Author: druginteractionchecker_lgaiz4

CLINICAL STUDIES

14 14.1 Combination Adjuvant Therapy with Oxaliplatin and Infusional 5-fluorouracil/leucovorin in Patients with Colon Cancer An international, multicenter, randomized study compared the efficacy and evaluated the safety of oxaliplatin in combination with an infusional schedule of 5-fluorouracil/leucovorin to infusional 5-fluorouracil/leucovorin alone, in patients with stage II (Dukes’ B2) or III (Dukes’ C) colon cancer who had undergone complete resection of the primary tumor.

The primary objective of the study was to compare the 3-year disease-free survival (DFS) in patients receiving oxaliplatin and infusional 5-fluorouracil/leucovorin to those receiving 5-fluorouracil/leucovorin alone.

Patients were to be treated for a total of 6 months (i.e., 12 cycles).

A total of 2246 patients were randomized; 1123 patients per study arm.

Patients in the study had to be between 18 and 75 years of age, have histologically proven stage II (T 3 to T 4 N0 M0; Dukes’ B2) or III (any T N 1-2 M0; Dukes’ C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., ≥ 15 cm from the anal margin) and undergone (within 7 weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease.

Patients had to have had no prior chemotherapy, immunotherapy or radiotherapy, and have an ECOG performance status of 0, 1, or 2 (KPS ≥ 60%), absolute neutrophil count (ANC) > 1.5 × 10 9 /L, platelets ≥ 100 × 10 9 /L, serum creatinine ≤ 1.25 × ULN total bilirubin < 2 × ULN, AST/ALT < 2 × ULN and carcino-embyrogenic antigen (CEA) < 10 ng/mL.

Patients with preexisting peripheral neuropathy (NCI grade ≥ 1) were ineligible for this trial.

The following table shows the dosing regimens for the two arms of the study.

Table 15 – Dosing Regimens in Adjuvant Therapy Study Treatment Arm Dose Regimen Oxaliplatin + 5-FU/LV (FOLFOX4) (N = 1123) Day 1: Oxaliplatin: 85 mg/m 2 (2-hour infusion) + LV: 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV: 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks 12 cycles 5-FU/LV (N = 1123) Day 1: LV: 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV: 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks 12 cycles The following tables show the baseline characteristics and dosing of the patient population entered into this study.

The baseline characteristics were well balanced between arms.

Table 16 – Patient Characteristics in Adjuvant Therapy Study Oxaliplatin + infusional 5-FU/LV N = 1123 Infusional 5-FU/LV N = 1123 Sex: Male (%) 56.1 52.4 Female (%) 43.9 47.6 Median age (years) 61 60 < 65 years of age (%) 64.4 66.2 ≥ 65 years of age (%) 35.6 33.8 Karnofsky Performance Status (KPS) (%) 100 29.7 30.5 90 52.2 53.9 80 4.4 3.3 70 13.2 11.9 ≤ 60 0.6 0.4 Primary site (%) Colon including cecum 54.6 54.4 Sigmoid 31.9 33.8 Recto sigmoid 12.9 10.9 Other including rectum 0.6 0.9 Bowel obstruction (%) Yes 17.9 19.3 Perforation (%) Yes 6.9 6.9 Stage at Randomization (%) II (T = 3,4 N = 0, M = 0) 40.1 39.9 III (T = any, N = 1,2, M = 0) 59.6 59.3 IV (T = any, N = any, M = 1) 0.4 0.8 Staging – T (%) T1 0.5 0.7 T2 4.5 4.8 T3 76 75.9 T4 19 18.5 Staging – N (%) N0 40.2 39.9 N1 39.4 39.4 N2 20.4 20.7 Staging – M (%) M1 0.4 0.8 Table 17 – Dosing in Adjuvant Therapy Study Oxaliplatin + infusional 5-FU/LV N = 1108 Infusional 5-FU/LV N = 1111 Median Relative Dose Intensity (%) 5-FU 84.4 97.7 Oxaliplatin 80.5 N/A Median Number of Cycles 12 12 Median Number of cycles With Oxaliplatin 11 N/A The following table and figures summarize the disease-free survival (DFS) results in the overall randomized population and in patients with stage II and III disease based on an ITT analysis.

The median duration of follow-up was approximately 77 months.

Table 18 – Summary of DFS analysis – ITT analysis Oxaliplatin + Infusional 5-FU/LV Infusional 5-FU/LV Parameter Overall N 1123 1123 Number of events – relapse or death (%) 304 (27.1) 360 (32.1) Disease-free survival % [95% CI] * 73.3 [70.7, 76] 67.4 [64.6, 70.2] Hazard ratio [95% CI] ** 0.80 [0.68, 0.93] Stratified Logrank test p = 0.003 Stage III (Dukes’ C) N 672 675 Number of events – relapse or death (%) 226 (33.6) 271 (40.1) Disease-free survival % [95% CI] * 66.4 [62.7, 70] 58.9 [55.2, 62.7] Hazard ratio [95% CI] ** 0.78 [0.65, 0.93] Logrank test p = 0.005 Stage II (Dukes’ B2) N 451 448 Number of events – relapse or death (%) 78 (17.3) 89 (19.9) Disease-free survival % [95% CI] * 83.7 [80.2, 87.1] 79.9 [76.2, 83.7] Hazard ratio [95% CI] ** 0.84 [0.62, 1.14] Logrank test p = 0.258 Data cut off for disease free survival 1 June 2006 *Disease-free survival at 5 years **A hazard ratio of less than 1 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin In the overall and stage III colon cancer populations DFS was statistically significantly improved in the oxaliplatin combination arm compared to infusional 5-fluorouracil/leucovorin alone.

However, a statistically significant improvement in DFS was not noted in Stage II patients.

Figure 2 shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone for the overall population (ITT analysis).

Figure 3 shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone in Stage III patients.

Figure 2 – DFS Kaplan-Meier curves by treatment arm (cutoff: 1 June 2006) – ITT population Figure 2 – DFS Kaplan-Meier curves by treatment arm (cutoff: 1 June 2006) – ITT population Figure 3 – DFS Kaplan-Meier curves by treatment arm in Stage III patients (cutoff: 1 June 2006) – ITT population The following table summarizes the overall survival (OS) results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.

Table 19 – Summary of OS analysis – ITT analysis Parameter Oxaliplatin + Infusional 5-FU/LV Infusional 5-FU/LV Overall N 1123 1123 Number of death events (%) 245 (21.8) 283 (25.2) Hazard ratio* [95% CI] 0.84 [0.71, 1] Stage III (Dukes’ C) N 672 675 Number of death events (%) 182 (27.1) 220 (32.6) Hazard ratio* [95% CI] 0.80 [0.65, 0.97] Stage II (Dukes’ B2) N 451 448 Number of death events (%) 63 (14) 63 (14.1) Hazard ratio* [95% CI] 1 [0.70, 1.41] Data cut off for overall survival 16 January 2007 *A hazard ratio of less than 1 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin Figure 2 Figure 3 14.2 Combination Therapy with Oxaliplatin and 5-fluorouracil/leucovorin in Patients Previously Untreated for Advanced Colorectal Cancer A North American, multicenter, open-label, randomized controlled study was sponsored by the National Cancer Institute (NCI) as an intergroup study led by the North Central Cancer Treatment Group (NCCTG).

The study had 7 arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity, or simplification.

During the study, the control arm was changed to irinotecan plus 5-fluorouracil/leucovorin.

The results reported below compared the efficacy and safety of two experimental regimens, oxaliplatin in combination with infusional 5-fluorouracil/leucovorin and a combination of oxaliplatin plus irinotecan, to an approved control regimen of irinotecan plus 5-fluorouracil/leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer.

After completion of enrollment, the dose of irinotecan plus 5-fluorouracil/leucovorin was decreased due to toxicity.

Patients had to be at least 18 years of age, have known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent, histologically proven colorectal adenocarcinoma, measurable or evaluable disease, with an ECOG performance status 0, 1, or 2.

Patients had to have granulocyte count ≥ 1.5 × 10 9 /L, platelets ≥ 100 × 10 9 /L, hemoglobin ≥ 9 gm/dL, creatinine ≤ 1.5 × ULN, total bilirubin ≤ 1.5 mg/dL, AST ≤ 5 × ULN, and alkaline phosphatase ≤ 5 × ULN.

Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months.

The patients were stratified for ECOG performance status (0, 1 vs.

2), prior adjuvant chemotherapy (yes vs.

no), prior immunotherapy (yes vs.

no), and age (< 65 vs.

≥ 65 years).

Although no post study treatment was specified in the protocol, 65% to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms.

Fifty-eight percent of patients on the oxaliplatin plus 5-fluorouracil/leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus 5-fluorouracil/leucovorin arm received oxaliplatin-containing regimens.

Oxaliplatin was not commercially available during the trial.

The following table presents the dosing regimens of the three arms of the study.

Table 20 – Dosing Regimens in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial Treatment Arm Dose Regimen Oxaliplatin + 5-FU/LV (FOLFOX4) (N = 267) Day 1: Oxaliplatin: 85 mg/m 2 (2-hour infusion) + LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks Irinotecan + 5-FU/LV (IFL) (N = 264) Day 1: irinotecan 125 mg/m 2 as a 90-min infusion + LV 20 mg/m 2 as a 15 minute infusion or intravenous push, followed by 5-FU 500 mg/m 2 intravenous bolus weekly × 4 every 6 weeks Oxaliplatin + Irinotecan (IROX) (N = 264) Day 1: Oxaliplatin: 85 mg/m 2 intravenous (2- hour infusion) + irinotecan 200 mg/m 2 intravenous over 30 minutes every 3 weeks The following table presents the demographics of the patient population entered into this study.

Table 21 – Patient Demographics in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial Oxaliplatin + 5-FU/LV N = 267 Irinotecan + 5-FU/LV N = 264 Oxaliplatin + irinotecan N = 264 Sex: Male (%) 58.8 65.2 61 Female (%) 41.2 34.8 39 Median age (years) 61 61 61 < 65 years of age (%) 61 62 63 ≥ 65 years of age (%) 39 38 37 ECOG (%) 0 to 1 94.4 95.5 94.7 2 5.6 4.5 5.3 Involved organs (%) Colon only 0.7 0.8 0.4 Liver only 39.3 44.3 39 Liver + other 41.2 38.6 40.9 Lung only 6.4 3.8 5.3 Other (including lymph nodes) 11.6 11 12.9 Not reported 0.7 1.5 1.5 Prior radiation (%) 3 1.5 3 Prior surgery (%) 74.5 79.2 81.8 Prior adjuvant (%) 15.7 14.8 15.2 The length of a treatment cycle was 2 weeks for the oxaliplatin and 5-fluorouracil/leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/leucovorin regimen; and 3 weeks for the oxaliplatin plus irinotecan regimen.

The median number of cycles administered per patient was 10 (23.9 weeks) for the oxaliplatin and 5-fluorouracil/leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus 5-fluorouracil/leucovorin regimen, and 7 (21 weeks) for the oxaliplatin plus irinotecan regimen.

Patients treated with the oxaliplatin and 5-fluorouracil/leucovorin combination had a significantly longer time to tumor progression based on investigator assessment, longer overall survival, and a significantly higher confirmed response rate based on investigator assessment compared to patients given irinotecan plus 5-fluorouracil/leucovorin.

The following table summarizes the efficacy results.

Table 22 – Summary of Efficacy Oxaliplatin + 5-FU/LV N = 267 irinotecan + 5-FU/LV N = 264 Oxaliplatin + irinotecan N = 264 Survival (ITT) Number of deaths N (%) 155 (58.1) 192 (72.7) 175 (66.3) Median survival (months) 19.4 14.6 17.6 Hazard Ratio and (95% confidence interval) 0.65 (0.53 to 0.80)* P-value < 0.0001* – – TTP (ITT, investigator assessment) Percentage of progressors 82.8 81.8 89.4 Median TTP (months) 8.7 6.9 6.5 Hazard Ratio and (95% confidence interval) *** 0.74 (0.61 to 0.89)* P-value 0.0014* – – Response Rate (investigator assessment)** Patients with measurable disease 210 212 215 Complete response N (%) 13 (6.2) 5 (2.4) 7 (3.3) Partial response N (%) 82 (39) 64 (30.2) 67 (31.2) Complete and partial response N (%) 95 (45.2) 69 (32.5) 74 (34.4) 95% confidence interval (38.5 to 52) (26.2 to 38.9) (28.1 to 40.8) P-value 0.0080* – – *Compared to irinotecan plus 5-fluorouracil/leucovorin (IFL) arm **Based on all patients with measurable disease at baseline The numbers in the response rate and TTP analysis are based on unblinded investigator assessment.

***A hazard ratio of less than 1 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin Figure 4 illustrates the Kaplan-Meier survival curves for the comparison of oxaliplatin and 5-fluorouracil/leucovorin combination and oxaliplatin plus irinotecan to irinotecan plus 5-fluorouracil/leucovorin.

* Log rank test comparing oxaliplatin plus 5-FU/LV to irinotecan plus 5-FU/LV.

Figure 4 – Kaplan-Meier Overall Survival by treatment arm A descriptive subgroup analysis demonstrated that the improvement in survival for oxaliplatin plus 5-fluorouracil/leucovorin compared to irinotecan plus 5-fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved.

An estimated survival advantage in oxaliplatin plus 5-fluorouracil/leucovorin versus irinotecan plus 5-fluorouracil/leucovorin was seen in both genders; however it was greater among women than men.

Insufficient subgroup sizes prevented analysis by race.

Figure 4 14.3 Combination Therapy with Oxaliplatin and 5-fluorouracil/leucovorin in Previously Treated Patients with Advanced Colorectal Cancer A multicenter, open-label, randomized, three-arm controlled study was conducted in the US and Canada comparing the efficacy and safety of oxaliplatin in combination with an infusional schedule of 5-fluorouracil/leucovorin to the same dose and schedule of 5-fluorouracil/leucovorin alone and to single agent oxaliplatin in patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first-line therapy with bolus 5-fluorouracil/leucovorin and irinotecan.

The study was intended to be analyzed for response rate after 450 patients were enrolled.

Survival will be subsequently assessed in all patients enrolled in the completed study.

Accrual to this study is complete, with 821 patients enrolled.

Patients in the study had to be at least 18 years of age, have unresectable, measurable, histologically proven colorectal adenocarcinoma, with a Karnofsky performance status > 50%.

Patients had to have SGOT(AST) and SGPT(ALT) ≤ 2× the institution’s upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case ≤ 5× ULN was permitted.

Patients had to have alkaline phosphatase ≤ 2× the institution’s ULN, unless liver metastases were present and documented at baseline by CT or MRI scan, in which cases ≤ 5× ULN was permitted.

Prior radiotherapy was permitted if it had been completed at least 3 weeks before randomization.

The dosing regimens of the three arms of the study are presented in the table below.

Table 23 – Dosing Regimens in Refractory and Relapsed Colorectal Cancer Clinical Trial Treatment Arm Dose Regimen Oxaliplatin + 5-FU/LV (N = 152) Day 1: Oxaliplatin: 85 mg/m 2 (2-hour infusion) + LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks 5-FU/LV (N = 151) Day 1: LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks Oxaliplatin (N = 156) Day 1: Oxaliplatin 85 mg/m 2 (2-hour infusion) every 2 weeks Patients entered into the study for evaluation of response must have had at least one unidimensional lesion measuring ≥ 20mm using conventional CT or MRI scans, or ≥ 10mm using a spiral CT scan.

Tumor response and progression were assessed every 3 cycles (6 weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) until radiological documentation of progression or for 13 months following the first dose of study drug(s), whichever came first.

Confirmed responses were based on two tumor assessments separated by at least 4 weeks.

The demographics of the patient population entered into this study are shown in the table below.

Table 24 – Patient Demographics in Refractory and Relapsed Colorectal Cancer Clinical Trial 5-FU/LV (N = 151) Oxaliplatin (N = 156) Oxaliplatin + 5-FU/LV (N = 152) Sex: Male (%) 54.3 60.9 57.2 Female (%) 45.7 39.1 42.8 Median age (years) 60 61 59 Range 21 to 80 27 to 79 22 to 88 Race (%) Caucasian 87.4 84.6 88.8 Black 7.9 7.1 5.9 Asian 1.3 2.6 2.6 Other 3.3 5.8 2.6 KPS (%) 70 to 100 94.7 92.3 95.4 50 to 60 2.6 4.5 2 Not reported 2.6 3.2 2.6 Prior radiotherapy (%) 25.2 19.2 25 Prior pelvic radiation (%) 18.5 13.5 21.1 Number of metastatic sites (%) 1 27.2 31.4 25.7 ≥ 2 72.2 67.9 74.3 Liver involvement (%) Liver only 22.5 25.6 18.4 Liver + other 60.3 59 53.3 The median number of cycles administered per patient was 6 for the oxaliplatin and 5-fluorouracil/leucovorin combination and 3 each for 5-fluorouracil/leucovorin alone and oxaliplatin alone.

Patients treated with the combination of oxaliplatin and 5-fluorouracil/leucovorin had an increased response rate compared to patients given 5-fluorouracil/leucovorin or oxaliplatin alone.

The efficacy results are summarized in the tables below.

Table 25 – Response Rates (ITT Analysis) Best Response 5-FU/LV (N = 151) Oxaliplatin (N = 156) Oxaliplatin + 5-FU/LV (N = 152) CR 0 0 0 PR 0 2 (1%) 13 (9%) p-value 0.0002 for 5-FU/LV vs.

Oxaliplatin + 5-FU/LV 95% CI 0 to 2.4% 0.2 to 4.6% 4.6 to 14.2% Table 26 – Summary of Radiographic Time to Progression* Arm 5-FU/LV (N = 151) Oxaliplatin (N = 156) Oxaliplatin + 5-FU/LV (N = 152) No.

of Progressors 74 101 50 No.

of patients with no radiological evaluation beyond baseline 22 (15%) 16 (10%) 17 (11%) Median TTP (months) 2.7 1.6 4.6 95% CI 1.8 to 3 1.4 to 2.7 4.2 to 6.1 *This is not an ITT analysis.

Events were limited to radiographic disease progression documented by independent review of radiographs.

Clinical progression was not included in this analysis, and 18% of patients were excluded from the analysis based on unavailability of the radiographs for independent review.

At the time of the interim analysis 49% of the radiographic progression events had occurred.

In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to 5-fluorouracil/leucovorin alone.

Of the 13 patients who had tumor response to the combination of oxaliplatin and 5-fluorouracil/leucovorin, 5 were female and 8 were male, and responders included patients < 65 years old and ≥ 65 years old.

The small number of non-Caucasian participants made efficacy analyses in these populations uninterpretable.

CLINICAL STUDIES

14 Methylphenidate HCl Extended-Release Tablets was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in 4 randomized, double-blind, placebo-controlled studies in children and adolescents and 2 double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4 th edition (DSM-IV) criteria for ADHD.

14.1 Children Three double-blind, active- and placebo-controlled studies were conducted in 416 children aged 6 to 12 years.

The controlled studies compared Methylphenidate HCl Extended-Release Tablets given once daily (18, 36, or 54 mg), methylphenidate given three times daily over 12 hours (15, 30, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3).

The primary comparison of interest in all three trials was Methylphenidate HCl Extended-Release Tablets versus placebo.

Symptoms of ADHD were evaluated by community schoolteachers using the Inattention / Overactivity with Aggression (IOWA) Conners scale.

Statistically significant reduction in the Inattention / Overactivity subscale versus placebo was shown consistently across all three controlled studies for Methylphenidate HCl Extended-Release Tablets.

The scores for Methylphenidate HCl Extended-Release Tablets and placebo for the three studies are presented in Figure 2.

Figure 2: Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with Methylphenidate HCl Extended-Release Tablets once-daily (18, 36, or 54 mg) and placebo.

Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm.

Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at week 4.

Error bars represent the mean plus standard error of the mean.

In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMP Swanson, Kotkin, Agler, M-Fynn, and Pelham laboratory school rating scale.

The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with Methylphenidate HCl Extended-Release Tablets versus placebo that were maintained through 12 hours after dosing.

Figure 3 presents the laboratory schoolteacher SKAMP ratings for Methylphenidate HCl Extended-Release Tablets and placebo.

Figure 3: Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2) Figure 2 Figure 3 14.2 Adolescents In a randomized, double-blind, multi-center, placebo-controlled trial (Study 4) involving 177 patients, Methylphenidate HCl Extended-Release Tablets was demonstrated to be effective in the treatment of ADHD in adolescents aged 13 to 18 years at doses up to 72 mg/day (1.4 mg/kg/day).

Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability.

Patients who met these criteria were then randomized to receive either their individualized dose of Methylphenidate HCl Extended-Release Tablets (18 – 72 mg/day, n=87) or placebo (n=90) during a two-week double-blind phase.

At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that Methylphenidate HCl Extended-Release Tablets was statistically significantly superior to placebo.

14.3 Adults Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years.

The controlled studies compared Methylphenidate HCl Extended-Release Tablets administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 to 108 mg/day) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18, 36, and 72 mg/day).

Study 5 demonstrated the effectiveness of Methylphenidate HCl Extended-Release Tablets in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS).

Of 226 patients who entered the 7-week trial, 110 were randomized to Methylphenidate HCl Extended-Release Tablets and 116 were randomized to placebo.

Treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific improvement criteria with acceptable tolerability.

At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that Methylphenidate HCl Extended-Release Tablets was statistically significantly superior to placebo.

Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed dose groups (18, 36, and 72 mg).

Patients were randomized to receive Methylphenidate HCl Extended-Release Tablets administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96).

All three doses of Methylphenidate HCl Extended-Release Tablets were statistically significantly more effective than placebo in improving CAARS (Conners’ Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.

CLINICAL STUDIES

14 14.1 Studies in Neurogenic Orthostatic Hypotension Clinical studies (described below) examined the efficacy of NORTHERA in the short-term (1 to 2 weeks) and over longer-term periods (8 weeks; 3 months).

Studies 301 and 306B showed a treatment effect of NORTHERA at Week 1, but none of the studies demonstrated continued efficacy beyond 2 weeks of treatment.

Study 306B was a multi-center, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic nOH and Parkinson’s disease.

Patients entering the study were required to have a decrease of at least 20 mm Hg or 10 mm Hg, respectively, in systolic or diastolic blood pressure, within 3 minutes after standing, as well as symptoms associated with neurogenic orthostatic hypotension.

The study had an initial dose titration period that lasted up to 2 weeks in which patients received placebo or 100 to 600 mg of NORTHERA three times daily, followed by an 8-week treatment period.

Efficacy was measured using the OHSA Item #1 score (“dizziness, lightheadedness, feeling faint, and feeling like you might black out”) at Week 1, in patients who had completed titration and 1 week of maintenance therapy.

A total of 171 patients were enrolled, and 147 patients were included in the efficacy analysis.

The mean age was 72 years, and patients were mostly Caucasian.

During the study, 94% of placebo-treated patients and 88% on NORTHERA were taking dopa-decarboxylase inhibitors; 17% of placebo-treated patients and 26% on NORTHERA were taking fludrocortisone.

There were more premature discontinuations in the NORTHERA group (28%) than in the placebo group (20%).

In both groups, the mean baseline dizziness score was 5.1 on an 11-point scale.

At Week 1, patients showed a statistically significant mean 0.9 unit decrease in dizziness with NORTHERA versus placebo ( P =0.028), but the effect did not persist beyond Week 1.

The data at all time points are shown in Figure 1.

Patients receiving NORTHERA also had a greater increase, compared to placebo, in the Week 1 lowest standing systolic blood pressure within 3 minutes after standing (5.6 mm Hg; P =0.032).

Figure 1.

Mean Change in OHSA Item 1 Score by Week in Study 306B Note: The graph is based on observed data only.

The error bars are the 95% confidence interval of the mean change from baseline in OHSA Item 1 scores.

Figure 2.

Distribution of Patients by Change in OHSA Item 1, Baseline to Week 1, in Study 306B Figure 2 shows the distribution of changes from Baseline to Week 1 in the OHSA Item #1 score.

Overall the figure shows that patients treated with NORTHERA improved more than those treated with placebo.

Study 301 was a multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic neurogenic orthostatic hypotension.

The study included an initial open-label dose titration period, a 7-day washout period, and a randomized double-blind 7-day treatment period.

To be eligible for enrollment, patients were required to have a decrease in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, within 3 minutes after standing.

The study was enriched, such that only patients who had been identified as “responders” during the titration period were randomized to NORTHERA or placebo.

To be considered a responder, a patient had to demonstrate improvement on the OHSA Item #1 score by at least 1 point, as well as an increase in systolic blood pressure of at least 10 mm Hg post-standing, during the open-label dose titration period.

Patients who dropped out during the titration period because of side effects or other reasons were also not included in the double-blind portion of the study.

Patients had a primary diagnosis of Parkinson’s disease (n=60), pure autonomic failure (n=36), or multiple system atrophy (n=26).

The mean age was 60 years, and most were Caucasian.

45% of patients were taking dopa-decarboxylase inhibitors, and 29% were taking fludrocortisone.

Efficacy was measured using the Orthostatic Hypotension Questionnaire (OHQ), a patient-reported outcome that measures symptoms of nOH and their impact on the patient’s ability to perform daily activities that require standing and walking.

The OHQ includes OHSA Item #1 as one of several components.

A statistically significant treatment effect was not demonstrated on OHQ (treatment effect of 0.4 unit, P =0.19).

The mean baseline dizziness score on OHSA Item #1 (“dizziness, lightheadedness, feeling faint, and feeling like you might black out”) was 5.2 units on an 11-point scale.

At Week 1 of treatment, patients showed a mean 0.7 unit decrease in dizziness with NORTHERA versus placebo ( P =0.06).

Study 302 (n=101) was a placebo-controlled, 2-week randomized withdrawal study of NORTHERA in patients with symptomatic nOH.

Study 303 (n=75) was an extension of Studies 301 and 302, where patients received their titrated dose of NORTHERA for 3 months and then entered a 2-week randomized withdrawal phase.

Neither study showed a statistically significant difference between treatment arms on its primary endpoint.

Considering these data, the effectiveness of NORTHERA beyond 2 weeks is uncertain, and patients should be evaluated periodically to determine whether NORTHERA is continuing to provide a benefit.

Mean Change in OHSA Distribution of Patients by Change in OHSA

CLINICAL STUDIES

14 14.1 Locally Advanced or Metastatic Breast Cancer The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens).

Randomized Trials In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m 2 every 3 weeks) or the combination of mitomycin (12 mg/m 2 every 6 weeks) and vinblastine (6 mg/m 2 every 3 weeks).

Two hundred three patients were randomized to docetaxel and 189 to the comparator arm.

Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy.

Three-quarters of patients had measurable, visceral metastases.

The primary endpoint was time to progression.

The following table summarizes the study results (see Table 12 ).

Table 12 – Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis) Efficacy Parameter Docetaxel (n = 203) Mitomycin/Vinblastine (n = 189) p-value Median Survival 11.4 months 8.7 months p = 0.01 Log Rank Risk Ratio*, Mortality (Docetaxel: Control) 0.73 95% CI (Risk Ratio) 0.58 to 0.93 Median Time to Progression 4.3 months 2.5 months p = 0.01 Log Rank Risk Ratio*, Progression (Docetaxel: Control) 0.75 95% CI (Risk Ratio) 0.61 to 0.94 Overall Response Rate 28.1% 9.5% p < 0.0001 Complete Response Rate 3.4% 1.6% Chi Square *For the risk ratio, a value less than 1.00 favors docetaxel.

In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m 2 ) or doxorubicin (75 mg/m 2 ) every 3 weeks.

One hundred sixty-one patients were randomized to docetaxel and 165 patients to doxorubicin.

Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy.

Three-quarters of patients had measurable, visceral metastases.

The primary endpoint was time to progression.

The study results are summarized below (see Table 13 ).

Table 13 – Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat Analysis) Efficacy Parameter Docetaxel (n = 161) Doxorubicin (n = 165) p-value Median Survival 14.7 months 14.3 months p = 0.39 Log Rank Risk Ratio*, Mortality (Docetaxel: Control) 0.89 95% CI (Risk Ratio) 0.68 to 1.16 Median Time to Progression 6.5 months 5.3 months p = 0.45 Log Rank Risk Ratio*, Progression (Docetaxel: Control) 0.93 95% CI (Risk Ratio) 0.71 to 1.16 Overall Response Rate 45.3% 29.7% p = 0.004 Chi Square Complete Response Rate 6.8% 4.2% *For the risk ratio, a value less than 1.00 favors docetaxel.

In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m 2 (n = 151), 75 mg/m 2 (n = 188) or 100 mg/m 2 (n = 188).

In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy.

Response rate was the primary endpoint.

Response rates increased with docetaxel dose: 19.9% for the 60 mg/m 2 group compared to 22.3% for the 75 mg/m 2 and 29.8% for the 100 mg/m 2 group; pair-wise comparison between the 60 mg/m 2 and 100 mg/m 2 groups was statistically significant (p = 0.037).

Single Arm Studies Docetaxel at a dose of 100 mg/m 2 was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed.

Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen.

In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31 to 44.8) and the complete response rate was 2.1%.

Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m 2 , in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer.

Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2 to 55.7), similar to the response rate in single arm studies of 100 mg/m 2 .

14.2 Adjuvant Treatment of Breast Cancer A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease.

After stratification according to the number of positive lymph nodes (1 to 3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m 2 administered 1 hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 (TAC arm), or doxorubicin 50 mg/m 2 followed by fluorouracil 500 mg/m 2 and cyclosphosphamide 500 mg/m 2 (FAC arm).

Both regimens were administered every 3 weeks for 6 cycles.

Docetaxel was administered as a 1 hour infusion; all other drugs were given as intravenous bolus on day 1.

In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years.

Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC.

Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio = 0.74; 2 sided 95% CI = 0.60, 0.92, stratified log rank p = 0.0047).

The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause.

The overall reduction in risk of relapse was 25.7% for TAC-treated patients (see Figure 1 ).

At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio = 0.69, 2 sided 95% CI = 0.53, 0.90) (see Figure 2 ).

There will be further analysis at the time survival data mature.

Figure 1 – TAX316 Disease Free Survival K-M Curve Figure 2 – TAX316 Overall Survival K-M Curve The following table describes the results of subgroup analyses for DFS and OS (see Table 14 ).

Table 14 – Subset Analyses-Adjuvant Breast Cancer Study Disease Free Survival Overall Survival Patient subset Number of patients Hazard ratio* 95% CI Hazard ratio* 95% CI No.

of positive nodes Overall 744 0.74 (0.60, 0.92) 0.69 (0.53, 0.90) 1 to 3 467 0.64 (0.47, 0.87) 0.45 (0.29, 0.70) 4+ 277 0.84 (0.63, 1.12) 0.93 (0.66, 1.32) Receptor status Positive 566 0.76 (0.59, 0.98) 0.69 (0.48, 0.99) Negative 178 0.68 (0.48, 0.97) 0.66 (0.44, 0.98) * a hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC.

Figure 1 Figure 2 14.3 Non-Small Cell Lung Cancer (NSCLC) The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve.

Monotherapy with Docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy Two randomized, controlled trials established that a docetaxel dose of 75 mg/m 2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below).

Docetaxel at a dose of 100 mg/m 2 , however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used [ see Boxed Warning, Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.3 ) ].

One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤ 2 to docetaxel or best supportive care.

The primary endpoint of the study was survival.

Patients were initially randomized to docetaxel 100 mg/m 2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m 2 .

A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m 2 or best supportive care.

In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤ 2 were randomized to docetaxel 75 mg/m 2 , docetaxel 100 mg/m 2 and a treatment in which the investigator chose either vinorelbine 30 mg/m 2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m 2 days 1 to 3 repeated every 3 weeks.

Forty percent of the patients in this study had a history of prior paclitaxel exposure.

The primary endpoint was survival in both trials.

The efficacy data for the docetaxel 75 mg/m 2 arm and the comparator arms are summarized in Table 15 and Figures 3 and 4 showing the survival curves for the two studies.

Table 15 – Efficacy of Docetaxel in the Treatment of Non-Small Cell Lung Cancer Patients Previously Treated with a Platinum-Based Chemotherapy Regimen (Intent-to-Treat Analysis) TAX317 TAX320 Docetaxel 75 mg/m 2 Best Supportive Care Docetaxel 75 mg/m 2 Control (V/I*) n = 55 n = 49 n = 125 n = 123 Overall Survival Log-rank Test p = 0.01 p = 0.13 Risk Ratio †† , Mortality (Docetaxel: Control) 0.56 0.82 95% CI (Risk Ratio) (0.35, 0.88) (0.63, 1.06) Median Survival 7.5 months** 4.6 months 5.7 months 5.6 months 95% CI (5.5, 12.8) (3.7, 6.1) (5.1, 7.1) (4.4, 7.9) % 1 year Survival 37%** † 12% 30%** † 20% 95% CI (24, 50) (2, 23) (22, 39) (13, 27) Time to Progression 12.3 weeks** 7 weeks 8.3 weeks 7.6 weeks 95% CI (9, 18.3) (6, 9.3) (7, 11.7) (6.7, 10.1) Response Rate 5.5% Not Applicable 5.7% 0.8% 95% CI (1.1, 15.1) (2.3, 11.3) (0, 4.5) * Vinorelbine/Ifosfamide ** p ≤ 0.05 † uncorrected for multiple comparisons †† a value less than 1.00 favors docetaxel Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year.

In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m 2 .

Figure 3 – TAX317 Survival K-M Curves – Docetaxel 75 mg/m 2 vs.

Best Supportive Care Figure 4 – TAX320 Survival K-M Curves – Docetaxel 75 mg/m 2 vs.

Vinorelbine or Ifosfamide Control Patients treated with docetaxel at a dose of 75 mg/m 2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.

Combination Therapy with Docetaxel for Chemotherapy-Naïve NSCLC In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: Docetaxel 75 mg/m 2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m 2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m 2 administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m 2 administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin.

The primary efficacy endpoint was overall survival.

Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below).

The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin.

The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2 month increase in median survival; Wozniak et al.

JCO, 1998) was maintained.

The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 16 .

Table 16 – Survival Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC Comparison Docetaxel+Cisplatin Vinorelbine+Cisplatin n = 408 n = 405 Kaplan-Meier Estimate of Median Survival 10.9 months 10 months p-value a 0.122 Estimated Hazard Ratio b 0.88 Adjusted 95% CI c (0.74, 1.06) a From the superiority test (stratified log rank) comparing docetaxel+cisplatin to vinorelbine+cisplatin b Hazard ratio of docetaxel+cisplatin vs.

vinorelbine+cisplatin.

A hazard ratio of less than 1 indicates that docetaxel+cisplatin is associated with a longer survival.

c Adjusted for interim analysis and multiple comparisons.

The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin.

Secondary endpoints evaluated in the trial included objective response and time to progression.

There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 17 ).

Table 17 – Response and TTP Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC Endpoint Docetaxel+Cisplatin Vinorelbine+Cisplatin p-value Objective Response Rate (95% CI) a 31.6% (26.5%, 36.8%) 24.4% (19.8%, 29.2%) Not significant Median Time to Progression b (95% CI) a 21.4 weeks (19.3, 24.6) 22.1 weeks (18.1, 25.6) Not significant a Adjusted for multiple comparisons.

b Kaplan-Meier estimates.

Figure 3 Figure 4 14.4 Hormone Refractory Prostate Cancer The safety and efficacy of docetaxel in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial.

A total of 1006 patients with Karnofsky Performance Status (KPS) ≥ 60 were randomized to the following treatment groups: Docetaxel 75 mg/m 2 every 3 weeks for 10 cycles.

Docetaxel 30 mg/m 2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles.

Mitoxantrone 12 mg/m 2 every 3 weeks for 10 cycles.

All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.

In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone.

In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm.

Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 18 and Figure 5 .

Table 18 – Efficacy of Docetaxel in the Treatment of Patients with Androgen Independent (Hormone Refractory) Metastatic Prostate Cancer (Intent-to-Treat Analysis) Docetaxel+Prednisone every 3 weeks Mitoxantrone+Prednisone every 3 weeks Number of patients Median survival (months) 95% CI Hazard ratio 95% CI p-value* 335 18.9 (17 to 21.2) 0.761 (0.619 to 0.936) 0.0094 337 16.5 (14.4 to 18.6) — — — *Stratified log rank test.

Threshold for statistical significance = 0.0175 because of 3 arms.

Figure 5 -TAX327 Survival K-M Curves Figure 5 14.5 Gastric Adenocarcinoma A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of docetaxel for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease.

A total of 445 patients with KPS > 70 were treated with either docetaxel (T) (75 mg/m 2 on day 1) in combination with cisplatin (C) (75 mg/m 2 on day 1) and fluorouracil (F) (750 mg/m 2 per day for 5 days) or cisplatin (100 mg/m 2 on day 1) and fluorouracil (1000 mg/m 2 per day for 5 days).

The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm.

The demographic characteristics were balanced between the two treatment arms.

The median age was 55 years, 71% were male, 71% were Caucasian, 24% were 65 years of age or older, 19% had a prior curative surgery and 12% had palliative surgery.

The median number of cycles administered per patient was 6 (with a range of 1 to 16) for the TCF arm compared to 4 (with a range of 1 to 12) for the CF arm.

Time to progression (TTP) was the primary endpoint and was defined as time from randomization to disease progression or death from any cause within 12 weeks of the last evaluable tumor assessment or within 12 weeks of the first infusion of study drugs for patients with no evaluable tumor assessment after randomization.

The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI: 1.19 to 1.83) with a significantly longer TTP (p = 0.0004) in the TCF arm.

Approximately 75% of patients had died at the time of this analysis.

Overall survival was significantly longer (p = 0.0201) in the TCF arm with a HR of 1.29 (95% CI: 1.04 to 1.61).

Efficacy results are summarized in Table 19 and Figures 6 and 7 .

Table 19 – Efficacy of Docetaxel in the Treatment of Patients with Gastric Adenocarcinoma Endpoint TCF n = 221 CF n = 224 Median TTP (months) (95%CI) Hazard ratio † (95%CI) *p-value 5.6 (4.86 to 5.91) 3.7 (3.45 to 4.47) 0.68 (0.55 to 0.84) 0.0004 Median survival (months) (95%CI) Hazard ratio † (95%CI) *p-value 9.2 (8.38 to 10.58) 8.6 (7.16 to 9.46) 0.77 (0.62 to 0.96) 0.0201 Overall Response Rate (CR+PR) (%) p-value 36.7 25.4 0.0106 *Unstratified log-rank test † For the hazard ratio (TCF/CF), values less than 1.00 favor the docetaxel arm.

Subgroup analyses were consistent with the overall results across age, gender and race.

Figure 6 – Gastric Cancer Study (TAX325) Time to Progression K-M Curve Figure 7 – Gastric Cancer Study (TAX325) Survival K-M Curve Figure 6 Figure 7 14.6 Head and Neck Cancer Induction chemotherapy followed by radiotherapy (TAX323) The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323).

In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms.

Patients on the docetaxel arm received docetaxel (T) 75 mg/m 2 followed by cisplatin (P) 75 mg/m 2 on Day 1, followed by fluorouracil (F) 750 mg/m 2 per day as a continuous infusion on Days 1 to 5.

The cycles were repeated every three weeks for 4 cycles.

Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT).

Patients on the comparator arm received cisplatin (P) 100 mg/m 2 on Day 1, followed by fluorouracil (F) 1000 mg/m 2 /day as a continuous infusion on Days 1 to 5.

The cycles were repeated every three weeks for 4 cycles.

Patients whose disease did not progress received RT according to institutional guidelines (PF/RT).

At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines.

Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy to 2 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively).

Surgical resection was allowed following chemotherapy, before or after radiotherapy.

The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p = 0.0077 (median PFS: 11.4 vs.

8.3 months respectively) with an overall median follow up time of 33.7 months.

Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs.

14.2 months respectively).

Efficacy results are presented in Table 20 and Figures 8 and 9 .

Table 20 – Efficacy of Docetaxel in the Induction Treatment of Patients with Inoperable Locally Advanced SCCHN (Intent-to-Treat Analysis) ENDPOINT Docetaxel + Cisplatin + Fluorouracil n = 177 Cisplatin + Fluorouracil n = 181 Median progression free survival (months) (95%CI) Adjusted Hazard ratio (95%CI) *p-value 11.4 (10.1 to 14) 8.3 (7.4 to 9.1) 0.71 (0.56 to 0.91) 0.0077 Median survival (months) (95%CI) Hazard ratio (95%CI) **p-value 18.6 (15.7 to 24) 14.2 (11.5 to 18.7) 0.71 (0.56 to 0.90) 0.0055 Best overall response (CR + PR) to chemotherapy (%) (95%CI) ***p-value 67.8 (60.4 to 74.6) 53.6 (46 to 61) 0.006 Best overall response (CR + PR) to study treatment [chemotherapy +/- radiotherapy] (%) (95%CI) ***p-value 72.3 (65.1 to 78.8) 58.6 (51 to 65.8) 0.006 A Hazard ratio of less than 1 favors Docetaxel+Cisplatin+Fluorouracil * Stratified log-rank test based on primary tumor site ** Stratified log-rank test, not adjusted for multiple comparisons *** Chi square test, not adjusted for multiple comparisons Figure 8 – TAX323 Progression-Free Survival K-M Curve Figure 9 – TAX323 Overall Survival K-M Curve Induction chemotherapy followed by chemoradiotherapy (TAX324) The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324).

In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms.

Patients on the docetaxel arm received docetaxel (T) 75 mg/m² by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m² administered as a 30 minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m²/day from day 1 to day 4.

The cycles were repeated every 3 weeks for 3 cycles.

Patients on the comparator arm received cisplatin (P) 100 mg/m² as a 30 minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m²/day from day 1 to day 5.

The cycles were repeated every 3 weeks for 3 cycles.

All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle.

During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses.

Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70 to 72 Gy).

Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT.

The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p = 0.0058) with the docetaxel-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54 to 0.90].

Overall survival results are presented in Table 21 and Figure 10 .

Table 21 – Efficacy of Docetaxel in the Induction Treatment of Patients with Locally Advanced SCCHN (Intent-to-Treat Analysis) ENDPOINT Docetaxel + Cisplatin + Fluorouracil n = 255 Cisplatin + Fluorouracil n = 246 Median overall survival (months) (95% CI) 70.6 (49 to NE) 30.1 (20.9 to 51.5) Hazard ratio: (95% CI) *p-value 0.70 (0.54 to 0.90) 0.0058 A Hazard ratio of less than 1 favors docetaxel+cisplatin+fluorouracil * un-adjusted log-rank test NE – not estimable Figure 10 -TAX324 Overall Survival K-M Curve Figure 8 Figure 9 Figure 10

CLINICAL STUDIES

14.

FENORTHO is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities.

Its exact mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved.

Results in humans demonstrate that fenoprofen has both anti-inflammatory and analgesic actions.

The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation.

The effects of FENORTHO, aspirin, and indomethacin were each compared with those of a placebo.

All 3 drugs demonstrated antierythemic activity.

In all patients with rheumatoid arthritis, the anti-inflammatory action of FENORTHO has been evidenced by relief of pain, increase in grip strength, and reductions in joint swelling, duration of morning stiffness, and disease activity (as assessed by both the investigator and the patient).

The anti-inflammatory action of FENORTHO has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion).

The use of FENORTHO in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis.

The studies, however, were inadequate in demonstrating whether further improvement is obtained by adding FENORTHO to maintenance therapy with gold salts or steroids.

Whether or not FENORTHO used in conjunction with partially effective doses of a corticosteroid has a “steroid-sparing” effect is unknown.

In patients with osteoarthritis, the anti-inflammatory and analgesic effects of FENORTHO have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling, and overall disease activity (as assessed by both the patient and the investigator).

These effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints.

In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown FENORTHO to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with FENORTHO than in aspirin-treated patients.

It is not known whether FENORTHO causes less peptic ulceration than does aspirin.

In patients with pain, the analgesic action of Fenoprofen calcium has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect.

CLINICAL STUDIES

14.

14.1 Major Depressive Disorder The efficacy of duloxetine, as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression.

In 2 studies, patients were randomized to duloxetine 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to duloxetine 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to duloxetine 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks.

There is no evidence that doses greater than 60 mg/day confer additional benefits.

In all 4 studies, duloxetine demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score.

In all of these clinical studies, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.

In another study, 533 patients meeting DSM-IV criteria for MDD received duloxetine 60 mg once daily during an initial 12-week open-label treatment phase.

Two hundred and seventy-eight patients who responded to open label treatment (defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD) were randomly assigned to continuation of duloxetine at the same dose (N=136) or to placebo (N=142) for 6 months.

Patients on duloxetine experienced a statistically significantly longer time to relapse of depression than did patients on placebo.

Relapse was defined as an increase in the CGI–S score of ≥2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit.

The effectiveness of duloxetine in hospitalized patients with major depressive disorder has not been studied.

14.2 Generalized Anxiety Disorder The efficacy of duloxetine in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD.

In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily.

Fifteen percent of patients were down titrated.

One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.

The 2 flexible-dose studies involved dose titration with duloxetine doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period.

The mean dose for completers at endpoint in the flexible-dose studies was 104.75 mg/day.

The fixed-dose study evaluated duloxetine doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period.

While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.

In all 3 studies, duloxetine demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score.

The SDS is a widely used and well-validated scale that measures the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/ home responsibilities.

In another study, 887 patients meeting DSM-IV-TR criteria for GAD received duloxetine 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase.

Four hundred and twenty-nine patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly assigned to continuation of duloxetine at the same dose (N=216) or to placebo (N=213) and were observed for relapse.

Of the patients randomized, 73% had been in a responder status for at least 10 weeks.

Relapse was defined as an increase in CGI-Severity score at least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy.

Patients taking duloxetine experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

14.3 Diabetic Peripheral Neuropathic Pain The efficacy of duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months.

Study DPNP-1 and Study DPNP-2 enrolled a total of 791 patients of whom 592 (75%) completed the studies.

Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months.

The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain).

Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to duloxetine.

Patients recorded their pain daily in a diary.

Both studies compared duloxetine 60 mg once daily or 60 mg twice daily with placebo.

DPNP-1 additionally compared duloxetine 20 mg with placebo.

A total of 457 patients (342 duloxetine, 115 placebo) were enrolled in DPNP-1 and a total of 334 patients (226 duloxetine, 108 placebo) were enrolled in DPNP-2.

Treatment with duloxetine 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain scores from baseline.

For various degrees of improvement in pain from baseline to study endpoint, Figures 1 and 2 show the fraction of patients achieving that degree of improvement.

The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

1 2 14.5 Chronic Musculoskeletal Pain Duloxetine is indicated for the management of chronic musculoskeletal pain.

This has been established in studies in patients with chronic low back pain and chronic pain due to osteoarthritis.

Studies in Chronic Low Back Pain — The efficacy of duloxetine in chronic low back pain (CLBP) was assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study CLBP-1 and Study CLBP-2), and one of 12-weeks duration (CLBP-3).

CLBP-1 and CLBP-3 demonstrated efficacy of duloxetine in the treatment of chronic low back pain.

Patients in all studies had no signs of radiculopathy or spinal stenosis.

Study CLBP-1: Two hundred thirty-six adult patients (N=115 on duloxetine, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase.

After 7 weeks of treatment, duloxetine patients with less than 30% reduction in average daily pain and who were able to tolerate duloxetine 60 mg once daily had their dose of duloxetine, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the study.

Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain).

After 13 weeks of treatment, patients taking duloxetine 60-120 mg daily had a significantly greater pain reduction compared to placebo.

Randomization was stratified by the patients’ baseline NSAIDs-use status.

Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.

Study CLBP-2: Four hundred and four patients were randomized to receive fixed doses of duloxetine daily or a matching placebo (N=59 on duloxetine 20 mg, N=116 on duloxetine 60 mg, N=112 on duloxetine 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week study.

After 13 weeks of treatment, none of the three duloxetine doses showed a statistically significant difference in pain reduction compared to placebo.

Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of duloxetine 60 mg daily or placebo (N=198 on duloxetine, N=203 on placebo), and 303 (76%) completed the study.

Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain).

After 12 weeks of treatment, patients taking duloxetine 60 mg daily had significantly greater pain reduction compared to placebo.

For various degrees of improvement in pain from baseline to study endpoint, Figures 5 and 6 show the fraction of patients in CLBP-1 and CLBP-3 achieving that degree of improvement.

The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned the value of 0% improvement.

Figure 5: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – CLBP-1 Figure 6: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – CLBP-3 Studies in Chronic Pain Due to Osteoarthritis — The efficacy of duloxetine in chronic pain due to osteoarthritis was assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2).

All patients in both studies fulfilled the ACR clinical and radiographic criteria for classification of idiopathic osteoarthritis of the knee.

Randomization was stratified by the patients’ baseline NSAIDs-use status.

Patients assigned to duloxetine started treatment in both studies at a dose of 30 mg once daily for one week.

After the first week, the dose of duloxetine was increased to 60 mg once daily.

After 7 weeks of treatment with duloxetine 60 mg once daily, in OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated duloxetine 60 mg once daily had their dose increased to 120 mg.

However, in OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving duloxetine 60 mg once daily or have their dose increased to 120 mg once daily for the remainder of the study.

Patients in the placebo treatment groups in both studies received a matching placebo for the entire duration of studies.

For both studies, efficacy analyses were conducted using 13-week data from the combined duloxetine 60 mg and 120 mg once daily treatment groups compared to the placebo group.

Study OA-1: Two hundred fifty-six patients (N=128 on duloxetine, N=128 on placebo) enrolled and 204 (80%) completed the study.

Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain).

After 13 weeks of treatment, patients taking duloxetine had significantly greater pain reduction.

Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.

Study OA-2: Two hundred thirty-one patients (N=111 on duloxetine, N=120 on placebo) enrolled and 173 (75%) completed the study.

Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain).

After 13 weeks of treatment, patients taking duloxetine did not show a significantly greater pain reduction.

In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 7 shows the fraction of patients achieving that degree of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned the value of 0% improvement.

Figure 7: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – OA-1 Figure 5 Figure 6 Figure 7

CLINICAL STUDIES

14 14.1 Parkinson’s Disease The effectiveness of ropinirole tablets in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of 11 randomized, controlled trials.

Four trials were conducted in patients with early Parkinson’s disease and no concomitant L-dopa and seven trials were conducted in patients with advanced Parkinson’s disease with concomitant L-dopa.

Three placebo-controlled trials provide evidence of effectiveness of ropinirole tablets in the management of patients with Parkinson’s disease who were and were not receiving concomitant L-dopa.

Two of these three trials enrolled patients with early Parkinson’s disease (without L-dopa) and one enrolled patients receiving L-dopa.

In these trials a variety of measures were used to assess the effects of treatment (e.g., the Unified Parkinson’s Disease Rating Scale [UPDRS], Clinical Global Impression [CGI] scores, patient diaries recording time “on” and “off,” tolerability of L-dopa dose reductions).

In both trials of patients with early Parkinson’s disease (without L-dopa), the motor component (Part III) of the UPDRS was the primary outcome assessment.

The UPDRS is a multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV).

Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability) scored for different body regions and has a maximum (worst) score of 108.

In the trial of patients with advanced Parkinson’s disease (with L-dopa), both reduction in percent awake time spent “off” and the ability to reduce the daily use of L-dopa were assessed as a combined endpoint and individually.

Trials in Patients with Early Parkinson’s Disease (without L-dopa) Trial 1 was a 12-week multicenter trial in which 63 patients with idiopathic Parkinson’s disease receiving concomitant anti-Parkinson medication (but not L-dopa) were enrolled and 41 were randomized to ropinirole tablets and 22 to placebo.

Patients had a mean disease duration of approximately 2 years.

Patients were eligible for enrollment if they presented with bradykinesia and at least tremor, rigidity, or postural instability.

In addition, they must have been classified as Hoehn & Yahr Stage I-IV.

This scale, ranging from I = unilateral involvement with minimal impairment to V = confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinson’s disease.

The primary outcome measure in this trial was the proportion of patients experiencing a decrease (compared with baseline) of at least 30% in the UPDRS motor score.

Patients were titrated for up to 10 weeks, starting at 0.5 mg twice daily, with weekly increments of 0.5 mg twice daily to a maximum of 5 mg twice daily.

Once patients reached their maximally tolerated dose (or 5 mg twice daily), they were maintained on that dose through 12 weeks.

The mean dose achieved by patients at trial endpoint was 7.4 mg/day.

Mean baseline UPDRS motor score was 18.6 for patients treated with ropinirole tablets and 19.9 for patients treated with placebo.

At the end of 12 weeks, the percentage of responders was greater on ropinirole tablets than on placebo and the difference was statistically significant (Table 6).

Table 6.

Percent Responders for UPDRS Motor Score in Trial 1 (Intent-to-Treat Population) % Responders Difference from Placebo Placebo 41% NA Ropinirole tablets 71% 30% Trial 2 in patients with early Parkinson’s disease (without L-dopa) was a double-blind, randomized, placebo-controlled, 6-month trial.

In this trial, 241 patients were enrolled and 116 were randomized to ropinirole tablets and 125 to placebo.

Patients were essentially similar to those in the trial described above; concomitant use of selegiline was allowed, but patients were not permitted to use anticholinergics or amantadine during the trial.

Patients had a mean disease duration of 2 years and limited (not more than a 6-week period) or no prior exposure to L-dopa.

The starting dosage of ropinirole tablets in this trial was 0.25 mg three times daily.

The dosage was titrated at weekly intervals by increments of 0.25 mg three times daily to a dosage of 1 mg three times daily.

Further titrations at weekly intervals were at increments of 0.5 mg three times daily up to a dosage of 3 mg three times daily, and then weekly at increments of 1 mg three times daily.

Patients were to be titrated to a dosage of at least 1.5 mg three times daily and then to their maximally tolerated dosage, up to a maximum of 8 mg three times daily.

The mean dose attained in patients at trial endpoint was 15.7 mg/day.

The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in the UPDRS motor score.

At the end of the 6-month trial, patients treated with ropinirole tablets showed improvement in motor score compared with placebo and the difference was statistically significant (Table 7).

Table 7.

Mean Percentage Change from Baseline in UPDRS Motor Score at End of Treatment in Trial 2 (Intent-to-Treat Population) Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from Placebo Placebo 17.7 +4% NA Ropinirole tablets 17.9 -22% -26% Trial in Patients with Advanced Parkinson’s Disease (with L-dopa) Trial 3 was a double-blind, randomized, placebo-controlled, 6-month trial that randomized 149 patients (Hoehn & Yahr II-IV) who were not adequately controlled on L-dopa.

Ninety-five patients were randomized to ropinirole tablets and 54 were randomized to placebo.

Patients in this trial had a mean disease duration of approximately 9 years, had been exposed to L-dopa for approximately 7 years, and had experienced “on-off” periods with L-dopa therapy.

Patients previously receiving stable doses of selegiline, amantadine, and/or anticholinergic agents could continue on these agents during the trial.

Patients were started at a dosage of 0.25 mg three times daily of ropinirole tablets and titrated upward by weekly intervals until an optimal therapeutic response was achieved.

The maximum dosage of trial medication was 8 mg three times daily.

All patients had to be titrated to at least a dosage of 2.5 mg three times daily.

Patients could then be maintained on this dosage level or higher for the remainder of the trial.

Once a dosage of 2.5 mg three times daily was achieved, patients underwent a mandatory reduction in their L-dopa dosage, to be followed by additional mandatory reductions with continued escalation of the dosage of ropinirole tablets.

Reductions in the dosage of L-dopa were also allowed if patients experienced adverse reactions that the investigator considered related to dopaminergic therapy.

The mean dose attained at trial endpoint was 16.3 mg/day.

The primary outcome was the proportion of responders, defined as patients who were able both to achieve a decrease (compared with baseline) of at least 20% in their L-dopa dosage and a decrease of at least 20% in the proportion of the time awake in the “off” condition (a period of time during the day when patients are particularly immobile), as determined by subject diary.

In addition, the mean change in “off” time from baseline and the percent change from baseline in daily L-dopa dosage were examined.

At the end of 6 months, the percentage of responders was greater on ropinirole tablets than on placebo and the difference was statistically significant (Table 8).

Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of ropinirole tablets, patients treated with ropinirole tablets had a 19.4% mean reduction in L-dopa dosage while patients treated with placebo had a 3% reduction.

Mean daily L-dopa dosage at baseline was 759 mg for patients treated with ropinirole tablets and 843 mg for patients treated with placebo.

The mean number of daily “off” hours at baseline was 6.4 hours for patients treated with ropinirole tablets and 7.3 hours for patients treated with placebo.

At the end of the 6-month trial, there was a mean reduction of 1.5 hours of “off” time in patients treated with ropinirole tablets and a mean reduction of 0.9 hours of “off” time in patients treated with placebo, resulting in a treatment difference of 0.6 hours of “off” time.

Table 8.

Mean Responder Percentage of Patients Reducing Daily L-Dopa Dosage by at Least 20% and Daily Proportion of “Off” Time by at Least 20% at End of Treatment in Trial 3 (Intent-to-Treat Population) Treatment % Responders Difference from Placebo Placebo 11% NA Ropinirole tablets 28% 17% 14.2 Restless Legs Syndrome The effectiveness of ropinirole tablets in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled trials in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria.

Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS Rating Scale (IRLS scale) at baseline.

Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, anemia) were excluded.

All trials employed flexible dosing, with patients initiating therapy at 0.25 mg ropinirole tablets once daily.

Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily.

All doses were taken between 1 and 3 hours before bedtime.

A variety of measures were used to assess the effects of treatment, including the IRLS scale and Clinical Global Impression-Global Improvement (CGI-I) scores.

The IRLS scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS.

The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms.

Three of the controlled trials utilized the change from baseline in the IRLS scale at the Week 12 endpoint as the primary efficacy outcome.

Three hundred eighty patients were randomized to receive ropinirole tablets (n = 187) or placebo (n = 193) in a US trial (RLS-1); 284 were randomized to receive either ropinirole tablets (n = 146) or placebo (n = 138) in a multinational trial (excluding US) (RLS-2); and 267 patients were randomized to ropinirole tablets (n = 131) or placebo (n = 136) in a multinational trial (including US) (RLS-3).

Across the three trials, the mean duration of RLS was 16 to 22 years (range: 0 to 65 years), mean age was approximately 54 years (range: 18 to 79 years), and approximately 61% were women.

The mean dose at Week 12 was approximately 2 mg/day for the three trials.

At baseline, mean total IRLS score was 22 for ropinirole tablets and 21.6 for placebo in RLS-1, was 24.4 for ropinirole tablets and 25.2 for placebo in RLS-2, and was 23.6 for ropinirole tablets and 24.8 for placebo in RLS-3.

In all three trials, a statistically significant difference between the treatment group receiving ropinirole tablets and the treatment group receiving placebo was observed at Week 12 for both the mean change from baseline in the IRLS scale total score and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I (see Table 9).

Table 9.

Mean Change in Total IRLS Score and Percent Responders on CGI-I Ropinirole Tablets Placebo Difference from Placebo Mean change in total IRLS score at Week 12 RLS-1 -13.5 -9.8 -3.7 RLS-2 -11.0 -8.0 -3.0 RLS-3 -11.2 -8.7 -2.5 Percent responders on CGI-I at Week 12 RLS-1 73.3% 56.5% 16.8% RLS-2 53.4% 40.9% 12.5% RLS-3 59.5% 39.6% 19.9% Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week trial.

Following a 24-week, single-blind treatment phase (flexible dosages of ropinirole tablets of 0.25 to 4 mg once daily), patients who were responders (defined as a decrease of >6 points on the IRLS scale total score relative to baseline) were randomized in double-blind fashion to placebo or continuation of ropinirole tablets for an additional 12 weeks.

Relapse was defined as an increase of at least 6 points on the IRLS scale total score to a total score of at least 15, or withdrawal due to lack of efficacy.

For patients who were responders at Week 24, the mean dose of ropinirole tablets was 2 mg (range: 0.25 to 4 mg).

Patients continued on ropinirole tablets demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% versus 57.8%, P = 0.0156).

CLINICAL STUDIES

14 14.1 Irritable Bowel Syndrome with Constipation (IBS-C) The efficacy of LINZESS for the management of symptoms of IBS-C was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 1 (NCT00948818) and 2 (NCT00938717)).

A total of 800 patients in Trial 1 and 804 patients in Trial 2 [overall mean age of 44 years (range 18 to 87 years), 90% female, 77% white, 19% black, and 12% Hispanic] received treatment with LINZESS 290 mcg or placebo once daily and were evaluated for efficacy.

All patients met Rome II criteria for IBS and were required, during the 2-week baseline period, to meet the following criteria: a mean abdominal pain score of at least 3 on a 0-to-10-point numeric rating scale less than 3 complete spontaneous bowel movements (CSBMs) per week [a CSBM is a spontaneous bowel movement (SBM) that is associated with a sense of complete evacuation; a SBM is a bowel movement occurring in the absence of laxative use], and less than or equal to 5 SBMs per week.

The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment.

During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat IBS-C or chronic constipation.

Efficacy of LINZESS was assessed using overall responder analyses and change-from-baseline endpoints.

Results for endpoints were based on information provided daily by patients in diaries.

The 4 primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment.

For the 9 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain, at least 3 CSBMs and an increase of at least 1 CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment.

Each of the 2 components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint.

For the 6 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least 1 CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment.

To be considered a responder for this analysis, patients did not have to have at least 3 CSBMs per week.

The efficacy results for the 9 out of 12 weeks and the 6 out of 12 weeks responder endpoints are shown in Tables 3 and 4, respectively.

In both trials, the proportion of patients who were responders to LINZESS 290 mcg was statistically significantly higher than with placebo.

Table 3: Efficacy Responder Rates in the Two Placebo-controlled IBS-C Trials: At Least 9 Out of 12 Weeks Trial 1 Trial 2 LINZESS 290 mcg (N=405) Placebo (N=395) Treatment Difference [95% CI] LINZESS 290 mcg (N=401) Placebo (N=403) Treatment Difference [95% CI] Combined Responder* (Abdominal Pain and CSBM Responder) 12% 5% 7% [3.2%, 10.9%] 13% 3% 10% [6.1%, 13.4%] Abdominal Pain Responder* (≥ 30% Abdominal Pain Reduction) 34% 27% 7% [0.9%, 13.6%] 39% 20% 19% [13.2%, 25.4%] CSBM Responder* (≥ 3 CSBMs and Increase ≥1 CSBM from Baseline) 20% 6% 13% [8.6%, 17.7%] 18% 5% 13% [8.7%, 17.3%] * Primary Endpoints Note: Analyses based on first 12 weeks of treatment for both Trials 1 and 2 CI =Confidence Interval Table 4: Efficacy Responder Rates in the Two Placebo-controlled IBS-C Trials: At Least 6 Out of 12 Weeks Trial 1 Trial 2 LINZESS 290 mcg (N=405) Placebo (N=395) Treatment Difference [95% CI] LINZESS 290 mcg (N=401) Placebo (N=403) Treatment Difference [95% CI] Combined Responder* (Abdominal Pain and CSBM Responder) 34% 21% 13% [6.5%, 18.7%] 34% 14% 20% [14.0%, 25.5%] Abdominal Pain Responder** (≥ 30% Abdominal Pain Reduction) 50% 37% 13% [5.8%, 19.5%] 49% 34% 14% [7.6%, 21.1%] CSBM Responder** (Increase ≥ 1 CSBM from Baseline) 49% 30% 19% [12.4%, 25.7%] 48% 23% 25% [18.7%, 31.4%] * Primary Endpoint, ** Secondary Endpoints Note: Analyses based on first 12 weeks of treatment for both Trials 1 and 2 CI =Confidence Interval In each trial, improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment periods.

For change from baseline in the 11-point abdominal pain scale, LINZESS 290 mcg began to separate from placebo in the first week.

Maximum effects were seen at weeks 6 – 9 and were maintained until the end of the study.

The mean treatment difference from placebo at week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale).

Maximum effect on CSBM frequency occurred within the first week, and for change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs per week in both trials.

In each trial, in addition to improvements in abdominal pain and CSBM frequency over the first 12 weeks of the treatment period, improvements were observed in the following when LINZESS was compared to placebo: SBM frequency [SBMs/week], stool consistency [as measured by the Bristol Stool Form Scale (BSFS)], and amount of straining with bowel movements [amount of time pushing or physical effort to pass stool].

During the 4-week randomized withdrawal period in Trial 1, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on LINZESS 290 mcg.

In LINZESS-treated patients re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week and did not result in worsening compared to baseline.

Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks.

Patients on placebo who were allocated to LINZESS had an increase in CSBM frequency and a decrease in abdominal pain levels that were similar to the levels observed in patients taking LINZESS during the treatment period.

Trial 6 (NCT03573908) was a randomized, double-blind, placebo-controlled, parallel-group trial that evaluated the safety and efficacy of LINZESS in patients with IBS-C over a 12-week treatment period followed by a 4-week randomized withdrawal period.

A total of 614 patients [mean age of 47 years (range 18 to 85 years), 81% female, 63% white, 24% black, and 27% Hispanic] received treatment with LINZESS 290 mcg or placebo once daily and all patients met Rome III criteria for IBS-C.

The efficacy of LINZESS was assessed using a primary endpoint based on the mean abdominal score (composite of abdominal bloating, abdominal discomfort, and abdominal pain) across 12 weeks.

The secondary endpoint was a responder analysis based on at least a 2.5-point improvement in the abdominal score from baseline for at least 6 out of 12 weeks as shown in Table 5.

Table 5: Efficacy Endpoints in IBS-C Trial 6: Overall Change from Baseline in Abdominal Score and Responder Rates for a t Least 6 Out of 12 Weeks Trial 6 LINZESS 290 mcg (N= 306 ) Placebo (N= 308 ) Treatment Difference [95% CI] Baseline Abdominal Score 6.4 6.5 Least Squares 12-week Mean C hange from B aseline in Abdominal Score * -1.9 -1.2 -0.7 [-1.0, -0.4] Abdominal Score 6 of 12- W eek Responder* * 34% 18.5% 15.5% [8.6%, 22.3%] * Primary Endpoint, ** Secondary Endpoint Each abdominal symptom was rated on a 0-to-10-point numeric rating scale where 0=no [symptom] and 10=worst possible [symptom].

CI = Confidence Interval 14.2 Chronic Idiopathic Constipation (CIC) The efficacy of LINZESS for the management of symptoms of CIC was established in two double-blind, placebo-controlled, randomized, multicenter clinical trials in adult patients (Trials 3 and 4).

A total of 642 patients in Trial 3 and 630 patients in Trial 4 [overall mean age of 48 years (range 18 to 85 years), 89% female, 76% white, 22% black, 10% Hispanic] received treatment with LINZESS 145 mcg, 290 mcg, or placebo once daily and were evaluated for efficacy.

All patients met modified Rome II criteria for functional constipation.

Modified Rome II criteria were less than 3 Spontaneous Bowel Movements (SBMs) per week and 1 of the following symptoms for at least 12 weeks, which need not be consecutive, in the preceding 12 months: Straining during greater than 25% of bowel movements Lumpy or hard stools during greater than 25% of bowel movements Sensation of incomplete evacuation during greater than 25% of bowel movements Patients were also required to have less than 3 CSBMs per week and less than or equal to 6 SBMs per week during a 2-week baseline period.

Patients were excluded if they met criteria for IBS-C or had fecal impaction that required emergency room treatment.

The trial designs were identical through the first 12 weeks.

Trial 3 also included an additional 4-week randomized withdrawal (RW) period.

During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat chronic constipation.

The efficacy of LINZESS was assessed using a responder analysis and change-from-baseline endpoints.

Results for endpoints were based on information provided daily by patients in diaries.

A CSBM responder in the CIC trials was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period.

The CSBM responder rates are shown in Table 6.

During the individual double-blind placebo-controlled trials, LINZESS 290 mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with the LINZESS 145 mcg dose.

Therefore, the 145 mcg dose is the recommended dose.

Only the data for the approved 145 mcg dose of LINZESS are presented in Table 6.

In Trials 3 and 4, the proportion of patients who were CSBM responders was statistically significantly greater with the LINZESS 145 mcg dose than with placebo.

Table 6: Efficacy Responder Rates in the Two Placebo-controlled CIC Trials: at Least 9 Out of 12 Weeks Trial 3 Trial 4 LINZESS 145 mcg (N=217) Placebo (N=209) Treatment Difference [95% CI] LINZESS 145 mcg (N=213) Placebo (N=215) Treatment Difference [95% CI] CSBM Responder* (≥ 3 CSBMs and Increase ≥ 1 CSBM from Baseline) 20% 3% 17% [11.0%, 22.8%] 15% 6% 10% [4.2%, 15.7%] *Primary Endpoint CI=Confidence Interval CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4.

For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs.

On average, patients who received LINZESS across the 2 trials had significantly greater improvements compared with patients receiving placebo in stool frequency (CSBMs/week and SBMs/week), and stool consistency (as measured by the BSFS).

In each trial, in addition to improvements in CSBM frequency over the first 12 weeks of the treatment period, improvements were observed in each of the following when LINZESS was compared to placebo: SBM frequency [SBMs/week], stool consistency [as measured by the BSFS], and amount of straining with bowel movements [amount of time pushing or physical effort to pass stool].

During the 4-week randomized withdrawal period in Trial 3, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of LINZESS taken during the treatment period.

In LINZESS-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline.

Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks.

Patients on placebo who were allocated to LINZESS had an increase in CSBM and SBM frequency similar to the levels observed in patients taking LINZESS during the treatment period.

A 72 mcg dose of LINZESS was established in a randomized, double-blind, placebo-controlled, multicenter clinical trial in adult patients (Trial 5).

A total of 1223 patients [overall mean age of 46 years (range 18 to 90 years), 77% female, 71% white, 24% black, 43% Hispanic] received treatment with LINZESS 72 mcg or placebo once daily and were evaluated for efficacy.

All patients met modified Rome III criteria for functional constipation.

Trial 5 was identical to Trials 3 and 4 through the first 12 weeks.

The efficacy of the 72 mcg dose was assessed using a responder analysis where a CSBM responder was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period, which was the same as the one defined in Trials 3 and 4.

The response rates for the CSBM responder endpoint were 13% for LINZESS 72 mcg and 5% for placebo.

The difference between LINZESS 72 mcg and placebo was 9% (95% CI: 4.8%, 12.5%).

A separate analysis was performed using an alternate CSBM responder definition.

In this analysis a CSBM responder was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period and at least 3 of the last 4 weeks of the treatment period.

The response rates for the alternate CSBM responder endpoint were 12% for LINZESS 72 mcg and 5% for placebo.

The difference between LINZESS 72 mcg and placebo was 8% (95% CI: 3.9%, 11.5%).