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Trial registered on ANZCTR

Registration number

ACTRN12617000226303

Ethics application status

Approved

Date submitted

6/10/2016

Date registered

13/02/2017

Date last updated

18/04/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Treating preterm preeclampsia with sulfasalazine: An early phase clinical trial

Scientific title

Pharmacokinetics of sulfasalazine for the treatment of preterm preeclampsia: An early phase clinical trial

Secondary ID [1]

Nil known

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

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

3 grams of sulfasalazine will be administered orally daily to participants until they require delivery. Patients will be admitted and adherence monitored using the in patient drug chart.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

1) Our primary outcome is to assess the pharmacokinetic profile of sulfasalazine in patients with preeclampsia. Pharmacokinetic parameters include maximum concentration (Cmax) and time to maximum concentration (Tmax), area under the concentration time curve (AUC), apparent oral clearance (CL/F), half life and renal clearance.

2) These will be assessed in maternal blood and urine over a 24 hour period. We will also assess sulfasalazine levels in maternal blood, cord blood and placenta at delivery.

Timepoint [1]

* Serial blood samples of 6 mls will be collected over one 24 hour period, after at least 24 hours of sulfasalazine treatment, to assess levels of sulfasalazine levels at 0, 2, 4, 8, 12 and 24 hours.
* Urine will be collected before the dose, and then at 0-4, 4-8, 8-12 and 12-24 hours and sulfasalazine excretion assessed.
* Maternal, umbilical cord and placenta will be collected at time of delivery to assess sulfasalazine and sulfapyridine levels.

Secondary outcome [1]

To determine the effects of sulfasalazine on clinical markers of preeclampsia including:
Headache. This will be assessed by asking the patient daily whether they have a headache.

Timepoint [1]

This will be examined daily antenatally and postnatally until patient discharge.

Secondary outcome [2]

Biochemical markers of preeclampsia including full blood count in particular haemoglobin and platelet count, electrolytes: including creatinine, urea and uric acid and coagulation profile using a serum blood sample.

Timepoint [2]

These will be examined daily antenatally and postnatally until patient discharge.

Secondary outcome [3]

In the fetus/neonate we will assess mortality

Timepoint [3]

This will be obtained by accessing the patient records.

Secondary outcome [4]

Visual symptoms. This will be assessed by asking the patient daily whether they have spots in their vision or any visual disturbance.

Timepoint [4]

This will be assessed daily until patient discharge.

Secondary outcome [5]

Right upper quadrant abdominal pain. This will be assessed by asking the patient daily whether they have abdominal pain.

Timepoint [5]

This will be assessed daily until discharge

Secondary outcome [6]

Severe hypertension (blood pressure of systolic greater than or equal to 160 and diastolic greater than or equal to 110).

Timepoint [6]

This will be assessed daily until discharge

Secondary outcome [7]

Electrolytes: including creatinine, urea and uric acid using a serum blood sample.

Timepoint [7]

This will be examined daily until delivery

Secondary outcome [8]

coagulation profile in patient serum.

Timepoint [8]

This will be assessed as decided by the treating clinician

Secondary outcome [9]

proteinuria

Timepoint [9]

This will be assessed daily until delivery.

Secondary outcome [10]

In the neonate neurological morbidity including intraventricular haemorrhage diagnosed with clinical examination and ultrasound.

Timepoint [10]

This outcome will be assessed by paediatricians daily after delivery to the date of discharge of the neonate.

Secondary outcome [11]

In the neonate respiratory morbidity including respiratory distress syndrome will be assessed clinically by paediatricians and with x-ray if clinically indicated.

Timepoint [11]

This outcome will be assessed by paediatricians daily after delivery to the date of discharge of the neonate.

Secondary outcome [12]

In the neonate retinopathy of prematurity will be assessed clinically by the paediatrician.

Timepoint [12]

This outcome will be assessed daily by paediatricians after delivery to the date of discharge of the neonate.

Secondary outcome [13]

In the neonate gastrointestinal morbidity including necrotising enterocolitis will be assessed clinically by the paediatrician.

Timepoint [13]

This outcome will be assessed by paediatricians daily after delivery to the date of discharge of the neonate.

Eligibility

Key inclusion criteria

The diagnosis of preeclampsia will be made using the Society of Obstetric Medicine Australia and New Zealand guidelines. Eligible women will be 18 years or older with singleton, non-anomalous pregnancies between 30+0 and 36+0 weeks gestation.

Minimum age

18 Years

Maximum age

45 Years

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

We will exclude women with multiple pregnancy, known fetal malformation, contraindication to sulfasalazine treatment, women already taking sulfasalazine and women with an immunodeficiency disorder.

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)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Who is / are masked / blinded?

Intervention assignment

Other design features

Phase

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

1/03/2017

Actual

31/01/2018

Date of last participant enrolment

Anticipated

Actual

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

Recruitment hospital [2]

Sunshine Hospital - St Albans

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3021 - St Albans

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Norman Beischer Medical Research Foundation

Address [1]

Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria
3084

Country [1]

Australia

Primary sponsor type

Hospital

Name

Mercy Hospital for Women

Address

Mercy Hospital for Women
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 Human Research Ethics Committee

Ethics committee address [1]

Mercy Hospital for Women
163 Studley Road
Heidelberg 
Victoria
3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

10/10/2016

Approval date [1]

12/01/2017

Ethics approval number [1]

R16/65

Summary

Brief summary

Preeclampsia is a common, serious complication of pregnancy and leading cause of maternal, fetal and neonatal death and disability. Currently there is no medical treatment and the only way to stop disease progression is to deliver the pregnancy. At early gestations this inflicts the serious risks of prematurity on the newborn whilst the mother is exposed to the risk of disease progression during the delivery process. A treatment that stabilises the disease to allow the safe prolongation of pregnancy would be a major advance. 

Excitingly we have discovered that a medication safe in pregnancy, sulfasalazine, can reverse key features of preeclampsia disease pathophysiology in laboratory studies using primary human pregnancy tissues. Firstly we showed that sulfasalazine reduces the placental secretion of antiangiogenic factors sFlt-1 and soluble endoglin that cause preeclampsia. Secondly we demonstrated sulfasalazine reduced features of vascular dysfunction specific to preeclampsia. 

Given these promising findings and that sulfasalazine is safe in pregnancy (category B) we hope to progress this concept and translate these findings from the laboratory to the clinic with a proof of concept early phase clinical trial. We propose to recruit 20 women with preterm preeclampsia (30+0 weeks to 36+0 weeks gestation) at The Mercy Hospital for Women and treat them with 2-3 grams of sulfasalazine per day. We will assess the pharmacokinetics of sulfasalazine in women with preeclampsia and monitor key clinical and biochemical features of the disease. 

If successful, at the completion of this study, we will have evidence to progress the study of sulfasalazine as a treatment for preeclampsia to randomized clinical trial. It may form the basis for a medical treatment for preeclampsia and reduce the devastating burden of this common obstetric disease.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Fiona Brownfoot

Address

Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria
3084

Country

Australia

Phone

+61 3 8458 4000

Fax

fiona.brownfoot@unimelb.edu.au

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 4000

Fax

fiona.brownfoot@unimelb.edu.au

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 4000

Fax

fiona.brownfoot@unimelb.edu.au

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	Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia.	2022	https://dx.doi.org/10.1016/j.ajog.2020.09.014
Embase	An LC-MS/MS method for the simultaneous quantitation of sulfasalazine and sulfapyridine in human placenta.	2023	https://dx.doi.org/10.1016/j.jpba.2023.115633
Embase	Sulfasalazine for the treatment of preeclampsia in a nitric oxide synthase antagonist mouse model.	2023	https://dx.doi.org/10.1016/j.placenta.2023.01.001

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

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Documents added manually

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