This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Concentration Controlled Everolimus With Reduced Dose Cyclosporine Versus Mycophenolate Mofetil With Standard Dose Cyclosporine in de Novo Renal Transplant Adult Recipients Treated With Basiliximab and Corticosteroids (NCT00658320), a randomized phase 3 study. The primary outcome is Core Study: Number of Patients With Composite Efficacy Endpoint.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00658320 |
| Phase | Phase 3 |
| Condition | Kidney Transplantation |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 122 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Novartis |
| Results posted | Yes |
2. Clinical Question
Population
Adult recipients of a new renal transplant were eligible for the study. The primary endpoint population is defined as the Intent-To-Treat population: all patients randomized after transplantation. The registry record reports enrollment of 122 participants. Further eligibility criteria and demographic characteristics are not reported in the registry record.
Intervention
The intervention was concentration-controlled everolimus with reduced-dose cyclosporine and corticosteroids, with basiliximab used as induction therapy. The core study description gives an everolimus starting dose of 1.5 mg/day and describes adjustment according to trough levels. The complete dosing instructions for cyclosporine are not reported in the registry record.
Comparator
The comparator was mycophenolate mofetil (MMF) with standard-dose cyclosporine and corticosteroids, alongside basiliximab induction. The registry description specifies MMF at 2 g/day in the core study. Detailed cyclosporine dosing instructions are not reported in the registry record.
Primary question
The study compared the groups on a composite efficacy endpoint assessed at 12 months. The composite included treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up. The registry record does not report a single reduced comparison of the primary endpoint, so the relative outcome between groups cannot be described from a single posted estimate.
3. Trial Design
This was a phase 3, randomized, parallel-group, open-label study with enrollment of 122 participants. The registry record lists the study as completed. The primary completion date is 2010-08, and the start date is 2008-02. It was conducted in de novo adult renal transplant recipients and compared two immunosuppressive treatment strategies.
The core study was designed to assess efficacy and safety over 12 months. One group received concentration-controlled everolimus with reduced-dose cyclosporine and corticosteroids; the other received MMF with standard-dose cyclosporine and corticosteroids. Both groups also received basiliximab induction therapy. The registry record describes an initial everolimus dose of 1.5 mg/day, with dose adjustment based on trough levels. It describes MMF at 2 g/day in the comparator group. More complete regimen details, including the full cyclosporine schedules, are not reported in the registry record.
The study description also outlines an extension intended to evaluate long-term safety and efficacy through 24 months after transplantation. It describes continued everolimus treatment beyond 24 months for patients in the everolimus group until approval and marketing in Japan. Whether the extension proceeded as planned, and its results, are not reported in the registry record summarized for this analysis.
Open-label means the registry lists no masking. This matters when interpreting outcomes that involve assessment or treatment decisions, such as biopsy-proven rejection. Randomization is intended to balance prognostic factors across groups on average, but the allocation ratio, randomization procedure, and concealment method are not reported in the registry record. The record also does not report a sample-size justification or a detailed analysis plan.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Before assignment: Core Study randomization was conducted within 24 hours post reperfusion. Participants who completed the 12 month visit of the Core Study and met inclusion/exclusion criteria were eligible to participate in the Extension Study and continued the same treatment as the Core Study until Month 24.
Core Study: 12 Months
| Stage | Everolimus + Reduced Dose of Cyclosporine | Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine |
|---|---|---|
| STARTED | 61 | 61 |
| COMPLETED | 56 | 58 |
| NOT COMPLETED | 5 | 3 |
Reasons for not completing this period:
| Reason | Everolimus + Reduced Dose of Cyclosporine | Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine |
|---|---|---|
| Subject withdrew consent | 5 | 3 |
Extension Study: Month 12 to Month 24
| Stage | Everolimus + Reduced Dose of Cyclosporine | Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine |
|---|---|---|
| STARTED | 53 | 57 |
| Extension ITT: Received Study Drug | 50 | 50 |
| COMPLETED | 47 | 50 |
| NOT COMPLETED | 6 | 7 |
Reasons for not completing this period:
| Reason | Everolimus + Reduced Dose of Cyclosporine | Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine |
|---|---|---|
| Subject withdrew consent | 3 | 0 |
| Did not receive study drug in Extension | 3 | 7 |
Extension Study: After Month 24
| Stage | Everolimus + Reduced Dose of Cyclosporine | Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine |
|---|---|---|
| STARTED | 44 | 0 |
| COMPLETED | 42 | 0 |
| NOT COMPLETED | 2 | 0 |
Reasons for not completing this period:
| Reason | Everolimus + Reduced Dose of Cyclosporine | Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine |
|---|---|---|
| Subject withdrew consent | 2 | 0 |
Analysis population for the primary outcome, as defined in the registry: The Intent-To-Treat (ITT) population consisted of all patients randomized after transplantation.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
Population: Baseline Measures are based on the data obtained in the Core Study.
| Characteristic | Unit | Everolimus + Reduced Dose of Cyclosporine | Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine | Total |
|---|---|---|---|---|
| Participants analysed | 61 | 61 | 122 | |
| Age Continuous | years | 42.5 (SD 14.13) | 38.6 (SD 11.36) | 40.5 (SD 12.92) |
| Sex: Female, Male: Female | Participants | 15 | 24 | 39 |
| Sex: Female, Male: Male | Participants | 46 | 37 | 83 |
6. Primary Endpoint
The registry lists the primary outcome as Core Study: Number of Patients With Composite Efficacy Endpoint, measured over 12 months.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary outcome was the number of patients with a composite efficacy endpoint at 12 months. Its components were treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up. A treated biopsy-proven acute rejection episode required a biopsy graded IA, IB, IIA, IIB, or III and treatment with anti-rejection therapy. Graft loss was defined as the day dialysis began when the patient could not stop dialysis, or the day of graft nephrectomy. For the individual components, the registry states that patients are counted for the first event to occur.
A composite can capture several clinically important types of events in a single outcome. In general, this can provide a broader summary than assessing each event separately, but the components may differ in severity, frequency, and interpretation. A total composite count alone would not show which component drove the result. Component-specific results are therefore useful alongside the overall endpoint. The registry record does not report a single reduced comparison for this primary outcome, nor does it provide component-specific primary results in the registry record for this analysis.
The endpoint population was the Intent-To-Treat population, defined in the record as all patients randomized after transplantation. This definition aims to retain participants in their assigned groups for analysis, regardless of subsequent treatment changes; however, the precise handling of such changes is not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record establishes the study question and design, but it does not provide a single primary endpoint comparison that can be interpreted as an estimated difference between the treatment groups. It would therefore be inappropriate to claim that the posted primary results favor either regimen, or that they demonstrate equivalence or a lack of difference. The absence of a single reduced comparison is not itself evidence of no treatment effect.
The primary endpoint combines treated biopsy-proven acute rejection, graft loss, death, and loss to follow-up. These events are not interchangeable in meaning. An overall composite result, if available, would need to be read together with the component results to understand what contributed to it. The record defines how treated rejection and graft loss were identified, and specifies that a participant is counted for the first event among the individual components. It does not report the number of participants with each component or an estimate comparing the groups.
The design was randomized and open-label. Randomization supports a comparative interpretation by assigning participants to treatment groups, while open-label conduct means participants and study personnel were not masked according to the registry record. The record does not describe how outcome assessment was protected from knowledge of treatment assignment, nor does it give enough information to assess the consequences of the open-label design for specific outcomes.
For safety, the registry lists 37 participants affected by serious adverse events in each group, with 61 participants at risk in each group. These are the posted affected-participant counts, not a comparative analysis or a complete account of event severity, timing, or recurrence. The record also lists serious adverse event terms with percentages, including cytomegalovirus infection at 18.0% and cytomegalovirus test positive at 16.4%. The denominator and the extent of overlap between terms are not reported in the registry record, so those percentages should not be combined or treated as mutually exclusive categories.
Other outcome measures listed include graft loss, death, loss to follow-up, renal function, adverse events, and drug trough levels. The record does not provide results for those measures in the registry record for this analysis. Overall, the registry supports a description of the planned comparison and some safety counts, but not a conclusion about comparative efficacy or a quantified treatment effect.
9. Statistical Methods Explained
What does randomization contribute?
Randomization assigns participants to treatment groups by chance. In general, this helps reduce systematic differences in prognostic characteristics at the start of a trial, including characteristics that may not be measured. It does not guarantee that groups will be identical, particularly in a trial with limited enrollment. The registry identifies this study as randomized and parallel-group, but does not report the randomization sequence method, allocation concealment, or the allocation ratio. Those details are relevant to assessing how the assignment process was implemented.
A parallel-group design compares groups receiving different assigned regimens over the study period rather than having participants cross between regimens. Here, the comparison was concentration-controlled everolimus with reduced-dose cyclosporine versus MMF with standard-dose cyclosporine. Because these are treatment strategies involving more than a single drug difference, a group contrast would represent the overall assigned regimens; it would not isolate the effect of everolimus alone from the cyclosporine dosing strategy or the other shared treatments.
How should the composite endpoint be understood?
A composite endpoint treats the occurrence of any of several specified events as an outcome. This approach can summarize a wider range of events and can be useful when different events are relevant to the study question. Its interpretation depends on the component definitions and on how frequently and how seriously each component occurs. If one component is much more common than the others, it can account for much of the composite result, even when readers might consider another component more consequential.
In this study, the composite included treated biopsy-proven acute rejection, graft loss, death, and loss to follow-up. The registry defines treated rejection using biopsy grades and anti-rejection treatment, and defines graft loss by dialysis that cannot be stopped or by graft nephrectomy. The record says that a participant is counted for the first event among the individual components. It does not report the component counts or a single reduced primary comparison. Thus, the endpoint definition is available, but the comparative numerical result needed to evaluate the primary question is not reported in the registry record.
What is the role of the Intent-To-Treat population?
The Intent-To-Treat population is defined in the record as all patients randomized after transplantation. In general, retaining participants in their randomized groups helps preserve the benefits of randomization and estimates the effect of assignment to a treatment strategy. It can also be challenging when participants discontinue treatment, switch regimens, or have incomplete outcome information. The record does not describe how treatment discontinuations, crossovers, or missing primary endpoint data were handled. The population definition alone does not establish which participants contributed observed outcomes or what methods were used for incomplete data.
What can a confidence interval and a significance test tell a reader?
In general, a confidence interval describes the range of estimates compatible with the observed data under the statistical model and its assumptions. A narrower interval indicates greater precision, while a wider interval indicates greater uncertainty. A significance test evaluates how compatible the observed data are with a specified null hypothesis under its assumptions. Neither a confidence interval nor a p-value gives the probability that a treatment works, and neither substitutes for considering the size and clinical meaning of an effect.
The registry record does not report a primary effect estimate, confidence interval, or p-value in the registry record for this analysis. Without an estimate and its uncertainty, the direction, magnitude, and precision of a comparative primary effect cannot be assessed. The record lists no analyses for the outcomes described in the registry entries. This lack of posted analysis should not be mistaken for a statistical finding.
Why do analysis choices matter?
Statistical results depend on choices about outcome definitions, analysis populations, missing data, and the method used to compare groups. For a binary endpoint, a comparison might be expressed using a difference in event proportions or another measure, but the registry record does not report a primary comparison in a form that permits interpretation of such an estimate. No new estimate can be inferred from the study enrollment alone.
Planning illustrations based on an observed effect are not evidence of the trial’s achieved power. The stated planning assumptions use a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. For time-to-event planning, the stated approach concerns a total number of events; other planning outputs concern participants per arm. These are planning conventions, not outcomes observed in the trial. The actual planned sample-size justification and its assumptions are not reported in the registry record.
Over-dispersion is a general issue when observed variation exceeds what a simple statistical model assumes. If present, it can make standard errors too small and confidence intervals too narrow unless the analysis accounts for it. The registry record does not identify an over-dispersion assessment or report a model for the primary outcome. This is a general consideration, not a claim that over-dispersion occurred in this study.
10. Multiplicity, Missing Data and Analysis Populations
The study lists a composite primary endpoint and several secondary outcomes. The secondary outcomes include combined graft loss, death, or loss to follow-up; renal function measured with specified formulas; an extension composite that also includes treated biopsy-proven acute rejection; adverse and serious adverse events; and everolimus and cyclosporine trough levels. Testing multiple outcomes can increase the chance of at least one apparently unusual result arising by chance. Statistical plans commonly address this through prespecified hierarchies, adjustment procedures, or careful emphasis on estimation rather than isolated significance tests.
Whether this study used a multiplicity strategy, how outcomes were ordered, and whether subgroup or interim analyses were planned are not reported in the registry record. The record does not provide a detailed statistical analysis plan. There is no basis to infer that results were adjusted, or that unadjusted results were used, for any particular family of comparisons.
The primary endpoint population is defined as all patients randomized after transplantation. The record does not explain how missing endpoint data were handled, including the loss-to-follow-up component, or whether any imputation or sensitivity analyses were used. It also does not report how treatment discontinuations or deviations were handled in analysis. These details matter because incomplete outcome information can affect both the estimate and its precision.
The record’s definition of the composite includes loss to follow-up as an event and states that the first event is counted for each participant among the individual components. That definition does not, by itself, explain how missing data outside the endpoint definition were treated or how competing events were handled analytically. Those methods are not reported in the registry record. The absence of such information limits assessment of whether the reported analysis, if available, would be robust to different reasonable assumptions.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Everolimus + Reduced Dose of Cyclosporine | 37 | 61 | 60.7% |
| Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine | 37 | 61 | 60.7% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Everolimus + Reduced Dose of Cyclosporine | 61 of 61 |
| Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine | 61 of 61 |
Most frequent serious adverse event terms
| Event term | Organ system | Everolimus + Reduced Dose of Cyclosporine | Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine |
|---|---|---|---|
| Cytomegalovirus infection | Infections and infestations | 1 of 61 | 11 of 61 |
| Cytomegalovirus test positive | Investigations | 2 of 61 | 10 of 61 |
| Blood creatinine increased | Investigations | 5 of 61 | 6 of 61 |
| Proteinuria | Renal and urinary disorders | 5 of 61 | 2 of 61 |
| Gastroenteritis | Infections and infestations | 2 of 61 | 4 of 61 |
| Pyrexia | General disorders | 3 of 61 | 2 of 61 |
| Upper respiratory tract inflammation | Respiratory, thoracic and mediastinal disorders | 4 of 61 | 1 of 61 |
| Herpes zoster | Infections and infestations | 1 of 61 | 2 of 61 |
| Pneumonia | Infections and infestations | 2 of 61 | 1 of 61 |
| Urinary tract infection | Infections and infestations | 1 of 61 | 2 of 61 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Everolimus + Reduced Dose of Cyclosporine | Mycophenolate Mofetil (MMF) + Standard Dose of Cyclosporine |
|---|---|---|---|
| Nasopharyngitis | Infections and infestations | 37 of 61 | 38 of 61 |
| Hyperlipidaemia | Metabolism and nutrition disorders | 30 of 61 | 20 of 61 |
| Constipation | Gastrointestinal disorders | 19 of 61 | 27 of 61 |
| Acne | Skin and subcutaneous tissue disorders | 18 of 61 | 22 of 61 |
| Hypertension | Vascular disorders | 21 of 61 | 18 of 61 |
| Diarrhoea | Gastrointestinal disorders | 22 of 61 | 15 of 61 |
| Pyrexia | General disorders | 14 of 61 | 17 of 61 |
| Iron deficiency anaemia | Blood and lymphatic system disorders | 14 of 61 | 16 of 61 |
| Back pain | Musculoskeletal and connective tissue disorders | 12 of 61 | 16 of 61 |
| Hyperuricaemia | Metabolism and nutrition disorders | 12 of 61 | 15 of 61 |
Serious events with the highest arm-level rate: cytomegalovirus infection (18.0%), cytomegalovirus test positive (16.4%), blood creatinine increased (9.8%), proteinuria (8.2%), gastroenteritis (6.6%).
The registry lists 61 participants at risk for serious adverse events in each group and 37 participants affected in each group. These are counts of participants, not counts of all events. A participant may experience more than one event, so participant counts and event counts answer different questions. The record does not provide the total number of serious events, their timing, duration, or severity beyond their classification as serious adverse events.
The listed serious adverse event terms include cytomegalovirus infection at 18.0%, cytomegalovirus test positive at 16.4%, blood creatinine increased at 9.8%, proteinuria at 8.2%, gastroenteritis at 6.6%, and upper respiratory tract inflammation at 6.6%. The registry record does not specify the denominator for these term percentages in the registry record, or whether participants could appear under more than one term. They should not be added together or interpreted as mutually exclusive groups.
Deaths are not reported in the registry record. The serious adverse event counts alone do not establish a comparative safety difference, and they do not provide a complete profile of all adverse events. Interpretation would require consistent definitions, exposure and follow-up context, and comparative analyses; those details are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The record describes a randomized comparison of two immunosuppressive strategies in adult de novo renal transplant recipients. Its primary outcome combines treated biopsy-proven acute rejection, graft loss, death, and loss to follow-up over 12 months. The endpoint definitions and the stated Intent-To-Treat population help clarify what the study intended to measure.
However, the primary endpoint is not reduced to a single reported comparison in the registry record. The outcome counts by component and a comparative effect estimate with uncertainty are not reported in the record available for this analysis. Consequently, the posted information cannot establish the direction or size of a difference between groups, its precision, or whether the evidence is compatible with a range of effects. It also cannot establish equivalence or absence of an effect.
The serious adverse event counts show 37 affected participants in each group, with 61 at risk in each group. Those counts are descriptive. Without a reported comparative safety analysis and fuller information on event timing, severity, and exposure, they do not establish that the groups had the same safety experience. The listed event-term percentages offer additional descriptive information, but their denominator and overlap are not reported in the registry record.
In general, a trial’s design and its posted results answer different questions. Randomization describes how treatment assignment was made, while an estimated effect and its uncertainty describe what the observed outcomes suggest about the comparison. A complete interpretation would also consider adherence, missing data, outcome ascertainment, and the analysis plan. Several of these details are not reported in the registry record. The responsible conclusion is therefore limited: the registry documents the comparison and endpoint definitions, but does not provide enough primary outcome analysis to support a comparative efficacy conclusion.
13. Why This Trial Matters Statistically
This trial illustrates why the endpoint definition and the reported analysis must be read together. A composite outcome can cover several relevant events, but an overall count does not reveal whether the result was driven by rejection, graft loss, death, or loss to follow-up. Component-level reporting is important for understanding what an overall composite means. Here, the registry describes the components and their definitions but does not report a single reduced primary comparison or the component results in the registry record for this analysis.
The study also compares treatment strategies that differ in both the principal immunosuppressive drug and cyclosporine dosing. A randomized contrast would therefore describe the effect of assignment to the regimens as a whole. It would not isolate a drug-specific effect without additional design or analysis information. This distinction is important when translating a trial question into a statistical estimand: the effect being estimated should correspond to the treatment strategies actually compared.
Finally, the registry record makes clear that design labels alone do not provide evidence about the size or precision of an effect. Randomization and a phase 3 designation do not replace a reported estimate, uncertainty interval, and transparent account of analysis choices. The missing primary comparison limits what can be learned about efficacy from this registry record, while the posted safety counts remain descriptive rather than definitive comparative findings.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The main limitation for interpreting efficacy is that the registry record does not report a single reduced comparison for the primary composite endpoint. It also does not provide component-specific primary outcome counts or an estimate with a measure of uncertainty in the registry record for this analysis. This prevents assessment of effect direction, magnitude, and precision.
The record does not report the randomization sequence method, allocation concealment, or allocation ratio. It identifies the study as open-label but does not describe outcome-assessment safeguards. This is relevant because treated rejection involves both biopsy grading and treatment, and knowledge of assignment can potentially affect decisions surrounding assessment or management. That is a general concern, not evidence that bias occurred in this study.
Full eligibility criteria, baseline characteristics, treatment adherence, discontinuations, and the complete cyclosporine schedules are not reported in the registry record. The record defines the primary analysis population but does not describe handling of missing outcomes, treatment deviations, or sensitivity analyses. It also does not report a sample-size justification, interim-analysis plan, multiplicity approach, or detailed statistical analysis plan.
Safety information is limited to affected-participant counts and a list of serious adverse event terms with percentages. The denominator for the term percentages, event counts, timing, and overlap among terms are not reported in the registry record. Deaths are not reported there. The extension is described as intended, but its conduct and results are not reported in the registry record for this analysis. These limitations restrict interpretation of both efficacy and safety.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Concentration Controlled Everolimus With Reduced Dose Cyclosporine Versus Mycophenolate Mofetil With Standard Dose Cyclosporine in de Novo Renal Transplant Adult Recipients Treated With Basiliximab and Corticosteroids — NCT00658320.
- Registry record last updated 2013-06-21; status last verified 2013-05.
- Results first posted 2011-09-14.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
The registry describes a completed phase 3, randomized, parallel-group, open-label study with enrollment of 122 adult de novo renal transplant recipients. It compared concentration-controlled everolimus with reduced-dose cyclosporine against MMF with standard-dose cyclosporine, with basiliximab and corticosteroids in the treatment strategies. The core study assessed outcomes at 12 months.
The primary endpoint was a composite of treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up in an Intent-To-Treat population defined as all patients randomized after transplantation. The registry record does not report a single reduced primary comparison. Serious adverse event counts were 37 affected participants in each group, with 61 at risk in each group. The record does not provide enough comparative primary outcome analysis to support a conclusion about relative efficacy.