Safety and effect of mesenchymal derived Extracellular Vesicles in the prevention of Bronchopulmonary Dysplasia in extremely preterm newborns.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Exo Biologics

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

28 Dec 2023 → ongoing

Decision date (initial)

2023-07-11

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2022-500293-34-01

WHO UTN

U1111-1291-0283

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Safety

Phase I primary objective
To assess the acute and short-term safety of the intratracheal (IT) administration of EXOB-001 (single dose or multiple doses at different dose levels) at 36 weeks postmenstrual age (PMA).

Phase II primary objective
To assess the efficacy of EXOB-001 on the reduction of BPD grade II-III (modified NICHD severity grading case definition) at 36 weeks PMA as compared to a placebo group (saline solution).

Secondary objectives 30

1. Phase I: To assess medium-term safety of EXOB-001 up to hospital discharge.
2. Phase I: To assess the dose-limiting toxicity within 6 hours and 24 hours after (every) EXOB-001 administration.
3. Phase I: To assess the tolerability of EXOB-001 reported up to hospital discharge.
4. Phase I: To assess the number of cases and severity of BPD according to different definitions.
5. Phase I: To assess lung development.
6. Phase I: To confirm parenchymal lung disease.
7. Phase I: To assess pulmonary hypertension.
8. Phase I: To assess up to 2 years corrected age the overall health status of every subject with special attention to pulmonary morbidity.
9. Phase I: To assess mortality caused by lung failure.
10. Phase I: To assess the long-term safety of EXOB-001.
11. Phase I: To evaluate the duration of mechanical ventilation (MV)/respiratory support and hospital stay, assessment of lung capacity, assessment of known complications and sequelae of prematurity such as retinopathy of prematurity (ROP), necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH), sepsis, periventricular leukomalacia (PVL), hyaline membrane disease (HMD), apnoea, pneumothorax; concomitant medications/therapies/procedures up to hospital discharge.
12. Phase I and II: To assess up to 2 years corrected age the known complications and sequelae of prematurity; concomitant treatments/procedures/therapies during the passive surveillance.
13. Phase I: To evaluate the neurodevelopmental condition up to 2 years corrected age.
14. Phase I: To evaluate the respiratory morbidity up to 2 years corrected age.
15. Phase II: To assess the efficacy of EXOB-001 by comparing the number of subjects with Oxygen and/or respiratory support at 40 weeks PMA in active groups versus placebo according to Isayama et al, 2017 case definition.
16. Phase II: To assess the efficacy of EXOB-001 by comparing the number of subjects with oxygen dependence and ventilation support at day 28 chronological age and BPD incidence and severity at 36 weeks PMA in active groups versus placebo according to Jobe and Bancalari 2001 case definition.
17. Phase II: To assess the efficacy of EXOB-001 by comparing BPD incidence and severity in active groups versus placebo at 36 weeks PMA according to modified NICHD severity grading case definition.
18. Phase II: To assess the efficacy of each group of EXOB-001 on the reduction of BPD grade II-III (modified NICHD severity grading case definition) at 36 weeks PMA.
19. Phase II: To confirm parenchymal lung disease.
20. Phase II: To assess pulmonary hypertension.
21. Phase II: To assess up to 2 years corrected age the overall health status of every subject with special attention to pulmonary morbidity in all groups.
22. Phase II: To assess lung development in all groups.
23. Phase II: To assess mortality caused by lung failure in all groups.
24. Phase II: To assess the tolerability of EXOB-001 and SOC in active groups versus placebo.
25. Phase II: To assess the long-term safety of EXOB-001 in active groups versus placebo.
26. Phase II: To evaluate the duration of MV/respiratory support and hospital stay; assessment of lung capacity, assessment of known complications and sequelae of prematurity such as ROP, NEC, IVH, sepsis, PVL, HMD, apnoea, pneumothorax; concomitant treatments/procedures/therapies in all groups up to hospital discharge.
27. Phase II: To assess up to 2 years corrected age known complications of prematurity concomitant treatments/procedures/therapies in all groups during the passive surveillance.
28. Phase II: To test immune markers in tracheal aspirate fluid in a subset of subjects in all groups.
29. Phase II: To evaluate the neurodevelopmental condition up to 2 years corrected age in all groups.
30. Phase II: To evaluate the respiratory morbidity up to 2 years corrected age in all groups.

Conditions and MedDRA coding

Bronchopulmonary Dysplasia

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Istituto Superiore Di Sanità, Federal Agency For Medicines And Health Products

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. From birth up to 10 days chronological age
2. From 23 weeks up to 28 weeks (27 week+6 days) gestational age at birth
3. Birth weight ≥ 500g but ≤1500g
4. Endotracheally intubated and receiving mechanical ventilation anytime between at least 24 hours of life and 10 days postnatally or alternatively, needing re-intubation due to respiratory complications.
5. Written informed consent from parents/legally designated representative

Exclusion criteria 12

1. Surfactant administration less than 12 hours prior to (first) IMP administration.
2. Has active pulmonary haemorrhage
3. Has periventricular leukomalacia
4. The subject is currently participating in any other interventional clinical study
5. The subject is, in the opinion of the Investigator, so ill that death is inevitable, or is considered inappropriate for the study such as an infant that received thoracic compressions and/or adrenaline administration during stabilization in the delivery room and for any reason(s) other than those listed above
6. Has a congenital heart defect, except for patent ductus arteriosus (PDA), atrial septal defect or a small/moderate, restrictive ventricular septal defect
7. Has a serious malformation of the lung, such as pulmonary hypoplasia/aplasia, congenital diaphragmatic hernia, or any other congenital lung anomaly
8. Has a known chromosomal abnormality (e.g., Trisomy 18, Trisomy 13, or Trisomy 21) or a severe congenital malformation (e.g., hydrocephalus and encephalocele, trachea-oesophageal fistula, abdominal wall defects, and major renal anomalies)
9. Has had a known severe congenital infectious disease (i.e., herpes, toxoplasmosis rubella, syphilis, human immunodeficiency virus, cytomegalovirus, etc.)
10. Active systemic infection, severe sepsis, or septic shock at screening up to baseline (phase I) or randomization (phase II).
11. Underwent a surgical procedure (requiring admission to an operating room) within 72 hours before baseline (phase I)/randomization (phase II) or who is anticipated to have a surgical procedure (requiring admission to an operating room) within 72 hours before or following baseline (phase I)/randomization (phase II)
12. Has had a Grade 3 or 4 intraventricular haemorrhage

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I: Treatment-emergent adverse events (TEAEs) assessed from EXOB-001 administration up to 36 weeks PMA.
2. Phase II: BPD grade II-III incidence rate per groups assessed at 36 weeks PMA. Severity of BPD assessed according to the modified NICHD severity grading (Grade I to IIIA) definition.

Secondary endpoints 31

1. Phase I: Treatment-emergent adverse events (TEAEs), and clinical examination and blood tests.
2. Phase I: Dose limiting toxicity measured as: cardiorespiratory decompensation (hypotension with tachycardia, lactic acidosis, oliguria, with echocardiographic confirmation if possible); decrease in SpO2/FiO2 ratio of more than 100 points or increase in FiO2 by > 30% (defined as 30% increase from the baseline, e.g. from 40% to 70%) that persist for at least 4 hours; stable (> 3 hours) increase in required mean airway pressure >3 cm H2O; death; anaphylactic reaction; any serious adverse reaction
3. Phase II: All adverse events (AEs) and serious adverse events (SAEs) (including case fatalities), both related and non-related.
4. Phase I: Need for oxygen and ventilation support (case definition according to Jobe and Bancalari 2001, case definition according to Isayama et al. 2017].
5. Phase I: The number of cases and severity of BPD measured according to modified NICHD severity grading (Grade I to IIIA) case definition and according to Jobe and Bancalari 2001 (mild, moderate, severe) case definition. The number of cases of BPD according to Isayama et al. 2017 case definition.
6. Phase I: Lung ultrasound (LUS).
7. Phase I: Chest X-Ray(s).
8. Phase I: Functional and anatomic echocardiography.
9. Phase I: Clinical examination, blood tests.
10. Phase I: Number of deaths caused by lung failure.
11. Phase I: All SAEs (including all-cause deaths).
12. Phase I: Duration of MV/respiratory support (i.e., total time receiving supplemental oxygen). Respiratory Severity Score. Duration of hospitalisation. Assessment of ROP, NEC, IVH, sepsis, PVL, HMD, apnoea, pneumothorax. Concomitant treatments, such as steroids, and surfactant. Concomitant procedures and therapies.
13. Phase I: Occurrence of ROP, NEC, IVH, sepsis, PVL, HMD, apnoea, pneumothorax; concomitant treatments such as steroids and others, procedures and therapies.
14. Phase I: ASQ3 Ages & Stages questionnaire for parents.
15. Phase I: Liverpool Respiratory Symptom Questionnaire (LRSQ).
16. Phase II: Need for oxygen and ventilation support, and BPD incidence (BPD case definition according to Isayama et al. 2017). Per group.
17. Phase II: Need for oxygen and ventilation support at day 28 chronological age, and BPD incidence and severity rate at 36 weeks PMA (BPD case definition according to Jobe and Bancalari 2001). Per group.
18. Phase II: BPD grade I-II-III incidence rate per group. Severity of BPD assessed according to the modified NICHD severity grading (Grade I to IIIA) definition.
19. Phase II: BPD grade II-III incidence rate in each EXOB-001 group. Severity of BPD assessed according to the modified NICHD severity grading (Grade I to IIIA) definition.
20. Phase II: Chest X-Ray(s). Per group.
21. Phase II: Functional and anatomic echocardiography. Per group.
22. Phase II: Clinical examination, blood tests. Per group.
23. Phase II: Lung ultrasound (LUS). Per group.
24. Phase II: Number of deaths caused by lung failure per group.
25. Phase II: All AEs and SAEs (related and non-related) per group.
26. Phase II: All SAEs (including all-cause deaths). Per group.
27. Phase II: Duration of MV/respiratory support and hospitalisation. Assessment of RSS. Assessment of ROP, NEC, IVH, sepsis, PVL, HMD, apnoea, pneumothorax. Concomitant treatments, such as steroids, and surfactant. Per group.
28. Phase II: Occurrence of ROP, NEC, IVH, sepsis, PVL, HMD, apnoea, pneumothorax. Concomitant treatments such as steroids and others, procedures, and therapies. Per group.
29. Phase II: IL-6, IL-8, TNFa, TGFb1, IL1b and IL1ra. Subset of subjects in all groups.
30. Phase II: ASQ3 Ages and Stages questionnaire for parents. Per group.
31. Phase II: Liverpool Respiratory Symptom Questionnaire (LRSQ). Per group.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Exo Biologics

Sponsor organisation

Exo Biologics

Address

Boulevard Gustave-Kleyer 17

City

Liege

Postcode

4000

Country

Belgium

Scientific contact point

Organisation

Exo Biologics

Contact name

Clinical Department

Public contact point

Organisation

Exo Biologics

Contact name

Administrative Department

Third parties 4

Locations

2 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

10 submissions — initial application plus substantial / non-substantial modifications