Cotrimoxazole Prophylaxis in Severely Malnourished Children

Condition(s) targeted: Nutrition Disorders; Life-threatening Infection

Intervention: Cotrimoxazole dispersible tablet (Drug); Placebo dispersible tablet (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: University of Oxford

Official(s) and/or principal investigator(s):
James A Berkley, FRCPCH, Principal Investigator, Affiliation: Universitiy of Oxford & Kenya Medical Research Institute

Overall contact:
James Berkley, Phone: +254 041 7522535/7522063, Ext: 624, Email: jberkley@kilifi.kemri-wellcome.org

This trial aims to test the hypothesis that mortality among Kenyan children with severe malnutrition following initial stabilisation is due to ongoing vulnerability to infectious disease, and that co-trimoxazole prophylaxis will reduce mortality.

The objective is to conduct a randomized, double blind, placebo-controlled trial of cotrimoxazole prophylaxis for 6 months among HIV-uninfected children with severe malnutrition following stabilization. The primary outcome will be survival at one year. Secondary outcomes are toxicity, survival at two years, growth, hospitalisation and microbial resistance and ecology.

Cotrimoxazole has striking protective efficacy against mortality among children with HIV, despite not altering the underlying immune deficiency. It is hypothesised that co-trimoxazole prophylaxis will have a similar effect in children immunocompromised because of severe malnutrition. Worldwide, severe malnutrition is commoner than HIV in childhood and co-trimoxazole is cheap and widely available, making it easily translatable to policy.

Official title: Randomized, Placebo Controlled Trial of Cotrimoxazole Prophylaxis Amongst HIV-uninfected Children With Severe Malnutrition

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Primary outcome: Mortality

Secondary outcome:

Frequency and causes of hospital re-admission

Growth

Microbial population and antimicrobial resistance

Immune activation and inflammatory markers; markers of immune function

Detailed description: Malnutrition is the most important underlying risk factor for childhood death in developing countries. Severely malnourished children are at greatly increased risk of death from infectious diseases in the community, in hospital and following discharge. Malnutrition and infection are synergistic, in part because malnutrition causes secondary immune deficiency, whilst infections cause losses and diversion of nutrients. This synergy is exacerbated by a high level of exposure to pathogens. Among children treated for severe malnutrition in Africa, mortality following discharge from hospitals ranges between 8% and 41%.

Cotrimoxazole is a synthetic antibacterial combination that blocks two steps of folate metabolism involved in the biosynthesis of nucleic acids and proteins essential to many bacteria and some parasites, including Plasmodium falciparum. It is cheap, widely available and has an established safety profile in African populations. Cotrimoxazole prophylaxis dramatically reduces mortality among children with HIV, irrespective of the degree of immune suppression. The primary effect is in reducing bacterial infection, especially pneumonia. the effect has been demonstrated in areas with high levels of cotrimoxazole resistance bacteria. It is also widely used in developed countries among children with other immune deficiencies to prevent infection. Children with severe malnutrition are immune deficient, as evidenced by their susceptibility to infectious diseases, and may therefore benefit from daily antimicrobial prophylaxis.

The objective is to conduct a randomized, double blind, placebo-controlled trial of co-trimoxazole prophylaxis for 6 months among HIV-uninfected children with severe malnutrition following stabilization. The primary outcome will be survival at one year. Secondary outcomes are toxicity, survival at two years, growth, hospitalisation and microbial resistance and ecology.

Minimum age: 2 Months. Maximum age: 5 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Age 2 months to 5 years

- Admitted to hospital

- Severe malnutrition: age 6 months to 5 years: MUAC <11cm; age 2 to 6 months: MUAC for

age <-3 z scores compared to the WHO growth standards; or kwashiorkor at any age (defined in current WHO guidelines) for enrollments up to 24th March 2011.

- Severe malnutrition: age 6 months to 5 years: MUAC <11. 5cm; age 2 to 6 months: MUAC

<11. 0cm; or kwashiorkor at any age (defined in current WHO guidelines) for enrollments from 24th March 2011, following protocol amendment.

- HIV rapid test negative, or if under 18 months, PCR negative and no longer

breastfeeding for at least 6 weeks

- Planning to remain within study area and willing to come for all protocol specified

visits

Exclusion Criteria:

- Refusal to give informed consent

- Cotrimoxazole is specifically contra-indicated (e. g. porphyria)

- Known hypersensitivity reaction to sulpha drugs or trimethoprim

James Berkley, Phone: +254 041 7522535/7522063, Ext: 624, Email: jberkley@kilifi.kemri-wellcome.org

Mbagathi District Hospital, Nairobi, Kenya; Not yet recruiting
Beatrice Mutai, MB ChB, Email: mutaibc@yahoo.co.uk
Beatrice Mutai, MBChB MMed, Principal Investigator
Molline Timbwa, HND, Sub-Investigator

KEMRI/Wellcome Trust Research Programme, Kilifi, Coast 80108, Kenya; Recruiting
Email: jberkley@kilifi.kemri-wellcome.org
Johnstone Thitiri, BSc, Email: jthitiri@kilifi.kemri-wellcome.org
James A Berkley, MD, Principal Investigator
Johnstone Thitiri, BSc, Sub-Investigator
Rehema Ali, RN, Sub-Investigator

Malindi District Hospital, Malindi, Coast, Kenya; Recruiting
Morris Buni, MB ChB
Email: fhamid@kilifi.kemri-wellcome.org
Morris Buni, MBChB, Principal Investigator
Fauzat Hamid, DipClinMed, Sub-Investigator

Coast Provincial General Hospital, Mombasa, Coast, Kenya; Recruiting
Laura Mwalekwa, Email: lmwalekwa@kilifi.kemri-wellcome.org
Twahir Hemed, MBChB MMed, Principal Investigator
Laura Mwakela, HND, Sub-Investigator
Victor Bandika, MB ChB MMed, Sub-Investigator

Starting date: November 2009
Last updated: January 15, 2013