Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202107604428217 Date of Approval: 08/07/2021
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title A Prospective PreecLampsia/Eclampsia Preventative Intervention – Metformin (APPLE PIE) study
Official scientific title A Prospective PreecLampsia/Eclampsia Preventative Intervention – Metformin (APPLE PIE) study
Brief summary describing the background and objectives of the trial Preeclampsia is one of the most severe complications of pregnancy, globally responsible for more than 60,000 maternal deaths a year, and far greater numbers of fetal losses. It is caused by the excessive release of anti-angiogenic factors from the placenta into the maternal circulation. These factors cause hypertension and injury to multiple organs and can also affect placental function and cause stillbirth. Finding agents that prevent preeclampsia could save the lives of many. Metformin is commonly prescribed to pregnant women to treat gestational diabetes mellitus and has an established safety profile in pregnancy. There is accumulating evidence suggesting it has potential to prevent preeclampsia. Preclinical studies support the concept that metformin could prevent or treat preeclampsia. A meta-analysis of trials comparing metformin administration versus insulin to treat gestational diabetes reported an incidental reduction in the incidence of hypertensive diseases among those receiving metformin. We have just completed a randomised clinical trial of metformin extended release (XR) to treat women with preterm preeclampsia (26-32 weeks’ gestation). Metformin XR was associated with a possible prolongation in pregnancy, meaning the baby could be safely delivered at a less preterm gestation (with likely better immediate and long-term health outcomes). If metformin can prolong pregnancy, it is worthwhile investigating whether it can also prevent preeclampsia.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) APPLE PIE
Disease(s) or condition(s) being studied Pregnancy and Childbirth
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Prevention
Anticipated trial start date 01/04/2022
Actual trial start date
Anticipated date of last follow up 03/07/2028
Actual Last follow-up date
Anticipated target sample size (number of participants) 1430
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Permuted block randomization Central randomisation by phone/fax Masking/blinding used Care giver/Provider,Outcome Assessors,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Metformin Extended release 1000mg oral metformin XR twice a day From recruitment until delivery Metformin XR 715
Control Group Control Group Identical matched placebo orally twice a day From recruitment until delivery Control group 715 Placebo
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
All these criteria must be met to be eligible for inclusion: A) At high risk of developing preeclampsia: Pregnant women who have chronic hypertension AND/OR have had a previous pregnancy complicated by preterm preeclampsia (before 34 weeks gestation) AND/OR had preeclampsia complicating 2 or more previous pregnancies B) Gestational age between 12w 0d and 26w 0d C) Viable singleton pregnancy D) Be able to understand the information provided, with the use of an interpreter if needed, and be able to give informed consent E) Be willing to take the trial medication daily until delivery Any of the following will be considered an exclusion criterion: A) Under 18 years of age B) Known fetal anomaly C) Unable or not willing to give consent D) Diabetes E) Contraindication to the use of metformin F) Currently using metformin G) Previously enrolled in this trial. Participants will only be able to enrol for this trial once and not again in the next pregnancy. Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 65 Year(s) Female
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 30/07/2021 Stellenbosch University Health Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zyl Drive, Tygerberg, 7505 Cape Town 7505 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Diagnosis of preeclampsia or super-imposed preeclampsia 6 weeks after the due date
Secondary Outcome Diagnosis of preeclampsia or super-imposed preeclampsia <37 weeks 6 weeks after the due date
Secondary Outcome Diagnosis of preeclampsia or super-imposed preeclampsia <34 weeks 6 weeks after the due date
Secondary Outcome Diagnosis of any hypertensive disorder of pregnancy after enrollment 6 weeks after the due date
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Tygerberg Hospital Francie van Zyl Drive Cape Town 7505 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Merck KGaA Frankfurter Str. 250, Darmstadt 64293 Germany
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Stellenbosch University RW Wilcocks Building, room 2037, Victoria street Stellenbosch 7600 South Africa University
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Catherine Cluver cathycluver@sun.ac.za +27823210298 Preeclampsia Research Unit, Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zyl Drive, Tygerberg
City Postal code Country Position/Affiliation
Cape Town 7505 South Africa Associate Professor
Role Name Email Phone Street address
Public Enquiries Catherine Cluver cathycluver@sun.ac.za +27823210298 Preeclampsia Research Unit, Department Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zyl Drive
City Postal code Country Position/Affiliation
Cape Town 7505 South Africa Associate Professor
Role Name Email Phone Street address
Scientific Enquiries Catherine Cluver cathycluver@sun.ac.za +27823210298 Preeclampsia Research Unit, Department Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zyl Drive
City Postal code Country Position/Affiliation
Cape Town 7505 South Africa Associate Professor
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes All of the individual participant data collected during the trial, after deidentification will be made available after publication to researchers who provide a methodological sound proposal for any purpose. Proposals should be directed to cathycluver@sun.ac.za Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol IPD/documents will be available indefinitely from publication of the trial results Data will be made available to researchers who provide a methodological sound proposal for any purpose. Proposals should be directed to cathycluver@sun.ac.za
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information