Ulcerative Colitis
Conditions
Brief summary
The main objectives of this study were to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple doses of vedolizumab in patients with ulcerative colitis (UC).
Detailed description
At the end of the study, eligible participants could enroll and receive treatment and follow-up in Study C13004 (NCT00619489). Participants who did not proceed into Study C13004 were followed by telephone contact at 6-month intervals for 2 years after the last administration of study treatment to collect reports of adverse events, including colectomy, severe infections \[including progressive multifocal leukoencephalopathy (PML)\], and dysplasia/cancer.
Interventions
DRUGVedolizumab
Vedolizumab for intravenous infusion
DRUGPlacebo
Placebo intravenous infusion
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study. * Males or non-pregnant, non-lactating females voluntarily able to give informed consent * All patients must agree to use 2 effective forms of contraception from screening to the end of the study * Negative surveillance colonoscopy within the last 6 months if indicated by standard clinical practice guidelines * Confirmed and active ulcerative colitis (UC) * Partial Mayo Score 1 - 7 * Disease involvement extending proximal to the rectum * May be receiving a therapeutic dose of conventional therapies for UC as defined by the protocol
Exclusion criteria
Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From the first date of study drug administration through Day 253 | An adverse event (AE) is any untoward medical occurrence in a patient administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. The investigator systematically collected information adequate to determine both the outcome and severity of the AE, and whether or not it was drug-related or met the criteria for classification as a serious adverse event (SAE). An SAE was defined as an AE that resulted in (or posed risk for) death, inpatient hospitalization (or prolonging hospitalization), or congenital, persistent or significant disability/incapacity. The intensity for each AE was defined according to the following criteria: Mild: Awareness of sign or symptom, but easily tolerated Moderate: Discomfort enough to cause interference with normal daily activities Severe: Inability to perform normal daily activities. |
| Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85 | Days 1 and 85, prior to and 2, 12, 24, 48, and 72 hours after dosing. | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. |
| Cmin: Minimum Observed Plasma Concentration of Vedolizumab | Day 85, prior to and 2, 12, 24, 48, and 72 hours after dosing. | Minimum observed plasma concentration (Cmin) is the lowest plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. |
| Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | Days 0-14, Days 85-99, Days 85-141 | AUC was calculated for 3 time intervals during the study: 1. AUC (Day 0-14): from administration on Day 0 to last quantifiable concentration on Day 14, selected to capture the AUC following the first dose of vedolizumab until administration of the second dose 2. AUC(Day 85-99): from administration on Day 85 to last quantifiable concentration on Day 99, selected to assess the amount of drug accumulation with the planned loading regimen by comparing it to AUC(Day 0-14) 3. AUC(Day 85-141): from the first quantifiable concentration on Day 85 to the last quantifiable concentration on Day 141, selected to assess the drug exposure over an 8-week period |
| Terminal Phase Elimination Half-life (t½) of Vedolizumab | Pre-dose through Day 253 | Terminal phase elimination half-life (t½) is the time required for half of the drug to be eliminated from the plasma. |
| Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | Days 1, 2, 3, 4, 8, 15, 29, 43, 57, 71, 85, 86, 87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, and 253 | The target of vedolizumab is α4β7 integrin, a receptor found on inflammatory immune cells that guides these inflammatory cells to the gut and binds to the Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) on gut endothelial cells. The extent of the α4β7 receptor saturation by vedolizumab was assessed using the Act-1 binding interference assay. Act-1 is a mouse antibody similar to vedolizumab that also binds α4β7 integrin. The assay measures the percent inhibition of the Act-1 due to the presence of vedolizumab binding. Emax was calculated on Day 1, Day 85 and based on all available data. |
| Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | Days 1, 2, 3, 4, 8, 15, 29, 43, 57, 71, 85, 86, 87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, and 253 | The target of vedolizumab is α4β7 integrin, a receptor found on inflammatory immune cells that guides these inflammatory cells to the gut and binds to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on gut endothelial cells. The extent of the α4β7 receptor saturation by vedolizumab was assessed using the MAdCAM-1-Fc binding interference assay. MAdCAM-1-Fc is a fusion of human MAdCAM-1 with parts of a mouse monoclonal antibody. The assay measures the percent inhibition of the MAdCAM-1-Fc binding to α4β7 integrin due to the presence of vedolizumab binding. Emax was calculated on Day 1, Day 85, and based on all available data. |
| Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the ACT-1 Marker | Days 1, 2, 3, 4, 8, 15, 29, 43, 57, 71, 85, 86, 87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, and 253 | AUEC (0-last) is the area under the drug effect-time curve until the last available time point. Mean percent inhibition over time \[AUEC(0-last)\] was determined for the Act-1 marker. Act-1 is a mouse antibody similar to vedolizumab that also binds α4β7 integrin. |
| Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the MAdCAM-1-Fc Marker | Days 1, 2, 3, 4, 8, 15, 29, 43, 57, 71, 85, 86, 87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, and 253 | AUEC (0-last) is the area under the drug effect-time curve until the last available time point. Mean percent inhibition over time \[AUEC(0-last)\] was determined for the MAdCAM-1-Fc marker. MAdCAM-1-Fc is a fusion of human MAdCAM-1 with parts of a mouse monoclonal antibody. |
Participant flow
Recruitment details
Participants took part in the study at 2 study centers in Canada and 9 study centers in Russia, from 02 May 2007 to 16 June 2008.
Pre-assignment details
Participants with active ulcerative colitis were randomized in a 4:1 ratio of vedolizumab to placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Vedolizumab-matching placebo, intravenous (IV), one 30-minute infusion on Days 1, 15, 29 and 85. | 9 |
| Vedolizumab 2 mg/kg Vedolizumab 2 mg/kg IV infusion on Days 1, 15, 29 and 85. | 12 |
| Vedolizumab 6 mg/kg Vedolizumab 6 mg/kg, IV infusion on Days 1, 15, 29 and 85. | 14 |
| Vedolizumab 10 mg/kg Vedolizumab 10 mg/kg IV infusion on Days 1, 15, 29 and 85. | 11 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Positive tuberculosis test | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
| Overall Study | Worsening disease activity | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Vedolizumab 2 mg/kg | Vedolizumab 6 mg/kg | Vedolizumab 10 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 34.2 years STANDARD_DEVIATION 8.11 | 39.0 years STANDARD_DEVIATION 6.06 | 44.4 years STANDARD_DEVIATION 12.37 | 44.3 years STANDARD_DEVIATION 14.99 | 41.0 years STANDARD_DEVIATION 11.46 |
| Body Mass Index (BMI) | 26.22 kg/m² STANDARD_DEVIATION 8.46 | 26.03 kg/m² STANDARD_DEVIATION 5.58 | 28.51 kg/m² STANDARD_DEVIATION 6.66 | 25.29 kg/m² STANDARD_DEVIATION 5.07 | 26.64 kg/m² STANDARD_DEVIATION 6.37 |
| Body Surface Area (BSA) | 1.84 m² STANDARD_DEVIATION 0.31 | 1.88 m² STANDARD_DEVIATION 0.3 | 1.92 m² STANDARD_DEVIATION 0.21 | 1.86 m² STANDARD_DEVIATION 0.2 | 1.88 m² STANDARD_DEVIATION 0.25 |
| Height | 168.0 cm STANDARD_DEVIATION 7.33 | 169.8 cm STANDARD_DEVIATION 10.52 | 167.9 cm STANDARD_DEVIATION 9.87 | 170.7 cm STANDARD_DEVIATION 8.15 | 169.1 cm STANDARD_DEVIATION 9 |
| Participants Hospitalized for UC in Past 12 Months No | 4 participants | 9 participants | 12 participants | 7 participants | 32 participants |
| Participants Hospitalized for UC in Past 12 Months Yes | 5 participants | 3 participants | 2 participants | 4 participants | 14 participants |
| Participants with Acute Exacerbations in Past 12 Months No | 0 participants | 0 participants | 1 participants | 2 participants | 3 participants |
| Participants with Acute Exacerbations in Past 12 Months Yes | 9 participants | 12 participants | 13 participants | 9 participants | 43 participants |
| Participants with Ongoing Therapy for UC at Enrollment No | 0 participants | 1 participants | 1 participants | 2 participants | 4 participants |
| Participants with Ongoing Therapy for UC at Enrollment Yes | 9 participants | 11 participants | 13 participants | 9 participants | 42 participants |
| Participants with Significant Medical Conditions in Past 6 Months No | 4 participants | 1 participants | 2 participants | 2 participants | 9 participants |
| Participants with Significant Medical Conditions in Past 6 Months Yes | 5 participants | 11 participants | 12 participants | 9 participants | 37 participants |
| Race/Ethnicity, Customized White, Not Hispanic or Latino | 9 participants | 12 participants | 14 participants | 11 participants | 46 participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 7 Participants | 6 Participants | 27 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants | 5 Participants | 19 Participants |
| Time Since Diagnosis | 2.29 years STANDARD_DEVIATION 2.43 | 5.26 years STANDARD_DEVIATION 4.92 | 5.38 years STANDARD_DEVIATION 4.79 | 5.46 years STANDARD_DEVIATION 9.72 | 4.76 years STANDARD_DEVIATION 6.01 |
| Time Since Onset of Symptoms | 3.92 years STANDARD_DEVIATION 2.79 | 6.25 years STANDARD_DEVIATION 5 | 6.85 years STANDARD_DEVIATION 4.31 | 7.03 years STANDARD_DEVIATION 10.13 | 6.16 years STANDARD_DEVIATION 6.08 |
| Weight | 74.01 kg STANDARD_DEVIATION 24.04 | 75.76 kg STANDARD_DEVIATION 20.98 | 79.61 kg STANDARD_DEVIATION 16.65 | 73.46 kg STANDARD_DEVIATION 13.6 | 76.04 kg STANDARD_DEVIATION 18.38 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 9 | 9 / 12 | 9 / 14 | 6 / 11 |
| serious Total, serious adverse events | 0 / 9 | 1 / 12 | 0 / 14 | 1 / 11 |
Outcome results
Primary
Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the ACT-1 Marker
AUEC (0-last) is the area under the drug effect-time curve until the last available time point. Mean percent inhibition over time \[AUEC(0-last)\] was determined for the Act-1 marker. Act-1 is a mouse antibody similar to vedolizumab that also binds α4β7 integrin.
Time frame: Days 1, 2, 3, 4, 8, 15, 29, 43, 57, 71, 85, 86, 87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, and 253
Population: PD Analysis Set; participants with available data (indicated by n)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the ACT-1 Marker | 4281.7 percent inhibition*days | Standard Deviation 3035.3 |
| Vedolizumab 2 mg/kg | Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the ACT-1 Marker | 20195.9 percent inhibition*days | Standard Deviation 3814.2 |
| Vedolizumab 6 mg/kg | Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the ACT-1 Marker | 22675.2 percent inhibition*days | Standard Deviation 2211.8 |
| Vedolizumab 10 mg/kg | Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the ACT-1 Marker | 23613.7 percent inhibition*days | Standard Deviation 1574.4 |
Primary
Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the MAdCAM-1-Fc Marker
AUEC (0-last) is the area under the drug effect-time curve until the last available time point. Mean percent inhibition over time \[AUEC(0-last)\] was determined for the MAdCAM-1-Fc marker. MAdCAM-1-Fc is a fusion of human MAdCAM-1 with parts of a mouse monoclonal antibody.
Time frame: Days 1, 2, 3, 4, 8, 15, 29, 43, 57, 71, 85, 86, 87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, and 253
Population: PD Analysis Set; participants with available data (indicated by n)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the MAdCAM-1-Fc Marker | 2139.2 percent inhibition*days | Standard Deviation 1513.4 |
| Vedolizumab 2 mg/kg | Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the MAdCAM-1-Fc Marker | 18802.0 percent inhibition*days | Standard Deviation 3556.1 |
| Vedolizumab 6 mg/kg | Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the MAdCAM-1-Fc Marker | 22322.1 percent inhibition*days | Standard Deviation 1974.2 |
| Vedolizumab 10 mg/kg | Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the MAdCAM-1-Fc Marker | 22484.6 percent inhibition*days | Standard Deviation 1716 |
Primary
Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab
AUC was calculated for 3 time intervals during the study: 1. AUC (Day 0-14): from administration on Day 0 to last quantifiable concentration on Day 14, selected to capture the AUC following the first dose of vedolizumab until administration of the second dose 2. AUC(Day 85-99): from administration on Day 85 to last quantifiable concentration on Day 99, selected to assess the amount of drug accumulation with the planned loading regimen by comparing it to AUC(Day 0-14) 3. AUC(Day 85-141): from the first quantifiable concentration on Day 85 to the last quantifiable concentration on Day 141, selected to assess the drug exposure over an 8-week period
Time frame: Days 0-14, Days 85-99, Days 85-141
Population: PK Analysis Set; participants with available data at each time point (indicated by n).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | AUC(Day 85-99) (n=9, 14, 11) | 473 day*μg/mL | Standard Deviation 92 |
| Placebo | Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | AUC(Day 85-141) (n=9, 14, 11) | 1082 day*μg/mL | Standard Deviation 243 |
| Placebo | Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | AUC (Day 0-14) (n=10, 14, 11) | 375 day*μg/mL | Standard Deviation 59 |
| Vedolizumab 2 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | AUC(Day 85-141) (n=9, 14, 11) | 3318 day*μg/mL | Standard Deviation 698 |
| Vedolizumab 2 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | AUC (Day 0-14) (n=10, 14, 11) | 1058 day*μg/mL | Standard Deviation 270 |
| Vedolizumab 2 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | AUC(Day 85-99) (n=9, 14, 11) | 1532 day*μg/mL | Standard Deviation 227 |
| Vedolizumab 6 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | AUC(Day 85-141) (n=9, 14, 11) | 5633 day*μg/mL | Standard Deviation 1927 |
| Vedolizumab 6 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | AUC (Day 0-14) (n=10, 14, 11) | 1765 day*μg/mL | Standard Deviation 822 |
| Vedolizumab 6 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | AUC(Day 85-99) (n=9, 14, 11) | 2608 day*μg/mL | Standard Deviation 795 |
Primary
Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: Days 1 and 85, prior to and 2, 12, 24, 48, and 72 hours after dosing.
Population: Pharmacokinetic (PK) Analysis Set, defined as all vedolizumab participants for whom there were sufficient data to estimate PK. Analyses only include participants with available data at each time point (indicated by n).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85 | Cmax, Day 1 (n=10, 14, 11) | 54.0 µg/mL | Standard Deviation 8.9 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85 | Cmax, Day 85 (n=9, 14, 11) | 60.4 µg/mL | Standard Deviation 12.5 |
| Vedolizumab 2 mg/kg | Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85 | Cmax, Day 1 (n=10, 14, 11) | 154.3 µg/mL | Standard Deviation 41.5 |
| Vedolizumab 2 mg/kg | Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85 | Cmax, Day 85 (n=9, 14, 11) | 191.9 µg/mL | Standard Deviation 42.6 |
| Vedolizumab 6 mg/kg | Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85 | Cmax, Day 1 (n=10, 14, 11) | 279.0 µg/mL | Standard Deviation 167.9 |
| Vedolizumab 6 mg/kg | Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85 | Cmax, Day 85 (n=9, 14, 11) | 291.9 µg/mL | Standard Deviation 95 |
Primary
Cmin: Minimum Observed Plasma Concentration of Vedolizumab
Minimum observed plasma concentration (Cmin) is the lowest plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: Day 85, prior to and 2, 12, 24, 48, and 72 hours after dosing.
Population: PK Analysis Set; participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cmin: Minimum Observed Plasma Concentration of Vedolizumab | 7.25 μg/mL | Standard Deviation 2.41 |
| Vedolizumab 2 mg/kg | Cmin: Minimum Observed Plasma Concentration of Vedolizumab | 29.33 μg/mL | Standard Deviation 13.36 |
| Vedolizumab 6 mg/kg | Cmin: Minimum Observed Plasma Concentration of Vedolizumab | 44.74 μg/mL | Standard Deviation 19.8 |
Primary
Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker
The target of vedolizumab is α4β7 integrin, a receptor found on inflammatory immune cells that guides these inflammatory cells to the gut and binds to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on gut endothelial cells. The extent of the α4β7 receptor saturation by vedolizumab was assessed using the MAdCAM-1-Fc binding interference assay. MAdCAM-1-Fc is a fusion of human MAdCAM-1 with parts of a mouse monoclonal antibody. The assay measures the percent inhibition of the MAdCAM-1-Fc binding to α4β7 integrin due to the presence of vedolizumab binding. Emax was calculated on Day 1, Day 85, and based on all available data.
Time frame: Days 1, 2, 3, 4, 8, 15, 29, 43, 57, 71, 85, 86, 87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, and 253
Population: PD Analysis Set; participants with available data (indicated by n)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | Day 1 (n=8, 10, 11, 10) | 11.9 percent inhibition | Standard Deviation 15.3 |
| Placebo | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | All available (n=8, 10, 11, 10) | 43.3 percent inhibition | Standard Deviation 27.3 |
| Placebo | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | Day 85 (n=8, 9, 11, 10) | 8.5 percent inhibition | Standard Deviation 7.9 |
| Vedolizumab 2 mg/kg | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | All available (n=8, 10, 11, 10) | 99.3 percent inhibition | Standard Deviation 0.6 |
| Vedolizumab 2 mg/kg | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | Day 85 (n=8, 9, 11, 10) | 98.3 percent inhibition | Standard Deviation 1.1 |
| Vedolizumab 2 mg/kg | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | Day 1 (n=8, 10, 11, 10) | 96.4 percent inhibition | Standard Deviation 1.8 |
| Vedolizumab 6 mg/kg | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | Day 85 (n=8, 9, 11, 10) | 98.3 percent inhibition | Standard Deviation 2.3 |
| Vedolizumab 6 mg/kg | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | All available (n=8, 10, 11, 10) | 99.8 percent inhibition | Standard Deviation 0.3 |
| Vedolizumab 6 mg/kg | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | Day 1 (n=8, 10, 11, 10) | 89.8 percent inhibition | Standard Deviation 29.8 |
| Vedolizumab 10 mg/kg | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | All available (n=8, 10, 11, 10) | 99.3 percent inhibition | Standard Deviation 0.7 |
| Vedolizumab 10 mg/kg | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | Day 1 (n=8, 10, 11, 10) | 96.8 percent inhibition | Standard Deviation 2.9 |
| Vedolizumab 10 mg/kg | Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker | Day 85 (n=8, 9, 11, 10) | 96.2 percent inhibition | Standard Deviation 2.6 |
Primary
Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker
The target of vedolizumab is α4β7 integrin, a receptor found on inflammatory immune cells that guides these inflammatory cells to the gut and binds to the Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) on gut endothelial cells. The extent of the α4β7 receptor saturation by vedolizumab was assessed using the Act-1 binding interference assay. Act-1 is a mouse antibody similar to vedolizumab that also binds α4β7 integrin. The assay measures the percent inhibition of the Act-1 due to the presence of vedolizumab binding. Emax was calculated on Day 1, Day 85 and based on all available data.
Time frame: Days 1, 2, 3, 4, 8, 15, 29, 43, 57, 71, 85, 86, 87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, and 253
Population: Pharmacodynamic (PD) Analysis Set, defined as all participants for whom there were sufficient data to estimate PD. Analyses only include participants with available data (indicated by n).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | Day 1 (n=8, 10, 12, 11) | 18.4 percent inhibition | Standard Deviation 19.3 |
| Placebo | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | Day 85 (n=8, 9, 12, 11) | 22.8 percent inhibition | Standard Deviation 15.3 |
| Placebo | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | All available (n=8, 10, 12, 11) | 56.3 percent inhibition | Standard Deviation 29.4 |
| Vedolizumab 2 mg/kg | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | Day 85 (n=8, 9, 12, 11) | 98.7 percent inhibition | Standard Deviation 1.2 |
| Vedolizumab 2 mg/kg | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | Day 1 (n=8, 10, 12, 11) | 98.0 percent inhibition | Standard Deviation 1.1 |
| Vedolizumab 2 mg/kg | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | All available (n=8, 10, 12, 11) | 99.5 percent inhibition | Standard Deviation 0.6 |
| Vedolizumab 6 mg/kg | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | Day 1 (n=8, 10, 12, 11) | 99.0 percent inhibition | Standard Deviation 0.8 |
| Vedolizumab 6 mg/kg | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | Day 85 (n=8, 9, 12, 11) | 99.1 percent inhibition | Standard Deviation 0.7 |
| Vedolizumab 6 mg/kg | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | All available (n=8, 10, 12, 11) | 99.8 percent inhibition | Standard Deviation 0.3 |
| Vedolizumab 10 mg/kg | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | All available (n=8, 10, 12, 11) | 99.8 percent inhibition | Standard Deviation 0.3 |
| Vedolizumab 10 mg/kg | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | Day 85 (n=8, 9, 12, 11) | 98.6 percent inhibition | Standard Deviation 0.8 |
| Vedolizumab 10 mg/kg | Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker | Day 1 (n=8, 10, 12, 11) | 98.3 percent inhibition | Standard Deviation 1.3 |
Primary
Number of Participants With Adverse Events
An adverse event (AE) is any untoward medical occurrence in a patient administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. The investigator systematically collected information adequate to determine both the outcome and severity of the AE, and whether or not it was drug-related or met the criteria for classification as a serious adverse event (SAE). An SAE was defined as an AE that resulted in (or posed risk for) death, inpatient hospitalization (or prolonging hospitalization), or congenital, persistent or significant disability/incapacity. The intensity for each AE was defined according to the following criteria: Mild: Awareness of sign or symptom, but easily tolerated Moderate: Discomfort enough to cause interference with normal daily activities Severe: Inability to perform normal daily activities.
Time frame: From the first date of study drug administration through Day 253
Population: Safety Analysis Set, defined as all enrolled participants who received at least 1 dose of study treatment. One participant was randomized but not dosed and is not included in this population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events | Any Adverse Event | 7 participants |
| Placebo | Number of Participants With Adverse Events | Drug-related Serious Adverse Event | 0 participants |
| Placebo | Number of Participants With Adverse Events | Serious Adverse Event | 0 participants |
| Placebo | Number of Participants With Adverse Events | On-study Deaths | 0 participants |
| Placebo | Number of Participants With Adverse Events | Serious Adverse Event Resulting in Discontinuation | 0 participants |
| Placebo | Number of Participants With Adverse Events | Drug-related Adverse Event | 3 participants |
| Placebo | Number of Participants With Adverse Events | Severe Adverse Event | 0 participants |
| Vedolizumab 2 mg/kg | Number of Participants With Adverse Events | Serious Adverse Event Resulting in Discontinuation | 0 participants |
| Vedolizumab 2 mg/kg | Number of Participants With Adverse Events | Any Adverse Event | 9 participants |
| Vedolizumab 2 mg/kg | Number of Participants With Adverse Events | Severe Adverse Event | 0 participants |
| Vedolizumab 2 mg/kg | Number of Participants With Adverse Events | Drug-related Serious Adverse Event | 0 participants |
| Vedolizumab 2 mg/kg | Number of Participants With Adverse Events | Drug-related Adverse Event | 2 participants |
| Vedolizumab 2 mg/kg | Number of Participants With Adverse Events | Serious Adverse Event | 1 participants |
| Vedolizumab 2 mg/kg | Number of Participants With Adverse Events | On-study Deaths | 0 participants |
| Vedolizumab 6 mg/kg | Number of Participants With Adverse Events | Drug-related Serious Adverse Event | 0 participants |
| Vedolizumab 6 mg/kg | Number of Participants With Adverse Events | Serious Adverse Event Resulting in Discontinuation | 0 participants |
| Vedolizumab 6 mg/kg | Number of Participants With Adverse Events | On-study Deaths | 0 participants |
| Vedolizumab 6 mg/kg | Number of Participants With Adverse Events | Severe Adverse Event | 1 participants |
| Vedolizumab 6 mg/kg | Number of Participants With Adverse Events | Any Adverse Event | 9 participants |
| Vedolizumab 6 mg/kg | Number of Participants With Adverse Events | Serious Adverse Event | 0 participants |
| Vedolizumab 6 mg/kg | Number of Participants With Adverse Events | Drug-related Adverse Event | 1 participants |
| Vedolizumab 10 mg/kg | Number of Participants With Adverse Events | On-study Deaths | 0 participants |
| Vedolizumab 10 mg/kg | Number of Participants With Adverse Events | Severe Adverse Event | 1 participants |
| Vedolizumab 10 mg/kg | Number of Participants With Adverse Events | Drug-related Adverse Event | 1 participants |
| Vedolizumab 10 mg/kg | Number of Participants With Adverse Events | Serious Adverse Event | 1 participants |
| Vedolizumab 10 mg/kg | Number of Participants With Adverse Events | Serious Adverse Event Resulting in Discontinuation | 0 participants |
| Vedolizumab 10 mg/kg | Number of Participants With Adverse Events | Any Adverse Event | 6 participants |
| Vedolizumab 10 mg/kg | Number of Participants With Adverse Events | Drug-related Serious Adverse Event | 0 participants |
Primary
Terminal Phase Elimination Half-life (t½) of Vedolizumab
Terminal phase elimination half-life (t½) is the time required for half of the drug to be eliminated from the plasma.
Time frame: Pre-dose through Day 253
Population: PK Analysis Set; participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Terminal Phase Elimination Half-life (t½) of Vedolizumab | 15.1 days | Standard Deviation 2 |
| Vedolizumab 2 mg/kg | Terminal Phase Elimination Half-life (t½) of Vedolizumab | 22.0 days | Standard Deviation 6.7 |
| Vedolizumab 6 mg/kg | Terminal Phase Elimination Half-life (t½) of Vedolizumab | 20.6 days | Standard Deviation 7.2 |