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Nitrite Infusion in Children With Malaria

Primary Purpose

Falciparum Malaria

Status

Withdrawn

Phase

Phase 1

Locations

Tanzania

Study Type

Interventional

Intervention

Sodium Nitrite

About this trial

This is an interventional treatment trial for Falciparum Malaria focused on measuring falciparum malaria, malaria, Africa, Duke, Tanzania, sodium nitrite, Phase I, infectious disease, hematology

Eligibility Criteria

4 Years - 10 Years (Child)MaleDoes not accept healthy volunteers

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:
1. Positive rapid diagnostic test result: AND
2. >2,500 parasites/microliter by microscopy
Diagnosis of MSM, as follows:
1. 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
2. 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

Sites / Locations

Hubert Kairuki Memorial University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sodium Nitrite

Arm Description

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)

Outcomes

Primary Outcome Measures

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

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

Secondary Outcome Measures

Full Information

NCT ID

NCT04289558

First Posted

February 27, 2020

Last Updated

March 12, 2021

Sponsor

Duke University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT04289558

Brief Title

Nitrite Infusion in Children With Malaria

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2021

Overall Recruitment Status

Withdrawn

Why Stopped

current grant expiration in May, insufficient funds remaining, travel restrictions, COVID-19 restrictions in Tanzania, etc.

Study Start Date

June 1, 2021 (Anticipated)

Primary Completion Date

October 1, 2021 (Anticipated)

Study Completion Date

October 1, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Duke University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Falciparum Malaria

Keywords

falciparum malaria, malaria, Africa, Duke, Tanzania, sodium nitrite, Phase I, infectious disease, hematology

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sodium Nitrite

Arm Type

Experimental

Arm Description

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)

Intervention Type

Drug

Intervention Name(s)

Sodium Nitrite

Intervention Description

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

Primary Outcome Measure Information:

Title

Safety as measured by number of subjects with at least one adverse event

Description

Time Frame

48 hours post infusion

Title

Percent change in microvascular function/activation for each of the 4 dosing levels by linear regression

Description

We will assess possible covariate relationships. A model will be developed that links the pharmacokinetics with the pharmacodynamic measures of endothelial function and activation

Time Frame

48 hours post infusion

10. Eligibility

Sex

Male

Gender Based

Yes

Gender Eligibility Description

Presence of G6PD deficiency increases the risk of RBC hemolysis occurring with administration of sodium nitrite and occurrence of methemoglobinemia. G6PD deficiency is an X-linked trait, thus males are either positive or negative, while females can exhibit a range of deficiency with heterozygotes commonly having an intermediate level

Minimum Age & Unit of Time

4 Years

Maximum Age & Unit of Time

10 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Facility Information:

Facility Name

Hubert Kairuki Memorial University

City

Dar es Salaam

Country

Tanzania

12. IPD Sharing Statement

Plan to Share IPD

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Nitrite Infusion in Children With Malaria

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