Serological Screen and Treat Trial for Plasmodium Vivax

Study Overview
=================
Brief Summary
-----------------
This is a clinical trial to evaluate an experimental serological diagnostic technique intended to identify people at high risk of having dormant malaria parasites in their liver. The study is designed to evaluate the efficacy of serological screening vs. routine care for the prevention of recurrent P. vivax infections. A total of 960 schoolchildren will be randomized into the interventional or control arm.

Detailed Description
-----------------
This is a randomized controlled trial to evaluate an experimental serological diagnostic technique intended to identify people at high risk of having dormant malaria parasites in their liver. The study is designed to show a superiority of SSAT vs. routine care for the prevention of recurrent P. vivax infections. With the estimated prevalence of 20%, the investigators will have a power of >90% to detect a significant difference with the sample size of 350 children per group. The investigators will recruit 480 children per group to anticipate subject loss due to exclusion and drop out. After obtaining informed consent from their parents/legal guardians, 800 schoolchildren living in Batubara regency, North Sumatra, Indonesia, will be individually randomized to intervention (SSAT) or control (routine care) group. During enrollment, all participants will be tested with Pv serological test by standard Luminex, and standard finger stick microscopic. Their hemoglobin (Hb) and Glucose-6-Phosphate Dehydrogenase (G6PD) level will be measured. Children with Hb level<9 g/dL and/or G6PD <4 U/g Hb (male) or <6 U/g Hb (female) will be excluded. In the intervention arm (SSAT), children who are seropositive by standard Luminex and/or symptomatic LMF positive will be treated with dihydroartemisinin-piperaquine (DHA-PP) for 3 days according to national guideline and primaquine/PQ high dose (1 mg/kg BW/day for 7 days for Pv/Po, 0.25 mg/kg BW for Pf). In the control arm, children will be treated only when they show symptoms (body temperature>=36.5oC or history of fever within last 3 days) and proven positive by LMF. All treatment will be provided under direct supervision by the research team during which any adverse event/severe adverse event will be recorded. Hemoglobin level and urine will be monitored daily for 7 days of PQ administration. Post-hoc qPCR detection will be performed to determine their initial malaria status. Several additional tests will also be performed to all participants during this initial screening: microscopic examination of shallow vasculature of the ankle (light microscopy-skin/LMS), magneto-optical detection of hemozoin, and post-hoc point-of-care/POC serological test. After enrollment, all children will be actively followed for 9 months every 4 weeks for post-hoc assessment by qPCR. Anytime during this follow up period, children becoming acutely ill will be tested for malaria by LMF, and referred to Primary Health Center to receive treatment when positive. Furthermore, household members of these infected children will also be screened for malaria infection by LMF and post-hoc LMS and qPCR. This family screening will be performed by 2x house visit (7-10 AM and 7-10 PM). Treatment will be given for those found positive by LMF regardless of their symptoms. Antimalarial treatment provided during this follow up period will be according to national standard guideline: 3 days of DHA-PP plus PQ (single 0.25 mg/kg BW dose for Pf, daily 0.25 mg/kg BW dose for 14 days for Pv/Po). At the end of study, Pv serological test and LMF will be performed to all schoolchildren. Those found positive by LMF will be referred to Primary Health Center to receive treatment according to national standard guideline. Sponsor: WEHI, Funding: NHMRC, Grant number: GNT1102297

Official Title
-----------------
Serological Screen and Treat Trial for P. Vivax: a Proof-of-concept Trial in Western Indonesia

Conditions
-----------------
Malaria, Vivax

Intervention / Treatment
-----------------
* Diagnostic Test: Serological screen and treat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: resident of study area and attending selected elementary school in Grade 1-5 or middle school Grade 1-3 no evidence of health condition that would interfere with study participation assent of child and documented parental informed consent Exclusion Criteria: G6PD deficiency as determined by SD Biosensor quantitative determination of <70% G6PD activity (<6 U/g Hb). Haemoglobin < 9 g/dL

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 15 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study evaluates an experimental serological diagnostic technique intended to identify people at high risk of having dormant malaria parasites in their liver. 960 children living in western Indonesia will be individually randomised to the experimental serologic test or routine care. Children in the serological diagnosis arm will be screened for the presence of antibodies to a previously validated panel of malaria antigens optimized for sensitivity to infection during the prior 9 months. Furthermore, they also will be screened by microscopy. If positive by either test, they will be treated for that malaria infection. Children assigned to routine care will be screened by microscopic examination and treated when they show or have history of symptoms in the last 3 days. After initial screening and treating according to diagnostic technique, all children will be actively followed for 9 months with PCR detection every 4 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Serological screen and treat<br>Children who screened with sero test and microscopy. A 7-day high dose PQ will be provided for those with Pv seropositive regardless of their symptoms and symptomatic children with microscopic Pv/Po positive. | Diagnostic Test: Serological screen and treat<br>* Multi-antigen sero-diagnostic test for measurement of P. vivax antibodies in plasma from finger stick as a means to detect hypnozoite carriers for treatment<br>|
| No Intervention: Routine care<br>Children who screened with sero test and microscopy. A 7-day high dose PQ will be provided only for symptomatic children with microscopic Pv/Po positive. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence reduction | Difference of P. vivax incidence by PCR between children serologically screened and those receiving routine care. | 9 month of follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to recur | Difference in the time-to recur of P. vivax by PCR in SSAT and control arms. | 9 month | 
| Recurrence number | Difference in the number of recurrent P. vivax by PCR in SSAT vs. control arms | 9 month | 
| Recurrent symptomatic P. vivax | Difference in the incidence of recurrent symptomatic P. vivax by microscopy in SSAT vs control arms | 9 month | 
| Seroconversion rate | Seroconversion rate before and after intervention in SSAT and control arms. | 9 month | 
| point-of-care assay performance | Sensitivity and specificity of point-of-care antibody detection test vs. gold standard Luminex assay | one month | 
| Adverse event and severe adverse event | Adverse event (AE) and Severe Adverse Event (SAE) of high dose PQ in schoolchildren. | 9 month | 
| Sahli Hb | Hb level in Sahli's method, Standard G6PD (SD Biosensor Inc., ROK) in comparison with (HemoCue AB, Angelholm, Sweden). | One month | 
| Skin gametocyte | Sensitivity and specificity of microscopic examination to detect parasitemia from the shallow skin vasculature of the ankle (light microscopy-skin/LMS) compared to standard microscopic (light microscopy-finger/LMF) and PCR. | 9 month | 
| Gametocyte duration | Mean duration time of gametocyte in LMS and LMF | 9 month | 
| Hemozoin detection | Sensitivity and specificity of magneto-optical hemozoin detection (MOD) compared to standard malaria detection and PCR. | One month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
serology, screen, treat, recurrent, vivax