a quasi-experimental design). A qualitative evaluation of the implementation of the intervention at multiple levels (target population, professionals involved in the study, stakeholders). The modelling study of surveillance data from national malaria programmes.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module A<br>• Module A - PART (Presumptive anti-relapse treatment): This is the core of the strategy for targeting the P. vivax reservoir by identifying individuals with a high probability of being asymptomatic carriers of blood forms and/or hypnozoites (by epidemiological criteria combined with a rapid serological test), and treating these individualswith chloroquine (by 150mgs tablet, according to the following posology: 600mgs on the first day, 450mgs on the second and 300mgs on the third day, or weight-adjusted dosing) and primaquine (in a short regimen of 30 mg per day for seven days, or weight-adjusted dosing) or tafenoquine (300 mg as a single observed dose), after exclusion of contraindications to these treatments. This intervention aims to reduce the likelihood of relapse of a previous infection, and subsequent transmission in forest and urban settings, ultimately helping to reduce the circulation of P. vivax. | Drug: PART<br>* Chloroquine(150mgs tablets) according the following posology: 600mgs on the first day, 450mgs on the second and 300mgs on the third day, or weight-adjusted dosage; An 8-aminoquinoline drug Primaquine (PQ) (15 mg tablets): 2 tablets a day for 7 days or weight-adjusted dosage. (Rationale: this short-course posology has been chosen to facilitate the adherence to treatment for asymptomatic individuals participating to the Module A, Primaquine will be administered to all participants to Module A during the induction phase of the intervention. OR tafenoquine (TQ) (150 mg tablets): 2 tablets as a single dose (orally), (Rationale: the posology chosen corresponds to that used in phase III trials for the radical cure of P. vivax and the therapeutic recommendation in Brazil). Tafenoquine will only be administered during the full implementation phase to participants who do not meet exclusion criteria.<br>* Other names: module A;|
| Other: Module B<br>• Module B - Malakit: distribution of a self-test and self-treatment kit to individuals in the target population who agree to be trained (and demonstrate understanding of the use of the kit), in order to maintain access to quality test and treatment for malaria attacks that occur in extreme isolation in illegal mining towns in French Guiana | Drug: Malakit<br>* delivery of a sturdy, lightweight, waterproof plastic involucre that contains: 1 laminated sheet with illustrated instruction 1 complete anti-malarial treatment targeting P. falciparum, but also effective in acute forms of P. vivax with association with artemisinin derivatives oA blister of 24 tablets of Artemether 20 mg + lumefantrine 120 mg of generic medication oTwo 15 mg tablets of primaquine, to be given as a single dose (145) 1 symptomatic treatment (analgesic, antipyretic): a blister pack of 10 paracetamol 500 mg tablets 3 CareStartTM Malaria pLDH rapid diagnostic tests (RDTs) (Pan), in individual packs and with easy-to-use retractable lancets. Three tests will be included, taking into account the possibility of having one or two negative or invalid tests before returning to a distribution site for further supplies. 1 small yellow plastic EC bag for non-perforated materials and infectious health risk waste.<br>* Other names: module B;|
| Other: Pre/post intervention surveys<br>Two cross-sectional surveys will be conducted in the inclusion sites before and at the end of intervention implementation, during the same period of the year (preferably the last quarter of 2022 and 2024), in order to limit biases associated with seasonality. | Other: CROSS-SECTIONAL PRE- AND POST-INTERVENTION SURVEYS<br>* Surveys will include the collection of a detailed questionnaire on recent malaria and mobility history, a clinical examination, and a venous blood sample<br>* Other names: ORPAL 3;|
| Other: QUALITATIVE STUDY<br>The CUREMA project includes qualitative research that will be conducted before, during and after the intervention by a trained social science researcher. The aim of this research will be to analyse the specific constraints and levers of the intervention under study and the pre-elimination context, in order to draw out lessons that are context-specific but also potentially of universal value. As described above, the study population will be broader and include not only the garimpeiros, but also the study field workers as well as other stakeholders. | Other: QUALITATIVE STUDY<br>* Systematic mapping of stakeholders in the pre-intervention period Semi-structured interviews and focus groups. Observational techniques Participatory approach. Participatory design of a community-based adverse event surveillance system<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness focus | To reduce overall the prevalence of symptomatic and asymptomatic infections with Plasmodium spp. as a result of reduced malaria transmission among people involved in gold mining activities in the South of the Guiana Shield | through study completion, an average of 3 years | 
| Implementation focus | Evaluate the intervention's reach among the target public: reduction in the malaria burden at the collective level in the mining sites and at staging areas | through study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| prevalence reduction - Focus on effectiveness | To reduce the species-specific prevalence of P. vivax and P. falciparum among people involved in gold mining activities in the South of the Guiana Shield; | through study completion, an average of 3 years | 
| contact reduction - Focus on effectiveness | To reduce the proportion of garimpeiros with a high probability of recent P. vivax infection (and probably hypnozoite carriers); | through study completion, an average of 3 years | 
| malaria incidence reduction - Focus on effectiveness | To reduce the incidence of malaria cases associated with gold mining activity in the southern Guyanese Shield, as detected by the epidemiological surveillance systems of the countries involved; | through study completion, an average of 3 years | 
| Good use of antimalarial treatment - Focus on effectiveness | To increase the proportion of garimpeiros who adequately take anti-malarial treatment when they fall ill in illegal garimpos in French Guiana; | through study completion, an average of 3 years | 
| preventing P. vivax parasitaemia - Focus on effectiveness | level of P vivax parasietaemia (percentage of red blood cells which contains P. vivax) : estimate the individual-level effectiveness of module A intervention in preventing P. vivax parasitaemia | through study completion, an average of 3 years | 
| increase adherence in asymptomatic - Focus on implementation | Number of medication taken by the participants related to number of medication delivered to the participants: adherence to the primaquine posology among asymptomatic individuals; | through study completion, an average of 3 years | 
| safety - Focus on implementation | To assess the safety of medicines for Modules A and B on a community level; | through study completion, an average of 3 years | 
| increase health education with specific scales on level of disease comprehension by the participants - Focus on implementation | To evaluate the effectiveness of the health education activity carried out during the intervention with specifics scales on level of disease comprehension by the participants; | through study completion, an average of 3 years | 
| acceptability of digital tool - Focus on implementation | number of participants who regularly use the smartphone application To assess the acceptability of digital tools (smartphone app): | through study completion, an average of 3 years | 
| feasability of digital tool - Focus on implementation | number of participants who can regularly use the smartphone application:To assess the feasibility of digital tools (smartphone app); | through study completion, an average of 3 years | 
| effectiveness of training measured with specifics scales - Focus on implementation | Level of comprehension of the training measured with specifics scales: to evaluate the quality and effectiveness of the training received by facilitators; | through study completion, an average of 3 years | 
| increase inclusion process - Focus on implementation | To assess the fidelity of the inclusion and follow-up process; | through study completion, an average of 3 years | 
| quality of rapid serological test - Focus on implementation | To evaluate the sensitivity and specificity of the rapid serological test and to estimate the discriminatory capacity of this test to detect recent P. vivax infections in the epidemiological context of the study | through study completion, an average of 3 years | 
| intervention's costs measured in euros - Focus on implementation | To estimate the programmatic cost of the intervention | through study completion, an average of 3 years | 
| needs identification - Focus on implementation | highlighting health risk factors by assessing the health situation of garimpeiros and additional health needs beyond malaria elimination | through study completion, an average of 3 years | 
| identify facilitating factors and barriers of the intervention - Focus on implementation | highlighting the obstacles and levers by assessing facilitating factors as well as barriers to delivering such an intervention in a pre-elimination setting and community involvement to be taken into account for further implementation | through study completion, an average of 3 years |