Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial

Study design

Single-centre, phase III, double-blind, placebo-controlled randomised trial.

Duration of the trial

We anticipate that it will take 6 years to complete the trial (2022–2028), based on recruitment rates of our previous trials.7 10

Confidentiality

Patient confidentiality will be protected according to the regulations set forth by Stellenbosch University’s Human Research Ethics Committee or Institutional Review Board (IRB). Participants are free to withdraw from the study at any time and this will not affect clinical care. In the event of withdrawal, we will ask permission to use participant’s clinical information and laboratory samples collected thus far in subsequent analyses.

Data management

Data will be collected prospectively using a research electronic data capture (REDCap) database hosted at Stellenbosch University.11 Data entry and checking will be continuous, and queries will be addressed contemporaneously to ensure clarification without delay. All data will be double checked for accuracy and cleaned. Any queries will be addressed by reviewing source documents. The database will be locked before unblinding.

Study population

Pregnant women diagnosed with pre-eclampsia at a gestational age between 26+0 weeks and 31+6 weeks who are being managed expectantly for preterm pre-eclampsia by the Obstetric Special Care Unit, at Tygerberg hospital (Western Cape Provence of South Africa) will be invited to participate. To be eligible for inclusion, the treating clinicians must agree that the patient is suitable for expectant management of preterm pre-eclampsia and that delivery is not immediately required or anticipated in the next 48 hours.

Inclusion criteria

We will include women with a singleton pregnancy with preterm pre-eclampsia or chronic hypertension with superimposed pre-eclampsia, all defined according to the International Society for the Study of Hypertension In Pregnancy (ISSHP).12 We will also require the presence of significant proteinuria (more than 300 mg in a 24-hour urine collection). Tygerberg hospital is a referral centre servicing a population of over 2 million people. The Obstetrics Department only manages complicated pregnancies (such as those affected by preterm pre-eclampsia) and delivers more than 8000 women per year.

Gestational age will be determined by either last normal menses dates (if the woman is certain of her last menstrual period) or by an early, or mid trimester pregnancy ultrasound. If the gestational age is uncertain, we will recruit participants with an estimated fetal weight between 500 and 1800 g, determined by ultrasound performed at presentation. A full list of inclusion criteria is provided in box 1 and are the same as the PI 2 trial.13

Exclusion criteria

We will exclude the following women from the trial: those who do not qualify for expectant management (delivery is anticipated in the next 48 hours) are already using metformin or have contraindications to using metformin. We will also exclude women with diabetes. The exclusion criteria are similar to the PI 2 trial (box 2).13

Participant enrolment

Potential participants will be identified after they are admitted to Tygerberg Hospital with a diagnosis of preterm pre-eclampsia and deemed suitable for expectant management by the Obstetric Special Care Unit (ie, their disease is not so severe as to require immediate birth).13 A trial information leaflet and a consent form will be given to potential participants (see online supplemental material). Written informed consent will be obtained before recruitment.

Randomisation and allocation concealment

Women will be randomised to metformin XR or an identical placebo in a 1:1 ratio. We will use an online, web-based sequence generator system, managed by TASK (a South African headquartered, multinational clinical research institute: https://www.task.org.za/). Researchers and participants will be blinded until the database has been locked.

Gestation at enrolment may be a potential predictor for the outcome. To ensure that treatment group allocation is balanced, we will stratify by gestational age. Stratum 1 will include gestational ages between 26+0 up to and including 28+6 weeks gestation. Stratum 2 will include gestational ages from 29+0 up to and including 31+6 weeks gestation.

Once women are randomised, the allocated treatment pack will be dispensed to the participant. All treatment packs will be identical and will contain either active tablets or placebo. The researchers will have no access to the randomisation list. This process will ensure that there is allocation concealment throughout the conduct of the trial. Only the trial pharmacist who packages the trial medication will have access to the randomisation listing.

Active and placebo tablets will be produced in bulk by Merck Healthcare, KGaA, Darmstadt, Germany (https://www.merckgroup.com/en) and supplied to the trial pharmacy (https://www.task.org.za/services/clinical-pharmacy/). The trial pharmacy will be responsible for packaging and labelling the trial medication according to the requirements of the South African Health Products Regulatory Authority (SAHPRA) (https://www.sahpra.org.za/). Treatment packs will be delivered to the trial site where they will be kept in a locked, temperature-monitored storage area until they are dispensed after randomisation.

Once a participant has been included and randomised, they will receive a treatment pack and diary. Each pack will contain treatment for 3 weeks. A second treatment pack will be available for each participant if needed. This will be used if they remain pregnant for more than 3 weeks, or if the original treatment pack is lost or damaged. The packs will either contain 500 mg metformin XR or identical placebo tablets. They will be identical in shape, colour, weight and feel. The treatment pack will be labelled with the participants name and trial number. Participants will start by taking one tablet three times a day. If they develop side effects, the dose will be decreased until the drug is tolerated. If the participant is able to increase the dose, it will be increased to a maximum of two tablets three times a day until birth. Each participant will be given a treatment diary to monitor compliance and side effects. Research nurses will monitor the treatment diary daily.

Metformin XR may interact with certain medications like dolutegravir and rifampicin. Dolutegravir is an integrase inhibitor used in a fixed highly active antiretroviral therapy combination called TLD (Tenofovir Disoproxil Fumurate (TDF), Lamivudine (3TC) and Dolutegravir (DTG)). TLD is used as first-line treatment to treat HIV/AIDS in South Africa. In pharmacokinetic studies, dolutegravir increases metformin plasma exposure, possibly by organic cation transporter 2 inhibitions.14 For this reason, if a participant is taking TLD, she will be limited to a maximum dose of 1500 mg Metformin XR daily.

Rifampicin is used to treat tuberculosis which is endemic to South Africa. Pharmacokinetic studies have shown that metformin exposure is increased when coadministered with rifampicin.15 It is hypothesised that the increased exposure is due to increased absorption as renal clearance and tubular secretion were unaffected by rifampicin. Because of the increased exposure, we will also limit women who are taking rifampicin to a maximum dose of 1500 mg Metformin XR daily.

Once the infant is born, the treatment pack will be collected, and a pill count will be performed.

Cointerventions

Participants will remain under the care of the Obstetric Special Care management team. The study will not interfere with routine care provided for women with preterm pre-eclampsia, including the decision to deliver the pregnancy. Management for preterm pre-eclampsia involves admission to hospital with close maternal and fetal surveillance. The Obstetric Special Care Unit follows a strict protocol for expectant management for preterm pre-eclampsia. Maternal surveillance includes 4 hourly blood pressure measurement, two times daily clinical assessment, daily urinalysis and two times weekly assessments with blood tests that monitor signs of disease progression (full blood count, renal function tests and hepatocellular enzymes if haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is suspected). Fetal surveillance includes 6 hourly cardiotocography. Ultrasound assessments are done every 2 weeks (or more frequently if clinically indicated) to assess fetal growth.16

Indications for delivery will be a clinical decision (made independently from the research team) and may include inability to achieve blood pressure control, the development of major maternal or fetal complications or intrauterine fetal death. At Tygerberg hospital, it is part of the protocol to end expectant management at 34 weeks gestation.

All participants receive two doses of betamethasone at the time of admission, 24 hours apart, to reduce the risks of neonatal respiratory distress syndrome, intracranial haemorrhage and necrotising enterocolitis. A single dose may be repeated 1 week later as per hospital protocol.16 Most participants will be on antihypertensive treatment, and the dose and number of antihypertensives will be recorded.

Sample collection

Blood samples are collected routinely twice a week for measurements of the haemoglobin, the platelet count, urea and creatinine levels. These are used by clinicians to determine disease progression and severity and it may trigger a decision to deliver the pregnancy. Plasma samples will be collected at each routine blood draw and stored in an ultra-low temperature freezer for analysis after the trial is completed. They will be analysed for biomarkers known to be associated with pre-eclampsia.

Outcomes

The primary outcome is prolongation of pregnancy, measured from the time of enrolment to the time of delivery, in hours and days. The primary endpoint will be considered as right censored if delivery is induced at 34 weeks of gestation with no other fetal or maternal indications of delivery.

There are two secondary outcomes. The first secondary outcome will be to determine if metformin XR can reduce the time from birth to neonatal discharge from hospital. For neonates that are not admitted for neonatal care, the length of stay in neonatal care will be zero. Neonatal death or stillbirth will be considered a competing event. With this method, stillborn babies and babies that die during neonatal care will remain in the risk set also after death and hence contribute to a longer length of neonatal stay. Length of stay in neonatal care will be considered a confirmatory finding if both prolongation of pregnancy and time to neonatal discharge to home are statistically significant. The other secondary outcome will be birth weight. We aim to determine whether metformin can increase birth weight of babies born to women with preterm pre-eclampsia. This will also be considered a confirmatory finding if both the primary and both secondary outcomes are statistically significant.

All other outcomes, including a composite maternal and a composite perinatal outcome will be classified as exploratory outcomes (table 1). We will monitor for known side effects of metformin including nausea, vomiting and diarrhoea. The pre-eclampsia research endpoints were chosen using a consensus core outcome set.17

Statistical methodology

Numerical variables will be summarised with mean and SD, median and IQR and range (minimum and maximum value). Categorical variables will be summarised as number and percent. All randomised subjects will be included in the efficacy analyses according to the intention-to-treat principle.

Sample size

The target sample size was set to 500 women to fulfil the following:

• 90% power to detect a 50% prolongation of gestation (mean log difference=0.405) with metformin XR compared with placebo (primary outcome). This corresponds to a 5 day prolongation from 10 to 15 days and hence comparable to the results of the PI 2 trial.10 Assumptions were a coefficient of variation=2.04 (log SD=1.28 in both groups), log-normal distribution, two-sample t-test on log-transformed data, significance level alpha=0.05, two-sided test. This requires a total sample size of n=422 women.

• 90% power to detect median difference of 9 days in length of neonatal stay with metformin XR compared with placebo (main secondary outcome). This is 3 days less than that found in post-hoc PI2 analysis.10 Assumptions included a median length of neonatal stay of 30 days in the placebo group, subdistribution HR=0.70 with metformin XR compared with placebo and 20% censoring (withdrawal) or competing events (stillbirths or neonatal deaths). This requires a total sample size of n=422 women.

• Sample size uplift by 18% to account for participants stopping trial medication, resulting in a total sample size of n=500 women. With this sample size, we also have 80% to detect a 10% increase in neonatal birth weight (minor secondary outcome), assuming a coefficient of variation=0.37, which is similar to that found in post-hoc PI 2 analysis.10

Serious adverse events

Reporting and handling of serious adverse events will be in accordance with good clinical practice guidelines. Serious adverse events will be reported to the principal investigator by the research midwife. Within 24 hours of reporting, the Data Safety and Monitoring Committee, the Ethics Committee and the South African Health Products Regulatory Authority will be notified. Table 2 lists potential adverse and serious adverse events.

Protocol violations and deviations

All protocol violations and deviations will also be reported to the clinical trial monitor and Data Safety and Monitoring Committee, the Ethics Committee and the South African Health Products Regulatory Authority. All violations and deviations will be reported in the final publication.

Unblinding

If unblinding is required, the principal investigator will be contacted (CAC). She will contact the randomisation centre. Ideally, the principal investigator will remain blinded, and a member of the randomisation team will contact the clinical team directly. If there is a clinical need to unblind the principal investigator, this will be approved by the Data Monitoring Safety Committee.

Early termination of the trial

Any decision for early termination of the trial can be made by the Data Safety and Monitoring Committee and trial sponsor.

Patient and public involvement

We have run a study assessing women’s perspectives on types of therapeutics and what they view as important outcomes. In small group interactions, women have expressed that the most important outcome is the health of their baby (unpublished data). We have therefore added neonatal outcomes as secondary outcomes. Our research group is facilitating the development of a South African patient organisation for pre-eclampsia. The results of the PI 3 trial will be made publicly available on our website (www.preeclampsiaresearch.org).