Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP) IgAN trial: rationale and study protocol Frank Eitner1, Diana Ackermann2, Ralf-Dieter Hilgers2, Jürgen Floege1
ABSTRACT Introduction: The best treatment of IgA nephropathy (IgAN) is currently not well defined. The Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP IgAN) trial aims to answer if, in IgAN patients, an immunosuppressive treatment is more effective than a supportive treatment. Methods: In a randomized prospective multicenter study (www.clinicaltrials.gov, NCT00554502), we will treat 148 patients at risk for progressive IgA nephropathy following a 6-month run-in phase, in 2 groups: (group a) supportive treatment: patients with a persistent proteinuria >0.75 g/day will receive a maximized therapy to reduce blood pressure and urinary protein loss using angiotensin-converting enzyme inhibitors and AT1 blockers, statins, dietary counseling for a low-sodium and low-protein diet and education/intervention programs to stop smoking. (group b) immunosuppressive treatment: in addition to the identical treatment of group a, patients will receive treatment with steroids (glomerular filtration rate [GFR] ≥60 ml/min) or steroids plus cyclophosphamide/azathioprine (GFR 140/90 mm Hg or the use of antihypertensive medication; or (b) impaired renal function, defined as creatinine clearance or estimated GFR 50% of glomeruli or minimal change GN with glomerular IgA deposits). • 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). • Contraindication for immunosuppressive therapy. • Any prior immunosuppressive therapy. • Known allergy or intolerance to study medication (except in the case of ACE inhibitors, in which case a change to an ARB is possible). • Women who are pregnant or breastfeeding. • Women without sufficient contraception.
Treatment details Run-in phase (all patients) All eligible patients will receive ACE inhibitor and statin therapy for a run-in period of 6 months (Fig. 1). The target blood pressure for all patients during this run-in period is below 125/75 mm Hg. Those patients who then decrease their proteinuria below 0.75 g/day will not be included in the trial but may enter the trial at a later time should their proteinuria increase again above 0.75 g/day. Patients with a proteinuria >3.5 g/day after 6 months of supportive treatment and patients with a very rapid decline of their renal function (GFR loss >20% within 6 months) likely suffer from particular subtypes of IgAN and/or additional diseases and will not be included in the study. They should be treated following the usual practice of the individual centers. Those who maintain a proteinuria above 0.75 g/day despite supportive therapy will then be randomized to 1 of the following groups.
Treatment S (supportive group) (a) Antihypertensive therapy with a target blood pressure below 125/75 mm Hg (ideally below 120 mm Hg systolic) and antiproteinuric therapy with a target proteinuria below 0.5 g/day will be instituted. Antihypertensive therapy in these patients follows current clinical guidelines. Study centers are not limited to the use of specific compounds. Dose equivalence tables for ACE 286
inhibitors and ARBs will be provided. 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. All other antihypertensive medications, including diuretics, aldosterone antagonists, calcium channel blockers and b-blockers can be used at any time point during the study depending on the clinical decision of the individual study center. (b) 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 (
