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Steroid Treatment of Idiopathic Nephrotic Syndrome

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ClinicalTrials.gov Identifier: NCT01386957
Recruitment Status : Unknown
Verified March 2012 by Giovanni Montini, Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi.
Recruitment status was:  Recruiting
First Posted : July 1, 2011
Last Update Posted : March 8, 2012
Sponsor:
Collaborators:
IL Sogno di Stefano
Nando Peretti Foundation
Information provided by (Responsible Party):
Giovanni Montini, Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi

Brief 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

Condition or disease
Nephrotic Syndrome

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Detailed 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)

Study Type : Observational
Estimated Enrollment : 120 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Steroid Treatment of Childhood Idiopathic Nephrotic Syndrome: Epidemiology, Therapeutic Adequacy, Medium and Long Term Outcomes. A Prospective Observational Cohort Study.
Study Start Date : July 2011
Estimated Primary Completion Date : July 2013
Estimated Study Completion Date : July 2015

Resource links provided by the National Library of Medicine


Group/Cohort
Study group
children aged 6 months - 18 years, diagnosed with an initial episode of INS occurring from the first of July 2011 to the 31st of june 2013.



Biospecimen Retention:   Samples Without DNA
Whole Blood and Urine


Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

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 31st of June 2013 from the following Italian regions Emilia Romagna, Lombardia, Toscana, Trentino Alto Adige, Friuli Venezia Giulia, Marche and Sicilia; the follow-up of each subject will continue for 24 months.

Criteria

Inclusion Criteria:

  1. Age > 6 months and< 18 years
  2. Idiopathic nephrotic syndrome
  3. Ethical committee approval

Exclusion Criteria:

  1. Age < 6 months or > 18 years
  2. Congenital nephrotic syndrome
  3. Secondary nephrotic syndrome (post-infectious, SLE, Schonlein-Henoch) defined by clinical features, low C3 and C4 levels, severe hypertension and macrohematuria
  4. nephrotic syndrome associated to other syndromes (Dennys Drash, Frasier syndrome, et.cet) or to Wilms'tumor.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01386957


Contacts
Contact: montini giovanni, MD +390516364617 giovanni.montini@aosp.bo.it
Contact: pasini andrea, MD +390516364334 andrea.pasini@aosp.bo.it

Locations
Italy
Azienda Ospedaliera-Universitaria Sant'Orsola Malpighi Recruiting
Bologna, Emilia Romagna, Italy, 40138
Contact: Giovanni Montini, MD       giovanni.montini@aosp.bo.it   
Sub-Investigator: Andrea Pasini, MD         
PO Salesi, SOS Centro di Riferimento Regionale di Nefrologia e Dialisi Pediatrica Not yet recruiting
Ancona, Italy
Contact: Ilse Ratsch, MD       ilsemaria.r@gmail.com   
Ospedale Pediatrico Giovanni XXIII Recruiting
Bari, Italy, 70126
Contact: Giovanni Messina, MD    +390805596803    giovanni.messina1952@libero.it   
Principal Investigator: Giovanni Messina, MD         
Azienda Ospedaliera Universitaria Meyer, SOD Complessa Nefrologia Pediatrica Recruiting
Firenze, Italy
Contact: Marco Materassi, MD       m.materassi@meyer.it   
Principal Investigator: Marco Materassi, MD         
Istituto Giannina Gaslini, Dept of Pediatric Nephrology Recruiting
Genova, Italy, 16100
Contact: Gianmarco Ghiggeri, MD    +39010 380742    GMarcoGhiggeri@ospedale-gaslini.ge.it   
Principal Investigator: Gianmarco Ghiggeri, MD         
AOU Policlinico G Martino UOS dipartimentale Nefrologia e Reumatologia pediatrica Not yet recruiting
Messina, Italy
Contact: Giovanni Conti, MD       giovanniconti@hotmail.com   
Principal Investigator: Giovanni Conti, MD         
Fondazione IRCCS Ca' Granda Ospedale MAggiore Policlinico, UOC Nefrologia e Dialisi Recruiting
Milano, Italy
Contact: Alberto Edefonti, MD       aedefonti@hotmail.com   
Sub-Investigator: Luciana Ghio, MD         
Sub-Investigator: Gianluigi Ardissino, MD         
Ospedale dei bambini Di Cristina, UOC Nefrologia Pediatrica Not yet recruiting
Palermo, Italy
Contact: Silvio Maringhini, MD       s.maringhini@ospedalecivicopa.org   
Principal Investigator: Silvio Maringhini, MD         
Ospedale degli Angeli, Dept of Pediatrics Not yet recruiting
Pordenone, Italy, 33170
Contact: Roberto Dall'Amico, MD       roberto.dallamico@aopn.fvg.it   
Principal Investigator: Roberto Dall'Amico, MD         
Ospedale Pediatrico Burlo Garofalo Recruiting
Trieste, Italy
Contact: Marco Pennesi, MD       pennesi@burlo.trieste.it   
Sub-Investigator: Ines L'Erario, MD         
Università di Trieste, Department of Life Sciences Not yet recruiting
Trieste, Italy
Contact: Giuliana De Corti, MD       decorti@units.it   
Sponsors and Collaborators
Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi
IL Sogno di Stefano
Nando Peretti Foundation
Investigators
Study Chair: Giovanni Montini, MD Azienda Ospedaliero-Universitaria Sant'Orsola Malpighi, Bologna, Italy

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Giovanni Montini, MD, Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi
ClinicalTrials.gov Identifier: NCT01386957     History of Changes
Other Study ID Numbers: SNI-NET 2011
First Posted: July 1, 2011    Key Record Dates
Last Update Posted: March 8, 2012
Last Verified: March 2012

Keywords provided by Giovanni Montini, Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi:
Nephrotic Syndrome
Steroid treatment
Proteinuria
Child

Additional relevant MeSH terms:
Syndrome
Nephrotic Syndrome
Nephrosis
Nephrosis, Lipoid
Disease
Pathologic Processes
Kidney Diseases
Urologic Diseases