Clinical trial NCT01891240: IMproved PRegnancy Outcome by Early Detection
Official title: Personalized Medicine for Pregnant Women: Novel Metabolomic and Proteomic Biomarkers to Detect Pre-eclampsia and Improve Outcome.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Pre-eclampsia
Pregnancy
Pregnancy, High-risk
Pregnancy Complications
Keywords: Diagnostic
Pre-eclampsia
Pregnancy outcome
Mass screening
Diagnostic Techniques and Procedures
Lead sponsor: University College Cork
Sponsor class: OTHER
Collaborators: name: Keele University
name: University of Liverpool
name: Karolinska University
name: Erasmus Medical Center
name: Copenhagen Trial Unit, Center for Clinical Intervention Research
name: MedSciNet AB, Stockholm, Sweden
name: MyCartis, Ghent, Belgium
name: Metabolomic Diagnostics Ltd, Cork, Ireland
name: Accelopment AG
name: University of Groningen, The Netherlands
name: INFANT centre, University College Cork, Republic of Ireland
First posted: 2013-07-03
Enrollment: 5000
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: First time, low risk mothers attending antenatal care units. Women will be referred to IMPROvED through a number of routes including referral by their midwife, obstetrician or general practitioner and self-referral following exposure to the study through friends, posters, advertisements, website and news stories. Maternity caregivers in each centre will provide information about the study to eligible women in early pregnancy.

Brief summary: The overall objective of the IMPROvED project is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for preeclampsia.

This will involve a multicentre, phase IIa clinical predictive study to assess and refine novel and innovative prototype tests based on emerging metabolomic and proteomic technologies developed by SMEs (small to medium size enterprise) within the consortium. The study will i) recruit 5000 first-time pregnant women; ii) establish a high calibre biobank, augmented by accurate clinical metadata; iii) determine whether prototype predictive assays and algorithms translate to the clinical environment; iv) assess potential synergy of a combined metabolomic and proteomic approach and v) progress regulatory approval and development of the selected test into the clinical arena.

Detailed description: Sample size calculations have been considered extensively and given the complexity of the study; there is no single simple solution. For the purpose of sample size estimation in the overall study, we used a binary outcome and associated measures of sensitivity and likelihood ratio as determinants of the value of these tests. Although the predictive algorithms will produce a continuous risk score, the use of a categorical outcome fits with the final binary decision process (to treat or not to treat) based on the risk score. Based on the lowest estimated prevalence of pre-eclampsia of 3% and a test sensitivity of 93% and a test specificity of 97%, then to be 90% certain that the true specificity of the patient population is no less than 95%, a sample size of 4,800 participants is required. Thus, allowing for patient dropout, a study population of 5,000 women is needed.

Eligibility criteria: Inclusion Criteria:

* Nulliparous.
* Singleton pregnancy, between 9+0 and 16+6 weeks' gestation.
* Signed informed consent.

Exclusion Criteria:

* Unsure of last menstrual period (LMP) and unwilling to have ultrasonography screening (USS) at ≤ 20 weeks.
* ≥ 3 miscarriages.
* ≥3 terminations of pregnancy.
* Known or suspected major fetal anomaly/abnormal karyotype.
* Essential hypertension treated pre-pregnancy.
* Moderate-severe hypertension at booking (BP \>160/100 mmHg).
* Diabetes mellitus.
* Renal disease.
* Systemic lupus erythematosus.
* Anti-phospholipid syndrome.
* Sickle cell disease.
* HIV positive.
* Hepatitis B or C positive.
* Major uterine anomaly.
* Cervical suture in situ.
* Knife cone biopsy.
* Long-term steroids.
* Treatment with low-dose aspirin.
* Treatment with heparin/LMW heparin.
* Lack of informed consent.

After recruitment, if the woman is found to be outside the stated gestation limits for the IMPROvED 1st visit of 9 weeks 0 days to 13 weeks 6 days she will be retained in the study if she is willing to take part in the second and third visit and is otherwise eligible. There is one pre-specified criteria for discontinuation of a participant. If a woman is recruited into the IMPROvED study and later identified as having a pregnancy exclusion criterion, i.e., ≥ 3 miscarriages, ≥ 3 TOPS, or using low-dose aspirin at the time of recruitment, she shall be excluded. However, women diagnosed during the pregnancy but after recruitment with an exclusion criterion, e.g., diseases such as renal disease, anti-phospholipid syndrome, etc. shall be retained within the study. Women who are recruited but later discontinue from the study do not count towards recruitment targets for each centre. Accordingly, such dropouts must be replaced.

Primary outcomes:
measure: Pre-eclampsia.
timeFrame: 7 days after birth
measure: Spontaneous pre-term birth
timeFrame: Up to 37+0 weeks´ gestation
measure: Small for gestational age (SGA)
timeFrame: Within 24 hours after birth
Secondary outcomes:
measure: Early onset pre-eclampsia
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Multisystem complications of pre-eclampsia
timeFrame: Between 20 weeks´gestation and 6 weeks after birth
measure: Pre-eclampsia with severe fetal or neonatal complications
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Major neonatal morbidity in preterm infants
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Major neonatal morbidity in term infants
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Pre-eclampsia with severe maternal complications
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Preeclampsia with either severe maternal complication or severe fetal or neonatal complications
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Early onset SGA
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: SGA with severe fetal or neonatal complications
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Early onset spontaneous preterm birth
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Spontaneous preterm birth with severe fetal or neonatal complications
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Spontaneous preterm birth with PPROM
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
measure: Spontaneous preterm birth without PPROM
timeFrame: Followed for the duration of hospital stay, an expected average of 6 weeks
Other outcomes:
Locations:
city: Wilton
country: Ireland
facility: Cork University Maternity Hospital, University College Cork
state: Cork
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center Rotterdam
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Huddinge, Karolinska Institute
city: Liverpool
country: United Kingdom
facility: Liverpool Women's Hospital, University of Liverpool
state: Merseyside
city: Shrewsbury
country: United Kingdom
facility: Keele University School of Medicine, Shrewsbury and Telford Hospital NHS Trust
state: Shropshire
city: Stoke-on-Trent
country: United Kingdom
facility: Keele University School of Medicine, University Hospital of North Midlands
state: Staffordshire
Study officials:
affiliation: INFANT Centre, University College Cork, Ireland
name: Louise Kenny, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Keele Univeristy School of Medicine
name: Philip N Baker, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Navaratnam K, Alfirevic Z, Baker PN, Gluud C, Gruttner B, Kublickiene K, Zeeman G, Kenny LC. A multi-centre phase IIa clinical study of predictive testing for preeclampsia: improved pregnancy outcomes via early detection (IMPROvED). BMC Pregnancy Childbirth. 2013 Dec 7;13:226. doi: 10.1186/1471-2393-13-226.