Reducing the Risk of P. Vivax After Falciparum Infections in Co-endemic Areas (PRIMA)

Reducing the Risk of P. Vivax After Falciparum Infections in Co-endemic Areas - a Randomized Controlled Trial

This study is designed as a multi-centre randomized, open label trial to compare the safety and efficacy of a high dose primaquine (PQ) treatment in G6PD normal patients with P. falciparum to reduce the risk of subsequent P. vivax episodes to current standard practice of providing only schizontocidal treatment.

Study Overview

• Status: Completed
• Conditions: Malaria; Vivax Malaria; Falciparum Malaria
• Intervention / Treatment: Drug: primaquine

Detailed Description

Plasmodium vivax forms dormant liver stages that reactivate weeks or months following an acute infection. Recurrent infections can be associated with a febrile illness, a cumulative risk of severe anaemia, direct and indirect mortality, and are the most important source of onward transmission of the parasite. In co-endemic areas, there is a very high risk (up to 50%) of patients representing with P. vivax malaria following treatment of P. falciparum. Hence, in co-endemic regions there is a strong rationale for eradicating P. vivax hypnozoites from the liver in patients presenting with uncomplicated P. falciparum infections.

The recently completed multicentre IMPROV study compared the efficacy of a 7 day primaquine regimen (1.0 mg/kg/day for 7 days) with a 14 day regimen (0.5 mg/kg/day for 14 days). The 7 day PQ regimen was non-inferior to the 14 day regimen and 5-fold more efficacious at reducing P. vivax recurrence than the control.

This study is designed as a multicentre randomized, open label trial to compare the safety and efficacy of a high dose PQ treatment in G6PD normal patients with P. falciparum to reduce the risk of subsequent P. vivax episodes to current standard practice of providing only schizontocidal treatment.

• Study Type: Interventional
• Enrollment (Actual): 500
• Phase: Phase 4

Contacts and Locations

Study Locations

• Bangladesh
  • Upazila, Bangladesh
    • ICDDRB
• Ethiopia
  • Arba Minch, Ethiopia
    • Arba Minch University
• Indonesia
  • Dusun Tenggara, Indonesia
    • Puskesmas Mangili

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• P. falciparum mono-infection
• Fever (axillary temperature ≥37.5⁰C) or history of fever in preceding 48 hours
• Age >1 years (≥ 18 years at the Ethiopia site)
• G6PD normal as defined by the Biosensor (SD Biosensor, ROK) at ≥70% of the adjusted male median (AMM) for each site
• Written informed consent
• Able to comply with all study procedures and timelines

Exclusion Criteria:

• General danger signs or symptoms of severe malaria
• Anaemia, defined as Hb <8g/dl
• Pregnant women as determined by Urine β-HCG pregnancy test
• Breast feeding women
• Known hypersensitivity to any of the drugs given
• Regular use of drugs with haemolytic potential
• Blood transfusion within the last 4 months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PQ7; high dose primaquine regimen over 7 days (1.0 mg/kg/day for 7 days)	Drug: primaquine; Primaquine regimen over 7 days (1.0 mg/kg/day for 7 days)
No Intervention: standard care; As per national guidelines for P. falciparum treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence risk of any P. vivax parasitaemia at day 63	The incidence risk of any P. vivax parasitaemia at day 63	63 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence risk of symptomatic P. vivax parasitaemia at day 63	incidence risk of symptomatic P. vivax parasitaemia at day 63	63 days
Incidence risk of all any P. vivax parasitaemia at day 28 and 42	Incidence risk of all any P. vivax parasitaemia at day 28 and 42	28 and 42 days
Incidence risk of any P. falciparum malaria at day 28, 42 and 63	incidence risk of any P. falciparum malaria at day 28, 42 and 63	28/42/63 days
proportion of patients vomiting their medication within 1 hour of administration	proportion of patients vomiting their medication on the day of enrollment within 1 hour of administration	1 hour
proportion of patients vomiting any of their PQ doses within 1 hour of administration	proportion of patients vomiting any of their PQ doses within 1 hour of administration	7 days
proportion of adverse events and serious adverse events	proportion of adverse events and serious adverse events	63 days
incidence risk of severe anaemia (Hb<5g/dl) and moderately severe anaemia (<7g/dl) and/or the risk for blood transfusion between day 3 and 7	incidence risk of severe anaemia (Hb<5g/dl) and moderately severe anaemia (<7g/dl) and/or the risk for blood transfusion between day 3 and 7	7 days
• The incidence risk of ≥25% fall in haemoglobin since baseline with and without hemoglobinuria at day 3 and day 7	• The incidence risk of ≥25% fall in haemoglobin since baseline with and without hemoglobinuria at day 3 and day 7	7 days
The incidence risk of ≥25% fall in haemoglobin to under 7g/dl with and without hemoglobinuria at day 3 and day 7	The incidence risk of ≥25% fall in haemoglobin to under 7g/dl with and without hemoglobinuria at day 3 and day 7	day 7
Incidence risk of P. falciparum gametocytaemia between day 7 and 63	Incidence risk of P. falciparum gametocytaemia between day 7 and 63	63 days
Parasite clearance on day 1, 2 and 3	Parasite clearance on day 1, 2 and 3	3 days
Fever clearance on day 1, 2 and 3	Fever clearance on day 1, 2 and 3	3 days

Collaborators and Investigators

• Sponsor: Menzies School of Health Research
• Collaborators: International Centre for Diarrhoeal Disease Research, Bangladesh; Addis Ababa University; Tribhuvan University, Nepal; Arba Minch University
• Investigators: Principal Investigator: Kamala Thriemer, MD, Menzies School of Health Research

Publications and helpful links

General Publications

• Thriemer K, Degaga TS, Christian M, Alam MS, Ley B, Hossain MS, Kibria MG, Tego TT, Abate DT, Weston S, Karahalios A, Rajasekhar M, Simpson JA, Rumaseb A, Mnjala H, Lee G, Anose RT, Kidane FG, Woyessa A, Baird K, Sutanto I, Hailu A, Price RN. Reducing the risk of Plasmodium vivax after falciparum infections in co-endemic areas-a randomized controlled trial (PRIMA). Trials. 2022 May 18;23(1):416. doi: 10.1186/s13063-022-06364-z.

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2019
• Primary Completion (Actual): May 14, 2022
• Study Completion (Actual): July 30, 2022

Study Registration Dates

• First Submitted: April 12, 2019
• First Submitted That Met QC Criteria: April 12, 2019
• First Posted (Actual): April 16, 2019

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 19, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Malaria, Vivax; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Primaquine
• Other Study ID Numbers: 19-3288

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study Protocol and Statistical Analysis Plan will be made available to others. Data collected for the study, including individual patient data and the final trial dataset are reserved for the chief investigator and co-investigators of the trial. The trial will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Trial results will be published in peer-reviewed open access journals and disseminated to trial stakeholders, including participants, as per ethical guidelines.
• IPD Sharing Access Criteria: The data are available for access via the WorldWide Antimalarial Resistance Network (WWARN.org). Requests for access will be reviewed by a Data Access Committee to ensure that use of data protects the interests of the participants and researchers according to the terms of ethics approval and principles of equitable data sharing. Requests can be submitted by email to malariaDAC@iddo.org via the Data Access Form available at WWARN.org/accessing-data. The WWARN is registered with the Registry of Research Data Repositories (re3data.org).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No