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Trial registered on ANZCTR


Registration number
ACTRN12613000268741
Ethics application status
Approved
Date submitted
26/02/2013
Date registered
6/03/2013
Date last updated
24/11/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Treating early onset severe preeclampsia with pravastatin: an early phase clinical trial
Scientific title
In patients with early onset preeclampsia does the addition of pravastatin compared to current practice (historical cohort from 2006) lead to a reduction in symptoms and signs and prolongation of pregnancy?
Secondary ID [1] 282032 0
nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Preeclampsia 288483 0
Condition category
Condition code
Reproductive Health and Childbirth 288828 288828 0 0
Fetal medicine and complications of pregnancy
Reproductive Health and Childbirth 288829 288829 0 0
Antenatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
40mg oral pravastatin daily to women with early onset preeclampsia between 23 and 27+6 weeks gestation until delivery
Intervention code [1] 286621 0
Treatment: Drugs
Comparator / control treatment
We will use a historical retrospective cohort from the Mercy Hospital for Women Heidelberg to assess efficacy of treatment with pravastatin from 2006 to present. There is no treatment for preeclampsia so this cohort were observed and delivered when it was deemed necessary by the treating obstetrician.
Control group
Historical

Outcomes
Primary outcome [1] 288962 0
Reduction in proteinuria (24hour urine protein analysis)
Timepoint [1] 288962 0
2x weekly until delivery
This is routine management for preterm preeclamptic patients
Primary outcome [2] 289020 0
Prolongation of pregnancy (weeks from diagnosis of preeclampsia to delivery)
Timepoint [2] 289020 0
Assessed on a daily basis until delivery
This is routine management for preterm preeclamptic patients
Secondary outcome [1] 301453 0
liver dysfunction (blood analysis)
Timepoint [1] 301453 0
3x per week until delivery
This is routine management for preterm preeclamptic patients
Secondary outcome [2] 301586 0
renal dysfunction (blood analysis)
Timepoint [2] 301586 0
3 x per week until delivery
This is routine management for preterm preeclamptic patients
Secondary outcome [3] 301587 0
hematological dysfunction (blood analysis)
Timepoint [3] 301587 0
3 x per week until delivery
This is routine management for preterm preeclamptic patients
Secondary outcome [4] 301588 0
biomarkers of preeclampsia (soluble Flt, soluble endoglin, markers of endothelial dysfunction) via blood test
Timepoint [4] 301588 0
3 x per week until delivery
Secondary outcome [5] 301589 0
adverse effects (reported by participant or treating doctor)
We expect the proposed treatment will be safe and well tolerated. However we will observe for any fetal anomalies both on ultrasound and post delivery.We will observe the mother for rare side effects including myalgias, transient GIT symptoms, headache, insomnia, dizziness and transient elevated transaminases. We will also observe them for the more serious but very rare complications which include renal failure, hepatitis, liver failure, alopecia, paraesthesia, peripheral neuropathy and anaphylasis. Very rarely statins can lead to myopathy and rhabdomyolysis.
Timepoint [5] 301589 0
Daily until delivery

Eligibility
Key inclusion criteria
We will include women with a singleton pregnancy between 23+0 weeks to 32+6 weeks, diagnosed with preeclampsia as per the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) guidelines, confined to proteinuric preeclampsia between 0.5 – 1.5g per 24hour period at recruitment. This is because it is likely those with other organ involvement, or severe fetal growth restriction, are likely to be offered delivery very soon and it is unlikely there will be an adequate window of opportunity for the pravastatin to have effect.

Further inclusion criteria:
- the admitting clinicians have already made the decision not to immediately deliver.
- no major anomalies on morphology ultrasound
- Patient is capable of understanding the study and their involvement in it.
Minimum age
18 Years
Maximum age
50 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- The presence of growth restriction (<10th percentile) at the time of involvement
- Obvious organ involvement other than renal at the time of recruitment
- Current use of statins
- Contraindication to statins (liver failure, muscular disease, hypersensitivity, current use of erythromycin)

Note: these are only exclusion criteria at the time of recruitment. If these complications develop, patients will remain in the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will be recruited from The Mercy Hospital for Women in Heidelberg. At the Mercy, patients will be recruited from birth suite, antenatal wards or the emergency department. The study will be advertised to receiving and treating obstetrician colleagues.

Colleagues will refer patients once they are satisfied the diagnosis of early onset preeclampsia is correct and would otherwise be proceeding to monitoring the patient on the ward until they necessitated delivery.

The investigators, trained clinicians, will approach potential participants and firstly introduce and explain the study verbally and address any questions. We will provide written information (Patient information and consent form) that includes contact details of the investigators. Once the potential participant has had a chance to reflect on the information provided and agrees to participate, written consent will be obtained.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A historical retrospective cohort will be used
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Clinical variables and the clinical course will be presented as a descriptive statistics.

When comparing the outcomes against the historical cohort we will assess the number of patients that reached 30 and 32 weeks gestation in the trial with chi-squared analysis. We will also graph and compare change in the degree of proteinuria.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
9/04/2013
Actual
2/06/2014
Date of last participant enrolment
Anticipated
Actual
7/08/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
12
Accrual to date
Final
4
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 687 0
Mercy Hospital for Women - Heidelberg

Funding & Sponsors
Funding source category [1] 286808 0
Hospital
Name [1] 286808 0
The Medical Research Foundation for Women and Babies (Mercy Hospital for Women)
Country [1] 286808 0
Australia
Primary sponsor type
Hospital
Name
The Mercy Hospital for Women
Address
163 Studley Road
Heidelberg
Victoria 3084
Country
Australia
Secondary sponsor category [1] 285598 0
None
Name [1] 285598 0
Address [1] 285598 0
Country [1] 285598 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288875 0
Mercy Health HREC
Ethics committee address [1] 288875 0
163 Studley Road
Heidelberg
Victoria 3084
Ethics committee country [1] 288875 0
Australia
Date submitted for ethics approval [1] 288875 0
04/03/2013
Approval date [1] 288875 0
09/05/2013
Ethics approval number [1] 288875 0

Summary
Brief summary
Preeclampsia is pregnancy specific and complicates 5-8%. It is the leading cause of maternal and fetal morbidity and mortality. It is thought to occur as a result of abnormal attachment of the placenta to the uterine wall. This leads to a lack of oxygen and nutrient supply to the placenta. The ‘stressed’ and oxygen starved placenta releases ‘toxins’ that spread throughout the mother’s bloodsteam. They cause widespread injury of the mother’s blood vessels which then cause further damage to major organs: liver, kidneys and haematological impairment, nerves and the brain (causing seizures).

Despite considerable research the only treatment available is termination of the pregnancy or delivery. In women that develop the disease early in pregnancy this exposes the fetus to considerable risk of the serious complications of preterm delivery.
Pravastatin is a drug commonly taken by non-pregnant adults to lower the cholesterol in the blood. Importantly however, more recent research has found these drugs have also been shown to protect blood vessels. Therefore, it is possible they could mitigate the damage caused by the ‘toxins’ coming out of the placenta that injure the maternal blood vessels. If so, it could be potentially used as a treatment for severe preeclampsia. Just possibly, giving this drug to women with preterm preeclampsia might sufficiently quench the injury to the mother’s internal organs, allowing the pregnancy to safely continue to a gestation where the fetus is much less premature.

Impressively, pravastatin has been tested in many animal models of preeclampsia and found to improve the disease. Importantly pravastatin didn’t cause harm in these animal models or when taken inadvertently in human case studies to either the mother or the fetus/neonate.

We therefore propose a proof of concept early phase unblinded single arm study on the effect of pravastatin on the clinical course of early onset severe preeclampsia in humans. We will recruit 12 women and treat them with 40mg daily pravastatin. Inclusion criteria will be gestation 23+0 to 27+6 weeks, singleton pregnancy, with diagnosis of preeclampsia (increased blood pressure and high levels of protein in the urine).
Trial website
Trial related presentations / publications
Brownfoot FC, Tong S, Hannan NJ, Kinder NK, Walker SP, Cannon P, Hastie R, Onda K, Kaitu'u-Lino TJ. Effects of pravastatin on human placenta and women with severe preeclampsia. Hypertension 2015
Public notes

Contacts
Principal investigator
Name 38162 0
A/Prof Stephen Tong
Address 38162 0
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084
Country 38162 0
Australia
Phone 38162 0
+61 3 8458 4808
Fax 38162 0
Email 38162 0
[email protected]
Contact person for public queries
Name 38163 0
Fiona Brownfoot
Address 38163 0
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084
Country 38163 0
Australia
Phone 38163 0
+61 3 8458 4808
Fax 38163 0
Email 38163 0
[email protected]
Contact person for scientific queries
Name 38164 0
Fiona Brownfoot
Address 38164 0
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084
Country 38164 0
Australia
Phone 38164 0
+61 3 8458 4808
Fax 38164 0
Email 38164 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffects of Pravastatin on Human Placenta, Endothelium, and Women with Severe Preeclampsia.2015https://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05445
N.B. These documents automatically identified may not have been verified by the study sponsor.