Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01386957 |
| Other study ID # |
SNI-NET 2011 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 2011 |
| Est. completion date |
December 2017 |
Study information
| Verified date |
July 2021 |
| Source |
IRCCS Azienda Ospedaliero-Universitaria di Bologna |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Idiopathic nephrotic syndrome (INS) is the most frequent glomerular disease in childhood.
Currently, all children with INS are treated at onset with steroids. The optimal duration and
dosage of steroid therapy is debated. For each patient, the challenge is to minimise
potential side effects of steroids, while achieving a good clinical response.
The aim of our study is to assess the benefits and potential adverse effects of a prolonged
initial corticosteroid regimen, for the treatment of the initial episode. The results will be
compared with data obtained retrospectively. In addition genetic studies will be undertaken
with the aim of evaluating pharmacodynamics of steroid treatment with the ultimate goal to
individualise treatment in single patients.
1. Study group: children aged 6 months - 18 years, diagnosed with an initial episode of
idiopathic nephrotic syndrome
2. Control group: data of children with a onset INS between January 2007 and December 2009
from the same area of the study group and treated with a short steroid regimen will be
retrospectively analysed and compared
Description:
Background Idiopathic nephrotic syndrome (INS) is the most frequent glomerular disease in
childhood, with an incidence of 2-4 cases per 100,000 children. Currently, all children with
INS are treated at onset with steroids. Approximately 80% of cases respond to oral
corticosteroid therapy, but 75-80% of these children will experience relapses which can recur
over many years. The optimal duration and dosage of steroid therapy at onset and during
subsequent relapses is debated. For each patient, the challenge is to minimise potential side
effects of steroid therapy (hypertension, bone disease, Cushing syndrome, obesity, growth
retardation, cataracts and a variety of psychological, social and behavioural disturbances)
while achieving a good clinical response. This is particularly difficult at the beginning of
the illness, because of the lack of reliable indicators that allow the identification of
patients who will respond poorly or will experience frequent relapses. In 2006 the Cochrane
Collaboration published the first systematic review of corticosteroid therapy for childhood
idiopathic nephrotic syndrome. They concluded that children with the first episode of steroid
sensitive INS should be treated for a minimum of three months, to achieve a reduction in the
subsequent relapse rate.
The fine border between the optimal dose of steroids and the collateral effects can not be
overlooked given the results of some recent studies (relative to patients with chronic
inflammatory bowel disease or children with acute lymphoblastic leukemia subject to prolonged
cycles of steroid therapy) based on the pharmacogenetic evaluation of the diverse individual
responses to steroids. Clinical data supports the concept that the collateral effects of
steroids are not exclusively dose related, but can depend on constitutional hypersensitivity
or resistance, at times specific for a particular corticosteroid.
This diverse individual response can depend on a number of factors. The activity of the
corticosteroids is mediated by interactions with the DNA (genomic mechanism) or by a direct
interaction with the cellular membranes (non-genomic mechanism). The genomic effects are by
far the most important and are mediated by the interactions of the steroids with a specific
cytoplasmic receptor (GR). The binding of the steroid determines the activation of the
receptor and its translocation within the nucleus where it induces (transactivation) or
inhibits (transcriptional interference) the synthesis of numerous regulatory proteins. The
mechanism of transactivation is likely responsible for the major part of collateral effects
(suppression of the hypothalamic-hypophysial-adrenal axis, genesis of glaucoma and diabetes),
while the anti-inflammatory effects are for the most part tied to transcriptional inhibition
(with reduced synthesis of pro-inflammatory cytokines, cyclic oxygenase2, inducible forms of
nitrite synthesis and finally a reduction in synthesis of receptors for Fc and C3).
There are individual diverse molecular anomalies of the gene for the glucocorticoid receptors
(hGR/NR3C1) that have bean uncovered: for example the presence of polymorphisms of the gene
hGR is correlated with receptor hyperactivity (Bcl1 e N3635) or relative resistance of the
glucocorticoid receptor (polymorphism ER22/23EK); a further 15 mutations have already been
identified to be associated with corticosteroid resistance.
These facts open interesting possibilities for pharmacological research with the hypothesis
of being able to adjust steroid therapy in response to an individuals genetic make-up and
predict the appearance of side effects.
AIM The aim of our study is to assess the benefits and potential adverse effects of a
prolonged initial corticosteroid regimen across four Italian regions, for the treatment of
the initial episode of INS. The results will be compared with data obtained retrospectively
from the analysis of a control group of INS, treated with a short steroid regimen during the
previous 3 years in the same area. In addition genetic studies will be undertaken with the
aim of evaluating pharmacogenetics and pharmacodynamics of steroid treatment with the
ultimate goal to individualise treatment in single patients.
Study population:
1. Study group: children aged 6 months - 18 years, diagnosed with an initial episode of
idiopathic nephrotic syndrome (proteinuria> 40mg/m2/h or urine protein/creatine ratio >
2 mg/mg and hypoalbuminemia <2.5g/dL).
Subjects will be enrolled from the first of July 2011 to the 30th of June 2013; the
follow-up of each subject will continue for 24 months.
2. Control group: data of children with a onset INS between January 2007 and December 2009
from the same area of the study group and treated with a short steroid regimen will be
retrospectively analysed and compared. Data will be recorded anonymously through an
online database. The epidemiological, clinical, therapeutic parameters collected will be
the same of the intervention group, except for pharmacogenetic and pharmacodynamic
tests, and behavioral questionnaires.
All study group patients will be subjected to the following protocol:
Induction therapy: prednisone 60mg/m2/day in 2 divided doses. Patients achieving remission
within 10 days, will continue this dosage until the 28th day, whereas patients not achieving
remission within 10 days, will continue this dosage until the 42nd day. Moreover, from the
3rd day of remission prednisone will be given in a single morning dose.
Maintenance therapy:
Patients going into remission during the induction therapy will have steroids tapered over a
16 weeks period:
- 40 mg/m2/alt day in a single morning dose for 4 weeks,
- 30 mg/m2/alt day in a single morning dose for 2 weeks,
- 22.5 mg/m2/alt day in a single morning dose for 2 weeks,
- 15 mg/m2/alt day in a single morning dose for 2 weeks,
- 7.5 mg/m2/alt day in a single morning dose for 2 weeks,
- 4.5 mg/m2/alt day in a single morning dose for 4 weeks,
- stop therapy. A subgroup of patients (estimated to be 100) will undergo pharmacogenetic
and pharmacodynamic studies. The pharmacogenetic study will evaluate the presence of
gene polymorphisms that modifies the numbers of functioning receptors and their affinity
for steroids (genes studied are showed in Tab 3). The pharmacodynamic study will
evaluate the in vitro response to steroids on blood mononuclear cells: individual
sensibility to steroids will be detected before and during steroid treatment and
compared with the clinical response, in order to tailor treatment in the future.
Relapses. Relapses will be treated with a further prolonged steroid regimen witch is
described in the protocol per extenso.
Patient monitoring:
1. Clinical examination Height, weight, BMI, blood pressure Parent heights recording (for
familial target) (at onset, remission, 4th, 20th weeks, 6, 12, 18, 24 months)
2. Biochemistry (at onset, 4th week, 24 months)
Blood CBC; serum glycemia, urea, creatinine, uric acid, proteins, albumin, cholesterol,
HDL, LDL, triglycerides, a2globulins, gammaglobulins, PT, PTT, fibrinogen, Anti-Thrombin
III°, Na, K, Cl, Ca, P, blood sample for pharmacogenetic and pharmacodynamic study
Urine Urine examination. Proteinuria and creatininuria on a 24h sample
3. Behavioral questionnaires(at onset, 4th, 6, 12, 24 months)
ASEBA CBCL Achenbach System of Empirically Based Assessment Child Behavior Checklist.
EQ-5D-PROXY EuroQol Group (version for parents) PedsQL Pediatric Quality of Life Inventory
(version for parents and children) EQ-5D-Y EuroQol Group (version for children)
The following epidemiological and therapeutical data will be collected
Epidemiological data
- Sex
- Age at onset
- Season
- Ethnicity
- Days of hospitalization.
- Number of blood tests performed during the follow-up
Therapeutic data
- Time to remission (days), number of relapses at 6-12-24 months
- Time and total dose (mg/m2) of induction therapy
- Time and total dose (mg/m2) of maintenance therapy
- Prednisone total dose at the end of the 2yrs of follow-up
- Albumin infusions (g/kg/patient)
- Use of albumin infusions and diuretics
- Number of immunosuppressive drugs associated to prednisone (and total dose in mg/kg)
