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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Kidney Diseases	Drug: Tacrolimus (TAC)+ Mycophenolate Mofetil (MMF) + Withdrawal Prednisone; Drug: Tacrolimus (TAC)+ Mycophenolate Mofetil (MMF) + prednisolone	Phase 3

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	28 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	June 2008
Actual Primary Completion Date :	December 2012
Actual Study Completion Date :	December 2014

Arms and Interventions

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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

Outcome Measures

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Primary Outcome Measures :

1. Stimulation of Growth After 12 Months (Delta Z-score) [ Time Frame: 12 months ]

Secondary Outcome Measures :

1. 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 [ Time Frame: 12 months ]

Eligibility Criteria

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Ages Eligible for Study:	1 Year to 16 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

Chile
Calvo Mackenna Children Hospital
Santiago, Metropolitan Region, Chile

Sponsors and Collaborators

Fondo Nacional de Desarrollo Científico y Tecnológico, Chile

Investigators

Principal Investigator:	Maria Angela Delucchi, MD	Calvo Mackenna Children´s Hospital-University of Chile

More Information

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Responsible Party:	Maria Angela Delucchi Bicocchi, Physician, Fondo Nacional de Desarrollo Científico y Tecnológico, Chile
ClinicalTrials.gov Identifier:	NCT00707759 History of Changes
Other Study ID Numbers:	Fondecyt1080166
First Posted:	July 1, 2008
Results First Posted:	November 10, 2015
Last Update Posted:	November 10, 2015
Last Verified:	October 2015

Keywords provided by Maria Angela Delucchi Bicocchi, Fondo Nacional de Desarrollo Científico y Tecnológico, Chile:

Pediatric renal transplantation,Bone metabolism (DXA-pQCT); mRNAFOXP3/IL-17,Steroid withdrawal

Additional relevant MeSH terms:

Kidney Diseases; Urologic Diseases; Prednisolone acetate; Methylprednisolone acetate; Prednisone; Prednisolone; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone hemisuccinate; Prednisolone phosphate; Mycophenolic Acid; Tacrolimus; Anti-Inflammatory Agents; Glucocorticoids; Hormones

Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antibiotics, Antineoplastic; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Antiemetics