Study of Vedolizumab Following Multiple Intravenous Doses in Patients With Ulcerative Colitis

Primary outcomes

1. Number of Participants With Adverse Events

   Time frame: 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.

2. Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85

   Time frame: 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.

3. Cmin: Minimum Observed Plasma Concentration of Vedolizumab

   Time frame: 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.

4. Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab

   Time frame: Days 0-14, Days 85-99, Days 85-141

   AUC was calculated for 3 time intervals during the study:

   • 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
   • 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)
   • 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

5. Terminal Phase Elimination Half-life (t½) of Vedolizumab

   Time frame: 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.

6. Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker

   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

   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.

7. Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker

   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

   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.

8. Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the ACT-1 Marker

   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

   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.

9. Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the MAdCAM-1-Fc Marker

   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

   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.