Identification of Hypnozoite Biomarkers and Relapse Patterns of Plasmodium Vivax
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Therapeutic efficacy of a radical cure course of primaquine for uncomplicated P. vivax infection
研究概览
简要总结
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.
详细描述
Plasmodium vivax, the most widely distributed human malaria, has resisted control largely due to a relapsing hypnozoite liver stage that is clinically silent until emergence and replication in the blood weeks to months later. Curative treatment with primaquine is often not achieved due to potential toxicity in those with G6PD deficiency, poor adherence to the two-week course, and ineffective metabolism of primaquine in those with polymorphisms in cytochrome P450 isoenzyme 2D6 (CYP2D6). Identifying those who harbor hypnozoites will allow for judicious use of primaquine in returning travelers/active duty personnel as well as targeted administration to those living in endemic areas to interrupt parasite transmission in the community. The trial will be conducted in patients presenting with uncomplicated P. vivax malaria at clinical trial sites run by Armed Forces Research Institute of Medical Sciences (AFRIMS) in Southeast Asia. It is designed to capture vivax patients who still harbor the dormant liver stage hypnozoites after treatment with a short acting oral blood schizonticide, and subsequently relapse during the follow-up period while staying in in study-provided housing to reduce risk of reinfection and surveilled daily for parasites or clinical signs of relapse. Longitudinal blood and urine sampling will be done to allow for retrospective analysis to identify biomarkers of hypnozoite infection and subsequent relapse using a systems biology approach. A smaller arm will be enrolled and will receive the short-activing schizonticide with primaquine radical cure at time of admission and followed similarly for relapse. All subjects will be followed for a total of 6 months in order to assess effectiveness of primaquine radical cure for P. vivax infections.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •For P. vivax-infected malaria subjects
- •Are a Thai male or non-pregnant/non-lactating female aged at least 18 years and are able to fluently speak and understand Thai
- •Willingness to participate in the study as evidenced by witnessed, signed informed consent from the subject (written or thumb print)
- •Have P. vivax malaria mono-infection as determined by blood smear, with a parasitemia range of 100-400,000 parasites/microliter
- •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
- •Resides in Sisaket or Ubon Ratchathani Province
- •Are of normal (non-deficient or >30% activity) G6PD phenotype as defined by WHO
- •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
- •Are a Thai male or non-pregnant/non-lactating female aged at least 18 years and are able to fluently speak and understand Thai
- •Willingness to participate in the study as evidenced by witnessed, signed informed consent from the subject (written or thumb print)
- •Free of malaria and other significant health problems as established by medical history, laboratory assessment and clinical examination by clinical investigator
- •Normal (non-deficient or > 30% activity) G6PD phenotype as defined by World Health Organization (WHO)
- •Resides in Sisaket or Ubon Ratchathani Province
排除标准
- •For P. vivax-infected malaria subjects
- •Have an allergic reaction to artesunate or primaquine
- •History of anti-malarial drug use within the past 28 days
- •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
- •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
- •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)
- •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
- •Has history of malaria infection in the past 10 years
- •Positive for any Plasmodium species by blood smear or PCR at time of screening
- •Pregnant or lactating female
- •G6PD deficient as defined by WHO
- •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.
研究组 & 干预措施
Early primaquine group
Thirty (30) P. vivax-infected adults will be enrolled in Khun Han Hospital to receive 5 days or oral artesunate (4 mg/kg) and 15 mg/day of oral primaquine for 14 days
干预措施: Primaquine (Drug)
Delayed Primaquine group
Sixty (60) P. vivax-infected adults will be enrolled in Khun Han Hospital to receive 5 days or oral artesunate (4 mg/kg) and the primaquine regimen (15 mg/day for 14 days) not given until 42 days after enrollment
干预措施: Primaquine (Drug)
结局指标
主要结局
Therapeutic efficacy of a radical cure course of primaquine for uncomplicated P. vivax infection
时间窗: 6 months
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
Build a biorepository of prospectively collected blood and urine samples in P. vivax patients prior to relapse to analyze for hypnozoite biomarkers
时间窗: 6 months
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
次要结局
- Determine primaquine pharmacokinetics in this study population(56 days)
- Characterize hepatic cytochrome P450 (CYP450) 2D6 enzyme genotypes and predicted phenotypes in this study population(1 day)
- Assess impact of risk factors of travel and prior malaria history on P. vivax relapse kinetics(6 months)
- Characterize the rate glucose 6-phosphate dehydrogenase (G6PD) deficiency of study population(3 months)
- Characterize the patterns of relapsing Southeast Asian P. vivax in infected subjects(28 days)
- Determine percentage of P. vivax isolates resistant to antimalarial drugs used for treatment(6 months)
- Establish rates of P. vivax relapse versus new infection with vivax using molecular methods(6 months)
- Delineate relapse kinetics of P. vivax infection using molecular diagnostic methods,(42 days)
- Measure rates of gametocyte carriage(6 months)
- Determine if humoral immunity contributes to protection against P. vivax recurrence(6 months)