U01AI155300

Don in Pediatric Cerebral Malaria: A Phase I/II Dose-Escalation Safety Study - Project Summary/Abstract

Cerebral malaria (CM) is defined as an otherwise unexplained coma in a patient with Plasmodium falciparum parasitemia. The condition is common, primarily affects African children less than five years old, and has a large public health impact in endemic areas. Of the ~350,000 children diagnosed annually with CM, 15% die and 30% of survivors have neurological abnormalities at the time of hospital discharge.

The mainstay of treatment is intravenous antimalarial drugs and supportive care. No adjunctive therapy has previously been proven effective in decreasing the high rates of mortality and morbidity in this condition. Our long-term goal is to establish feasible therapies that decrease death and disability rates in this vulnerable population.

We will investigate 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, as a candidate adjunctive therapy for pediatric CM. We identified DON through a rational drug discovery process and tested its efficacy in several pre-clinical studies. Mice with experimental CM have radiographic and pathological abnormalities similar to those seen in human pediatric CM. DON administered to severely clinically ill mice rescues animals clinically, radiographically, and reverses abnormal histopathology.

We will test DON's safety and preliminary efficacy in human pediatric CM. To do so, we will first perform a dose escalation study of DON in healthy Malawian adults and adults with uncomplicated malaria, evaluating safety. After review, we will perform a randomized placebo-controlled double-blind safety and preliminary efficacy study of adjunctive DON in 70 Malawian children with CM. Participants in the first pediatric cohort (N=35) will receive lower doses of adjunctive DON or placebo. Doses of adjunctive DON administered to the second cohort of pediatric participants (N=35) will be informed by pharmacokinetic and safety data gathered from those previously enrolled.

Our primary outcome is the proportion of participants with any Grade 3 or severe adverse events (SAEs). Concurrently with safety studies, DON's preliminary efficacy in pediatric CM will be evaluated using brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and transcranial Doppler (TCD). We hypothesize that Malawian children with CM who receive adjunctive DON will have no increase in mortality or rates of SAEs compared to participants receiving placebo. We hypothesize that children with CM receiving adjunctive DON will have biomarker changes (MRI, EEG, TCD) associated with improved outcome.

In summary, this research is significant because the adjunctive therapy, DON, when used in a murine model of CM, reverses brain swelling, the most important risk factor for death in children with CM. If successful in subsequent human clinical trials, this would be the first adjunctive therapy with a demonstrable effect on decreasing death or disability in this patient population. We anticipate that with widespread dissemination of such a scalable intervention, the public health impact of this devastating infectious disease would finally decrease.

Children's Research Institute

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]

Washington, District Of Columbia 20010 United States

Single Zip Code

NIAID Clinical Trial Implementation Cooperative Agreement (U01 Clinical Trial Required) (PAR-18-633)

Amendment Since initial award the total obligations have increased 412% from $1,088,316 to $5,567,850.