14 CLINICAL STUDIES

14.1 Clinical Studies in Ulcerative Colitis

Intravenous Administration

The safety and efficacy of intravenous ENTYVIO were evaluated in two randomized, double-blind, placebo-controlled trials (UC Trials I and II) in adult patients with moderately to severely active ulcerative colitis (UC) defined as Mayo score of 6 to 12 with endoscopy subscore of two or three. The Mayo score ranges from 0 to 12 and has four subscales that are each scored from zero (normal) to three (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of two is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of three is defined by spontaneous bleeding and ulceration.

Enrolled patients in the U.S. had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine or 6-mercaptopurine) and/or an inadequate response, loss of response, or intolerance to a TNF blocker. Outside the U.S., prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response or intolerance to corticosteroids.

Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.

UC Trial I - Intravenous

In UC Trial I, 374 patients were randomized in a double-blind fashion (3:2) to receive ENTYVIO 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤30 mg/day or equivalent), and immunomodulators (azathioprine or 6-mercaptopurine) were permitted through Week 6.

At baseline, patients received corticosteroids (54%), immunomodulators (azathioprine or 6-mercaptopurine) (30%), and/or aminosalicylates (74%). Thirty-nine percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Eighteen percent of patients had an inadequate response, inability to taper or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline Mayo score was 9 in the ENTYVIO group and 8 in the placebo group.

In UC Trial I, a greater percentage of patients treated with intravenous ENTYVIO compared to patients treated with placebo achieved clinical response at Week 6 (defined in Table 4). A greater percentage of patients treated with intravenous ENTYVIO compared to patients treated with placebo also achieved clinical remission at Week 6 (defined in Table 4). In addition, a greater percentage of patients treated with ENTYVIO had improvement of endoscopic appearance of the mucosa at Week 6 (defined in Table 4).

Table 4. Proportion of Patients Meeting Efficacy Endpoints at Week 6 (UC Trial I)
Endpoint	Placebo N=149	ENTYVIO IV N=225	p-value	Treatment Difference and 95% CI
* Clinical response: reduction in complete Mayo score of ≥3 points and ≥30% from baseline with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. † Clinical remission: complete Mayo score of ≤2 points and no individual subscore >1 point. ‡ Improvement of endoscopic appearance of the mucosa: Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability).
Clinical Response* at Week 6	26%	47%	<0.001	22% (12%, 32%)
Clinical Remission† at Week 6	5%	17%	0.001	12% (5%, 18%)
Improvement of Endoscopic Appearance of the Mucosa‡ at Week 6	25%	41%	0.001	16% (6%, 26%)

UC Trial II - Intravenous

In order to be randomized to treatment in UC Trial II, patients had to have received intravenous ENTYVIO and be in clinical response at Week 6. Patients could have come from either UC Trial I or from a group who received ENTYVIO open-label.

In UC Trial II, 373 patients were randomized in a double-blind fashion (1:1:1) to one of the following regimens beginning at Week 6: intravenous ENTYVIO 300 mg every eight weeks, intravenous ENTYVIO 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine or 6-mercaptopurine) were permitted outside the U.S. but were not permitted beyond Week 6 in the U.S.

At Week 6, patients were receiving corticosteroids (61%), immunomodulators (azathioprine or 6-mercaptopurine) (32%), and aminosalicylates (75%). Thirty-two percent of patients had an inadequate response, loss of response or intolerance to a TNF blocker therapy. At Week 6, the median Mayo score was 8 in the ENTYVIO every eight week group, the ENTYVIO every four week group, and the placebo group. Patients who had achieved clinical response at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.

In UC Trial II, a greater percentage of patients in groups treated with intravenous ENTYVIO as compared to placebo achieved clinical remission at Week 52, and maintained clinical response (clinical response at both Weeks 6 and 52) (Table 5). In addition, a greater percentage of patients in groups treated with intravenous ENTYVIO as compared to placebo were in clinical remission at both Weeks 6 and 52, and had improvement of endoscopic appearance of the mucosa at Week 52 (Table 5). In the subgroup of patients who achieved clinical response at Week 6 and were receiving corticosteroid medication at baseline, a greater proportion of patients in groups treated with intravenous ENTYVIO as compared to placebo discontinued corticosteroids and were in clinical remission at Week 52 (Table 5).

The ENTYVIO every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen [see Dosage and Administration (2.2)].

Table 5. Proportion of Patients Meeting Efficacy Endpoints at Week 52* (UC Trial II)
Endpoint	Placebo† N=126	ENTYVIO IV Every 8 Weeks N=122	p-value	Treatment Difference and 95% CI
* Patients must have achieved clinical response at Week 6 to continue into UC Trial II. This group includes patients that were not in clinical remission at Week 6. † The placebo group includes those patients who received ENTYVIO at Week 0 and Week 2 and were randomized to receive placebo from Week 6 through Week 52. ‡ Improvement of endoscopic appearance of the mucosa: Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability) at Week 52. § Corticosteroid-free clinical remission: Assessed in the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response at Week 6 (n=72 for placebo and n=70 for ENTYVIO every eight weeks). Corticosteroid-free clinical remission was defined as the proportion of patients in this subgroup that discontinued corticosteroids by Week 52 and were in clinical remission at Week 52.
Clinical Remission at Week 52	16%	42%	<0.001	26% (15%, 37%)
Clinical Response at both Weeks 6 and 52	24%	57%	<0.001	33% (21%, 45%)
Improvement of Endoscopic Appearance of the Mucosa‡ at Week 52	20%	52%	<0.001	32% (20%, 44%)
Clinical Remission at both Weeks 6 and 52	9%	21%	0.008	12% (3%, 21%)
Corticosteroid-free Clinical Remission§	14%§	31%§	0.012	18% (4%, 31%)

Subcutaneous Administration

SC UC Trial - Subcutaneous

The safety and efficacy of subcutaneous ENTYVIO was evaluated in a randomized, double-blind, placebo-controlled trial (SC UC Trial; NCT02611830) in adult patients with moderately to severely active ulcerative colitis defined as Mayo score of 6 to 12 with endoscopy subscore of two or three. The baseline Mayo score was between 9 to 12 in about 62% and six to eight in about 38% of the overall trial population.

The trial included patients who had experienced an inadequate response to, loss of response to, or intolerance to at least one of the following: at least one 12-week regimen of azathioprine or 6-mercaptopurine, induction with a TNF blocker, or corticosteroids. Patients were permitted to use concomitant stable doses of oral aminosalicylates, oral corticosteroids (prednisone ≤30 mg/day or budesonide ≤9 mg/day), azathioprine or 6-mercaptopurine, probiotics and/or antidiarrheals. Concomitant biologic therapies, rectal treatment with 5-aminosalicylic acid or corticosteroid enemas/suppositories were prohibited.

All patients received open-label intravenous ENTYVIO 300 mg at Week 0 and Week 2. In order to be randomized to treatment in SC UC Trial, patients had to be in clinical response at Week 6. A total of 162 patients were randomized at Week 6 in a double-blind fashion (2:1) to ENTYVIO 108 mg administered by subcutaneous injection or placebo every 2 weeks. Efficacy assessments were at Week 52.

Beginning at Week 6, patients who were receiving corticosteroids were required to begin a corticosteroid tapering regimen.

At the time of randomization into the double-blind phase (Week 6), patients were receiving corticosteroids (51%), immunomodulators (azathioprine or 6-mercaptopurine) (33%), and aminosalicylates (80%). Thirty-seven percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy prior to enrollment.

Patients in the double-blind phase had a mean age of 39 years (range 18 to 69 years); 61% were male; 83% identified as White, 17% as Asian, and <1% identified as another racial group.

The primary endpoint was the proportion of patients in clinical remission defined as a Mayo score of ≤2 points and no individual subscore >1 point at Week 52. Secondary endpoints included the proportion of patients with improvement of endoscopic appearance of the mucosa at Week 52 and clinical response at both Weeks 6 and 52 (see Table 6).

Table 6. Proportion of Patients Meeting Efficacy Endpoints at Week 52* (SC UC Trial)
Endpoint	Placebo†	ENTYVIO 108 mg SC Every 2 Weeks‡	Estimate§ of Treatment Difference vs. Placebo (95% CI)
* Patients must have achieved clinical response at Week 6 to continue into SC UC Trial. † The placebo group includes those subjects who received intravenous vedolizumab at Week 0 and Week 2 and were randomized to receive placebo from Week 6 through Week 52. ‡ Starting at Week 6 following two intravenous doses of ENTYVIO 300 mg administered as an intravenous infusion at Weeks 0 and 2. § Estimated treatment difference is based on the Cochran-Mantel-Haenszel method. ¶ Clinical remission: Complete Mayo score of ≤2 points and no individual subscore >1 point at Week 52. # p <0.001 Þ Improvement of endoscopic appearance of the mucosa: Mayo endoscopic subscore of ≤1 point. ß Clinical response: reduction in complete Mayo score of ≥3 points and ≥30% from baseline with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point.
Clinical Remission¶ at Week 52
Total Population	N=56 14%	N=106 46%	32 (20, 45)#
Prior TNF blocker failure	N=20 10%	N=40 35%
Without prior TNF blocker failure	N=36 17%	N=66 53%
Improvement of Endoscopic Appearance of the Mucosa at Week 52Þ
Total Population	N=56 21%	N=106 57%	36 (22, 49)#
Prior TNF blocker failure	N=20 10%	N=40 48%
Without prior TNF blocker failure	N=36 28%	N=66 62%
Clinical Response at both Weeks 6 and 52ß
Total Population	N=56 29%	N=106 64%	36 (21, 51)#
Prior TNF blocker failure	N=20 20%	N=40 68%
Without prior TNF blocker failure	N=36 33%	N=66 62%

Maintenance of remission at Week 52 in the subgroup of patients who were in remission at Week 6, was 64% (16/25) in the ENTYVIO-treated group compared to 20% (3/15) in the placebo group. The treatment difference was 44% (95% CI: 9%, 69%).

14.2 Clinical Studies in Crohn's Disease

Intravenous Administration

The safety and efficacy of intravenous ENTYVIO were evaluated in three randomized, double-blind, placebo-controlled clinical trials (CD Trials I, II, and III) in adult patients with moderately to severely active Crohn's disease (CD) (Crohn's Disease Activity Index [CDAI] score of 220 to 450).

Enrolled patients in the U.S. had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine, 6-mercaptopurine, or methotrexate) and/or an inadequate response, loss of response, or intolerance to one or more TNF blockers. Outside the U.S., prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of CD) or had an inadequate response or intolerance to corticosteroids.

Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 30 to 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.

CD Trial I - Intravenous

In CD Trial I, 368 patients were randomized in a double-blind fashion (3:2) to receive ENTYVIO 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤30 mg/day or equivalent), and immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) were permitted through Week 6.

At baseline, patients were receiving corticosteroids (49%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (35%), and/or aminosalicylates (46%). Forty-eight percent of the patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Seventeen percent of patients had inadequate response, inability to taper, or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline CDAI score was 324 in the intravenous ENTYVIO group and 319 in the placebo group.

In CD Trial I, a statistically significantly higher percentage of patients treated with intravenous ENTYVIO achieved clinical remission (defined as CDAI ≤150) as compared to placebo at Week 6 (Table 7). The difference in the percentage of patients who demonstrated clinical response (defined as a ≥100-point decrease in CDAI score from baseline), was however, not statistically significant at Week 6.

CD Trial II - Intravenous

Compared to CD Trial I, CD Trial II enrolled a higher number of patients who had over the previous five-year period had an inadequate response, loss of response, or intolerance to one or more TNF blockers (76%); this was the primary analysis population. In CD Trial II, 416 patients were randomized in a double-blind fashion (1:1) to receive either intravenous ENTYVIO 300 mg or placebo at Weeks 0, 2, and 6. Efficacy assessments were at Weeks 6 and 10. Concomitant aminosalicylates, corticosteroids, and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted through Week 10.

At baseline, patients were receiving corticosteroids (54%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (34%), and aminosalicylates (31%). The median baseline CDAI score was 317 in the ENTYVIO group and 301 in the placebo group.

For the primary endpoint (clinical remission at Week 6), treatment with intravenous ENTYVIO did not result in statistically significant improvement over placebo (Table 7). Secondary endpoints including assessments at Week 10 were not tested because the primary endpoint was not statistically significant.

Table 7. Proportion of Patients in Clinical Remission at Week 6 (CD Trials I and II)
Endpoint	Placebo	ENTYVIO IV	p-value	Treatment Difference and 95% CI
* Clinical Remission: CDAI ≤150. † Adjusted p-value for multiple comparisons of two primary endpoints. ‡ The primary analysis population for CD Trial II was patients that had an inadequate response, loss of response, or intolerance to one or more TNF blockers (76% of the overall population). § NS: Not significant (Secondary endpoints including assessments at Week 10 were not tested because the CD Trial II primary endpoint was not statistically significant).
CD Trial I: Clinical Remission* at Week 6	7% (10/148)	15% (32/220)	0.041†	8% (1%, 14%)
CD Trial II‡: Clinical Remission* at Week 6	12% (19/157)	15% (24/158)	NS§	3% (-5%, 11%)

CD Trial III - Intravenous

In order to be randomized to treatment in CD Trial III, patients had to have received intravenous ENTYVIO and be in clinical response (defined as a ≥70-point decrease in CDAI score from baseline) at Week 6. Patients could have come from either CD Trial I or from a group who received intravenous ENTYVIO open-label.

In CD Trial III, 461 patients were randomized in a double-blind fashion (1:1:1) to one of the following regimens beginning at Week 6: intravenous ENTYVIO 300 mg every eight weeks, intravenous ENTYVIO 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted outside the U.S. but were not permitted beyond Week 6 in the U.S.

At Week 6, patients were receiving corticosteroids (59%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (31%), and aminosalicylates (41%). Fifty-one percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. At Week 6, the median CDAI score was 322 in the intravenous ENTYVIO every eight week group, 316 in the intravenous ENTYVIO every four week group, and 315 in the placebo group. Patients who had achieved clinical response (≥70 decrease in CDAI score from baseline) at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.

In CD Trial III a greater percentage of patients in groups treated with intravenous ENTYVIO as compared to placebo were in clinical remission (defined as CDAI score ≤150) at Week 52. A greater percentage of patients in groups treated with intravenous ENTYVIO as compared to placebo had a clinical response (defined as ≥100 decrease in CDAI score from baseline) at Week 52 (Table 8). In the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response at Week 6 (defined as ≥70 decrease in CDAI score from baseline), a greater proportion of patients in groups treated with intravenous ENTYVIO as compared to placebo discontinued corticosteroids by Week 52 and were in clinical remission at Week 52 (Table 8).

The ENTYVIO every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen [see Dosage and Administration (2.2)].

Table 8. Proportion of Patients Meeting Efficacy Endpoints at Week 52* (CD Trial III)
Endpoint	Placebo† N=153	ENTYVIO IV Every 8 Weeks N=154	p-value	Treatment Difference and 95% CI
* This group includes patients that were not in clinical remission at Week 6. Patients must have achieved clinical response (defined as ≥70 decrease in CDAI from baseline) at Week 6 to continue into CD Trial III. † The placebo group includes those patients who received ENTYVIO at Week 0 and Week 2, and were randomized to receive placebo from Week 6 through Week 52. ‡ Clinical remission: CDAI ≤150. § Clinical response: ≥100 decrease in CDAI from baseline. ¶ Corticosteroid-free clinical remission: Assessed in the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response (defined as ≥70 decrease in CDAI from baseline) at Week 6 (n=82 for placebo and n=82 for ENTYVIO every eight weeks). Corticosteroid-free clinical remission was defined as the proportion of patients in this subgroup that discontinued corticosteroids by Week 52 and were in clinical remission at Week 52.
Clinical Remission‡ at Week 52	22%	39%	0.001	17% (7%, 28%)
Clinical Response§ at Week 52	30%	44%	0.013	13% (3%, 24%)
Corticosteroid-free Clinical Remission¶	16%¶	32%¶	0.015	16% (3%, 29%)

Subcutaneous Administration

SC CD Trial - Subcutaneous

The safety and efficacy of subcutaneous ENTYVIO was evaluated in a randomized, double-blind, placebo-controlled trial (SC CD Trial; NCT02611817) in adult patients with moderately to severely active Crohn’s disease defined as CDAI score of 220 to 450. At baseline, the median CDAI score was 316 (range: 198 to 559).

The trial included patients who had experienced an inadequate response to, loss of response to, or intolerance to at least one of the following: corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate), or TNF blockers (including primary non-responders). Patients were permitted to use concomitant stable doses of oral aminosalicylates, oral corticosteroids (prednisone ≤30 mg/day, budesonide ≤9 mg/day, or equivalent steroid), immunomodulators, probiotics, antidiarrheals, and/or antibiotics. Concomitant biologic therapies, rectal treatment with 5-aminosalicylic acid or corticosteroid enemas/suppositories were prohibited.

All patients received open-label intravenous ENTYVIO 300 mg at Week 0 and Week 2. In order to be randomized to treatment in SC CD Trial, patients had to be in clinical response (defined as a ≥70-point decrease in the CDAI score from baseline) at Week 6. A total of 409 patients were randomized at Week 6 in a double-blind fashion (2:1) to ENTYVIO 108 mg administered by subcutaneous injection or placebo every 2 weeks. Efficacy assessments were at Week 52.

Beginning at Week 6, patients who were receiving corticosteroids were required to begin a corticosteroid tapering regimen.

At the time of randomization into the double-blind phase (Week 6), patients were receiving corticosteroids (45%), immunomodulators (32%), and aminosalicylates (45%). Fifty-one percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy prior to enrollment.

Patients in the double-blind phase had a mean age of 38 years (range 18 to 76 years); 55% were male; 91% identified as White, 6% as Asian, and 3% identified as another racial group.

The primary endpoint was the proportion of patients with clinical remission (CDAI score ≤150) at Week 52 (see Table 9).

Table 9. Proportion of Patients in Clinical Remission at Week 52* (SC CD Trial)
Endpoint	Placebo†	ENTYVIO SC 108 mg Every 2 Weeks	Estimate‡ of Treatment Difference (95% CI) Vedolizumab SC vs. Placebo
Clinical Remission§ at Week 52
* Patients must have achieved clinical response at Week 6 to continue into SC CD Trial. † The placebo group includes those subjects who received intravenous vedolizumab at Week 0 and Week 2, and were randomized to receive placebo from Week 6 through Week 52. ‡ Estimate of treatment difference and the p-value are based on the Cochran-Mantel-Haenszel method. § Clinical remission: CDAI score ≤150, at Week 52. ¶ p <0.01
Total Population	N=134 34%	N=275 48%	14 (4, 24)¶
Prior TNF blocker failure /exposure	N=71 27%	N=168 48%
Without prior TNF blocker failure /exposure	N=63 43%	N=107 49%

Among patients using oral corticosteroids at baseline (Week 0) and achieving clinical response at Week 6, 45% (43/95) treated with subcutaneous ENTYVIO compared to 18% (8/44) treated with placebo discontinued corticosteroids and were in clinical remission at Week 52. This result was not statistically significant under the prespecified multiple testing procedure.