Study of Vedolizumab (MLN0002) in Patients With Moderate to Severe Ulcerative Colitis (GEMINI I)

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition:	Ulcerative Colitis
Interventions:	Drug: vedolizumab; Other: Placebo

  Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants took part in the study at 211 investigative sites worldwide. The Induction Phase contained 2 cohorts. The eligibility criteria for both cohorts were identical. The purpose of Cohort 2 was to provide enough responders to power the Maintenance Phase primary efficacy analysis.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
In Cohort 1, eligible patients who met entry criteria were randomized to treatment with double-blind vedolizumab 300 mg or placebo in a 3:2 ratio. All Cohort 2 patients were treated with open-label vedolizumab. In the Maintenance Phase participants were assigned to treatment groups based on their Induction Phase treatment and response to therapy.

Reporting Groups

	Description
Placebo	In the Induction Phase participants in Cohort 1 were randomized to receive double-blind placebo intravenous infusions at Week 0 and Week 2. Participants continued to receive placebo every 4 weeks from Week 6 through Week 50 during the Maintenance Phase, regardless of treatment response during induction.
Induction Phase: DB Vedolizumab	In the Induction Phase participants in Cohort 1 were randomized to receive double-blind (DB) vedolizumab 300 mg, administered by intravenous infusion at Week 0 and Week 2.
Induction Phase: OL Vedolizumab	In the Induction Phase participants in Cohort 2 received open-label (OL) vedolizumab 300 mg, administered by intravenous infusion at Week 0 and Week 2.
Maintenance Phase: Placebo	Participants who received vedolizumab during the Induction Phase and demonstrated a clinical response at Week 6 were then randomized to receive double-blind treatment with placebo every 4 weeks up to Week 50 during the Maintenance Phase.
Maintenance Phase: Vedolizumab Q8W	Participants who received vedolizumab during the Induction Phase and demonstrated a clinical response at Week 6 were then randomized to receive double-blind treatment with vedolizumab 300 mg every 8 weeks (Q8W) at Weeks 6, 14, 22, 30, 38, and 46, and, to maintain blinding, placebo infusions at Weeks 10, 18, 26, 34, 42, and 50.
Maintenance Phase: Vedolizumab Q4W	Participants who received vedolizumab during the Induction Phase and demonstrated a clinical response at Week 6 were then randomized to receive double-blind treatment with vedolizumab 300 mg every 4 weeks (Q4W) from Week 6 to Week 50.
Maintenance Phase: Non-responders	Participants who received vedolizumab during the Induction Phase who did not demonstrate a clinical response at Week 6 received open-label treatment with vedolizumab 300 mg every 4 weeks from Week 6 to Week 50.

Participant Flow for 2 periods

Period 1:   Induction Phase

	Placebo	Induction Phase: DB Vedolizumab	Induction Phase: OL Vedolizumab	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab Q8W	Maintenance Phase: Vedolizumab Q4W	Maintenance Phase: Non-responders
STARTED	149	225	521	0	0	0	0
COMPLETED	135	218	485	0	0	0	0
NOT COMPLETED	14	7	36	0	0	0	0
Adverse Event	4	0	7	0	0	0	0
Protocol Violation	1	1	6	0	0	0	0
Lack of Efficacy	5	2	14	0	0	0	0
Withdrawal by Subject	3	4	8	0	0	0	0
Lost to Follow-up	1	0	1	0	0	0	0

Period 2:   Maintenance Phase

	Placebo	Induction Phase: DB Vedolizumab	Induction Phase: OL Vedolizumab	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab Q8W	Maintenance Phase: Vedolizumab Q4W	Maintenance Phase: Non-responders
STARTED	135	0	0	126	122	125	330
COMPLETED	30	0	0	48	77	84	135
NOT COMPLETED	105	0	0	78	45	41	195
Adverse Event	12	0	0	15	7	6	16
Protocol Violation	1	0	0	0	0	0	2
Lack of Efficacy	83	0	0	61	31	33	155
Withdrawal by Subject	6	0	0	2	5	2	20
Lost to Follow-up	3	0	0	0	2	0	2

  Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Baseline characteristics are provided for the Induction Phase Safety Population, defined as all participants, in both Cohort 1 and Cohort 2, who received any amount of study drug in the Induction Phase (Weeks 0-6), according to the actual study drug received.

Reporting Groups

	Description
Placebo	In the Induction Phase participants in Cohort 1 were randomized to receive double-blind placebo intravenous infusions at Week 0 and Week 2. Participants continued to receive placebo every 4 weeks from Week 6 through Week 50 during the Maintenance Phase, regardless of treatment response during induction.
Induction Phase: DB Vedolizumab	In the Induction Phase participants in Cohort 1 were randomized to receive double-blind vedolizumab 300 mg, administered by intravenous infusion at Week 0 and Week 2.
Induction Phase: OL Vedolizumab	In the Induction Phase participants in Cohort 2 received open-label vedolizumab 300 mg, administered by intravenous infusion at Week 0 and Week 2.
Total	Total of all reporting groups

Baseline Measures

	Placebo	Induction Phase: DB Vedolizumab	Induction Phase: OL Vedolizumab	Total
Overall Participants Analyzed; [Units: Participants]	149	225	521	895
Age; [Units: Years]; Mean (Standard Deviation)	41.2 (12.50)	40.1 (13.11)	40.1 (13.27)	40.3 (13.09)
Age, Customized; [Units: Participants]
< 35	53	86	214	353
≥ 35	96	139	307	542
Age, Customized; [Units: Participants]
< 65	142	217	503	862
≥ 65	7	8	18	33
Gender; [Units: Participants]
Female	57	93	220	370
Male	92	132	301	525
Race/Ethnicity, Customized; [Units: Participants]
White	115	183	436	734
Black	2	5	5	12
Asian	32	36	67	135
Other	0	1	13	14
Race/Ethnicity, Customized; [Units: Participants]
Hispanic or Latino	5	10	31	46
Not Hispanic or Latino	140	211	481	832
Not reported	4	4	9	17
Region of Enrollment; [Units: Participants]
Australia	7	17	29	53
Austria	4	3	12	19
Belgium	7	14	35	56
Bulgaria	2	1	3	6
Canada	16	14	62	92
Czech Republic	7	12	19	38
Denmark	2	7	5	14
Estonia	1	4	5	10
France	1	3	13	17
Germany	0	1	16	17
Greece	0	1	4	5
Hong Kong	0	0	1	1
Hungary	2	6	8	16
Iceland	0	1	2	3
India	18	16	24	58
Ireland	0	0	1	1
Israel	0	1	1	2
Italy	1	9	11	21
Korea, Republic of	5	10	26	41
Latvia	1	2	0	3
Malaysia	5	2	2	9
Netherlands	1	0	2	3
New Zealand	0	5	6	11
Norway	2	1	6	9
Poland	2	6	52	60
Russian Federation	9	15	25	49
Singapore	0	0	1	1
South Africa	4	5	10	19
Spain	0	0	2	2
Switzerland	2	1	3	6
Turkey	0	3	3	6
United Kingdom	2	0	4	6
United States	47	64	127	238
Body Weight [1]; [Units: Kg]; Mean (Standard Deviation)	72.4 (17.65)	72.4 (17.11)	74.2 (19.32)	73.4 (18.51)
[1] Body weight data only available for 148 participants in the placebo arm.
Body Mass Index (BMI) [1]; [Units: Kg/m^2]; Mean (Standard Deviation)	24.6 (5.11)	24.9 (4.85)	25.3 (6.05)	25.1 (5.62)
[1] BMI data only available for 148 participants in the placebo arm.
Duration of Ulcerative Colitis [1]; [Units: Years]; Mean (Standard Deviation)	7.1 (7.25)	6.1 (5.08)	7.2 (6.61)	6.9 (6.39)
[1] Duration of ulcerative colitis data only available for 519 participants in the Induction Phase: OL Vedolizumab arm.
Categorical Duration of Ulcerative Colitis; [Units: Participants]
< 1 year	13	13	38	64
≥1 - < 3 years	44	63	121	228
≥ 3 - < 7 years	39	77	163	279
≥ 7 years	53	72	197	322
Missing	0	0	2	2
Baseline Mayo Score [1]; [Units: Units on a scale]; Mean (Standard Deviation)	8.6 (1.68)	8.5 (1.78)	8.6 (1.76)	8.6 (1.75)
[1] The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 components: two that are patient reported (rectal bleeding and stool frequency), a global assessment by the physician, and an endoscopic subscore. Each component is scored on a scale from 0 to 3 and the complete score ranges from 1 to 12 (higher scores indicate greater disease activity).
Baseline Disease Activity; [Units: Participants]
Complete Mayo score < 6	5	6	14	25
Complete Mayo score of 6 to 8 (inclusive)	70	105	249	424
Complete Mayo score of 9 to 12 (inclusive)	74	114	258	446
Baseline Fecal Calprotectin [1]; [Units: μg/g]; Mean (Standard Deviation)	2369.9 (3258.82)	2552.2 (3800.36)	1442.7 (1855.61)	1868.8 (2753.28)
[1] Number of participants for whom baseline fecal calprotectin data were available were 139, 213, and 505, respectively.
Categorical Baseline Fecal Calprotectin; [Units: Participants]
≤ 250 μg/g	27	37	94	158
> 250 to ≤ 500 μg/g	20	20	82	122
> 500 μg/g	92	156	329	577
Missing	10	12	16	38
Disease Localization; [Units: Participants]
Proctosigmoiditis	22	25	69	116
Left-sided colitis	59	92	188	339
Extensive colitis	18	25	66	109
Pancolitis	50	83	198	331
Smoking Status; [Units: Participants]
Current smoker	11	12	32	55
Nonsmoker	88	145	322	555
Former smoker	50	68	167	285
History of Extraintestinal Manifestations; [Units: Participants]
Yes	44	74	180	298
No	105	151	341	597

  Outcome Measures

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1. Primary:

Induction Phase: Percentage of Participants With a Clinical Response at Week 6 [ Time Frame: Baseline and Week 6 ]

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2. Primary:

Maintenance Phase: Percentage of Participants in Clinical Remission at Week 52 [ Time Frame: Week 52 ]

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3. Secondary:

Induction Phase: Percentage of Participants in Clinical Remission at Week 6 [ Time Frame: Week 6 ]

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4. Secondary:

Induction Phase: Percentage of Participants With Mucosal Healing at Week 6 [ Time Frame: Week 6 ]

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5. Secondary:

Maintenance Phase: Percentage of Participants With Durable Clinical Response [ Time Frame: Baseline, Week 6 and Week 52 ]

  Show Outcome Measure 5

6. Secondary:

Maintenance Phase: Percentage of Participants With Mucosal Healing at Week 52 [ Time Frame: Week 52 ]

  Show Outcome Measure 6

7. Secondary:

Maintenance Phase: Percentage of Participants With Durable Clinical Remission [ Time Frame: Week 6 and Week 52 ]

  Show Outcome Measure 7

8. Secondary:

Maintenance Phase: Percentage of Participants With Corticosteroid-free Remission at Week 52 [ Time Frame: Week 52 ]

  Show Outcome Measure 8

  Serious Adverse Events

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  Other Adverse Events

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  Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information

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Certain Agreements:  

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is: The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo. The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.; Restriction Description: The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.

Results Point of Contact:  

Name/Title: Medical Director
Organization: Millennium Pharmaceuticals Inc
phone: 800-778-2860
e-mail: clinicaltrialregistry@tpna.com

Publications of Results:

Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, Van Assche G, Axler J, Kim HJ, Danese S, Fox I, Milch C, Sankoh S, Wyant T, Xu J, Parikh A; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013 Aug 22;369(8):699-710. doi: 10.1056/NEJMoa1215734.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Arijs I, De Hertogh G, Lemmens B, Van Lommel L, de Bruyn M, Vanhove W, Cleynen I, Machiels K, Ferrante M, Schuit F, Van Assche G, Rutgeerts P, Vermeire S. Effect of vedolizumab (anti-α4β7-integrin) therapy on histological healing and mucosal gene expression in patients with UC. Gut. 2018 Jan;67(1):43-52. doi: 10.1136/gutjnl-2016-312293. Epub 2016 Oct 7.

Feagan BG, Rubin DT, Danese S, Vermeire S, Abhyankar B, Sankoh S, James A, Smyth M. Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol. 2017 Feb;15(2):229-239.e5. doi: 10.1016/j.cgh.2016.08.044. Epub 2016 Sep 14.

Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D'Haens G, Panaccione R, Loftus EV Jr, Sankoh S, Fox I, Parikh A, Milch C, Abhyankar B, Feagan BG. The safety of vedolizumab for ulcerative colitis and Crohn's disease. Gut. 2017 May;66(5):839-851. doi: 10.1136/gutjnl-2015-311079. Epub 2016 Feb 18.

Rosario M, Dirks NL, Gastonguay MR, Fasanmade AA, Wyant T, Parikh A, Sandborn WJ, Feagan BG, Reinisch W, Fox I. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease. Aliment Pharmacol Ther. 2015 Jul;42(2):188-202. doi: 10.1111/apt.13243. Epub 2015 May 20. Erratum in: Aliment Pharmacol Ther. 2015 Nov;42(9):1135.

Responsible Party:	Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT00783718 History of Changes
Other Study ID Numbers:	C13006; U1111-1156-8422 ( Registry Identifier: WHO ); 2008-002782-32 ( EudraCT Number ); NL25207.096.08 ( Registry Identifier: CCMO ); CTRI/2009/091/000128 ( Registry Identifier: CTRI ); NMRR-08-1046-2201 ( Registry Identifier: NMRR ); C13006CTIL ( Other Identifier: Israel MoH ); 09/H1102/66 ( Registry Identifier: NRES )
First Submitted:	October 31, 2008
First Posted:	November 3, 2008
Results First Submitted:	June 19, 2014
Results First Posted:	July 18, 2014
Last Update Posted:	July 18, 2014