| Study name |
Sequential therapy with tacrolimus and rituximab in primary membranous nephropathy (STARMEN) |
| Methods |
Study design: parallel, open‐label RCT Study duration: January 2014 to December 2018, Completion date April 2019 Sample size: planned 106 Duration of follow‐up: 24 months |
| Participants |
Setting: unknown Country: Spain Inclusion criteria: > 18 years that provide written informed consent; biopsy‐proven primary MN within 2 years of enrolment; patients with nephrotic syndrome relapse after remission (either spontaneous or induced by immunosuppression) can be included without a new renal biopsy if they meet all the other inclusion/exclusion criteria; eGFR ≥ 45 mL/min/1.73 m² in at least 2 measurements performed within the 2 weeks prior to randomisation; nephrotic‐range proteinuria (> 4 g/day and remaining > 50% of the baseline value) plus hypoalbuminaemia (< 3 g/dL) during at least a 3‐month period before screening. These values must be met in at least two measurements performed within the 2 weeks prior to randomizations. Patients showing severe or disabling symptoms related to the nephrotic syndrome or severe hypoalbuminaemia (< 2 g/dL) can be included before the completion of this 6‐month observation period, at the investigator’s discretion; 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 BP that could induce side effects, at the investigator’s discretion, with a controlled BP for at least last 3 months (target < 140/90 mm Hg); negative urine pregnancy test for potentially fertile females Exclusion criteria: diagnosis of secondary causes of MN: diagnosis of type 1 or 2 DM, cancer, systemic infections, systemic autoimmune diseases (e.g. SLE), amyloidosis, or any other acute or chronic inflammatory disease; moderate or severe liver disease (aspartate amino‐transferase and alanine amino‐transferase > 2.5 times upper range limit and total bilirubin > 1.5 times upper range limit); patients who are taking part in any other investigational study and/or are receiving or have received treatment with another investigational drug or intervention (within 1 month prior to the study); suspected or known hypersensitivity, allergy and/or immunogenic reaction history of any interventional drug or any of their ingredients (including excipients); previous treatment with corticosteroids or any other immunosuppressive agent in the 6‐month period before screening; previous treatment with RTX or any other biological agent in the 2‐year period before screening; patients who were non‐responders to previous immunosuppressant drugs; women showing a positive pregnancy test or during lactation period or plans to become pregnant; 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 increase the associated risk of the patient’s participation in the study; current drug or alcohol use or dependence that would interfere with adherence to study requirements |
| Interventions |
Group 1
TAC: initial dose of 0.05 mg/kg/day oral, adjusted to achieve blood trough levels of 5 to 7 ng/mL for 6 months. Starting at the end of month 6, TAC dosage will be reduced by 25%/month, resulting in a complete withdrawal at the end of month 9 RTX: single dose of 1 g IV will be given at day 180, before the onset of TAC dose reduction
Group 2
Steroids: months 1, 3 and 5: 1 g IV methylprednisolone daily (days 1 to 3) then oral methylprednisolone (0.5 mg/kg/day) for 27 days (days 4 to 30) CPA (oral): months 2, 4 and 6 2.0 mg/kg/day for 30 days
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| Outcomes |
Proportion of patients reaching either complete or partial remission at 24 months of study treatment the number of patients with an increase of SCr ≥ 50% at the end of follow‐up (renal survival) The proportion of patients with relapsing nephrotic syndrome among patients who previously underwent partial remission or complete remission The time to nephrotic syndrome relapse The number of patients with limited response at 12, 18 and 24 months of study treatment The percentage of patients with preserved renal function (eGFR ≥ 45 mL/min/1.73 m²) at the end of follow‐up Serum anti‐PLA2R levels before treatment and at 12 and 24 months post‐therapy The number of immune cells (CD4+ and CD8+ T cells, and CD19+ B cells) before treatment and at 12 and 24 months post‐therapy Proportion of patients with drug‐related adverse events during the study |
| Starting date |
January 2014 |
| Contact information |
MANUEL PRAGA, mpragat@senefro.org and Jorge Rojas jerori2003@yahoo.com |
| Notes |
Complete remission: reduction of proteinuria to ≤ 0.3 g/24 hours plus stable renal function (eGFR ≥ 45 mL/min/1.73 m²) Partial remission: reduction of proteinuria to 0.3 to 3.5 g/24 hours and 50% lower than baseline with stable renal function (eGFR ≥ 45 mL/min/1.73 m²) Limited response: proteinuria is reduced from baseline level > 50% but remains > 3.5 g/24 hours Non‐response: reduction of proteinuria < 50% from baseline level Kidney survival: at the end of the follow‐up, SCr does not increase ≥ 50% of baseline SCr concentrations Relapse: reappearance of proteinuria > 3.5 g/24 hours and at least 50% higher than the lowest post‐treatment value in at least 3 consecutive visits in those who previously presented a partial or complete remission. Kidney function: this will be evaluated by means of SCr values and eGFR, calculated by the MDRD‐4 Protocol paper: Rojas‐Rivera 2015 |
