PREPARE, Prematurity Reduction by Pre-eclampsia Care

Premature Birth Clinical Trial

— PREPARE  

Official title:

PREPARE, Prematurity Reduction by Pre-eclampsia Care

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03073317
• Other study ID #: PRES-023-PPE-15
• Status: Completed
• Phase: N/A
• Start date: December 1, 2016
• Est. completion date: June 20, 2020

Study information

• Verified date: July 2023
• Source: Instituto Fernandes Figueira
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Investigators will test a novel system of integrated care, to promote the use of the WORLD HEALTH ORGANIZATION Guidelines for the management of pre-eclampsia and initiate the use of a structured risk assessment strategy to reduce the incidence of preterm delivery from pre-eclampsia by providing obstetricians with the confidence to safely defer delivery of women with pre-eclampsia, identified to be of low risk.

Description:

This proposal (PREPARE), led by Brazilian investigators in collaboration with the Global Pregnancy Collaboration (CoLab) is centred on 7 hospital centres and their 23 satellite community health centres (UBSs). There are two clinical initiatives: First, a programme of systematic knowledge transfer (KT) to encourage adoption of the WHO Guidelines to prevent pre-eclampsia as part of routine antenatal care (Objective 1); second an intervention to reduce unnecessary preterm deliveries for the management of pre-eclampsia. CoLab investigators have developed methods to identify those women with preterm pre-eclampsia whose pregnancies can be safely prolonged.4-6 In Objective 2.1, these methods will be applied to women presenting with definite or suspected pre-eclampsia at < 37 weeks' gestation. Investigators will determine the likelihood of an imminent adverse outcome in these women using Soluble fms-Like Tyrosine Kinase-1-to-Placental Growth Factor Ratio (sFlT-1/PlGF) measurement and fullPIERS clinical assessment. Prior studies with these approaches indicate more than 98% negative predictive value for adverse outcomes for both.4-6 Investigators will delay delivery in those whose risk is low, caring for patients in accordance with evidence-based WHO guidelines.Unlike medications, management cannot be tested in a blinded way. Management needs integrated skills and commitment from caregivers. Hence, a standard randomized controlled trial is inappropriate. Instead investigators propose a Stepped Wedge Design to study outcomes in the 7 geographically diverse study centres, throughout Brazil. At least 6 women with preterm pre-eclampsia will deliver at each centre every month. The primary outcome will be a lower rate of PRETERM BIRTH due to pre-eclampsia as a proportion of total deliveries in the centre(s) after implementation of the plan compared to prior to its introduction. The study will have 80% power to demonstrate a 25% reduction (2.0 - 1.5%). Investigators will assess maternal and foetal adverse events as secondary outcomes. Objective 2.2 will institute an intense program of knowledge transfer to implement the new management techniques. In Objectives 2.3 and 2.4 will determine patient and provider satisfaction and the economic impact of the care plan. In Objective 3 will establish a biobank and database to begin to assess demographic factors and biological analytes that may help identify unique predictive and diagnostic/pathophysiological features for pre-eclampsia in the Brazilian population (that may extend to other low and middle income countries (LMIC)). For two years at routine visits (≤16 weeks, 28-32 weeks) at each UBS, relevant data and plasma, serum, urine and DNA samples will be stored to the appropriate standards in the biorepository (at least 7000 cases). Investigators estimate that will acquire samples at delivery in at least 5000 of these women. For four years, biological samples from women with pre-eclampsia or other adverse outcomes and 2 matched controls will be collected at admission for labour (an additional 3,000 subjects). Objective 4 will initiate pilot studies to identify novel biomarkers, and compare these and other known pathophysiological factors with those from LMIC (Africa, India) and HIC using samples from CoLab. Additional funding will be sought for expansion and validation (e.g. Merck for Mothers). Investigators will also seek funding to address risk stratification in apparently low risk women, based on the samples collected at 28-32 weeks. Objective 5 will promote intellectual interactions and collaboration between the seven centres and CoLab. Ability to understand and cure complex adverse pregnancy outcomes leading to acute and long-range disability in children requires intensive collaboration across usual "silos" including hospitals and nations. The coordinators anticipate the interaction of investigators and care providers in the seven centres will foster intellectual collaboration and improved standardized care. Brazilian investigators will become members of CoLab, increasing its unique vision, expertise and resources (current data and biological materials from 28 centres). worldwide).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1250
• Est. completion date: June 20, 2020
• Est. primary completion date: December 30, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 10 Years to 50 Years

Eligibility

Inclusion Criteria:

• pregnancy before 16 weeks

• delivery at designed maternity center

Exclusion Criteria:

• not viable fetus

Related Conditions & MeSH terms

• Eclampsia
• Pre-Eclampsia
• Premature Birth

Intervention

Diagnostic Test:
• FullPIERS and sFlit/PLGF (Soluble fms-Like Tyrosine Kinase-1-to-Placental Growth Factor Ratio)
Once the centre is randomised to receive the intervention, all eligible women will have serum sFlt1/PlGF measurement performed and fullPIERS assessment and both results will be revealed to the care providers. This will include all women with pre-eclampsia or suspected pre-eclampsia cared for at the main hospital centres (and not be limited to women referred to the hospital from the community health centres). sFlt-1/PlGF will be tested by immunoassays (Roche Platform®). The result read out is provided by specific machines provided by Roche in less than one hour, which permits rapid clinical decision-making. Risk stratification using fullPIERS will be performed on tablet computers using a pre-defined risk scoring system integrated within the MedSciNet database.

Locations

Country	Name	City	State
Brazil	Maternidade Unesp Botucatu	Botucatu	SAO Paulo
Brazil	Caism - Unicamp	Campinas	SAO Paulo
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre	Rio Gde Do Sul
Brazil	Instituto Fernandes Figueira	Rio de Janeiro
Brazil	Maternidade Leila Diniz	Rio de Janeiro
Brazil	Maternidade Maria Amelia Buarque de Holanda	Rio de Janeiro
Brazil	Hospital Guilherme Alvaro	Santos	SAO Paulo
Brazil	Hospital Maternidade Leonor Mendes de Barros	Sao Paulo

Sponsors (8)

Lead Sponsor	Collaborator
Instituto Fernandes Figueira	CoLab, HGA, Hospital de Clinicas de Porto Alegre, HOSPITAL MATERNIDADE LEONOR MENDES DE BARROS, SMSDC/RJ, University of Campinas, Brazil, UPECLIN HC FM Botucatu Unesp

Country where clinical trial is conducted

Brazil, 

References & Publications (18)

Ananth CV, Vintzileos AM. Medically indicated preterm birth: recognizing the importance of the problem. Clin Perinatol. 2008 Mar;35(1):53-67, viii. doi: 10.1016/j.clp.2007.11.001. — View Citation

Brown CA, Lilford RJ. The stepped wedge trial design: a systematic review. BMC Med Res Methodol. 2006 Nov 8;6:54. doi: 10.1186/1471-2288-6-54. — View Citation

Camargo EB, Moraes LF, Souza CM, Akutsu R, Barreto JM, da Silva EM, Betran AP, Torloni MR. Survey of calcium supplementation to prevent preeclampsia: the gap between evidence and practice in Brazil. BMC Pregnancy Childbirth. 2013 Nov 11;13:206. doi: 10.11 — View Citation

Chappell LC, Milne F, Shennan A. Is early induction or expectant management more beneficial in women with late preterm pre-eclampsia? BMJ. 2015 Apr 10;350:h191. doi: 10.1136/bmj.h191. No abstract available. — View Citation

Dantas EM, Pereira FV, Queiroz JW, Dantas DL, Monteiro GR, Duggal P, Azevedo Mde F, Jeronimo SM, Araujo AC. Preeclampsia is associated with increased maternal body weight in a northeastern Brazilian population. BMC Pregnancy Childbirth. 2013 Aug 8;13:159. — View Citation

Harvey G, Loftus-Hills A, Rycroft-Malone J, Titchen A, Kitson A, McCormack B, Seers K. Getting evidence into practice: the role and function of facilitation. J Adv Nurs. 2002 Mar;37(6):577-88. doi: 10.1046/j.1365-2648.2002.02126.x. — View Citation

Hussey MA, Hughes JP. Design and analysis of stepped wedge cluster randomized trials. Contemp Clin Trials. 2007 Feb;28(2):182-91. doi: 10.1016/j.cct.2006.05.007. Epub 2006 Jul 7. — View Citation

Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJ. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke. 2009 Apr;40(4):1176-80. doi: 10.1161/STROKEAHA.108.538025. Epub 2009 Mar — View Citation

Myers JE, Kenny LC, McCowan LM, Chan EH, Dekker GA, Poston L, Simpson NA, North RA; SCOPE consortium. Angiogenic factors combined with clinical risk factors to predict preterm pre-eclampsia in nulliparous women: a predictive test accuracy study. BJOG. 201 — View Citation

Passini R Jr, Tedesco RP, Marba ST, Cecatti JG, Guinsburg R, Martinez FE, Nomura ML; Brazilian Network of Studies on Reproductive and Perinatal Health. Brazilian multicenter study on prevalence of preterm birth and associated factors. BMC Pregnancy Childb — View Citation

Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005 Jun 10;308(5728):1592-4. doi: 10.1126/science.1111726. — View Citation

Roberts JM, Hubel CA. The two stage model of preeclampsia: variations on the theme. Placenta. 2009 Mar;30 Suppl A(Suppl A):S32-7. doi: 10.1016/j.placenta.2008.11.009. Epub 2008 Dec 13. — View Citation

Vigil-De Gracia P, Reyes Tejada O, Calle Minaca A, Tellez G, Chon VY, Herrarte E, Villar A, Ludmir J. Expectant management of severe preeclampsia remote from term: the MEXPRE Latin Study, a randomized, multicenter clinical trial. Am J Obstet Gynecol. 2013 — View Citation

von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003;22(2):143-8. doi: 10.1081/PRG-120021060. — View Citation

von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton Pipkin F, Cote AM, Douglas MJ, Gruslin A, Hutcheon JA, Joseph KS, Kyle PM, Lee T, Loughna P, Menzies JM, Merialdi M, Millman AL, Moore MP, Moutquin JM, Ouellet AB, Smith GN, Walker JJ, Walley KR, Wal — View Citation

von Dadelszen P, Sawchuck D, McMaster R, Douglas MJ, Lee SK, Saunders S, Liston RM, Magee LA; Translating Evidence-Based Surveillance and Treatment Strategies (TESS) Group. The active implementation of pregnancy hypertension guidelines in British Columbia — View Citation

WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia. Geneva: World Health Organization; 2011. Available from http://www.ncbi.nlm.nih.gov/books/NBK140561/ — View Citation

Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstrom M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med. 20 — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	patients with preterm preeclampsia	proportion of women delivered in the centres with preterm pre-eclampsia (deliveries with preterm pre-eclampsia/ total deliveries), where preterm is <37 weeks' gestation	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	proportion of women delivered in the centers who delivered prematurely	proportion of women delivered with preterm pre-eclampsia/ total deliveries for pre-eclampsia, where preterm is <37 weeks' gestation	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	proportion of women delivered in the centres with preterm pre-eclampsia	proportion of women delivered in the centres with preterm pre-eclampsia (deliveries with preterm pre-eclampsia/ total deliveries), where preterm is <34 weeks' gestation	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	RATE PRETERM PRE-ECLAMPSIA DELIVERIES	proportion of women delivered with preterm pre-eclampsia/ total deliveries for pre-eclampsia, where preterm is <34 weeks' gestation	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	maternal morbidity and mortality defined as a composite of maternal mortality and features of 4a-4f	4a. HELLP syndrome cases of HELLP syndrome in women with pre-eclampsia; 4b. pulmonary oedema cases of pulmonary oedema in women with pre-eclampsia; 4c. eclampsia proportion of women with eclampsia; 4d. cerebrovascular accident (CVA) cases of maternal cerebrovascular accident (stroke or coma) in women with pre-eclampsia; 4e. renal dysfunction cases of renal dysfunction in women with pre-eclampsia, where criteria is serum creatinine of >150	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	frequency of severe hypertension	systolic BP = 160 mmHg or diastolic BP = 110 mm/Hg	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	placental abruption	cases of placental abruption	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	mode of delivery (total C-sections)	total number of reported C-sections	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	stillbirth	cases of stillbirth at >20 weeks	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	early neonatal mortality	cases of neonatal mortality at <7 days	researchers will be assessing and reporting outcome through month 1 to month 34 of the study
Secondary	admission to the neonatal care unit	cases of admission to the neonatal care unit due to prematurity related to pre-eclampsia	researchers will be assessing and reporting outcome through month 1 to month 34 of the study