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Keywords:

  • Calcineurin inhibitor toxicity;
  • drug development;
  • efficacy;
  • mycophenolic acid;
  • renal function;
  • renal transplantation;
  • safety;
  • T-cell activation;
  • tacrolimus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statement
  9. References

Sotrastaurin, a novel protein-kinase-C inhibitor, blocks early T-cell activation. In this 12-month, Phase II study, de novo renal-transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard-exposure tacrolimus (SET) or reduced-exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor-free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m2, respectively. Study-drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer-term evaluation of sotrastaurin + tacrolimus is warranted.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statement
  9. References

With organ transplantation becoming an increasingly common medical procedure, there is a growing need for a range of immunosuppressive therapies to allow better tailoring of therapy to optimize patient outcomes. Currently, immunosuppressive therapy commonly involves using a combination of drugs with different mechanisms of action to maximize efficacy and minimize toxicity. Often, this means using a calcineurin inhibitor (CNI), cyclosporine or tacrolimus, which inhibit T-cell activation, together with a drug that inhibits lymphocyte proliferation, for example drugs based on mycophenolic acid (MPA).

While highly efficacious in preventing organ rejection, current regimens are associated with safety and tolerability concerns, limiting their benefit in many transplant recipients. In particular, despite being the cornerstone of immunosuppression in the prevention of acute rejection, CNIs are nephrotoxic and increase the risk of cardiovascular disease by predisposing patients to new-onset diabetes mellitus (NODM), hypertension and dyslipidemia (1), which impact graft and long-term patient survival. Meanwhile, a key challenge with MPA, the most common adjunctive therapy used with CNIs, is managing gastrointestinal (GI) side effects, which limit tolerability and can impact efficacy through the frequent need for dose adjustments (2). Furthermore, MPA is associated with myelosuppression (3), often leading to dose reduction or the use of costly comedication.

These factors highlight the need for new agents that provide immunosuppressive efficacy and safety via novel mechanisms of action, thus providing alternative multidrug regimens to meet the needs of an expanding transplant population (4). Protein kinase C (PKC) has been identified as an attractive new therapeutic target for immunosuppression (5), with isoforms PKCθ and PKCα being crucial for IL-2 (6) and IFN-γ production (7), respectively. Sotrastaurin is a new, small-molecular-weight immunosuppressant that selectively blocks these PKC isoforms and inhibits early T-cell activation via a calcineurin-independent pathway. In monotherapy and in combination with other immunosuppressants, sotrastaurin markedly prolonged graft-survival times in experimental heart and kidney allotransplantation models (8–11). Preclinical and early clinical safety data demonstrated no signs of nephrotoxicity or hepatotoxicity, and no metabolic or blood pressure effects at standard exposures (Data on file; Novartis Pharma AG, Basel, Switzerland). GI effects were the dose-limiting toxicities in all species tested preclinically. In vitro tests indicated a modest potential for QT-prolongation (Data on file; Novartis Pharma AG). However, in healthy-volunteer studies QT effects could not be confirmed at therapeutic doses (12). A reversible increase in mean ventricular heart rate was observed at a single dose of 500 mg, with mean heart rates remaining within the normal range (12). In a proof-of-concept study sotrastaurin 200 mg b.i.d. or 300 mg b.i.d. was highly effective and well tolerated in the treatment of patients with psoriasis, a disease driven mostly by T cells (12).

This Phase II study was the first time the efficacy and safety of oral sotrastaurin was evaluated in de novo renal-transplant recipients. In the first 3 months sotrastaurin was combined with tacrolimus (either standard- or reduced-exposure) with subsequent conversion to a CNI-free regimen of sotrastaurin + MPA. Tacrolimus was the CNI selected because, unlike cyclosporine (13), it does not influence sotrastaurin exposure (14). Based on the good efficacy results in the proof-of-concept psoriasis study (12), 200 mg b.i.d. rather than 300 mg b.i.d. sotrastaurin was used to minimize potential over-immunosuppression when combined with tacrolimus.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statement
  9. References

Design and population

CAEB071A2203 (NCT00403416) was a 12-month, open-label, randomized, three-arm, Phase II study in de novo renal-transplant recipients conducted between October 2006 and March 2008 in 28 centers in Europe and North America.

Patients ≥18 years who were recipients of a primary deceased or non-HLA-identical living-donor renal transplant were eligible. Important exclusion criteria included recipients of multiorgan transplants, cold ischemia time (CIT) ≥30 h, donation after cardiac death or ABO-incompatible or T-cell crossmatched-positive transplants, patients with panel-reactive antibodies >50% and high-risk cardiac history (e.g. long QT-syndrome, hospitalization for heart failure or significant and persistent left ventricular dysfunction experienced during the previous 6 months). Recipients with delayed graft function at 36 h posttransplant were also excluded (<250 mL/12 h urinary output in patients with no residual urinary output from native kidneys, or no decrease in serum creatinine). Written informed consent was obtained from all patients and the study was approved by the Institutional Review Board and performed in accordance with the Declaration of Helsinki. An independent data-monitoring committee (DMC) was established prior to study initiation.

Postscreening, patients were randomized (1:1:1) using blinded treatment-allocation cards to one of the two sotrastaurin groups or the control group. Patients in the sotrastaurin groups received sotrastaurin 200 mg b.i.d. + tacrolimus (Prograf®, Astellas Pharma AG, Wallisellen, Switzerland), either standard exposure (sotrastaurin + standard-exposure tacrolimus [SET]) or reduced exposure (sotrastaurin + reduced-exposure tacrolimus [RET]). Tacrolimus target levels were: Month 1: 8–15 ng/mL (SET) or 5–8 ng/mL (RET), Months 2–3: 6–12 ng/mL (SET) or 3–6 ng/mL (RET) in the standard- and reduced-exposure groups, respectively. Sotrastaurin-treated recipients who met conversion criteria at Month 3 were converted to a CNI-free regimen of sotrastaurin 200 mg b.i.d. + MPA 720 mg b.i.d. (Myfortic®; Novartis Pharma AG). Control-group recipients received SET + 720 mg b.i.d. MPA. Tacrolimus target levels from Month 4 onwards were 5–10 ng/mL. All patients received two doses of basiliximab (Simulect®; Novartis Pharma AG) induction therapy; the first dose was administered within 24 h of grafting. Steroids were started and tapered as per local practice to ≥5.0 mg/day prednisone (or equivalent dose of another steroid) for the study period.

Conversion criteria and procedure

Conversion eligibility was assessed for all patients in all study groups who were on study drug at Month 3. Key eligibility criteria were: absence of acute rejection, stable graft function (serum creatinine <2.5 mg/dL and no change >30% from nadir) and the absence of proteinuria >1 g/24 h or major hematologic abnormalities (leukocytes <2500/μL, neutrophils <1500/μL, hemoglobin <10 g/dL). Eligible patients in the two sotrastaurin groups were converted from tacrolimus to MPA over a 2-week period, introducing MPA 360 mg b.i.d. as add-on treatment a week before tacrolimus was reduced to 50% and MPA was increased to full dose, with complete tacrolimus discontinuation after another week. Patients in all groups who did not meet the eligibility criteria were converted from their study regimen to local standard of care. Patients who completed the study were evaluated on 15 occasions (plus three additional evaluations during the conversion period between Months 3 and 4 in each sotrastaurin group). Patients who prematurely discontinued study drug were converted to local standard of care, remained in the study and underwent follow-up visits at Months 3, 6 and 12.

Biopsies were evaluated according to Banff 2003 criteria (15). Biopsy-proven acute rejection (BPAR) was defined as a clinically suspected rejection episode confirmed by a biopsy (graded IA, IB, IIA, IIB or III or antibody-mediated rejection) and treated with antirejection therapy. Acute rejections were initially treated with steroids according to local practice. Patients who experienced a BPAR ≥Grade II, a steroid-resistant rejection or more than one rejection per treatment period, were discontinued from study treatment and converted to local standard of care.

Efficacy and safety assessments

The primary efficacy variable was the composite endpoint of treated BPAR, graft loss, death or loss to follow-up at Month 6. The main safety endpoint was renal function calculated using the Modification of Diet in Renal Disease (MDRD) formula (16) for glomerular filtration rate (GFR) at Month 6. Safety assessments included the recording of adverse events (AEs), infections, hematologic and biochemical laboratory evaluations, vital signs and electrocardiograms (ECGs).

Statistical analyses

Demographic and background information for all randomized patients were summarized using frequency distributions (categorical variables) and descriptive statistics (continuous variables). All efficacy analyses were performed on the intent-to-treat (ITT) population (all randomized patients). Efficacy events that occurred within 7 days of study-drug discontinuation were included in the primary analyses. General safety analyses were performed on the safety population (all randomized patients who received at least one dose of study medication and had at least one safety assessment). The primary analysis population for renal function was patients who met conversion eligibility criteria using only data obtained while on study drug (safety-2 population). Noninferiority of the sotrastaurin regimens compared with the control group with respect to efficacy was tested using a confidence interval (CI) approach. Event rates between arms were estimated using Kaplan–Meier (K–M) methodology. Median GFRs between treatment groups were compared using a Wilcoxon rank-sum test (α= 0.05, two-sided). CIs for the median were computed using a robust estimator based on the interquartile range (17).

To investigate the relationship between trough levels of sotrastaurin and tacrolimus and efficacy and infections, events were cross-classified to tertiles of the time-weighted average trough levels for the period including the first 3 months of the study. All trough values up to the time of the event or Month 3, whichever was earlier, were included in these analyses.

Sample size and power considerations

The study was designed to show that each of the two sotrastaurin regimens was noninferior to the control regimen with regard to primary efficacy failure using a predefined noninferiority margin of 15%. A sample size of 65 patients per regimen had 81% power to demonstrate that a sotrastaurin regimen was ≤15% worse than the control regimen, assuming the efficacy-failure rate was 10% in each regimen (two-sided test, α= 0.050). The primary endpoint was evaluated by computing a Z-test-based 95% CI for the difference in efficacy-failure probabilities (obtained from K–M estimates) for each sotrastaurin regimen versus the control regimen. Noninferiority of the sotrastaurin regimens was demonstrated if the upper bound of the 95% CI (sotrastaurin regimen − control regimen) was <15%. No multiplicity adjustment was made for multiple treatment comparisons.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statement
  9. References

Of the 263 screened patients, 216 were randomized to the control (n = 74), sotrastaurin + SET (n = 76) or sotrastaurin + RET (n = 66) groups (Figure 1). The main reason for screening failure was an unacceptable laboratory value. The three treatment groups consisted mainly of Caucasian patients, and were well matched for all baseline characteristics (Table 1).

image

Figure 1. Flow of patients through the study.*Subjects may have had more than one reason for exclusion; †MPA 720 mg b.i.d.; ‡sotrastaurin 200 mg b.i.d.; **Fewer patients than other groups owing to administrative reasons. MPA, mycophenolic acid; RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus.

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Table 1.  Demographic and background characteristics of donors and recipients (intent-to-treat population)
 Control (n = 74)Sotrastaurin + SET (n = 76)Sotrastaurin + RET (n = 66)
  1. 1Cold ischemia time is for deceased donors only.

  2. HLA, human leukocyte antigen; MPA, mycophenolic acid; RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus.

Recipient
Age in years, mean (range)44.6 (19–70)43.7 (18–65)44.9 (18–67)
Male, n (%)53 (71.6)54 (71.1)48 (72.7)
Race, n (%)
 Caucasian71 (95.9)73 (96.1)63 (95.5)
 Black2 (2.7)1 (1.3)1 (1.5)
 Other1 (1.4)2 (2.6)2 (3.0)
End-stage renal disease leading to transplant, n (%)
 Glomerulonephritis21 (28.4)16 (21.1)14 (21.2)
 Polycystic disease15 (20.3)15 (19.7)13 (19.7)
 Diabetes mellitus5 (6.8)2 (2.6)1 (1.5)
 Hypertension5 (6.8) 9 (11.8)2 (3.0)
 Unknown5 (6.8)5 (6.6)4 (6.1)
 Other23 (31.1)29 (38.2)31 (47.0)
Pretransplant dialysis63 (85.2)67 (88.2)55 (83.3)
Panel reactive antibodies >5%, n (%)1 (1.4)01 (1.5)
Mean number of HLA mismatches (A, B or DR locus)3.22.92.9
Zero HLA mismatches (A, B, or DR locus), n (%)7 (9.5) 9 (11.8)6 (9.1)
Median cold ischemia time, hours114.014.714.6
Donor
 Age in years, mean (range)45.3 (13–64)43.9 (14–64)45.9 (15–68)
 Male, n (%)31 (41.9)37 (48.7)29 (43.9)
 Living unrelated, n (%)10 (13.5) 9 (11.8) 8 (12.1)
 Living related, n (%)14 (18.9)19 (25.0)14 (21.2)
 Deceased, n (%)50 (67.6)48 (63.2)43 (65.2)

The rate of study-drug (sotrastaurin, tacrolimus or MPA) discontinuations due to AEs was comparable between the three groups (control: 16.2%; sotrastaurin + SET: 18.4%; and sotrastaurin + RET: 12.1%). More patients in the sotrastaurin + SET and sotrastaurin + RET groups were ineligible for conversion at Month 3 versus the control group (14.5% and 23.6% vs. 8.3%; p = NS [based on pairwise comparisons using Fisher's exact test]). A similar number of patients in all groups were ineligible due to acute rejections (Figure 1); the most common reasons for ineligibility were ‘poor/unstable renal function’, and ‘compeling reason prohibiting full-dose MPA or discontinuation of tacrolimus’. The numerically higher proportion of sotrastaurin + SET-treated patients rated ineligible for conversion by the investigators was not reflected in the available laboratory data. In March 2008, on the DMC's recommendation, the study was terminated owing to increased risk of acute rejection in both sotrastaurin groups after conversion from tacrolimus to MPA. All patients were discontinued from study medication and switched to standard of care. At study termination, all patients on study drug had been in the study for ≥6 months. Median durations of exposure to study medication were, control: 282 (range: 1–535), sotrastaurin + SET: 237 (0–523) and sotrastaurin + RET: 247 (0–454) days.

Drug concentrations achieved

Tacrolimus trough blood levels are shown in Figure 2. In the control and sotrastaurin + SET groups, which both received SET, most patients were within the target trough range over Months 1, 2 and 3 (control: 63.0%, 74.2% and 77.4%; sotrastaurin + SET: 68.6%, 74.6% and 81.7%; respectively). Tacrolimus levels achieved in the sotrastaurin + RET group were ∼30–40% lower compared with the sotrastaurin + SET group, however, a substantial proportion of trough levels were above target at Months 1, 2 and 3 (45.3%, 55.4% and 46.4%, respectively). Sotrastaurin trough levels were generally stable throughout the study; mean (±SD) levels over the study period were 601 ± 289 ng/mL and 556 ± 234 ng/mL for sotrastaurin + SET and sotrastaurin + RET, respectively. Mean (±SD) daily MPA doses at Month 6 were 1233 ± 313 mg, 1352 ± 207 mg and 1331 ± 203 mg for control, sotrastaurin + SET and sotrastaurin + RET, respectively.

image

Figure 2. Median tacrolimus trough levels (intent-to-treat population). Target tacrolimus levels were Month 1: 8–15 ng/mL (control and sotrastaurin + SET) or 5–8 ng/mL (sotrastaurin + RET), Months 2–3: 6–12 ng/mL (control and sotrastaurin + SET) or 3–6 ng/mL (sotrastaurin + RET), and Months 4–12 (control group only): 5–10 ng/mL. MPA, mycophenolic acid; RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus.

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Efficacy

During the 3-month preconversion period, both sotrastaurin + tacrolimus regimens showed comparable efficacy to control for the composite endpoint. However, after conversion from tacrolimus to MPA, both sotrastaurin + MPA regimens were inferior to the control for the primary composite endpoint (Figure 3, Table 2). The majority of biopsies in the sotrastaurin groups (26/36) were Banff IA or IB (Table 3).

image

Figure 3. Kaplan–Meier plot of time to first on-treatment composite primary efficacy failure (intent-to-treat population). Note that the study was terminated in March 2008 when patients had been exposed to study medication for a median duration of 250 (range: 1–535), 212 (range: 0–523) and 222 (range: 0–454) days in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively. MPA, mycophenolic acid; RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus.

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Table 2.  Primary efficacy endpoint (composite of treated biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow-up) at Month 3 and end of study (intent-to-treat population)
 Control (n = 74)Sotrastaurin + SET (n = 76)Sotrastaurin + RET (n = 66)
nK–M estimate (%)nK–M estimate (%)95% CI of diff vs. controlnK–M estimate (%)95% CI of diff vs. control
  1. Patients on study drug, or within 7 days of discontinuation of study drug. Patients were converted at 3 months according to the criteria described in the methods.

  2. Treated BPAR: antirejection therapy given, Banff ≥1A, vascular acute rejection, clinical diagnosis consistent with rejection.

  3. CI, confidence interval; diff, difference; K–M, Kaplan–Meier; MPA, mycophenolic acid; RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus.

Month 3 (preconversion)
Composite34.14 5.4−5.6, 8.11 1.5−8.1, 2.9
 Treated BPAR22.83 4.1−4.6, 7.21 1.5−6.0, 3.6
 Graft loss11.40 −4.0, 1.30 −4.0, 1.3
 Death0 0  0  
End of study
 Composite57.824 44.8 21.5, 52.514 34.1  9.0, 43.5
 Treated BPAR34.621 40.2 20.9, 50.313 32.4 11.0, 44.5
 Graft loss11.40 −4.0, 1.30 −4.0, 1.3
 Death11.90 −5.5, 1.81 2.4−5.4, 6.4
Table 3.  Banff scores of acute rejection episodes detected by biopsy (intent-to-treat population)
 Control N = 74 nSotrastaurin + SET N = 76 nSotrastaurin + RET N = 66 n
  1. The worst grade is reported for patients with ≥1 BPAR.

  2. BPAR, biopsy-proven acute rejection; MPA, mycophenolic acid; RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus.

Total number of patients with biopsies showing acute rejection522 14 
   Grade Ia276
   Grade Ib294
   Grade IIa154
   Grade IIb010
   Grade III000

Immunosuppression exposure–efficacy relationship

No clear association was seen between tacrolimus and sotrastaurin trough levels and efficacy events, in part due to the low numbers of events in the first 3 months. Similarly, no clear correlation between sotrastaurin time-normalized trough levels and the primary efficacy endpoint was established.

Safety

Renal function:  Median GFR (MDRD) was not significantly different for sotrastaurin + SET or sotrastaurin + RET compared with control at any time point (Figure 4). At Month 3, median GFR values were 57.0, 53.0 and 60.0 mL/min/1.73 m2 in the control, sotrastaurin + SET and sotrastaurin+RET groups, respectively. At Month 6, after conversion to a CNI-free regimen in the sotrastaurin groups, GFR values remained generally unchanged (54.0, 56.5 and 64.0 mL/min/1.73 m2, respectively), with no significant differences relative to Month 3. These findings were confirmed by similar patterns of creatinine clearance (Cockcroft–Gault) and cystatin C-based calculated GFR (Table 4). The prespecified primary analyses for GFR were based on the safety-2 population; analysis of the ITT population yielded similar results.

image

Figure 4. Median glomerular filtration rate (GFR) calculated by Modification of Diet in Renal Disease (MDRD) formula by visit and group (safety-2 population). Safety-population-2: patients who met conversion eligibility criteria at Month 3 and data obtained only while patients were on study drug. No data were carried forward. MPA, mycophenolic acid; RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus. At Month 3: n = 53, 49 and 40, and at Month 6: n = 45, 40 and 34 patients in the control, sotrastaurin + SET and Sotrastaurin + RET groups, respectively.

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Table 4.  Median (standard error) values of glomerular filtration rate (GFR) calculated by Modification of Diet in Renal Disease (MDRD) formula, creatinine clearance (Cockcroft–Gault) and GFR (cystatin C; Filler-formula) at 3 months and at 6 months (safety-2 population)
 Month 3Month 6
GFR (MDRD), mL/min/1.73 m2Creatinine clearance, mL/minGFR (cystatin C), mL/min/1.73 m2GFR (MDRD), mL/min/1.73 m2Creatinine clearance, mL/minGFR (cystatin C), mL/min/1.73 m2
  1. Safety-2 population: patients who met conversion eligibility criteria at Month 3 and data obtained only while patients were on study drug. No data were carried forward.

  2. MPA, mycophenolic acid; RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus.

Control, N = 7457.0 (2.30) n = 5375.0 (4.04) n = 5158.0 (2.89) n = 5054.0 (2.50) n = 4575.0 (4.88) n = 4258.0 (2.18) n = 41
Sotrastaurin + SET, N = 7653.0 (2.92) n = 4971.0 (3.85) n = 4955.0 (3.49) n = 4856.5 (2.57) n = 4067.0 (4.32) n = 3967.0 (2.45) n = 37
Sotrastaurin + RET, N = 6660.0 (4.85) n = 4082.0 (5.81) n = 3959.0 (4.92) n = 3964.0 (4.31) n = 3472.0 (3.83) n = 3459.0 (3.01) n = 31

Adverse events:  The incidence of AEs was generally similar across the treatment groups. The most frequent AEs in all groups were GI disorders and metabolism and nutrition disorders (Table 5). The most frequent serious adverse events (SAEs) were: kidney-transplant rejection (control: 1.4%; sotrastaurin + SET: 6.7%; and sotrastaurin + RET: 6.2%), cytomegalovirus (CMV) infection (4.1%, 2.7% and 6.2%), gastroenteritis (1.4%, 4.0% and 6.2%), urinary tract infection (UTI; 4.1%, 2.7% and 6.2%), complications of the transplanted kidney (2.7%, 5.3% and 0%) and increased blood creatinine (1.4%, 12.0% and 10.8%). The highest incidence of SAEs was reported in the sotrastaurin + RET group, in part due to a higher incidence of infection SAEs. Because the overall pattern of AEs associated with sotrastaurin was similar to that of the control, it is noteworthy that three (4.6%) patients in the sotrastaurin + RET group reported dysgeusia.

Table 5.  Incidence of most frequent and notable adverse events (≥10% in any group and a difference of ≥5% between at least two groups) and the overall incidence of infections—safety population for the entire study period
 Control (n = 74) %Sotrastaurin + SET (n = 75) %Sotrastaurin + RET (n = 66) %
  1. 1More than one adverse event could be given as a reason for discontinuation of study medication.

  2. 2Infections determined from laboratory tests rather than investigator adverse event reports.

  3. MPA, mycophenolic acid; RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus.

At least one adverse event10094.7100
Any serious adverse event43.249.363.1
Adverse events leading to discontinuation of study medication116.232.027.7
Adverse events
 Anemia21.625.318.5
 Leukocytosis6.818.79.2
 Leukopenia13.52.76.2
 Tachycardia1.416.018.5
 Abdominal pain16.28.07.7
 Abdominal pain upper13.512.06.2
 Constipation25.737.332.3
 Diarrhea51.441.338.5
 Dyspepsia13.58.07.7
 Flatulence13.55.312.3
 Nausea25.734.727.7
 Vomiting16.220.027.7
 Pain2.710.71.5
 Peripheral edema18.913.321.5
 Pyrexia9.510.716.9
 CMV infection4.15.310.8
 Nasopharyngitis13.512.018.5
 Urinary tract infection33.837.332.3
 Wound complication13.514.79.2
 Blood creatinine increased12.229.327.7
 Diabetes mellitus14.96.77.7
 Hypercholesterolemia8.113.310.8
 Hyperlipidemia5.4010.8
 Hypocalcemia2.710.712.3
 Hypomagnesemia39.230.724.6
 Hypophosphatemia21.630.726.2
 Arthralgia4.15.312.3
 Back pain12.24.03.1
 Headache9.518.716.9
 Tremor24.314.721.5
 Anxiety2.74.010.8
 Insomnia21.68.010.8
 Hematuria6.88.012.3
 Proteinuria5.413.37.7
 Acne10.89.316.9
Infections270.370.770.8
 Bacterial infection35.137.335.4
   Escherichia coli12.222.715.4
 Viral infection18.916.020.0
   CMV infection4.15.312.3
   BK infection2.74.00
 Fungal infection4.16.74.6
 No living organism identified9.56.715.4
 Unknown type of infection50.050.744.7

GI adverse events:  GI AEs were the most common AEs reported and the incidence was broadly similar in the three groups. Diarrhea was the most common GI AE and occurred in a higher percentage of control versus sotrastaurin patients. Diarrhea also caused the most study-drug dose reduction/interruption in the first 3 months (control: 13.5% vs. sotrastaurin + SET: 1.3% and sotrastaurin + RET: 3.1%). The other GI AEs, vomiting, constipation and nausea were reported more frequently in the sotrastaurin groups (Table 5). Nausea, vomiting or constipation were responsible for both a study-drug dose reduction/interruption and hospitalization in <3% of patients and only in the sotrastaurin + SET group. One of these patients eventually permanently discontinued study drug because of protracted vomiting. Overall, the majority of GI events were reported during the first 3 weeks after surgery, and were mild.

Cardiac safety:  Cardiac AEs were reported in 21.6%, 22.7% and 27.7% of the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively. The only cardiac AE reported in >5% of patients in any group was tachycardia, which occurred at a higher incidence in both sotrastaurin groups compared with control (Table 5). The difference between the groups was less pronounced when tachycardia (defined as an increase of 25% leading to a heart rate >100 beats per minute [bpm]) was assessed by centrally read ECGs (control: 6.8%, sotrastaurin + SET: 11.3% and sotrastaurin + RET: 13.8%). Pulse rate increased in the peritransplant period (mean rates between 72.0–89.6, 83.5–88.0 and 82.4–110.0 bpm in the first 4 days posttransplant in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively) but returned to baseline levels by the Week 1 visit (mean rates of 75.7, 79.4 and 79.0 bpm, respectively) with no difference between groups.

Metabolic safety data:  The incidence of NODM AEs5 in the control group was approximately twice that of the sotrastaurin groups (14.9%, 6.7% and 7.7% in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively). The incidence of hypertension and dyslipidemia AEs was similar between the groups (hypertension: 23.0%, 20.0% and 20.0%; dyslipidemia: 2.7%, 2.7% and 0.0%, respectively).

Laboratory parameters including hematology:  Prior to conversion from tacrolimus to MPA at Month 3, the incidence of leukopenia (WBC ≤2.8 × 109/L) and neutropenia (absolute neutrophil count <1.3 × 109/L) was higher in the control compared with the sotrastaurin + SET and sotrastaurin + RET groups (leukopenia, 13.7% vs. 5.6% and 4.6%; neutropenia: 11.1% vs. 4.3% and 3.1%; Figure 5) while the incidence of leukocytosis (WBC ≥16 × 109/L) was lower in the control versus the sotrastaurin groups (6.8% vs. 25.4% and 15.4%, respectively) up to Month 3.

image

Figure 5. Incidence of leukopenia and neutropenia during the first 3 months (safety population*). RET, reduced-exposure tacrolimus; SET, standard-exposure tacrolimus; Neutropenia, absolute neutrophil count <1.3 × 109/L; leukopenia, WBC ≤2.8 × 109/L. *Numbers of patients evaluable for neutropenia: control, n = 72; sotrastaurin + SET, n = 70; sotrastaurin + RET, n = 65. Numbers of patients evaluable for leukopenia: control, n = 73; sotrastaurin + SET, n = 71; sotrastaurin + RET, n = 65.

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Over the study period the most frequent notable changes in laboratory parameters were neutropenia, leukopenia and elevated alanine aminotransferase (ALT; ≥3× Upper Limit of Normal); these all occurred more frequently in the control versus the sotrastaurin + SET and sotrastaurin + RET groups (neutropenia: 16.4% vs. 4.2% and 7.7%; leukopenia: 23.3% vs. 9.9% and 12.3%; and elevated ALT: 16.4% vs. 8.5% and 10.8%, respectively). The incidence of notable changes in laboratory parameters was otherwise comparable between groups.

Infections:  Although the overall incidence of infections and the type of infection (bacterial, viral and fungal) was comparable between groups (Table 5), infections considered to be serious occurred more frequently in the sotrastaurin + RET group compared with the sotrastaurin + SET and control groups (30.8% vs. 20.0% and 16.2%, respectively). The most common serious infection AEs were CMV and UTI; the incidence was comparable between groups (control: 4.1%; sotrastaurin + SET: 2.7%; and sotrastaurin + RET: 6.2% for each). It is important to note that 10.8%, 19.7% and 15.2% of the control, sotrastaurin + SET and sotrastaurin + RET groups did not receive the full protocol-mandated 14 weeks of CMV prophylaxis when either donor or recipient tested positive for CMV. BK virus infection occurred in 2.7%, 4.0% and 0% of patients in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively. No clear association was seen between tacrolimus and sotrastaurin trough levels and infections (data not shown).

Deaths:  One patient in the sotrastaurin + RET group died on Day 163 from a sudden, massive pulmonary embolism following five uneventful months on the study regimen: the elderly female patient experienced a fall, possibly related to long-standing hip arthrosis and died the following day. Four patients died after study-drug discontinuation: two were considered related to immunosuppressive treatment, one in the control group (cardiac arrest possibly due to a pulmonary embolism following a CMV chest infection diagnosed on Day 237. The patient died on Day 246, 3 days after study-drug discontinuation); and one in the sotrastaurin + SET group (septicemia following a Clostridium difficile infection and graft loss due to irreversible rejection. The patient died on Day 293, 28 days after study-drug discontinuation). One death in the sotrastaurin + RET group (pancreatic carcinoma on Day 251, 160 days after discontinuation) and one in the control group (GI hemorrhage on Day 47, 38 days after discontinuation) were considered unrelated to immunosuppressive treatment.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statement
  9. References

The development of new immunosuppressive drugs with novel modes of action that provide alternatives to existing drugs is a major priority in transplantation (4). Sotrastaurin is a novel immunosuppressant that blocks early T-cell activation via a calcineurin-independent pathway by selectively inhibiting PKC isoforms (12). This study showed that sotrastaurin, in combination with standard- or reduced-exposure tacrolimus and IL-2-receptor-antibody induction, had comparable efficacy to a standard-exposure tacrolimus + MPA regimen only in the first 3 months after renal transplantation. Subsequent conversion of tacrolimus to MPA in the sotrastaurin groups after Month 3 resulted in an increased incidence of acute rejection and hence inferior efficacy of both sotrastaurin + MPA regimens compared with the control group, culminating in early termination of the study.

Despite complete CNI withdrawal in the sotrastaurin groups at Month 3, there was no significant improvement in renal function over time versus control. Subclinical rejections, low patient numbers and the good renal function of the control group may have contributed to the lack of renal function benefit observed with sotrastaurin in the current study. Importantly, sotrastaurin has demonstrated no evidence of nephrotoxicity in previous clinical studies, and consistently better renal function has been observed after kidney transplantation with a sotrastaurin CNI-free immunosuppression regimen (18).

The overall pattern of AEs and infections across the three groups was similar and as expected for a de novo transplant population receiving MPA or tacrolimus. The tolerability and safety of sotrastaurin, a major objective of the study, was generally good with few patients discontinuing study drug because of AEs. Serious AEs were uncommon and tended to be associated with rejection or infections. Notably, some of the AEs reported in the sotrastaurin groups involving increased creatinine leading to discontinuation were related to rejections.

The most frequent AEs in the sotrastaurin groups were GI and were reported with a comparable incidence to the control. There was a low rate of discontinuations due to GI AEs in the sotrastaurin groups in this study indicating that the GI tolerability of sotrastaurin may be manageable without the frequent need to discontinue medication. In addition, most GI AEs in the sotrastaurin groups were mild, required limited intervention and occurred in the first 3 weeks postsurgery, a time at which patients frequently suffer from constipation or diarrhea due to surgery. Regarding cardiac findings, it is possible that the higher incidence of AE- versus ECG-reported tachycardia in this open-label study may have been influenced by increased awareness of this cardiac effect as a potential sotrastaurin side effect. Finally, the sotrastaurin + tacrolimus regimens were associated with a reduced incidence of hematologic toxicity versus control, consistent with the mechanism of action of sotrastaurin (12).

It is notable that numerically fewer patients in the sotrastaurin groups compared with the control group were eligible for conversion to a CNI free regimen at Month 3. This was primarily due to either the investigator considering that full-dose MPA or discontinuation of tacrolimus was prohibited or because of poor/unstable renal function. However, this difference between the groups was not confirmed by laboratory data, and may have been influenced by investigator anxiety in this open-label study.

Several other factors should be considered when interpreting the results of this study. Typical of early Phase II trials, the population in this study was an immunological low-risk population and not truly representative of the renal-transplant recipients who are treated in clinical practice: the majority of patients were Caucasian, the proportion with diabetes or hypertension as the cause of end-stage renal disease requiring transplantation was low and most importantly, patients with CIT ≥30 h or delayed graft function were excluded. In addition, the open-label design of this trial may have influenced some of the results (e.g. assessment of suitability for conversion at 3 months and AE reporting) of this first clinical study of sotrastaurin in renal transplantation.

In conclusion, the results of this study indicate that the use of sotrastaurin + MPA in a CNI-free regimen failed to maintain adequate efficacy for prevention of rejection in renal-transplant recipients. However, sotrastaurin warrants further investigation as a promising new drug offering potential benefits due to its distinct mechanism of action compared with CNIs. Studies are underway to determine the optimal regimen for sotrastaurin as part of multidrug immunosuppressive therapy.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statement
  9. References

This study was funded by Novartis Pharma AG. The authors would like to thank Marianne Soergel and Pieter Proot of Novartis Pharma AG for their invaluable contributions to the study, Caroline Barnett of Purple Hat Communications Ltd. for medical writing support on behalf of Novartis, and all study investigators and coordinators for their hard work in making this study possible. The authors also would like to thank the members of the CAEB071A2203 Study Group.

Funding sources: This study was funded by Novartis Pharma AG. The study was designed by the sponsor and selected investigators. The data were collected by the sponsor's monitors and by the members of the CAEB071A2203 study group. All authors had full access to the study data, reviewed and provided comments on the manuscript, and had final responsibility for the decision to submit for publication.

Conflict of Interest Statement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statement
  9. References

Klemens Budde has been a scientific advisor for Novartis Pharma AG and F Hoffmann-La Roche and has received grants/research support from Fujisawa, F Hoffmann-La Roche, Wyeth and Novartis Pharma AG; Claudia Sommerer has received grants/research support from Novartis Pharma AG and Astellas Pharma AG; Argiris Asderakis has received grants/research support from Novartis Pharma AG, F Hoffmann-La Roche, Astellas Pharma AG and Wyeth; Paolo Rigotti has been a scientific advisor for Novartis Pharma AG; Jennifer Ng is an employee of Novartis Pharma Corporation; Markus Barten was an employee of Novartis Pharma AG when this study was performed; Thomas Becker, Jacques Dantal, Josep Grinyo, Frank Pietruck and Markus Weber report no conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statement
  9. References
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