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Effect of dose reduction of supplemental zinc for childhood diarrhoea: study protocol for a double-masked, randomised controlled trial in India and Tanzania
  1. Sarah S Somji1,
  2. Pratibha Dhingra2,
  3. Usha Dhingra2,
  4. Arup Dutta2,
  5. Prabhabati Devi2,
  6. Jitendra Kumar2,
  7. Saikat Deb2,
  8. Om Prakash Semwal2,
  9. Sunil Sazawal2,
  10. Karim Manji1,
  11. Rodrick Kisenge1,
  12. Mohamed Bakari1,
  13. Said Aboud1,
  14. Enju Liu3,
  15. Christopher Sudfeld4,
  16. Christopher P Duggan5,6,
  17. Per Ashorn7,
  18. Rajiv Bahl8,
  19. Jonathon L Simon8
  1. 1Department of Pediatrics, Muhimbili University of Health and Allied Sciences, Dar es Salaam, United Republic of Tanzania
  2. 2Centre for Public Health Kinetics (CPHK), New Delhi, Delhi, India
  3. 3Boston Children’s Hospital, Boston, MA
  4. 4Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
  5. 5Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA
  6. 6Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA
  7. 7Tampereen yliopisto, Tampere, Finland
  8. 8Organisation mondiale de la Sante, Geneva, Switzerland
  1. Correspondence to Dr Jonathon L Simon; simonjo{at}who.int

Abstract

Background Diarrhoea-associated mortality and morbidity are highest in infants and young children in low-income and middle-income countries (LMICs). Zinc supplementation during acute diarrhoea has been shown to reduce the duration of illness and the risk of persistent diarrhoea. However, vomiting with zinc supplementation is a common side effect that may interfere with compliance and programmatic scale-up, and may be related to the dose prescribed.

Methods/design The Zinc Therapeutic Dose Trial (ZTDT) is a two-centre (Tanzania and India), three-arm randomised, double-blind controlled non-inferiority trial. Children 6–59 months of age with acute diarrhoea are eligible to participate. Enrolled children (1500 per arm; 4500 total) will be randomly allocated to receive 5, 10 or 20 mg of zinc sulfate daily for 14 days and will be followed up for 60 days after enrolment. All children will receive WHO/Unicef Integrated Management of Childhood Illness standard of care (oral or intravenous rehydration and zinc as indicated and feeding advice). The primary efficacy outcomes of the trial are the percentage of subjects with diarrhoea duration >5 days, the mean total number of loose or watery stools after enrolment and the proportion of children vomiting within 30 min of zinc administration.

Discussion The ZTDT trial will determine the optimal dose of therapeutic zinc supplements for treatment of acute diarrhoea in children aged 6–59 months in two LMICs. The results of the trial are likely to be generalisable to childhood acute diarrhoea in similar resource-limited settings and may influence global policy about zinc supplementation dosage during acute diarrhoea.

Trial registration number NCT03078842.

Trial status Enrolment began in January 2017 and follow-up is estimated to be completed by April 2019. As of 1 February 2019, 742 children are still contributing data to the ZTDT study.

  • general paediatrics
  • paediatric practice
  • pharmacology
  • tropical inf dis

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • SSS and PD are joint first authors

  • Contributors All the authors participated in conceptualisation, design, sample size calculations and writing of the analysis plan for the study. Two workshops held at WHO to develop joint harmonised SOP and CRFs for the study in which all the authors contributed. SSS and PD prepared the first draft of the paper. All authors contributed to revisions of the manuscript and contributed to the revision of the final draft of the manuscript. All the authors have read and approved the final manuscript.

  • Funding This study is funded by Bill and Melinda Gates Foundation (grant number: OPP1135491) (see online supplementary additional file 5).

  • Disclaimer The funder has no role in study design, collection, management, analysis and interpretation of data; writing of the report and decision to submit for publication.

  • Competing interests None declared.

  • Ethics approval The ZTDT protocol has been approved by WHO ethics committee (reference no. ERC.0002738), Boston Children’s Hospital IRB (reference no .IRB-P00024269), Tanzania Food and Drug Authority (reference no. TFDA0016/CTR/0015/03), the Tanzanian National Institute of Medical Research (reference no. NIMR/HQ/R.8a/Vol.IX/2333) and Muhimbili University of Health and Allied Sciences, Dar es Salaam (reference no. 2016-10-31/AEC/Vol.XI/314) and IEC of Subharti Medical College & Hospital, Meerut, Uttar Pradesh, India (reference no. SMC/EC/2016/84) (see online supplementary additional file 4). All participants will be asked to provide written informed consents before trial enrolment. Caregivers who consent for the trial will also be asked for consent to be escorted back to their home to register the address, to contact the participant and to be visited at home or followed at home if the participant misses the clinic visit, as well as to store and use all data and child blood samples for this study and future research studies.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Data sharing statement Full protocol is being published in a peer-reviewed open access journal. Additional information about the protocol/SOPs will be available on request. In addition, a commitment is made by the investigators: 1) to use data for research purposes and not to identify individual participants and 2) to use appropriate technology to secure the data. Consistent with WHO policies and practice, each site owns the data they generate from the national populations they serve. Sites voluntarily agree to share the data with WHO as the ZTDT Coordinating Body and share the final ’frozen data set' with BMGF for their internal use.

  • Author note CD was supported in part by NIH grants K24DK104676 and 2P30 DK 040561.

  • Patient consent for publication Not required.

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