RESPONSE: Recombinant surfactant protein D to prevent neonatal chronic lung disease – safety trial
| ISRCTN | ISRCTN17083028 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17083028 |
| EudraCT/CTIS number | 2021-001824-16 |
| IRAS number | 1004422 |
| ClinicalTrials.gov number | NCT05898633 |
| Secondary identifying numbers | 18/0564, IRAS 1004422 |
- Submission date
- 05/04/2023
- Registration date
- 26/07/2023
- Last edited
- 06/11/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Pregnancy and Childbirth
Plain English Summary
Background and study aims
Bronchopulmonary Dysplasia (BPD), also known as chronic lung disease (CLD), is a serious long-term lung condition that can affect up to 70% of infants born prematurely before 28 weeks of pregnancy. This is because their lungs have not fully developed, and they do not produce a soapy substance called surfactant. It is not clear why they develop CLD, but inflammation and infection have a role. Current surfactant replacement therapy consists of phospholipids and surfactant proteins B and C, but no surfactant protein A or surfactant protein D (SP-D). SP-D has anti-inflammatory and anti-infection properties, both of which play a role in the development of CLD. The RESPONSE study is a first-in-human study of recombinant SP-D (rfhSP-D), which is a manufactured version of SP-D that is a part of the naturally occurring protein. The study aims to find out the safest dose of rfhSP-D for premature infants (under 30 weeks gestation) who are at high risk of CLD, and how it helps to prevent CLD.
Who can participate?
Inborn infants born between 23 weeks and 0 days and 29 weeks and 6 days gestation requiring intubation or planned to be intubated for respiratory distress
What does the study involve?
Up to 24 participants will be recruited for the study. Each infant will receive up to three administrations of rfhSP-D, either 1 mg/kg, 2 mg/kg or 4 mg/kg. The infants will be enrolled in groups with a dose level increase in each group after it has been deemed safe to increase the dose level by an independent Data and Safety Monitoring Board and Study Steering Committee.
Participants will continue to be monitored in the Neonatal Unit until discharge.
What are the possible benefits and risks of participating?
As this is the first study of rfhSP-D in humans, possible adverse reactions to this Investigational Medicinal Product are not known. The safety of the participants in this study is paramount. The lowest possible dose of the drug will be used in the first cohort and the dose will only be escalated after review of safety data by an independent Data and Safety Monitoring Board. Safety data will be regularly monitored throughout the study, and an individual baby will stop receiving rfhSP-D if there are safety concerns. The study will be stopped if safety concerns meet pre-defined criteria.
The gastric and tracheal aspirates are routinely taken and usually, the sample is discarded, but we will use this sample for analysis.
The blood samples that are done, where possible, will be taken from any central lines that the baby has and otherwise, a heel lance will be done. These will be timed with routine care and blood tests to minimise discomfort for the baby. Standard comforting measures used when doing blood samples will be used.
Up to 4ml of blood will be collected in total in this study, in addition to routine blood tests that are done as part of clinical management. The volume of blood taken is considered to be low risk to participants as the samples are taken over time [depending on gestational age at enrolment] and alongside any routine clinical blood samples taken.
Where is the study run from?
University College London (UK)
When is the study starting and how long is it expected to run for?
April 2023 to December 2025
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
The RESPONSE Clinical Trial Manager, cctu.response@ucl.ac.uk
Contact information
Principal Investigator
University College London
Medical School Building
74 Huntley Street
London
WC1E 6AU
United Kingdom
| Phone | +44 (0)207 679 0834 |
|---|---|
| h.clark@ucl.ac.uk |
Scientific
University College London
Medical School Building
74 Huntley Street
London
WC1E 6AU
United Kingdom
| Phone | +44 (0)207 679 0834 |
|---|---|
| h.clark@ucl.ac.uk |
Public
-
London
-
United Kingdom
| Phone | None available |
|---|---|
| cctu.response@ucl.ac.uk |
Study information
| Study design | Phase I dose-ranging safety study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | RESPONSE - Phase I safety trial of recombinant surfactant protein D to prevent neonatal chronic lung disease |
| Study acronym | RESPONSE |
| Study hypothesis | Current study hypothesis as of 07/08/2024: The main objectives of the RESPONSE trial are to: 1. To assess the safety profile of rfhSP-D across 3 dose levels based on the occurrence of dose-limiting events (DLEs) 2. To establish the Recommended Phase II Dose (RP2D) of rfhSP-D for preterm infants born at a gestational age of <30 weeks The trial will also aim: 1. To assess the safety profile of rfhSP-D across 3 dose levels based on the occurrence of SAE/AEs 2. To evaluate systemic absorption of rfhSP-D using serial measurements of rfhSP-D in serum and its continued presence in tracheal fluid 3. To determine the effect of rfhSP-D on inflammatory markers in the lung secretions (eg. cell counts of neutrophils, macrophages, MMPs, neutrophil elastase, IL-8, IL-6, IL-1) 4. To compare the clinical effects of endotracheal administration of rfhSP-D on physiological and intensive care parameters in treated infants in this trial with non-treated infants from a parallel observational study of untreated infants. _____ Previous study hypothesis: The main objectives of the RESPONSE trial are to: 1. To assess the safety profile of rfhSP-D across 3 dose levels based on the occurrence of dose-limiting events (DLEs) 2. To establish the Recommended Phase II Dose (RP2D) of rfhSP-D for preterm infants born at a gestational age of <28 weeks The trial will also aim: 1. To assess the safety profile of rfhSP-D across 3 dose levels based on the occurrence of SAE/AEs 2. To evaluate systemic absorption of rfhSP-D using serial measurements of rfhSP-D in serum and its continued presence in tracheal fluid 3. To determine the effect of rfhSP-D on inflammatory markers in the lung secretions (eg. cell counts of neutrophils, macrophages, MMPs, neutrophil elastase, IL-8, IL-6, IL-1) 4. To compare the clinical effects of endotracheal administration of rfhSP-D on physiological and intensive care parameters in treated infants in this trial with non-treated infants from a parallel observational study of untreated infants. |
| Ethics approval(s) |
Approved 23/06/2023, London - Brent Research Ethics Committee (Health Research Authority, 2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)20 7104 8128, (0)207 104 8131 ; brent.rec@hra.nhs.uk), ref: 23/LO/0381 |
| Condition | Bronchopulmonary dysplasia; congenital, hereditary, and neonatal diseases and abnormalities |
| Intervention | Recombinant fragment of human surfactant protein D (rfhSP-D) administration. This is a single-arm trial with the administration of rfhSP-D. All participants will be administered IMP via an endotracheal tube in 1-3 doses in the first 24-48hrs after birth whilst the infant is still intubated and ventilated. A dose escalation design from 1mg/kg to 4mg/kg will be used. Infants are enrolled in cohorts of three, with the first cohort receiving the lowest dose of 1mg/kg. Participants are followed up until they are discharged from the hospital. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | Recombinant surfactant protein D (rfhSP-D) |
| Primary outcome measure | Current primary outcome measure as of 07/08/2024: The following primary outcome measures will be measured using the occurrence of dose-limiting events (DLEs) recorded in the patient study records until 3 days post-last administration of the investigational medicinal product (IMP): 1. Safety profile of recombinant surfactant protein D (rfhSP-D) across 3 dose levels 2. Recommended phase II dose (RP2D) of rfhSP-D for preterm infants born at a gestational age of <30 weeks _____ Previous primary outcome measure: The following primary outcome measures will be measured using the occurrence of dose-limiting events (DLEs) recorded in the patient study records until 3 days post-last administration of the investigational medicinal product (IMP): 1. Safety profile of recombinant surfactant protein D (rfhSP-D) across 3 dose levels 2. Recommended phase II dose (RP2D) of rfhSP-D for preterm infants born at a gestational age of <28 weeks |
| Secondary outcome measures | The following secondary outcome measures will be measured using patient study records for a follow-up of 40 weeks post-menstrual age, or hospital discharge, whichever is soonest: 1. Safety profile of rfhSP-D across 3 dose levels based on the occurrence of SAE/AEs 2. Systemic absorption of rfhSP-D using serial measurements of rfhSP-D in serum and its continued presence in tracheal fluid 3. Effect of rfhSP-D on inflammatory markers in the lung secretions (eg. cell counts of neutrophils, macrophages, MMPs, neutrophil elastase, IL-8, IL-6, IL-1) 4. Clinical effects of endotracheal administration of rfhSP-D on physiological and intensive care parameters in treated infants in this trial with non-treated infants from a parallel observational study of untreated infants |
| Overall study start date | 01/09/2023 |
| Overall study end date | 31/12/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Neonate |
| Sex | Both |
| Target number of participants | 24 |
| Participant inclusion criteria | Current inclusion criteria as of 07/08/2024: 1. Inborn infants born between 23 weeks and 0 days and 29 weeks and 6 days gestation 2. Infant must be intubated or planned to be intubated for respiratory distress at the time of eligibility check, and this should be done within 12 hours from the time of birth 3. Receiving standard surfactant therapy 4. Clinically stable on mechanical ventilation. Stability is defined at the time of IMP instillation and is defined below 5. Written informed consent from parents/guardians/person with legal responsibility Definition of stability: 1. Blood gases within the normal range for preterm infants (pH>7.20; paCO2 <60mmHg) 2. Mean blood pressure with or without inotropic support at least gestational age or above (mmHg) 3. No evidence of a pneumothorax 4. Clinical observations within acceptable range for an infant of that gestational age 5. No stability concerns from the attending neonatologist _____ Previous inclusion criteria: 1. Inborn infants born between 23 weeks and 0 days and 27 weeks and 7 days gestation 2. Infant must be intubated or planned to be intubated for respiratory distress at the time of eligibility check, and this should be done within 12 hours from the time of birth 3. Receiving standard surfactant therapy 4. Clinically stable on mechanical ventilation. Stability is defined at the time of IMP instillation and is defined below 5. Written informed consent from parents/guardians/person with legal responsibility Definition of stability: 1. Blood gases within the normal range for preterm infants (pH>7.20; paCO2 <60mmHg) 2. Mean blood pressure with or without inotropic support at least gestational age or above (mmHg) 3. No evidence of a pneumothorax 4. Clinical observations within acceptable range for an infant of that gestational age 5. No stability concerns from the attending neonatologist |
| Participant exclusion criteria | 1. Congenital anomalies i.e any major antenatal diagnosed congenital abnormalities such as congenital heart disease, suspected or known chromosomal abnormalities 2. Parents/legal guardians unable to give consent due to learning or other difficulties 3. Infants requiring only CPAP support without the need for surfactant replacement therapy, i.e. without endotracheal intubation 4. Infants born in very poor conditions and judged too sick or unstable to be included (high risk of mortality) in an experimental first-in-human study, for example, infants that are requiring maximal intensive care therapy and have findings such as a grade IV intraventricular haemorrhage that is likely to be life-limiting 5. Infants that are born out of the participating site 6. Participation in any other interventional study (participation in an observational study is permissible) |
| Recruitment start date | 06/04/2024 |
| Recruitment end date | 30/06/2025 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
London
NW1 2PG
United Kingdom
Sponsor information
University/education
Comprehensive Clinical Trials Unit
90 High Holborn
2nd Floor
London
WC1V 6LJ
England
United Kingdom
| Phone | +44 (0)203 1084255 |
|---|---|
| cctu.response@ucl.ac.uk | |
| Website | http://www.ucl.ac.uk/ |
"ROR" |
https://ror.org/02jx3x895 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/12/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Conference presentation 3. Publication on a website |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date |
Editorial Notes
06/11/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 30/11/2024 to 30/06/2025.
2. The overall study end date was changed from 31/12/2024 to 31/12/2025.
3. The intention to publish date was changed from 31/12/2025 to 31/12/2026.
07/08/2024: The following changes were made to the trial record:
1. The study hypothesis was changed.
2. The primary outcome measure was changed.
3. The inclusion criteria were changed.
4. The recruitment start date was changed from 30/04/2024 to 06/04/2024.
5. The plain English summary was updated to reflect these changes.
05/04/2024: The following changes were made to the study record:
1. The recruitment start date was changed from 02/07/2023 to 30/04/2024.
2. The recruitment end date was changed from 01/04/2024 to 30/11/2024.
3. The overall study end date was changed from 31/12/2023 to 31/12/2024.
4. The intention to publish date was changed from 31/12/2024 to 31/12/2025.
5. ClinicalTrials.gov number added.
23/06/2023: ISRCTN received notification of combined HRA/MHRA approval for this trial on 23/06/2023
05/04/2023: Trial's existence confirmed by Health Research Authority (HRA) (UK).
