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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2, Randomized, Placebo-Controlled, Double-Blind Study to Determine the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MLN0002 Following Multiple Intravenous Doses in Patients With Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Vedolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria are not to be enrolled in the study. Patients who require ulcerative colitis (UC) surgical intervention or for whom surgical intervention is anticipated during the study Patients who fail to meet laboratory values as specified in the protocol or have a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist during the screening period Low-grade dysplasia, high-grade dysplasia, dysplasia-associated lesion or mass, or colorectal cancer Treatment with cyclosporine, FK506 (tacrolimus) or infliximab within 60 days prior to study Patients receiving any of the following within 14-days prior to the study: antibiotics for treatment of irritable bowel syndrome, heparin or warfarin, narcotics, tube feeding, defined formula diets or parenteral alimentation Colostomy, fistulae or known fixed symptomatic stenosis of the intestine Immunologic or ischemic intestinal condition Toxic megacolon Chronic hepatitis B or C or human immunodeficiency virus (HIV) infection Any vaccinations within 30 days prior to study drug administration History of imaging abnormalities, multiple sclerosis (MS), brain tumor or neurodegenerative disease Significantly impaired liver or renal function Current or recent history of alcohol dependence Current use of illicit drugs Active or recent serious infections or serious underlying disease as specified in protocol Active psychiatric problems that might interfere with compliance to study Previous exposure to MLN0002 Participated in an investigational study within 30 days prior to study drug administration or received treatment with an investigational monoclonal antibody within the last 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Vedolizumab-matching placebo, intravenous (IV), infusion on Days 1, 15, 29 and 85. | Drug: Placebo<br>* Placebo intravenous infusion<br>|
| Experimental: Vedolizumab 2 mg/kg<br>Vedolizumab, 2 mg/kg, IV infusion on Days 1, 15, 29 and 85. | Drug: Vedolizumab<br>* Vedolizumab for intravenous infusion<br>* Other names: LDP-02;|
| Experimental: Vedolizumab 6 mg/kg<br>Vedolizumab 6 mg/kg, IV infusion on Days 1, 15, 29 and 85. | Drug: Vedolizumab<br>* Vedolizumab for intravenous infusion<br>* Other names: LDP-02;|
| Experimental: Vedolizumab 10 mg/kg<br>Vedolizumab 10 mg/kg, IV infusion on Days 1, 15, 29 and 85. | Drug: Vedolizumab<br>* Vedolizumab for intravenous infusion<br>* Other names: LDP-02;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the first date of study drug administration through Day 253 | 
| 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. | Days 1 and 85, prior to and 2, 12, 24, 48, and 72 hours after dosing. | 
| 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. | Day 85, prior to and 2, 12, 24, 48, and 72 hours after dosing. | 
| Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab | 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 | Days 0-14, Days 85-99, Days 85-141 | 
| 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. | Pre-dose through Day 253 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 |