Study of Artificial Intelligence-based Personalized Rituximab Treatment Protocol in Membranous nephropathy - iRITUX

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nice

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02]

Trial duration

29 Nov 2024 → ongoing

Decision date (initial)

2024-09-09

Transition trial

No

Low-intervention

Yes

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

DGOS

External identifiers

EU CT number

2024-510718-34-00

ClinicalTrials.gov

NCT06341205

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To compare, in nephrotic rituximab-treated membranous nephropathy, the efficacy of a standard-of-care treatment versus a personalized treatment driven by the recommendation of the algorithm that predicts the risk of drug underexposure at month-3, in inducing clinical remission 6 months after rituximab treatment initiation.

Secondary objectives 19

1. To compare a personalized treatment of membranous nephropathy driven by the recommendation of the algorithm versus the standard-of-care treatment regarding: 1. Complete clinical remission according to KDIGO or French guidelines at month-12
2. Partial clinical remission according to KDIGO or French guidelines at month-12
3. Immunological remission according to KDIGO or French guidelines at month-3, month-6, month-12 (patients with identified immunological activity only)
4. Changes in proteinuria and albuminuria from baseline to month-3, month-6, month-9, month-12
5. Changes in serum creatinine and CKD-EPI estimated Glomerular Filtration Rate (eGFR) from baseline to month-3, month-6, month-9, month-12
6. Changes in anti-PLA2R1 autoantibodies ELISA titer from baseline to month-3, month-6, month-9, month-12 (patients with PLA2R1-associated membranous nephropathy only)
7. Anti-rituximab antibody occurrence at month-3, month-6, month-9, month-12
8. Serum rituximab level at month-3 after the last rituximab infusion
9. Recording adverse events related to treatment during study follow-up
10. Changes in non-immunosuppressive antiproteinuric treatment during study follow-up
11. Evaluation of clinicians' satisfaction with the algorithm for calculating the risk of rituximab underdosing (in the experimental group only)
12. Response to treatment according to the epitope spreading status at day-0 (in PLA2R1 and THSD7A positive patients)
13. External validation of the iRITUX algorithm
14. Association of rituximab urine loss and disease severity, drug exposure and treatment response
15. Model improvement through machine learning
16. Monitoring of the B immune response
17. Monitoring of the T immune response
18. Effect of rituximab on immune profiles
19. Stools biorepository samples will be collected at Day-0 and Month-6 visits for future exploratory biomarker analysis to better understand disease and the impact of the microbiota on the treatment response.

Conditions and MedDRA coding

Membranous nephropathy

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Age ≥ 18 years
2. Ongoing episode of membranous nephropathy diagnosed either by: the presence of anti-PLA2R1 or anti-THSD7A antibodies, or renal biopsy
3. Nephrotic syndrome defined by proteinuria > 3.5 g/24h (or UPCR > 3.5 g/g) and serum albumin < 30 g/L at screening
4. Indication for rituximab treatment according to the KDIGO or French guidelines
5. Non-immunosuppressive antiproteinuric treatment at stable dose for 2 weeks according to French guidelines, including a renin angiotensin aldosterone system inhibitor, a diuretic and a low-salt diet
6. Estimated Glomerular Filtration Rate CKD-EPI > 30 mL/min/1,73 m²

Exclusion criteria 11

1. Secondary membranous nephropathy related to cancer, infection, systemic lupus, drug
2. Pregnancy or breastfeeding
3. Immunosuppressive treatment (including rituximab) in the 6 months preceding inclusion
4. Presence of anti-rituximab antibodies detected by Central Lab (if negative result available within 6 weeks before screening, or if the patient is naïve of rituximab treatment, the patient is eligible)
5. Cancer under treatment
6. Patients with active, severe infections
7. Hypersensitivity to the active substance or excipients
8. Patients severely immunocompromised who, in the opinion of the investigator, cannot receive more than two 1-gram doses of rituximab
9. Severe heart failure or severe, uncontrolled cardiac disease
10. Patient refusing to follow the algorithm recommendation approved by their referring nephrologist
11. Patient who, in the opinion of the investigator, cannot receive the treatment recommended by the iRITUX algorithm (safety or compliance reasons)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Clinical remission (complete or partial) according to KDIGO or French guidelines: - Complete: urine protein/creatinine ratio (UPCR) <0.3 g/g and serum albumin>30 g/L - Partial: UPCR <3.5 g/g with a decrease >50% from baseline (i.e., at first rituximab infusion) and serum albumin improvement or normalization

Secondary endpoints 19

1. Complete clinical remission at month-12 according to KDIGO or French guidelines
2. Partial clinical remission at month-12 according to KDIGO or French guidelines
3. Immunological remission: If membranous nephropathy anti-PLA2R1 associated: anti-PLA2R1 depletion (i.e., PLA2R1 titer < 14 RU/mL by ELISA EUROIMMUN kit) at month-3, month-6, month-12 ✓ If membranous nephropathy anti-THSD7A associated: anti-THSD7A depletion (i.e., positive or negative immunofluorescence)
4. Percentage of change in urine protein/creatinine ratio (UPCR) (g/g) and urine albumin/creatinine ratio (mg/g) from day-0 to month-3, month-6, month-9, month-12
5. Percentage of change in serum creatinine (μmol/L) and Glomerular Filtration Rate estimated by CKD-EPI formula (mL/min/1.73m²) from day-0 to month-3, month-6, month-9, month-12
6. Percentage of change in anti-PLA2R1 titer (RU/mL) by ELISA (EUROIMMUN Kit) from day-0 to month-3, month-6, month-9, month-12 (membranous nephropathy anti-PLA2R1 associated only)
7. Serum anti-rituximab antibodies (ng/mL) at month-3, month-6, month-9, month-12
8. Percentage of patients with serum rituximab (μg/mL) >2 μg/mL 3 months after the last infusion
9. Serious adverse events related to treatment during study follow-up
10. Modification of non-immunosuppressive anti-proteinuric treatment during study follow-up
11. Pharmacokinetics in all patients with serum creatinine and serum albumin levels, weight, anti- PLA2R1 and rituximab level at day-0, day-15, day-30, day-45, month-3, month-6
12. Correlation between epitope spreading at day-0 and response to treatment in both groups (in PLA2R1 and THSD7A positive patients).
13. Predictive rate (%) of the algorithm for rituximab underdosing (i.e. serum level <2 mg/ml at month-3) in the control group (i.e. patients treated according to the standard-of-care strategy).
14. Correlation between urine rituximab levels at day-15 and disease severity (defined as lowering of estimated glomerular filtration rate, proteinuria), drug exposure (measured with serum rituximab level), clinical response (partial or complete as defined above), immunological response (negative anti-PLA2R1 titer)
15. Pharmacokinetics in all patients with serum creatinine and serum albumin levels, weight, anti- PLA2R1 and rituximab level at day-0, day-15 (predose and postdose), day-30, day-45, month-3, month-6
16. Immunophenotying of B cells subsets as follows: naïve cells (CD19+CD27-IgD+), non-switched memory cells (CD19+CD27+IgD+), switched memory cells (CD19+CD27+IgD-), double negative cells (CD19+CD27-IgD), transitional cells (CD19+CD38++CD27-IgD+) and plasmablasts (CD19+CD38++CD27+IgD-), expressed as the percentage of total lymphocytes.
17. Immunophenotying of T cells subsets as follows: T helper cells (CD3+CD4+), cytotoxic T lymphocytes (CD3+ CD8+), regulatory T cells (CD3+ CD4+ Foxp3+ CD25high), Th1 cells (CD3+ CD4+ T-bet +) and Th17 cells (CD3+ CD4+ RORγt +).
18. Cytokine levels in pg/mL (IFN-γ, IFN-α, IL-12p70, IL-17A, IL-4, IL-5, IL-10, IL-1, IL-6) at day- 0 and month-6 (Nice patients only). 19. Optional: stools biorepository samples
19. Optional: stools biorepository samples will be collected at Day-0 and Month-6 visits for future exploratory biomarker analysis to better understand disease and the impact of the microbiota on the treatment response (Nice patients only).

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nice

Sponsor organisation

Centre Hospitalier Universitaire De Nice

Address

4 Avenue Reine Victoria

City

Nice

Postcode

06000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nice

Contact name

Fernandez Céline

Public contact point

Organisation

Centre Hospitalier Universitaire De Nice

Contact name

Fernandez Céline

Locations

1 EU/EEA country · 15 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

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