Cotrimoxazole Prophylaxis in Severely Malnourished Children

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Nutrition Disorders, Life-threatening Infection

Intervention / Treatment
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* Drug: Cotrimoxazole dispersible tablet
* Drug: Placebo dispersible tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cotrimoxazole dispersible tablet<br>Children between 2-6 months will receive single dispersible tablet of 120mg,daily while children over 6 months to 5 years will receive 240 mg dispersible tablet daily for six months. | Drug: Cotrimoxazole dispersible tablet<br>* Cotrimoxazole dispersible tablets 120/240mg daily for six consecutive months.<br>* Other names: Bactrim;|
| Placebo Comparator: Placebo dispersible tablet<br>Children between 2-6 months will receive single dispersible Placebo tablet of 120mg,daily while children over 6 months to 5 years will receive 240 mg dispersible Placebo tablet daily for six months. | Drug: Placebo dispersible tablet<br>* Placebo dispersible tablets 120/240mg daily for six consecutive months.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and causes of hospital re-admission |  | 12 months | 
| Growth |  | 12 months | 
| Microbial population and antimicrobial resistance |  | 12 months | 
| Immune activation and inflammatory markers; markers of immune function |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malnutrition, Wasting, Kwashiorkor, Immune deficiency, Infection, Prophylaxis, Mortality, Kenya