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Clinical Trial Summary

Although Plasmodium vivax (P. vivax), one of the five malaria species causing parasites, has the widest geographical distribution, it is rare in sub-Saharan Africa due to the absence of a red blood cell receptor (Duffy antigen) in black Africans. Duffy-negative individuals are, for the most part, therefore refractory to P. vivax infection and the Duffy-negative phenotype is found at highest frequencies in Africa, whereas it is relatively rare elsewhere. P. vivax has however, been observed as single infections in up to 5% of Duffy-negative febrile patients in one health facility in Dschang, a region of low malaria transmission in Western highlands of Cameroon. Whereas in the littoral South West and Southern forest of Cameroon characterised by high malaria transmission, areas, there are contrasting molecular evidence of human P. vivax infection. While important, the significance is limited from an epidemiological point of view, concerning the source, transmission, distribution range of P. vivax. There is thus a challenge in the true estimation of malaria burden, as well as the attributable parasite species in infections occurring in the low transmission areas of Western Cameroon. As a consequence, our understanding of the local epidemiology of malaria in Western Cameroon warrants formal investigation. The current proposal is a multi-centre observational study. Its purpose is to characterise the malaria species composition and particularly exposure and burden of P. vivax across malaria endemic settings in Cameroon. It will use multiplex serological methods based on quantitative suspension array on finger-stick blood samples collected from febrile patients of ages 1-100 during two malaria transmission seasons in different eco-climatic regions in Cameroon.


Clinical Trial Description

Type of study: The current proposal is a multi-centre observational study in different eco-climatic regions in Cameroon. Study locations: Dschang health district(Low transmission, highland) , Maroua (Sahel, high transmission) and Bertoua-Batouri (East region, forest, perennial transmission). Study period: The study will be conducted over a period of 36 months beginning from June, 2021. Study population: In each selected health facility, children 1 year and above, and adult of both gender will be eligible for participation. Selection criteria: inclusion criteria, exclusion criteria. Inclusion criteria: 1. Patient must be febrile (temperature >37.50 C or history of fever within 24 hours of arrival to the hospital) 2. Patient must be aged 1 year or older 3. Both males and females alike 4. The patient must be able to sign a consent/assent form 5. The patient must be seeking care and be suspected of malaria infection Non-inclusion criteria: 1. Patient less than 1 year 2. Patient not having fever 3. Patient not being suspected of malaria infection Exclusion criteria: 1. Eligible patient who refuses consent to study procedures 2. Patient withdraws consent before or during the start of study procedures 3. Patient, who, for any reason, refuses that sensitive data should not be processed. 6) Recruitment strategies for the study population Sample size and justification: This study is a cross sectional study that will determine a point estimate of the seroprevalence of parasite species, and in particular Plasmodium vivax in Cameroon. For this reason, we calculated the sample size based on an estimate of Plasmodium vivax in febrile patients as reported in a study in 2017((1)https://malariajournal.biomedcentral.com/articles/10.1186/s12936-017-1722-2), to get the highest power to calculate the sample population size for use in our study. Using the formula n = [DEFF*Np(1-p)]/ [(d2/Z21-α/2*(N-1)+p*(1-p)] in which DEFF=design effect=1, p =Hypothesised percentage frequency of outcome factor in the population=25%, from above study, d=confidence limit=5%, n=sample size, we calculated the for the study in three sites to be 867 or 300 per site, taking into consideration a refusal rate 4%. The software OpenEpi was used or the calculations (http://www.openepi.com/SampleSize/SSPropor.htm).The primary outcome is the spatial seroprevalence of Plasmodium vivax among febrile patients in the three epidemiological facies in Cameroon. For entomological component, WHO methods for Human landing catch (HLC) will be used to catch mosquitoes in 12-15 houses in each of four neighbourhoods over the periods corresponding to the beginning of malaria transmission, the peak malaria transmission and at the end of the malaria transmission season. 8) Sample collection procedure: In each selected health facility, febrile individuals 1 year and above will be eligible for biological sample collection. Volunteers who have provided written informed consent/assent will have a finger prick sampling (approximately 500μl). The skin will be cleaned and sterilised using an alcohol wipe. A sterile lancet will be used for the procedure. Blood collected will then be divided for use between the desired assays. Haemostasis will be achieved and a bandage placed on. This 500μL of blood will be used for a malaria smear (70 μL), RDT based on P. falciparum and PAN-lactate dehydrogenase (pLDH) antigen (10 μL), and to prepare four Dried Blood Spots (DBS, Whatman 903 Protein Saver) for immunological and molecular assays (4 x 100 μL). Serological analysis Six Plasmodium antigens will be used to screen patient samples: two P.f antigens (Merozoite Surface Protein-1 19kD (MSP-1) and Apical Merozoite Antigen-1 (AMA-1), three P. vivax antigens (PvMSP-1 and PvAMA-1, pvRBPII), one P. malariae (PmMSP-1) and one P. ovale (PoMSP-1) selected on the basis of previous studies (20). Recombinant antigen will serve as a generic protein to assess immunoglobulin G (IgG) non-specific binding. Antigens for other species of malaria causing parasites are used in order to eliminate cross reacting sera and identify co-infections from pure P. vivax infections. All antigens will be coupled to magnetic beads (Luminex Corp, Austin, TX, USA) as per prior studies (18) in ISGlobal, Spain. Coupled beads will be run with a panel of known malaria seronegatives to assure minimal non-specific MFI signal would be given by beads used in subsequent assays. The DBS elution will be assayed for total IgM and IgG antibodies using bead-based innovative multiplex technology developed and published by the training host institution(18) (ISGlobal, Barcelona, Spain). Negative control samples and a dilution curve of hyperimmune serum will be added to each assay plate to monitor any change in control values over the course of the study. All staff working directly with patients will be required to take safety measures such as vaccinating against hepatitis B, the use of COVID-19 barrier measures and distancing, as is practiced in the hospital or higher. In addition, all study staff will undergo training in a workshop on all study procedures before implementation. One module in the training package will be on biosafety. Data analysis and management. Data Management: Field data will be entered into a password-protected database designed for the study through hand held tablets at each study site. Primary data collection tool such as paper questionnaires will be stored in metal cupboards with access control maintained by the principal investigator of the study. Geographical location will be collected, but in the dataset, it will be perturbed as well, by replacing with other coordinates which will not distort the utility of the geolocation data and at minimum that the exact location of study participants is not discernable. Data analysis Data will be cleaned centrally by visual inspection for outliers. The primary study outcome for this will be the seroprevalence of P. vivax in the enrolled population of febrile patients in different geo-ecological regions of Cameroon. A cut-off for seropositivity will be determined based on the mean of log MFI values plus three standard deviations of the seronegative controls. Separate cut-off values will be generated for each of the studied antigens. By so doing, participants will be classified as seropositive or seronegative depending on whether their antibody levels lie above or below the cut-off values. The seroprevalence will be calculated for each antigen, as the proportion of seropositive individuals of the total study population, per study site, and overall. The estimates will be determined together with their 95% confidence intervals. Antibody responses data will be log10 transformed and then adjusted for age for subsequent spatial analysis. The Bayesian analytical framework using several different tools such as geographical positioning system, will be used to characterise the spatial seroprevalence across different ecologies using individual and geographical covariates in the model. Secondary outcomes will be the prevalence and spatial distribution of malaria by infecting species. We will use bivariate analysis to test for association of potential risk factors with P. vivax exposure among study participants. The spatial software SaTScan will be used to identify clusters of antibody responses against each antigen. The spatial analysis will be run separately for each survey and spatial autocorrelation of clusters for each of the two survey time points assessed using Moran's I in ArcGIS software, as done previously (22). Age-adjusted antibody residuals from the regression model will be used for this analysis. Risk factors for P. vivax infection will be assessed using mixed effect logistic regression analysis with sampling site (health facility) considered a random effect variable. The Microsoft Excel suite as well as the latest version of STATA or R-package will be used as the statistical software. Ethical considerations: potential risks, benefits, measures taken for data confidentiality and respect for the privacy of participants This is a minimal risk study that has an ethical clearance renewal from the IRB of the Cameroon Baptist Convention health Services. This clearance will be renewed yearly until close of study from the National Ethics Committee for Human Health Research (CNERSH). Before any study related procedure starts, we will obtain written informed consent/assent from participants, and from parents or guardians if children. Febrile volunteers already seeking malaria care in health facilities will participate. A 0.5ml of blood sample obtained by finger stick will be used. The same blood sample will be used for a peripheral smear, rapid diagnostic test, microscopy and dried blood spots. Data gathered from participants will be limited to their age, gender, malaria history, symptom status, and geolocation. Geolocation data will be adjusted by displacing exact coordinates within 2-3 km in the final dataset as a measure of participant security and data anonymisation. Measures will be in place to ensure confidentiality of participants and data generated. Malaria is a common childhood illness and does not carry any significant stigma associated with it. No remuneration to participants will be made. To guarantee the privacy of patients, data and biologic samples transported between countries and research sites will only use the study ID and be de-identified to the users of the data. No identifiable information will be transferred between countries. At database lock, only authorized study individuals will have access to the computer account containing the database. Data entry clerks will have individualised password-protected accounts during entry and cleaning. As all data analysis and testing of biological specimens will be done using de-identified samples, the results of the analysis will only be presented and evaluated by the scientific community in a de-identified manner. At the completion of all analyses and the end of the study, all hard copy materials and the study key will be destroyed. This will follow local regulations that state a maximum of 15 years for data and 10 years for biological materials. Data collection will involve collection of personal data including age, gender, location, clinical information including temperature, and information on the use of malaria preventive measures such as availability and use of insecticide treated bed nets, previous episodes of malaria etc. Data will be recorded in the hospital using electronic personal data assistants directly, or in case of unavailability paper. If recorded on paper, the data will be transcribed to electronic form and stored in a database designed for the study. To ensure the quality of the data transcribed, the database will automatically generate a pop up in case an improper data is input in the system. The applicant will verify on 10 % of all data collected that they have been properly entered into the database. The data operator will access the database through a secured user account created in the computer containing the database. The password will be changed every six months by the principal investigator until the study comes to an end. The full database will not be accessible to any other person apart from designated study individuals. Data may be temporally stored in a password protected external hard drive. The data stored in the hard drive will provide a backup in case there are problems with the computer. The second reason will be to have the data when traveling. However, the data which will be shared for education and training will be de-identified, and will be anonymised dataset. In accordance with national law, the data will not be stored for more than 10 years, and this will be included in the information sheet in the consent process. Study volunteers will also be requested to provide consent for secondary use of their data or sample during the consent process prior to joining the study. All study data will be destroyed on or before 10 years after the study ends. Paper data will be destroyed by shredding while electronic data will be destroyed by permanent deletion in all electronic devices containing data from the study. The rights of persons providing data in a clinical setting is covered by the code of medical practice and enshrined in the Cameroon constitution, when they are considered persons. The volunteers in this research will be adequately informed of the detailed study procedures and the use of secondary data and biological specimen collected, their rights, the protection of their privacy and confidentiality, their freedom to withdraw from the research at any time without any prejudice whatsoever concerning routine care, any form of indemnity, and telephone contacts of hospital doctor, the principal investigator of the study and the mobile phone contact of the responsible officers at the ethical committee(s) that granted clearance. The ethical committee requires that they be reached in case a study participant feels his/her rights are being violated. In all information sheets (of which the participant will have a copy), the mobile phone number of the responsible contact of the ethical committee will be mentioned. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT05058885
Study type Observational
Source University of Dschang
Contact Innocent Ali, PhD
Phone +237677021275
Email [email protected]
Status Not yet recruiting
Phase
Start date October 2, 2021
Completion date July 1, 2024

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