Cotrimoxazole Prophylaxis in Severely Malnourished Children (CTX)

August 15, 2014 updated by: University of Oxford

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

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

1781

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Nairobi, Kenya
        • Mbagathi District Hospital
    • Coast
      • Kilifi, Coast, Kenya, 80108
        • KEMRI/Wellcome Trust Research Programme
      • Malindi, Coast, Kenya
        • Malindi District Hospital
      • Mombasa, Coast, Kenya
        • Coast Provincial General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 months to 5 years (CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Cotrimoxazole dispersible tablet
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.
Cotrimoxazole dispersible tablets 120/240mg daily for six consecutive months.
Other Names:
  • Bactrim
  • Septrin
  • Cosatrim
PLACEBO_COMPARATOR: Placebo dispersible tablet
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.
Placebo dispersible tablets 120/240mg daily for six consecutive months.
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Mortality
Time Frame: 12 months
12 months

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: James A Berkley, FRCPCH, Universitiy of Oxford & Kenya Medical Research Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2009

Primary Completion (ACTUAL)

April 1, 2014

Study Completion (ACTUAL)

April 1, 2014

Study Registration Dates

First Submitted

July 7, 2009

First Submitted That Met QC Criteria

July 7, 2009

First Posted (ESTIMATE)

July 8, 2009

Study Record Updates

Last Update Posted (ESTIMATE)

August 18, 2014

Last Update Submitted That Met QC Criteria

August 15, 2014

Last Verified

August 1, 2014

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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