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Obstetrics and gynaecology
Protocol
A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol
  1. Catherine Cluver1,2,
  2. Susan P Walker2,3,
  3. Ben W Mol4,
  4. David Hall5,
  5. Richard Hiscock6,
  6. Fiona C Brownfoot2,3,
  7. Tu’uhevaha J Kaitu’u-Lino7,8,
  8. Stephen Tong2,3
  1. 1 Department of Obstetrics and Gynaecology, Stellenbosch University Faculty of Science, Cape Town, Western Cape, South Africa
  2. 2 Translational Obstetrics Group, University of Melbourne, Mercy Hospital for Women, Melbourne, Victoria, Australia
  3. 3 Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Victoria, Australia
  4. 4 Department of Obstetrics and Gynaecology, School of Medicine, Monash University, Melbourne, Victoria, Australia
  5. 5 Department of Obstetrics and Gynaecology, Stellenbosch University Faculty of Science, Matieland, Western Cape, South Africa
  6. 6 Department of Anaesthetics, University of Melbourne, Mercy Hospital for Women, Melbourne, Victoria, Australia
  7. 7 Translational Obstetrics Group and Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Victoria, Australia
  8. 8 Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
  1. Correspondence to Dr Catherine Cluver; cathycluver{at}hotmail.com

Abstract

Introduction Pre-eclampsia is a major complication of pregnancy, globally responsible for 60 000 maternal deaths per year, and far more fetal losses. There is no definitive treatment other than delivery. A therapeutic that could quench the disease process would be useful to treat preterm pre-eclampsia, as it could allow these pregnancies to safely continue to a gestation where fetal outcomes are significantly improved. We have published preclinical data to show that metformin, a drug known to be safe in pregnancy and commonly used to treat gestational diabetes, has potent biological effects making it another promising candidate to treat pre-eclampsia. Here, we describe a phase II clinical trial to examine whether administering extended-release metformin may be effective in treating women with preterm pre-eclampsia (PI2 Trial).

Methods The PI2 Trial is a phase II, double blind, randomised controlled trial that aims to recruit 150 women with preterm pre-eclampsia (gestational age 26+0 to 31+6 weeks) who are being managed expectantly. Participants will be randomised to receive either 3 g of metformin or placebo daily. The primary outcome is time from randomisation until delivery. A delay in delivery of 5 days is assumed to be clinically relevant. The secondary outcomes will be a maternal composite and neonatal composite outcome. All other outcomes will be exploratory. We will record adverse events.

Ethics and dissemination This study has ethical approval (Protocol number M16/09/037 Federal Wide Assurance Number 00001372, Institutional Review Board Number IRB0005239), is registered with the Pan African Clinical Trial Registry (PACTR201608001752102) and the South African Medicine Control Council (20170322). Data will be presented at international conferences and published in peer-reviewed journals.

Trial registration number PACTR201608001752102; Pre-results.

  • pre-eclampsia
  • metformin
  • preterm preeclampsia
  • treatment
  • clinical trials
  • preeclampsia

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/.

http://dx.doi.org/10.1136/bmjopen-2018-025809

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    Footnotes

    • Contributors CC, SPW and ST developed and designed the trial and obtained funding for the trial. CC, SPW and ST wrote the first draft of this manuscript. BWM and DH assisted with the study design. RH designed the statistical aspects of this protocol. FCB and TJK-L were involved in the design of the laboratory arm of this trial. All were involved in revision of the manuscript. All authors approved the final version to be submitted. CC and RH responded to the reviewer’s comments.

    • Funding This work is supported by the Mercy Perinatal Foundation, the South African Medical Research Council and the Preeclampsia Foundation. NHMRC provides salary support to ST and BWM. The trial medication was donated by Merck pharmaceuticals.

    • Competing interests None declared.

    • Ethics approval Stellenbosch University HREC Protocol number M16/09/037

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

    • Patient consent for publication Not required.