Biomarkers of P. Vivax Relapse

NCT ID: NCT04228315

Last Updated: 2020-01-14

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-19
• Study Completion Date: 2024-12-31

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.

Conditions

Malaria; Vivax Malaria; Relapse; CYP2D6 Polymorphism

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Primaquine

Intervention Type: DRUG

radical cure dosing

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

Group Type: ACTIVE_COMPARATOR

Primaquine

Intervention Type: DRUG

radical cure dosing

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Primaquine

radical cure dosing

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: collaborator

Armed Forces Research Institute of Medical Sciences, Thailand

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Norman Waters, PhD

Role: STUDY_DIRECTOR

Armed Forces Research Institute of Medical Sciences, Thailand

Michele Spring, MD

Role: PRINCIPAL_INVESTIGATOR

Armed Forces Research Institute of Medical Sciences, Thailand

Ladaporn Bodhidatta, MD

Role: PRINCIPAL_INVESTIGATOR

Armed Forces Research Institute of Medical Sciences, Thailand

Locations

Khun Han Hospital

Khun Han, , Thailand

Site Status: RECRUITING

Countries

Thailand

Central Contacts

Michele D Spring, MD

Role: CONTACT

michele.spring.ctr@afrims.org

+66(0)2696-2700 ext. 4630

Norman Waters, PhD

Role: CONTACT

Norman.Waters.mil@afrims.org

+66-(0)81 902 6756

Facility Contacts

Ratchadaporn Runcharoen, MD

Role: primary

Other Identifiers

WR2643

Identifier Type: -

Identifier Source: org_study_id