Cotrimoxazole Prophylaxis in Severely Malnourished Children (CTX)

This study has been completed.
Sponsor:
Collaborator:
Kenya Medical Research Institute
Information provided by (Responsible Party):
University of Oxford
ClinicalTrials.gov Identifier:
NCT00934492
First received: July 7, 2009
Last updated: August 15, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Nutrition Disorders
Life-threatening Infection
Drug: Cotrimoxazole dispersible tablet
Drug: Placebo dispersible tablet
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: Randomized, Placebo Controlled Trial of Cotrimoxazole Prophylaxis Amongst HIV-uninfected Children With Severe Malnutrition

Resource links provided by NLM:


Further study details as provided by University of Oxford:

Primary Outcome Measures:
  • Mortality [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Frequency and causes of hospital re-admission [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Growth [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Microbial population and antimicrobial resistance [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Immune activation and inflammatory markers; markers of immune function [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Enrollment: 1781
Study Start Date: November 2009
Study Completion Date: April 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Cotrimoxazole dispersible tablet
Cotrimoxazole dispersible tablets 120/240mg daily for six consecutive months.
Other Names:
  • Cosatrim
  • Septrin
  • Bactrim
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.
Drug: Placebo dispersible tablet
Placebo dispersible tablets 120/240mg daily for six consecutive months.
Other Name: Placebo

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.

  Eligibility

Ages Eligible for Study:   2 Months to 5 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00934492

Locations
Kenya
KEMRI/Wellcome Trust Research Programme
Kilifi, Coast, Kenya, 80108
Malindi District Hospital
Malindi, Coast, Kenya
Coast Provincial General Hospital
Mombasa, Coast, Kenya
Mbagathi District Hospital
Nairobi, Kenya
Sponsors and Collaborators
University of Oxford
Kenya Medical Research Institute
Investigators
Principal Investigator: James A Berkley, FRCPCH Universitiy of Oxford & Kenya Medical Research Institute
  More Information

No publications provided

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT00934492     History of Changes
Other Study ID Numbers: SSC 1562, OXTREC 18 09, WT 083579
Study First Received: July 7, 2009
Last Updated: August 15, 2014
Health Authority: Kenya: Ethical Review Committee

Keywords provided by University of Oxford:
Malnutrition
Wasting
Kwashiorkor
Immune deficiency
Infection
Prophylaxis
Mortality
Kenya

Additional relevant MeSH terms:
Malnutrition
Nutrition Disorders
Trimethoprim-Sulfamethoxazole Combination
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Infective Agents, Urinary
Renal Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents

ClinicalTrials.gov processed this record on August 26, 2014