22.05.2019

SYNOPSIS

Objectives -- Study Design -- Inclusion Criteria -- Exclusion Criteria -- Treatment
Efficay -- Safety -- Flow Chart

Synopsis

Protocol title

Supportive versus Immunosuppressive Therapy for the treatment Of Progressive IgA Nephropathy (STOP IgAN)

EudraCT number

2007-000871-41

Coordinating Investigator (LKP)

Prof. Dr. Jürgen Floege

Objectives

  • Evaluation of the efficacy of an immunosuppressive therapy added to a comprehensive supportive therapy to induce a clinical remission in patients at risk for progressive IgAN
  • Investigation of differences between the treatments regarding the number of patients loosing more than 15 ml/min of GFR.

Study Design

  • Randomised, prospective, multicentre, open-label therapeutic clinical trial
  • Parallel group design
  • 6-months Run-in Phase and 3-years Treatment Phase

Number of patients

148 patients (74 per Treatment)

Number of Study Visits

6 visits (run-in phase) plus 16 visits (in 3 years study period)

Inclusion Criteria

  • Male or female patients from 18-70 years with histologically proven primary IgAN with typical mesangioproliferative features. Diagnosis has to be made by a nephropathologist.
  • Proteinuria above 0.75 g/day within 12 weeks prior to or at the first visit in the run-in phase (month -6) and presence of at least one further risk factor for the development of end stage renal disease
    • arterial hypertension, defined as ambulatory blood pressure >140/90 mm Hg or the use of antihypertensive medication or
    • impaired renal function, defined as creatinine clearance or estimated GFR <90 ml/min.

Main Exclusion Criteria

  • Known allergy or intolerance to study medication (except in case of ACE-inhibitor, in which case a change to an angiotensin receptor blocker is possible).
  • Women who are pregnant or breastfeeding and women without sufficient contraception.
  • Any prior immunosuppressive therapy.
  • Variants of primary IgAN (e.g. rapidly progressive IgAN with crescents in >50% of glomeruli or minimal change GN with glomerular IgA deposits).
  • Contraindication for immunosuppressive therapy, like
  • acute or chronic infectious disease incl. hepatitis and HIV positive patients
  • any malignancy
  • leukocytopenia, thrombocytopenia or known allergy against prednisolone, cyclophosphamide or azathioprine
  • active intestinal bleeding, active gastric or duodenal ulcer
  • Need of permanent immunosuppression, (e.g. transplanted patients, steroid-dependent inflammatory diseases)
  • Secondary IgAN or diseases associated with glomerular deposits of IgA.
  • Additional other chronic renal disease.
  • Creatinine clearance below 30 ml/min (mean of 3 measurements).

Treatment: Run-in phase (all patients)

  • Antihypertensive therapy with a target blood pressure below 125/75 mmHg. Antihypertensive therapy in these patients follows current clinical guidelines. ACE-inhibitors should be used as first-line therapy and increased to the maximum daily dose depending on the degree of arterial hypertension and proteinuria. Patients can be converted to an ARB when an ACE-inhibitor is not tolerated. Dose equivalence tables for ACE-inhibitors and ARB's will be provided. All other antihypertensive medications, including diuretics, aldosterone antagonists, calcium-channel blockers and ß-blocker can be used at any time-point during the study depending on the clinical decision of the individual study center and following current guidelines.
  • All patients will receive statin therapy at the start of the run-in phase. Study centers are not limited to the use of specific compounds. Dose equivalence tables for statins will be provided. Statins should be increased to maximum daily dose if target cholesterol level (<200 mg/dl) is not reached.
  • Dietary counseling for a low-sodium diet and, if GFR is below 60 ml/min, for a protein intake of 0.8 g/kg/day. Verify dietary restriction using 24h urinary sodium and urea excretion.
  • Those, who maintain a proteinuria above 0.75 g/d and where GFR loss is ≤ 30% (if GFR at visit -1 week < 90 ml/min) despite supportive therapy will then be randomized to Treatment S or Treatment I. In case the GFR at visit -1 week is ≥ 90 ml/min, any amount of GFR loss during the 6 month run-in phase will not be considered as an exclusion criterion.

Treatment S (supportive group):

  • Continue supportive therapy as initiated in the run-in phase.

Treatment I (immunosuppressive group):

  • Supportive care identical to Treatment group S.
  • Additional immunosuppressive therapy:
  • In patients with a GFR equal or above 60 ml/min, an additional 6 month course of corticosteroid-monotherapy will be given. Patients will receive 1g methylprednisolone i.v. per day for 3 days at the start of month 1, 3, 5 and 0.5 mg/kg prednisolone orally/48h for 6 months on the remaining days.
  • In patients with a GFR between 30 and 60 ml/min, oral cyclophosphamide (1.5 mg/kg per day, adjusted down to the nearest 50 mg) will be administered for 3 months, together with oral prednisolone (40 mg/day, tapered to 10 mg at 3 months). After 3 months patients will receive azathioprine (1.5 mg/kg/day), together with oral prednisolone (10 mg/day for months 4-6 and 7.5 mg/day after 6 months) for 3 years.
  • Concomitant medication is recommended to be administered with the immunosuppressive treatment following current clinical practice. This includes vitamin D and calcium supplementations in patients receiving corticosteroids and pneumocystis jirovecii prophylaxis with cotrimoxacol and Mesna-prophylaxis in patients receiving cyclophosphamide.

Efficacy

  • Primary Endpoints:
    • Patients reaching full clinical remission of their disease. Full clinical remission is defined as proteinuria < 0.2 g/d and stable renal function (GFR loss of < 5 ml/min from baseline GFR at the end of the 3 year study period).
    • GFR loss of 15 ml/min or higher from baseline GFR at the end of the 3 year study period.
  • Secondary Endpoints:
    • Absolute GFR-change.
    • GFR loss greater or equal 30 ml/min from baseline GFR
    • Onset of end stage renal disease.
    • Mean annual change in one over serum creatinine concentration
    • Proteinuria at 12 and 36 months
    • Disappearance of microhematuria

Safety

Clinical and laboratory safety variables include:

  • History and physical examination
  • Systolic and diastolic arterial blood pressure
  • Frequency, type, severity and duration of adverse events
  • Laboratory tests including repeated blood glucose and blood counts

Study Flowchart

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