Gene Therapy for Crigler-Najjar Syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Genethon

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

9 Apr 2018 → ongoing

Decision date (initial)

2023-11-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

European Commission · Genethon

External identifiers

EU CT number

2023-507007-60-00

EudraCT number

2017-000506-37

ClinicalTrials.gov

NCT03466463

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Safety, Dose response, Therapy

Dose escalation part: To assess the safety and tolerability of an intravenous single-dose administration of GNT0003 in patients with severe Crigler-Najjar syndrome requiring phototherapy
Confirmatory part: To assess the efficacy of the intravenous single-dose administration of GNT0003 selected dose in patients with severe Crigler-Najjar syndrome requiring phototherapy

Secondary objectives 6

1. Dose escalation part: To assess the pharmacokinetics of GNT0003
2. Dose escalation part: To assess the efficacy of the intravenous single-dose administration of GNT0003 in patients with severe Crigler-Najjar syndrome requiring phototherapy
3. Confirmatory part: To assess the safety of the intravenous single dose administration of GNT0003 selected dose
4. Confirmatory part: To evaluate the impact of GNT0003 selected dose in patients’ Quality of Life
5. Confirmatory part: To assess pharmacokinetics of GNT0003 selected dose
6. Confirmatory part: To assess pharmacodynamic of GNT0003 selected dose

Conditions and MedDRA coding

severe Crigler-Najjar syndrome in patients requiring phototherapy

Regulatory references

Scientific advice from competent authorities

Italian National Institute Of Health, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002021-PIP01-16

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Patients with severe Crigler-Najjar syndrome requiring daily phototherapy (≥ 6h/day)
2. Molecular confirmation of mutations in the UGT1A1 gene by DNA sequencing

Exclusion criteria 2

1. Fibrosis score ≥ 3 (METAVIR) or 10 kPa
2. Patients who underwent liver transplantation

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Dose escalation part: Incidence of treatment-emergent adverse events (TEAEs) or treatment-emergent serious adverse events (TESAEs) up to Week 17
2. Dose escalation part: Change in laboratory parameters, vital signs and in physical examination from baseline to Week 17
3. Confirmatory part: The proportion of patients having received the selected dose of GNT0003 with serum total bilirubin ≤ 300 µmol/L at Week 48 after IMP infusion and without phototherapy from Week 16

Secondary endpoints 10

1. Dose escalation part: Time to GNT0003 vector clearance from blood, urine, saliva and feces
2. Dose escalation part: Number of patients with serum total bilirubin ≤ 300 µmol/L within 7 days after interruption of daily phototherapy
3. Confirmatory part: Incidence of treatment-emergent adverse events (TEAEs) or treatment-emergent serious adverse events (TESAEs) up to Week 48
4. Confirmatory part: Change in laboratory parameters, vital signs and in the physical examination from baseline up to Week 48
5. Confirmatory part: Change in serum total bilirubin from baseline up to Week 48
6. Confirmatory part: Change in bilirubin/albumin ratio from baseline up to Week 48
7. Confirmatory part: Change in Health-related quality of life as measured by QOL questionnaires, SF-36 (adult) and PedsQL (pediatric), and by the quality of sleep questionnaire from baseline up to Week 48.
8. Confirmatory part: Time to GNT0003 vector clearance from blood, urine, saliva and feces
9. Proportion of patients achieving sustained discontinuation of phototherapy up to 120 months, with assessment of: Duration of phototherapy discontinuation, Time to phototherapy restart (if applicable), Daily duration of phototherapy after restart.
10. Proportion of patients achieving sustained discontinuation of phototherapy up to Week 48, with assessment of: - Duration of phototherapy discontinuation, - Time to phototherapy restart (if applicable), - Daily duration of phototherapy after restart.

Investigational products

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

Test 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Genethon

Sponsor organisation

Genethon

Address

1 Rue De L Internationale

City

Evry-Courcouronnes

Postcode

91000

Country

France

Scientific contact point

Organisation

Genethon

Contact name

Clinical Development Department

Public contact point

Organisation

Genethon

Contact name

Clinical Development Department

Third parties 5

Locations

3 EU/EEA countries · 4 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 67 files

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

Application history

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