Obinutuzumab for primary membranous nephropathy: a pilot study in patients with rituximab-resistant or rituximab-dependent nephrotic syndrome and in patients intolerant to rituximab (the ORION study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Istituto Di Ricerche Farmacologiche Mario Negri

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

17 Dec 2021 → 20 Feb 2026

Decision date (initial)

2024-10-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Roche S.p.A.

External identifiers

EU CT number

2024-515857-93-00

EudraCT number

2021-004864-81

ClinicalTrials.gov

NCT05050214

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

To evaluate whether rescue therapy with Obinutuzumab may induce remission of MN-related nephrotic syndrome in (1) Rituximab-Intolerant patients and in (2) Rituximab-Resistant or Rituximab-Dependent patients, and whether this drug is safe and well tolerated in these cohorts.

Secondary objectives 6

1. To assess, in patients who are treated with Obinutuzumab, the levels of proteinuria and urinary markers of glomerular selectivity over time.
2. To assess, in patients who are treated with Obinutuzumab, the renal function parameters over time.
3. To assess, in patients who are treated with Obinutuzumab, the circulating leukocyte subsets over time.
4. To assess, in patients who are treated with Obinutuzumab, the serum BAFF levels.
5. To assess, in patients who are treated with Obinutuzumab, the immunologic disease activity in the subset of patients with detectable anti-PLA2R antibodies.
6. To assess, in patients who are treated with Obinutuzumab, patient health-related quality of life.

Conditions and MedDRA coding

Primary Membranous Nephropathy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Adults (≥18 years old) on the day of signing informed consent.
2. Biopsy-proven primary membranous nephropathy.
3. Availability of a recent (over the last six months) diagnostic kidney biopsy to confirm the diagnosis of membranous nephropathy and quantify the severity of chronic changes and the number of glomerular podocytes.
4. High-risk of progression to end-stage kidney disease due to persistent nephrotic-range proteinuria (urinary protein excretion > 3.5 g/24-hours as a median of three consecutive measurements) despite background treatment with RASinhibitors (ACEi and/or ARBs) at the maximum tolerated doses for at least six months before inclusion.
5. Failure to definitively and effectively respond to rituximab therapy because of RITUXIMAB-INTOLERANCE: i.e. any previous severe hypersensitivity reaction to rituximab (acute grade III or IV adverse reactions requiring advanced care, or late reactions including delayed serum sickness syndrome) that, independent of response to treatment, preclude further exposure to the drug
6. Failure to definitively and effectively respond to rituximab therapy because of RITUXIMAB-RESISTANCE: no evidence of nephrotic syndrome complete remission (24-hour proteinuria < 0.3 g/day, normal serum albumin and stable renal function) or partial remission (24-hour proteinuria < 3.5 g/day with > 50% decrease from baseline, normal serum albumin and stable renal function) along with detectable circulating CD19+ lymphocytes for at least 6 months after rituximab administration
7. Failure to definitively and effectively respond to rituximab therapy because of RITUXIMAB-DEPENDENCE: frequently-relapsing nephrotic syndrome (≥ 2 relapses) with nephrotic-range proteinuria for ≥ 50% of time in the 24 months preceding enrolment in patients who achieved initial remission after rituximab administration
8. Estimated GFR/eGFR) ≥30 mL/min/1.73 m2 (calculated using the CKD-EPI equation) or qualified endogenous creatinine clearance ≥30 mL/min/1.73 m2 based on 24-hour urine collection during screening.
9. Ability to understand and provide a valid written consent to the study according to the guidelines of the Declaration of Helsinki.
10. Compliance with an effective contraception without interruption, from 28 days before treatment start up to 18 months after treatment discontinuation, agreeing not to donate semen during treatment and for 18 months after discontinuation (if the patient is male), or to undergo pregnancy test during the course of the study (if the patient is female). (According to 2014 CTFG “Recommendations related to contraception and pregnancy testing in clinical trials”).

Exclusion criteria 13

1. Secondary forms of membranous nephropathy (associated with systemic lupus erythematosus, active hepatitis B, malignancy, drugs such as gold salts and penicillamine, and others).
2. Rituximab treatment or any other prolonged (i.e. for more than two weeks) immunosuppressive treatment in the 6 months preceding anti-CD20 infusion.
3. Uncontrolled hypertension (systolic BP ≥160 and/or diastolic BP >90 mmHg despite therapy).
4. Active bacterial, viral and/or fungal infections.
5. Seropositivity for HIV, regardless of viral load.
6. Active or recent (< 5 years before enrolment) history of malignancy.
7. Known hypersensitivity or allergy to any of the medicaments under investigation.
8. Any other serious medical condition, uncontrolled intercurrent illness or laboratory abnormality that, according to the investigator’s judgement, would constitute an unacceptable risk of premature discontinuation from the study.
9. Patients with previous hepatitis B virus infection (seropositive for anti-HBcAb), planning a vaccination with live virus vaccines.
10. Known history of drug induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extra-hepatic obstruction caused by cholelithiasis, cirrhosis of the liver or portal hypertension.
11. Pregnancy or breast-feeding.
12. Childbearing potential and unwillingness or impossibility to comply with a scientifically acceptable birth-control method (According to 2014 CTFG “Recommendations related to contraception and pregnancy testing in clinical trials”).
13. Legal incapacity, limited legal capacity, intellectual disability, uncooperative attitude or any other evidence that the patient will not be able to understand the study aims and procedures.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Incidence of complete or partial remission of nephrotic syndrome at 12 months from Obinutuzumab treatment in (1) Rituximab-Intolerant patients and (2) Rituximab-Resistant and Rituximab-Dependent patients considered separately and as a whole.
2. Incidence of serious and non-serious adverse events (in particular, infusion-related reactions (IRRs)) during and after Obinutuzumab treatment in (1) Rituximab-Intolerant patients and (2) Rituximab-Resistant and Rituximab- Dependent patients considered separately and as a whole.

Secondary endpoints 9

1. To evaluate, in the both cohorts, the incidence of complete or partial remission of nephrotic syndrome at 6 and 24 months from Obinutuzumab treatment.
2. To evaluate, in the both cohorts, the incidence and time to nephrotic syndrome relapse in patients who previously achieved complete or partial remission during the study.
3. To evaluate, in the both cohorts, the incidence and time to complete immunologic remission (defined as anti-PLA2R levels below the positivity threshold of the assay) in anti-PLA2R positive patients during the whole follow- up period.
4. To evaluate, in the both cohorts, the change in proteinuria and serum anti-PLA2R antibody levels (in anti-PLA2R positive patients) considered as continuous variables at each time point during the follow-up as compared to baseline.
5. To evaluate, in the both cohorts, the change in measured GFR, albumin and IgG fractional clearances at 6 and 12, 18 and 24 months from treatment as compared to baseline.
6. To evaluate, in the both cohorts, the safety parameters including clinical and laboratory tests evaluated at each time point during the follow-up and any intercurrent serious and non-serious adverse event.
7. To evaluate, in the both cohorts, the changes in peripheral leukocyte subpopulations (B, T, NK cells) and BAFF levels at every time point included in the study flow-chart.
8. To evaluate, in both the cohorts, the changes in the number of podocytes lost in the urine (podocituria) evaluated at each time point, and relationships between podocituria and proteinuria or the number of glomerular podocytes in baseline and repeat, optional patients’ renal biopsies.
9. To evaluate, in the both cohorts, patient health-related quality of life as measured by means of the SF-12 questionnaire.

Investigational products

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

Test 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Istituto Di Ricerche Farmacologiche Mario Negri

Sponsor organisation

Istituto Di Ricerche Farmacologiche Mario Negri

Address

Via Mario Negri 2

City

Milan

Postcode

20156

Country

Italy

Scientific contact point

Organisation

Istituto Di Ricerche Farmacologiche Mario Negri

Contact name

[email protected]

Public contact point

Organisation

Istituto Di Ricerche Farmacologiche Mario Negri

Contact name

[email protected]

Locations

1 EU/EEA country · 2 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 10 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