Author: druginteractionchecker_lgaiz4

CLINICAL STUDIES

14 14.1 Chronic Idiopathic Constipation Two double-blinded, placebo-controlled studies of identical design were conducted in patients with chronic idiopathic constipation.

Chronic idiopathic constipation was defined as, on average, less than 3 spontaneous bowel movements (SBMs) per week (a SBM is a bowel movement occurring in the absence of laxative use) along with one or more of the following symptoms of constipation for at least 6 months prior to randomization: 1) very hard stools for at least a quarter of all bowel movements; 2) sensation of incomplete evacuation following at least a quarter of all bowel movements; and 3) straining with defecation at least a quarter of the time.

Following a 2-week baseline/washout period, a total of 479 patients (mean age 47.2 [range 20–81] years; 88.9% female; 80.8% Caucasian, 9.6% African American, 7.3% Hispanic, 1.5% Asian; 10.9% ≥ 65 years of age) were randomized and received Amitiza 24 mcg twice daily or placebo twice daily for 4 weeks.

The primary endpoint of the studies was SBM frequency.

The studies demonstrated that patients treated with Amitiza had a higher frequency of SBMs during Week 1 than the placebo patients.

In both studies, results similar to those in Week 1 were also observed in Weeks 2, 3, and 4 of therapy (Table 5).

Table 5: Spontaneous Bowel Movement Frequency Rates Frequency rates are calculated as 7 times (number of SBMs) / (number of days observed for that week).

(Efficacy Studies) Trial Study Arm Baseline Mean ± SD Median Week 1 Mean ± SD Median Week 2 Mean ± SD Median Week 3 Mean ± SD Median Week 4 Mean ± SD Median Week 1 Change from Baseline Mean ± SD Median Week 4 Change from Baseline Mean ± SD Median Placebo 1.6 ± 1.3 1.5 3.5 ± 2.3 3.0 3.2 ± 2.5 3.0 2.8 ± 2.2 2.0 2.9 ± 2.4 2.3 1.9 ± 2.2 1.5 1.3 ± 2.5 1.0 Study 1 Amitiza 24 mcg Twice Daily 1.4 ± 0.8 1.5 5.7 ± 4.4 5.0 5.1 ± 4.1 4.0 5.3 ± 4.9 5.0 5.3 ± 4.7 4.0 4.3 ± 4.3 3.5 3.9 ± 4.6 3.0 Placebo 1.5 ± 0.8 1.5 4.0 ± 2.7 3.5 3.6 ± 2.7 3.0 3.4 ± 2.8 3.0 3.5 ± 2.9 3.0 2.5 ± 2.6 1.5 1.9 ± 2.7 1.5 Study 2 Amitiza 24 mcg Twice Daily 1.3 ± 0.9 1.5 5.9 ± 4.0 5.0 5.0 ± 4.2 4.0 5.6 ± 4.6 5.0 5.4 ± 4.8 4.3 4.6 ± 4.1 3.8 4.1 ± 4.8 3.0 In both studies, Amitiza demonstrated increases in the percentage of patients who experienced SBMs within the first 24 hours after administration when compared to placebo (56.7% vs.

36.9% in Study 1 and 62.9% vs.

31.9% in Study 2, respectively).

Similarly, the time to first SBM was shorter for patients receiving Amitiza than for those receiving placebo.

Signs and symptoms related to constipation, including abdominal bloating, abdominal discomfort, stool consistency, and straining, as well as constipation severity ratings, were also improved with Amitiza versus placebo.

The results were consistent in subpopulation analyses for gender, race, and elderly patients (≥ 65 years of age).

During a 7-week randomized withdrawal study, patients who received Amitiza during a 4-week treatment period were then randomized to receive either placebo or to continue treatment with Amitiza.

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

Patients who continued on Amitiza maintained their response to therapy over the additional 3 weeks of treatment.

14.2 Opioid-induced Constipation The efficacy of Amitiza in the treatment of opioid-induced constipation in patients receiving opioid therapy for chronic, non-cancer-related pain was assessed in three randomized, double-blinded, placebo-controlled studies.

In Study 1, the median age was 52 years (range 20–82) and 63.1% were female.

In Study 2, the median age was 50 years (range 21–77) and 64.4% were female.

In Study 3, the median age was 50 years (range 21–89) and 60.1% were female.

Patients had been receiving stable opioid therapy for at least 30 days prior to screening, which was to continue throughout the 12-week treatment period.

At baseline, mean oral morphine equivalent daily doses (MEDDs) were 99 mg and 130 mg for placebo-treated and Amitiza-treated patients, respectively, in Study 1.

Baseline mean MEDDs were 237 mg and 265 mg for placebo-treated and Amitiza-treated patients, respectively, in Study 2.

In Study 3, baseline mean MEDDs were 330 mg and 373 mg for placebo-treated and Amitiza-treated patients, respectively.

The Brief Pain Inventory-Short Form (BPI-SF) questionnaire was administered to patients at baseline and monthly during the treatment period to assess pain control.

Patients had documented opioid-induced constipation at baseline, defined as having less than 3 spontaneous bowel movements (SBMs) per week, with at least 25% of SBMs associated with one or more of the following conditions: (1) hard to very hard stool consistency; (2) moderate to very severe straining; and/or (3) having a sensation of incomplete evacuation.

Laxative use was discontinued at the beginning of the screening period and throughout the study.

With the exception of the 48-hour period prior to first dose and for at least 72 hours (Study 1) or 1 week (Study 2 and Study 3) following first dose, use of rescue medication was allowed in cases where no bowel movement had occurred in a 3-day period.

Median weekly SBM frequencies at baseline were 1.5 for placebo patients and 1.0 for Amitiza patients in Study 1 and, for both Study 2 and Study 3, median weekly SBM frequencies at baseline were 1.5 for both treatment groups.

In Study 1, patients receiving non-diphenylheptane (e.g., non-methadone) opioids (n = 431) were randomized to receive placebo (n = 217) or Amitiza 24 mcg twice daily (n = 214) for 12 weeks.

The primary efficacy analysis was a comparison of the proportion of “overall responders” in each treatment arm.

A patient was considered an “overall responder” if ≥1 SBM improvement over baseline were reported for all treatment weeks for which data were available ≥3 SBMs/week were reported for at least 9 of 12 treatment weeks.

The proportion of patients in Study 1 qualifying as an “overall responder” was 27.1% in the group receiving Amitiza 24 mcg twice daily compared to 18.9% of patients receiving placebo twice daily (treatment difference = 8.2%; p-value = 0.03).

Examination of gender and race subgroups did not identify differences in response to Amitiza among these subgroups.

There were too few elderly patients (≥ 65 years of age) to adequately assess differences in effects in that population.

and In Study 2, patients receiving opioids (N = 418) were randomized to receive placebo (n = 208) or Amitiza 24 mcg twice daily (n = 210) for 12 weeks.

Study 2 did not exclude patients receiving diphenylheptane opioids (e.g., methadone).

The primary efficacy endpoint was the mean change from baseline in SBM frequency at Week 8; 3.3 vs.

2.4 for Amitiza and placebo-treated patients, respectively; treatment difference = 0.9; p-value = 0.004.

The proportion of patients in Study 2 qualifying as an “overall responder,” as prespecified in Study 1, was 24.3% in the group receiving Amitiza compared to 15.4% of patients receiving placebo.

In the subgroup of patients in Study 2 taking diphenylheptane opioids (baseline mean [median] MEDDs of 691 [403] mg and 672 [450] mg for placebo and Amitiza patients, respectively), the proportion of patients qualifying as an “overall responder” was 20.5% (8/39) in the group receiving Amitiza compared to 6.3% (2/32) of patients receiving placebo.

Examination of gender and race subgroups did not identify differences in response to Amitiza among these subgroups.

There were too few elderly patients (≥ 65 years of age) to adequately assess differences in effects in that population.

In Study 3, patients receiving opioids (N = 451) were randomized to placebo (n = 216) or Amitiza 24 mcg twice daily (n = 235) for 12 weeks.

Study 3 did not exclude patients receiving diphenylheptane opioids (e.g., methadone).

The primary efficacy endpoint was the change from baseline in SBM frequency at Week 8.

The study did not demonstrate a statistically significant improvement in SBM frequency rates at Week 8 (mean change from baseline of 2.7 vs.

2.5 for Amitiza and placebo-treated patients, respectively; treatment difference = 0.2; p-value = 0.76).

The proportion of patients in Study 3 qualifying as an “overall responder,” as prespecified in Study 1, was 15.3% in the patients receiving Amitiza compared to 13.0% of patients receiving placebo.

In the subgroup of patients in Study 3 taking diphenylheptane opioids (baseline mean [median] MEDDs of 730 [518] mg and 992 [480] mg for placebo and Amitiza patients, respectively), the proportion of patients qualifying as an “overall responder” was 2.1% (1/47) in the group receiving Amitiza compared to 12.2% (5/41) of patients receiving placebo.

14.3 Irritable Bowel Syndrome with Constipation Two double-blinded, placebo-controlled studies of similar design were conducted in patients with IBS-C.

IBS was defined as abdominal pain or discomfort occurring over at least 6 months with two or more of the following: 1) relieved with defecation; 2) onset associated with a change in stool frequency; and 3) onset associated with a change in stool form.

Patients were sub-typed as having IBS-C if they also experienced two of three of the following: 1) 25% hard stools, and 3) > 25% SBMs associated with straining.

Following a 4-week baseline/washout period, a total of 1154 patients (mean age 46.6 [range 18–85] years; 91.6% female; 77.4% Caucasian, 13.2% African American, 8.5% Hispanic, 0.4% Asian; 8.3% ≥ 65 years of age) were randomized and received Amitiza 8 mcg twice daily (16 mcg/day) or placebo twice daily for 12 weeks.

The primary efficacy endpoint was assessed weekly utilizing the patient’s response to a global symptom relief question based on a 7-point, balanced scale (“significantly worse” to “significantly relieved”): “How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week compared to how you felt before you entered the study?” The primary efficacy analysis was a comparison of the proportion of “overall responders” in each arm.

A patient was considered an “overall responder” if the criteria for being designated a “monthly responder” were met in at least 2 of the 3 months on study.

A “monthly responder” was defined as a patient who had reported “significantly relieved” for at least 2 weeks of the month or at least “moderately relieved” in all 4 weeks of that month.

During each monthly evaluation period, patients reporting “moderately worse” or “significantly worse” relief, an increase in rescue medication use, or those who discontinued due to lack of efficacy, were deemed non-responders.

The percentage of patients in Study 1 qualifying as an “overall responder” was 13.8% in the group receiving Amitiza 8 mcg twice daily compared to 7.8% of patients receiving placebo twice daily.

In Study 2, 12.1% of patients in the Amitiza 8 mcg group were “overall responders” versus 5.7% of patients in the placebo group.

In both studies, the treatment differences between the placebo and Amitiza groups were statistically significant.

The two randomized, placebo-controlled, double-blinded studies comprised 97 (8.4%) male patients, which is insufficient to determine whether men with IBS-C respond differently to Amitiza from women.

Results in men: During a 4-week randomized withdrawal period following Study 1, patients who received Amitiza during the 12-week treatment period were re-randomized to receive either placebo or to continue treatment with Amitiza.

In Amitiza-treated patients who were “overall responders” during Study 1 and who were re-randomized to placebo, SBM frequency rates did not result in worsening compared to baseline.

CLINICAL STUDIES

Clinical Studies Support for the indications Support for treatment of vasomotor symptoms and vaginal and vulvar atrophy was shown through bioequivalence of the E2 component of the combination product with a currently marketed E2 product (Estrace®).

The multiple-dose bioequivalence study evaluated the bioequivalence of E2 from a tablet containing DRSP (2 mg) and E2 (1 mg) relative to Estrace (1 mg) tablet.

DRSP/E2 tablets met the criteria for bioequivalence to Estrace.

Effects on Endometrium In a one year clinical trial of 1,142 postmenopausal subjects treated with E2 alone or E2 + 0.5, 1, 2, or 3 mg DRSP, endometrial biopsies were performed on 966 (84.6%) subjects during the treatment period.

Eight subjects in the E2 monotherapy group developed endometrial hyperplasia (4 simple hyperplasia with no cytological atypia, 3 complex hyperplasia with no cytological atypia, and 1 complex hyperplasia with cytological atypia), and one subject in the 1 mg E2 + 2 mg DRSP group developed simple hyperplasia with no cytological atypia.

Table 2 shows that there were no diagnoses of endometrial hyperplasia in the ANGELIQ group.

Table 2: Incidence of Endometrial Hyperplasia after up to 12 Months of Treatment E2 1 mg ANGELIQ Total No.

Subjects 226 227 Total No.

of On-Treatment Biopsies 197 (87.2%) 191 (84.1%) Hyperplasia 8 (4.0%) 0 (0%) Effects on Uterine Bleeding or Spotting In a cumulative analysis performed over 12 months in a double blind trial, the proportions of women with amenorrhea increased and at one year, 73.5% of subjects on ANGELIQ had amenorrhea.

Results are shown in Figure 2.

Figure 2: Cumulative proportion of subjects with amenorrhea at a given cycle through cycle 13, LOCF Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated equine estrogens (CE) per day alone or the use of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases.

The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied.

A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause.

The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA sub-study was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”.

Results of the CE/MPA sub-study, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 3 below: Table 3: Relative and Absolute Risk Seen in the CE/MPA Substudy of WHI Event c Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI) Placebo n = 8102 CE/MPA n = 8506 Absolute Risk per 10,000 Person-years CHD events Non-fatal MI CHD death 1.29 (1.02 – 1.63) 1.32 (1.02 – 1.72) 1.18 (0.70 – 1.97) 30 23 6 37 30 7 Invasive breast cancer 1.26 (1.00 – 1.59) 30 38 Stroke 1.41 (1.07 – 1.85) 21 29 Pulmonary embolism 2.13 (1.39 – 3.25) 8 16 Colorectal cancer 0.63 (0.43 – 0.92) 16 10 Endometrial cancer 0.83 (0.47 – 1.47) 6 5 Hip fracture 0.66 (0.45 – 0.98) 15 10 Death due to causes other than the events above 0.92 (0.74 – 1.14) 40 37 Global Index 1.15 (1.03 – 1.28) 151 170 Deep vein thrombosis not included in Global Index 2.07 (1.49 – 2.87) 13 26 Vertebral fractures 0.66 (0.44 – 0.98) 15 9 Other osteoporotic fractures 0.77 (0.69 – 0.86) 170 131 For those outcomes included in the “global index,” absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

The absolute excess risk of events included in the “global index” was 19 per 10,000 person-years.

There was no difference between the groups in terms of all-cause mortality.

(See Boxed Warnings , Warnings , and Precautions .) Women’s Health Initiative Memory Study The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia.

The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo.

Differences between groups became apparent in the first year of treatment.

It is unknown whether these findings apply to younger postmenopausal women.

(See Boxed Warnings and Warnings , 3.

Dementia .)

CLINICAL STUDIES

14 14.1 Healing of Erosive Esophagitis The healing rates of NEXIUM 40 mg, NEXIUM 20 mg, and omeprazole 20 mg (the approved dose for this indication) were evaluated in patients with endoscopically diagnosed erosive esophagitis in four multicenter, double-blind, randomized studies.

The healing rates at Weeks 4 and 8 were evaluated and are shown in the Table 9: Table 9: Erosive Esophagitis Healing Rate (Life-Table Analysis) Study No.

of Patients Treatment Groups Week 4 Week 8 Significance Level log-rank test vs.

omeprazole 20 mg 1 588 NEXIUM 20 mg 68.7% 90.6% N.S.

N.S.

= not significant (p > 0.05) 588 Omeprazole 20 mg 69.5% 88.3% 2 654 NEXIUM 40 mg 75.9% 94.1% p < 0.001 656 NEXIUM 20 mg 70.5% 89.9% p < 0.05 650 Omeprazole 20 mg 64.7% 86.9% 3 576 NEXIUM 40 mg 71.5% 92.2% N.S.

572 Omeprazole 20 mg 68.6% 89.8% 4 1216 NEXIUM 40 mg 81.7% 93.7% p < 0.001 1209 Omeprazole 20 mg 68.7% 84.2% In these same studies of patients with erosive esophagitis, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in the Table 10: Table 10: Sustained Resolution Defined as 7 consecutive days with no heartburn reported in daily patient diary.

of Heartburn (Erosive Esophagitis Patients) Cumulative Percent Defined as the cumulative proportion of patients who have reached the start of sustained resolution with Sustained Resolution Study No.

of Patients Treatment Groups Day 14 Day 28 Significance Level log-rank test vs.

omeprazole 20 mg 1 573 NEXIUM 20 mg 64.3% 72.7% N.S.

N.S.

= not significant (p > 0.05) 555 Omeprazole 20 mg 64.1% 70.9% 2 621 NEXIUM 40 mg 64.8% 74.2% p <0.001 620 NEXIUM 20 mg 62.9% 70.1% N.S.

626 Omeprazole 20 mg 56.5% 66.6% 3 568 NEXIUM 40 mg 65.4% 73.9% N.S.

551 Omeprazole 20 mg 65.5% 73.1% 4 1187 NEXIUM 40 mg 67.6% 75.1% p <0.001 1188 Omeprazole 20 mg 62.5% 70.8% In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive days with no heartburn) was 5 days for NEXIUM 40 mg, 7 to 8 days for NEXIUM 20 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 40 mg of NEXIUM with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of erosive esophagitis.

Long-Term Maintenance of Healing of Erosive Esophagitis Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients with endoscopically confirmed, healed erosive esophagitis to evaluate NEXIUM 40 mg (n=174), 20 mg (n=180), 10 mg (n=168) or placebo (n=171) once daily over six months of treatment.

No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg.

The percentages of patients that maintained healing of erosive esophagitis at the various time points are shown in the Figures 2 and 3: Figure 2: Maintenance of Healing Rates by Month (Study 177) s= scheduled visit Figure 3: Maintenance of Healing Rates by Month (Study 178) s= scheduled visit Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with NEXIUM compared to placebo.

In both studies, the proportion of patients on NEXIUM who remained in remission and were free of heartburn and other GERD symptoms was well differentiated from placebo.

In a third multicenter open label study of 808 patients treated for 12 months with NEXIUM 40 mg, the percentage of patients that maintained healing of erosive esophagitis was 93.7% for six months and 89.4% for one year.

Fig2 Fig3 14.2 Symptomatic Gastroesophageal Reflux Disease (GERD) Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 patients comparing four weeks of treatment with NEXIUM 20 mg or 40 mg once daily versus placebo for resolution of GERD symptoms.

Patients had ≥ 6-month history of heartburn episodes, no erosive esophagitis by endoscopy, and heartburn on at least four of the seven days immediately preceding randomization.

The percentage of patients that were symptom-free of heartburn was significantly higher in the NEXIUM groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4).

No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg.

The percent of patients symptom-free of heartburn by day are shown in the Figures 4 and 5: Figure 4: Percent of Patients Symptom-Free of Heartburn by Day (Study 225) Figure 5: Percent of Patients Symptom-Free of Heartburn by Day (Study 226) In three European symptomatic GERD trials, NEXIUM 20 mg and 40 mg and omeprazole 20 mg were evaluated.

No significant treatment related differences were seen.

Fig4 FIg5 14.3 Pediatric Gastroesophageal Reflux Disease (GERD) 1 to 11 Years of Age In a multicenter, parallel-group study, 109 pediatric patients with a history of endoscopically-proven GERD (1 to 11 years of age; 53 female; 89 Caucasian, 19 Black, 1 Other) were treated with NEXIUM once daily for up to 8 weeks to evaluate safety and tolerability.

Dosing by patient weight was as follows: weight < 20 kg: once daily treatment with NEXIUM 5 mg or 10 mg weight ≥ 20 kg: once daily treatment with NEXIUM 10 mg or 20 mg Patients were endoscopically characterized as to the presence or absence of erosive esophagitis.

Of the 109 patients, 53 had erosive esophagitis at baseline (51 had mild, 1 moderate, and 1 severe esophagitis).

Although most of the patients who had a follow up endoscopy at the end of 8 weeks of treatment healed, spontaneous healing cannot be ruled out because these patients had low grade erosive esophagitis prior to treatment, and the trial did not include a concomitant control.

12 to 17 Years of Age In a multicenter, randomized, double-blind, parallel-group study, 149 adolescent patients (12 to 17 years of age; 89 female; 124 Caucasian, 15 Black, 10 Other) with clinically diagnosed GERD were treated with either NEXIUM 20 mg or NEXIUM 40 mg once daily for up to 8 weeks to evaluate safety and tolerability.

Patients were not endoscopically characterized as to the presence or absence of erosive esophagitis.

14.4 Risk Reduction of NSAID-Associated Gastric Ulcer Two multicenter, double-blind, placebo-controlled studies were conducted in patients at risk of developing gastric and/or duodenal ulcers associated with continuous use of non-selective and COX-2 selective NSAIDs.

A total of 1429 patients were randomized across the 2 studies.

Patients ranged in age from 19 to 89 (median age 66.0 years) with 70.7% female, 29.3% male, 82.9% Caucasian, 5.5% Black, 3.7% Asian, and 8.0% Others.

At baseline, the patients in these studies were endoscopically confirmed not to have ulcers but were determined to be at risk for ulcer occurrence due to their age (≥60 years) and/or history of a documented gastric or duodenal ulcer within the past 5 years.

Patients receiving NSAIDs and treated with NEXIUM 20 mg or 40 mg once-a-day experienced significant reduction in gastric ulcer occurrences relative to placebo treatment at 26 weeks.

See Table 11.

No additional benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg.

These studies did not demonstrate significant reduction in the development of NSAID-associated duodenal ulcer due to the low incidence.

Table 11: Cumulative percentage of patients without gastric ulcers at 26 weeks: Study No.

of Patients Treatment Group % of Patients Remaining Gastric Ulcer Free %= Life Table Estimate.

Significant difference from placebo (p<0.01).

1 191 194 184 NEXIUM 20 mg NEXIUM 40 mg Placebo 95.4 96.7 88.2 2 267 271 257 NEXIUM 20 mg NEXIUM 40 mg Placebo 94.7 95.3 83.3 14.5 Helicobacter pylori (H.pylori) Eradication in Patients with Duodenal Ulcer Disease Triple Therapy (NEXIUM/amoxicillin/clarithromycin): Two multicenter, randomized, double-blind studies were conducted using a 10 day treatment regimen.

The first study (191) compared NEXIUM 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to NEXIUM 40 mg once daily plus clarithromycin 500 mg twice daily.

The second study (193) compared NEXIUM 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to NEXIUM 40 mg once daily.

H.

pylori eradication rates, defined as at least two negative tests and no positive tests from CLOtest ® , histology and/or culture, at 4 weeks post-therapy were significantly higher in the NEXIUM plus amoxicillin and clarithromycin group than in the NEXIUM plus clarithromycin or NEXIUM alone group.

The results are shown in Table 12: Table 12: H.

pylori Eradication Rates at 4 Weeks after 10 Day Treatment Regimen % of Patients Cured [95% Confidence Interval] (Number of Patients) Study Treatment Group Per-Protocol Patients were included in the analysis if they had H.

pylori infection documented at baseline, had at least one endoscopically verified duodenal ulcer ≥ 0.5 cm in diameter at baseline or had a documented history of duodenal ulcer disease within the past 5 years, and were not protocol violators.

Patients who dropped out of the study due to an adverse reaction related to the study drug were included in the analysis as not H.

pylori eradicated.

Intent-to-Treat Patients were included in the analysis if they had documented H.

pylori infection at baseline, had at least one documented duodenal ulcer at baseline, or had a documented history of duodenal ulcer disease, and took at least one dose of study medication.

All dropouts were included as not H.

pylori eradicated.

191 NEXIUM plus amoxicillin and clarithromycin 84% p < 0.05 compared to NEXIUM plus clarithromycin.

[78, 89] (n=196) 77% [71, 82] (n=233) NEXIUM plus clarithromycin 55% [48, 62] (n=187) 52% [45, 59] (n=215) 193 NEXIUM plus amoxicillin and clarithromycin 85% p < 0.05 compared to NEXIUM alone.

[74, 93] (n=67) 78% [67, 87] (n=74) NEXIUM 5% [0, 23] (n=22) 4% [0, 21] (n=24) The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10 day treatment regimen in the NEXIUM plus amoxicillin and clarithromycin group was 75% (n=156) and 57% (n=60) respectively, in the 191 and 193 studies (per-protocol analysis).

14.6 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome In a multicenter, open-label dose-escalation study of 21 patients (15 males and 6 females, 18 Caucasian and 3 Black, mean age of 55.5 years) with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, NEXIUM significantly inhibited gastric acid secretion.

Initial dose was 40 mg twice daily in 19/21 patients and 80 mg twice daily in 2/21 patients.

Total daily doses ranging from 80 mg to 240 mg for 12 months maintained gastric acid output below the target levels of 10 mEq/h in patients without prior gastric acid-reducing surgery and below 5 mEq/hr in patients with prior gastric acid-reducing surgery.

At the Month 12 final visit, 18/20 (90%) patients had Basal Acid Output (BAO) under satisfactory control (median BAO = 0.17 mmol/hr).

Of the 18 patients evaluated with a starting dose of 40 mg twice daily, 13 (72%) had their BAO controlled with the original dosing regimen at the final visit.

See Table 13.

Table 13: Adequate Acid Suppression at Final Visit by Dose Regimen NEXIUM dose at the Month 12 visit BAO under adequate control at the Month 12 visit (N=20) One patient was not evaluated.

40 mg twice daily 13/15 80 mg twice daily 4/4 80 mg three times daily 1/1

CLINICAL STUDIES

14 14.1 Adult Rheumatoid Arthritis Description of Clinical Studies of Intravenous ORENCIA for the Treatment of Patients with RA The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria.

Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization, and Study V did not require any specific number of tender or swollen joints.

ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in Studies I, II, III, IV, and VI.

• Study I (NCT00279760) evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept.

• In Study II (NCT00162266) and Study III (NCT00048568), the efficacy of ORENCIA were assessed in patients with an inadequate response to MTX and who were continued on their stable dose of MTX.

• In Study IV (NCT00048581), the efficacy of ORENCIA was assessed in patients with an inadequate response to a TNF antagonist, with the TNF antagonist discontinued prior to randomization; other DMARDs were permitted.

• Study V (NCT00048932) primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued.

Patients in Study V were not excluded for comorbid medical conditions.

• In Study VI (NCT00122382), the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration.

In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo.

Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8.

Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months.

Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV).

The dose of ORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg.

Description of Clinical Studies of Subcutaneous or Intravenous ORENCIA for the Treatment of Patients with Adult RA The efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1 (NCT00559585), which was a randomized, double-blind, double-dummy, non-inferiority study that compared ORENCIA administered subcutaneously to ORENCIA administered intravenously in 1457 patients with moderate to severely active RA, receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR).

In Study SC-1, patients were randomized with stratification by body weight (100 kg) to receive (1) ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or (2) ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter.

Subjects continued taking their current dose of MTX from the day of randomization.

Clinical Response in Adult RA Patients The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 9.

ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients.

Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III.

In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus MTX in Study VI.

In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients.

ACR responses were maintained up to three years in the open-label extension of Study II.

In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness.

In Study VI, a greater proportion of patients treated with ORENCIA plus MTX achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with MTX plus placebo (Table 9).

Of patients treated with ORENCIA plus MTX who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both.

In Study SC-1, the main outcome measure was ACR 20 at 6 months.

The pre-specified non-inferiority margin was a treatment difference of −7.5%.

As shown in Table 10, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment.

ACR 50 and 70 responses are also shown in Table 9.

No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown).

Table 9: Clinical Responses in Controlled Trials in Patients with RA Percent of Patients Intravenous Administration Subcutaneous or Intravenous Administration Inadequate Response to DMARDs Inadequate Response to Methotrexate (MTX) Inadequate Response to TNF Antagonists MTX-Naive Inadequate Response to MTX Study I Study III Study IV Study VI Study SC-1 * p<0.05, ORENCIA (ORN) vs placebo (PBO) or MTX.

† p<0.01, ORENCIA vs placebo or MTX.

‡ p<0.001, ORENCIA vs placebo or MTX.

§ 95% CI: −4.2, 4.8 (based on prespecified margin for non-inferiority of −7.5%).

a 10 mg/kg.

b Dosing based on weight range [ see Dosage and Administration (2.1) ] .

c Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.

d Refer to text for additional description of remaining joint activity.

e Per protocol data is presented in table.

For ITT; n=736, 721 for SC and IV ORENCIA, respectively.

Response Rate ORN a n=32 PBO n=32 ORN b +MTX n=424 PBO +MTX n=214 ORN b + DMARDs n=256 PBO + DMARDs n=133 ORN b +MTX n=256 PBO +MTX n=253 ORN e SC +MTX n=693 ORN e IV +MTX n=678 ACR 20 Month 3 53% 31% 62% ‡ 37% 46% ‡ 18% 64%* 53% 68% 69% Month 6 NA NA 68% ‡ 40% 50% ‡ 20% 75% † 62% 76% § 76% Month 12 NA NA 73% ‡ 40% NA NA 76% ‡ 62% NA NA ACR 50 Month 3 16% 6% 32% ‡ 8% 18% † 6% 40% ‡ 23% 33% 39% Month 6 NA NA 40% ‡ 17% 20% ‡ 4% 53% ‡ 38% 52% 50% Month 12 NA NA 48% ‡ 18% NA NA 57% ‡ 42% NA NA ACR 70 Month 3 6% 0 13% ‡ 3% 6%* 1% 19% † 10% 13% 16% Month 6 NA NA 20% ‡ 7% 10% † 2% 32% † 20% 26% 25% Month 12 NA NA 29% ‡ 6% NA NA 43% ‡ 27% NA NA Major Clinical Response c NA NA 14% ‡ 2% NA NA 27% ‡ 12% NA NA DAS28-CRP <2.6 d Month 12 NA NA NA NA NA NA 41% ‡ 23% NA NA The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 10 (results at Baseline [BL] and 6 months [6 M]).

In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients.

Table 10: Components of ACR Responses at 6 Months in Adult Patients with RA Intravenous Administration Subcutaneous or Intravenous Administration Inadequate Response to MTX Inadequate Response to TNF Antagonists Inadequate Response to MTX Study III Study IV Study SC-1 c † p<0.01, ORENCIA (ORN) vs placebo (PBO), based on mean percent change from baseline.

‡ p<0.001, ORENCIA vs placebo, based on mean percent change from baseline.

a Visual analog scale: 0 = best, 100 = worst.

b Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

c SC-1 is a non-inferiority study.

Per protocol data is presented in table.

ORN +MTX n=424 PBO +MTX n=214 ORN +DMARDs n=256 PBO +DMARDs n=133 ORN SC +MTX n=693 ORN IV +MTX n=678 Component (median) BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M Number of tender joints (0-68) 28 7 ‡ 31 14 30 13 ‡ 31 24 27 5 27 6 Number of swollen joints (0-66) 19 5 ‡ 20 11 21 10 ‡ 20 14 18 4 18 3 Pain a 67 27 ‡ 70 50 73 43 † 74 64 71 25 70 28 Patient global assessment a 66 29 ‡ 64 48 71 44 ‡ 73 63 70 26 68 27 Disability index b 1.75 1.13 ‡ 1.75 1.38 1.88 1.38 ‡ 2.00 1.75 1.88 1.00 1.75 1.00 Physician global assessment a 69 21 ‡ 68 40 71 32 ‡ 69 54 65 16 65 15 CRP (mg/dL) 2.2 0.9 ‡ 2.1 1.8 3.4 1.3 ‡ 2.8 2.3 1.6 0.7 1.8 0.7 The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1.

The time course for the ORENCIA group in Study VI was similar to that in Study III.

Figure 1: Percent of Patients Achieving ACR 50 Response by Visit* (Study III) *The same patients may not have responded at each time point.

The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15—SC 3%, IV 5%; Day 29—SC 11%, IV 14%; Day 57—SC 24%, IV 30%; Day 85—SC 33%, IV 38%; Day 113—SC 39%, IV 41%; Day 141—SC 46%, IV 47%; Day 169—SC 51%, IV 50%.

Figure 1 ACR50 Response Study III Radiographic Response in Adult RA Patients In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score.

ORENCIA/MTX slowed the progression of structural damage compared to placebo/MTX after 12 months of treatment as shown in Table 11.

Table 11: Mean Radiographic Changes in Study III a and Study VI b Parameter ORENCIA/MTX Placebo/MTX Differences P-value d a Patients with an inadequate response to MTX.

b MTX-naive patients.

c Patients received 1 year of placebo/MTX followed by 1 year of ORENCIA/MTX.

d Based on a nonparametric ANCOVA model.

Study III First Year TSS 1.07 2.43 1.36 <0.01 ES 0.61 1.47 0.86 <0.01 JSN score 0.46 0.97 0.51 <0.01 Second Year TSS 0.48 0.74 c – – ES 0.23 0.22 c – – JSN score 0.25 0.51 c – – Study VI First Year TSS 0.6 1.1 0.5 0.04 In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/MTX and 65% of patients initially randomized to placebo/MTX were evaluated radiographically at Year 2.

As shown in Table 11, progression of structural damage in ORENCIA/MTX-treated patients was further reduced in the second year of treatment.

Following 2 years of treatment with ORENCIA/MTX, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline.

Fifty-six percent (56%) of ORENCIA/MTX-treated patients had no progression during the first year compared to 45% of placebo/MTX-treated patients.

In their second year of treatment with ORENCIA/MTX, more patients had no progression than in the first year (65% vs 56%).

Physical Function Response and Health-Related Outcomes in Adult RA Patients Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI).

In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus MTX in Study VI.

In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous ORENCIA administration.

The results from Studies II and III are shown in Table 12.

Similar results were observed in Study V compared to placebo and in Study VI compared to MTX.

During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years.

Table 12: Mean Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) in Adult Patients with RA Inadequate Response to Methotrexate Study II Study III *** p<0.001, ORENCIA vs placebo.

a 10 mg/kg.

b Dosing based on weight range [ see Dosage and Administration (2.1) ] .

c Modified Health Assessment Questionnaire: 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

d Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

HAQ Disability Index ORENCIA a +MTX (n=115) Placebo +MTX (n=119) ORENCIA b +MTX (n=422) Placebo +MTX (n=212) Baseline (Mean) 0.98 c 0.97 c 1.69 d 1.69 d Mean Improvement Year 1 0.40 c, *** 0.15 c 0.66 d, *** 0.37 d Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III.

In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS).

14.2 Polyarticular Juvenile Idiopathic Arthritis Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration The safety and efficacy of ORENCIA with intravenous administration were assessed in Study JIA-1 (NCT00095173), a three-part study including an open-label extension in pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA).

Patients 6 to 17 years of age (n=190) with moderately to severely active pJIA who had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists, were treated.

Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h).

The patients enrolled had JIA subtypes that at disease onset included oligoarticular (16%), polyarticular (64%; 20% were rheumatoid factor positive), and systemic JIA without systemic manifestations (20%).

At study entry, 74% of patients were receiving MTX (mean dose, 13.2 mg/m 2 per week) and remained on a stable dose of MTX (those not receiving MTX did not initiate MTX treatment during the study).

In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1,000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter.

Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables.

Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare.

Disease flare was defined as a ≥30% worsening in at least 3 of the 6 JIA core set variables with ≥30% improvement in not more than 1 of the 6 JIA core set variables; ≥2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare.

At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively.

Pediatric ACR 30 responses were similar in all subtypes of JIA studied.

During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients (intravenous) experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%).

The risk of disease flare among patients continuing on intravenous ORENCIA was less than one-third than that for patients withdrawn from intravenous ORENCIA treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]).

Among patients who received intravenous ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year.

Polyarticular Juvenile Idiopathic Arthritis – Subcutaneous Administration ORENCIA for subcutaneous administration without an intravenous loading dose was assessed in Study JIA-2 (NCT01844518), a 2-period, open-label study that included pediatric patients 2 to 17 years of age (n=205).

Patients had active polyarticular disease at the time of the study and had inadequate response to at least one nonbiologic or biologic DMARD.

The JIA patient subtypes at study entry included polyarticular (79%; 22% were rheumatoid factor positive), extended and persistent oligoarticular (14%), enthesitis-related arthritis (1%), and systemic JIA without systemic manifestations (2%).

Patients had a mean disease duration of 2.5 years with active joints (mean, 11.9), joints with loss of motion (mean, 10.4), and elevated C-reactive protein (CRP) levels (mean, 1.2 mg/dL).

At study entry, 80% of patients were receiving MTX and remained on a stable dose of MTX.

Patients received weekly open-label ORENCIA subcutaneously by a weight-tiered dosing regimen.

The primary objective of the study was evaluation of PK in order to support the extrapolation of efficacy based on exposure to ORENCIA supported by descriptive efficacy [see Clinical Pharmacology (12.3) ] .

JIA ACR 30/50/70 responses assessed at 4 months in the 2- to 17-year-old patients treated with subcutaneous ORENCIA were consistent with the results from intravenous ORENCIA in Study JIA-1.

14.3 Psoriatic Arthritis The efficacy of ORENCIA was assessed in 594 adult patients (18 years and older) with psoriatic arthritis (PsA), in two randomized, double-blind, placebo-controlled studies (Studies PsA-I [NCT00534313] and PsA-II [NCT01860976]).

Patients had active PsA (≥3 swollen joints and ≥3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin lesion of at least 2 cm in diameter.

In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNF antagonists previously.

During the initial 24-week, double-blind period of Study PsA-I, 170 patients were randomized to receive one of four intravenous treatments on Days 1, 15, 29, and then every 28 days (there was no escape during the 24-week period): • Placebo • ORENCIA 3 mg/kg • ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg (weight-range-based dosing), or • ORENCIA 30 mg/kg on Days 1 and 15 followed by weight range-based ORENCIA dosing (i.e., 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg).

After the 24-week double blind period in Study PsA-I, patients received open-label intravenous ORENCIA every 28 days.

Patients were allowed to receive stable doses of concomitant MTX, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial.

At enrollment, approximately 60% of patients were receiving MTX.

At baseline, the mean (SD) CRP for ORENCIA IV was 17 mg/L (33.0) and mean number (SD) of tender joints and swollen joints was 22.2 (14.3) and 10.9 (7.6), respectively.

In PsA-II, 424 patients were randomized 1:1 to receive weekly doses of subcutaneous placebo or ORENCIA 125 mg without a loading dose for 24 weeks-in a double-blind manner, followed by open-label subcutaneous ORENCIA 125 mg weekly.

Patients were allowed to receive stable doses of concomitant MTX, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial.

At randomization, 60% of patients were receiving MTX.

The baseline disease characteristics included presence of joint erosion on X-rays in 84% (341/407) with a mean (SD) PsA-modified Sharp van der Heijde erosion score (SHS) of 10.8 (24.2), elevated serum C reactive protein (CRP) in 66% [277/421]) with a mean (SD) of 14.1 mg/L (25.9), and polyarticular disease in 98% (416/424) of patients with a mean number (SD) of tender joints and swollen joints of 20.2 (13.3) and 11.6 (7.5), respectively.

Patients who had not achieved at least a 20% improvement from baseline in their swollen and tender joint counts by Week 16 escaped to open-label subcutaneous ORENCIA 125 mg weekly.

The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response at Week 24 (Day 169).

Clinical Response in Adults with PsA A greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with intravenous ORENCIA (weight-range-based dosing as described above) compared to placebo in Study PsA-I and a greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with subcutaneous 125 mg compared to placebo in Study PsA-II at Week 24.

Responses were seen regardless of prior TNF antagonist treatment and regardless of concomitant non-biologic DMARD treatment.

The percent of patients achieving ACR 20, 50, or 70 responses in Studies PsA‑I and PsA-II are presented in Table 13 below.

Table 13: Proportion of Patients With ACR Responses at Week 24 in Studies PsA-I and PsA-II a PsA-I PsA-II * p<0.05 versus placebo.

a Patients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and were considered non-responders.

b Weight range-based intravenous dosing: ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg.

ORENCIA Weight-Range-Based Intravenous Dosing b N=40 Placebo N=42 ORENCIA 125 mg Subcutaneous N=213 Placebo N=211 ACR 20 47.5%* 19.0% 39.4%* 22.3% ACR 50 25.0% 2.4% 19.2% 12.3% ACR 70 12.5% 0% 10.3% 6.6% The percentage of patients in PsA-II achieving ACR 20 response through Week 24 is shown below in Figure 2.

Figure 2: Percent of Patients Achieving ACR 20 Response a in PsA-II Study Through Week 24 (Day 169) Results were generally consistent across the ACR components in Study PsA-I and PsA-II.

Improvements in enthesitis and dactylitis were seen with ORENCIA treatment at Week 24 in both PsA-I and PsA-II.

Orencia Figure 2 % of Patients achieving ACR 20 Physical Function Response in Adults with PsA In study PsA-I, there was a higher proportion of patients with at least a 0.30 decrease from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24, with an estimated difference for ORENCIA weight range-based dosing as described above (45%) vs.

placebo (19%) of 26.1 (95% confidence interval: 6.8, 45.5).

In study PsA-II, the proportion of patients with at least a 0.35 decrease from baseline in HAQ-DI on ORENCIA was 31%, as compared to 24% on placebo (estimated difference: 7%; 95% confidence interval: -1%, 16%).

There was a higher adjusted mean change from baseline in HAQ-DI on ORENCIA (-0.33) vs.

placebo (-0.20) at Week 24, with an estimated difference of -0.13 (95% confidence interval: -0.25, -0.01).

14.4 Prophylaxis of Acute Graft versus Host Disease Study GVHD-1 The efficacy of ORENCIA, in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), for the prophylaxis of acute graft versus host disease (aGVHD), was evaluated in a multicenter, two cohort clinical study (GVHD-1, NCT01743131) in patients age 6 years and older who underwent hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor (URD).

The two cohorts in GVHD-1 included: 1) an open-label, single-arm study of 43 patients who underwent a 7 of 8 Human Leukocyte Antigen (HLA)-matched HSCT (7 of 8 cohort); and 2) a randomized (1:1), double-blind, placebo-controlled study of patients who underwent an 8 of 8 HLA-matched HSCT who received ORENCIA or placebo in combination with a CNI and MTX (8 of 8 cohort).

In both the 7/8 and 8/8 cohorts, ORENCIA was administered at a dose of 10 mg/kg (1,000 mg maximum dose) as an intravenous infusion over 60 minutes, beginning on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation.

Baseline demographic and clinical characteristics of both the 7 of 8 and 8 of 8 cohorts are outlined below in Table 14.

Table 14: Baseline Demographic and Clinical Characteristics: 7 of 8 and 8 of 8 Cohort Treated Analysis Population in Study GVHD-1 7 of 8 Cohort 8 of 8 Cohort ORENCIA (+ CNI and MTX) N=43 ORENCIA (+ CNI and MTX) N=73 Placebo (+CNI and MTX) N=69 Age – Median 38 44 40 Age – Range 6-76 6-71 7-74 Gender – Male 27 (63) 41 (56) 37 (54) White 31 (72) 63 (86) 61 (88) Black or African American 7 (16) 3 (4.1) 2 (2.9) Asian 2 (4.7) 4 (6) 2 (2.9) Hispanic 7 (16) 4 (6) 2 (2.9) Malignancy type Acute Myeloid Leukemia (AML) 15 (35) 30 (41) 22 (32) Myelodysplastic Syndrome (MDS) 11 (26) 15 (21) 12 (17) Acute Lymphoblastic Leukemia (ALL) 8 (19) 20 (27) 22 (32) Acute leukemia or ambiguous lineage 1 (2.3) 0 1 (1.4) Hodgkin and Non-Hodgkin lymphoma 1 (2.3) 1 (1.4) 1 (1.4) Acute Lymphoblastic Lymphoma in 2nd or Greater Complete Remission 1 (2.3) 4 (6) 1 (1.4) Chronic Myelomonocytic leukemia 1 (2.3) 1 (1.4) 4 (6) Chronic Myelogenous leukemia 4 (9) 1 (1.4) 5 (7) Not reported 1 (2.3) 1 (1.4) 1 (1.4) GVHD Prophylaxis Cyclosporine 16 (37) 11 (15) 11 (16) Tacrolimus 27 (63) 62 (85) 58 (84) Type of Graft Bone Marrow 21 (49) 33 (45) 26 (38) Cytokine Mobilized Peripheral Blood (PBSC) 22 (51) 40 (55) 43 (62) Conditioning Regimen TBI and Chemotherapy 11 (26) 20 (27) 26 (38) Busulfan and Cyclophosphamide 13 (30) 28 (38) 21 (30) Busulfan and Fludarabine 8 (19) 7 (10) 2 (2.9) Melphalan and Fludarabine 11 (26) 18 (25) 20 (29) Efficacy was established based on overall survival (OS) and grade II-IV aGVHD free survival (GFS) results assessed at Day 180 post-transplantation.

ORENCIA + CNI and MTX did not significantly improve grade III-IV GFS versus placebo + CNI and MTX at Day 180 post-transplantation.

The efficacy results of the GVHD-1 8 of 8 cohort are shown in Table 15.

Table 15: Efficacy Results in 8 of 8 Cohort in Study GVHD-1 at Day 180 Post-Transplantation a Gr III-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade III-IV aGVHD, or death by any cause up to Day 180 post-transplantation.

b Gr II-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade II-IV aGVHD, or death by any cause up to Day 180 post-transplantation.

Endpoint ORENCIA (+CNI and MTX) n=73 Placebo (+CNI and MTX) n=69 Gr III-IV aGVHD Free Survival a Rate (95% CI) 87% (77%, 93%) 75% (63%, 84%) Hazard Ratio (95% CI) 0.55 (0.26, 1.18) Gr II-IV aGVHD Free Survival b Rate (95% CI) 50% (38%, 61%) 32% (21%, 43%) Hazard Ratio (95% CI) 0.54 (0.35, 0.83) Overall Survival Rate (95% CI) 97% (89%, 99%) 84% (73%, 91%) Hazard Ratio (95% CI) 0.33 (0.12, 0.93) In an exploratory analysis of the 7 of 8 cohort of ORENCIA-treated patients (n=43), the rates of Grade III-IV GVHD-free survival, Grade II-IV GVHD-free survival, and overall survival at day 180 post-transplantation were 95% (95% CI 83%, 99%), 53% (95% CI 38%, 67%), and 98% (95% CI 85%, 100%), respectively.

Study GVHD-2 GVHD-2 (NCT05421299) was a clinical study that used data from the Center for International Blood and Marrow Transplant Research (CIBMTR).

The study analyzed outcomes of ORENCIA in combination with a CNI and MTX, versus a CNI and MTX alone, for the prophylaxis of aGVHD, in patients 6 years of age or older who underwent HSCT from a 1 allele-mismatched URD between 2011 and 2018.

The ORENCIA + CNI and MTX-treated group (n=54) included 42 patients from GVHD-1, in addition to 12 patients treated with ORENCIA outside of GVHD-1.

The comparator group (n=162) was randomly selected in a 3:1 ratio to the ORENCIA-treated group from the CIBMTR registry from patients who had not received ORENCIA during the study period.

Analyses used propensity score matching and inverse probability of treatment weighting to help address the impact of selection bias.

Efficacy was based on Overall Survival (OS) at Day 180 post-HSCT.

The OS rate at Day 180 in the ORENCIA in combination with CNI and MTX group was 98% (95% CI: 78, 100) and the OS rate at Day 180 in the CNI and MTX group was 75% (95% CI: 67, 82).

CLINICAL STUDIES

In a randomized, single-blind clinical trial of non-pregnant women with bacterial vaginosis who received metronidazole vaginal gel USP, 0.75% daily for 5 days, the clinical cure rates for evaluable patients determined at 4 weeks after completion of therapy for the QD and BID regimens were 98/185 (53%) and 109/190 (57%), respectively.

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CLINICAL STUDIES

14 14.1 Description of Clinical Studies The efficacy and safety of TIVICAY were evaluated in the studies summarized in Table 13 .

Table 13.

Trials Conducted with TIVICAY in HIV‑1‑Infected Subjects Population Trial Trial Arms Timepoint (Week) Adults: Treatment-naïve SPRING-2 (ING113086) (NCT01227824) TIVICAY + 2 NRTIs (n = 403) Raltegravir +3 NRTIs (n = 405) 96 SINGLE (ING114467) (NCT01263015) TIVICAY + EPZICOM (n = 414) ATRIPLA (n = 419) 144 FLAMINGO (ING114915) (NCT01449929) TIVICAY + NRTI BR (n = 243) Darunavir/ritonavir + NRTI BR (n = 242) 96 Treatment-experienced, INSTI-naïve SAILING (ING111762) (NCT01231516) TIVICAY + BR (n = 354) Raltegravir + BR (n = 361) 48 INSTI-experienced VIKING-3 (ING112574) (NCT01328041) TIVICAY + OBT (n = 183) 48 Virologically suppressed SWORD-1 (NCT02429791) SWORD-2 (NCT02422797) Pooled presentation TIVICAY + Rilpivirine (n = 513) CAR (n = 511) 48 Pediatrics: 6 years and older without INSTI resistance IMPAACT P1093 (NCT01302847) TIVICAY + BR (n = 46) 48 BR = Background regimen; CAR = Current antiretroviral regimen; OBT = Optimized background therapy 14.2 Adult Subjects Treatment-Naïve Subjects In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual NRTI treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]).

There were 808 subjects included in the efficacy and safety analyses.

At baseline, the median age of subjects was 36 years, 13% female, 15% non-white, 11% had hepatitis B and/or C virus co-infection, 2% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, 48% had CD4+ cell count less than 350 cells per mm 3 , and 39% received EPZICOM; these characteristics were similar between treatment groups.

In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily with fixed-dose abacavir sulfate and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA).

At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm 3 ; these characteristics were similar between treatment groups.

Outcomes for SPRING-2 (Week 96 analysis) and SINGLE (Week 144 open-label phase analysis which followed the Week 96 double-blind phase) are provided in Table 14 .

Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Table 14.

Virologic Outcomes of Randomized Treatment in SPRING-2 at Week 96 and SINGLE at Week 144 (Snapshot Algorithm) SPRING-2 Week 96 SINGLE Week 144 TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) HIV-1 RNA <50 copies/mL 82% 78% 71% 63% Treatment difference a 4.9% (95% CI: -0.6%, 10.3%) d 8.3% (95% CI: 2.0%, 14.6%) e Virologic nonresponse 5% 10% 10% 7% Data in window not <50 copies/mL 1% 3% 4% < 1% Discontinued for lack of efficacy 2% 3% 3% 3% Discontinued for other reasons while not suppressed < 1% 3% 3% 4% Change in ART regimen < 1% < 1% 0 0 No virologic data 12% 12% 18% 30% Reasons Discontinued study/study drug due to adverse event or death b 2% 2% 4% 14% Discontinued study/study drug for other reasons c 8% 9% 12% 13% Missing data during window but on study 2% < 1% 2% 3% Proportion (%) of Subjects with HIV-1 RNA 100,000 79% 63% 69% 61% Gender Male 84% 79% 72% 66% Female 70% 68% 69% 48% Race White 83% 78% 72% 71% African-American/African Heritage/Other 77% 75% 71% 47% a Adjusted for pre-specified stratification factors.

b Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window.

c Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.

d The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 86% in the raltegravir group, with a treatment difference of 2.6% and 95% CI of (-1.9%, 7.2%).

e The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with a treatment difference of 7.4% and 95% CI of (2.5%, 12.3%).

SPRING-2: Virologic outcomes were also comparable across baseline characteristics including CD4+ cell count, age, and use of EPZICOM or TRUVADA as NRTI background regimen.

The median change in CD4+ cell counts from baseline was 276 cells per mm 3 in the group receiving TIVICAY and 264 cells per mm 3 for the raltegravir group at 96 weeks.

There was no treatment-emergent resistance to dolutegravir or to the NRTI background.

SINGLE: Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race.

The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm 3 in the group receiving TIVICAY + EPZICOM and 332 cells per mm 3 for the ATRIPLA group at 144 weeks.

The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm 3 (15.6 cells per mm 3 , 78.2 cells per mm 3 ) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, and baseline CD4+ cell count).

There was no treatment-emergent resistance to dolutegravir, abacavir, or lamivudine.

FLAMINGO: In FLAMINGO, 485 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily (n = 243) or darunavir + ritonavir 800 mg/100 mg once daily (n = 242), both in combination with investigator-selected NRTI background regimen (either fixed-dose abacavir and lamivudine [EPZICOM] or fixed-dose emtricitabine/tenofovir disoproxil fumarate [TRUVADA]).

There were 484 subjects included in the efficacy and safety analyses.

At baseline, the median age of subjects was 34 years, 15% female, 28% non-white, 10% had hepatitis B and/or C virus co-infection, 3% were CDC Class C (AIDS), 25% had HIV‑1 RNA greater than 100,000 copies per mL, and 35% had CD4+ cell count less than 350 cells per mm 3 ; these characteristics were similar between treatment groups.

Overall response rates by Snapshot algorithm through Week 96 were 80% for TIVICAY and 68% for darunavir/ritonavir.

The proportion of subjects who were non-responders (HIV-1 RNA greater than or equal to 50 copies per mL) at Week 96 was 8% and 12% in the arms receiving TIVICAY and darunavir + ritonavir, respectively; no virologic data were available for 12% and 21% for subjects treated with TIVICAY and darunavir + ritonavir, respectively.

The adjusted overall response rate difference in proportion and 95% CI was 12.4% (4.7%, 20.2%).

No treatment-emergent primary resistance substitutions were observed in either treatment group.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects In the international, multicenter, double-blind trial (SAILING), 719 HIV‑1‑infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least 1 fully active agent.

There were 715 subjects included in the efficacy and safety analyses.

At baseline, the median age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or C virus co-infection, 46% were CDC Class C (AIDS), 20% had HIV-1 RNA greater than 100,000 copies per mL, and 72% had CD4+ cell count less than 350 cells per mm 3 ; these characteristics were similar between treatment groups.

All subjects had at least 2-class antiretroviral treatment resistance, and 49% of subjects had at least 3-class antiretroviral treatment resistance at baseline.

Week 48 outcomes for SAILING are shown in Table 15 .

Table 15.

Virologic Outcomes of Randomized Treatment in SAILING at 48 Weeks (Snapshot Algorithm) TIVICAY 50 mg Once Daily + BR a (n = 354) Raltegravir 400 mg Twice Daily + BR a (n = 361) HIV-1 RNA <50 copies/mL 71% 64% Adjusted b treatment difference 7.4% (95% CI: 0.7%, 14.2%) Virologic nonresponse 20% 28% No virologic data 9% 9% Reasons Discontinued study/study drug due to adverse event or death 3% 4% Discontinued study/study drug for other reasons c 5% 4% Missing data during window but on study 2% 1% Proportion (%) with HIV-1 RNA 50,000 copies/mL 62% 47% Background regimen No darunavir use 67% 60% Darunavir use with primary PI substitutions 85% 67% Darunavir use without primary PI substitutions 69% 70% Gender Male 70% 66% Female 74% 60% Race White 75% 71% African-American/African Heritage/Other 67% 57% a BR = Background regimen.

Background regimen was restricted to less than or equal to 2 antiretroviral treatments with at least 1 fully active agent.

b Adjusted for pre-specified stratification factors.

c Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.

Treatment differences were maintained across the baseline characteristics including CD4+ cell count and age.

The mean changes in CD4+ cell counts from baseline were 162 cells per mm 3 in the group receiving TIVICAY and 153 cells per mm 3 in the raltegravir group.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects VIKING-3 examined the effect of TIVICAY 50 mg twice daily over 7 days of functional monotherapy, followed by optimized background therapy (OBT) with continued treatment of TIVICAY 50 mg twice daily.

In the multicenter, open-label, single-arm VIKING-3 trial, 183 HIV‑1‑infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days, then received TIVICAY with OBT from Day 8.

A total of 183 subjects enrolled: 133 subjects with INSTI resistance at screening and 50 subjects with only historical evidence of resistance (and not at screening).

At baseline, median age of subjects was 48 years; 23% were female, 29% non-white, and 20% had hepatitis B and/or C virus co-infection.

Median baseline CD4+ cell count was 140 cells per mm 3 , median duration of prior antiretroviral treatment was 13 years, and 56% were CDC Class C.

Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had greater than or equal to 2 NRTI, 75% greater than or equal to 1 NNRTI, and 71% greater than or equal to 2 PI major substitutions; 62% had non-R5 virus.

Mean reduction from baseline in HIV-1 RNA at Day 8 (primary endpoint) was 1.4 log 10 (95% CI: 1.3 log 10 , 1.5 log 10 ).

Response at Week 48 was affected by baseline INSTI substitutions [see Microbiology ( 12.4 )] .

After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible.

Week 48 virologic outcomes for VIKING-3 are shown in Table 16 .

Table 16.

Virologic Outcomes of Treatment of VIKING-3 at 48 Weeks (Snapshot Algorithm) TIVICAY 50 mg Twice Daily + OBT (n = 183) HIV-1 RNA <50 copies/mL 63% Virologic nonresponse 32% No virologic data Reasons Discontinued study/study drug due to adverse event or death 3% Proportion (%) with HIV-1 RNA <50 copies/mL by Baseline Category Gender Male 63% Female 64% Race White 63% African-American/African Heritage/Other 64% Subjects harboring virus with Q148 and with additional Q148-associated secondary substitutions also had a reduced response at Week 48 in a stepwise fashion [see Microbiology ( 12.4 )].

The median change in CD4+ cell count from baseline was 80 cells per mm 3 at Week 48.

Virologically Suppressed Subjects SWORD-1 and SWORD-2 are identical 148-week, Phase 3, randomized, multicenter, parallel-group, non-inferiority trials.

A total of 1,024 adult HIV–1-infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 NRTIs plus either an INSTI, an NNRTI, or a PI) for at least 6 months (HIV-1 RNA less than 50 copies per mL), with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine received treatment in the trials.

Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to TIVICAY 50 mg plus rilpivirine 25 mg administered once daily.

The primary efficacy endpoint for the SWORD trial was the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL at Week 48.

The proportion of subjects with HIV-1 RNA less than 50 copies per mL at Week 48 was 95% for both treatment groups; treatment difference and 95% CI was -0.2% (-3.0%, 2.5%).

The proportion of subjects with HIV-1 RNA greater than or equal to 50 copies per mL (virologic failure) at Week 48 was 0.6% and 1.2% for the dolutegravir plus rilpivirine treatment group and the current antiretroviral regimen treatment groups, respectively; treatment difference and 95% CI was -0.6% (-1.7%, 0.6%).

Refer to the Prescribing Information for JULUCA (dolutegravir and rilpivirine) tablet for complete virologic outcome information.

14.3 Pediatric Subjects IMPAACT P1093 is a Phase 1/2, 48-week, multicenter, open-label trial to evaluate the pharmacokinetic parameters, safety, tolerability, and efficacy of TIVICAY in combination treatment regimens in HIV‑1‑infected infants, children, and adolescents.

Subjects were stratified by age, enrolling adolescents first (Cohort 1: aged 12 to less than 18 years) and then younger children (Cohort 2A: aged 6 to less than 12 years).

All subjects received a weight-based dose of TIVICAY [see Dosage and Administration ( 2.2 )] .

These 46 subjects had a mean age of 12 years (range: 6 to 17), were 54% female and 52% black.

At baseline, mean plasma HIV-1 RNA was 4.6 log 10 copies per mL, median CD4+ cell count was 639 cells per mm3 (range: 9 to 1,700), and median CD4+% was 23% (range: 1% to 44%).

Overall, 39% had baseline plasma HIV-1 RNA greater than 50,000 copies per mL and 33% had a CDC HIV clinical classification of category C.

Most subjects had previously used at least 1 NNRTI (50%) or 1 PI (70%).

At Week 24, the proportion of subjects with HIV-1 RNA less than 50 copies per mL in Cohort 1 and Cohort 2A was 70% (16/23) and 61% (14/23), respectively.

At Week 48, the proportion of subjects from Cohort 1 with HIV-1 RNA less than 50 copies per mL was 61% (14/23).

Virologic outcomes were also evaluated based on body weight.

Across both cohorts, virologic suppression (HIV-1 RNA less than 50 copies per mL) at Week 24 was achieved in 75% (18/24) of subjects weighing at least 40 kg and 55% (6/11) of subjects in the 30 to less than 40 kg weight-band.

At Week 48, 63% (12/19) of the subjects in Cohort 1 weighing at least 40 kg were virologically suppressed.

The median CD4+ cell count increase from baseline to Week 48 was 84 cells per mm 3 in Cohort 1.

For Cohort 2A, the median CD4+ cell count increase from baseline to Week 24 was 209 cells per mm 3 .

CLINICAL STUDIES

14 The use of lamivudine is based on the results of clinical studies in HIV-1-infected patients in combination regimens with other antiretroviral agents.

Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-l RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.

14.1 Adults Clinical Endpoint Study : NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled study comparing continued current therapy (zidovudine alone [62% of patients] or zidovudine with didanosine or zalcitabine [38% of patients]) to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1.

A total of 1,816 HIV-l-infected adults with 25 to 250 CD4+ cells/mm 3 (median = 122 cells/mm 3 ) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive.

The median duration on study was 12 months.

Results are summarized in Table 8.

Table 8.

Number of Patients (%) With at Least One HIV-1 Disease Progression Event or Death Endpoint Current Therapy (n= 460) Lamivudine plus Current Therapy (n=896) Lamivudine plus an NNRTI a plus Current Therapy (n=460) HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%) Death 27 (5.9%) 23 (2.6%) 14 (3.0%) a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States Surrogate Endpoint Studies : Dual Nucleoside Analogue Studies : Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine.

These studies demonstrated the antiviral effect of lamivudine in a 2-drug combination.

More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple- drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.

Dose Regimen Comparison Surrogate Endpoint Studies in Therapy-Naive Adults : EPV20001 was a multi-center, double-blind, controlled study in which patients were randomized 1:1 to receive lamivudine 300 mg once daily or lamivudine 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily.

A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm 3 (median = 362 cells/mm 3 ), and median baseline plasma HIV-1 RNA of 4.66 log 10 copies/mL.

Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9.

Figure 2.

Virologic Response Through Week 48, EPV20001 ab (Intent-to-Treat) a Roche AMPLICOR HIV-1 MONITOR.

b Responders at each visit are patients who had achieved and maintained HIV-1 RNA<400 copies/mL without discontinuation by that visit.

Table 9.

Outcomes of Randomized Treatment Through 48 Weeks (Intent-to- Treat) Outcome Lamivudine300mg Once Daily plus Zidovudine plus Efavirenz (n = 278) Lamivudine150mg Twice Daily plus Zidovudine plus Efavirenz (n = 276) Responder a 67% 65% Virologic failure b 8% 8% Discontinued due to clinical progression <1% 0% Discontinued due to adverse events 6% 12% Discontinued due to other reasons c 18% 14% a Achieved confirmed plasma HIV-1 RNA <400 copies/mL and maintained through 48 weeks.

b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48.

c Includes consent withdrawn, lost to followup, protocol violation, data outside the study-defined schedule, and randomized but never initiated treatment.

The proportions of patients with HIV-l RNA <50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for patients receiving lamivudine 300 mg once daily and 63% for patients receiving lamivudine 150 mg twice daily.

Median increases in CD4+ cell counts were 144 cells/mm 3 at Week 48 in patients receiving lamivudine 300 mg once daily and 146 cells/mm 3 for patients receiving lamivudine 150 mg twice daily.

A small, randomized, open-label pilot study, EPV40001, was conducted in Thailand.

A total of 159 treatment-naive adult patients (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm 3 , median plasma HIV-1 RNA 4.8 log 10 copies/mL) were enrolled.

Two of the treatment arms in this study provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily.

In intent-to-treat analyses of 48-week data, the proportions of patients with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-l RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice- daily group; and the median increases in CD4+ cell counts were 166 cells/mm 3 in the once-daily lamivudine group and 216 cells/mm 3 in the all-twice-daily group.

Figure2.jpg 14.2 Pediatric Patients Clinical Endpoint Study: ACTG300 was a multi-center, randomized, double-blind study that provided for comparison of lamivudine plus RETROVIR (zidovudine) with didanosine monotherapy.

A total of 471 symptomatic, HIV-1-infected therapy-naive (≤56 days of antiretroviral therapy) pediatric patients were enrolled in these 2 treatment arms.

The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-Caucasian.

The mean baseline CD4+ cell count was 868 cells/mm 3 (mean: 1,060 cells/mm3 and range: 0 to 4,650 cells/mm3 for patients ≤5 years of age; mean: 419 cells/mm 3 and range: 0 to 1,555 cells/mm 3 for patients >5 years of age) and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies/mL.

The median duration on study was 10.1 months for the patients receiving lamivudine plus zidovudine and 9.2 months for patients receiving didanosine monotherapy.

Results are summarized in Table 10.

Table 10.

Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or-Death) Endpoint Lamivudine plus Zidovudine (n = 236) Didanosine (n = 235) HIV-1 disease progression or death (total) 15 (6.4%) 37 (15.7%) Physical growth failure 7 (3.0%) 6 (2.6%) Central nervous system deterioration 4 (1.7%) 12 (5.1%) CDC Clinical Category C 2 (0.8%) 8 (3.4%) Death 2 (0.8%) 11 (4.7%)