IMproved PRegnancy Outcome by Early Detection (IMPROvED)

This study is currently recruiting participants.
Verified March 2014 by University College Cork
Sponsor:
Collaborators:
Keele University
University of Liverpool, UK
Karolinska University, Stockholm, Sweden
Erasmus Medical Center
University of Cologne, Germany
University of Bonn
Copenhagen Trial Unit, Denmark
MedSciNet AB, Stockholm, Sweden
Pronota NV, Ghent, Belgium
Metabolomic Diagnostics Ltd, Cork, Ireland
Accelopment,Zürich, Switzerland
Information provided by (Responsible Party):
Louise Kenny, University College Cork
ClinicalTrials.gov Identifier:
NCT01891240
First received: May 20, 2013
Last updated: March 18, 2014
Last verified: March 2014
  Purpose

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 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.


Condition
Pre-eclampsia
Pregnancy
Pregnancy, High-risk
Pregnancy Complications

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Personalized Medicine for Pregnant Women: Novel Metabolomic and Proteomic Biomarkers to Detect Pre-eclampsia and Improve Outcome.

Resource links provided by NLM:


Further study details as provided by University College Cork:

Primary Outcome Measures:
  • Pre-eclampsia. [ Time Frame: 7 days after birth ] [ Designated as safety issue: No ]
    Preeclampsia is defined as gestational hypertension defined as systolic BP ≥140mmHg and/or diastolic BP ≥90mmHg (Korotkoff V) on at least 2 occasions 4h apart after 20 weeks' gestation, but before the onset of labour or postpartum systolic BP ≥140mmHg and/or diastolic BP ≥90mmHg on at least 2 occasions 4h apart with either proteinuria ≥300mg/24h or spot urine protein:creatinine ratio ≥30mg/mmol creatinine or urine dipstick protein ≥++.

  • Spontaneous pre-term birth [ Time Frame: Up to 37+0 weeks´ gestation ] [ Designated as safety issue: No ]
    Spontaneous pre-term birth is defined as spontaneous preterm labour or preterm premature rupture of the membranes resulting in preterm birth at <37+0 weeks' gestation.

  • Small for gestational age (SGA) [ Time Frame: Within 24 hours after birth ] [ Designated as safety issue: No ]
    The birth weight is converted to a customized centile, adjusting for gestation, maternal weight, height, parity, ethnicity and infant sex. SGA is defined as <10th customised centile.


Secondary Outcome Measures:
  • Early onset pre-eclampsia [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
    Pre-eclampsia resulting in delivery at <34+0 weeks' gestation.

  • Multisystem complications of pre-eclampsia [ Time Frame: Between 20 weeks´gestation and 6 weeks after birth ] [ Designated as safety issue: No ]

    Defined as one or more of the following:

    • Acute renal insufficiency defined as new increase in serum creatinine to >100μmol/L antepartum or >130μmol/L postpartum.
    • Liver disease defined as raised aspartate transaminase and/or alanine transaminase >45 IU/L and/or severe right upper quadrant or epigastric pain or liver rupture.
    • Neurological problems defined as eclampsia, imminent eclampsia (severe headache with hyperreflexia and persistent visual disturbance) or cerebral haemorrhage.
    • Haematological abnormalities including thrombocytopenia (platelets <100x109/L), disseminated intravascular coagulation or haemolysis, diagnosed by features on blood film (such as fragmented cells, helmet cells) and reduced haptoglobin.

  • Pre-eclampsia with severe fetal or neonatal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
    Pre-eclampsia resulting in either delivery at < 32+0 weeks' gestation or major neonatal morbidity or stillbirth or neonatal death or post-neonatal death.

  • Major neonatal morbidity in preterm infants [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]

    One or more of the following amongst babies delivered before 37 weeks' gestation:

    Grade III or IV intraventricular haemorrhage; Chronic lung disease; Necrotizing enterocolitis; Retinopathy of prematurity stage 3 or 4; Sepsis (blood or CSF culture proven); Or cystic periventricular leukomalacia. These conditions will be defined using the Australian and New Zealand neonatal network definitions.


  • Major neonatal morbidity in term infants [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]

    One or more of the following amongst babies delivered at or after 37 weeks' gestation:

    Grade II or III hypoxic ischaemic encephalopathy; Ventilation >24 hours; Neonatal unit care admission >4 days; Apgars < 4 at 5 minutes; Cord arterial pH <7.0 and/or base excess >-15; Or neonatal seizures.


  • Pre-eclampsia with severe maternal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]

    The development of pre-eclampsia with one or more of the following:

    Maternal death; Persistent severe hypertension (systolic blood pressure ≥170mmHg or diastolic blood pressure ≥110mmHg on more than one occasion antepartum or postpartum); Or multi-system complication (as defined in outcome above.


  • Preeclampsia with either severe maternal complication or severe fetal or neonatal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
    Pregnancies affected by severe maternal or severe fetal or neonatal complications (as defined in Major neonatal morbidity in preterm infants or Major neonatal morbidity term infants).

  • Early onset SGA [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
    SGA resulting in delivery at <34+0 weeks' gestation.

  • SGA with severe fetal or neonatal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
    SGA and either delivery at <32+0 weeks' gestation or major neonatal morbidity (as defined in Major neonatal morbidity in preterm infants) or stillbirth or neonatal death or post-neonatal death.

  • Early onset spontaneous preterm birth [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
    Spontaneous pre-term birth resulting in delivery < 34+0 weeks' gestation.

  • Spontaneous preterm birth with severe fetal or neonatal complications [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
    Spontaneous preterm birth (PTB) resulting in either delivery at <32+0 weeks' or spontaneous PTB resulting in major neonatal morbidity (as defined in Major neonatal morbidity in preterm infants) or stillbirth or neonatal death or post-neonatal death.

  • Spontaneous preterm birth with PPROM [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
    Spontaneous PTB following preterm premature rupture of the membranes (PPROM).

  • Spontaneous preterm birth without PPROM [ Time Frame: Followed for the duration of hospital stay, an expected average of 6 weeks ] [ Designated as safety issue: No ]
    Spontaneous PTB with intact membranes at the onset of labour.


Biospecimen Retention:   Samples With DNA

EDTA plasma and serum.


Estimated Enrollment: 5000
Study Start Date: November 2013
Estimated Study Completion Date: February 2016
Estimated Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Groups/Cohorts
First time, low risk mothers
The study population will consist of first time, low risk mothers attending for antenatal care in one of the participating clinical centres.

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

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

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.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01891240

Locations
Germany
University of Bonn Not yet recruiting
Bonn, Germany
Contact: Christoph Berg    +49 (0)221 478 4910    christoph.berg@ukb.uni-bonn.de   
University Hospital of Cologne Not yet recruiting
Cologne, Germany
Contact: Berthold Grüttner    +49 (0)221 478 4910    Berthold.Gruettner@uk-koeln.de   
Ireland
Cork University Maternity Hospital, University College Cork Recruiting
Wilton, Cork, Ireland
Contact: Louise Kenny    +353 (0)21 420 5023    l.kenny@ucc.ie   
Netherlands
Erasmus Medical Center Rotterdam Recruiting
Rotterdam, Netherlands
Contact: Hans Duvekot       j.j.duvekot@erasmusmc.nl   
Sweden
Karolinska University Hospital Huddinge, Karolinska Institute Not yet recruiting
Stockholm, Sweden
Contact: Marius Kublickas    +46 708 494221    Marius.Kublickas@ki.se   
United Kingdom
Liverpool Women's Hospital, University of Liverpool Recruiting
Liverpool, Merseyside, United Kingdom
Contact: Zarko Alfirevic    +44 (0)151 795 9550    Zarko@liverpool.ac.uk   
Keele University School of Medicine, University Hospital of North Staffordshire Recruiting
Stoke-on-Trent, Staffordshire, United Kingdom
Contact: Philip N Baker    +64 9 923 1637    Philip.baker31@me.com   
Contact: Shaughn O'Brien    + 44 (0)1782 672377    shaughn.obrien@uhns.nhs.uk   
Sponsors and Collaborators
Louise Kenny
Keele University
University of Liverpool, UK
Karolinska University, Stockholm, Sweden
Erasmus Medical Center
University of Cologne, Germany
University of Bonn
Copenhagen Trial Unit, Denmark
MedSciNet AB, Stockholm, Sweden
Pronota NV, Ghent, Belgium
Metabolomic Diagnostics Ltd, Cork, Ireland
Accelopment,Zürich, Switzerland
Investigators
Principal Investigator: Louise Kenny, Professor University Collage Cork, Ireland
Principal Investigator: Philip N Baker, Professor Keele Univeristy School of Medicine
  More Information

Additional Information:
No publications provided

Responsible Party: Louise Kenny, Professor, University College Cork
ClinicalTrials.gov Identifier: NCT01891240     History of Changes
Other Study ID Numbers: Study Protocol v. 8.0 20122013, Project no: 305169
Study First Received: May 20, 2013
Last Updated: March 18, 2014
Health Authority: Germany:Regional Ethics Commission. Cologne: 13-333.
Sweden: Regional Ethical Review Board. Stockholm:2013/306-31/2.
Netherlands: Medical Ethics Review Committee(METC). Rotterdam: MEC-2013-215.
United Kingdom: Research Ethics Committee. Keele inc. Liverpool:13/WM/0268

Keywords provided by University College Cork:
Diagnostic
Pre-eclampsia
Pregnancy outcome
Mass screening
Diagnostic Techniques and Procedures

Additional relevant MeSH terms:
Eclampsia
Pre-Eclampsia
Pregnancy Complications
Hypertension, Pregnancy-Induced

ClinicalTrials.gov processed this record on April 17, 2014