LEOPARD Study
Study code
LEOPARD trial
DRKS registration
DRKS00038651
Funding source
Emmy-Noether Programme by the German Research Foundation (DFG)
Protocol title
Low versus high positive distending pressure during respiratory stabilization of very preterm infants immediately after delivery – the LEOPARD trial
Study design
Randomized controlled multicenter trial in two parallel groups
Inclusion Criteria
1) Very preterm infants (22 0/7 to 31 6/7 weeks gestational age at birth)
Exclusion Criteria
1) directed towards palliative care, 2) not born at the recruiting center (outborn), 3) severe congenital malformation, which is affecting initial respiratory management after birth, 4) declined parental consent
Trial Intervention and Control
Infants will be randomized immediately before birth. After placement of the infant on a resuscitation bed, a positive end-expiratory pressure (PEEP; +/- noninvasive positive pressure ventilation - NIPPV) will be provided. The intervention and control groups will receive different PEEP levels:
- Intervention: High PEEP (10-12 mbar) during the first ten minutes after birth.
- Control: Low PEEP (standard care, 5-7 mbar) during the first ten minutes after birth.
Peak inspiratory pressures (PIP) and frequency during NIPPV, as well as all other interventions remain at the clinician’s discretion. After ten minutes, the PEEP level can be freely adjusted by the treating clinician.
Primary Outcome Measure
Primary endpoint is a hierarchical outcome, i.e. the “Desirability of Outcome Ranking” (DOOR) including the “Response Adjusted for DuratIon of respIratOry support” (RADIO) which will be used as tie-breaker (DOOR/RADIO-approach). Outcomes will be assessed at 44 weeks PMA.
- Rank 6) Dead
- Rank 5) Alive with both of the following major morbidities: moderate/severe BPD, and severe brain lesion (IVH ≥ III°, cPVL, any cerebellar hemorrhage, any ventricular shunt/reservoir)
- Rank 4) Alive with one major morbidity (list see above)
- Rank 3) Alive without major morbidities but with any of the following moderate morbidities: Sum of hours of invasive mechanical ventilation ≥ 72 hours within the first seven days or IVH I/II° or pneumothorax requiring drainage
- Rank 2) Alive without major or moderate morbidities but with respiratory failure in the first 72 hours
- Rank 1) Alive and well (none of the above)
Secondary Outcome Measures
Mortality, any severe brain lesion, severe IVH, any IVH, cystic PVL, need for ventricular shunt/reservoir, cerebellar hemorrhage, moderate/severe BPD, pneumothorax requiring drainage, need for invasive mechanical ventilation, respiratory failure within the first 72 hours after birth, overall duration of respiratory support, need for escalation of respiratory support in the delivery room
LEOPARD Study
Infants <32 weeks require respiratory support after birth in order to establish and maintain functional residual capacity (FRC) and to prevent hypoxemia. Usually, infants are initially supported using continuous positive airway pressure (CPAP), which provides a positive end-expiratory pressure (PEEP), thereby preventing alveolar collapse. Neonatal resuscitation guidelines recommend to use a minimum of 5-6 mbar as initial PEEP, allowing higher pressures. This recommendation is largely due to insufficient data for initial higher pressures. However, pressure levels vary largely with some centers across the world starting as high as 15-20 mbar. The initial pressure level for very preterm infants immediately after birth remains an area of controversial debates and there is clinical equipoise as to the chosen level. This study will provide meaningful evidence to the effect of the chosen pressure levels.
Recent smaller studies showed an improved spontaneous breathing efforts, as well as improved physiological stability with higher pressures and no safety concerns with a higher pressure. The right initial level of positive distending pressure during neonatal stabilization after birth remains unknown. This study will provide meaningful evidence with a large sample size to the effect of a higher initial pressure level on a clinically important outcome using the Desirability of Outcomes Ranking (DOOR-) approach
Traditionally, clinical trials in neonatology use composite outcomes such as survival without bronchopulmonary dysplasia. However, parental and patient initiatives have criticized this approach as it equates death with a chronic lung disease. Recently, statisticians and infectious disease specialists have proposed the Desirability Of Outcome Ranking (DOOR) approach where dichotomous outcomes are ranked according to their importance to families and caregivers. The DOOR approach has not been implemented in prospective trials in the neonatal population so far. In collaboration with parent representatives, we have developed a ranking of outcomes varying between healthy infants and infants with various degrees of morbidities and death (Desirability Of Outcome Ranking, DOOR). The ranking reflects the outcomes’ relative importance to affected families. This is the first study to implement this novel approach in a prospective study in the neonatal population.
Coordinating Study Team
Coordinating Principal Investigator
Vincent D. Gaertner, MD BSc
Lindwurmstr. 4
80337 Munich
089-4400-57783
Local investigators
Universitätsspital Zürich: PD Dr. Christoph Rüegger (Swiss PI), christoph.rueegger@usz.ch
Universitätsklinikum Tübingen: Prof. Dr. Laila Springer, laila.springer@med.uni-tuebingen.de
Universitätsklinikum Erlangen: Prof. Dr. Heiko Reutter, heiko-reutter@uk-erlangen.de
Universitätsklinikum Dresden: Prof. Dr. Mario Rüdiger, mario.ruediger@ukdd.de
Krankenhaus Barmherzige Brüder Regensburg, Kinder-Universitätsklinik Ostbayern: Prof. Dr. Sven Wellmann, sven.wellmann@barmherzige-regensburg.de
The Royal Women’s Hospital Melbourne: Prof. Dr. Louise Owen: louise.owen@thewomens.org.au
Data Management and Statistician
Data Management: Prof. Dr. Axel Franz, Center for Pediatric Clinical Studies Tübingen: axel.franz@med.uni-tuebingen.de
Statistician: Dr. Corinna Engel, Center for Pediatric Clinical Studies Tübingen: corinna.engel@med.uni-tuebingen.de
Thank you for your interest in the LEOPARD study.
This study includes babies who are born very prematurely and require respiratory support immediately after birth. We hope that the FAQs (Frequently Asked Questions) will answer your questions.
If you cannot find the information you need here, please feel free to contact us.
FAQs
This research project examines the effectiveness of higher airway pressure (10–12 centimeters of water, cm H₂O) for very preterm infants immediately after birth and compares it with lower airway pressure (current standard, 5–7 cm H₂O).
All extremely preterm infants receive respiratory support in the form of positive airway pressure immediately after birth to keep their lungs open. Current recommendations suggest starting with an air pressure of at least 5–6 cm H₂O. However, the guidelines also allow for higher pressure levels, and there is no clear evidence regarding which pressure level is the most effective and safest for preterm infants. Consequently, practices vary widely around the world. However, animal studies and small clinical trials suggest that a higher pressure level might improve the child’s spontaneous breathing. Ultimately, higher airway pressure could increase the oxygen content in the child’s blood, potentially eliminating the need for invasive respiratory support with mechanical ventilation. Avoiding mechanical ventilation, in turn, could protect the infants from chronic lung disease, which typically occurs in very small and immature preterm infants.
The study is open to preterm infants born between 22 and 32 weeks' gestation who do not have congenital malformations and are not receiving palliative care.
The intervention (higher vs. lower blood pressure level) is administered only during the first 10 minutes after birth. Additional clinical data will be collected until the patient is discharged home.
The study will use data about your child (e.g., general information such as birth weight or clinical course, which is routinely collected at our hospital during initial care), as well as maternal information regarding the course of the pregnancy. All of this data is routinely collected for all premature infants.
This international, multicenter study compares a higher level of pressure with a lower level of pressure for respiratory support in very preterm infants. A predetermined randomization process—similar to flipping a coin—will determine which treatment your child receives if they participate; this is called randomization. The probability that your child will receive the higher or lower pressure level is 50% in each case. After the first 10 minutes following birth, treatment in both groups will continue in the same manner, in accordance with our clinical standards.
This study is not blinded. This means that the treating team knows which treatment was administered. This project is being conducted in accordance with the laws of all participating countries (Germany, Switzerland). The relevant ethics committees have reviewed and approved this project.
There is currently no proven benefit for your child. Your child’s participation may help improve future care for premature babies.
Participation in the study is voluntary. If your child chooses not to participate, or if you as parents later decide to withdraw your consent, you are not required to provide a reason. Your child’s medical care and treatment will be provided regardless of this decision. You may ask questions about participation and the project at any time. Please contact the person listed under Contact.
There are no obligations linked to the study.
It is theoretically possible that higher airway pressure could be associated with an increased risk of a small air leak in the lung (pneumothorax) and an increased risk of a brain hemorrhage. However, studies conducted to date—including large-scale ones—do not indicate such a risk, and the pressure levels used here fall within the range recommended by clinical guidelines. Overall, based on current knowledge, there are no known side effects associated with treating preterm infants at a higher pressure level during the first 10 minutes after birth, within the range examined in this study. There may be risks that are not known at this time.
The study team will keep you, as parents, informed of any new findings that may affect the benefits or safety of the study and, consequently, your decision to participate. Once the study is completed and the data is published, you may request a layperson’s summary from the study team or search for it on the following website: https://www.drks.de/search/de (search term “LEOPARD”).
This study collects personal and medical information about your child. This information is only partially encrypted; that is, your child’s name is encrypted, but the date of birth is required for data analysis. Encryption means that identifying information that could identify your child (e.g., name) is deleted and replaced with a code. This code list is kept by the principal investigator. Only encrypted data is accessible to the specialists (statisticians, researchers conducting the study) for scientific analysis. Specialized professionals (monitors) may review the conduct of the study as part of quality control procedures. They may access the uncoded medical records through your study physician. However, confidentiality is strictly maintained throughout the entire study and during the aforementioned reviews. Your child’s name will not be published in any way in reports or publications resulting from the study.
Yes, you may decide at any time to withdraw your child from the study and have them stop participating. Data collected up to that point will still be analyzed. After the analysis, the data will be completely anonymized—that is, the encryption key will be destroyed—so that no one will be able to determine that the data originally came from your child. Blood and urine samples will be disposed of at that time, if they have not already been.
The study-specific examinations mentioned in this information letter are free of charge. Neither you nor your health insurance provider will incur any additional costs in connection with your participation.
You will not receive any compensation for participating in this clinical trial.
This study is funded by the German Research Foundation (DFG).
Contact
Vincent D. Gaertner, MD BSc
Principal Investigator