Improve the Survival Without Morbidity of Extremely Preterm Infants (PREMEX)

Newborn Clinical Trial

— PREMEX  

Official title:

Improve the Survival Without Morbidity of Extremely Preterm Infants: A Stepped-wedge Cluster-randomized Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05248477
• Other study ID #: APHP211004
• Secondary ID: 2021-A02520-41
• Status: Recruiting
• Phase: N/A
• Start date: June 1, 2022
• Est. completion date: December 2026

Study information

• Verified date: June 2022
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: François GOFFINET, MD, PhD
• Phone: +33 1 58 41 37 98
• Email: francois.goffinet[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The intervention proposed is a new organization of care, based on the EXPRIM (EXtrem PRematurity Innovative Management) protocol, involving early, standardized, and multidisciplinary management of women hospitalized for a risk of extremely preterm birth and their children. It will take place in each perinatal network for all pregnant women hospitalized between 22 and 26 weeks with a risk of preterm delivery.

Setting up the protocol requires taking into account the parents' time and timing issues, and its potential for change, to plan the implementation of the protocol, especially the degree of emergency of the situation and the probability of imminent delivery.

The follow-up collected for this study will take place:

• At D4 post-delivery: A questionnaire about the parents' experience of the information delivered and the decisions made will be given to and collected from the parents

• At the child's discharge from the hospital, or if he or she dies in the hospital:

• Collection of clinical data (principal endpoint) from data in the medical file.

• Data to measure practices and adherence to the intervention will be collected

• When the child reaches the corrected age of 2 years:

• a short questionnaire will be completed by the physician caring for the child at the corrected age of 2 years. The data collected will concern motor and sensory development, in particular, cerebral palsy, blindness, and deafness..

• Information about the child's development will also be collected with a questionnaire including a standardized assessment scale, the ASQ (Ages and Stages Questionnaire), which the parents will complete.

Description:

Extremely preterm infants, those born between 22 and 26 weeks of gestation, are at very high risk of neonatal death, severe morbidity, and disabilities. These children's survival basically depends on the obstetric-pediatric team's willingness to provide active care. In France, practices vary strongly according to the child's place of birth. The rates of active antenatal care (reflects the intention to manage the child actively at birth), standardized by gestational age, vary from 22% to 61% between regions. One of the consequences of this heterogeneity is that the survival rate in France of these extremely premature infants is much lower than that of countries offering similar levels of care. Among the children live-born in France, survival rates at hospital discharge were 0% at 22 weeks, 1% at 23, 31% at 24, 59% at 25, and 75% at 26 weeks. Survival in the USA, Great Britain, Japan, Australia, and Sweden ranges from 10 to 50% higher than in France.

The great variability of antenatal practices for the management of extremely preterm infants reflects the disarray of medical teams. In the absence of consensus and written decision-making processes, this uncertainty culminates in management decisions based at best on local habits and at worst on the individual habits of the clinician present. These habits vary with the physicians' beliefs or convictions, and their level of knowledge and experience of extremely preterm births. This variability of practices between hospitals presents a problem of equity.

The hypothesis is that standardization of the management of extremely preterm infants, from the moment that the pregnant woman is hospitalized until the child's birth should improve survival without severe morbidity in this group of children at very high risk

The intervention proposed is a new organization of care, based on the EXPRIM (EXtrem PRematurity Innovative Management) protocol (MC Lamau, et al, PMID: 34059380), involving early, standardized, and multidisciplinary management of women hospitalized for a risk of extremely preterm birth and their children. It will take place in each perinatal network for all pregnant women hospitalized between 22 and 26 weeks with a risk of preterm delivery.

Setting up the protocol requires taking into account the parents' time and timing issues, and its potential for change, to plan the implementation of the protocol, especially the degree of emergency of the situation and the probability of imminent delivery.

Complex intervention, named the EXPRIM protocol, aimed at standardizing the organization of care. It is based on the following principles:

• A collective obstetric-pediatric prognostic assessment, in a non-emergency setting, no longer based only on gestational age, and ensuring better team consistency in terms of the attitude to propose to parents;

• A consensus decision by the multidisciplinary team about the obstetric and neonatal management proposed-either active or palliative care-at the conclusion of this prognostic evaluation

• An interview with the parents to:

• inform them about the obstetric situation and the child's prognosis

• answer their questions

• propose either active or palliative care to them as management

• and then ask their opinion.

• The administration of corticosteroid therapy, independently of the decision about management (active or palliative care), starting at 23 weeks will be of broad indication;

If the hospitalization takes place in a level-1 or 2 hospital: after general information about preterm delivery, a proposal to transfer the woman to the perinatal network's level-3 hospital, starting at 23 weeks

The choice of a stepped-wedge cluster randomization design allows all perinatal networks to implement the intervention.

After the random drawing of clusters for the intervention, the teams will be trained in the EXPRIM protocol and then will undergo a 3-month transition period (not considered either a control or intervention period) to learn the protocol thoroughly. The data collected during this period will not be used in the analysis. In summary, the 3 stages before recruitment during the intervention are:

1. allocation of clusters

2. training of perinatal teams

3. transition period After random drawing, 4 perinatal networks will be allocated to the intervention in 5 waves every 3 months, with 3 months of recruitment for the last wave. Twenty perinatal networks will be randomized and will participate in the trial with a total recruitment period of 21 months (including the 3-month transition periods). Overall, the duration of the study at each center will be 49 months. All perinatal networks will have a period with and without the intervention and will participate in the comparison accordingly. After 15 months all the networks will have begun the intervention.

No specific follow-up visit for the purposes of the study is planned. The hospital staff physicians will perform follow-up as part of the standard usual care for women and their newborns.

The follow-up collected for this study will take place:

• At D4 post-delivery (or before, if the woman leaves the hospital before then): A questionnaire about the parents' experience of the information delivered and the decisions made (see section 4.2) will be given to and collected from the parents

• At the child's discharge from the hospital, or if he or she dies in the hospital:

• Collection of clinical data (principal endpoint) from data in the medical file. If the patient was transferred to another hospital, the PREMEX investigator and/or the CRT will obtain the follow-up data to enter on the e-CRF.

• Data to measure practices and adherence to the intervention will be collected

• The neonatologist-investigator will ask the parents at the child's discharge from hospitalization for written consent to continue their participation in this study for the follow-up at age 2.

• When the child reaches the corrected age of 2 years:

• Nearly all the surviving children will be receiving care within structured networks for the follow-up of vulnerable children, responsible for "detailded description"optimizing their medical care and follow-up. Accordingly, a short questionnaire will be completed by the physician caring for the child at the corrected age of 2 years. The data collected will concern motor and sensory development, in particular, cerebral palsy, blindness, and deafness. The questionnaire will be sent to the parents, who will ask the physician to complete it at the medical visit planned at this age. The parents may be contacted by email or telephone if necessary. The physician will send the completed questionnaire to the project coordinators.

• Information about the child's development will also be collected with a questionnaire including a standardized assessment scale, the ASQ (Ages and Stages Questionnaire), which the parents will complete. The ASQ will be sent to them by either the postal service or email, together with the questionnaire to transmit to the physician. A telephone call will be made if necessary to recover the questionnaire data and remind the parents who have not responded. Once the parents have completed the questionnaire, they will send it to the project coordinating team.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2100
• Est. completion date: December 2026
• Est. primary completion date: August 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

all newborns (live- and stillborn) delivered between 22 and 26 weeks

Exclusion Criteria

any fetus or child with a severe congenital anomaly (from the EPIPAGE-2 list)

Related Conditions & MeSH terms

• Extreme Prematurity
• Newborn
• Premature Birth

Intervention

Other:
• Premex Protocol
This protocol presupposes stages during which staff are informed and trained. It is based on the following principles: Administration of corticosteroid therapy to all eligible women, independent of the decision about active or palliative care A prognostic evaluation in a non-emergency meeting of the obstetricians and neonatologists/pediatricians involved, no longer based only on gestational age, and enabling the team to provide consistent, consensual, and individualized information to parents; A joint decision about the obstetric and neonatal (active or palliative) care to be proposed to parents at the end of this evaluation; An interview with parents, also on non-emergency basis, to give them information about the child's prognosis and the management proposed, to answer their questions, and to obtain their opinion; Management at birth consistent with that decided in consultation with the parents.

Locations

Country	Name	City	State
France	Hôpital Cochin	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (1)

Lamau MC, Ruiz E, Merrer J, Sibiude J, Huon C, Lepercq J, Goffinet F, Jarreau PH. A new individualized prognostic approach to the management of women at risk of extreme preterm birth in France: Effect on neonatal outcome. Arch Pediatr. 2021 Jul;28(5):366-373. doi: 10.1016/j.arcped.2021.04.005. Epub 2021 May 28. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	survival at hospital discharge without severe morbidity (composite outcome)	Severe morbidity is a composite criterion assessed up to 40 post-menstrual age (PMA) and defined by at least one of the following severe neonatal morbidities: Severe bronchopulmonary dysplasia, defined by the need for oxygen therapy and/or mechanical ventilatory support (endotracheal or noninvasive) at 36 weeks PMA (Jobe 2001).; Severe intraventricular hemorrhage (IVH), defined by IVH of either grade 3, associated with ventricular dilation, or grade 4, which is associated with a hemorrhagic lesion of the adjacent parenchyma) (Volpe 2009).; Severe retinopathy, defined as retinopathy of prematurity (ROP) of type 3 or higher according to the international classification (ICCROP 2005) and/or need for laser treatment.; Severe enterocolitis, defined as types 2 and 3 in the modified Bell's classification (Bell, 1978).; Periventricular leukomalacia, defined by cavities in the periventricular white matter on ultrasound.	Up to 24 Weeks
Secondary	Child's survival at hospital discharge	Number of living children	Up to 24 Weeks
Secondary	Neurosensory condition ( composite outcome)	Neurosensory condition, assessed by the pediatrician responsible for monitoring the child; cerebral palsy, defined by the European classification (European Cerebral Palsy Network 2000) as any permanent motor deficiency resulting from a nonprogressive lesion of the immature brain. This term makes it possible to cover all motor impairments. The severity of the motor impairment will be assessed by the 5-level international GMFCS (classification system of gross motor function, Ghassabian 2016): the child walks w/o limitations (level 1), walks w/ limitations (level 2), walks using a handheld mobility device (level 3), has self-mobility w/ limitations (level 4), is transported in a manual wheelchair (level 5). Cerebral palsies of level 1 are minor, those of level 2 moderate, and those of levels 3-5 severe; visual deficiency is defined by unilateral (moderate) or bilateral (severe) blindness; auditory deficiency is defined by unilateral (moderate) or bilateral (severe) deafness	at a corrected age of 2 years.
Secondary	child's global development	Assessment of the child's global development will be based on a standardized parent-completed questionnaire: the Ages and Stages Questionnaire (ASQ). It allows the assessment of 5 major domains of child development (communication, gross motor skills, fine motor skills, problem resolution, and social relations). When the score on one of these five dimensions is lower than 2 standard deviations below the norm, children are considered to be at risk of developmental disorders	at a corrected age of 2 years.
Secondary	Medical economics:	Incremental cost-effectiveness ratio (ICER) defined by the ratio of the cost difference from the hospital's oint of view to the difference in survival, both overall and without severe morbidity; budgetary impact, assuming the widespread dissemination of these practices throughout France.	at a corrected age of 2 years
Secondary	Parents' experience of the information they received, their involvement in decision making, and the decisions made	This experience will be assessed by 2 simple questions to obtain responses on a scale ranging from 0 ("No, not at all") to 10 ("Yes, agree completely"). These 2 questions will concern their satisfaction, first with the care of the pregnancy and the child, and then with their participation or degree of involvement in decisions.	on day 4