Oral Propranolol for prevention of threshold retinopathy of prematurity

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Tuebingen AöR, Universität Zürich - Klinik für Neonatologie

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

24 Jul 2024 → ongoing

Decision date (initial)

2024-10-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DFG and BMBF (BMBF/ DLR Projektträger)

External identifiers

EU CT number

2024-511338-10-01

EudraCT number

2017-002124-24

ClinicalTrials.gov

NCT03083431

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To assess the safety and efficacy of orally administered propranolol to reduce the risk of threshold retinopathy of prematurity in extremely preterm infants

Secondary objectives 1

1. To assess the safety and efficacy of orally administered propranolol to reduce the rate of extremely preterm infants requiring local interventions for severe retinopathy of prematurity

Conditions and MedDRA coding

Retinopathy of prematurity

Regulatory references

Plan to share IPD

No

IPD plan description

Results will be published in scientific journals, parental consent does not include sharing of individual participant data

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Preterm infant born before 28 weeks gestation
2. Birth weight below 1250 g
3. Alive at 5 weeks of age
4. Postmenstrual age 31 0/7 – 36 6/7 weeks
5. Ophthalmoscopic evidence of incipient ROP (stage 1 or 2, with or without plus disease)
6. Written informed consent by parents or legal guardian, including saving and propagation of pseudonymous medical data for study purposes, according to national requirements

Exclusion criteria 28

1. ROP stage ≥ 3, AP-ROP or suspected AP-ROP, or any other ROP requiring an intervention (study endpoint already reached)
2. PHACE syndrome (posterior fossa anomalies, large infantile hemangiomas of the face, neck, and/or scalp, arterial lesions, cardiac abnormalities/coarctation of the aorta, eye anomalies) (risk of cerebrovascular complications)
3. Very large hemangioma (risk of hyperkalemia), as judged by the attending physician
4. Heart rate consistently (>1 h) < 100/min
5. Noninvasive mean arterial pressure consistently (>1 h) <40 mmHg
6. Medication of the infant or the mother if breastfeeding with clonidine, reserpine, angiotensin-converting enzyme inhibitors, angiotensinreceptor antagonists, or antiarrhythmic drugs including amiodarone, propafenone, lidocaine, digoxin/digitoxin, quinidine, verapamil, diltiazem, or bepridil (pharmacodynamic interaction)
7. Medication of the infant with rifampicin or phenobarbitone (enhanced metabolic clearance), clonidine, antiarrhythmic drugs (amiodarone, propafenone, lidocaine, digoxin/digitoxin, quinidine), verapamil, diltiazem, bepridil), antihypertensive agents (reserpine, angiotensinconverting enzyme inhibitors, angiotensin-receptor antagonists, (pharmacodynamic drug interaction)
8. Concurrent treatment with insulin (risk of hypoglycemia)
9. Severe liver dysfunction (GPT > 900 U/l)
10. Chronic kidney impairment (creatinine > 1.3 mg/dl [100 μM])
11. Persistent hypoglycemia (blood glucose < 36 mg/dl [2.0 mM] in 3 consecutive samples immediately preceding enrollment)
12. Thyrotoxicosis, arterial hypertension or congenital heart diseases requiring open-label propranolol treatment (such as tetralogy of Fallot, paroxysmal supraventricular tachycardia, or long QT syndrome)
13. Persistent hyperkalemia (venous serum potassium > 5.9 mM in 3 consecutive samples immediately preceding enrollment)
14. Persistent neutropenia (absolute neutrophil counts <1,000/μL in 3 consecutive samples immediately preceding enrollment)
15. Known hypersensitivity to propranolol or any of the excipients
16. Prinzmetal's angina, Raynaud's phenomenon (severe peripheral arterial circulatory disturbance), or pheochromocytoma (contraindications for propranolol in adults, not occurring in newborn infants)
17. Participation in another pharmacological interventional clinical trial
18. Any circumstances that make the investigator believe that in the infant’s own interest, he/she should no longer receive the study medication
19. Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial
20. Atrio-ventricular block grade 2 or 3 (contraindication for propranolol)
21. Sinuatrial block (contraindication for propranolol)
22. Uncontrolled heart failure or cardiogenic shock (contraindication for propranolol)
23. Acute severe infection (inclusion may be postponed until infection has resolved)
24. Bronchial asthma
25. Major congenital malformations or known chromosomal anomalies
26. Colobomas and other eye malformations
27. > 7 days after first ROP diagnosis (day 1 = first ROP diagnosis)
28. Previous or current conditions that indicated/indicate beta-blocker therapy, open label propranolol such as: thyrotoxicosis, arterial hypertension or certain heart diseases (such as tetralogy of Fallot, paroxysmal supraventricular tachycardia long QT syndrome, or hypertrophic cardiomyopathy)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Survival without threshold ROP (stage 3 or more severe ROP(including aggressive posterior ROP))

Secondary endpoints 6

1. Time to adverse ophthalmological outcome in days
2. Ophthalmological outcome categorized as survival without adverse ophthalmological outcome, or death
3. Survival until 48 weeks PMA without ROP, treated with ablative laser surgery or intravitreal VEGF antagonists
4. Death until discharge
5. Death until 48 weeks PMA
6. ROP retreatment: Need for repeated ROP therapy in infants treated with anti-VEGF-antagonists until 70 ( 2 weeks) PMA

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Tuebingen AöR

Sponsor organisation

Universitaetsklinikum Tuebingen AöR

Address

Geissweg 3, Innenstadt Innenstadt

City

Tübingen

Postcode

72076

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Axel Franz

Public contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Axel Franz

Universität Zürich - Klinik für Neonatologie

Sponsor organisation

Universität Zürich - Klinik für Neonatologie

Address

Frauenklinikstraße 10

City

Zürich

Postcode

8091

Country

Switzerland

Sponsor responsibilities

Article 77 compliance

Universitaetsklinikum Tuebingen AöR

Contact point sponsor

Universitaetsklinikum Tuebingen AöR

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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