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Statins to Ameliorate early onset Pre-eclampsia
ISRCTN ISRCTN23410175
DOI 10.1186/ISRCTN23410175
ClinicalTrials.gov identifier
EudraCT number 2009-012968-13
Public title Statins to Ameliorate early onset Pre-eclampsia
Scientific title A proof of principle, double-blind, randomised placebo-controlled, multicentre trial of pravastatin to ameliorate early onset pre-eclampsia
Acronym StAmP
Serial number at source MRC ref: G0701824, MRCIES10215; Sponsor ref: UCLH08/0350
Study hypothesis The aim of the trial is to establish whether a significant reduction of angiogenic markers by statins will alleviate the severity of early-onset pre-eclampsia (PE) in women. To test this hypothesis, we will ask the following questions:
1. Do statins, compared to placebo, inhibit anti-angiogenic factors in women with early-onset PE?
2. If this principle is established, how best can a substantive trial/health technology assessment be undertaken to develop guidance for routine use of statins in PE?
3. Are there any adverse effects to the mother or the baby?

Protocol can be found at: http://www.birmingham.ac.uk/Documents/college-mds/trials/bctu/stamp/Stamp-protocol-version-7-0-22-11-2013.pdf

On 27/09/2010 this record was extensively updated to include changes to the protocol. At this time, the scientific title of this trial was amended from ‘A proof of principle randomized controlled trial for use of statins to ameliorate early severe pre-eclampsia’ to the above scientific title. All other changes can be found in the relevant field with the above update date. At this time, the anticipated start and end dates of this trial were also amended; the initial trial dates at the time of registration were as follows:
Initial anticipated start date: 01/04/2009
Initial anticipated end date: 31/03/2011

On 14/01/2013 the following changes were made to this trial record:
1. The anticipated start date for this trial was updated from 01/12/2010 to 01/06/2011
2. The anticipated end date for this trial was updated from 01/06/2012 to 30/09/2013

On 26/06/2014 the following changes were made to this trial record:
1. The anticipated end date was changed from 30/09/2013 to 31/07/2014
2. The target number of participants was changed from 128 to 64
Lay summary Background and study aims
Pre-eclampsia is a serious condition of pregnancy, where the mother develops high blood pressure and high levels of protein in the urine (proteinuria). There are no effective drug treatments for pregnant women to reverse pre-eclampsia. Drugs can be given to help reduce blood pressure and prevent seizures. Doctors monitor the mother’s blood pressure, blood tests and the baby’s wellbeing and then recommend birth of the baby if the mother or her baby’s health is threatened. However, if pre-eclampsia develops between 24-32 weeks and the baby is born prematurely, he or she will almost always need special care on a neonatal unit. Recent scientific research has identified that changes in some specific blood chemicals (biomarkers) can lead to pre-eclampsia. Initial studies on samples of placenta and blood vessels, as well as animal experiments, suggest that statins can reduce the level of these blood chemicals, and perhaps reduce or eliminate the effects and risks of pre-eclampsia. This study is the first step in determining if these same beneficial effects are seen in pregnant women.

Who can participate?
Pregnant women with severe pre-eclampsia.

What does the study involve?
Participants will not have to do anything extra if they take part in the study. The pre-eclampsia will be managed carefully in the usual way by the same doctors who would normally look after the pregnancy. The only difference will be the taking of an extra capsule each day until delivery, either pravastatin or an identical looking placebo (sugar) capsule. This is in addition to any other drugs that the doctors think is appropriate for the pre-eclampsia. Neither the woman nor her doctor can choose which treatment is given. The decision is made randomly by computer at the trial office. This is essential so that a fair comparison can be made between the two treatment groups. Clinical information about the mother and her baby’s health will be collected from your medical notes every day, including your blood pressure, protein in the urine and side effects. Routine monitoring will also involve taking regular blood and urine samples, which will also be used to measure specific blood chemicals (biomarkers) thought to be important in pre-eclampsia. Permission will also be sought to take a sample of blood from the umbilical cord and samples of the placenta, following delivery. We will only do this if the umbilical cord blood or placenta would otherwise be discarded. The blood samples will be used to measure the level of treatment drug. The placenta samples will be used to measure specific blood chemicals thought to be important in pre-eclampsia and also to measure the level of treatment drug that passes into your baby's bloodstream. Once the participant has left hospital, she will be asked to come back once or twice, until her baby is 6 weeks old, for check-ups, with further blood samples from the mother.

What are the possible benefits and risks of participating?
All drugs have side-effects, but we do not anticipate any side effects of the study drugs in the relatively short time that they are taken. Statins are taken by millions of non-pregnant people worldwide and side effects are rare. Participants are encouraged to tell their doctor if they feel ill in any way at all, so that the doctor can check to see whether the pre-eclampsia is worsening or if it is a side effect of the drug. Participants may not gain any individual benefit, as only half of the women taking part will receive pravastatin whilst the other half will receive a dummy (placebo) drug. We hope pravastatin will help improve the symptoms and problems associated with pre-eclampsia, so some participants may feel better and their baby may not need to be born early. However, we cannot be sure in advance whether this is the case – that is the reason for doing this trial. The main benefit from this study will be that the information gained will help improve the treatment of women with pre-eclampsia in the future.

Where is the study run from?
Birmingham Clinical Trials Unit, University of Birmingham (UK).

When is the study starting and how long is it expected to run for?
The study started in June 2011 and will run until July 2014.

Who is funding the study?
Medical Research Council (UK).

Who is the main contact?
Prof Asif Ahmed
asif.ahmed@aston.ac.uk
Ethics approval Wales Research Ethics Committee, 03/09/2010, ref: 10/MRE09/10
Study design Double-blind randomised placebo-controlled trial
Countries of recruitment United Kingdom
Disease/condition/study domain Pre-eclampsia
Participants - inclusion criteria Current inclusion criteria as of 27/09/2010:
To be eligible for the StAmP Trial, the women must:
1. Be between 24+0 weeks' and 31+6 weeks' gestation
2. Have a singleton pregnancy
3. Have a diagnosis of early onset pre-eclampsia
4. Be considered capable of safely continuing the pregnancy for 48 hours or more, as determined by the attending clinician
5. Obstetrician and neonatologist believe the fetus is likely to be viable
6. No major anomalies evident on the 20-week anomaly scan. Any anomaly should be assessed by the Principal Investigator and discussed with the Chief Clinical Investigator, following classification of the anomaly according to the ICD-10 codes. All major anomalies will be excluded, but minor anomalies, subject to agreement between the PI and CI will be included
7. Be capable of understanding the information provided, with use of an interpreter if required
8. Give written informed consent

Previous inclusion criteria:
To be eligible for the StAmP Trial, the women must:
1. Be at least 24 weeks and less than 33 weeks' gestation (no age limits on participant)
2. Have a diagnosis of pre-eclampsia
3. Have a normal cardiotocograph
4. Be considered capable of safely continuing the pregnancy for 12 hours or more
5. Be capable of understanding the information provided, with use of interpreter if required
6. Give written informed consent
Participants - exclusion criteria Current exclusion criteria as of 27/09/2010:
Any women, who at the point of randomisation, exhibit any of the following are not eligible for the trial:
1. Eclampsia
2. Current use of statins
3. Contraindications to statin use (other than pregnancy) including:
3.1. Hypersensitivity to pravastatin or any of its excipients
3.2. Active liver disease or elevation of serum transaminases not thought to be related to pre-eclampsia
3.3. Pre-pregnant renal insufficiency (creatine clearance less than 30 ml/min)
3.4. Concomitant administration of potent CYP3A4 inhibitors
4. Imminent transfer to a non-trial centre due to unavailability of neonatal cots
5. Participation in any other blinded, placebo-controlled trials of investigational medicinal products in pregnancy
6. Significant uncertainty regarding gestational age. Under 24 weeks' gestation, pregnancies are often not considered viable and therefore women with pre-eclampsia less than 24 weeks gestation will be excluded. Women with pre-eclampsia around 32 weeks' gestation are often delivered when the mother is stable and therefore we will exclude women who develop pre-eclampsia over 32 weeks' gestation. For this reason, if there is any uncertainty about the gestational age, the mother should not be approached for randomisation.

Previous exclusion criteria:
Any women, who at the point of randomisation, exhibits any of the following symptoms or contraindications, are not eligible for the trial:
1. Eclampsia
2. Absent or reversed end-diastolic flow
3. Pre-pregnant or continuing use of statins
4. Contraindications to statin use (other than pregnancy)
Anticipated start date 01/06/2011
Anticipated end date 31/07/2014
Status of trial Completed
Patient information material Patient information can be found at: http://www.birmingham.ac.uk/Documents/college-mds/trials/bctu/stamp/Stamp-PIS-version-6-0-22-11-13.pdf
Target number of participants 64
Interventions On 27/09/2010 the drug of treatment was changed to pravastatin; this was previously simvastatin.

Oral pravastatin, 40 mg, or placebo, once daily until delivery of the baby.
Primary outcome measure(s) Effect of statins on soluble fms-like tyrosine kinase 1 (sFlt-1) at 48 hours post-randomisation.
Secondary outcome measure(s) Maternal:
1. Blood pressure and proteinuria at delivery
2. Use of anti-hypertensives during pregnancy and until 1 month post delivery
3. Severe morbidity (Haemolysis, Elevated Liver enzyme levels and a Low Platelet count [HELLP], cerebrovascular accident [CVA]). Duration of follow-up: until 1 month post-delivery.
4. Days in high dependency unit
5. Total hospital stay
6. Mortality (up to 42 days post delivery)
7. Drug adverse effects during pregnancy

Neonatal outcomes:
1. Apgar at 5 min
2. Birth weight
3. Complications of prematurity (retinopathy, necrotizing enterocolitis [NEC], intraventricular haemorrhage [IVH])
4. Days in special care dependency unit
5. Mortality up to 28 days old
6. Drug adverse effects apparent at delivery
7. Congenital anomalies
Sources of funding Medical Research Council (UK) (ref: G0701824, MRCIES10215)
Trial website http://www.birmingham.ac.uk/stamp
Publications
Contact name Prof  Asif  Ahmed
  Address Aston University
Life & Health Sciences
Aston Triangle
  City/town Birmingham
  Zip/Postcode B4 7ET
  Country United Kingdom
  Email asif.ahmed@aston.ac.uk
Sponsor University College London Hospitals NHS Foundation Trust (UK)
  Address (Chief Investigator: Dr David Williams)
c/o Ms Salwa Beydoun
Joint UCLH/UCL Biomedical Research and Development (R&D) Unit
(1st Floor, Maple House)
Ground Floor, Rosenheim Wing
25 Grafton Way
  City/town London
  Zip/Postcode WC1E 6DB
  Country United Kingdom
  Email a.downey@ucl.ac.uk
  Sponsor website: http://www.uclh.nhs.uk
Date applied 17/11/2008
Last edited 27/06/2014
Date ISRCTN assigned 08/05/2009
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