Biomarkers of P. Vivax Relapse

January 10, 2020 updated by: Armed Forces Research Institute of Medical Sciences, Thailand

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
100

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Thailand
      • Khun Han, Thailand
        • Recruiting
        • Khun Han Hospital
        • Contact:
          • Ratchadaporn Runcharoen, MD
        • Sub-Investigator:
          • Mariusz Wojnarski, MD
        • Sub-Investigator:
          • Phimpan Pisutsan, MD
        • Sub-Investigator:
          • Norman Waters, PhD
        • Sub-Investigator:
          • Jessica Lin, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: 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
Drug: Primaquine
radical cure dosing
Active Comparator: 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
Drug: Primaquine
radical cure dosing
No Intervention: Healthy control group
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 the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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
6 months
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
6 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Characterize the patterns of relapsing Southeast Asian P. vivax in infected subjects
Time Frame: 28 days
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
Delineate relapse kinetics of P. vivax infection using molecular diagnostic methods,
Time Frame: 42 days
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
Determine percentage of P. vivax isolates resistant to antimalarial drugs used for treatment
Time Frame: 6 months
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
Establish rates of P. vivax relapse versus new infection with vivax using molecular methods
Time Frame: 6 months
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
Characterize the rate glucose 6-phosphate dehydrogenase (G6PD) deficiency of study population
Time Frame: 3 months
Incidence of G6PD deficiency (<30% activity) using quantitative spectrophotometry diagnostics
3 months
Characterize hepatic cytochrome P450 (CYP450) 2D6 enzyme genotypes and predicted phenotypes in this study population
Time Frame: 1 day
Genotype CYP450 2D6 alleles in this study population and resultant predicted metabolism phenotypes using Activity Score A (AS-A)
1 day
Determine primaquine pharmacokinetics in this study population
Time Frame: 56 days
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
Determine primaquine pharmacokinetics in this study population
Time Frame: 56 days
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
Assess impact of risk factors of travel and prior malaria history on P. vivax relapse kinetics
Time Frame: 6 months
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
Measure rates of gametocyte carriage
Time Frame: 6 months
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
Determine if humoral immunity contributes to protection against P. vivax recurrence
Time Frame: 6 months
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Armed Forces Research Institute of Medical Sciences, Thailand

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of North Carolina, Chapel Hill

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Norman Waters, PhD, Armed Forces Research Institute of Medical Sciences, Thailand
  • Principal Investigator: Michele Spring, MD, Armed Forces Research Institute of Medical Sciences, Thailand
  • Principal Investigator: Ladaporn Bodhidatta, MD, Armed Forces Research Institute of Medical Sciences, Thailand

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 19, 2019

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 30, 2021

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 10, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 10, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 14, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 14, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 10, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • WR2643

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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