Clinical trial NCT04228315: Biomarkers of P. Vivax Relapse
Official title: Identification of Hypnozoite Biomarkers and Relapse Patterns of Plasmodium Vivax
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Malaria
Vivax Malaria
Relapse
CYP2D6 Polymorphism
Keywords: primaquine
biomarker
hypnozoite
efficacy
Lead sponsor: Armed Forces Research Institute of Medical Sciences, Thailand
Sponsor class: OTHER_GOV
Collaborators: name: University of North Carolina, Chapel Hill
First posted: 2020-01-14
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The clinical study is a two arm, randomized, open-label treatment study of Thai adults with acute infection with P. vivax. All subjects will be treated with a short acting oral antimalarial, artesunate, to eradicate P. vivax malaria from the bloodstream. Radical cure with primaquine (15 mg/ day for 14 days) to eliminate the relapsing hypnozoite of P. vivax will be given at different times, depending on this study arm. Ten healthy controls will also be enrolled for 1 day to provide baseline samples.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Therapeutic efficacy of a radical cure course of primaquine for uncomplicated P. vivax infection
timeFrame: 6 months
measure: Build a biorepository of prospectively collected blood and urine samples in P. vivax patients prior to relapse to analyze for hypnozoite biomarkers
timeFrame: 6 months
Secondary outcomes:
measure: Characterize the patterns of relapsing Southeast Asian P. vivax in infected subjects
timeFrame: 28 days
measure: Delineate relapse kinetics of P. vivax infection using molecular diagnostic methods,
timeFrame: 42 days
measure: Determine percentage of P. vivax isolates resistant to antimalarial drugs used for treatment
timeFrame: 6 months
measure: Establish rates of P. vivax relapse versus new infection with vivax using molecular methods
timeFrame: 6 months
measure: Characterize the rate glucose 6-phosphate dehydrogenase (G6PD) deficiency of study population
timeFrame: 3 months
measure: Characterize hepatic cytochrome P450 (CYP450) 2D6 enzyme genotypes and predicted phenotypes in this study population
timeFrame: 1 day
measure: Determine primaquine pharmacokinetics in this study population
timeFrame: 56 days
measure: Determine primaquine pharmacokinetics in this study population
timeFrame: 56 days
measure: Assess impact of risk factors of travel and prior malaria history on P. vivax relapse kinetics
timeFrame: 6 months
measure: Measure rates of gametocyte carriage
timeFrame: 6 months
measure: Determine if humoral immunity contributes to protection against P. vivax recurrence
timeFrame: 6 months
Other outcomes:
Locations:
city: Khun Han
country: Thailand
facility: Khun Han Hospital
Study officials:
affiliation: Armed Forces Research Institute of Medical Sciences, Thailand
name: Norman Waters, PhD
role: STUDY_DIRECTOR
affiliation: Armed Forces Research Institute of Medical Sciences, Thailand
name: Michele Spring, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Armed Forces Research Institute of Medical Sciences, Thailand
name: Ladaporn Bodhidatta, MD
role: PRINCIPAL_INVESTIGATOR
References: