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Nitrite Infusion in Children With Malaria

12. mars 2021 oppdatert av: Duke University

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

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

Studieoversikt

Status

Tilbaketrukket

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

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.

Studietype

Intervensjonell

Fase

  • Fase 1

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

  • Tanzania
      • Dar es Salaam, Tanzania
        • Hubert Kairuki Memorial University

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

4 år til 10 år (Barn)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Mann

Beskrivelse

Inclusion Criteria:

  1. Provision of signed and dated informed consent from parent or legal guardian
  2. Males, >4 to 10 years of age
  3. Body weight > 12 kg

  4. Parasitemia with Plasmodium falciparum including:

    1. Positive rapid diagnostic test result: AND
    2. >2,500 parasites/microliter by microscopy

  5. 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]
  6. A negative G6PD deficiency test (careSTART G6PD quantitative biosensor)
  7. Requires inpatient parenteral treatment because of inability to tolerate oral therapy
  8. Hemoglobin > 8 g/dL (subjects with prior blood transfusion will be eligible).
  9. Systolic blood pressure > 85 mmHg
  10. Baseline quantitative methemoglobin measurement less than 2%
  11. Creatinine less than the upper limit of normal

Exclusion Criteria:

  1. Female gender
  2. Diagnosis of severe malaria
  3. Presence of infection, or mixed infection, with non-falciparum strains of malaria

  4. 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%)
  5. Presence of concomitant non-malarial infection
  6. Known G6PD deficiency
  7. Known chronic illness including renal, cardiac, pulmonary, epilepsy
  8. History of a reaction to a substance or medication consisting of dyspnea and cyanosis
  9. History of trauma or bleeding in the 2 weeks prior to presentation
  10. Clinical impression of disseminated intravascular coagulation
  11. Subjects treated with parenteral anti-malarial drugs for more than 12 hours
  12. Current use of drugs with oxidative potential (e.g., nitrates, dapsone, primaquine); or drugs that cause hypotension.
  13. Known allergic reactions to sodium nitrite injection

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: N/A
  • Intervensjonsmodell: Enkeltgruppeoppdrag
  • Masking: Ingen (Open Label)

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: Sodium Nitrite
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)
Legemiddel: Sodium Nitrite
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

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Safety as measured by number of subjects with at least one adverse event
Tidsramme: 48 hours post infusion
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
Tidsramme: 48 hours post infusion
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

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Duke University

Samarbeidspartnere

National Heart, Lung, and Blood Institute (NHLBI)

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Forventet)

1. juni 2021

Primær fullføring (Forventet)

1. oktober 2021

Studiet fullført (Forventet)

1. oktober 2021

Datoer for studieregistrering

Først innsendt

27. februar 2020

Først innsendt som oppfylte QC-kriteriene

27. februar 2020

Først lagt ut (Faktiske)

28. februar 2020

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

16. mars 2021

Siste oppdatering sendt inn som oppfylte QC-kriteriene

12. mars 2021

Sist bekreftet

1. januar 2021

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • Pro00100364
  • R01HL130763 (U.S. NIH-stipend/kontrakt)

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

NEI

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Ja

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

produkt produsert i og eksportert fra USA

Ja

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Kliniske studier på Falciparum malaria

Kliniske studier på Sodium Nitrite

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Sponsorer og samarbeidspartnere

Medisinsk tilstand

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