Preeclampsia intervention trials

Pre-eclampsia is a disease of pregnancy that occurs when the placenta releases toxic substances into the mother's bloodstream. These toxins can affect vital organs such as the brain, kidneys, heart and liver. To this day, pre-eclampsia is a disease without a cure. 

A drug that could treat preeclampsia would be a major breakthrough for the health of women and babies. The Translational Obstetric Group at Mercy Perinatal have discovered a number of drugs that have the potential to treat severe preeclampsia.

Mercy Perinatal runs the world’s leading centre of clinical trials into treatments for preeclampsia. Our clinical trials unit is led by Professor Cathy Cluver based in South Africa (Mercy Perinatal ‘Fellow at Large’), and run in partnership with our friends, University of Stellenbosch. We have randomised far more women into preeclampsia treatment trials than any other centre in the world.

Over the last decade, Mercy Perinatal has been involved in eight clinical trials of candidate drugs to treat or prevent preeclampsia.

PIE – Clinical trial of esomeprazole

Laboratory studies done by Mercy Perinatal researchers a decade ago found esomeprazole may be effective treatment for preeclampsia. Esomeprazole is a tablet commonly taken to treat gastric reflux.

The PIE trial was a double blind, randomised controlled clinical trial to examine whether administering 40 mg esomeprazole daily could prolong gestation in women with early onset pre-eclampsia. Remarkably, the trial was completed in just over 12 months in Cape Town where 120 women were enrolled.

We published the trial findings  in the American Journal of Obstetrics and Gynaecology. While there was a trend towards benefit, it was not statistically significant.

We then run a small pharmacokinetics study where we measured drug levels in the blood. We concluded 40 mg might not have worked because the dose was too low to treat women with preeclampsia. A future trial that tests a higher dose might find the drug could be beneficial to treat preeclampsia.

A carefully curated biobank was collected from the entire PIE cohort as well. These samples have added value in aiding laboratory studies to advance our understanding of preeclampsia.

PI2 – Clinical trial of metformin

In 2016, researchers at Mercy Perinatal reported metformin may be a treatment for preeclampsia. Metformin is a tablet taken to treat diabetes, including those with diabetes that arises during pregnancy. Hence, it is likely to be safely given to pregnant women.

Given this, the team at South Africa undertook the PI2 trial (Preeclampsia Intervention 2). It was a randomised clinical trial recruiting 180 to see whether metformin could be useful in treating preterm preeclampsia.

Having learnt our lesson from esomeprazole, we did a pharmacokinetic study before we embarked on our main trial. We confirmed the hefty dose of 3 mg of daily metformin resulted in excellent blood levels of the drug when given to women with preterm preeclampsia.

We were pleased to find those treated with metformin delivered 1 week later, meaning the baby was born less preterm. The was a strong trend towards the newborns weighing heavier and spending less days in the neonatal nursery and going home earlier with mum. This suggests newborns in the metformin arm may have been born healthier.

PI2 was a major breakthrough as it identifies metformin as potentially the first disease modifying drug for preeclampsia ever discovered. However, the findings from PI2 needs validation before metformin can be used in the clinical worldwide.

Global network of metformin trials

To generate final proof that metformin can be used to treat preeclampsia, we are part of a consortium running three large metformin trials across three countries – South Africa, Sweden and the Netherlands. Mercy Perinatal researchers are leading one, co-leading another, and involved in the third.

Mercy Perinatal is leading PI3 trial, aiming to recruit 500 women with preterm preeclampsia. We are more than half way through recruiting.

We are partnering with friends to run similar trials in Sweden (PI4) and the Netherlands (PI-NL). At the end of these trials, we may find metformin as the first ever drug treatment for preeclampsia,

We have also started the APPLE PIE trial, a large clinical trial running at many sites across South Africa to see whether metformin can prevent preeclampsia from happening at all.

Clinical trial of DM199 a novel treatment

Working with a commercial company (Diamedica Therapeutics), the team in South Africa have commenced an early phase trial to test whether an interesting protein drug (called DM199) could be used to treat preeclampsia.

The Mercy Perinatal researchers are excited to partner with this company because this is a biological therapy. Pregnancy therapeutics have lagged behind other fields in devising novel drugs tailored to tackle specific diseases.

Clinical trial of sulfasalazine

Researchers at Mercy Perinatal have just completed an early phase clinical trial to test whether sulfasalazine – a drug they found in their drug discovery pipeline – could be a possible treatment for preeclampsia.

The team

Team members

• Professor Cathy Cluver, University of Stellenbosch, Cape Town
• Professor Stephen Tong
• Professor Sue Walker AO
• Professor Tu’uhevaha Kaitu’u-Lino
• Associate Professor Fiona Brownfoot
• Professor Natalie Hannan

Support

This research is supported by:

• Mercy Health Foundation
• Medical Research Council (UK)
• Merck KGaA
• Diamedica Therapeutics