MalariaNCT04228315
Biomarkers of P. Vivax Relapse
A study testing Primaquine in people with Malaria and Vivax Malaria, run by Armed Forces Research Institute of Medical Sciences, Thailand at 1 site in Thailand.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Malaria, Vivax Malaria, Relapse
- What is being tested?
- Primaquine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 100 participants
- Where
- 1 siteThailand
- Study dates
- 19 Nov 2019to 31 Dec 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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)
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- 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.
Trial locations and contacts
1 site in 1 country.
Thailand1 site, 1 recruiting
- Recruiting
Khun Han Hospital
Khun Han
Ratchadaporn Runcharoen, MD
Mariusz Wojnarski, MD
About this study
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.
Read the 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.
- Conditions
- Malaria, Vivax Malaria, Relapse, CYP2D6 Polymorphism
- Being tested
- Primaquine
- Keywords
- primaquine, biomarker, hypnozoite, efficacy
- Medical subject headings
- Malaria, Malaria, Vivax, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PrimaquineDrug
radical cure dosing
| Study group | Role | What they receive |
|---|---|---|
| Early primaquine group | Experimental | 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 Receives: Drug: Primaquine |
| Delayed Primaquine group | Active comparator | 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 Receives: Drug: Primaquine |
| Healthy control group | No intervention | Ten (10) age- and gender-matched controls will be enrolled for one day to obtain biological samples to be compared to the 2 intervention arms |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 6 months
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
Measured: 6 months
Secondary outcomes (11)
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
Measured: 28 days
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
Measured: 42 days
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
Measured: 6 months
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
Measured: 6 months
Characterize the rate glucose 6-phosphate dehydrogenase (G6PD) deficiency of study population
Incidence of G6PD deficiency (<30% activity) using quantitative spectrophotometry diagnostics
Measured: 3 months
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)
Measured: 1 day
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
Measured: 56 days
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
Measured: 56 days
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
Measured: 6 months
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
Measured: 6 months
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
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jan 2020
- Study start19 Nov 2019
- Primary completion30 Jun 2021 (estimated)
- Study completion31 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- None (open label)
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Armed Forces Research Institute of Medical Sciences, Thailand
- Sponsor type
- Other government
- Collaborators
- University of North Carolina, Chapel Hill
- Responsible party
- Sponsor
- Investigators
- Norman Waters, PhD, Study director, Armed Forces Research Institute of Medical Sciences, ThailandMichele Spring, MD, Principal investigator, Armed Forces Research Institute of Medical Sciences, ThailandLadaporn Bodhidatta, MD, Principal investigator, Armed Forces Research Institute of Medical Sciences, Thailand
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04228315
- Sponsor's protocol ID
- WR2643
- Status last verified
- Dec 2019
- First submitted
- 10 Jan 2020
- Last updated
- 14 Jan 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identification of Hypnozoite Biomarkers and Relapse Patterns of Plasmodium Vivax
- ClinicalTrials.gov ID
- NCT04228315
- Acronym / sponsor ID
- WR2643
- Conditions
- Malaria, Vivax Malaria, Relapse, CYP2D6 Polymorphism
- Keywords
- primaquine, biomarker, hypnozoite, efficacy
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Armed Forces Research Institute of Medical Sciences, ThailandOther government
- Collaborators
- University of North Carolina, Chapel Hill
- Study start
- 19 Nov 2019 (actual)
- Primary completion
- 30 Jun 2021 (estimated)
- Study completion
- 31 Dec 2024 (estimated)
- First posted
- 14 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| Early primaquine group | Experimental | Drug: PrimaquineThirty (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 |
| Delayed Primaquine group | Active comparator | Drug: PrimaquineSixty (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 |
| Healthy control group | No intervention | –Ten (10) age- and gender-matched controls will be enrolled for one day to obtain biological samples to be compared to the 2 intervention arms |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Primaquineradical cure dosing | Drug | Delayed Primaquine group, Early primaquine group |
Primary outcome
Therapeutic efficacy of a radical cure course of primaquine for uncomplicated P. vivax infection
Time frame: 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
Time frame: 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
11 secondary outcomes
Characterize the patterns of relapsing Southeast Asian P. vivax in infected subjects
Time frame: 28 days
Delineate relapse kinetics of P. vivax infection using molecular diagnostic methods,
Time frame: 42 days
Determine percentage of P. vivax isolates resistant to antimalarial drugs used for treatment
Time frame: 6 months
Establish rates of P. vivax relapse versus new infection with vivax using molecular methods
Time frame: 6 months
Characterize the rate glucose 6-phosphate dehydrogenase (G6PD) deficiency of study population
Time frame: 3 months
Characterize hepatic cytochrome P450 (CYP450) 2D6 enzyme genotypes and predicted phenotypes in this study population
Time frame: 1 day
Determine primaquine pharmacokinetics in this study population
Time frame: 56 days
Determine primaquine pharmacokinetics in this study population
Time frame: 56 days
Assess impact of risk factors of travel and prior malaria history on P. vivax relapse kinetics
Time frame: 6 months
Measure rates of gametocyte carriage
Time frame: 6 months
Determine if humoral immunity contributes to protection against P. vivax recurrence
Time frame: 6 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jan 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Norman Waters, PhD study director
Armed Forces Research Institute of Medical Sciences, Thailand
Michele Spring, MD principal investigator
Armed Forces Research Institute of Medical Sciences, Thailand
Ladaporn Bodhidatta, MD principal investigator
Armed Forces Research Institute of Medical Sciences, Thailand
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Primaquine in people with Malaria and Vivax Malaria, run by Armed Forces Research Institute of Medical Sciences, Thailand at 1 site in Thailand.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 14 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Thailand. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Michele D Spring, MD (+66(0)2696-2700 ext. 4630, michele.spring.ctr@afrims.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Therapeutic efficacy of a radical cure course of primaquine for uncomplicated P. vivax infection (time frame: 6 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jan 2020.