Cotrimoxazole Prophylaxis in Severely Malnourished Children
Condition: Nutrition Disorders; Life-threatening Infection
MeSH terms: Nutrition Disorders
Study type: Interventional
Phase: Phase 3

Summary: 
      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 long term daily 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, growth, the frequency and causes of hospitalisation and microbial resistance to
      antibiotics.

      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.
    

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
      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, growth, hospitalisation, microbial resistance in carriage and pathogenic
      organisms and markers of inflammation and immune function.

      On 26th September 2012, on advice from an independent senior statistician who reviewed the
      actual event rate in the control arm, the rates of recruitment and loss to follow up, the
      Trial Steering Committee recommended that the trial team to recruit at least 1750
      participants to achieve the original objective of having >90% power to detect a reduction in
      mortality during 12 months follow up of 33%. Recruitment was stopped on 31st March 2013 at
      1781 participants.
    

Intervention name(s): Cotrimoxazole dispersible tablet; Placebo dispersible tablet
Intervention type(s): Drug; Drug
Intervention description(s): Cotrimoxazole dispersible tablets 120/240mg daily for six consecutive months.; Placebo dispersible tablets 120/240mg daily for six consecutive months.
Other intervention name(s): Cosatrim; Septrin; Bactrim; Placebo
Intervention MeSH terms: Trimethoprim, Sulfamethoxazole Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Malnutrition; Wasting; Kwashiorkor; Immune deficiency; Infection; Prophylaxis; Mortality; Kenya