Plain English Summary
Background and study aims
Down's syndrome, also called also called trisomy 21, is a genetic condition that causes learning disability and characteristic physical features. Screening during pregnancy can determine the likelihood of a baby being born with Down's syndrome. The gold standard screening test is called the combined test because it combines an ultrasound scan with a blood test. The mother’s age and the information from these two tests is used to work out the risk of the baby having Down's syndrome. However, recent research suggests that the test can be improved by adding another test called cell-free fetal DNA screening. Cell-free fetal DNA is DNA from the baby that is found circulating freely in the mother’s blood stream. This additional test could improve screening by reducing the false-positive rate (the number of babies incorrectly diagnosed as having Down’s syndrome). The aim of this study is to compare the false-positive rates of combined screening and cell-free DNA screening for Down's syndrome.
Who can participate?
Women with single pregnancies coming for Down's syndrome screening at 11-13 weeks of pregnancy
What does this study involve?
Participants undergo an ultrasound scan at 11-13 weeks of pregnancy. If fetal defects are found screening is not appropriate and invasive testing is performed. If no anomalies are found then participants are randomly allocated to undergo either cell-free DNA screening or combined screening. Both tests involve blood samples being taken. If there is a positive result invasive testing is offered. The numbers of false-positive cases in the two groups are compared.
What are the possible benefits and risks of participating?
There are no risks as all the tests are already considered to be standard procedures
Where is the study run from?
University of Tuebingen (Germany)
When is the study starting and how long is it expected to run for?
July 2016 to October 2017
Who is funding the study?
Cenata GmbH (Germany)
Who is the main contact?
Prof. Karl Oliver Kagan
Trial website
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
2015 - 1
Study information
Scientific title
Comparison of false positive rates in prenatal combined screening and cell free DNA screening for trisomy 21
Acronym
ReFaPo study
Study hypothesis
After a detailed ultrasound examination at 11 - 13 weeks with a normal result, cell-free DNA can reduce the false positive rate compared to combined screening based on maternal age, fetal nuchal translucency, PAPP-A and free beta-hCG.
Ethics approval
University of Tuebingen medical faculty ethics committee, 06/10/2015, ref: 572/2015BO1
Study design
Single-center randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Screening
Patient information sheet
Not available in web format, please use contact details to request a participant information sheet
Condition
Prenatal screening for trisomy 21
Intervention
Following the normal ultrasound examination, randomization is performed into cell-free DNA screening or combined screening (maternal age, fetal NT, PAPP-A and free beta hCG).
In the cell free DNA (cfDNA) screening group, the risk for trisomy 21 will be calculated based on cell free DNA. For this analysis, blood will be taken and sent to CENATA GmbH who does the analysis. In general the analysis takes 3-5 days. The result will be a risk score. The case is considered to be screen positive if the risk is 1:100 or higher.
In the combined screening group, blood is taken for the analysis of PAPP-A and free beta hCG. The analysis will also done by a commercially driven laboratory. The risk will be calculated by the software of the Fetal Medicine Foundation UK. A risk for trisomy 21 of 1:100 or more is considered to be screen positive. In case of a screen positive result, invasive testing is offered. If the patient opts against invasive testing, we wait until the end of the pregnancy. Screen positive euploid cases are considered to be false positive cases.
All methods (screening by cfDNA, combined screening and invasive testing) are standard procedures in fetal medicine.
Intervention type
Other
Phase
Drug names
Primary outcome measure
Number and proportion of false positive cases in each arm. False positive cases are defined as euploid cases with a risk for trisomy 21 > 1:100. The karyotype will either be obtained by invasive testing somedays after the screening test or after birth.
Secondary outcome measures
1. Number of cases that cannot be randomized (due to fetal defects, increased NT, multiple gestations). This data will become available at 11-13 weeks’ gestation.
2. Time interval between randomization and return of the blood results
3. Number of cases without results in each study arm. This data will be become available latest 2 weeks after the blood sample is taken.
4. Number of women who opt for invasive testing. This data will generally be available within the consecutive 4 weeks after the screening test but theoretically the invasive test can be carried out through the pregnancy.
5. Acceptance of each screening test. The patient will be contacted by us to assess the acceptance level of each of the screening tests. This will be done 4 weeks after the screening test and after birth.
Overall trial start date
01/07/2016
Overall trial end date
01/10/2017
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Patients coming for prenatal screening for trisomy at 11-13 weeks’ gestation
2. Singleton pregnancies
3. Normal ultrasound examination without increased nuchal translucency thickness >3.5mm and without fetal defects. If NT is increased or there are fetal defects, screening is not appropriate and invasive testing is performed
4. Informed consent
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
1400
Total final enrolment
1376
Participant exclusion criteria
1. Increased nuchal translucency thickness
2. Fetal defects
3. Multiple gestations
Recruitment start date
01/08/2016
Recruitment end date
01/03/2017
Locations
Countries of recruitment
Germany
Trial participating centre
University of Tuebingen
Department of Obstetrics and Gynaecology
72076
Germany
Funders
Funder type
Industry
Funder name
Cenata GmbH (Germany)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
We aim to publish the data (results, methodology etc) after the birth of the last enrolled pregnancy. The results will be published in a scientific journal. The data will also be presented at scientific meetings following publication. The data can be made available on an individual basis but an additional statement of the local ethical committee is required for this purpose.
Intention to publish date
01/10/2018
Participant level data
Other
Basic results (scientific)
Publication list
2019 results in https://www.ncbi.nlm.nih.gov/pubmed/29940565 (added 05/08/2019)