Steroid Withdrawal in Pediatric Renal Transplant: Impact on Growth, Bone Metabolism and Acute Rejection

Multicenter, Open-Label, Randomized Study on Steroid-Free Immunosuppression, in Comparison With Daily Steroid Therapy, in Pediatric Renal Transplant : Impact on Growth, Bone Metabolism and Acute Rejection

The present study investigates the safety and efficacy of steroid withdrawal at six days post-transplant in pediatric renal recipients under concomitant immunosuppression based on antibodies anti IL2 (interleukin 2), Tacrolimus (TAC) and Mycophenolate Mofetil (MMF). To investigate the impact of this protocol in growth, bone metabolism, insulin- sensitivity and evaluate the expression of IL17 (interleukin 17) and mRNA FOXP3 (messenger ribonucleic acid forkhead box protein 3) as early markers of acute rejection (blood, urine and renal biopsy).

Hypothesis:Steroid withdrawal in renal pediatric transplant patients improves growth and bone metabolism without increasing the risk of acute rejection. The expression of FoxP3/IL17 in urine cells could be an early molecular markers of acute rejection.

Study Overview

• Status: Completed
• Conditions: Kidney Diseases
• Intervention / Treatment: Drug: Tacrolimus (TAC)+ Mycophenolate Mofetil (MMF) + Withdrawal Prednisone; Drug: Tacrolimus (TAC)+ Mycophenolate Mofetil (MMF) + prednisolone

Detailed Description

The intention of this investigation is to evaluate a prospective immunosuppressive protocol based on antibodies anti IL-2 (Ac-IL-2), Tacrolimus (TAC) and Mycophenolate Mofetil (MMF)and withdrawal steroids in renal transplant and to compare with a steroid-based protocol.

Objectives:

1. To evaluate growth and the impairment in the GH/IGF (growth hormone/insulin like growth factor) axis
2. To determine the impact of steroids on bone metabolism (biochemical parameters, DXA and pQCT)
3. To determine the steroid effect on metabolic factors (dyslipidemia, insulin- sensitivity and arterial hypertension)
4. To determine acute rejection incidence (protocol renal biopsy)
5. To evaluate the expression of IL-17 and mRNA FoxP3 as early markers of acute rejection (blood, urine and renal biopsy).

Two treatment regimes (Arms)will be compared in randomized form in the course of 12 months after transplantation.

Arm A: TAC + MMF + withdrawal of steroids over a six-days following randomization.

Arm B: TAC + MMF + prednisolone (see schedule)/day

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 3

Contacts and Locations

Study Locations

• Chile
  • Metropolitan Region
    • Santiago, Metropolitan Region, Chile
      • Calvo Mackenna Children Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 16 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age < 16.0 years
• Bone age of boys < 15 years, of girls < 13 years
• Prepuberal Tanner Status I
• First or second kidney transplant, living or deceased kidney donation
• Immunosuppression with Tacrolimus (TAC),Mycophenolate mofetil (MMF)
• Patients and parents, respectively, have given their written consent after enlightenment (informed consent)

Exclusion Criteria:

• Irreversible rejection of former transplant
• Highly reactive (> 30%) lymphocytotoxic antibodies within 12 months prior to transplantation
• Suspected insufficient medication compliance in dialysis
• Patients receiving a basic immunosuppression other than that prescribed in this protocol
• Simultaneous therapy with growth hormone after renal transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: A: withdrawal steroids; Arms A: TAC + MMF + withdrawal steroids over a six-days following randomization. 1°day: Methylprednisolone iv, 2-3 mg/kg/d 3 doses 2ºday: Methylprednisolone iv, 2-3 mg/kg/d 3 doses 3°day: Prednisone 2 mg/kg/d in 2 doses 4ºday: Prednisone 1 mg/kg/d in 2 doses 5ºday: Prednisone 0.5 mg/kg/d in 2 doses 6ºday: Prednisone 0.25 mg/kg/d in 2 doses 7ºday: Stop Prednisone	Drug: Tacrolimus (TAC)+ Mycophenolate Mofetil (MMF) + Withdrawal Prednisone; Arms A: Tacrolimus (TAC)+ Mycophenolate Mofetil (MMF) + withdrawal steroids over a six-days following randomization. 1°day: Methylprednisolone iv, 2-3 mg/kg/d 3 doses 2ºday: Methylprednisolone iv, 2-3 mg/kg/d 3 doses 3°day: Prednisone 2 mg/kg/d in 2 doses 4ºday: Prednisone 1 mg/kg/d in 2 doses 5ºday: Prednisone 0.5 mg/kg/d in 2 doses 6ºday: Prednisone 0.25 mg/kg/d in 2 doses 7ºday: Stop Prednisone
ACTIVE_COMPARATOR: B; Arms B: TAC + MMF + prednisolone (see schedule)/day 10°days after Tx: 2 mg/kg/d Day 11 - 20: 1 mg/kg/d Day 21 - 30: 0.5 mg/kg/d Day 31 - 60: 0.3 mg/k/d Week 8 - 12: 0.25 mg/k/d Week 12 - 16: 0.20 mg/k/d Week 16 - 20: 0.15 mg/k/d Month 6 - 12: 0.10 - 0.12 mg/k/d	Drug: Tacrolimus (TAC)+ Mycophenolate Mofetil (MMF) + prednisolone; Arms B: Tacrolimus (TAC)+ Mycophenolate Mofetil (MMF) + prednisolone (see schedule)/day 10°days after Tx: 2 mg/kg/d Day 11 - 20: 1 mg/kg/d Day 21 - 30: 0.5 mg/kg/d Day 31 - 60: 0.3 mg/k/d Week 8 - 12: 0.25 mg/k/d Week 12 - 16: 0.20 mg/k/d Week 16 - 20: 0.15 mg/k/d Month 6 - 12: 0.10 - 0.12 mg/k/d

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Stimulation of Growth After 12 Months (Delta Z-score)	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Growth-factors (IGF-I, IGFBP-3) Bone Metabolism (FA, Ca/Cru, CaxP, 25(OH)VitD, FGF23, Klotho, PTH, DXA, pQCT) Insulin-sensitivity by ISI Method. Molecular Markers - Acute Rejection (FOXP3/IL-17). Acute Rejection Incidence/Protocol Renal Biopsy	12 months

Collaborators and Investigators

• Sponsor: Fondo Nacional de Desarrollo Científico y Tecnológico, Chile
• Investigators: Principal Investigator: Maria Angela Delucchi, MD, Calvo Mackenna Children´s Hospital-University of Chile

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (ACTUAL): December 1, 2012
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: June 26, 2008
• First Submitted That Met QC Criteria: June 27, 2008
• First Posted (ESTIMATE): July 1, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): November 10, 2015
• Last Update Submitted That Met QC Criteria: October 13, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Pediatric renal transplantation,Bone metabolism (DXA-pQCT); mRNAFOXP3/IL-17,Steroid withdrawal
• Additional Relevant MeSH Terms: Urologic Diseases; Kidney Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Prednisolone; Prednisone; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: Fondecyt1080166