|- candidate number||23623|
|- NTR Number||NTR5670|
|- ISRCTN||ISRCTN no longer applicable|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||16-jan-2016|
|- Secondary IDs||15OKG16 Dutch Kidney Foundation|
|- Public Title||REduceren van STEroiden bij kinderen met een Recidief Nefrotisch syndroom – de RESTERN studie|
|- Scientific Title||REducing STEroids in Relapsing Nephrotic syndrome – the RESTERN study|
|- hypothesis||The main hypothesis is that relapses of the nephrotic syndrome in children can be treated adequately by a reduced duration of alternate day prednisone (2 weeks instead of the currently used 6 weeks) after a similar induction of remission.|
|- Healt Condition(s) or Problem(s) studied||Nephrotic syndrome|
|- Inclusion criteria||• Age over 1 and less than 18 years|
• Steroid sensitive nephrotic syndrome with at least 1 episode of nephrotic syndrome in the preceding 12 months. This will include the following groups:
o Subjects without maintenance immunosuppressive therapy;
o Subjects with maintenance immunosuppressive therapy:
• Long-term immunosuppressive therapies, including levamisole, ciclosporine, tacrolimus, MMF, mycophenolate sodium;
• Subjects who have previously received a course of oral or intravenous cyclophosphamide; Must have experienced at least 1 relapses following completion of cyclophosphamide therapy; Must be at least 3 months post completion of cyclophosphamide therapy
• Subjects who have previously received a single dose or course of intravenous rituximab: Must have experienced at least 1 relapses following completion of rituximab therapy; Must be at least 3 months post completion of rituximab therapy
• The last prednisone use for the treatment of a previous relapse was at least 4 weeks ago.
• Subjects experience a relapse nephrotic syndrome, defined as Albustix positive proteinuria (3+ or greater) for three consecutive days or the presence of generalised oedema plus 3+ proteinuria;
• Informed consent.
|- Exclusion criteria||• Steroid resistant nephrotic syndrome;|
• Receiving, or within 3 months after receiving, cyclophosphamide or rituximab;
• Documented or suspected significant non-compliance.
- Daily prednisolone maintenance therapy at any dose
- Alternate day prednisolone maintenance therapy at a dose over 4 mg/m2
- Stimulant drug use
o Kidney transplant recipient
o 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.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-dec-2016|
|- planned closingdate|
|- Target number of participants||144|
|- Interventions||Treatment schedule|
• Prednisone 60mg/m2 (max 60mg) daily in 1 dose until complete remission for 3 days (according to the KDIGO guideline)
o Standard treatment: 6 weeks prednisone 40mg/m2 (max 40mg) every other day, then stop (no tapering)
o Study treatment: 2 weeks prednisone 40mg/m2 (max 40mg) every other day, then 4 weeks placebo every other day, then stop (no tapering)
Treatment of subsequent relapses according to Dutch standards (prednisone 60mg/m2 (max 60mg) daily in 1 dose until complete remission for 3 days, continued with prednisone 40mg/m2 (max 40mg) every other day during 6 weeks)
|- 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)
|- Timepoints||12 months|
|- Trial web site||www.restern.nl|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||Dr. Michiel F Schreuder|
|- CONTACT for SCIENTIFIC QUERIES||Dr. Michiel F Schreuder|
|- Sponsor/Initiator ||Radboud University Medical Center Nijmegen|
(Source(s) of Monetary or Material Support)
|Dutch Kidney Foundation (Nierstichting Nederland)|
|- Brief summary||Most children with steroid sensitive nephrotic syndrome experience several relapses, which are treated with steroids. For most children, long-term prognosis is for complete resolution of their disease over time and maintenance of normal kidney function. It is therefore vital to focus on minimizing adverse events of the disease and its therapy. Unfortunately, no randomized controlled trials are available to determine the optimal steroid treatment of an infrequent relapse of the nephrotic syndrome.|
Recent studies show that treatment schedules of the first episode can safely be reduced (Hahn et al., 2015; Hoyer, 2015), which may reduce steroid toxicity. The hypothesis of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is that a 4-week reduction of alternate day steroids after inducing remission is effective and safe, reduces steroid exposure by 35% on average, and is therefore preferable.
Using a nation-wide placebo-controlled randomized controlled trial, this hypothesis will be tested. A similar daily dose of prednisone is used until the induction of remission. Randomization in blocks (immunosuppressive maintenance therapy vs. no maintenance therapy) will be performed for either 6 weeks of alternate day prednisone (standard therapy) or 2 weeks alternate day prednisone followed by 4 weeks of alternate day placebo. For a non-inferiority trial with 80% power, 72 patients per group are needed, for which an estimated inclusion rate of 53% is needed.
A second objective is to establish a Dutch Nephrotic Syndrome registry. Via collaboration with the Canadian Childhood Nephrotic Syndrome (CHILDNEPH) Project, a translated version of the up-and-running Canadian registry will be used. This is a web-based registry, in which both pediatricians as well as parents/patients are able to enter data.
Thirdly, a biobank will be set up to include blood and urine samples during relapse and in remission, DNA, and/or biopsy material. Combining this biobank with well-phenotyped patients will allow for (inter)national collaborative research into causative pathways of nephrotic syndrome in children. The biobank will be accommodated by the Radboudumc institutional biobank-facility (Radboud Biobank) that provides an excellent infrastructure to succeed.
With the combination of these 3 objectives (clinical trial, registry and biobank), the proposed RESTERN project aims to improve clinical care for children with nephrotic syndrome by showing that at least equal clinical benefits can be obtained by reduced corticosteroid exposure, which minimizes toxicity.
|- Main changes (audit trail)||3-jan-2017:
• 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
Changes in inclusion criteria:
• 'Steroid sensitive nephrotic syndrome with at least 1 episode of nephrotic syndrome in the preceding 12 months' replaced by 'Steroid sensitive nephrotic syndrome with at least 1 episode of nephrotic syndrome in the preceding 24 months.'
• 'Subjects who have previously received a course of oral or intravenous cyclophosphamide; Must have experienced at least 1 relapses following completion of cyclophosphamide therapy; Must be at least 3 months post completion of cyclophosphamide therapy'replaced by ' Subjects who have previously received a course of oral or intravenous cyclophosphamide, must be at least 3 months post completion of cyclophosphamide therapy'
• 'Subjects who have previously received a single dose or course of intravenous rituximab: Must have experienced at least 1 relapses following completion of rituximab therapy; Must be at least 3 months post completion of rituximab therapy'replaced by 'Subjects who have previously received a single dose or course of intravenous rituximab, must be at least 3 months post completion of rituximab therapy'
|- RECORD||16-jan-2016 - 8-sep-2017|