Trial Outcomes & Findings for Study of Vedolizumab in Patients With Moderate to Severe Crohn's Disease (NCT NCT01224171)

Last Updated: 2014-07-21

Results Overview

Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) score ≤ 150 points. The CDAI is used to quantify the symptoms of patients with Crohn's disease and consists of eight factors, each summed after adjustment with a weighting factor. The components of the CDAI are: * Number of liquid or soft stools each day for 7 days; * Abdominal pain (graded from 0-3 on severity) each day for 7 days; * General well-being, subjectively assessed from 0 (well) to 4 (terrible) each day for 7 days; * Presence of complications; * Taking Lomotil or opiates for diarrhea; * Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); * Hematocrit of \< 0.47 in men and \< 0.42 in women; * Percentage deviation from standard weight. The total score ranges from 0 to approximately 600 and with higher scores indicating greater disease activity. All participants who prematurely discontinued for any reason were considered as not achieving clinical remission.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

416 participants

Primary outcome timeframe

Week 6

Results posted on

2014-07-21

Participant Flow

Participants with moderately to severely active Crohn's Disease took part in the study at 107 sites worldwide from 24 November 2010 to 12 April 2012. Approximately 75% of participants were to have previously failed tumor necrosis factor alpha (TNFα) antagonist therapy and approximately 25% were to have been naïve to TNFα antagonist therapy.

Participants were randomized 1:1 to receive either 300 mg vedolizumab or placebo. Randomization to treatment assignment was stratified by the presence or absence of previous failure of TNFα antagonist therapy or naïve to TNFα antagonist therapy, concomitant use of oral corticosteroids and concomitant use of immunomodulators.

Participant milestones

Participant milestones
Measure	Placebo Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Overall Study STARTED	207	209
Overall Study TNFα Antagonist Failure Population	157	158
Overall Study COMPLETED	192	196
Overall Study NOT COMPLETED	15	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Overall Study Adverse Event	8	4
Overall Study Protocol Violation	0	1
Overall Study Lack of Efficacy	5	1
Overall Study Withdrawal of Consent	2	4
Overall Study Lost to Follow-up	0	3

Baseline Characteristics

Study of Vedolizumab in Patients With Moderate to Severe Crohn's Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=207 Participants Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=209 Participants Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.	Total n=416 Participants Total of all reporting groups
Age, Continuous	37.1 years STANDARD_DEVIATION 13.15 • n=39 Participants	38.6 years STANDARD_DEVIATION 12.14 • n=41 Participants	37.9 years STANDARD_DEVIATION 12.66 • n=35 Participants
Age, Customized < 35 years	105 participants n=39 Participants	88 participants n=41 Participants	193 participants n=35 Participants
Age, Customized ≥ 35 years	102 participants n=39 Participants	121 participants n=41 Participants	223 participants n=35 Participants
Age, Customized < 65 years	202 participants n=39 Participants	206 participants n=41 Participants	408 participants n=35 Participants
Age, Customized ≥ 65 years	5 participants n=39 Participants	3 participants n=41 Participants	8 participants n=35 Participants
Sex: Female, Male Female	118 Participants n=39 Participants	118 Participants n=41 Participants	236 Participants n=35 Participants
Sex: Female, Male Male	89 Participants n=39 Participants	91 Participants n=41 Participants	180 Participants n=35 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=39 Participants	4 Participants n=41 Participants	8 Participants n=35 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	199 Participants n=39 Participants	204 Participants n=41 Participants	403 Participants n=35 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=39 Participants	1 Participants n=41 Participants	5 Participants n=35 Participants
Race/Ethnicity, Customized White	186 participants n=39 Participants	188 participants n=41 Participants	374 participants n=35 Participants
Race/Ethnicity, Customized Black	5 participants n=39 Participants	4 participants n=41 Participants	9 participants n=35 Participants
Race/Ethnicity, Customized Asian	9 participants n=39 Participants	9 participants n=41 Participants	18 participants n=35 Participants
Race/Ethnicity, Customized Other	7 participants n=39 Participants	6 participants n=41 Participants	13 participants n=35 Participants
Race/Ethnicity, Customized Not Reported	0 participants n=39 Participants	2 participants n=41 Participants	2 participants n=35 Participants
Body Weight	71.3 kg STANDARD_DEVIATION 19.22 • n=39 Participants	69.5 kg STANDARD_DEVIATION 17.76 • n=41 Participants	70.4 kg STANDARD_DEVIATION 18.50 • n=35 Participants
Body Mass Index	24.6 kg/m^2 STANDARD_DEVIATION 6.13 • n=39 Participants	24.0 kg/m^2 STANDARD_DEVIATION 5.13 • n=41 Participants	24.3 kg/m^2 STANDARD_DEVIATION 5.65 • n=35 Participants
Geographic Region North America	95 participants n=39 Participants	102 participants n=41 Participants	197 participants n=35 Participants
Geographic Region Western/Northern Europe	37 participants n=39 Participants	38 participants n=41 Participants	75 participants n=35 Participants
Geographic Region Central Europe	46 participants n=39 Participants	41 participants n=41 Participants	87 participants n=35 Participants
Geographic Region Eastern Europe	15 participants n=39 Participants	10 participants n=41 Participants	25 participants n=35 Participants
Geographic Region Asia/Australia/Africa	14 participants n=39 Participants	18 participants n=41 Participants	32 participants n=35 Participants
Duration of Crohn's Disease (CD)	10.0 years STANDARD_DEVIATION 7.98 • n=39 Participants	10.6 years STANDARD_DEVIATION 8.75 • n=41 Participants	10.3 years STANDARD_DEVIATION 8.37 • n=35 Participants
Duration of Crohn's Disease - Categorical < 1 year	12 participants n=39 Participants	11 participants n=41 Participants	23 participants n=35 Participants
Duration of Crohn's Disease - Categorical ≥ 1 to < 3 years	25 participants n=39 Participants	28 participants n=41 Participants	53 participants n=35 Participants
Duration of Crohn's Disease - Categorical ≥ 3 to < 7 years	52 participants n=39 Participants	52 participants n=41 Participants	104 participants n=35 Participants
Duration of Crohn's Disease - Categorical ≥ 7 years	118 participants n=39 Participants	118 participants n=41 Participants	236 participants n=35 Participants
Baseline Disease Activity - Crohn's Disease Activity Index (CDAI)	301.3 units on a scale STANDARD_DEVIATION 54.97 • n=39 Participants	313.9 units on a scale STANDARD_DEVIATION 53.17 • n=41 Participants	307.7 units on a scale STANDARD_DEVIATION 54.38 • n=35 Participants
Baseline Disease Activity - Categorical CDAI ≤ 330	148 participants n=39 Participants	132 participants n=41 Participants	280 participants n=35 Participants
Baseline Disease Activity - Categorical CDAI > 330	59 participants n=39 Participants	77 participants n=41 Participants	136 participants n=35 Participants
C-reactive Protein (CRP)	18.5 mg/L STANDARD_DEVIATION 21.98 • n=39 Participants	19.0 mg/L STANDARD_DEVIATION 23.17 • n=41 Participants	18.8 mg/L STANDARD_DEVIATION 22.56 • n=35 Participants
CRP - Categorical ≤ 2.87 mg/L	41 participants n=39 Participants	46 participants n=41 Participants	87 participants n=35 Participants
CRP - Categorical > 2.87 to ≤ 5 mg/L	19 participants n=39 Participants	14 participants n=41 Participants	33 participants n=35 Participants
CRP - Categorical > 5 to ≤ 10 mg/L	42 participants n=39 Participants	48 participants n=41 Participants	90 participants n=35 Participants
CRP - Categorical > 10 mg/L	105 participants n=39 Participants	101 participants n=41 Participants	206 participants n=35 Participants
Fecal Calprotectin	1426.5 μg/g STANDARD_DEVIATION 2357.76 • n=39 Participants	1148.1 μg/g STANDARD_DEVIATION 1878.58 • n=41 Participants	1288.0 μg/g STANDARD_DEVIATION 2134.79 • n=35 Participants
Fecal Calprotectin - Categorical ≤ 250 μg/g	47 participants n=39 Participants	52 participants n=41 Participants	99 participants n=35 Participants
Fecal Calprotectin - Categorical > 250 to ≤ 500 μg/g	35 participants n=39 Participants	35 participants n=41 Participants	70 participants n=35 Participants
Fecal Calprotectin - Categorical > 500 μg/g	124 participants n=39 Participants	117 participants n=41 Participants	241 participants n=35 Participants
Fecal Calprotectin - Categorical Missing	1 participants n=39 Participants	5 participants n=41 Participants	6 participants n=35 Participants
Disease Localization Ileum only	29 participants n=39 Participants	33 participants n=41 Participants	62 participants n=35 Participants
Disease Localization Colon only	52 participants n=39 Participants	48 participants n=41 Participants	100 participants n=35 Participants
Disease Localization Ileocolonic (both ileum and colon)	126 participants n=39 Participants	128 participants n=41 Participants	254 participants n=35 Participants
History of Prior Surgery for Crohn's Disease Yes	89 participants n=39 Participants	92 participants n=41 Participants	181 participants n=35 Participants
History of Prior Surgery for Crohn's Disease No	118 participants n=39 Participants	117 participants n=41 Participants	235 participants n=35 Participants
Smoking Status Current Smoker	58 participants n=39 Participants	65 participants n=41 Participants	123 participants n=35 Participants
Smoking Status Never Smoked	102 participants n=39 Participants	93 participants n=41 Participants	195 participants n=35 Participants
Smoking Status Former Smoker	47 participants n=39 Participants	51 participants n=41 Participants	98 participants n=35 Participants
History of Fistulizing Disease Yes	77 participants n=39 Participants	71 participants n=41 Participants	148 participants n=35 Participants
History of Fistulizing Disease No	130 participants n=39 Participants	138 participants n=41 Participants	268 participants n=35 Participants
Draining Fistula at Baseline Yes	25 participants n=39 Participants	25 participants n=41 Participants	50 participants n=35 Participants
Draining Fistula at Baseline All Closed	0 participants n=39 Participants	1 participants n=41 Participants	1 participants n=35 Participants
Draining Fistula at Baseline No Fistula	182 participants n=39 Participants	183 participants n=41 Participants	365 participants n=35 Participants
Extraintestinal Manifestations at Baseline Yes	130 participants n=39 Participants	116 participants n=41 Participants	246 participants n=35 Participants
Extraintestinal Manifestations at Baseline No	77 participants n=39 Participants	93 participants n=41 Participants	170 participants n=35 Participants

PRIMARY outcome

Timeframe: Week 6

Population: TNFα Antagonist Failure Intent-to-treat (ITT) subpopulation which consisted of all randomized participants who received any amount of blinded study drug who met the TNFα antagonist failure criterion.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=158 Participants Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Percentage of Participants in Clinical Remission in the Tumor Necrosis Factor Alpha (TNFα) Antagonist Failure Subpopulation	12.1 percentage of participants Interval 7.0 to 17.2	15.2 percentage of participants Interval 9.6 to 20.8

SECONDARY outcome

Timeframe: Week 6

Population: Overall ITT population, consisting of all randomized participants who received any amount of blinded study drug.

Outcome measures

Outcome measures
Measure	Placebo n=207 Participants Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=209 Participants Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Percentage of Participants in Clinical Remission at Week 6 in the Overall Population	12.1 percentage of participants Interval 7.6 to 16.5	19.1 percentage of participants Interval 13.8 to 24.5

SECONDARY outcome

Timeframe: Week 10

Population: TNFα Antagonist Failure Intent-to-treat (ITT) Subpopulation

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=158 Participants Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Percentage of Participants in Clinical Remission at Week 10 in the TNFα Antagonist Failure Subpopulation	12.1 percentage of participants Interval 7.0 to 17.2	26.6 percentage of participants Interval 19.7 to 33.5

SECONDARY outcome

Timeframe: Week 10

Population: Overall ITT population

Outcome measures

Outcome measures
Measure	Placebo n=207 Participants Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=209 Participants Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Percentage of Participants in Clinical Remission at Week 10 in the Overall Population	13.0 percentage of participants Interval 8.5 to 17.6	28.7 percentage of participants Interval 22.6 to 34.8

SECONDARY outcome

Timeframe: Week 6 and Week 10

Population: TNFα Antagonist Failure ITT Subpopulation

Sustained clinical remission is defined as a CDAI score ≤ 150 points at both Week 6 and Week 10. The CDAI is used to quantify the symptoms of patients with Crohn's disease and consists of eight factors, each summed after adjustment with a weighting factor. The components of the CDAI are: * Number of liquid or soft stools each day for 7 days; * Abdominal pain (graded from 0-3 on severity) each day for 7 days; * General well-being, subjectively assessed from 0 (well) to 4 (terrible) each day for 7 days; * Presence of complications; * Taking Lomotil or opiates for diarrhea; * Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); * Hematocrit of \< 0.47 in men and \< 0.42 in women; * Percentage deviation from standard weight. The total score ranges from 0 to approximately 600 and with higher scores indicating greater disease activity. All participants who prematurely discontinued for any reason were considered as not achieving sustained clinical remission.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=158 Participants Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Percentage of Participants With Sustained Clinical Remission in the TNFα Antagonist Failure Population	8.3 percentage of participants Interval 4.0 to 12.6	12.0 percentage of participants Interval 7.0 to 17.1

SECONDARY outcome

Timeframe: Week 6 and Week 10

Population: Overall ITT population

Outcome measures

Outcome measures
Measure	Placebo n=207 Participants Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=209 Participants Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Percentage of Participants With Sustained Clinical Remission in the Overall Population	8.2 percentage of participants Interval 4.5 to 12.0	15.3 percentage of participants Interval 10.4 to 20.2

SECONDARY outcome

Timeframe: Baseline and Week 6

Population: TNFα Antagonist Failure ITT Subpopulation

Enhanced clinical response is defined as a ≥ 100-point decrease in CDAI score from Baseline. The CDAI is used to quantify the symptoms of patients with Crohn's disease and consists of eight factors, each summed after adjustment with a weighting factor. The components of the CDAI are: * Number of liquid or soft stools each day for 7 days; * Abdominal pain (graded from 0-3 on severity) each day for 7 days; * General well-being, subjectively assessed from 0 (well) to 4 (terrible) each day for 7 days; * Presence of complications; * Taking Lomotil or opiates for diarrhea; * Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); * Hematocrit of \< 0.47 in men and \< 0.42 in women; * Percent deviation from standard weight. The total score ranges from 0 to approximately 600 and with higher scores indicating greater disease activity. All participants who prematurely discontinued for any reason were considered as not achieving enhanced clinical response.

Outcome measures

Outcome measures
Measure	Placebo n=157 Participants Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=158 Participants Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Percentage of Participants With Enhanced Clinical Response at Week 6 in the TNFα Antagonist Failure Subpopulation	22.3 percentage of participants Interval 15.8 to 28.8	39.2 percentage of participants Interval 31.6 to 46.9

SECONDARY outcome

Timeframe: From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments.

Population: Overall Safety Population

An AE was defined as any untoward medical occurrence in a patient administered a pharmaceutical product, which did not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) was any AE, occurring at any dose and regardless of causality that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was an important medical event based upon appropriate medical judgment that may have jeopardized the patient and may have required medical or surgical intervention to prevent 1 of the outcomes listed above, or any diagnosis of progressive multifocal leukoencephalopathy (PML). Relationship to study drug administration was determined by the investigator responding yes or no to the question: Is there a reasonable possibility that the AE is associated with the study drug?

Outcome measures

Outcome measures
Measure	Placebo n=207 Participants Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=209 Participants Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Number of Participants With Adverse Events (AEs) Death	0 participants	0 participants
Number of Participants With Adverse Events (AEs) Any adverse event	124 participants	117 participants
Number of Participants With Adverse Events (AEs) Drug-related adverse event	34 participants	34 participants
Number of Participants With Adverse Events (AEs) Adverse event resulting in study discontinuation	8 participants	4 participants
Number of Participants With Adverse Events (AEs) Serious adverse event	16 participants	13 participants
Number of Participants With Adverse Events (AEs) Serious infection adverse event	0 participants	2 participants
Number of Participants With Adverse Events (AEs) Drug-related serious adverse event	1 participants	1 participants
Number of Participants With Adverse Events (AEs) Serious adverse event resulting in discontinuation	5 participants	4 participants

Adverse Events

Placebo

Serious events: 16 serious events

Other events: 29 other events

Deaths: 0 deaths

Vedolizumab

Serious events: 13 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=207 participants at risk Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=209 participants at risk Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Gastrointestinal disorders Nausea	2.4% 5/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.7% 12/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Headache	7.2% 15/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 11/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Pyrexia	6.3% 13/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.3% 7/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Additional Information

Medical Director

Millennium Pharmaceuticals Inc.

Phone: 800-778-2860

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=207 participants at risk Participants received placebo intravenous infusion at Weeks 0, 2 and 6.	Vedolizumab n=209 participants at risk Participants received 300 mg intravenous vedolizumab at Weeks 0, 2, and 6.
Gastrointestinal disorders Crohn's disease	5.3% 11/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.96% 2/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal pain	0.48% 1/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Pancreatitis	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Gastric ulcer	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Gastritis	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Anal abscess	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Urinary tract infection	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Dehydration	0.48% 1/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Joint effusion	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Polyarthritis	0.48% 1/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Anaemia	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ependymoma	0.00% 0/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.48% 1/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders General physical health deterioration	0.48% 1/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Demyelination	0.48% 1/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Urticaria	0.48% 1/207 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/209 • From the date of first study drug administration to Week 22, through the 14 March 2012 database lock date. At the time of this database lock, 7 patients had completed Week 10 or early termination assessments but not Week 22 assessments. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.