Malaria Clinical Trial
Official title:
Identification of Hypnozoite Biomarkers and Relapse Patterns of Plasmodium Vivax
Plasmodium vivax malaria is difficult to manage because even after taking medicine that kills the infection in the blood, it can continue to hide quietly in the liver, later re-emerging into the blood and causing another episode of malaria illness (relapse). This clinical trial aims to enroll patient with P. vivax infections and try to detect signals in blood, urine and/or saliva coming from the silent liver stages to help identify who could benefit from treatment with primaquine. It also will explore if certain factors of patients negatively impact primaquine efficacy.
Status | Recruiting |
Enrollment | 100 |
Est. completion date | December 31, 2024 |
Est. primary completion date | June 30, 2021 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 18 Years and older |
Eligibility |
Inclusion Criteria: For P. vivax-infected malaria subjects 1. Are a Thai male or non-pregnant/non-lactating female aged at least 18 years and are able to fluently speak and understand Thai 2. Willingness to participate in the study as evidenced by witnessed, signed informed consent from the subject (written or thumb print) 3. Have P. vivax malaria mono-infection as determined by blood smear, with a parasitemia range of 100-400,000 parasites/microliter 4. Are available to stay in a controlled setting for the first 28 days of this study to minimize exposure to mosquitoes and available for follow-up for anticipated study duration 5. Resides in Sisaket or Ubon Ratchathani Province 6. Are of normal (non-deficient or >30% activity) G6PD phenotype as defined by WHO 7. Agree to not seek outside medical care prior to contacting the Armed Forces Research Institute of Medical Sciences (AFRIMS) study team if a fever develops during study participation (approximately 180 days), unless emergency medical care is required For healthy control group 1. Are a Thai male or non-pregnant/non-lactating female aged at least 18 years and are able to fluently speak and understand Thai 2. Willingness to participate in the study as evidenced by witnessed, signed informed consent from the subject (written or thumb print) 3. Free of malaria and other significant health problems as established by medical history, laboratory assessment and clinical examination by clinical investigator 4. Normal (non-deficient or > 30% activity) G6PD phenotype as defined by World Health Organization (WHO) 5. Resides in Sisaket or Ubon Ratchathani Province Exclusion Criteria: For P. vivax-infected malaria subjects 1. Have an allergic reaction to artesunate or primaquine 2. History of anti-malarial drug use within the past 28 days 3. Have symptoms of severe malaria needing urgent treatment, such as serious vomiting, unable to eat or drink, prostration, or other signs/symptoms of concern to the doctors 4. Are a pregnant or lactating female, or female of childbearing age, up to 50 years of age or otherwise individually assessed for childbearing potential, who does not agree to use an acceptable form of contraception (e.g. pills or injectable) during this study and for 1 month after study completion 5. Chronic use of medications known to cause drug interactions with primaquine or CYP450 2D6 (selective serotonin reuptake inhibitors (SSRIs) or other medications used for psychological conditions, as well as antihistamines, antihypertensives, codeine) 6. Any other significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in this study For healthy control group 1. Has history of malaria infection in the past 10 years 2. Positive for any Plasmodium species by blood smear or PCR at time of screening 3. Pregnant or lactating female 4. G6PD deficient as defined by WHO 5. Any other significant finding that in the opinion of the investigator would increase the risk of compromising the validity of being a control (eg., chronic daily chewing of betel nut (may impact saliva assays) or menstruating females (whereby urine collections may have blood and impact assay results), etc. |
Country | Name | City | State |
---|---|---|---|
Thailand | Khun Han Hospital | Khun Han |
Lead Sponsor | Collaborator |
---|---|
Armed Forces Research Institute of Medical Sciences, Thailand | University of North Carolina, Chapel Hill |
Thailand,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Therapeutic efficacy of a radical cure course of primaquine for uncomplicated P. vivax infection | In subjects presenting with uncomplicated P. vivax infection, determine frequency of P. vivax recurrence throughout the study period after being administered a 14-day course of primaquine | 6 months | |
Primary | Build a biorepository of prospectively collected blood and urine samples in P. vivax patients prior to relapse to analyze for hypnozoite biomarkers | At pre-determined time points, collect biological samples to be processed and stored for proteomic, metabolomic, genomic and transcriptomic markers of latent hypnozoites, allowing for comparisons of markers in those who did and those who did not relapse | 6 months | |
Secondary | Characterize the patterns of relapsing Southeast Asian P. vivax in infected subjects | Percentage of P. vivax relapse in subjects with uncomplicated P. vivax mono-infection in the 28 days following treatment with oral blood stage anti-malarial treatment with comparisons between those administered primaquine at enrollment and those who did not receive primaquine | 28 days | |
Secondary | Delineate relapse kinetics of P. vivax infection using molecular diagnostic methods, | At pre-determined time points starting at admission and prior to P. vivax relapse, compare limit of detection of recently emerged erythrocytic forms by blood smear, polymerase chain reaction (PCR) and ultra sensitive PCR | 42 days | |
Secondary | Determine percentage of P. vivax isolates resistant to antimalarial drugs used for treatment | Parasite growth inhibition as measured by concentration at which 50% of growth is inhibited (IC50) to antimalarial drug panel using pLDH ELISA techniques | 6 months | |
Secondary | Establish rates of P. vivax relapse versus new infection with vivax using molecular methods | Perform genome sequencing to determine genetic signatures of the vivax parasite, comparing initial infection with recurrences to identify relapse versus a new infection | 6 months | |
Secondary | Characterize the rate glucose 6-phosphate dehydrogenase (G6PD) deficiency of study population | Incidence of G6PD deficiency (<30% activity) using quantitative spectrophotometry diagnostics | 3 months | |
Secondary | Characterize hepatic cytochrome P450 (CYP450) 2D6 enzyme genotypes and predicted phenotypes in this study population | Genotype CYP450 2D6 alleles in this study population and resultant predicted metabolism phenotypes using Activity Score A (AS-A) | 1 day | |
Secondary | Determine primaquine pharmacokinetics in this study population | Measure plasma concentrations of primaquine and its major metabolites at 0,2,4,8,10 and 24 hours after initial primaquine dose and calculate the area under the curve (AUC) for each subject | 56 days | |
Secondary | Determine primaquine pharmacokinetics in this study population | Measure urine concentrations of primaquine and its major metabolites at 0-4 hours, 4-10 hours and 10-24 hours after initial primaquine dose and calculate the area under the curve (AUC) for each subject | 56 days | |
Secondary | Assess impact of risk factors of travel and prior malaria history on P. vivax relapse kinetics | Determine number of days of travel to high malaria risk areas in 30 days prior to enrollment for each subject to compare with parasite genetic relatedness of initial and recurrent vivax infections | 6 months | |
Secondary | Measure rates of gametocyte carriage | Determine rate and duration of sexual stage infections based on light microscopy and molecular analyses (PCR) from samples drawn at enrollment and pre-determined time points over study period | 6 months | |
Secondary | Determine if humoral immunity contributes to protection against P. vivax recurrence | Measure antibody levels against vivax antigens merozoite surface protein-1 (MSP-1) and circumsporozoite protein (CSP) at Day 0,28,90 and 180 and compare to rate of P. vivax recurrence | 6 months |
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