First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition

NCT03174236 | Unknown Phase 3 DMC

• 3 other identifiers: KEMRI/SERU/CGMR-C/063/33991-17105431/Z/14/Z
• Study Type: interventional
• Target: 2,000
• Locations: 2 countries
• Sites: 8

Brief Summary

Children with severe malnutrition who are admitted sick to hospitals have a high mortality(death rate), usually because of infection. All children with severe malnutrition admitted to hospitals are treated with antibiotics(medication used to kill bacteria). However, the current antibiotics used in hospitals may not be the most effective. It is possible that the antibiotics that are currently used after initial antibiotics should be used first. No studies have been carried out to determine if the current antibiotics used for treating malnourished children who are sick and admitted in hospital are the most appropriate. The aim of this study is to find out if a changed antibiotic system for children with malnutrition is safe, reduces the risk of death and improves nutritional recovery.

Conditions

Malnutrition Severe; Antibiotic Resistance; Antibiotic Toxicity

Outcome Measures

Primary Outcomes (1)

• Mortality

  Mortality is measured using source documents from medical records, verbal autopsy, or death or burial certificates in the community.

  90 days after enrolment.

Secondary Outcomes (13)

• Mortality during the first 7 days

  7 days

• Mortality during the first 30 days

  7 days

• Index admission inpatient mortality

  Through index hospital admission, an average of 7 days.

• Mortality after discharge from index admission.

  90 days after enrolment

• Grade 4 toxicity

  Up to 7 days following enrolment

Study Arms (4)

Ceftriaxone

EXPERIMENTAL

Arm 1 IV Ceftriaxone: Participants in this group receive 80mg/kg IV ceftriaxone once a day for a minimum of 48 hours and a usual maximum of seven days.

Drug: Ceftriaxone

Benzyl penicillin plus gentamicin

ACTIVE COMPARATOR

Arm 2 IV Benzyl penicillin plus gentamicin (usual care): Participants in this group receive 50 000 U/kg IV benzyl penicillin every six hours for a minimum of two days and a maximum of seven days.

Drug: Benzyl penicillin; Drug: Gentamicin

Metronidazole

EXPERIMENTAL

Arm 1 Metronidazole: Participants receive 10 to 16 mg/kg oral metronidazole twice a day for seven days.

Drug: Metronidazole

Placebo

PLACEBO COMPARATOR

Arm 2 Placebo: Participants receive an oral placebo dose to match that for Metronidazole twice a day for seven days.

Other: Placebo

Interventions

Ceftriaxone DRUG

Ceftriaxone a third-generation cephalosporin. Ceftriaxone is active against a broad spectrum of Gram positive and Gram negative bacteria.

Ceftriaxone

Benzyl penicillin DRUG

The currently recommended first-line antibiotics for the treatment of severe acute malnutrition are gentamicin plus ampicillin or penicillin.

Benzyl penicillin plus gentamicin

Metronidazole DRUG

The WHO guidelines recommend that Metronidazole may be given in addition to broad-spectrum antibiotics, "however, the efficacy of this treatment has not been established in clinical trials."

Metronidazole

Placebo OTHER

Suspension manufactured to match metronidazole

Placebo

Gentamicin DRUG

The currently recommended first-line antibiotics for the treatment of severe acute malnutrition are gentamicin plus ampicillin or penicillin.

Benzyl penicillin plus gentamicin

Eligibility Criteria

• Age: 2 Months - 13 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age 2 months to 13 years inclusive
• Severe malnutrition defined as:
• kwashiorkor at any age or:
• for children between 2 to 5 months: MUAC \<11cm or weight-for length Z score \<-3
• for children between 6 to 59 months: MUAC \<11.5cm or weight-for length Z score \<-3
• for children between 5 to 13 years: MUAC \<11.5cm or BMI-for-age Z score \<-3
• Admitted to hospital and eligible for intravenous antibiotics according to WHO guidelines
• Planning to remain within the hospital catchment area and willing to come for specified visits during the 90 day follow up period
• Informed consent provided by the parents/guardian

You may not qualify if:

• Known allergy or contraindication to penicillin, gentamicin, ceftriaxone or metronidazole
• A specific and documented clinical indication for another class of antibiotic
• Previously enrolled in this study

Sponsors & Collaborators

• University of Oxford: lead
• University College, London: collaborator
• London School of Hygiene and Tropical Medicine: collaborator
• Swansea Trials Unit: collaborator
• Kenya Medical Research Institute: collaborator
• KEMRI-Wellcome Trust Collaborative Research Program: collaborator

Study Sites (8)

Kemri Wellcome Trust Research Programme

Kilifi, Coast Province, 80108, Kenya

Location

Kilifi County Hospital

Kilifi, Coast, 80108, Kenya

Location

KEMRI WT Clinical Trials Facility

Kilifi, 80800, Kenya

Location

Kilifi County Hospital

Kilifi, Kenya

Location

Coast General Hospital - Study site

Mombasa, Kenya

Location

Mbagathi District Hospital

Nairobi, Kenya

Location

Mbagathi Hospital

Nairobi, Kenya

Location

Mbale Regional Referral Hospital

Mbale, Uganda

Location

Related Publications (25)

• Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, Ezzati M, Grantham-McGregor S, Katz J, Martorell R, Uauy R; Maternal and Child Nutrition Study Group. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013 Aug 3;382(9890):427-451. doi: 10.1016/S0140-6736(13)60937-X. Epub 2013 Jun 6.

  PMID: 23746772 BACKGROUND

• Acquah SE, Quaye L, Sagoe K, Ziem JB, Bromberger PI, Amponsem AA. Susceptibility of bacterial etiological agents to commonly-used antimicrobial agents in children with sepsis at the Tamale Teaching Hospital. BMC Infect Dis. 2013 Feb 18;13:89. doi: 10.1186/1471-2334-13-89.

  PMID: 23419199 BACKGROUND

• Talbert A, Thuo N, Karisa J, Chesaro C, Ohuma E, Ignas J, Berkley JA, Toromo C, Atkinson S, Maitland K. Diarrhoea complicating severe acute malnutrition in Kenyan children: a prospective descriptive study of risk factors and outcome. PLoS One. 2012;7(6):e38321. doi: 10.1371/journal.pone.0038321. Epub 2012 Jun 4.

  PMID: 22675542 BACKGROUND

• Heikens GT, Bunn J, Amadi B, Manary M, Chhagan M, Berkley JA, Rollins N, Kelly P, Adamczick C, Maitland K, Tomkins A; Blantyre Working Group. Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet. 2008 Apr 12;371(9620):1305-7. doi: 10.1016/S0140-6736(08)60565-6. No abstract available.

  PMID: 18406865 BACKGROUND

• Chimhuya S, Kambarami RA, Mujuru H. The levels of malnutrition and risk factors for mortality at Harare Central Hospital-Zimbabwe: an observation study. Cent Afr J Med. 2007 May-Aug;53(5-8):30-4. doi: 10.4314/cajm.v53i5-8.62612.

  PMID: 20355679 BACKGROUND

• Fergusson P, Tomkins A. HIV prevalence and mortality among children undergoing treatment for severe acute malnutrition in sub-Saharan Africa: a systematic review and meta-analysis. Trans R Soc Trop Med Hyg. 2009 Jun;103(6):541-8. doi: 10.1016/j.trstmh.2008.10.029. Epub 2008 Dec 5.

  PMID: 19058824 BACKGROUND

• Moisi JC, Gatakaa H, Berkley JA, Maitland K, Mturi N, Newton CR, Njuguna P, Nokes J, Ojal J, Bauni E, Tsofa B, Peshu N, Marsh K, Williams TN, Scott JA. Excess child mortality after discharge from hospital in Kilifi, Kenya: a retrospective cohort analysis. Bull World Health Organ. 2011 Oct 1;89(10):725-32, 732A. doi: 10.2471/BLT.11.089235. Epub 2011 Jul 13.

  PMID: 22084510 BACKGROUND

• Berkley JA, Lowe BS, Mwangi I, Williams T, Bauni E, Mwarumba S, Ngetsa C, Slack MP, Njenga S, Hart CA, Maitland K, English M, Marsh K, Scott JA. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med. 2005 Jan 6;352(1):39-47. doi: 10.1056/NEJMoa040275.

  PMID: 15635111 BACKGROUND

• Trehan I, Goldbach HS, LaGrone LN, Meuli GJ, Wang RJ, Maleta KM, Manary MJ. Antibiotics as part of the management of severe acute malnutrition. N Engl J Med. 2013 Jan 31;368(5):425-35. doi: 10.1056/NEJMoa1202851.

  PMID: 23363496 BACKGROUND

• Babirekere-Iriso E, Musoke P, Kekitiinwa A. Bacteraemia in severely malnourished children in an HIV-endemic setting. Ann Trop Paediatr. 2006 Dec;26(4):319-28. doi: 10.1179/146532806X152845.

  PMID: 17132297 BACKGROUND

• Blomberg B, Manji KP, Urassa WK, Tamim BS, Mwakagile DS, Jureen R, Msangi V, Tellevik MG, Holberg-Petersen M, Harthug S, Maselle SY, Langeland N. Antimicrobial resistance predicts death in Tanzanian children with bloodstream infections: a prospective cohort study. BMC Infect Dis. 2007 May 22;7:43. doi: 10.1186/1471-2334-7-43.

  PMID: 17519011 BACKGROUND

• Aiken AM, Mturi N, Njuguna P, Mohammed S, Berkley JA, Mwangi I, Mwarumba S, Kitsao BS, Lowe BS, Morpeth SC, Hall AJ, Khandawalla I, Scott JAG; Kilifi Bacteraemia Surveillance Group. Risk and causes of paediatric hospital-acquired bacteraemia in Kilifi District Hospital, Kenya: a prospective cohort study. Lancet. 2011 Dec 10;378(9808):2021-2027. doi: 10.1016/S0140-6736(11)61622-X. Epub 2011 Nov 29.

  PMID: 22133536 BACKGROUND

• Woerther PL, Angebault C, Jacquier H, Hugede HC, Janssens AC, Sayadi S, El Mniai A, Armand-Lefevre L, Ruppe E, Barbier F, Raskine L, Page AL, de Rekeneire N, Andremont A. Massive increase, spread, and exchange of extended spectrum beta-lactamase-encoding genes among intestinal Enterobacteriaceae in hospitalized children with severe acute malnutrition in Niger. Clin Infect Dis. 2011 Oct;53(7):677-85. doi: 10.1093/cid/cir522.

  PMID: 21890771 BACKGROUND

• Paterson DL. "Collateral damage" from cephalosporin or quinolone antibiotic therapy. Clin Infect Dis. 2004 May 15;38 Suppl 4:S341-5. doi: 10.1086/382690.

  PMID: 15127367 BACKGROUND

• Jones KD, Hunten-Kirsch B, Laving AM, Munyi CW, Ngari M, Mikusa J, Mulongo MM, Odera D, Nassir HS, Timbwa M, Owino M, Fegan G, Murch SH, Sullivan PB, Warner JO, Berkley JA. Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial. BMC Med. 2014 Aug 14;12:133. doi: 10.1186/s12916-014-0133-2.

  PMID: 25189855 BACKGROUND

• Ignatius R, Gahutu JB, Klotz C, Steininger C, Shyirambere C, Lyng M, Musemakweri A, Aebischer T, Martus P, Harms G, Mockenhaupt FP. High prevalence of Giardia duodenalis Assemblage B infection and association with underweight in Rwandan children. PLoS Negl Trop Dis. 2012;6(6):e1677. doi: 10.1371/journal.pntd.0001677. Epub 2012 Jun 12.

  PMID: 22720102 BACKGROUND

• Heikens GT, Schofield WN, Christie CD, Gernay J, Dawson S. The Kingston Project. III. The effects of high energy supplement and metronidazole on malnourished children rehabilitated in the community: morbidity and growth. Eur J Clin Nutr. 1993 Mar;47(3):174-91.

  PMID: 8458315 BACKGROUND

• Dubray C, Ibrahim SA, Abdelmutalib M, Guerin PJ, Dantoine F, Belanger F, Legros D, Pinoges L, Brown V. Treatment of severe malnutrition with 2-day intramuscular ceftriaxone vs 5-day amoxicillin. Ann Trop Paediatr. 2008 Mar;28(1):13-22. doi: 10.1179/146532808X270635.

  PMID: 18318945 BACKGROUND

• Berkley JA, Ngari M, Thitiri J, Mwalekwa L, Timbwa M, Hamid F, Ali R, Shangala J, Mturi N, Jones KD, Alphan H, Mutai B, Bandika V, Hemed T, Awuondo K, Morpeth S, Kariuki S, Fegan G. Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial. Lancet Glob Health. 2016 Jul;4(7):e464-73. doi: 10.1016/S2214-109X(16)30096-1. Epub 2016 Jun 2.

  PMID: 27265353 BACKGROUND

• Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 1971 Oct;44(526):793-7. doi: 10.1259/0007-1285-44-526-793. No abstract available.

  PMID: 4940475 BACKGROUND

• Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer. 1976 Dec;34(6):585-612. doi: 10.1038/bjc.1976.220.

  PMID: 795448 BACKGROUND

• Standing JF, Ongas MO, Ogwang C, Kagwanja N, Murunga S, Mwaringa S, Ali R, Mturi N, Timbwa M, Manyasi C, Mwalekwa L, Bandika VL, Ogutu B, Waichungo J, Kipper K, Berkley JA; FLACSAM-PK Study Group. Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition. Clin Pharmacol Ther. 2018 Dec;104(6):1165-1174. doi: 10.1002/cpt.1078. Epub 2018 Apr 19.

  PMID: 29574688 BACKGROUND

• Ongas M, Standing J, Ogutu B, Waichungo J, Berkley JA, Kipper K. Liquid chromatography-tandem mass spectrometry for the simultaneous quantitation of ceftriaxone, metronidazole and hydroxymetronidazole in plasma from seriously ill, severely malnourished children. Wellcome Open Res. 2017 Jun 19;2:43. doi: 10.12688/wellcomeopenres.11728.2. eCollection 2017.

  PMID: 29479566 BACKGROUND

• Williams PCM, Berkley JA. Guidelines for the treatment of severe acute malnutrition: a systematic review of the evidence for antimicrobial therapy. Paediatr Int Child Health. 2018 Nov;38(sup1):S32-S49. doi: 10.1080/20469047.2017.1409453.

  PMID: 29790840 BACKGROUND

• Williams PCM, Isaacs D, Berkley JA. Antimicrobial resistance among children in sub-Saharan Africa. Lancet Infect Dis. 2018 Feb;18(2):e33-e44. doi: 10.1016/S1473-3099(17)30467-X. Epub 2017 Oct 9.

  PMID: 29033034 BACKGROUND

Related Links

• Pocket book of hospital care for children Guidelines for the management of common illnesses with limited resources Author: World Health Organization

MeSH Terms

Interventions

Ceftriaxone; Penicillin G; Metronidazole; Gentamicins

Intervention Hierarchy (Ancestors)

Cefotaxime; Cephacetrile; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Penicillins; Nitroimidazoles; Nitro Compounds; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• James A Berkely, FRCPCH

  KEMRI/Wellcome Trust Research Programme & University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Metronidazole and its placebo will be masked. They will both be contained in similar bottles labelled with sequential study numbers according to a prepared blocked randomisation list before the trial begins. They will also be of similar appearance. Ceftriaxone and penicillin + gentamicin will not be masked.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The trial will investigate two separate antimicrobial interventions in a 2x2 factorial design randomised controlled clinical trial. A factorial design allows more than one intervention to be tested and is useful in assessing a potential package of care. Two randomisations will be made. The two interventions will be analysed separately. Ceftriaxone and metronidazole is an effective and commonly used antibiotic combination, hence major interactions that interfere with efficacy are considered unlikely. However, evidence for interaction between the two interventions will be tested.

Study Record Dates

• First Submitted: May 15, 2017
• First Posted: June 2, 2017
• Study Start: September 4, 2017
• Primary Completion: January 31, 2020
• Study Completion: December 31, 2020
• Last Updated: May 19, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: 2 years after study end, no end date foreseen
• Access Criteria: Managed access. Apply to the Data Governance Committee: dgc@kemri-wellcome.org

Locations

KE (7); UG (1)