Sequential Therapy With Tacrolimus and Rituximab in Primary Membranous Nephropathy

NCT ID: NCT01955187

Last Updated: 2020-01-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 86 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-01-31
• Study Completion Date: 2019-06-26

Brief Summary

In this study, investigators will evaluated the long-term efficacy and safety (two years) of Tacrolimus-Rituximab (RTX) therapy compared to Methylprednisolone-Cyclophosphamide (CYC) therapy in patients with primary Membranous Nephropathy (MN).

PRINCIPAL OBJECTIVE To evaluate whether sequential therapy with tacrolimus leads to a greater increase in the proportion of primary MN patients with Complete or Partial Remission when compared with patients receiving standard treatment. It will be assessed 24 months after the beginning of treatment.

Phase of the trial: and design: Phase III study, open label, randomized, and active controlled trial.

This study will have 3 stages: screening and recruitment of patients for 18 months, treatment period for six months in corticosteroids plus CYC group and 9 months in Tacrolimus-RTX group, and finally post-treatment follow-up period until to complete 24 months of follow-up since initial treatment.

This study will compare the standard therapy for primary MN patients with nephrotic range proteinuria (active control of steroids plus CYC) with a novel sequential therapy of tacrolimus and RTX, an approach of potential high efficacy, low toxicity and more acceptable safety profile.

Detailed Description

PRIMARY AND SECONDARY ENDPOINTS/OUTCOME MEASURES

Primary end-point:

The proportion of patients reaching CR defined as a reduction of proteinuria since baseline level to a value equal or lower than 0.5 g/24 h proteinuria plus stable renal function (eGFR ≥ 45 ml/min/1.73m2) or PR defined as a reduction of proteinuria since baseline level to a value less than 3.5 g/24 h and 50% lower than baseline proteinuria plus stable renal function (eGFR ≥ 45ml/min/1.73m2) at 24 months of study treatment.

Secondary end-points

• The proportion of patients with Limited response (LR) defined as a reduction of proteinuria since baseline level > 50% but to a value > 3.5g/24 h. at 12, 18 and 24 months of study treatment..
• The number of patients with an increase ≥ 50% of serum creatinine (SCr) from baseline at 12, 18 and 24 months (end of the follow-up).
• The time of renal survival (status free of increase ≥ 50% of baseline SCr) in both arms overall after the study.
• The proportion of patients with preserved renal function (estimated GFR ≥ 60 ml/min) in both treatment arms after the treatment period.
• The proportion of patients with relapse (defines as the reappearance of proteinuria > 3.5 gr/24h and at least 50% increase over the lowest baseline value in at least three consecutive visits in those patients who previously presented a PR or CR) and the time to relapse after the treatment period.
• Serum levels of anti-phospholipase A2 receptor antibodies (anti-PLA2R), before of treatment and at 3, 6, 9, 12, 18 and 24 months of study, in both treatment arms.
• The proportion of patient with drug-related adverse events and serious adverse events.

STUDY POPULATION

Patients with biopsy-proven idiopathic or primary membranous nephropathy with nephrotic proteinuria and normal or slight decrease of renal function will be enrolled.

Conditions

MEMBRANOUS NEPHROPATHY

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Sequential therapy: Tacrolimus-Rituximab

Tacrolimus: Initial dose of 0.05 mg/Kg/day PO, adjusted to blood levels (5- 7 ng/ml) for six months. Starting at the end of month 6, tacrolimus will be reduced by 25% per month, resulting in a complete withdrawal at the end of month 9.

Group Type: EXPERIMENTAL

TACROLIMUS

Intervention Type: DRUG

Initial dose: 0.05 mg/Kg/day, adjusted to achieve blood trough levels of 5-7 ng/ml) for six months. Starting at the end of month 6, tacrolimus dosage will be reduced by 25% per month, resulting in a complete withdrawal at the end of month 9.

RITUXIMAB

Intervention Type: DRUG

A dose 1 g IV will be given during month 6 (at day 180), before the onset of tacrolimus dose reduction

Cyclical therapy: Corticosteroids and Cyclophosphamide

Month 1, 3 and 5: 1g IV methylprednisolone daily for three doses, oral methylprednisolone (0.5mg/kg/day) Month 2, 4 and 6: Oral Cyclophosphamide (2.0 mg/kg/day)

Group Type: ACTIVE_COMPARATOR

METHYLPREDNISOLONE

Intervention Type: DRUG

Month 1: 1g IV methylprednisolone daily for three doses (days 1, 2, and 3), Oral methylprednisolone (0.5mg/kg/day) for 27 days (days 4 to 30). Months 3, and 5: Repeat Month 1.

CYCLOPHOSPHAMIDE

Intervention Type: DRUG

Month 2: Oral Cyclophosphamide (2.0 mg/kg/day) for 30 days. Months 4, and 6: Repeat month 2.

Interventions

TACROLIMUS

Initial dose: 0.05 mg/Kg/day, adjusted to achieve blood trough levels of 5-7 ng/ml) for six months. Starting at the end of month 6, tacrolimus dosage will be reduced by 25% per month, resulting in a complete withdrawal at the end of month 9.

Intervention Type: DRUG

RITUXIMAB

A dose 1 g IV will be given during month 6 (at day 180), before the onset of tacrolimus dose reduction

Intervention Type: DRUG

METHYLPREDNISOLONE

Month 1: 1g IV methylprednisolone daily for three doses (days 1, 2, and 3), Oral methylprednisolone (0.5mg/kg/day) for 27 days (days 4 to 30). Months 3, and 5: Repeat Month 1.

Intervention Type: DRUG

CYCLOPHOSPHAMIDE

Month 2: Oral Cyclophosphamide (2.0 mg/kg/day) for 30 days. Months 4, and 6: Repeat month 2.

Intervention Type: DRUG

Other Intervention Names

TACROLIMUS, ADVAGRAF; RITUXIMAB, MABTHERA; METHYLPREDNISOLONE, URBASON, SOLUMODERIN; CYCLOPHOSPHAMIDE, GENOXAL

Eligibility Criteria

Inclusion Criteria

• Patients are willing and able to read and correctly understand the patient's information sheet and give their consent for participation in the study (by correctly signing and dating the informed consent form document, which has been previously approved by an Ethics Committee/ International Review Board), before initiating any protocol specific selection procedure.
• Patients are able to understand study procedures and to comply with them for the entire length of the study.
• Age older than 18 years.

Exclusion Criteria

• Estimated GFR ≥ 45 ml/min/1.73m2 in one measurement performed within the screening period (in the 30 days after informed consent signature).
• Nephrotic-range proteinuria (>4 g/day and not decreasing >50% in the last 6 months) accompanied by hypoalbuminemia ≤ 3, 5 g/dL during the screening period OR patients showing severe or disabling symptoms related to the nephrotic syndrome or severe hypoalbuminemia (<2 g/dL), that can be included before the completion of this 6-month observation period, at the investigator's discretion, independently of proteinuria values.
• Treatment with an ACEI or ARB for at least 2 months before screening (unless intolerance to ACEI/ARB, contraindications to their use or a low blood pressure that could induce side effects at the investigator's discretion) with a controlled blood pressure for at least the last three months (Mean SBP/DBP ≤ 150/90 mmHg in the last three months).
• Negative urine pregnancy test for potentially fertile female.

• Diagnosis of secondary causes of membranous nephropathy: malignancy (cancer), systemic infections (which include B and C hepatitis), systemic autoimmune diseases (e.g. Systemic Lupus Erythematosus; SLE) or any other acute or chronic inflammatory disease.
• HIV infection.
• Moderate or severe liver disease (AST and ALT > 2.5x upper range limit and total bilirubin > 1.5 x upper range limit).
• Patients are taking part in any other study with an investigational study and/or are receiving or have received treatment with another investigational drug or intervention (within the first month prior to the signature of the informed consent).
• Suspected or known hypersensitivity, allergy and/or immunogenic reaction history to either rituximab, cyclosporine, tacrolimus, corticosteroids, CYC or any of their ingredients (which include excipients) and of any other drug from the same pharmacotherapeutic group (i.e. calcineurin inhibitors, specific monoclonal antibodies or alkylating agents).
• Previous treatment with corticosteroids in the three months period before screening, or previous treatment with other immunosuppressive agent in the six month period before screening.
• Previous treatment with rituximab or any other biological agent in the two years period before screening.
• Patients who were non-responders to previous immunosuppressants.
• Women with a positive pregnancy test at screening or in lactation period or planning to become pregnant within the next 24 months. Women not willing to use contraceptive methods during the complete study period.
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
• Any other medical unstable, uncontrolled, or severe condition or any other relevant laboratory test finding which, at the investigator's own discretion, could possibly increase the associated risk of the patient's participation in the study.
• Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz

OTHER

Sponsor Role: collaborator

Hospital Universitario Fundación Alcorcón

OTHER

Sponsor Role: collaborator

Fundación para la Investigación Biomédica Hospital Universitario 12 de Octubre

UNKNOWN

Sponsor Role: collaborator

Biobanco REDinREN

UNKNOWN

Sponsor Role: collaborator

ERA-EDTA

UNKNOWN

Sponsor Role: collaborator

REDinREN

UNKNOWN

Sponsor Role: collaborator

Spanish Society of Nephrology

OTHER

Sponsor Role: collaborator

Fundación de Investigación Biomédica - Hospital Universitario de La Princesa

OTHER

Sponsor Role: collaborator

University Hospital, Aachen

OTHER

Sponsor Role: collaborator

Hospital Universitario 12 de Octubre

OTHER

Sponsor Role: lead

Responsible Party

Manel Praga, MD

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

GEMA FERNÁNDEZ-JUÁREZ, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario Fundación Alcorcón, Madrid. Spain

JESUS EGIDO, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

IIS Fundación Jiménez Díaz, Madrid. Spain

MARIAN GOICOCHEA, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario Gregorio Marañón, Madrid. Spain

ALFONS SEGARRA, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitari Vall d´Hebron, Barcelona. Spain

GUILLERMO MARTÍN, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Regional de Málaga, Spain

ILDEFONSO VALERA, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Virgen de la Victoria de Málaga. Spain

VIRGINIA CABELLO, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Virgen del Rocío, Sevilla. Spain

QUINTANA LUIS, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Clinic de Barcelona. Spain

CAO MERCEDES, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario de A Coruña. Spain

AVILA ANA, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Dr. Peset, Valencia. Spain

ESPINOSA MARIO, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Reina Sofía, Córdoba. Spain

MONTSERRAT DIAZ, MD

Role: PRINCIPAL_INVESTIGATOR

Fundación Puigvert, Barcelona. Spain

BONET JOSÉ, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Germans Trias i Pujol, Barcelona. Spain

JUAN RAMÓN GÓMEZ-MARTINO, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital San Pedro de Alcántara, Cáceres. Spain

RIVAS BEGOÑA, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario La Paz

RODRIGUEZ ANTOLINA, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Clínico San Carlos, Madrid. Spain

GALEANO CRISTINA, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario Ramón y Cajal, Madrid. Spain

RIVERA FRANCISCO, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital de Ciudad Real. Spain

WETZELS JACK, MD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

JORGE ROJAS, MD

Role: PRINCIPAL_INVESTIGATOR

IIS Fundación Jiménez Díaz, Madrid. Spain

MARUJA NAVARRO, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Germans Trias i Pujol, Barcelona. Spain

ANA ROMERA, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital de Ciudad Real. Spain

IRENE AGRAZ, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitari Vall d´Hebron, Barcelona. Spain

Locations

Hospital 12 de Octubre

Madrid, , Spain

Countries

Spain

References

von Groote TC, Williams G, Au EH, Chen Y, Mathew AT, Hodson EM, Tunnicliffe DJ. Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2021 Nov 15;11(11):CD004293. doi: 10.1002/14651858.CD004293.pub4.

Reference Type: DERIVED

PMID: 34778952 (View on PubMed)

Other Identifiers

2013-000226-55

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

STARMEN 01-2013

Identifier Type: -

Identifier Source: org_study_id