Nitrite Infusion in Children With Malaria

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety of intravenous sodium nitrite in African children who have moderately severe malaria.

Detailed Description
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This is a Phase I, open-label, dose-escalation study that will enroll up to 24 patients total, using a 3+3 dose escalation design, with 3 to 6 patients per dose level at up to 4 sequential dose levels (0.16, 0.32, 0.64 and 1.28 mcg/kg/minute). At each dose level patients with moderately severe malaria will receive a single 60-minute intravenous infusion of sodium nitrite in 0.9% sodium chloride. Blood pressure and methemoglobin levels will be closely monitored during the infusion and for 24 hours post infusion. This study will allow a preliminary analysis of the safety of intravenous sodium nitrite in children with moderately severe malaria and is expected to provide preliminary data on its effects on endothelial function. The hypothesis is that sodium nitrite infusion will be safe at low dosage levels. Additionally, since deficiency of nitric oxide is linked to endothelial dysfunction in malaria, there is the hypothesis that sodium nitrite will result in improved markers of endothelial function. Children are the largest group affected by falciparum malaria. The study population will be male children residing in Tanzania, ages 4-10 years old diagnosed with moderately severe malaria, who have been hospitalized for treatment of their malaria at Hubert Kairuki Medical University in Dar es Salaam, Tanzania. Patients will receive standard anti-malaria and supportive care treatment. The study will enroll up to 24 subjects. Participants will receive a single intravenous infusion of sodium nitrite diluted in 0.9% sodium chloride. The infusion will be administered over 60 minutes with an infusion pump. Escala-ting doses of sodium nitrite will be administered to patients in 4 dose level cohorts. Patients will be sequentially enrolled starting at the lowest dose level. Individual patients at the same dose level will also be enrolled sequentially, such that the next patient will not receive treatment until completion of a 24- hour safety monitoring period for the prior patient. Dose assign-ment will be based on the order of study enrollment. The maximum tolerated dose (MTD) is the highest dose level wherein ≤ 1 of 6 evaluable patients experiences dose limiting toxicity (DLT). If the MTD is exceeded at the first dose level, then dosing will cease.

Official Title
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Safety, Feasibility, and Endothelial Effects of Sodium Nitrite Infusion in Children With Falciparum Malaria

Conditions
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Falciparum Malaria

Intervention / Treatment
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* Drug: Sodium Nitrite


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent from parent or legal guardian Males, >4 to 10 years of age Body weight > 12 kg Parasitemia with Plasmodium falciparum including: Positive rapid diagnostic test result: AND >2,500 parasites/microliter by microscopy Diagnosis of MSM, as follows: Clinical syndrome consistent with malaria associated with documented fever (axillary temperature >38C) or reported history of fever in the past 48 hours with no other cause present; AND Exhibiting no WHO warning signs or criteria for SM [27] A negative G6PD deficiency test (careSTART G6PD quantitative biosensor) Requires inpatient parenteral treatment because of inability to tolerate oral therapy Hemoglobin > 8 g/dL (subjects with prior blood transfusion will be eligible). Systolic blood pressure > 85 mmHg Baseline quantitative methemoglobin measurement less than 2% Creatinine less than the upper limit of normal Exclusion Criteria: Female gender Diagnosis of severe malaria Presence of infection, or mixed infection, with non-falciparum strains of malaria Signs of severe malaria[27], including 1 or more of the following: impaired consciousness (Blantyre coma score <3 in children) prostration multiple convulsions (>2 within 24 hours) acidosis (base deficit >8 mEq/L or bicarbonate <15 mmol/L or lactate > 5 mmol/L) hypoglycemia (blood glucose < 40 mg/dL or <2.2 mmol/L) severe anemia (Hb < 5g/dL ) renal impairment (serum creatinine >265 uMol/L or 3 mg/dL; or blood urea >20 mmol/L) jaundice (bilirubin >50 umol or 3 mg/dL with parasite count >100000/ µL) pulmonary edema (including O2sat <92% with RR >30/min) circulatory collapse or shock significant bleeding hyperparasitemia (>10%) Presence of concomitant non-malarial infection Known G6PD deficiency Known chronic illness including renal, cardiac, pulmonary, epilepsy History of a reaction to a substance or medication consisting of dyspnea and cyanosis History of trauma or bleeding in the 2 weeks prior to presentation Clinical impression of disseminated intravascular coagulation Subjects treated with parenteral anti-malarial drugs for more than 12 hours Current use of drugs with oxidative potential (e.g., nitrates, dapsone, primaquine); or drugs that cause hypotension. Known allergic reactions to sodium nitrite injection

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 10 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium Nitrite<br>Single 60-minute intravenous infusion of sodium nitrite in 0.9% sodium chloride at up to 4 sequential dose levels (0.16, 0.32, 0.64 and 1.28 mcg/kg/minute) | Drug: Sodium Nitrite<br>* Single 60 minute infusion at 1 of 4 sequential dose levels (0.16, 0.32, 0.64 and 1.28 mcg/kg/minute). The dose amount will depend on when the participant enters the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as measured by number of subjects with at least one adverse event | Adverse events will be assessed according to the NIH's Table for Grading the Severity of Adult and Pediatric Adverse Events. Events will be numerically graded 1-5; 1 being a mild event and 5 being death | 48 hours post infusion | 
| Percent change in microvascular function/activation for each of the 4 dosing levels by linear regression | We will assess possible covariate relationships. A model will be developed that links the pharmacokinetics with the pharmacodynamic measures of endothelial function and activation | 48 hours post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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falciparum malaria, malaria, Africa, Duke, Tanzania, sodium nitrite, Phase I, infectious disease, hematology