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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]

nil

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Preeclampsia

Condition category

Condition code

Reproductive Health and Childbirth

Fetal medicine and complications of pregnancy

Reproductive Health and Childbirth

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]

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]

Reduction in proteinuria (24hour urine protein analysis)

Timepoint [1]

2x weekly until delivery
This is routine management for preterm preeclamptic patients

Primary outcome [2]

Prolongation of pregnancy (weeks from diagnosis of preeclampsia to delivery)

Timepoint [2]

Assessed on a daily basis until delivery
This is routine management for preterm preeclamptic patients

Secondary outcome [1]

liver dysfunction (blood analysis)

Timepoint [1]

3x per week until delivery
This is routine management for preterm preeclamptic patients

Secondary outcome [2]

renal dysfunction (blood analysis)

Timepoint [2]

3 x per week until delivery
This is routine management for preterm preeclamptic patients

Secondary outcome [3]

hematological dysfunction (blood analysis)

Timepoint [3]

3 x per week until delivery
This is routine management for preterm preeclamptic patients

Secondary outcome [4]

biomarkers of preeclampsia (soluble Flt, soluble endoglin, markers of endothelial dysfunction) via blood test

Timepoint [4]

3 x per week until delivery

Secondary outcome [5]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Mercy Hospital for Women - Heidelberg

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

The Medical Research Foundation for Women and Babies (Mercy Hospital for Women)

Address [1]

The Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084

Country [1]

Australia

Primary sponsor type

Hospital

Name

The Mercy Hospital for Women

Address

163 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Mercy Health HREC

Ethics committee address [1]

163 Studley Road 
Heidelberg    
Victoria    3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

04/03/2013

Approval date [1]

09/05/2013

Ethics approval number [1]

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

A/Prof Stephen Tong

Address

Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61 3 8458 4808

Fax

[email protected]

Contact person for public queries

Name

Fiona Brownfoot

Address

Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61 3 8458 4808

Fax

[email protected]

Contact person for scientific queries

Name

Fiona Brownfoot

Address

Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61 3 8458 4808

Fax

[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

Source	Title	Year of Publication	DOI
Embase	Effects of Pravastatin on Human Placenta, Endothelium, and Women with Severe Preeclampsia.	2015	https://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05445

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically