A Proof of Principle Randomised Placebo-Controlled Trial for Use of Statins to Ameliorate Early Onset Preeclampsia

Lead Research Organisation: Aston University
Department Name: Sch of Life and Health Sciences

Abstract

Preeclampsia (PE) is a potentially dangerous condition of pregnancy in which the mother?s blood pressure is higher than normal and there is protein in the urine. About 1 in 100 women experience preeclampsia before 32 weeks of pregnancy. The only effective treatment is to deliver the baby prematurely, but this has serious consequences for the baby. Watchful waiting, often employed clinically to allow the baby?s lungs to mature, risks progression of disease severity in the mother. A cheap and effective therapy for prevention of preeclampsia complications is urgently needed.

It is not known what causes preeclampsia but recently some blood molecules (called anti-angiogenic factors) known to affect blood flow are higher in women with PE. These anti-angiogenic factors when given to pregnant animals mimic preeclampsia. Drugs called statins, which lower cholesterol, reduce the levels of these molecules. It is not known whether statins can reduce the severity and complications of preeclampsia.

We will test the idea that statins can reduce these molecules in preeclamptic women before 32 weeks of pregnancy and decrease the severity of preeclampsia. Doctors from six hospitals will seek consent from these women. Those who are suitable and agree, will be randomly divided into two groups. One group will get a daily dose of statin. The other will get a dummy sugar pill (placebo). We hope to recruit 128 women. Neither the women nor their doctors will know what group they are in. In this way, we can be confident that any differences between the two groups are due to treatment. Women will stay in hospital and be closely monitored, and if the preeclampsia gets worse, their baby will be delivered.

This trial is unique because it is the first to test whether statins can reduce the severity of preeclampsia and because statins are not prescribed normally to pregnant women. There is some concern that statins may cause congenital defects in the baby, but we have found no convincing evidence to support this. Furthermore, we believe it is safe to give statins later in pregnancy once the baby?s organs have already developed. However, all side effects and complications will be closely monitored.

If this small trial shows that the severity of preeclampsia is reduced, and there are few side effects, a bigger trial will be organised to determine if statins can increase the length of pregnancy and reduce the number of premature deliveries.

Technical Summary

Preeclampsia (PE) is a systemic endothelial disease characterised by hypertension, proteinuria, exacerbated inflammation, dysregulated angiogenesis and can lead to morbidity and mortality in both mother and baby. Currently the only effective treatment for PE is delivery of the baby. However, early delivery, especially before 32 weeks gestation, often has serious consequences for the health of the baby. A cheap and effective therapy for prevention of PE complications is urgently needed. Increasing evidence shows that excess circulating soluble Flt-1 (sFlt-1) plays a role in the pathogenesis of PE. We showed that statins (HMG-CoA reductase inhibitors), a class of lipid-lowering drugs, inhibit cytokine-mediated release of sFlt-1 in ex vivo human placental model. This IES platform will test the hypothesis that statin use during early onset PE would lead to a significant reduction of sFlt-1 and alleviate the severity of PE. We will undertake a proof of principle randomised placebo-controlled multi-centre RCT trial for use of statins to ameliorate early onset PE. A minimum of 128 pregnancies will be randomised from six maternity units in the UK. Minimum inclusion clinical criteria will be gestational age range of 24-32 weeks with new onset hypertension; systolic 140mmHg and diastolic 90mmHg; Protein/creatinine ratio 30mg/mmol or 300mg proteinuria/24 hours. Consenting mothers will be randomised to receive either 40mg pravastatin capsules once a day or identical placebo until delivery with conservative management of their PE. The primary outcome measures will be changes in plasma levels of biomarkers (sFlt-1/sEng/PlGF). Secondary outcomes measures will be severity of PE, prolongation of pregnancy post treatment, maternal and neonatal outcomes and adverse effects. We will also formally assess the feasibility of a definitive trial by examining recruitment rates, compliance and physcian and patient readiness for randomisaiton to statins. This study will identify a novel intervention based on strong scientific rationale, which will inform a future large-scale multi-centre randomised trial.
 
Description Rationale for statin use in preeclampsia
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Biotech are making contact to take our approach to therapy.
 
Description Health Technology Assessment programme
Amount £700,000 (GBP)
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2012
 
Title PreDict 
Description We have identified potentially a new biomarker using our mouse model, which we are planing to test in our human population samples. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Too early to talk about it as its too preliminary. 
 
Description Trial Centres 
Organisation Birmingham Women's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Description Trial Centres 
Organisation Guy's and St Thomas' NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Description Trial Centres 
Organisation Heart of England NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Description Trial Centres 
Organisation Imperial College Healthcare NHS Trust
Country United Kingdom 
Sector Hospitals 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Description Trial Centres 
Organisation Liverpool Womens NHS Foundation Trust
Department Liverpool Women's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Description Trial Centres 
Organisation NHS Lothian
Country United Kingdom 
Sector Public 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Description Trial Centres 
Organisation Newcastle upon Tyne Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Description Trial Centres 
Organisation Sandwell and West Birmingham Hospitals NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Description Trial Centres 
Organisation University College London Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Description Trial Centres 
Organisation University Hospital of North Staffordshire NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution We have coordinated and pooled all these centres to work with us on this trial.
Collaborator Contribution Recruitment of patients to StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmp trialRecruitment of patients to the StAmP trialRecruitment of patients to the StAmP trial
Impact This is too early to report.
Start Year 2010
 
Title Abbott Diagnostics Inc. 
Description Established collaboration and obtained joint MRC Strategic funds in Translational Medicine. However, Abbott Diagnostics Inc. later pulled out due to financial downturn. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2009
Development Status Closed
Impact Potentially it could lead to early diagnosis of preeclampsia which will allow StAmP trial output to provide a potential treatment for such patients. 
 
Title StAmP 
Description Statins for use in Preeclampsia 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2008
Development Status Under active development/distribution
Impact World's first RCT underway. - StAmP. 
 
Description BBC Regional News 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact BBC Regional News (TV) - Other UK
Place duration: 3:14
Date of coverage 20/04/11

Patients called to learn more about the trial and when they could see benefits
Year(s) Of Engagement Activity 2011
 
Description Central FM 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Heart disease trials



N/A
Year(s) Of Engagement Activity 2011
 
Description STV 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 5-7 min feature news

N/A
Year(s) Of Engagement Activity 2011
 
Description The Daily Express 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Heart disease drug that could help beat deadly disease in mums-to-be

N/A
Year(s) Of Engagement Activity 2011
 
Description The Daily Mail 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Heart pill may help slash the pregnancy death toll

contacted by public following this
Year(s) Of Engagement Activity 2011
 
Description The Daily Telegraph 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Statins could treat pregnant women at risk of fatal condition

increased public awareness for the condition of preeclampsia
Year(s) Of Engagement Activity 2011
 
Description The Sun 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact "Drugs to save tots" was the headline.

N/A
Year(s) Of Engagement Activity 2011