CLINICAL STUDIES

14 14.1 Prophylaxis of Organ Rejection in Renal Transplant Patients Rapamune Oral Solution The safety and efficacy of Rapamune Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials.

These studies compared two dose levels of Rapamune Oral Solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids.

Study 1 was conducted in the United States at 38 sites.

Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive Rapamune Oral Solution 2 mg/day; 274 were randomized to receive Rapamune Oral Solution 5 mg/day, and 161 to receive azathioprine 2–3 mg/kg/day.

Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites.

Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive Rapamune Oral Solution 2 mg/day; 219 were randomized to receive Rapamune Oral Solution 5 mg/day, and 130 to receive placebo.

In both studies, the use of antilymphocyte antibody induction therapy was prohibited.

In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation.

Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death.

The tables below summarize the results of the primary efficacy analyses from these trials.

Rapamune Oral Solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure (statistically significant at the < 0.025 level; nominal significance level adjusted for multiple [2] dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo.

TABLE 8: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 24 MONTHS FOR STUDY 1 Patients received cyclosporine and corticosteroids.

, Includes patients who prematurely discontinued treatment.

Parameter Rapamune Oral Solution 2 mg/day (n = 284) Rapamune Oral Solution 5 mg/day (n = 274) Azathioprine 2–3 mg/kg/day (n = 161) Efficacy failure at 6 months Primary endpoint.

18.7 16.8 32.3 Components of efficacy failure Biopsy-proven acute rejection 16.5 11.3 29.2 Graft loss 1.1 2.9 2.5 Death 0.7 1.8 0 Lost to follow-up 0.4 0.7 0.6 Efficacy failure at 24 months 32.8 25.9 36.0 Components of efficacy failure Biopsy-proven acute rejection 23.6 17.5 32.3 Graft loss 3.9 4.7 3.1 Death 4.2 3.3 0 Lost to follow-up 1.1 0.4 0.6 TABLE 9: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 36 MONTHS FOR STUDY 2 Patients received cyclosporine and corticosteroids.

, Includes patients who prematurely discontinued treatment.

Parameter Rapamune Oral Solution 2 mg/day (n = 227) Rapamune Oral Solution 5 mg/day (n = 219) Placebo (n = 130) Efficacy failure at 6 months Primary endpoint.

30.0 25.6 47.7 Components of efficacy failure Biopsy-proven acute rejection 24.7 19.2 41.5 Graft loss 3.1 3.7 3.9 Death 2.2 2.7 2.3 Lost to follow-up 0 0 0 Efficacy failure at 36 months 44.1 41.6 54.6 Components of efficacy failure Biopsy-proven acute rejection 32.2 27.4 43.9 Graft loss 6.2 7.3 4.6 Death 5.7 5.9 5.4 Lost to follow-up 0 0.9 0.8 Patient and graft survival at 1 year were co-primary endpoints.

The following table shows graft and patient survival at 1 and 2 years in Study 1, and 1 and 3 years in Study 2.

The graft and patient survival rates were similar in patients treated with Rapamune and comparator-treated patients.

TABLE 10: GRAFT AND PATIENT SURVIVAL (%) FOR STUDY 1 (12 AND 24 MONTHS) AND STUDY 2 (12 AND 36 MONTHS) Patients received cyclosporine and corticosteroids.

, Includes patients who prematurely discontinued treatment.

Parameter Rapamune Oral Solution 2 mg/day Rapamune Oral Solution 5 mg/day Azathioprine 2–3 mg/kg/day Placebo Study 1 (n = 284) (n = 274) (n = 161) Graft survival Month 12 94.7 92.7 93.8 Month 24 85.2 89.1 90.1 Patient survival Month 12 97.2 96.0 98.1 Month 24 92.6 94.9 96.3 Study 2 (n = 227) (n = 219) (n = 130) Graft survival Month 12 89.9 90.9 87.7 Month 36 81.1 79.9 80.8 Patient survival Month 12 96.5 95.0 94.6 Month 36 90.3 89.5 90.8 The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with Rapamune compared with the control groups included a reduction in all grades of rejection.

In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for Rapamune Oral Solution 2 mg/day and lower for Rapamune Oral Solution 5 mg/day compared with azathioprine in Black patients.

In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both Rapamune Oral Solution doses compared with placebo in Black patients.

The decision to use the higher dose of Rapamune Oral Solution in Black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the Rapamune Oral Solution 5-mg dose [ see Adverse Reactions (6.1) ].

TABLE 11: PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHS Patients received cyclosporine and corticosteroids.

, Includes patients who prematurely discontinued treatment.

Parameter Rapamune Oral Solution 2 mg/day Rapamune Oral Solution 5 mg/day Azathioprine 2–3 mg/kg/day Placebo Study 1 Black (n = 166) 34.9 (n = 63) 18.0 (n = 61) 33.3 (n = 42) Non-Black 14.0 (n = 221) 16.4 (n = 213) 31.9 (n = 119) (n = 553) Study 2 Black (n = 66) 30.8 (n = 26) 33.7 (n = 27) 38.5 (n = 13) Non-Black 29.9 (n = 201) 24.5 (n = 192) 48.7 (n = 117) (n = 510) Mean glomerular filtration rates (GFR) post-transplant were calculated by using the Nankivell equation at 12 and 24 months for Study 1, and 12 and 36 months for Study 2.

Mean GFR was lower in patients treated with cyclosporine and Rapamune Oral Solution compared with those treated with cyclosporine and the respective azathioprine or placebo control.

TABLE 12: OVERALL CALCULATED GLOMERULAR FILTRATION RATES (Mean ± SEM, cc/min) BY NANKIVELL EQUATION POST-TRANSPLANT Includes patients who prematurely discontinued treatment.

, Patients who had a graft loss were included in the analysis with GFR set to 0.0.

Parameter Rapamune Oral Solution 2 mg/day Rapamune Oral Solution 5 mg/day Azathioprine 2–3 mg/kg/day Placebo Study 1 Month 12 57.4 ± 1.3 (n = 269) 54.6 ± 1.3 (n = 248) 64.1 ± 1.6) (n = 149) Month 24 58.4 ± 1.5 (n = 221) 52.6 ± 1.5 (n = 222) 62.4 ± 1.9 (n = 132) Study 2 Month 12 52.4 ± 1.5 (n = 211) 51.5 ± 1.5 (n = 199) 58.0 ± 2.1 (n = 117) Month 36 48.1 ± 1.8 (n = 183) 46.1 ± 2.0 (n = 177) 53.4 ± 2.7 (n = 102) Within each treatment group in Studies 1 and 2, mean GFR at one-year post-transplant was lower in patients who experienced at least one episode of biopsy-proven acute rejection, compared with those who did not.

Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels [ see Warnings and Precautions (5.8) ].

Rapamune Tablets The safety and efficacy of Rapamune Oral Solution and Rapamune Tablets for the prevention of organ rejection following renal transplantation were demonstrated to be clinically equivalent in a randomized, multicenter, controlled trial [ see Clinical Pharmacology (12.3) ].

14.2 Cyclosporine Withdrawal Study in Renal Transplant Patients The safety and efficacy of Rapamune as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation.

Study 3 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe.

Five hundred twenty-five (525) patients were enrolled.

All patients in this study received the tablet formulation.

This study compared patients who were administered Rapamune, cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine.

During cyclosporine withdrawal, the Rapamune dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values).

At 3 months, 430 patients were equally randomized to either continue Rapamune with cyclosporine therapy or to receive Rapamune as a maintenance regimen following cyclosporine withdrawal.

Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode in the 4 weeks before random assignment, serum creatinine ≤ 4.5 mg/dL, and adequate renal function to support cyclosporine withdrawal (in the opinion of the investigator).

The primary efficacy endpoint was graft survival at 12 months after transplantation.

Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death).

The following table summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial.

At 12, 24, and 36 months, graft and patient survival were similar for both groups.

TABLE 13: GRAFT AND PATIENT SURVIVAL (%): STUDY 3 Includes patients who prematurely discontinued treatment.

Parameter Rapamune with Cyclosporine Therapy (n = 215) Rapamune Following Cyclosporine Withdrawal (n = 215) Graft Survival Month 12 Primary efficacy endpoint.

95.3 Survival including loss to follow-up as an event.

97.2 Month 24 91.6 94.0 Month 36 Initial planned duration of the study.

87.0 91.6 Patient Survival Month 12 97.2 98.1 Month 24 94.4 95.8 Month 36 91.6 94.0 The following table summarizes the results of first biopsy-proven acute rejection at 12 and 36 months.

There was a significant difference in first biopsy-proven rejection rates between the two groups after randomization and through 12 months.

Most of the post-randomization acute rejections occurred in the first 3 months following randomization.

TABLE 14: INCIDENCE OF FIRST BIOPSY-PROVEN ACUTE REJECTION (%) BY TREATMENT GROUP AT 36 MONTHS: STUDY 3 Includes patients who prematurely discontinued treatment.

, All patients received corticosteroids.

Period Rapamune with Cyclosporine Therapy (n = 215) Rapamune Following Cyclosporine Withdrawal (n = 215) Pre-randomization Randomization occurred at 3 months ± 2 weeks.

9.3 10.2 Post-randomization through 12 months 4.2 9.8 Post-randomization from 12 to 36 months 1.4 0.5 Post-randomization through 36 months 5.6 10.2 Total at 36 months 14.9 20.5 Patients receiving renal allografts with ≥ 4 HLA mismatches experienced significantly higher rates of acute rejection following randomization to the cyclosporine withdrawal group, compared with patients who continued cyclosporine (15.3% versus 3.0%).

Patients receiving renal allografts with ≤ 3 HLA mismatches demonstrated similar rates of acute rejection between treatment groups (6.8% versus 7.7%) following randomization.

The following table summarizes the mean calculated GFR in Study 3 (cyclosporine withdrawal study).

TABLE 15: CALCULATED GLOMERULAR FILTRATION RATES (mL/min) BY NANKIVELL EQUATION AT 12, 24, AND 36 MONTHS POST-TRANSPLANT: STUDY 3 Includes patients who prematurely discontinued treatment.

, Patients who had a graft loss were included in the analysis and had their GFR set to 0.0.

, All patients received corticosteroids.

Parameter Rapamune with Cyclosporine Therapy Rapamune Following Cyclosporine Withdrawal Month 12 Mean ± SEM 53.2 ± 1.5 (n = 208) 59.3 ± 1.5 (n = 203) Month 24 Mean ± SEM 48.4 ± 1.7 (n = 203) 58.4 ± 1.6 (n = 201) Month 36 Mean ± SEM 47.0 ± 1.8 (n = 196) 58.5 ± 1.9 (n = 199) The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving Rapamune as a maintenance regimen following cyclosporine withdrawal than for those in the Rapamune with cyclosporine therapy group.

Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the Rapamune with cyclosporine group.

There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization.

Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study.

The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36.

Fifty-two percent (112/215) of the patients in the Rapamune with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR.

14.3 High-Immunologic Risk Renal Transplant Patients Rapamune was studied in a one-year, clinical trial in high risk patients (Study 4) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons and/or patients with high panel-reactive antibodies (PRA; peak PRA level > 80%).

Patients received concentration-controlled sirolimus and cyclosporine (MODIFIED), and corticosteroids per local practice.

The Rapamune dose was adjusted to achieve target whole blood trough sirolimus concentrations of 10–15 ng/mL (chromatographic method) throughout the 12-month study period.

The cyclosporine dose was adjusted to achieve target whole blood trough concentrations of 200–300 ng/mL through week 2, 150–200 ng/mL from week 2 to week 26, and 100–150 ng/mL from week 26 to week 52 [ see Clinical Pharmacology (12.3) ] for the observed trough concentrations ranges.

Antibody induction was allowed per protocol as prospectively defined at each transplant center, and was used in 88.4% of patients.

The study was conducted at 35 centers in the United States.

A total of 224 patients received a transplant and at least one dose of sirolimus and cyclosporine and was comprised of 77.2% Black patients, 24.1% repeat renal transplant recipients, and 13.5% patients with high PRA.

Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function as measured by the calculated GFR using the Nankivell formula.

The table below summarizes the result of these endpoints.

TABLE 16: EFFICACY FAILURE, GRAFT LOSS OR DEATH AND CALCULATED GLOMERULAR FUNCTION RATES (mL/min) BY NANKIVELL EQUATION AT 12 MONTHS POST-TRANSPLANT: STUDY 4 Parameter Rapamune with Cyclosporine, Corticosteroids (n = 224) Efficacy Failure (%) 23.2 Graft Loss or Death (%) 9.8 Renal Function (mean ± SEM) Calculated glomerular filtration rate by Nankivell equation.

, Patients who had graft loss were included in this analysis with GFR set to 0.

52.6 ± 1.6 (n = 222) Patient survival at 12 months was 94.6%.

The incidence of biopsy-confirmed acute rejection was 17.4% and the majority of the episodes of acute rejection were mild in severity.

14.4 Conversion from Calcineurin Inhibitors to Rapamune in Maintenance Renal Transplant Patients Conversion from calcineurin inhibitors (CNI) to Rapamune was assessed in maintenance renal transplant patients 6 months to 10 years post-transplant (Study 5).

This study was a randomized, multicenter, controlled trial conducted at 111 centers globally, including US and Europe, and was intended to show that renal function was improved by conversion from CNI to Rapamune.

Eight hundred thirty (830) patients were enrolled and stratified by baseline calculated glomerular filtration rate (GFR, 20–40 mL/min versus greater than 40 mL/min).

In this trial there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the Rapamune conversion arm.

In addition, enrollment of patients with baseline calculated GFR less than 40 mL/min was discontinued due to a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death [ see Adverse Reactions (6.4) ].

This study compared renal transplant patients (6–120 months after transplantation) who were converted from calcineurin inhibitors to Rapamune, with patients who continued to receive calcineurin inhibitors.

Concomitant immunosuppressive medications included mycophenolate mofetil (MMF), azathioprine (AZA), and corticosteroids.

Rapamune was initiated with a single loading dose of 12–20 mg, after which dosing was adjusted to achieve a target sirolimus whole blood trough concentration of 8–20 ng/mL (chromatographic method).

The efficacy endpoint was calculated GFR at 12 months post-randomization.

Additional endpoints included biopsy-confirmed acute rejection, graft loss, and death.

Findings in the patient stratum with baseline calculated GFR greater than 40 mL/min (Rapamune conversion, n = 497; CNI continuation, n = 246) are summarized below: There was no clinically or statistically significant improvement in Nankivell GFR compared to baseline.

TABLE 17: RENAL FUNCTION IN STABLE RENAL TRANSPLANT PATIENTS IN PATIENTS WITH BASELINE GFR > 40 mL/min THE RAPAMUNE CONVERSION STUDY (STUDY 5) Parameter Rapamune conversion N = 496 CNI continuation N = 245 Difference (95% CI) GFR mL/min (Nankivell) at 1 year 59.0 57.7 1.3 (-1.1, 3.7) GFR mL/min (Nankivell) at 2 year 53.7 52.1 1.6 (-1.4, 4.6) The rates of acute rejection, graft loss, and death were similar at 1 and 2 years.

Treatment-emergent adverse events occurred more frequently during the first 6 months after Rapamune conversion.

The rates of pneumonia were significantly higher for the sirolimus conversion group.

While the mean and median values for urinary protein to creatinine ratio were similar between treatment groups at baseline, significantly higher mean and median levels of urinary protein excretion were seen in the Rapamune conversion arm at 1 year and at 2 years, as shown in the table below [ see Warnings and Precautions (5.9) ].

In addition, when compared to patients who continued to receive calcineurin inhibitors, a higher percentage of patients had urinary protein to creatinine ratios > 1 at 1 and 2 years after sirolimus conversion.

This difference was seen in both patients who had a urinary protein to creatinine ratio ≤ 1 and those who had a protein to creatinine ratio > 1 at baseline.

More patients in the sirolimus conversion group developed nephrotic range proteinuria, as defined by a urinary protein to creatinine ratio > 3.5 (46/482 [9.5%] versus 9/239 [3.8%]), even when the patients with baseline nephrotic range proteinuria were excluded.

The rate of nephrotic range proteinuria was significantly higher in the sirolimus conversion group compared to the calcineurin inhibitor continuation group with baseline urinary protein to creatinine ratio > 1 (13/29 versus 1/14), excluding patients with baseline nephrotic range proteinuria.

TABLE 18: MEAN AND MEDIAN VALUES FOR URINARY PROTEIN TO CREATININE RATIO (mg/mg) BETWEEN TREATMENT GROUPS AT BASELINE, 1 AND 2 YEARS IN THE STRATUM WITH BASELINE CALCULATED GFR > 40 mL/min Study period Sirolimus Conversion CNI Continuation N Mean ± SD Median N Mean ± SD Median p-value Baseline 410 0.35 ± 0.76 0.13 207 0.28 ± 0.61 0.11 0.381 1 year 423 0.88 ± 1.61 0.31 203 0.37 ± 0.88 0.14 <0.001 2 years 373 0.86 ± 1.48 0.32 190 0.47 ± 0.98 0.13 <0.001 The above information should be taken into account when considering conversion from calcineurin inhibitors to Rapamune in stable renal transplant patients due to the lack of evidence showing that renal function improves following conversion, and the finding of a greater increment in urinary protein excretion, and an increased incidence of treatment-emergent nephrotic range proteinuria following conversion to Rapamune.

This was particularly true among patients with existing abnormal urinary protein excretion prior to conversion.

14.5 Conversion from a CNI-based Regimen to a Sirolimus-based Regimen in Liver Transplant Patients Conversion from a CNI-based regimen to a Rapamune-based regimen was assessed in stable liver transplant patients 6–144 months post-transplant.

The clinical study was a 2:1 randomized, multi-center, controlled trial conducted at 82 centers globally, including the US and Europe, and was intended to show that renal function was improved by conversion from a CNI to Rapamune without adversely impacting efficacy or safety.

A total of 607 patients were enrolled.

The study failed to demonstrate superiority of conversion to a Rapamune-based regimen compared to continuation of a CNI-based regimen in baseline-adjusted GFR, as estimated by Cockcroft-Gault, at 12 months (62 mL/min in the Rapamune conversion group and 63 mL/min in the CNI continuation group).

The study also failed to demonstrate non-inferiority, with respect to the composite endpoint consisting of graft loss and death (including patients with missing survival data) in the Rapamune conversion group compared to the CNI continuation group (6.6% versus 5.6%).

The number of deaths in the Rapamune conversion group (15/393, 3.8%) was higher than in the CNI continuation group (3/214, 1.4%), although the difference was not statistically significant.

The rates of premature study discontinuation (primarily due to adverse events or lack of efficacy), adverse events overall (infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the Rapamune conversion group compared to the CNI continuation group.

14.6 Pediatric Renal Transplant Patients Rapamune was evaluated in a 36-month, open-label, randomized, controlled clinical trial at 14 North American centers in pediatric (aged 3 to < 18 years) renal transplant patients considered to be at high-immunologic risk for developing chronic allograft nephropathy, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy.

Seventy-eight (78) subjects were randomized in a 2:1 ratio to Rapamune (sirolimus target concentrations of 5 to 15 ng/mL, by chromatographic assay, n = 53) in combination with a calcineurin inhibitor and corticosteroids or to continue calcineurin-inhibitor-based immunosuppressive therapy (n = 25).

The primary endpoint of the study was efficacy failure as defined by the first occurrence of biopsy-confirmed acute rejection, graft loss, or death, and the trial was designed to show superiority of Rapamune added to a calcineurin-inhibitor-based immunosuppressive regimen compared to a calcineurin-inhibitor-based regimen.

The cumulative incidence of efficacy failure up to 36 months was 45.3% in the Rapamune group compared to 44.0% in the control group, and did not demonstrate superiority.

There was one death in each group.

The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections [ see Warnings and Precautions (5.8) ].

This study does not support the addition of Rapamune to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients.

14.7 Lymphangioleiomyomatosis Patients The safety and efficacy of Rapamune for treatment of lymphangioleiomyomatosis (LAM) were assessed in a randomized, double-blind, multicenter, controlled trial.

This study compared Rapamune (dose-adjusted to maintain blood trough concentrations between 5–15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation period.

Eighty-nine (89) patients were enrolled; 43 patients were randomized to receive placebo and 46 patients to receive Rapamune.

The primary endpoint was the difference between the groups in the rate of change (slope) per month in forced expiratory volume in 1 second (FEV1).

During the treatment period, the FEV1 slope was -12±2 mL per month in the placebo group and 1±2 mL per month in the Rapamune group (treatment difference = 13 mL (95% CI: 7, 18).

The absolute between-group difference in the mean change in FEV1 during the 12-month treatment period was 153 mL, or approximately 11% of the mean FEV1 at enrollment.

Similar improvements were seen for forced vital capacity (FVC).

After discontinuation of Rapamune, the decline in lung function resumed in the Rapamune group and paralleled that in the placebo group (see Figure 1 ).

FIGURE 1: CHANGE IN FORCED EXPIRATORY VOLUME IN 1 SECOND (FEV1) DURING THE TREATMENT AND OBSERVATION PHASES OF THE STUDY IN LAM PATIENTS The rate of change over 12 months of vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor which has been shown to be elevated in patients with LAM, was significantly different in the Rapamune-treated group (-88.0 ± 16.6 pg/mL/month) compared to placebo (-2.42 ± 17.2 pg/mL/month) with a treatment difference of -86 pg/mL/month (95% CI: -133, -39).

The absolute between-group difference in the mean change in VEGF-D during the 12-month treatment period was -1017.2, or approximately 50% of the mean VEGF-D at enrollment.

Figure 1

CLINICAL STUDIES

14 14.1 Prophylaxis of Organ Rejection in Renal Transplant Patients Rapamune Oral Solution The safety and efficacy of Rapamune Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials.

These studies compared two dose levels of Rapamune Oral Solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids.

Study 1 was conducted in the United States at 38 sites.

Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive Rapamune Oral Solution 2 mg/day; 274 were randomized to receive Rapamune Oral Solution 5 mg/day, and 161 to receive azathioprine 2–3 mg/kg/day.

Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites.

Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive Rapamune Oral Solution 2 mg/day; 219 were randomized to receive Rapamune Oral Solution 5 mg/day, and 130 to receive placebo.

In both studies, the use of antilymphocyte antibody induction therapy was prohibited.

In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation.

Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death.

The tables below summarize the results of the primary efficacy analyses from these trials.

Rapamune Oral Solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure (statistically significant at the < 0.025 level; nominal significance level adjusted for multiple [2] dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo.

TABLE 8: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 24 MONTHS FOR STUDY 1 Patients received cyclosporine and corticosteroids.

, Includes patients who prematurely discontinued treatment.

Parameter Rapamune Oral Solution 2 mg/day (n = 284) Rapamune Oral Solution 5 mg/day (n = 274) Azathioprine 2–3 mg/kg/day (n = 161) Efficacy failure at 6 months Primary endpoint.

18.7 16.8 32.3 Components of efficacy failure Biopsy-proven acute rejection 16.5 11.3 29.2 Graft loss 1.1 2.9 2.5 Death 0.7 1.8 0 Lost to follow-up 0.4 0.7 0.6 Efficacy failure at 24 months 32.8 25.9 36.0 Components of efficacy failure Biopsy-proven acute rejection 23.6 17.5 32.3 Graft loss 3.9 4.7 3.1 Death 4.2 3.3 0 Lost to follow-up 1.1 0.4 0.6 TABLE 9: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 36 MONTHS FOR STUDY 2 Patients received cyclosporine and corticosteroids.

, Includes patients who prematurely discontinued treatment.

Parameter Rapamune Oral Solution 2 mg/day (n = 227) Rapamune Oral Solution 5 mg/day (n = 219) Placebo (n = 130) Efficacy failure at 6 months Primary endpoint.

30.0 25.6 47.7 Components of efficacy failure Biopsy-proven acute rejection 24.7 19.2 41.5 Graft loss 3.1 3.7 3.9 Death 2.2 2.7 2.3 Lost to follow-up 0 0 0 Efficacy failure at 36 months 44.1 41.6 54.6 Components of efficacy failure Biopsy-proven acute rejection 32.2 27.4 43.9 Graft loss 6.2 7.3 4.6 Death 5.7 5.9 5.4 Lost to follow-up 0 0.9 0.8 Patient and graft survival at 1 year were co-primary endpoints.

The following table shows graft and patient survival at 1 and 2 years in Study 1, and 1 and 3 years in Study 2.

The graft and patient survival rates were similar in patients treated with Rapamune and comparator-treated patients.

TABLE 10: GRAFT AND PATIENT SURVIVAL (%) FOR STUDY 1 (12 AND 24 MONTHS) AND STUDY 2 (12 AND 36 MONTHS) Patients received cyclosporine and corticosteroids.

, Includes patients who prematurely discontinued treatment.

Parameter Rapamune Oral Solution 2 mg/day Rapamune Oral Solution 5 mg/day Azathioprine 2–3 mg/kg/day Placebo Study 1 (n = 284) (n = 274) (n = 161) Graft survival Month 12 94.7 92.7 93.8 Month 24 85.2 89.1 90.1 Patient survival Month 12 97.2 96.0 98.1 Month 24 92.6 94.9 96.3 Study 2 (n = 227) (n = 219) (n = 130) Graft survival Month 12 89.9 90.9 87.7 Month 36 81.1 79.9 80.8 Patient survival Month 12 96.5 95.0 94.6 Month 36 90.3 89.5 90.8 The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with Rapamune compared with the control groups included a reduction in all grades of rejection.

In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for Rapamune Oral Solution 2 mg/day and lower for Rapamune Oral Solution 5 mg/day compared with azathioprine in Black patients.

In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both Rapamune Oral Solution doses compared with placebo in Black patients.

The decision to use the higher dose of Rapamune Oral Solution in Black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the Rapamune Oral Solution 5-mg dose [ see Adverse Reactions (6.1) ].

TABLE 11: PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHS Patients received cyclosporine and corticosteroids.

, Includes patients who prematurely discontinued treatment.

Parameter Rapamune Oral Solution 2 mg/day Rapamune Oral Solution 5 mg/day Azathioprine 2–3 mg/kg/day Placebo Study 1 Black (n = 166) 34.9 (n = 63) 18.0 (n = 61) 33.3 (n = 42) Non-Black 14.0 (n = 221) 16.4 (n = 213) 31.9 (n = 119) (n = 553) Study 2 Black (n = 66) 30.8 (n = 26) 33.7 (n = 27) 38.5 (n = 13) Non-Black 29.9 (n = 201) 24.5 (n = 192) 48.7 (n = 117) (n = 510) Mean glomerular filtration rates (GFR) post-transplant were calculated by using the Nankivell equation at 12 and 24 months for Study 1, and 12 and 36 months for Study 2.

Mean GFR was lower in patients treated with cyclosporine and Rapamune Oral Solution compared with those treated with cyclosporine and the respective azathioprine or placebo control.

TABLE 12: OVERALL CALCULATED GLOMERULAR FILTRATION RATES (Mean ± SEM, cc/min) BY NANKIVELL EQUATION POST-TRANSPLANT Includes patients who prematurely discontinued treatment.

, Patients who had a graft loss were included in the analysis with GFR set to 0.0.

Parameter Rapamune Oral Solution 2 mg/day Rapamune Oral Solution 5 mg/day Azathioprine 2–3 mg/kg/day Placebo Study 1 Month 12 57.4 ± 1.3 (n = 269) 54.6 ± 1.3 (n = 248) 64.1 ± 1.6) (n = 149) Month 24 58.4 ± 1.5 (n = 221) 52.6 ± 1.5 (n = 222) 62.4 ± 1.9 (n = 132) Study 2 Month 12 52.4 ± 1.5 (n = 211) 51.5 ± 1.5 (n = 199) 58.0 ± 2.1 (n = 117) Month 36 48.1 ± 1.8 (n = 183) 46.1 ± 2.0 (n = 177) 53.4 ± 2.7 (n = 102) Within each treatment group in Studies 1 and 2, mean GFR at one-year post-transplant was lower in patients who experienced at least one episode of biopsy-proven acute rejection, compared with those who did not.

Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels [ see Warnings and Precautions (5.8) ].

Rapamune Tablets The safety and efficacy of Rapamune Oral Solution and Rapamune Tablets for the prevention of organ rejection following renal transplantation were demonstrated to be clinically equivalent in a randomized, multicenter, controlled trial [ see Clinical Pharmacology (12.3) ].

14.2 Cyclosporine Withdrawal Study in Renal Transplant Patients The safety and efficacy of Rapamune as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation.

Study 3 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe.

Five hundred twenty-five (525) patients were enrolled.

All patients in this study received the tablet formulation.

This study compared patients who were administered Rapamune, cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine.

During cyclosporine withdrawal, the Rapamune dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values).

At 3 months, 430 patients were equally randomized to either continue Rapamune with cyclosporine therapy or to receive Rapamune as a maintenance regimen following cyclosporine withdrawal.

Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode in the 4 weeks before random assignment, serum creatinine ≤ 4.5 mg/dL, and adequate renal function to support cyclosporine withdrawal (in the opinion of the investigator).

The primary efficacy endpoint was graft survival at 12 months after transplantation.

Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death).

The following table summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial.

At 12, 24, and 36 months, graft and patient survival were similar for both groups.

TABLE 13: GRAFT AND PATIENT SURVIVAL (%): STUDY 3 Includes patients who prematurely discontinued treatment.

Parameter Rapamune with Cyclosporine Therapy (n = 215) Rapamune Following Cyclosporine Withdrawal (n = 215) Graft Survival Month 12 Primary efficacy endpoint.

95.3 Survival including loss to follow-up as an event.

97.2 Month 24 91.6 94.0 Month 36 Initial planned duration of the study.

87.0 91.6 Patient Survival Month 12 97.2 98.1 Month 24 94.4 95.8 Month 36 91.6 94.0 The following table summarizes the results of first biopsy-proven acute rejection at 12 and 36 months.

There was a significant difference in first biopsy-proven rejection rates between the two groups after randomization and through 12 months.

Most of the post-randomization acute rejections occurred in the first 3 months following randomization.

TABLE 14: INCIDENCE OF FIRST BIOPSY-PROVEN ACUTE REJECTION (%) BY TREATMENT GROUP AT 36 MONTHS: STUDY 3 Includes patients who prematurely discontinued treatment.

, All patients received corticosteroids.

Period Rapamune with Cyclosporine Therapy (n = 215) Rapamune Following Cyclosporine Withdrawal (n = 215) Pre-randomization Randomization occurred at 3 months ± 2 weeks.

9.3 10.2 Post-randomization through 12 months 4.2 9.8 Post-randomization from 12 to 36 months 1.4 0.5 Post-randomization through 36 months 5.6 10.2 Total at 36 months 14.9 20.5 Patients receiving renal allografts with ≥ 4 HLA mismatches experienced significantly higher rates of acute rejection following randomization to the cyclosporine withdrawal group, compared with patients who continued cyclosporine (15.3% versus 3.0%).

Patients receiving renal allografts with ≤ 3 HLA mismatches demonstrated similar rates of acute rejection between treatment groups (6.8% versus 7.7%) following randomization.

The following table summarizes the mean calculated GFR in Study 3 (cyclosporine withdrawal study).

TABLE 15: CALCULATED GLOMERULAR FILTRATION RATES (mL/min) BY NANKIVELL EQUATION AT 12, 24, AND 36 MONTHS POST-TRANSPLANT: STUDY 3 Includes patients who prematurely discontinued treatment.

, Patients who had a graft loss were included in the analysis and had their GFR set to 0.0.

, All patients received corticosteroids.

Parameter Rapamune with Cyclosporine Therapy Rapamune Following Cyclosporine Withdrawal Month 12 Mean ± SEM 53.2 ± 1.5 (n = 208) 59.3 ± 1.5 (n = 203) Month 24 Mean ± SEM 48.4 ± 1.7 (n = 203) 58.4 ± 1.6 (n = 201) Month 36 Mean ± SEM 47.0 ± 1.8 (n = 196) 58.5 ± 1.9 (n = 199) The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving Rapamune as a maintenance regimen following cyclosporine withdrawal than for those in the Rapamune with cyclosporine therapy group.

Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the Rapamune with cyclosporine group.

There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization.

Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study.

The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36.

Fifty-two percent (112/215) of the patients in the Rapamune with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR.

14.3 High-Immunologic Risk Renal Transplant Patients Rapamune was studied in a one-year, clinical trial in high risk patients (Study 4) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons and/or patients with high panel-reactive antibodies (PRA; peak PRA level > 80%).

Patients received concentration-controlled sirolimus and cyclosporine (MODIFIED), and corticosteroids per local practice.

The Rapamune dose was adjusted to achieve target whole blood trough sirolimus concentrations of 10–15 ng/mL (chromatographic method) throughout the 12-month study period.

The cyclosporine dose was adjusted to achieve target whole blood trough concentrations of 200–300 ng/mL through week 2, 150–200 ng/mL from week 2 to week 26, and 100–150 ng/mL from week 26 to week 52 [ see Clinical Pharmacology (12.3) ] for the observed trough concentrations ranges.

Antibody induction was allowed per protocol as prospectively defined at each transplant center, and was used in 88.4% of patients.

The study was conducted at 35 centers in the United States.

A total of 224 patients received a transplant and at least one dose of sirolimus and cyclosporine and was comprised of 77.2% Black patients, 24.1% repeat renal transplant recipients, and 13.5% patients with high PRA.

Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function as measured by the calculated GFR using the Nankivell formula.

The table below summarizes the result of these endpoints.

TABLE 16: EFFICACY FAILURE, GRAFT LOSS OR DEATH AND CALCULATED GLOMERULAR FUNCTION RATES (mL/min) BY NANKIVELL EQUATION AT 12 MONTHS POST-TRANSPLANT: STUDY 4 Parameter Rapamune with Cyclosporine, Corticosteroids (n = 224) Efficacy Failure (%) 23.2 Graft Loss or Death (%) 9.8 Renal Function (mean ± SEM) Calculated glomerular filtration rate by Nankivell equation.

, Patients who had graft loss were included in this analysis with GFR set to 0.

52.6 ± 1.6 (n = 222) Patient survival at 12 months was 94.6%.

The incidence of biopsy-confirmed acute rejection was 17.4% and the majority of the episodes of acute rejection were mild in severity.

14.4 Conversion from Calcineurin Inhibitors to Rapamune in Maintenance Renal Transplant Patients Conversion from calcineurin inhibitors (CNI) to Rapamune was assessed in maintenance renal transplant patients 6 months to 10 years post-transplant (Study 5).

This study was a randomized, multicenter, controlled trial conducted at 111 centers globally, including US and Europe, and was intended to show that renal function was improved by conversion from CNI to Rapamune.

Eight hundred thirty (830) patients were enrolled and stratified by baseline calculated glomerular filtration rate (GFR, 20–40 mL/min versus greater than 40 mL/min).

In this trial there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the Rapamune conversion arm.

In addition, enrollment of patients with baseline calculated GFR less than 40 mL/min was discontinued due to a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death [ see Adverse Reactions (6.4) ].

This study compared renal transplant patients (6–120 months after transplantation) who were converted from calcineurin inhibitors to Rapamune, with patients who continued to receive calcineurin inhibitors.

Concomitant immunosuppressive medications included mycophenolate mofetil (MMF), azathioprine (AZA), and corticosteroids.

Rapamune was initiated with a single loading dose of 12–20 mg, after which dosing was adjusted to achieve a target sirolimus whole blood trough concentration of 8–20 ng/mL (chromatographic method).

The efficacy endpoint was calculated GFR at 12 months post-randomization.

Additional endpoints included biopsy-confirmed acute rejection, graft loss, and death.

Findings in the patient stratum with baseline calculated GFR greater than 40 mL/min (Rapamune conversion, n = 497; CNI continuation, n = 246) are summarized below: There was no clinically or statistically significant improvement in Nankivell GFR compared to baseline.

TABLE 17: RENAL FUNCTION IN STABLE RENAL TRANSPLANT PATIENTS IN PATIENTS WITH BASELINE GFR > 40 mL/min THE RAPAMUNE CONVERSION STUDY (STUDY 5) Parameter Rapamune conversion N = 496 CNI continuation N = 245 Difference (95% CI) GFR mL/min (Nankivell) at 1 year 59.0 57.7 1.3 (-1.1, 3.7) GFR mL/min (Nankivell) at 2 year 53.7 52.1 1.6 (-1.4, 4.6) The rates of acute rejection, graft loss, and death were similar at 1 and 2 years.

Treatment-emergent adverse events occurred more frequently during the first 6 months after Rapamune conversion.

The rates of pneumonia were significantly higher for the sirolimus conversion group.

While the mean and median values for urinary protein to creatinine ratio were similar between treatment groups at baseline, significantly higher mean and median levels of urinary protein excretion were seen in the Rapamune conversion arm at 1 year and at 2 years, as shown in the table below [ see Warnings and Precautions (5.9) ].

In addition, when compared to patients who continued to receive calcineurin inhibitors, a higher percentage of patients had urinary protein to creatinine ratios > 1 at 1 and 2 years after sirolimus conversion.

This difference was seen in both patients who had a urinary protein to creatinine ratio ≤ 1 and those who had a protein to creatinine ratio > 1 at baseline.

More patients in the sirolimus conversion group developed nephrotic range proteinuria, as defined by a urinary protein to creatinine ratio > 3.5 (46/482 [9.5%] versus 9/239 [3.8%]), even when the patients with baseline nephrotic range proteinuria were excluded.

The rate of nephrotic range proteinuria was significantly higher in the sirolimus conversion group compared to the calcineurin inhibitor continuation group with baseline urinary protein to creatinine ratio > 1 (13/29 versus 1/14), excluding patients with baseline nephrotic range proteinuria.

TABLE 18: MEAN AND MEDIAN VALUES FOR URINARY PROTEIN TO CREATININE RATIO (mg/mg) BETWEEN TREATMENT GROUPS AT BASELINE, 1 AND 2 YEARS IN THE STRATUM WITH BASELINE CALCULATED GFR > 40 mL/min Study period Sirolimus Conversion CNI Continuation N Mean ± SD Median N Mean ± SD Median p-value Baseline 410 0.35 ± 0.76 0.13 207 0.28 ± 0.61 0.11 0.381 1 year 423 0.88 ± 1.61 0.31 203 0.37 ± 0.88 0.14 <0.001 2 years 373 0.86 ± 1.48 0.32 190 0.47 ± 0.98 0.13 <0.001 The above information should be taken into account when considering conversion from calcineurin inhibitors to Rapamune in stable renal transplant patients due to the lack of evidence showing that renal function improves following conversion, and the finding of a greater increment in urinary protein excretion, and an increased incidence of treatment-emergent nephrotic range proteinuria following conversion to Rapamune.

This was particularly true among patients with existing abnormal urinary protein excretion prior to conversion.

14.5 Conversion from a CNI-based Regimen to a Sirolimus-based Regimen in Liver Transplant Patients Conversion from a CNI-based regimen to a Rapamune-based regimen was assessed in stable liver transplant patients 6–144 months post-transplant.

The clinical study was a 2:1 randomized, multi-center, controlled trial conducted at 82 centers globally, including the US and Europe, and was intended to show that renal function was improved by conversion from a CNI to Rapamune without adversely impacting efficacy or safety.

A total of 607 patients were enrolled.

The study failed to demonstrate superiority of conversion to a Rapamune-based regimen compared to continuation of a CNI-based regimen in baseline-adjusted GFR, as estimated by Cockcroft-Gault, at 12 months (62 mL/min in the Rapamune conversion group and 63 mL/min in the CNI continuation group).

The study also failed to demonstrate non-inferiority, with respect to the composite endpoint consisting of graft loss and death (including patients with missing survival data) in the Rapamune conversion group compared to the CNI continuation group (6.6% versus 5.6%).

The number of deaths in the Rapamune conversion group (15/393, 3.8%) was higher than in the CNI continuation group (3/214, 1.4%), although the difference was not statistically significant.

The rates of premature study discontinuation (primarily due to adverse events or lack of efficacy), adverse events overall (infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the Rapamune conversion group compared to the CNI continuation group.

14.6 Pediatric Renal Transplant Patients Rapamune was evaluated in a 36-month, open-label, randomized, controlled clinical trial at 14 North American centers in pediatric (aged 3 to < 18 years) renal transplant patients considered to be at high-immunologic risk for developing chronic allograft nephropathy, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy.

Seventy-eight (78) subjects were randomized in a 2:1 ratio to Rapamune (sirolimus target concentrations of 5 to 15 ng/mL, by chromatographic assay, n = 53) in combination with a calcineurin inhibitor and corticosteroids or to continue calcineurin-inhibitor-based immunosuppressive therapy (n = 25).

The primary endpoint of the study was efficacy failure as defined by the first occurrence of biopsy-confirmed acute rejection, graft loss, or death, and the trial was designed to show superiority of Rapamune added to a calcineurin-inhibitor-based immunosuppressive regimen compared to a calcineurin-inhibitor-based regimen.

The cumulative incidence of efficacy failure up to 36 months was 45.3% in the Rapamune group compared to 44.0% in the control group, and did not demonstrate superiority.

There was one death in each group.

The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections [ see Warnings and Precautions (5.8) ].

This study does not support the addition of Rapamune to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients.

14.7 Lymphangioleiomyomatosis Patients The safety and efficacy of Rapamune for treatment of lymphangioleiomyomatosis (LAM) were assessed in a randomized, double-blind, multicenter, controlled trial.

This study compared Rapamune (dose-adjusted to maintain blood trough concentrations between 5–15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation period.

Eighty-nine (89) patients were enrolled; 43 patients were randomized to receive placebo and 46 patients to receive Rapamune.

The primary endpoint was the difference between the groups in the rate of change (slope) per month in forced expiratory volume in 1 second (FEV1).

During the treatment period, the FEV1 slope was -12±2 mL per month in the placebo group and 1±2 mL per month in the Rapamune group (treatment difference = 13 mL (95% CI: 7, 18).

The absolute between-group difference in the mean change in FEV1 during the 12-month treatment period was 153 mL, or approximately 11% of the mean FEV1 at enrollment.

Similar improvements were seen for forced vital capacity (FVC).

After discontinuation of Rapamune, the decline in lung function resumed in the Rapamune group and paralleled that in the placebo group (see Figure 1 ).

FIGURE 1: CHANGE IN FORCED EXPIRATORY VOLUME IN 1 SECOND (FEV1) DURING THE TREATMENT AND OBSERVATION PHASES OF THE STUDY IN LAM PATIENTS The rate of change over 12 months of vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor which has been shown to be elevated in patients with LAM, was significantly different in the Rapamune-treated group (-88.0 ± 16.6 pg/mL/month) compared to placebo (-2.42 ± 17.2 pg/mL/month) with a treatment difference of -86 pg/mL/month (95% CI: -133, -39).

The absolute between-group difference in the mean change in VEGF-D during the 12-month treatment period was -1017.2, or approximately 50% of the mean VEGF-D at enrollment.

Figure 1

CLINICAL STUDIES

14 14.1 Osteoarthritis and Rheumatoid Arthritis The use of meloxicam for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a 12-week, double-blind, controlled trial.

meloxicam (3.75 mg, 7.5 mg, and 15 mg daily) was compared to placebo.

The four primary endpoints were investigator’s global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function, and stiffness).

Patients on meloxicam 7.5 mg daily and meloxicam 15 mg daily showed significant improvement in each of these endpoints compared with placebo.

The use of meloxicam for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S.

ranging from 4 weeks’ to 6 months’ duration.

In these trials, the efficacy of meloxicam, in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S.

trial.

The use of meloxicam for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a 12-week, double-blind, controlled multinational trial.

meloxicam (7.5 mg, 15 mg, and 22.5 mg daily) was compared to placebo.

The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory, and functional measures of RA response.

Patients receiving meloxicam 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo.

No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose.