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.: PACTR202104532026017 Date of Approval: 19/04/2021
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Pre-eclampsia Intervention 3 Trial
Official scientific title Pre-eclampsia Intervention 3 Trial: a double blind randomised, placebo-controlled trial of metformin to treat preterm pre-eclampsia
Brief summary describing the background and objectives of the trial INTRODUCTION Pre-eclampsia is globally responsible for 60,000 maternal deaths per year, and far greater numbers of fetal losses. It is a leading cause of maternal mortality in South Africa and a major problem in all developing countries. Preterm pre-eclampsia is a severe variant with the highest rates of neonatal morbidity and mortality due to iatrogenic premature delivery (clinicians are forced to deliver the baby preterm for maternal or fetal health reasons). The PI 2 trial has shown that metformin may be a disease modifying treatment for preterm pre-eclampsia. Here we plan to confirm these findings in a larger, double blinded, randomised trial, powered to assess whether metformin XR prolongs pregnancy and improves neonatal outcome. RESEARCH QUESTION Can administering metformin to women and decrease length of neonatal admission in hospital? AIMS Primary aim To examine whether metformin SR can safely further prolong gestation for 5 days in pregnancies complicated by preterm pre-eclampsia diagnosed 26+0 – 31+6 weeks, compared to current standard of care. Main secondary aim: To determine whether metformin SR can reduce the time that babies born to women with preterm pre-eclampsia are admitted under neonatal hospital care. Other secondary aim: To determine whether metformin SR can increase neonatal birthweight in pregnancies complicated by preterm pre-eclampsia. METHODS We will perform a double blind randomised controlled trial of 500 women with preterm pre-eclampsia. Informed consent will be obtained. Pregnant women between the ages of 18 and 50 years who present with preterm pre-eclampsia at a gestation of 26+0 to 31+6 weeks at Tygerberg Hospital and considered stable enough to undergo expectant management will be randomised to receive either metformin SR or an identical placebo in divided doses daily.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) PI 3
Disease(s) or condition(s) being studied Pregnancy and Childbirth
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 03/01/2022
Actual trial start date 25/05/2022
Anticipated date of last follow up 02/10/2028
Actual Last follow-up date
Anticipated target sample size (number of participants) 500
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL https://bmjopen.bmj.com/content/14/6/e082880
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 Allocation was determined by the holder of the sequence who is situated off site 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 SR 1 gram of metformin SR three times a day From recruitment until delivery Metformin SR tablets 250
Control Group Placebo Matched placebo tablets From recruitment until delivery Identical placebo tablets 250 Placebo
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
A diagnosis of pre-eclampsia, gestational hypertension with evidence of pre-eclampsia, preexisting hypertension with evidence of pre-eclampsia or unclassified proteinuric hypertension has been made by the attending clinician who believes the patient and fetus would benefit from expectant management. AND all of the following are present: • Gestational age between 26 + 0 weeks and 31 + 6 weeks • Estimated fetal weight by ultrasound between 500gm and 1800 gm (if gestation is not certain) • Singleton pregnancy • The managing clinicians have made the assessment to proceed with expectant management and that delivery is not expected within 48 hours • The managing clinician and neonatologist believe that the fetus could potentially be delivered in a viable condition. ALSO: • The mother must be able to understand the information provided, with the use of an interpreter if needed, and must be able to give informed consent • Patient will be admitted to hospital for expectant management and standard care • Mother must be older than 18 years of age. • Patient is unable or unwilling to give consent • Established fetal compromise that necessitates delivery. This will be decided by the clinical team before expectant management is offered to the patient. • Suspicion of a major known fetal anomaly or malformation. A major fetal anomaly is defined as anomalies or malformations that create significant medical problems for the patient or that require specific surgical or medical management. Major anomalies or malformations are not considered a variation of the normal spectrum. • The presence of any of the following at presentation (given these are typically contra-indications to expectant management):  Eclampsia defined as the new onset of grand mal seizure activity and/or an unexplained coma during pregnancy with signs or symptoms of pre-eclampsia.51,52  Severe hypertension defined as a systolic blood pressure greater than or equal to 160 mmHg or diastolic blood pressure greater than or equal to 110 mmHg that cannot be controlled with antihypertensive medication within 48 hours of admission.  Cerebrovascular event defined as an ischaemic or haemorrhagic stroke associated with clinical symptoms and definitive signs on imaging.  Posterior reversible encephalopathy syndrome (PRES) associated with pre-eclampsia defined on imaging as reversible vasogenic oedema, usually in the occipital or parietal lobes.  Severe renal impairment with a creatinine level of greater or equal to 125 μmol/l or a need for dialysis.  Signs of left ventricular failure which include pulmonary oedema requiring treatment or oxygen saturations of less than 90% caused by left sided heart failure.  Disseminated intravascular coagulation defined as an INR greater than 2  Platelet count at presentation less than 50x109 (platelet aggregation excluded)  Haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome defined as a platelet count less than 100 × 109/L, aspartate aminotransferase greater than 70 μ/L, and haemolysis as demonstrated by lactate dehydrogenase > 600 μ/L or haemolysis on a peripheral blood smear.  Liver transaminases (aspartate aminotransferase and/or alanine transferase) greater than or equal to 500IU/L  Liver haematoma or rupture  Fetal distress on cardiotocography  Severe ascites on ultrasound as defined by the sonographer • Contra-indications for expectant management of pre-eclampsia • Current use of metformin or a clinical indication for the use of metformin • Contraindications to the use of metformin  Renal disease or dysfunction, suggested by a creatinine level greater than or equal to 125umol/L  Known hypersensitivity to metformin  Acute or chronic metabolic acidosis, including diabetic ketoacidosis • Current use of a drug that may be affected by metformin  Glyburide  Furosemide  Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) Adult: 19 Year-44 Year 18 Year(s) 50 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
Yes 10/08/2021 Stellenbosch University Health Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
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 Prolongation of gestation measured from the time of enrolment to the time of delivery, in hours and days. Delivery
Secondary Outcome Length of neonatal hospital admission measured from date of birth until final discharge home. 6 weeks after the due date
Secondary Outcome Neonatal birthweight Delivery
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Tygerberg Hospital Francie van Zyl Drive, Tygerberg, 7505 Cape Town 7505 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Mercy Health Foundation Mercy Hospital for Women, 163 Studley Street, Heidelberg Melbourne 3084 Australia
Merck Healthcare KGaA 250 Frankfurter street Darmstadt Germany
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Stellenbosch University Francie van Zyl Drive, Tygerberg Cape Town 8001 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 Department of Obstetrics and Gynaecology, 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 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
Scientific Enquiries Catherine Cluver cathycluver@sun.ac.za +27823210298 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
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes All of the data collected after completing the trial and deidentification will be available for sharing to researchers who provide a sound methodological proposal. Analytic Code,Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol Immediately after publication Any researcher with a sound methodological proposal may request access to the data. All data except identifying data may be requested. Please email Prof Catherine Cluver at cathycluver@sun.ac.za with requests. All proposals will be assessed by the trial steering committee and if any concerns the trial data monitoring and safety committee will be approached.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
https://www.preeclampsiaresearch.com/ 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
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Trial description 20/04/2023 Corrected the acronym for metformin slow release (SR). Changed from extended release (ER) to slow release (SR) INTRODUCTION Pre-eclampsia is globally responsible for 60,000 maternal deaths per year, and far greater numbers of fetal losses. It is a leading cause of maternal mortality in South Africa and a major problem in all developing countries. Preterm pre-eclampsia is a severe variant with the highest rates of neonatal morbidity and mortality due to iatrogenic premature delivery (clinicians are forced to deliver the baby preterm for maternal or fetal health reasons). The PI 2 trial has shown that metformin may be a disease modifying treatment for preterm pre-eclampsia. Here we plan to confirm these findings in a larger, double blinded, randomised trial, powered to assess whether metformin XR prolongs pregnancy and improves neonatal outcome. RESEARCH QUESTION Can administering metformin to women and decrease length of neonatal admission in hospital? AIMS Primary aim To examine whether metformin XR can safely further prolong gestation for 5 days in pregnancies complicated by preterm pre-eclampsia diagnosed 26+0 – 31+6 weeks, compared to current standard of care. Main secondary aim: To determine whether metformin XR can reduce the time that babies born to women with preterm pre-eclampsia are admitted under neonatal hospital care. Other secondary aim: To determine whether metformin XR can increase neonatal birthweight in pregnancies complicated by preterm pre-eclampsia. METHODS We will perform a double blind randomised controlled trial of 500 women with preterm pre-eclampsia. Informed consent will be obtained. Pregnant women between the ages of 18 and 50 years who present with preterm pre-eclampsia at a gestation of 26+0 to 31+6 weeks at Tygerberg Hospital and considered stable enough to undergo expectant management will be randomised to receive either metformin XR or an identical placebo in divided doses daily. INTRODUCTION Pre-eclampsia is globally responsible for 60,000 maternal deaths per year, and far greater numbers of fetal losses. It is a leading cause of maternal mortality in South Africa and a major problem in all developing countries. Preterm pre-eclampsia is a severe variant with the highest rates of neonatal morbidity and mortality due to iatrogenic premature delivery (clinicians are forced to deliver the baby preterm for maternal or fetal health reasons). The PI 2 trial has shown that metformin may be a disease modifying treatment for preterm pre-eclampsia. Here we plan to confirm these findings in a larger, double blinded, randomised trial, powered to assess whether metformin XR prolongs pregnancy and improves neonatal outcome. RESEARCH QUESTION Can administering metformin to women and decrease length of neonatal admission in hospital? AIMS Primary aim To examine whether metformin SR can safely further prolong gestation for 5 days in pregnancies complicated by preterm pre-eclampsia diagnosed 26+0 – 31+6 weeks, compared to current standard of care. Main secondary aim: To determine whether metformin SR can reduce the time that babies born to women with preterm pre-eclampsia are admitted under neonatal hospital care. Other secondary aim: To determine whether metformin SR can increase neonatal birthweight in pregnancies complicated by preterm pre-eclampsia. METHODS We will perform a double blind randomised controlled trial of 500 women with preterm pre-eclampsia. Informed consent will be obtained. Pregnant women between the ages of 18 and 50 years who present with preterm pre-eclampsia at a gestation of 26+0 to 31+6 weeks at Tygerberg Hospital and considered stable enough to undergo expectant management will be randomised to receive either metformin SR or an identical placebo in divided doses daily.
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Actual trial start date 23/06/2022 Added start date 25 May 2022
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 23/06/2022 Changed status to recruiting Not yet recruiting Recruiting
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Publication URL 15/07/2024 Trial protocol has been published. https://bmjopen.bmj.com/content/14/6/e082880
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 20/04/2023 Changed acronym from ER (extended release) to SR (slow release) Experimental Group, Metformin XR, 1 gram of metformin XR three times a day, From recruitment until delivery, Metformin XR tablets, 250, Experimental Group, Metformin SR, 1 gram of metformin SR three times a day, From recruitment until delivery, Metformin SR tablets, 250,
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 09/04/2023 Letter confirming ethics approval FALSE, Stellenbosch University Health Research Ethics Committee, Stellenbosch University, Francie van Zyl Drive, Tygerberg, 7505, Cape Town, 7505, South Africa, 08 Mar 2021, , +27219389677, ethics@sun.ac.za, TRUE, Stellenbosch University Health Research Ethics Committee, Stellenbosch University, Francie van Zyl Drive, Tygerberg, 7505, Cape Town, 7505, South Africa, 08 Mar 2021, 10 Aug 2021, +27219389677, ethics@sun.ac.za, 15791_13156_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Funding Source FundingSources List 20/04/2023 Adding funder Merck Healthcare KGaA, 250 Frankfurter street, Darmstadt, , Germany, Commercial Sector / Industry,