Respiratory Distress Syndrome in Premature InfantsPhase 4NCT04073173
Stress Assessment With and Without Analgesia During Surfactant Therapy in Preterm Infants.
A Phase 4 study testing INSURE, LISA and Analgesic, Opioid in people with Respiratory Distress Syndrome in Premature Infants, run by Virgilio Paolo Carnielli.
Trial summary
This study will compare stress, changes in oxygenation and oxidative damage in preterm infants with respiratory distress syndrome (RDS) randomized to receive or not remifentanil as an analgesic drug during the administration of porcine surfactant (poractant alfa, Curosurf®) through the traditional (INSURE) or the less… Read more about this study
- Who is it for?
- Ages 168 to 223 days
- Conditions the study is for
- Respiratory Distress Syndrome in Premature Infants
- What is being tested?
- INSURE, LISA and Analgesic, Opioid
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- No sites listed yet
- Study dates
- 1 Nov 2020to 31 Oct 2022
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 168 to 223 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- gestational age at birth between 168 and 223 days,
- respiratory distress syndrome (diagnosed on the basis of clinical and/or radiological grounds) with a fraction of inspired oxygen ≥0.30 (for infants born ≤26 weeks' gestational age) or ≥0.40 (for infants born >26 weeks' gestational age) to achieve a peripheral oxygen saturation of 90-94% within 24 hours of life and good respiratory drive,
- written informed consent.
Who cannot join
- major malformations,
- late admission (after 24 hours of life),
- intubation in the delivery room,
- severe birth asphyxia,
- prolonged rupture of membranes,
- air leaks,
- no informed consent.
Trial locations and contacts
No sites are listed yet.
About this study
Official title: Stress Assessment in Preterm Infants With Respiratory Distress Syndrome Treated or Not With an Analgesic Drug During the Traditional or the Less Invasive Method of Surfactant Therapy.
This study will compare stress, changes in oxygenation and oxidative damage in preterm infants with respiratory distress syndrome (RDS) randomized to receive or not remifentanil as an analgesic drug during the administration of porcine surfactant (poractant alfa, Curosurf®) through the traditional (INSURE) or the less invasive (LISA) method.
Read the detailed description
At present, LISA and INSURE are both used for surfactant therapy in infants as comparable methods. However, a clear policy of using analgesics during surfactant therapy is still lacking: some neonatologists use analgesics to reduce stress and pain scores, whereas others do not approve their use due to interference with spontaneous breathing.
In this open-label, randomized, phase 4 clinical trial, infants admitted to our neonatal intensive unit care (NICU) will be evaluated according to the selection criteria and then randomized to receive or not remifentanil as an analgesic drug during the administration of porcine surfactant (poractant alfa, Curosurf®) via the INSURE or LISA method: Group-1) LISA-analgesic; Group 2) LISA-no analgesic; Group-3) INSURE-analgesic; Group-4) INSURE-no analgesic. Study patients will be stratified by gestational age at birth: Block A) 23.0-27.6 weeks of gestation; Block B) 28.0-31.6 weeks of gestation.
Early caffeine administration will be provided according to our NICU guidelines shortly after birth. Infants with adequate respiratory drive will be stabilized on nasal continuous positive airway pressure (CPAP; 4-8 cm of water) right after birth. Oxygen saturation targets will be 90-94%; moderate degrees of hypercarbia (PaCO2 < 60 mmHg, provided arterial pH >7.22) will be tolerated. Conditions mimicking respiratory distress syndrome (RDS; i.e. sepsis, air leaks, aspiration pneumonia, congenital heart disease) will be ruled out. RDS diagnosis will be clinical according to the European Guidelines. Nasal CPAP, bi-level CPAP or nasal intermittent positive pressure ventilation (synchronized or not) will be used at the discretion of the attending physician to stabilize the patients. Intubation criteria according to our NICU guidelines will be:
- severe acidosis (defined as arterial pH<7.20 with a partial pressure of carbon dioxide (PaCO2) > 55 mmHg and partial pressure of oxygen (PaO2) < 50 mmHg) with a fraction of inspired oxygen (FiO2) > 0.50;
- severe apnoea.
Enrolled infants will be evaluated from birth to day 7 of the hospital stay.
- Being tested
- INSURE, LISA, Analgesic, Opioid
- Keywords
- RDS, Preterm Infants, Surfactant, LISA, INSURE, Analgesia, Stress
- Medical subject headings
- Respiratory Distress Syndrome In Premature Infants, Agnosia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
INSUREProcedure or surgery
Patients will be intubated by endotracheal tube, exogenous surfactant (Poractant alfa) will be administered and then they will be extubated.
LISAProcedure or surgery
Surfactant (Poractant alfa) will be directly delivered into the lungs via a fine bore catheter inserted into the trachea and then patients will be extubated.
Analgesic, OpioidDrug
Remifentanil (0.5-2 micrograms/kg/dose)
| Study group | Role | What they receive |
|---|---|---|
| LISA-analgesic | Experimental | Less Invasive Surfactant Administration (LISA) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug. Receives: Procedure: LISA; Drug: Analgesic, Opioid |
| LISA-no analgesic | Experimental | Less Invasive Surfactant Administration (LISA) without an analgesic drug. Receives: Procedure: LISA |
| INSURE-analgesic | Experimental | INtubation-SURfactant-Extubation (INSURE) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug. Receives: Procedure: INSURE; Drug: Analgesic, Opioid |
| INSURE-no analgesic | Experimental | INSURE without an analgesic drug. Receives: Procedure: INSURE |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cortisol concentrations
Cortisol concentrations will be assessed in saliva, as salivary cortisol levels have been shown to be useful surrogate markers for plasma cortisol levels in neonates. Saliva samples will be collected using an absorbent swab stick, centrifuged at 4000 rpm for 10 minutes and kept at -80°C until assayed (minimum sample volume 25 µl). Enzyme immunoassay (ELISA kit) will be used. Basal samples will be obtained at the hospital admission and right before surfactant.
Measured: At 1, 3, 6 12, 24 hours after surfactant administration and then daily in the first week at the same time of the day (to avoid circadian variations).
Secondary outcomes (5)
Galvanic Skin Responses
An instrumental stress-test device measuring galvanic skin conductance will be used (Pain Monitor, Med-Storm, Norway): three electrodes will be attached to the infant's foot (sole and sides of the ankle); skin conductance is measured in micro Siemens (µS).
Measured: At 1, 3, 6 12, 24 hours after surfactant administration and then daily in the first week at the same time of the day (to avoid circadian variations).
Heart rate
Cardiac monitoring will assess heart rate. Traces will be saved onto a computer with a sampling frequency of 1 Hertz. Average heart rate, periods of tachycardia (>160 bpm for ≥5 seconds) and bradycardia (<100 bpm for ≥5 seconds) will be recorded. These parameters may be correlated with stress and hemodynamic instability during the procedures.
Measured: 6 hours before and after surfactant therapy will be analyzed.
Brain oxygenation
Brain oxygenation will be assessed by near-infrared spectroscopy (NIRS).
Measured: From the hospital admission to day 7 of the hospital stay.
Oxygen saturation (SpO2)
High precision oxygenation assessment will be attained by high frequency (1 Hz) sampling of SpO2 data from the cardio monitor to a computer, possibly by using multiple pulse oximeters in the same patient.
Measured: From the hospital admission to day 7 of the hospital stay.
Markers of oxidative stress
8-isoprostane and nitrites/nitrates will be dosed on urine samples.
Measured: At the hospital admission and at 6 and 12 hours after surfactant therapy.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Aug 2019
- Study start1 Nov 2020 (estimated)
- Primary completion31 Oct 2022 (estimated)
- Study completion31 Oct 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Respiratory Distress Syndrome in Premature InfantsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Virgilio Paolo Carnielli
- Sponsor type
- University, hospital or other
- Collaborators
- Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona, Istituto di Ricerca Pediatrica Città della Speranza
- Responsible party
- Sponsor-investigator, Virgilio Paolo Carnielli, Ospedali Riuniti Ancona
- Investigators
- Virgilio Carnielli, MD, PHD, Study director, Azienda Ospedaliero-Universitaria Ospedali Riuniti di AnconaClementina Rondina, MD, Principal investigator, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04073173
- Sponsor's protocol ID
- StrAAS
- Other IDs
- 2020-004269-38
- Status last verified
- Sep 2020
- First submitted
- 27 Aug 2019
- Last updated
- 3 Sep 2020
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, Saugstad OD, Simeoni U, Speer CP, Vento M, Visser GH, Halliday HL. European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2016 Update. Neonatology. 2017;111(2):107-125. doi: 10.1159/000448985. Epub 2016 Sep 21.
PubMed 27649091Okamura H, Kinoshita M, Saitsu H, Kanda H, Iwata S, Maeno Y, Matsuishi T, Iwata O. Noninvasive surrogate markers for plasma cortisol in newborn infants: utility of urine and saliva samples and caution for venipuncture blood samples. J Clin Endocrinol Metab. 2014 Oct;99(10):E2020-4. doi: 10.1210/jc.2014-2009. Epub 2014 Jul 31.
PubMed 25078034Lago P, Benini F, Agosto C, Zacchello F. Randomised controlled trial of low dose fentanyl infusion in preterm infants with hyaline membrane disease. Arch Dis Child Fetal Neonatal Ed. 1998 Nov;79(3):F194-7. doi: 10.1136/fn.79.3.f194.
PubMed 10194990Guinsburg R, Kopelman BI, Anand KJ, de Almeida MF, Peres Cde A, Miyoshi MH. Physiological, hormonal, and behavioral responses to a single fentanyl dose in intubated and ventilated preterm neonates. J Pediatr. 1998 Jun;132(6):954-9. doi: 10.1016/s0022-3476(98)70390-7.
PubMed 9627585Guinsburg R, Kopelman BI, de Almeida MF, Miyoshi MH. [Pain in intubated and ventilated preterm neonate: multidimensional assessment and response to fentanyl analgesia]. J Pediatr (Rio J). 1994 Mar-Apr;70(2):82-90. doi: 10.2223/jped.727. Portuguese.
PubMed 14688879Badiee Z, Vakiliamini M, Mohammadizadeh M. Remifentanil for endotracheal intubation in premature infants: A randomized controlled trial. J Res Pharm Pract. 2013 Apr;2(2):75-82. doi: 10.4103/2279-042X.117387.
PubMed 24991608
Study at a glance
From the registry record, last updated by the sponsor on 3 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Stress Assessment in Preterm Infants With Respiratory Distress Syndrome Treated or Not With an Analgesic Drug During the Traditional or the Less Invasive Method of Surfactant Therapy.
- ClinicalTrials.gov ID
- NCT04073173
- Acronym / sponsor ID
- StrAAS
- Keywords
- RDS, Preterm Infants, Surfactant, LISA, INSURE, Analgesia, Stress
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Virgilio Paolo CarnielliUniversity, hospital or other
- Collaborators
- Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona, Istituto di Ricerca Pediatrica Città della Speranza
- Study start
- 1 Nov 2020 (estimated)
- Primary completion
- 31 Oct 2022 (estimated)
- Study completion
- 31 Oct 2022 (estimated)
- First posted
- 29 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will compare stress, changes in oxygenation and oxidative damage in preterm infants with respiratory distress syndrome (RDS) randomized to receive or not remifentanil as an analgesic drug during the administration of porcine surfactant (poractant alfa, Curosurf®) through the traditional (INSURE) or the less invasive (LISA) method.
Detailed description
At present, LISA and INSURE are both used for surfactant therapy in infants as comparable methods. However, a clear policy of using analgesics during surfactant therapy is still lacking: some neonatologists use analgesics to reduce stress and pain scores, whereas others do not approve their use due to interference with spontaneous breathing.
In this open-label, randomized, phase 4 clinical trial, infants admitted to our neonatal intensive unit care (NICU) will be evaluated according to the selection criteria and then randomized to receive or not remifentanil as an analgesic drug during the administration of porcine surfactant (poractant alfa, Curosurf®) via the INSURE or LISA method: Group-1) LISA-analgesic; Group 2) LISA-no analgesic; Group-3) INSURE-analgesic; Group-4) INSURE-no analgesic. Study patients will be stratified by gestational age at birth: Block A) 23.0-27.6 weeks of gestation; Block B) 28.0-31.6 weeks of gestation.
Early caffeine administration will be provided according to our NICU guidelines shortly after birth. Infants with adequate respiratory drive will be stabilized on nasal continuous positive airway pressure (CPAP; 4-8 cm of water) right after birth. Oxygen saturation targets will be 90-94%; moderate degrees of hypercarbia (PaCO2 < 60 mmHg, provided arterial pH >7.22) will be tolerated. Conditions mimicking respiratory distress syndrome (RDS; i.e. sepsis, air leaks, aspiration pneumonia, congenital heart disease) will be ruled out. RDS diagnosis will be clinical according to the European Guidelines. Nasal CPAP, bi-level CPAP or nasal intermittent positive pressure ventilation (synchronized or not) will be used at the discretion of the attending physician to stabilize the patients. Intubation criteria according to our NICU guidelines will be:
- severe acidosis (defined as arterial pH<7.20 with a partial pressure of carbon dioxide (PaCO2) > 55 mmHg and partial pressure of oxygen (PaO2) < 50 mmHg) with a fraction of inspired oxygen (FiO2) > 0.50;
- severe apnoea.
Enrolled infants will be evaluated from birth to day 7 of the hospital stay.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| LISA-analgesic | Experimental | Procedure: LISA, Drug: Analgesic, OpioidLess Invasive Surfactant Administration (LISA) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug. |
| LISA-no analgesic | Experimental | Procedure: LISALess Invasive Surfactant Administration (LISA) without an analgesic drug. |
| INSURE-analgesic | Experimental | Procedure: INSURE, Drug: Analgesic, OpioidINtubation-SURfactant-Extubation (INSURE) with remifentanil (0.5-2 micrograms/kg/dose) as the analgesic drug. |
| INSURE-no analgesic | Experimental | Procedure: INSUREINSURE without an analgesic drug. |
Who may qualify
- Ages
- 168 to 223 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- gestational age at birth between 168 and 223 days,
- respiratory distress syndrome (diagnosed on the basis of clinical and/or radiological grounds) with a fraction of inspired oxygen ≥0.30 (for infants born ≤26 weeks' gestational age) or ≥0.40 (for infants born >26 weeks' gestational age) to achieve a peripheral oxygen saturation of 90-94% within 24 hours of life and good respiratory drive,
- written informed consent.
Key exclusion criteria (7 listed)
- major malformations,
- late admission (after 24 hours of life),
- intubation in the delivery room,
- severe birth asphyxia,
- prolonged rupture of membranes,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| INSUREPatients will be intubated by endotracheal tube, exogenous surfactant (Poractant alfa) will be administered and then they will be extubated. | Procedure or surgery | INSURE-analgesic, INSURE-no analgesic |
| LISASurfactant (Poractant alfa) will be directly delivered into the lungs via a fine bore catheter inserted into the trachea and then patients will be extubated. | Procedure or surgery | LISA-analgesic, LISA-no analgesic |
| Analgesic, OpioidRemifentanil (0.5-2 micrograms/kg/dose) | Drug | INSURE-analgesic, LISA-analgesic |
Primary outcome
Cortisol concentrations
Time frame: At 1, 3, 6 12, 24 hours after surfactant administration and then daily in the first week at the same time of the day (to avoid circadian variations).
Cortisol concentrations will be assessed in saliva, as salivary cortisol levels have been shown to be useful surrogate markers for plasma cortisol levels in neonates. Saliva samples will be collected using an absorbent swab stick, centrifuged at 4000 rpm for 10 minutes and kept at -80°C until assayed (minimum sample volume 25 µl). Enzyme immunoassay (ELISA kit) will be used. Basal samples will be obtained at the hospital admission and right before surfactant.
5 secondary outcomes
Galvanic Skin Responses
Time frame: At 1, 3, 6 12, 24 hours after surfactant administration and then daily in the first week at the same time of the day (to avoid circadian variations).
Heart rate
Time frame: 6 hours before and after surfactant therapy will be analyzed.
Brain oxygenation
Time frame: From the hospital admission to day 7 of the hospital stay.
Oxygen saturation (SpO2)
Time frame: From the hospital admission to day 7 of the hospital stay.
Markers of oxidative stress
Time frame: At the hospital admission and at 6 and 12 hours after surfactant therapy.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Sep 2020.
- Background: PubMed 27649091Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, Saugstad OD, Simeoni U, Speer CP, Vento M, Visser GH, Halliday HL. European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2016 Update. Neonatology. 2017;111(2):107-125. doi: 10.1159/000448985. Epub 2016 Sep 21.
- Background: PubMed 25078034Okamura H, Kinoshita M, Saitsu H, Kanda H, Iwata S, Maeno Y, Matsuishi T, Iwata O. Noninvasive surrogate markers for plasma cortisol in newborn infants: utility of urine and saliva samples and caution for venipuncture blood samples. J Clin Endocrinol Metab. 2014 Oct;99(10):E2020-4. doi: 10.1210/jc.2014-2009. Epub 2014 Jul 31.
- Background: PubMed 10194990Lago P, Benini F, Agosto C, Zacchello F. Randomised controlled trial of low dose fentanyl infusion in preterm infants with hyaline membrane disease. Arch Dis Child Fetal Neonatal Ed. 1998 Nov;79(3):F194-7. doi: 10.1136/fn.79.3.f194.
- Background: PubMed 9627585Guinsburg R, Kopelman BI, Anand KJ, de Almeida MF, Peres Cde A, Miyoshi MH. Physiological, hormonal, and behavioral responses to a single fentanyl dose in intubated and ventilated preterm neonates. J Pediatr. 1998 Jun;132(6):954-9. doi: 10.1016/s0022-3476(98)70390-7.
- Background: PubMed 14688879Guinsburg R, Kopelman BI, de Almeida MF, Miyoshi MH. [Pain in intubated and ventilated preterm neonate: multidimensional assessment and response to fentanyl analgesia]. J Pediatr (Rio J). 1994 Mar-Apr;70(2):82-90. doi: 10.2223/jped.727. Portuguese.
- Background: PubMed 24991608Badiee Z, Vakiliamini M, Mohammadizadeh M. Remifentanil for endotracheal intubation in premature infants: A randomized controlled trial. J Res Pharm Pract. 2013 Apr;2(2):75-82. doi: 10.4103/2279-042X.117387.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Virgilio Carnielli, MD, PHD study director
Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona
Clementina Rondina, MD principal investigator
Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing INSURE, LISA and Analgesic, Opioid in people with Respiratory Distress Syndrome in Premature Infants, run by Virgilio Paolo Carnielli.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Virgilio Carnielli, MD, PHD (+390715962045, v.carnielli@staff.univpm.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cortisol concentrations (time frame: At 1, 3, 6 12, 24 hours after surfactant administration and then daily in the first week at the same time of the day (to avoid circadian variations).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04073173, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2020.