Oxygen Therapy for Children With Moderate Hypoxemia in Malawi

Pneumonia Clinical Trial

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Official title:

Oxygen Therapy for Children With Moderate Hypoxemia in Malawi: Pilot Randomized Control Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06176664
• Other study ID #: IRB00421624
• Status: Not yet recruiting
• Phase: N/A
• Start date: April 2024
• Est. completion date: July 2024

Study information

• Verified date: December 2023
• Source: Johns Hopkins University
• Contact: Eric D McCollum, MD, MPH
• Phone: 410-955-2035
• Email: emccol3[@]jhmi.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this pilot clinical trial is to compare standard of care, low-flow oxygen, and high-flow nasal canula oxygen in pediatric patients aged 1-59 months with pneumonia and an oxygen saturation of 90-93% in Malawi. The main question it aims to answer is:

• Does the protocol for the randomized control trial work well?

• Can the researchers safely conduct the protocol for the trial?

Participants will be randomly assigned to one of the three groups (normal care without oxygen, low-flow oxygen, and high-flow nasal cannula oxygen) and treated with that therapy in the hospital. Researchers will look at the ability to safely conduct each part of the study.

Description:

Pneumonia is the leading infectious cause of under 5-year-old deaths globally and responsible for >50% of deaths in Africa. The World Health Organization (WHO) defines low blood oxygen saturation (SpO2) levels (hypoxemia) as 90%. Hypoxemia is identified in 31% of child pneumonia cases in Africa and is a key marker of elevated mortality risk. When children are hypoxemic, the WHO recommends oxygen treatment. Importantly, the WHO threshold of 90% for hypoxemia was based on concerns over limited oxygen supply and hospital over-crowding in low- and middle-income countries (LMICs), rather than quality evidence. In most LMICs, low oxygen flow is the mainstay of oxygen delivery. Recently, in high-income settings high-flow nasal cannula (HFNC) oxygen has emerged as a safe and effective alternative. HFNC oxygen delivers higher flow warmed, humidified gas via nasal prongs to reverse hypoxemia, and potentially improve outcomes.

Recent evidence challenges whether the WHO & 90% hypoxemia threshold is optimal for identifying all children at higher risk of mortality in LMICs. One meta-analysis from 13 LMICs reported 3.66-fold-higher odds of death (95% confidence interval (CI), 1.42, 9.47) for children with a SpO2 93%. The investigators research from Malawi and Bangladesh established children with pneumonia and SpO2 between 90-93% (moderate hypoxemia) is common, and, compared to higher SpO2 levels, conveys higher mortality risk. To date, African children with a SpO2 90-93% are not recommended for oxygen treatment. Observational data from Malawi found children with moderate hypoxemia and treated with oxygen had higher survival than those referred with a SpO2 90%. Currently, no randomized trials have determined whether low flow oxygen or HFNC oxygen treatment reduces the mortality of children with moderate hypoxemia (SpO2 90-93%) in African LMICs.

Aim 1: Conduct a pilot open label, three armed, parallel, randomized controlled trial (RCT) comparing standard care, low-flow oxygen, and HFNC oxygen for children with clinical pneumonia and a SpO2 90-93% to determine feasibility of a larger trial. The investigators hypothesize it will be feasible to recruit, randomize, treat, and safely follow-up all participants. Children with SpO2 90-93% will be randomized 1:1:1 to standard care without oxygen (controls), low flow oxygen (intervention #1), or HFNC oxygen (intervention #2). The primary outcome will be feasibility, defined as the proportion of enrolled children with 2 protocol violations. Secondary outcomes include consent refusal, intervention efficacy, participant attrition, and safety.

Aim 2: Determine the prevalence of young Malawian children with a SpO2 90-93% at the designated study hospital. The investigators hypothesize a SpO2 90-93% will be common among children presenting to the trial hospital. The investigators will measure the SpO2 of all children under-five years old (not limited to pneumonia cases) presenting to the hospital 1 week per month over 12-months. Conservatively assuming an average volume of 30 children per day, based on prior data, the investigators will generate 1,400 SpO2 measurements.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 21
• Est. completion date: July 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 59 Months

Eligibility

Inclusion Criteria:

• 1-59 months of age

• Pneumonia (as defined by the World Health Organization)

• Oxygen saturation 90-93% without oxygen

Exclusion Criteria:

• Emergency signs (signs of severe illness as defined by the World Health Organization) including:

• absent or obstructed breathing,

• severe respiratory distress,

• shock,

• decreased mental status,

• convulsions, or

• severe dehydration

Related Conditions & MeSH terms

• Hypoxia
• Pneumonia

Intervention

Device:
• Low flow oxygen
Standard nasal cannula oxygen up to 2 liters/minute
• High-flow nasal cannula oxygen
High-flow nasal cannula with heating and humidification up to 2 liters/kilogram/minute

Locations

Country	Name	City	State
Malawi	Salima District Hospital	Salima	Central Region

Sponsors (3)

Lead Sponsor	Collaborator
Johns Hopkins University	Thrasher Research Fund, University of North Carolina Project- Lilongwe, Malawi

Country where clinical trial is conducted

Malawi, 

References & Publications (24)

Allardet-Servent J, Sicard G, Metz V, Chiche L. Benefits and risks of oxygen therapy during acute medical illness: Just a matter of dose! Rev Med Interne. 2019 Oct;40(10):670-676. doi: 10.1016/j.revmed.2019.04.003. Epub 2019 May 1. — View Citation

Chaparro CM, Suchdev PS. Anemia epidemiology, pathophysiology, and etiology in low- and middle-income countries. Ann N Y Acad Sci. 2019 Aug;1450(1):15-31. doi: 10.1111/nyas.14092. Epub 2019 Apr 22. — View Citation

Colbourn T, King C, Beard J, Phiri T, Mdala M, Zadutsa B, Makwenda C, Costello A, Lufesi N, Mwansambo C, Nambiar B, Hooli S, French N, Bar Zeev N, Qazi SA, Bin Nisar Y, McCollum ED. Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: A data linkage study. PLoS Med. 2020 Oct 23;17(10):e1003300. doi: 10.1371/journal.pmed.1003300. eCollection 2020 Oct. — View Citation

Hooli S, Colbourn T, Lufesi N, Costello A, Nambiar B, Thammasitboon S, Makwenda C, Mwansambo C, McCollum ED, King C. Predicting Hospitalised Paediatric Pneumonia Mortality Risk: An External Validation of RISC and mRISC, and Local Tool Development (RISC-Malawi) from Malawi. PLoS One. 2016 Dec 28;11(12):e0168126. doi: 10.1371/journal.pone.0168126. eCollection 2016. Erratum In: PLoS One. 2018 Feb 22;13(2):e0193557. — View Citation

Hooli S, King C, Zadutsa B, Nambiar B, Makwenda C, Masache G, Lufesi N, Mwansambo C, Malla L, Costello A, Colbourn T, McCollum ED. The Epidemiology of Hypoxemic Pneumonia among Young Infants in Malawi. Am J Trop Med Hyg. 2020 Mar;102(3):676-683. doi: 10.4269/ajtmh.19-0516. — View Citation

Hutchings FA, Hilliard TN, Davis PJ. Heated humidified high-flow nasal cannula therapy in children. Arch Dis Child. 2015 Jun;100(6):571-5. doi: 10.1136/archdischild-2014-306590. Epub 2014 Dec 1. — View Citation

Kawaguchi A, Yasui Y, deCaen A, Garros D. The Clinical Impact of Heated Humidified High-Flow Nasal Cannula on Pediatric Respiratory Distress. Pediatr Crit Care Med. 2017 Feb;18(2):112-119. doi: 10.1097/PCC.0000000000000985. — View Citation

King C, Zadutsa B, Banda L, Phiri E, McCollum ED, Langton J, Desmond N, Qazi SA, Nisar YB, Makwenda C, Hildenwall H. Prospective cohort study of referred Malawian children and their survival by hypoxaemia and hypoglycaemia status. Bull World Health Organ. 2022 May 1;100(5):302-314B. doi: 10.2471/BLT.21.287265. Epub 2022 Mar 25. — View Citation

Lazzerini M, Sonego M, Pellegrin MC. Hypoxaemia as a Mortality Risk Factor in Acute Lower Respiratory Infections in Children in Low and Middle-Income Countries: Systematic Review and Meta-Analysis. PLoS One. 2015 Sep 15;10(9):e0136166. doi: 10.1371/journal.pone.0136166. eCollection 2015. — View Citation

Lin J, Zhang Y, Xiong L, Liu S, Gong C, Dai J. High-flow nasal cannula therapy for children with bronchiolitis: a systematic review and meta-analysis. Arch Dis Child. 2019 Jun;104(6):564-576. doi: 10.1136/archdischild-2018-315846. Epub 2019 Jan 17. — View Citation

Liu L, Oza S, Hogan D, Chu Y, Perin J, Zhu J, Lawn JE, Cousens S, Mathers C, Black RE. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet. 2016 Dec 17;388(10063):3027-3035. doi: 10.1016/S0140-6736(16)31593-8. Epub 2016 Nov 11. Erratum In: Lancet. 2017 May 13;389(10082):1884. — View Citation

Luo J, Duke T, Chisti MJ, Kepreotes E, Kalinowski V, Li J. Efficacy of High-Flow Nasal Cannula vs Standard Oxygen Therapy or Nasal Continuous Positive Airway Pressure in Children with Respiratory Distress: A Meta-Analysis. J Pediatr. 2019 Dec;215:199-208.e8. doi: 10.1016/j.jpeds.2019.07.059. Epub 2019 Sep 27. — View Citation

McCollum ED, Ahmed S, Roy AD, Chowdhury NH, Schuh HB, Rizvi SJR, Hanif AAM, Khan AM, Mahmud A, Pervaiz F, Harrison M, Reller ME, Simmons N, Quaiyum A, Begum N, Santosham M, Checkley W, Moulton LH, Baqui AH; Projahnmo Study Group in Bangladesh. Effectiveness of the 10-valent pneumococcal conjugate vaccine against radiographic pneumonia among children in rural Bangladesh: A case-control study. Vaccine. 2020 Sep 29;38(42):6508-6516. doi: 10.1016/j.vaccine.2020.08.035. Epub 2020 Aug 29. — View Citation

McCollum ED, Bjornstad E, Preidis GA, Hosseinipour MC, Lufesi N. Multicenter study of hypoxemia prevalence and quality of oxygen treatment for hospitalized Malawian children. Trans R Soc Trop Med Hyg. 2013 May;107(5):285-92. doi: 10.1093/trstmh/trt017. — View Citation

McCollum ED, Ginsburg AS. Outpatient Management of Children With World Health Organization Chest Indrawing Pneumonia: Implementation Risks and Proposed Solutions. Clin Infect Dis. 2017 Oct 16;65(9):1560-1564. doi: 10.1093/cid/cix543. — View Citation

McCollum ED, King C, Hammitt LL, Ginsburg AS, Colbourn T, Baqui AH, O'Brien KL. Reduction of childhood pneumonia mortality in the Sustainable Development era. Lancet Respir Med. 2016 Dec;4(12):932-933. doi: 10.1016/S2213-2600(16)30371-X. Epub 2016 Nov 12. No abstract available. — View Citation

McCollum ED, Mvalo T, Eckerle M, Smith AG, Kondowe D, Makonokaya D, Vaidya D, Billioux V, Chalira A, Lufesi N, Mofolo I, Hosseinipour M. Bubble continuous positive airway pressure for children with high-risk conditions and severe pneumonia in Malawi: an open label, randomised, controlled trial. Lancet Respir Med. 2019 Nov;7(11):964-974. doi: 10.1016/S2213-2600(19)30243-7. Epub 2019 Sep 24. — View Citation

McKiernan C, Chua LC, Visintainer PF, Allen H. High flow nasal cannulae therapy in infants with bronchiolitis. J Pediatr. 2010 Apr;156(4):634-8. doi: 10.1016/j.jpeds.2009.10.039. Epub 2009 Dec 29. — View Citation

Moreel L, Proesmans M. High flow nasal cannula as respiratory support in treating infant bronchiolitis: a systematic review. Eur J Pediatr. 2020 May;179(5):711-718. doi: 10.1007/s00431-020-03637-0. Epub 2020 Mar 31. — View Citation

Rahman AE, Hossain AT, Nair H, Chisti MJ, Dockrell D, Arifeen SE, Campbell H. Prevalence of hypoxaemia in children with pneumonia in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Glob Health. 2022 Mar;10(3):e348-e359. doi: 10.1016/S2214-109X(21)00586-6. — View Citation

Sonego M, Pellegrin MC, Becker G, Lazzerini M. Risk factors for mortality from acute lower respiratory infections (ALRI) in children under five years of age in low and middle-income countries: a systematic review and meta-analysis of observational studies. PLoS One. 2015 Jan 30;10(1):e0116380. doi: 10.1371/journal.pone.0116380. eCollection 2015. — View Citation

Subhi R, Adamson M, Campbell H, Weber M, Smith K, Duke T; Hypoxaemia in Developing Countries Study Group. The prevalence of hypoxaemia among ill children in developing countries: a systematic review. Lancet Infect Dis. 2009 Apr;9(4):219-27. doi: 10.1016/S1473-3099(09)70071-4. — View Citation

Tortosa F, Izcovich A, Carrasco G, Varone G, Haluska P, Sanguine V. High-flow oxygen nasal cannula for treating acute bronchiolitis in infants: A systematic review and meta-analysis. Medwave. 2021 May 12;21(4):e8190. doi: 10.5867/medwave.2021.04.8190. English, Spanish. — View Citation

Walsh BK, Smallwood CD. Pediatric Oxygen Therapy: A Review and Update. Respir Care. 2017 Jun;62(6):645-661. doi: 10.4187/respcare.05245. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Treatment failure rate	Determine point estimates and 95% confidence intervals for treatment failure rate for standard of care, conventional low-flow oxygen, and HFNC oxygen arms for children with WHO-defined pneumonia and moderate hypoxemia	Enrollment up to 14 days
Other	Mortality rate	Determine point estimates and 95% confidence intervals for mortality rate for standard of care, conventional low-flow oxygen, and HFNC oxygen arms for children with WHO-defined pneumonia and moderate hypoxemia	Enrollment up to 14 days
Other	Number of Serious Adverse Events	Determine point estimate and 95% confidence interval for the rate of serious adverse events (SAEs) for standard of care, conventional low-flow oxygen, and HFNC oxygen arms for children with WHO-defined pneumonia and moderate hypoxemia	Enrollment up to 14 days
Other	Hospital length of stay (days)	Determine mean hospital length of stay with standard deviation for standard of care, conventional low-flow oxygen, and HFNC oxygen arms for children with World Health Organization (WHO)-defined pneumonia and moderate hypoxemia	Enrollment through hospital discharge up to 30 days
Primary	Feasibility of study protocol as assessed by protocol violations	Determine overall protocol fidelity, defined as the percentage of enrolled children with < 2 protocol violations, of an open-label, three arm randomized controlled trial comparing low-flow and high-flow nasal cannula (HFNC) oxygen to standard of care without oxygen therapy	Enrollment up to 14 days
Secondary	Caregiver Trial Acceptability	Determine caregiver trial acceptability, defined as the percentage of caregivers of eligible children who consent to study participation.	Day of screening and enrollment
Secondary	Feasibility of screening and enrollment as assessed by percentage of inclusion and exclusion violations	Determine the feasibility of screening and enrollment, defined as the percentage of enrolled children with no inclusion or exclusion criteria violations.	Day of screening and enrollment
Secondary	Feasibility of randomization as assessed by percentage of children receiving intervention	Determine feasibility of randomization, defined as percentage of children actively receiving the assigned intervention within 1 hours of randomization	1 hour after randomization
Secondary	Fidelity to treatment failure study definition as assessed by percentage of children with correct treatment failure classification	Determine fidelity to treatment failure study definition, defined as the percentage of children with a correct treatment failure classification	Enrollment up to 14 days
Secondary	Fidelity to respiratory supportive care protocol as assessed by percentage of children without a respiratory support protocol violation	Determine fidelity to respiratory supportive care protocol, defined as the proportion of children without a respiratory support protocol violation	Enrollment up to 14 days
Secondary	Feasibility of at home follow up as assessed by percentage of participants followed up at home	Determine feasibility of at home follow up defined as percentage of patients successfully followed up at home with assessment of vital status	Enrollment up to 14 days