Effect of Liver and Blood-stage Treatment on Subsequent Plasmodium Reinfection and Morbidity

Host and Parasites Factors Contributing to Risk of Plasmodium Re-infection and Morbidity in Elementary School Children in Maprik, East Sepik Province

This study specifically seeks to quantify the contribution of relapes to the burden of P. vivax infections and disease by determining on the effect of radical pre-erythrocytic and erythrocytic clearance on subsequent rates of Plasmodium spp. infection and disease in children aged 5-10 years in a treatment to re-infection study design. In order the clear liver-stage/blood-stages G6PD-normal children were randomised to receive Chloroquine (3 days, standard dose) and Coartem (3 days, standard dose) plus either i) primaquine (20 days, 0.5mg/kg) or ii) placebo (20days). These drugs were administered over a period of 4 weeks.

In addition to this epidemiological data, the study will assess the natural acquisition of cellular and humoral immune responses to P. falciparum and P. vivax, thus assisting in the determination of correlates of clinical immunity to P. falciparum and P. vivax in PNG children aged 5-10 years.

These data will not only be essential for development of future vaccines against P. vivax and P falciparum but provide invaluable insight into the contribution of long-lasting liver-stages to the force of infection with P. vivax that will contribute towards designing more rational approaches to the treatment of P. vivax both in the context of case management and future attempts at elimination.

Study Overview

• Status: Completed
• Conditions: Plasmodium Falciparum Infection; Plasmodium Vivax Infection; Plasmodium Vivax Clinical Episode; Plasmodium Falciparum Clinical Episode
• Intervention / Treatment: Drug: Primaquine; Drug: Chloroquine; Drug: Artemether Lumefantrine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 524
• Phase: Phase 4

Contacts and Locations

Study Locations

• Papua New Guinea
  • East Sepik Province
    • Maprik, East Sepik Province, Papua New Guinea
      • PNG Institute of Medical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• aged 5-10 years (±3 months)
• permanent residents of the area
• absence of history of hypersensitivity reactions to the drugs

Exclusion Criteria:

• chronic illness
• severe malnutrition (weight-for-age nutritional Z score [WAZ] <60th percentile)
• severe anemia (Hb <5 g/dL),
• G-6-PD deficiency (<60% G-6-PD activity)
• permanent disability, which prevents or impedes study participation. Any 1 or more of the criteria is sufficient to exclude study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Primaquine; Primaquine, 0.5mg/kg/day, 20 days directly observed treatment Chloroquine, 25mg/kg total dose, divided over 3 days directly observed treatment Artemether-Lumefantrine, 3 days BD	Drug: Primaquine; Drug: Chloroquine; Drug: Artemether Lumefantrine; Other Names: Coartem
Placebo Comparator: Placebo; Placebo, 20 days directly observed treatment Chloroquine, mg/kg, 3 days directly observed treatment Artemether-Lumefantrine, 3 days BD	Drug: Chloroquine; Drug: Artemether Lumefantrine; Other Names: Coartem; Drug: Placebo; Sugar pills, appearance identical to Primaquine tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to first or only Plasmodium vivax infection by light microscopy and PCR	8 months post-baseline
Time to first or only clinical P. vivax episode	8 months post-baseline

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to first or only P. falciparum infection by light microscopy and PCR	8 months post-baseline
Time to first or only P. ovale infection by light microscopy and PCR	8 months post-baseline
Time to first or only P. malariae infection by light microscopy and PCR	8 months post-baseline

Collaborators and Investigators

• Sponsor: Papua New Guinea Institute of Medical Research
• Collaborators: Swiss Tropical & Public Health Institute; Walter and Eliza Hall Institute of Medical Research; Barcelona Centre for International Health Research
• Investigators: Principal Investigator: Ivo Mueller, PhD, Walter and Eliza Hall Institute of Medical Research; Centre de Recerca en Salut Internacional de Barcelona (CRESIB); Principal Investigator: Inoni Betuela, MD PhD, PNG Institute of Medical Research; Principal Investigator: Louis Schofield, PhD, Walter and Eliza Hall Institute of Medical Research

Publications and helpful links

General Publications

• Holzschuh A, Gruenberg M, Hofmann NE, Wampfler R, Kiniboro B, Robinson LJ, Mueller I, Felger I, White MT. Co-infection of the four major Plasmodium species: Effects on densities and gametocyte carriage. PLoS Negl Trop Dis. 2022 Sep 13;16(9):e0010760. doi: 10.1371/journal.pntd.0010760. eCollection 2022 Sep.
• Hofmann NE, Karl S, Wampfler R, Kiniboro B, Teliki A, Iga J, Waltmann A, Betuela I, Felger I, Robinson LJ, Mueller I. The complex relationship of exposure to new Plasmodium infections and incidence of clinical malaria in Papua New Guinea. Elife. 2017 Sep 1;6:e23708. doi: 10.7554/eLife.23708.
• Wampfler R, Hofmann NE, Karl S, Betuela I, Kinboro B, Lorry L, Silkey M, Robinson LJ, Mueller I, Felger I. Effects of liver-stage clearance by Primaquine on gametocyte carriage of Plasmodium vivax and P. falciparum. PLoS Negl Trop Dis. 2017 Jul 21;11(7):e0005753. doi: 10.1371/journal.pntd.0005753. eCollection 2017 Jul.
• Robinson LJ, Wampfler R, Betuela I, Karl S, White MT, Li Wai Suen CS, Hofmann NE, Kinboro B, Waltmann A, Brewster J, Lorry L, Tarongka N, Samol L, Silkey M, Bassat Q, Siba PM, Schofield L, Felger I, Mueller I. Strategies for understanding and reducing the Plasmodium vivax and Plasmodium ovale hypnozoite reservoir in Papua New Guinean children: a randomised placebo-controlled trial and mathematical model. PLoS Med. 2015 Oct 27;12(10):e1001891. doi: 10.1371/journal.pmed.1001891. eCollection 2015 Oct.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: May 19, 2014
• First Submitted That Met QC Criteria: May 19, 2014
• First Posted (Estimate): May 21, 2014

Study Record Updates

• Last Update Posted (Estimate): May 21, 2014
• Last Update Submitted That Met QC Criteria: May 19, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Plasmodium falciparum; Plasmodium vivax; Primaquine; Hypnozoites; Liver-stage; Blood-stage
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Infections; Communicable Diseases; Malaria; Anti-Infective Agents; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Amebicides; Chloroquine; Lumefantrine; Artemether; Primaquine; Artemether, Lumefantrine Drug Combination
• Other Study ID Numbers: 07200734