Research information

Study Protocol

Link to the complete, published study protocol:

http://bmjopen.bmj.com/content/7/9/e018148.long

Research information

Nephrotic syndrome is treated with corticosteroids. The majority of patients will show a remission in response. However, approximately 80% do show at least one relapse, for which a new steroid regime is needed. In fact, about 70% of them will show a course of multiple relapses, leading to a huge steroid exposure with subsequent side-effects.

The aim of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is to show that at least equal clinical benefits can be obtained by reduced corticosteroid exposure, which minimizes toxicity in children with nephrotic syndrome. In order to achieve this aim, the RESTERN study will address the following objectives:
1. Conducting a nation-wide randomized placebo-controlled trial aiming to reduce steroid exposure in nephrotic syndrome relapses;
2. Starting a nephrotic syndrome registry, in which data can be added by patients and professionals;
3. Characterizing patients with nephrotic syndrome and creating a biobank for studies on the pathogenesis of nephrotic syndrome in children and the identification of biomarkers that predict diagnosis, prognosis and treatment efficacy.

Inclusion criteria

  • Age over 1 and less than 18 years
  • Steroid sensitive nephrotic syndrome with at least 1 episode in the preceding 24 months.
    • Subjects without maintenance immunosuppressive therapy
    • Subjects with maintenance immunosuppressive therapy
      • Longterm immunosuppressive therapies*
      • Cyclophosphamide (oral of intravenous)
        At least 3 months post completion of therapy
      • A single dose or course of intravenous rituximab
        At least 3 months post completion of therapy
  • The last prednisolone use (at a dose over 10 mg/m2 on alternate days) for the treatment of a previous episode was at least 4 weeks ago;
  • Relapse nephrotic syndrome**
  • Informed consent

* Levamisole, ciclosporine, tacrolimus, mycofenolaat mofetil (Cellcept®), mycofenolaat sodium (Myfortic®), prednisone max. 4mg/m2 on alternate days.
** defined as Albustix positive proteinuria (3+ or greater) for three consecutive days or the presence of generalised edema plus 3+ proteinuria

Exclusion criteria

  • Steroid resistant nephrotic syndrome;
  • Receiving, or within 3 months after receiving, cyclophosphamide or rituximab;
  • Daily prednisolone maintenance therapy at any dose;
  • Alternate day prednisolone maintenance therapy at a dose over 4 mg/m2;
  • Documented or suspected significant non-compliance;
  • Pregnancy;
  • Stimulant drug use;
  • Comorbidity;
    • Kidney transplant recipient
    • Any disease that requires the variation in oral prednisolone to be at the discretion of the treating physician(s);
  • Concomitant use of drugs that induce CYP 3A4: carbamazepine, phenobarbital, phenytoin and/or rifampicin;
  • Concomitant use of drugs that inhibit CYP 3A4: ketaconazole, itraconazole, ritonavir, indinavir, macrolide antibiotics (erythromycin), diltiazem, verapamil.

Treatment schedule

Outcome

Primary outcome

  • Time to first relapse after study randomization (censored at 12 and 24 months)

Secondary outcome

  • Number of relapses after study randomization at 12 or 24 months
  • Development of frequent relapsing nephrotic syndrome according to KDIGO criteria (four or more relapses in any 12-month period)
  • Development of steroid dependent nephrotic syndrome according to KDIGO criteria (two consecutive relapses during corticosteroid therapy, or within 14 days of ceasing therapy)
  • Cumulative dosage of prednisone during study period (at 12 and 24 months)

If you have any questions, comments or suggestions, please do not hesitate to contact us using the contact form or restern.kg@radboudumc.nl

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