U01AI165321

Optimizing the dose of tafenoquine for the radical cure of Plasmodium vivax malaria in Southeast Asia - Project Summary

In East Asia and Oceania, Plasmodium vivax is the most common cause of malaria. Relapses occur in over half the infections and comprise the main burden of P. vivax malaria. Relapses are the major cause of morbidity, particularly in children and pregnant women.

In recent years, targeted malaria elimination has driven down Plasmodium falciparum malaria in these populous regions, but P. vivax malaria has re-emerged rapidly because of relapse. Preventing relapse (radical cure) requires administration of an 8-aminoquinoline – which until recently meant a 7-14 day course of primaquine.

Tafenoquine is a recently registered slowly eliminated 8-aminoquinoline with the substantial operational advantage of providing single dose radical cure. However, phase 3 randomized controlled trials showed that the currently recommended 300mg adult dose (~5mg/kg) of tafenoquine had low radical curative efficacy against P. vivax malaria. Tafenoquine doses up to 14mg/kg have proved safe and well tolerated in adults and children with >70% G6PD activity.

We obtained the individual participant (N=1102) data from the phase 3 pre-registration trials (DETECTIVE and GATHER; see bibliography, references 22-24). Individual patient data meta-analysis (see bibliography, reference 32) shows clearly that a) the dose response curve is steep around the currently recommended dose (5mg/kg) and b) the odds ratio for P. vivax recurrence (<4 months) is 0.69 (95% CI 0.64 to 0.75; p=10-21) for each mg/kg increase in dose. Thus, increasing the dose by half (i.e., to 7.5mg/kg) is predicted to result in an overall >90% reduction of P. vivax recurrence.

To test this prediction, we propose conducting a multi-center double-blind randomized clinical trial in five countries in the Greater Mekong Sub-Region. Aim 1 compares the radical curative efficacies of the current tafenoquine dose and a 50% higher dose (e.g., 300mg versus 450mg in persons =35kg) in adults and children with acute vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) activity >70%. Relapses will be distinguished from reinfections probabilistically based on parasite genotyping and time to event information. To detect very low-density P. vivax parasitemias which might be suppressed by tafenoquine, ultrasensitive polymerase chain reaction (UPCR) will be performed.

Aim 2 assesses plasma, urine, and red blood cell tafenoquine concentrations and explores potential tafenoquine metabolites. Genotyping for CYP2D6 mutations and measurements of methemoglobinemia will be included as exposure correlates of radical curative efficacy.

Aim 3 assesses safety and tolerability of the higher tafenoquine dose. Tolerability, gastrointestinal symptoms, hematocrit, and elevated blood methemoglobin concentrations will be monitored.

This study will provide definitive evidence to guide tafenoquine dosing for the radical cure of P. vivax malaria. An efficacious, safe, and well-tolerated single dose anti-relapse therapeutic will substantially improve the treatment of P. vivax malaria and accelerate malaria elimination.

University Of Oxford

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

United Kingdom

Foreign

NIAID Clinical Trial Implementation Cooperative Agreement (U01 Clinical Trial Required) (PAR-21-083)

Amendment Since initial award the total obligations have increased 192% from $1,067,899 to $3,119,140.