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
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 3 |
Study Design
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
- 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.
- 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
- 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.
- 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)
- 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
- 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.
- 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
- 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.
- 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.
- 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
- 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
Inclusion Criteria:
Inclusion criteria at baseline:
-
Written informed consent/assent must be obtained from the parent(s) or legal guardian before any assessment is performed.
-
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:
-
Patients on TAC + MMF + steroids.
-
Renal function with eGFR > 40 ml/min/1.73 m2 (Schwartz formula - abbreviated).
Exclusion Criteria:
Exclusion criteria at baseline:
-
Recipients of kidneys from donors with known renal disease (such as diabetes nephropathy, nephrosclerosis), at the time of transplant.
-
Recipients of a kidney with a cold ischemia time > 24 hours.
-
History of hypersensitivity or contraindications to any of the study drugs or to drugs of similar chemical classes, or to any of the excipients.
-
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:
-
Use of other investigational drugs at the time of randomization, or within 30 days or 5 half-lives prior randomization, whichever is longer.
-
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.
-
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).
-
Patients with ongoing wound healing problems, clinically significant wound infection requiring continued therapy or other severe surgical complication in the opinion of the investigator.
-
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).
-
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.- CRAD001A2314
- 2010-024381-21
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
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 |
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 |
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%
|
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%
|
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%
|
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%
|
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%
|
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%
|
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)
|
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)
|
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
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 |
novartis.email@novartis.com |
- CRAD001A2314
- 2010-024381-21