Steroids and Azathioprine in Advanced IgAN
Condition: IgA Nephropathy; Chronic Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Glomerulonephritis, IGA
Study type: Interventional
Phase: Phase 3

Summary: 
      Some years ago the investigators designed a randomised trial to prospectively evaluate
      whether adding low-dose azathioprine (1.5 mg/kg/day for six months) to steroids
      (methylprednisolone 1 g i.v. for three consecutive days at months 1, 3 and 5, plus oral
      prednisone 0.5 mg/kg every other day for six months) can improve long-term renal survival in
      adult IgAN patients with proteinuria higher than 1g/24 hours and plasma creatinine <=2.0
      mg/dl.

      In order to test the efficacy of the combination of steroids with azathioprine at various
      degree of renal function deterioration by extending the trial to patients with more advanced
      disease (serum creatinine higher or equal to 2 mg/dl) without any time limit for renal
      biopsy. Treatment will last one year: methylprednisolone 1 g i.v. for three consecutive days
      at the beginning of months 1, 3 and 5, followed by oral prednisone 0.5 mg/kg every other day
      for six months, then 0.2 mg/kg every other day for further 6 months. The primary outcome was
      renal survival (a 50% increase in plasma creatinine from baseline); the secondary outcomes
      were proteinuria over time and the number and types of adverse events in the two groups
      assessed every month for the first six months, every two months from the 6th to the 12th
      month and every three months thereafter. The planned duration of follow up is five years.
    

Detailed description: 
      It is know well established that IgAN outcome is often unfavourable, with end-stage renal
      disease (ESRD) occurring in 5-25% of cases within ten years and in 25-50% of cases within 20
      years. The degree of impairment in renal function at presentation is certainly an important
      predictor of this poor outcome. However, although high serum creatinine at the time of
      diagnosis may allow the detection of patients who are more likely to progress (and perhaps
      may get some benefit from therapy), no established treatment exists in advanced IgAN. This is
      likely explained by the fact that renal impairment is often associated with renal biopsy
      indexes of chronicity such as glomerular sclerosis, tubulointerstitial atrophy or fibrosis.
      It has also been suggested that in this disease, as in other chronic nephropathy, there is "a
      point of no return" after which non-immunological mechanisms have been considered to play a
      central role in a relentless progression.

      Most patients with IgAN develop ESRD in middle age and this represents not only a significant
      problem for the patient itself but also a social and economic burden for society as a whole.
      For this reason, while waiting for more specific therapies able to complete prevent
      progression in IgAN, the possibility of delaying the beginning of renal replacement therapy
      of some years could be considered an important goal in these patients.

      In this regard, the investigators were impressed from the results of an uncontrolled
      retrospective study of combined treatment with corticosteroids for 18 months and azathioprine
      for 24 months. Although the treatment seemed to be ineffective in the patients with normal
      renal function (because of the very low number of events in this very-slowly progressive
      group) and the lack of randomisation led to a severe bias concerning the choice of the
      patients to be treated (higher risk patients), in those with impaired renal function, a
      smaller percentage of treated subjects had a progressive course (20.5% vs 63.4%, p < 0.001).
      Similarly, Tsuruya et al. retrospectively found that combination therapy with prednisolone
      and cyclophosphamide was effective in reducing urinary protein excretion and in slowing the
      rate of progression in histologically advanced IgAN.

      Given all these consideration, the investigators decided to test the efficacy of the
      combination of steroids with azathioprine at various degree of renal function deterioration
      by extending the trial to patients with more advanced disease (serum creatinine > 2 mg/dl).
      Considering the high likelihood of these patients to have a certain degree of sclerosis and
      that in focal segmental glomerulosclerosis longer treatments seem to lead to slightly better
      results in term of achievement and maintenance of partial and complete remissions, in the
      patients of amendment II the investigators decided to continue the treatment with steroids
      and azathioprine at a very low dose for other six months, with an overall one-year treatment
      duration.

      Study design The patients are randomly allocated to treatment with steroids
      (methylprednisolone 1 g i.v. for three consecutive days at the beginning of months 1, 3 and
      5, plus oral prednisone 0.5 mg/kg every other day for six months, then 0.2 mg/kg every other
      day for other six months) plus azathioprine 1.5 mg/kg/day for six months and 50 mg/day for
      other six months (experimental group) or steroids alone (methylprednisolone 1 g i.v. for
      three consecutive days at the beginning of months 1, 3 and 5, plus oral prednisone 0.5 mg/kg
      every other day for six months, then 0.2 mg/kg every other day for other six months) (control
      group).

      If leukocyte count is between 3,000 and 5,000 mmc the dose of azathioprine will be halved; if
      leukocyte count is below 3,000 mmc, azathioprine will be suspended.

      The planned duration of follow up is five years. Similarly to the original protocol, in the
      presence of proteinuria relapses without an increase in plasma creatinine of more than 50%
      from baseline, patients of both amendments who have experienced complete or partial remission
      of proteinuria may be treated again with the same schedule (not before six months after the
      end of the previous treatment).

      All patients will be administered diuretics, antihypertensive drugs and antiplatelet agents
      as needed. Cyclosporin, immunosuppressive drugs other than azathioprine and anti-inflammatory
      drugs will not be allowed. ACE-inhibitors and angiotensin II receptor antagonists will be
      allowed for the treatment of hypertension. Given the importance of blood pressure control in
      slowing down chronic renal failure progression, a target blood pressure of 130/80 mmHg is
      warranted.

      Treatment allocation Similarly to the original protocol, patients will be randomly allocated
      to one of the two treatment groups (steroids alone or steroids plus azathioprine). A 48-month
      recruitment period is estimated.

      Trial procedures Patients considered eligible on the basis of the inclusion/exclusion
      criteria are provided with information concerning the study and asked their informed consent.

      Patients will be examined at baseline, and every month for the first six months, every two
      months from the 6th to the 12th month and every three months thereafter. At each visit, the
      patients will be asked about their clinical symptoms, possible treatment complications and
      drug consumption. Their body weight, blood pressure, plasma creatinine levels, hemocrome with
      leukocyte and platelet counts, total plasma proteins, serum glucose, AST, ALT, GGT,
      bilirubin, alkaline phosphatase, 24-hour urinary protein excretion will be also measured and
      recorded.

      Histological evaluation Given that renal biopsy is not required to be recent, histological
      lesions could not reflect the actual state of the disease at the time of randomisation. For
      this reason, the histological evaluation will not be performed in the patients.

      Statistical analysis The results of the trial will be evaluated by intention-to-treat
      analysis. The primary endpoint will be the progression of renal disease, estimated on the
      basis of 50% increase of baseline plasma creatinine levels. The doubling of plasma creatinine
      from baseline will also be considered as a primary end-point. Secondary end-points will be
      the evolution of proteinuria over time (complete or partial remission respectively defined as
      proteinuria < 0.2 g/24h and the halving of baseline proteinuria), the number of relapses
      (defined as proteinuria equal or higher than baseline) and the number and types of adverse
      events in the two groups assessed every month for the first six months, every two months from
      the 6th to the 12th month and every three months thereafter. Renal survival without an
      endpoint will be analysed by means of the Kaplan-Meier method and the two groups will be
      compared using the log-rank and Breslow tests. Multivariate analysis based on Cox's
      regression proportional hazards model will be used to estimate the relative risk associated
      with possible prognostic factors such as sex, age, plasma creatinine levels, proteinuria,
      arterial hypertension, macroscopic hematuria, ACE-inhibitors, angiotensin II receptor
      antagonists.

      The minimum length of the follow up will be of five years.
    

Intervention name(s): methylprednisolone; azathioprine; prednisone
Intervention type(s): Drug; Drug; Drug
Intervention description(s): intravenous methylprednisolone 1 g for three consecutive days at the beginning of months 1, 3 and 5; azathioprine 1.5 mg/kg/day for six months followed by azathioprine 50 mg/day for a further six months.; prednisone 0.5 mg/kg every other day followed by prednisone 0.2 mg/kg every other day for a further six months.
Other intervention name(s): solumedrol; azatioprina; deltacortene
Intervention MeSH terms: Prednisone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Azathioprine; Prednisolone hemisuccinate; Prednisolone phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: iga nephropathy; chronic kidney disease; proteinuria; steroids; azathioprine