Efficacy, Tolerability and Safety of Early Introduction of Everolimus, Reduced Calcineurin Inhibitors and Early Steroid Elimination Compared to Standard CNI, Mycophenolate Mofetil and Steroid Regimen in Paediatric Renal Transplant Recipients

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01544491
Collaborator
(none)
106
31
2
73.2
3.4
0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if everolimus combined with reduced exposure CNI (TAC) is efficacious and safe and will support corticosteroid elimination compared to a standard exposure CNI (TAC) + MMF + steroid regimen after paediatric kidney transplantation. An additional purpose of the study is to assess the effect of the combination of EVR and reduced exposure CNI (TAC) on renal function.

This study is part of the requirements of the Paediatric Investigational Plan approved by Paediatric Committee at the European Medicines Agency (PDCO/EMA) on September 10, 2010, and is intended to support the indication of everolimus in the prevention of acute rejection in paediatric recipients of a renal transplant.

Study Design

Study Type:
Interventional
Actual Enrollment :
106 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A 12-month, Multicenter, Open Label, Randomized, Controlled Study to Evaluate the Efficacy, Tolerability and Safety of Early Introduction of Everolimus, Reduced CNI, and Early Steroid Elimination Compared to Standard CNI, Mycophenolate Mofetil and Steroid Regimen in Paediatric Renal Transplant Recipients With a 24-month Additional Safety Follow-up.
Actual Study Start Date :
Aug 17, 2012
Actual Primary Completion Date :
Oct 3, 2016
Actual Study Completion Date :
Sep 24, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Investigational arm

Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant

Drug: RAD001
Everolimus (C0 trough level of 3-8 ng/mL) in combination with reduced dose tacrolimus and steroids withdrawal at 6 months after transplant

Active Comparator: Control arm

MMF continuation (in combination with tacrolimus and standard dose steroids)

Drug: MMF
MMF (Cellcept®): 600mg/m2/dose twice daily (1200 mg/m2/day) in combination with tacrolimus (Prograf) and standard dose steroids

Outcome Measures

Primary Outcome Measures

  1. Number of Participants Having Reached the Composite Efficacy Endpoint of Biopsy-proven Acute Rejection [12 months, 36 months]

    To estimate the rate of the composite efficacy endpoint of biopsy-proven acute rejection (BPAR), graft loss or death at 12 months post transplantation in primary paediatric kidney transplant recipients converted at 4-6 weeks post-transplantation from MMF + standard TAC regimen and steroids, to everolimus + reduced dose TAC regimen and steroid withdrawal at 6 months, versus continuation of MMF + standard TAC regimen and steroids.

  2. To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Abbreviated), at Month 12 and 36 [12 months and 36 months post-transplantation]

    To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (abbreviated) (Schwartz, 2009).

Secondary Outcome Measures

  1. Composite Efficacy Endpoint [at 12 and 36 months post-transplantation]

    To evaluate the proportion of patients with the following efficacy events: Biopsy Proven Acute Rejection (BPAR), graft loss or death. The efficacy events will be descriptively summarized by treatment group.

  2. To Evaluate the Severity of BPAR (Acute T-cell Mediated Rejection Only) (Banff 2009) [month 12, month 36]

    T-cell mediated rejection severity : Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IIA - Mild to moderate intimal arteritis Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation)

  3. To Evaluate the Time to Event of BPAR [36 months]

    Time to incidence of Event, given in terms of number of participants with an Event according to time interval up to 36 months

  4. Incidence of Biopsy Proven Antibody Mediated Rejection. [at 12 and 36 months post-transplantation]

    To evaluate the proportion of patients with the following efficacy events: biopsy proven antibody mediated rejection/Steroid resistant BPAR and BPAR treated with T cell depleting therapy.

  5. Chronic Allograft Nephropathy / Interstitial Fibrosis and Tubular Atrophy [at 12 and 36 months post-transplantation.]

    To evaluate the proportion of patients with chronic allograft nephropathy (interstitial fibrosis and tubular atrophy, IF/TA) by histopathology and its progression.The term chronic allograft nephropathy was used inappropriately in the protocol and therefore, replaced by interstitial fibrosis and tubular atrophy

  6. Proteinuria (Urinary Protein/Creatinine Ratio) [at 12 and 36 months post-transplantation]

    The urinary protein/creatinine ratio will be descriptively summarized by treatment group at each visit. The incidence rate of patients with proteinuria will be categorized in <0.2 g/mg/mg, 0.2<2.0 mg/mg and ≥ 2.0 mg/mg and summarized by treatment groups at each visit.

  7. Growth/Development : Weight, Height, BMI : Change From Baseline [month 12 , month 36 post transplantation.]

    Evaluation of the potential effects upon the bone growth. The Z-score is a statistical tool which helps to assess data (here child growth parameters) relative to a reference or standard population. The Z-score describes the distance and direction of an observation away from the population median (or mean, however, here the median was used). A negative Z-score shows that data are lower than the median of the standard population, a positive Z-score shows that data are higher than the median of the standard population, and a Z-score of zero shows that the data are equal to the median of the standard population. The more the Z-score is distant from 0, the more expressed is for example underweight or overweight.

  8. Evaluation of Evolution of Renal Allograft Function Over Time [baseline, 6 months, 12 months , 24 months, 36 months]

    results given as eGFR values by time interval

  9. To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Extended), at Month 12 [12 months post-transplantation]

    To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (extended) (Schwartz, 2009). Results given as change from randomization

Eligibility Criteria

Criteria

Ages Eligible for Study:
1 Year to 18 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
Inclusion criteria at baseline:
  1. Written informed consent/assent must be obtained from the parent(s) or legal guardian before any assessment is performed.

  2. Primary or secondary paediatric kidney transplant recipient aged greater than or equal to 1 year and younger than 18 years receiving a deceased donor or non-HLA identical living donor (related or unrelated) renal transplant.

Inclusion criteria at randomization:
  1. Patients on TAC + MMF + steroids.

  2. Renal function with eGFR > 40 ml/min/1.73 m2 (Schwartz formula - abbreviated).

Exclusion Criteria:
Exclusion criteria at baseline:
  1. Recipients of kidneys from donors with known renal disease (such as diabetes nephropathy, nephrosclerosis), at the time of transplant.

  2. Recipients of a kidney with a cold ischemia time > 24 hours.

  3. History of hypersensitivity or contraindications to any of the study drugs or to drugs of similar chemical classes, or to any of the excipients.

  4. History of malignancy of any organ system treated or untreated, carrying possible risk of recurrence according to current guidelines (Appendix 10 of protocol).

Exclusion criteria at randomization:
  1. Use of other investigational drugs at the time of randomization, or within 30 days or 5 half-lives prior randomization, whichever is longer.

  2. Patients with ongoing or recently (within 2 weeks prior to randomization) treated episodes of acute rejection (any grade) or a steroid resistant acute rejection at the time of randomization.

  3. Patients who experienced acute cellular rejection (Banff ≥1B) or any antibody mediated acute rejection or patients considered at high risk of antibody mediated acute rejection by the investigator assessment (e.g. presence of newly formed DSA, histological suspicion) at any time before randomization (as the DSA quantitative threshold to define high risk is not fully established, the assessment of the risk will be made after discussion between the laboratory expert and the investigator who will take into account all information available and apply best judgment).

  4. Patients with ongoing wound healing problems, clinically significant wound infection requiring continued therapy or other severe surgical complication in the opinion of the investigator.

  5. Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) and can not discontinue the treatment (see Appendix 6 for list of medications).

  6. Patients with nephrotic range proteinuria (protein to creatinine ratio ≥2.0 mg/mg or 200 mg/mmol (Hogg, 2003).

Contacts and Locations

Locations

Site City State Country Postal Code
1 Novartis Investigative Site Los Angeles California United States 90095-1752
2 Novartis Investigative Site Ann Arbor Michigan United States 48109-0331
3 Novartis Investigative Site Saint Louis Missouri United States 63110
4 Novartis Investigative Site Santa Fe Argentina S3000EPV
5 Novartis Investigative Site Porto Alegre RS Brazil 90020-090
6 Novartis Investigative Site São Paulo SP Brazil 04038-002
7 Novartis Investigative Site Bron Cedex France 69677
8 Novartis Investigative Site Lille France 59000
9 Novartis Investigative Site Paris cedex 15 France 75015
10 Novartis Investigative Site Paris France 75019
11 Novartis Investigative Site Berlin Germany 13353
12 Novartis Investigative Site Essen Germany 45147
13 Novartis Investigative Site Hamburg Germany 20246
14 Novartis Investigative Site Hannover Germany 30625
15 Novartis Investigative Site Heidelberg Germany 69120
16 Novartis Investigative Site Muenster Germany 48149
17 Novartis Investigative Site Tübingen Germany 72076
18 Novartis Investigative Site Budapest Hungary 1082
19 Novartis Investigative Site Bologna BO Italy 40138
20 Novartis Investigative Site Genova GE Italy 16147
21 Novartis Investigative Site Roma ITA Italy 00165
22 Novartis Investigative Site Padova PD Italy 35128
23 Novartis Investigative Site Torino TO Italy 10126
24 Novartis Investigative Site Oslo Norway 0424
25 Novartis Investigative Site Warsaw Poland 04 730
26 Novartis Investigative Site Esplugues de Llobregat Barcelona Spain 08950
27 Novartis Investigative Site Stockholm Sweden 14186
28 Novartis Investigative Site Antalya Turkey 07070
29 Novartis Investigative Site London United Kingdom WC1N 1EH
30 Novartis Investigative Site Manchester United Kingdom M13 9WL
31 Novartis Investigative Site Nottingham United Kingdom NG7 2UH

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01544491
Other Study ID Numbers:
  • CRAD001A2314
  • 2010-024381-21
First Posted:
Mar 6, 2012
Last Update Posted:
May 31, 2019
Last Verified:
May 1, 2019
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
Keywords provided by Novartis Pharmaceuticals
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details Full Analysis set (FAS) 106 enrolled and randomized patients except misrandomized Per Protocol set (PPS) 90 patients in the FAS without major protocol deviations Safety set (SAF) 106 randomized patients who received at least one dose of study drug
Pre-assignment Detail
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Period Title: Overall Study
STARTED 52 54
COMPLETED 47 51
NOT COMPLETED 5 3

Baseline Characteristics

Arm/Group Title EVR+rTAC MMF+sTAC Total
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids) Total of all reporting groups
Overall Participants 52 54 106
Age, Customized (Count of Participants)
1 to <11 years
26
50%
27
50%
53
50%
11 <= 18 years
26
50%
27
50%
53
50%
Sex/Gender, Customized (Count of Participants)
Male
29
55.8%
31
57.4%
60
56.6%
Female
23
44.2%
23
42.6%
46
43.4%
Race/Ethnicity, Customized (Count of Participants)
Caucasian
42
80.8%
47
87%
89
84%
Black
1
1.9%
0
0%
1
0.9%
Asian
3
5.8%
2
3.7%
5
4.7%
Other
6
11.5%
5
9.3%
11
10.4%

Outcome Measures

1. Primary Outcome
Title Number of Participants Having Reached the Composite Efficacy Endpoint of Biopsy-proven Acute Rejection
Description To estimate the rate of the composite efficacy endpoint of biopsy-proven acute rejection (BPAR), graft loss or death at 12 months post transplantation in primary paediatric kidney transplant recipients converted at 4-6 weeks post-transplantation from MMF + standard TAC regimen and steroids, to everolimus + reduced dose TAC regimen and steroid withdrawal at 6 months, versus continuation of MMF + standard TAC regimen and steroids.
Time Frame 12 months, 36 months

Outcome Measure Data

Analysis Population Description
Full Analysis set (12 months and 36 months) Results given as number of participants with composite efficacy failures
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
12 months
5
9.6%
3
5.6%
36 months
5
9.6%
5
9.3%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EVR+rTAC, MMF+sTAC
Comments at 12 months
Type of Statistical Test Non-Inferiority
Comments Kaplan-Meier estimates and between treatment differences are estimated using the Kaplan-Meier product-limit formula and 80% confidence intervals derived using standard errors estimated from Greenwood's formula.
Statistical Test of Hypothesis p-Value 0.9712
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.1
Confidence Interval (2-Sided) 80%
-6.6 to 6.8
Parameter Dispersion Type: Standard Error of the Mean
Value: 5.25
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection EVR+rTAC, MMF+sTAC
Comments 36 months
Type of Statistical Test Non-Inferiority
Comments Kaplan-Meier estimates and between treatment differences are estimated using the Kaplan-Meier product-limit formula and 80% confidence intervals derived using standard errors estimated from Greenwood's formula.
Statistical Test of Hypothesis p-Value 0.9634
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.2
Confidence Interval (2-Sided) 80%
-7.3 to 7.7
Parameter Dispersion Type: Standard Error of the Mean
Value: 5.84
Estimation Comments
2. Primary Outcome
Title To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Abbreviated), at Month 12 and 36
Description To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (abbreviated) (Schwartz, 2009).
Time Frame 12 months and 36 months post-transplantation

Outcome Measure Data

Analysis Population Description
Full Analysis set 12 months and 36 months
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
12 months
76.7
(3.66)
71.7
(3.56)
36 months
68.1
(3.45)
67.3
(3.54)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection EVR+rTAC, MMF+sTAC
Comments at 12 months
Type of Statistical Test Non-Inferiority
Comments KM estimates and between treatment differences are estimated using the Kaplan-Meier product-limit formula and 80% confidence intervals derived using standard errors estimated from Greenwood's formula.
Statistical Test of Hypothesis p-Value 0.3455
Comments
Method t-test, 2 sided
Comments
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 5.0
Confidence Interval (2-Sided) 80%
-1.8 to 11.8
Parameter Dispersion Type: Standard Error of the Mean
Value: 5.26
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection EVR+rTAC, MMF+sTAC
Comments 36 months
Type of Statistical Test Non-Inferiority
Comments KM estimates and between treatment differences are estimated using the Kaplan-Meier product-limit formula and 80% confidence intervals derived using standard errors estimated from Greenwood's formula.
Statistical Test of Hypothesis p-Value 0.8642
Comments
Method t-test, 2 sided
Comments
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.8
Confidence Interval (2-Sided) 80%
-5.5 to 7.2
Parameter Dispersion Type: Standard Error of the Mean
Value: 4.95
Estimation Comments
3. Secondary Outcome
Title Composite Efficacy Endpoint
Description To evaluate the proportion of patients with the following efficacy events: Biopsy Proven Acute Rejection (BPAR), graft loss or death. The efficacy events will be descriptively summarized by treatment group.
Time Frame at 12 and 36 months post-transplantation

Outcome Measure Data

Analysis Population Description
full Analysis set 36 month analysis Results given as number of participants with composite efficacy failures
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
month 12 composite efficacy endpoint
5
9.6%
3
5.6%
graft loss 12 months
0
0%
0
0%
death 12 months
0
0%
0
0%
acute rejection 12 months
5
9.6%
4
7.4%
treated acute rejection 12 months
5
9.6%
4
7.4%
Biopsy proven acute rejection 12 months
5
9.6%
3
5.6%
treated Biopsy proven acute rejection 12 months
5
9.6%
3
5.6%
month 36 composite efficacy endpoint
5
9.6%
5
9.3%
graft loss 36 months
1
1.9%
2
3.7%
death 36 months
0
0%
0
0%
acute rejection 36 months
5
9.6%
7
13%
Biopsy proven acute rejection 36 months
5
9.6%
5
9.3%
treated Biopsy proven acute rejection 36 months
5
9.6%
5
9.3%
4. Secondary Outcome
Title To Evaluate the Severity of BPAR (Acute T-cell Mediated Rejection Only) (Banff 2009)
Description T-cell mediated rejection severity : Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IIA - Mild to moderate intimal arteritis Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation)
Time Frame month 12, month 36

Outcome Measure Data

Analysis Population Description
full Analysis set 36 months
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
month 12 grade IA
3
5.8%
1
1.9%
month 12 grade IB
1
1.9%
0
0%
month 12 grade IIA
0
0%
2
3.7%
month 12 grade IIB
0
0%
0
0%
month 12 grade III
0
0%
0
0%
month 36 grade IA
3
5.8%
1
1.9%
month 36 grade IB
2
3.8%
0
0%
month 36 grade IIA
0
0%
1
1.9%
month 36 grade IIB
0
0%
1
1.9%
month 36 grade III
0
0%
1
1.9%
5. Secondary Outcome
Title To Evaluate the Time to Event of BPAR
Description Time to incidence of Event, given in terms of number of participants with an Event according to time interval up to 36 months
Time Frame 36 months

Outcome Measure Data

Analysis Population Description
full Analysis set, 36 month analysis
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
day 1-7
0
0%
0
0%
day 8-14
0
0%
0
0%
day 15-28
1
1.9%
0
0%
day 29-56
0
0%
0
0%
day 57-84
0
0%
0
0%
day 85-150
2
3.8%
2
3.7%
day 151- 240
0
0%
0
0%
day 241-330
1
1.9%
2
3.7%
day 331- 510
0
0%
1
1.9%
day 511-690
1
1.9%
0
0%
day 691-870
0
0%
0
0%
day 871-1050
0
0%
0
0%
after day 1050
0
0%
0
0%
6. Secondary Outcome
Title Incidence of Biopsy Proven Antibody Mediated Rejection.
Description To evaluate the proportion of patients with the following efficacy events: biopsy proven antibody mediated rejection/Steroid resistant BPAR and BPAR treated with T cell depleting therapy.
Time Frame at 12 and 36 months post-transplantation

Outcome Measure Data

Analysis Population Description
Full Analysis set
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
patients with BPAR at 12 months
7
13.5%
8
14.8%
BPAR Steroid resistant,12 months
1
1.9%
0
0%
BPAR, T Cell depleting therapy 12 months
1
1.9%
1
1.9%
patients with BPAR at 36 months
6
11.5%
12
22.2%
BPAR Steroid resistant,36 months
1
1.9%
2
3.7%
BPAR, T Cell depleting therapy 36 months
2
3.8%
1
1.9%
7. Secondary Outcome
Title Chronic Allograft Nephropathy / Interstitial Fibrosis and Tubular Atrophy
Description To evaluate the proportion of patients with chronic allograft nephropathy (interstitial fibrosis and tubular atrophy, IF/TA) by histopathology and its progression.The term chronic allograft nephropathy was used inappropriately in the protocol and therefore, replaced by interstitial fibrosis and tubular atrophy
Time Frame at 12 and 36 months post-transplantation.

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
12 months
3
5.8%
3
5.6%
36 months
11
21.2%
7
13%
8. Secondary Outcome
Title Proteinuria (Urinary Protein/Creatinine Ratio)
Description The urinary protein/creatinine ratio will be descriptively summarized by treatment group at each visit. The incidence rate of patients with proteinuria will be categorized in <0.2 g/mg/mg, 0.2<2.0 mg/mg and ≥ 2.0 mg/mg and summarized by treatment groups at each visit.
Time Frame at 12 and 36 months post-transplantation

Outcome Measure Data

Analysis Population Description
full analysis set 36 months analysis
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
Baseline < 200mg/g
1
1.9%
2
3.7%
Baseline 200 - < 2000 mg/g
12
23.1%
12
22.2%
Baseline >= 2000 mg/g
14
26.9%
15
27.8%
Month 12 < 200mg/g
19
36.5%
28
51.9%
Month 12 200 - < 2000 mg/g
13
25%
11
20.4%
Month 12 >= 2000 mg/g
0
0%
0
0%
Month 36 < 200mg/g
23
44.2%
23
42.6%
Month 36 200 - < 2000 mg/g
10
19.2%
11
20.4%
Month 36 >= 2000 mg/g
1
1.9%
0
0%
9. Secondary Outcome
Title Growth/Development : Weight, Height, BMI : Change From Baseline
Description Evaluation of the potential effects upon the bone growth. The Z-score is a statistical tool which helps to assess data (here child growth parameters) relative to a reference or standard population. The Z-score describes the distance and direction of an observation away from the population median (or mean, however, here the median was used). A negative Z-score shows that data are lower than the median of the standard population, a positive Z-score shows that data are higher than the median of the standard population, and a Z-score of zero shows that the data are equal to the median of the standard population. The more the Z-score is distant from 0, the more expressed is for example underweight or overweight.
Time Frame month 12 , month 36 post transplantation.

Outcome Measure Data

Analysis Population Description
safety set, 36 months analysis
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
Height month 12
0.37
(0.625)
0.20
(0.537)
Height month 36
0.72
(1.131)
0.39
(0.776)
Weight month 12
0.30
(0.732)
0.42
(0.747)
Weight month 36
0.61
(0.987)
0.82
(1.268)
BMI month 12
0.00
(0.716)
0.24
(0.980)
BMI month 36
0.02
(0.860)
0.47
(1.231)
10. Secondary Outcome
Title Evaluation of Evolution of Renal Allograft Function Over Time
Description results given as eGFR values by time interval
Time Frame baseline, 6 months, 12 months , 24 months, 36 months

Outcome Measure Data

Analysis Population Description
full Analysis set 36 months
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
baseline
14.2
(11.38)
13.1
(15.62)
month 6
76.6
(28.29)
68.3
(21.02)
month 12
76.9
(21.61)
67.8
(23.57)
month 24
72.9
(28.43)
68.6
(23.26)
month 36
68.2
(21.60)
69.6
(20.01)
11. Secondary Outcome
Title To Evaluate Renal Function, Assessed by Glomerular Filtration Rate (eGFR) and Estimated by the Schwartz Formula (Extended), at Month 12
Description To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (extended) (Schwartz, 2009). Results given as change from randomization
Time Frame 12 months post-transplantation

Outcome Measure Data

Analysis Population Description
Full Analysis set 12 months months
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
Measure Participants 52 54
Mean (Standard Deviation) [mL/min/1.73m2]
4.6
(11.94)
-0.0
(23.92)

Adverse Events

Time Frame up to 36 months
Adverse Event Reporting Description AE additional description
Arm/Group Title EVR+rTAC MMF+sTAC
Arm/Group Description EVR+rTAC MMF+sTAC
All Cause Mortality
EVR+rTAC MMF+sTAC
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/52 (0%) 0/54 (0%)
Serious Adverse Events
EVR+rTAC MMF+sTAC
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/52 (0%) 0/54 (0%)
Other (Not Including Serious) Adverse Events
EVR+rTAC MMF+sTAC
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 46/52 (88.5%) 48/54 (88.9%)
Blood and lymphatic system disorders
Anaemia 10/52 (19.2%) 11/54 (20.4%)
Iron deficiency anaemia 3/52 (5.8%) 0/54 (0%)
Leukopenia 6/52 (11.5%) 6/54 (11.1%)
Neutropenia 2/52 (3.8%) 10/54 (18.5%)
Polycythaemia 3/52 (5.8%) 0/54 (0%)
Ear and labyrinth disorders
Ear pain 5/52 (9.6%) 5/54 (9.3%)
Gastrointestinal disorders
Abdominal pain 7/52 (13.5%) 6/54 (11.1%)
Abdominal pain upper 6/52 (11.5%) 5/54 (9.3%)
Aphthous ulcer 9/52 (17.3%) 1/54 (1.9%)
Constipation 3/52 (5.8%) 2/54 (3.7%)
Diarrhoea 13/52 (25%) 16/54 (29.6%)
Mouth ulceration 3/52 (5.8%) 2/54 (3.7%)
Nausea 4/52 (7.7%) 4/54 (7.4%)
Vomiting 10/52 (19.2%) 8/54 (14.8%)
General disorders
Fatigue 3/52 (5.8%) 2/54 (3.7%)
Pain 3/52 (5.8%) 3/54 (5.6%)
Pyrexia 14/52 (26.9%) 11/54 (20.4%)
Infections and infestations
BK virus infection 4/52 (7.7%) 8/54 (14.8%)
Bronchitis 2/52 (3.8%) 4/54 (7.4%)
Cystitis 3/52 (5.8%) 1/54 (1.9%)
Cytomegalovirus infection 3/52 (5.8%) 3/54 (5.6%)
Cytomegalovirus viraemia 0/52 (0%) 3/54 (5.6%)
Ear infection 1/52 (1.9%) 5/54 (9.3%)
Epstein-Barr viraemia 3/52 (5.8%) 2/54 (3.7%)
Epstein-Barr virus infection 7/52 (13.5%) 2/54 (3.7%)
Gastroenteritis 4/52 (7.7%) 5/54 (9.3%)
Influenza 3/52 (5.8%) 1/54 (1.9%)
Nasopharyngitis 16/52 (30.8%) 6/54 (11.1%)
Oral herpes 2/52 (3.8%) 3/54 (5.6%)
Otitis media 4/52 (7.7%) 1/54 (1.9%)
Pharyngitis 6/52 (11.5%) 1/54 (1.9%)
Rhinitis 7/52 (13.5%) 5/54 (9.3%)
Sinusitis 1/52 (1.9%) 3/54 (5.6%)
Tonsillitis 3/52 (5.8%) 8/54 (14.8%)
Upper respiratory tract infection 8/52 (15.4%) 6/54 (11.1%)
Urinary tract infection 13/52 (25%) 15/54 (27.8%)
Investigations
Blood creatinine increased 3/52 (5.8%) 6/54 (11.1%)
Hepatic enzyme increased 3/52 (5.8%) 1/54 (1.9%)
Weight decreased 0/52 (0%) 5/54 (9.3%)
Weight increased 5/52 (9.6%) 2/54 (3.7%)
Metabolism and nutrition disorders
Acidosis 1/52 (1.9%) 3/54 (5.6%)
Hypertriglyceridaemia 4/52 (7.7%) 2/54 (3.7%)
Hypokalaemia 3/52 (5.8%) 1/54 (1.9%)
Hypomagnesaemia 0/52 (0%) 4/54 (7.4%)
Iron deficiency 6/52 (11.5%) 0/54 (0%)
Metabolic acidosis 3/52 (5.8%) 0/54 (0%)
Obesity 2/52 (3.8%) 3/54 (5.6%)
Vitamin D deficiency 3/52 (5.8%) 4/54 (7.4%)
Musculoskeletal and connective tissue disorders
Pain in extremity 4/52 (7.7%) 1/54 (1.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma 1/52 (1.9%) 3/54 (5.6%)
Nervous system disorders
Headache 10/52 (19.2%) 11/54 (20.4%)
Tremor 1/52 (1.9%) 4/54 (7.4%)
Renal and urinary disorders
Haematuria 3/52 (5.8%) 3/54 (5.6%)
Proteinuria 4/52 (7.7%) 2/54 (3.7%)
Respiratory, thoracic and mediastinal disorders
Cough 11/52 (21.2%) 10/54 (18.5%)
Oropharyngeal pain 3/52 (5.8%) 3/54 (5.6%)
Skin and subcutaneous tissue disorders
Dermatitis diaper 3/52 (5.8%) 0/54 (0%)
Pruritus 0/52 (0%) 4/54 (7.4%)
Rash 5/52 (9.6%) 2/54 (3.7%)
Vascular disorders
Hypertension 7/52 (13.5%) 6/54 (11.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.

Results Point of Contact

Name/Title Study Director
Organization Novartis Pharmaceuticals
Phone 862-778-8300
Email novartis.email@novartis.com
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01544491
Other Study ID Numbers:
  • CRAD001A2314
  • 2010-024381-21
First Posted:
Mar 6, 2012
Last Update Posted:
May 31, 2019
Last Verified:
May 1, 2019