Phase I/II clinical trial of autologous hematopoietic stem cell gene therapy in rag1-deficient severe combined immunodeficiency

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Videja B.V.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

23 Jul 2021 → ongoing

Decision date (initial)

2024-12-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

European Union, Horizon 2020

External identifiers

EU CT number

2023-510204-50-00

EudraCT number

2019-002343-14

ClinicalTrials.gov

NCT04797260

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To evaluate the effect of RAG1 gene therapy on overall survival
To evaluate the efficacy of RAG1 gene therapy in achieving reconstitution of the T and B cell immune system in patients with RAG1-SCID at 6 months
To evaluate the safety and tolerability of the RAG1 gene therapy product, including identification of short- and long-term adverse events

Secondary objectives 5

1. To evaluate the effect of RAG1 gene therapy on event-free survival.
2. To evaluate the efficacy of RAG1 gene therapy in achieving independence of Immunoglobulin substitution and serologic response to vaccination.
3. To evaluate the long-term efficacy of RAG1 gene therapy in reconstituting the immune system in patients with RAG1-SCID.
4. To evaluate the pharmacodynamic effects of RAG1 gene therapy
5. To evaluate the effects of RAG1 gene therapy on quality of life.

Conditions and MedDRA coding

Severe combined immunodeficiency based on genetic defect in the Recombinase Activating Gene 1 (RAG1)

Regulatory references

Scientific advice from competent authorities

Central Committee On Research Involving Human Subjects

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. RAG1-deficient SCID as confirmed by genetic analysis
2. Peripheral blood T cells < 300/μL and/or naïve T cells < 1/μL
3. Age < 2 years
4. Age at least 8 weeks by the time of busulfan and fludarabine administration
5. Lack of an available HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)
6. Signed informed consent (parental or guardian)
7. Able to return to the local HSCT centre for follow-up (per protocol) during the 2-year study and the 15-year long-term off study review
8. Absence of peripheral blood naïve CD4+ T cells

Exclusion criteria 5

1. Omenn syndrome
2. Previous allogeneic HSCT
3. Significant organ dysfunction/co-morbidity (including but not limited to): Mechanical ventilation, Shortening fraction on echocardiogram <25%, Renal failure defined as dialysis dependence, uncontrolled seizure disorder.)
4. Any other condition that the investigator considers is a contraindication to collection and/or infusion of transduced cells for that individual or indicate patient's inability to follow the protocol, for example contraindication f to busulfan, major congenital abnormalities, ineligible to receive anaesthesia, or documented refusal or inability of the family to return for scheduled visits.
5. Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival Evaluation of immune reconstitution at Month 6 defined as -Presence of naive CD4+ T cells -Total CD3+ T-cells > 300 cells/µL -Total CD4+ T-cells > 200 cells/µL

Secondary endpoints 8

1. Event-free survival (survival without the need for rescue treatment defined as infusion of autologous unmanipulated backup stem cell product and/or allogeneic HSCT)
2. Independence from immunoglobulin substitution at Month 24
3. Serologic response to vaccination
4. Immune system reconstitution o T-cell repopulation: -Total CD3+ T-cells > 300 cells/µL (at Month 12, 18, 24, 30, 36, 42, 48, 54, 60) - Total CD4+ T-cells > 200 cells/µL (at Month 12, 18, 24, 30, 36, 42, 48, 54, 60) - Presence of naive CD4+ T cells (at Month 12, 18, 24, 30, 36, 42, 48, 54, 60)
5. o B-cell repopulation: - Total B-cell counts (at Month 6, 12, 18, 24, 30, 36, 42, 48, 54, 60) - Memory B-cell count (at Month 6, 12, 18, 24, 30, 36, 42, 48, 54, 60) - Switched memory B-cell count (at Month 6, 12, 18, 24, 30, 36, 42, 48, 54, 60)
6. o Immune function: - Level of IgG (at Month 6, 12, 18, 24, 36, 48, 60) - Level of IgA (at Month 6, 12, 18, 24, 36, 48, 60) - Level of IgM (at Month 6, 12, 18, 24, 36, 48, 60) - IG repertoire and T cell receptor (TCR) repertoire on PBMCs at Month 12
7. Pharmacodynamics o Vector copy number (VCN) in PBMCs and granulocytes o TRECs and KRECs
8. Quality of Life: Change from baseline in PedsQL

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Videja B.V.

Sponsor organisation

Videja B.V.

Address

De Limes 7

City

Oegstgeest

Postcode

2342 DH

Country

Netherlands

Scientific contact point

Organisation

Academisch Ziekenhuis Leiden

Contact name

W. Krebber

Public contact point

Organisation

Academisch Ziekenhuis Leiden

Contact name

W. Krebber

Locations

4 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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

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

Documents 24 files

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

Application history

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