Long Term Safety of Vedolizumab (MLN0002) in Patients With Ulcerative Colitis and Crohn's Disease

Study Overview
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Brief Summary
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This was an open-label study to provide an opportunity for participants with Ulcerative Colitis (UC) who previously completed Study C13002 (NCT01177228), and for treatment-naïve participants with UC or Crohn's Disease (CD) to receive treatment with vedolizumab, and to determine the long term safety of vedolizumab in patients afflicted with these diseases.

Detailed Description
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This was a phase 2, multiple-dose, open-label study of vedolizumab administered intravenously (IV) every 8 weeks. The study population included treatment-naïve ulcerative colitis (UC) or Crohn's Disease (CD) participants, as well as 38 UC participants who had tolerated vedolizumab well during Study C13002 (NCT01177228). In the original study protocol, all participants were randomized to receive vedolizumab at doses of either 6 mg/kg or 10 mg/kg. With the implementation of Amendment 1, the assigned doses of vedolizumab were decreased to 2.0 mg/kg and 6.0 mg/kg. To implement the dose changes, instead of randomizing all participants across both doses, those who rolled over from Study C13002 were reassigned to receive the 2.0 mg/kg dose and all participants who entered C13004 naïve to treatment were to receive the 6.0 mg/kg dose, starting on the next scheduled dosing day. Also, if participants assigned to the 2 mg/kg dose experienced flare, they were to receive the higher 6 mg/kg dose. In the results analyses for this study, participants are grouped according to the lowest dose received, i.e., 2.0 mg/kg or 6.0 mg/kg vedolizumab.

Official Title
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Phase 2, Multiple Dose, Open-Label Study to Determine the Long Term Safety of MLN0002 in Patients With Ulcerative Colitis and Crohn's Disease

Conditions
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Ulcerative Colitis, Crohn's Disease

Intervention / Treatment
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* Drug: vedolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed and active ulcerative colitis (UC) or Crohn's Disease (CD) Crohn's Disease Activity Index (CDAI) Score of 220 - 450 for participants with CD Partial Mayo score of 2 - 7 for participants with UC Patient should be appropriate candidate for biologic therapy per guidelines Up-to-date on cancer screening No severe systemic disease Patients with evidence of abscess Agree to comply with study procedures including contraception Exclusion Criteria: Low lymphocyte counts History of imaging abnormalities, multiple sclerosis (MS), brain tumor or other neurological illness Active or recent serious infections Recent treatment with biologic (i.e., Remicade) or investigational drug Impending surgery Any participants with vedolizumab human anti-human antibody (HAHA) titers ≥1:125 or with a previous immediate hypersensitivity reaction during or shortly after vedolizumab infusion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vedolizumab 2 mg/kg<br>Participants received vedolizumab, 2 mg/kg, intravenously (IV), on Days 1, 15 and 43, and thereafter once every 8 weeks for up to 78 weeks. | Drug: vedolizumab<br>* Vedolizumab for intravenous (IV) infusion<br>* Other names: LDP-02;|
| Experimental: Vedolizumab 6 mg/kg<br>Participants received vedolizumab, 6 mg/kg, IV, on Days 1, 15 and 43, and thereafter once every 8 weeks for up to 78 weeks. | Drug: vedolizumab<br>* Vedolizumab for intravenous (IV) 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 (AEs) | 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 Day 1 to Day 637 | 
| Number of Participants With Clinically Significant Laboratory Findings | Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are enzymes in the blood. | through Day 637 | 
| Number of Participants With Signs and Symptoms of Progressive Multifocal Leukoencephalopathy (PML) | At every visit, before receiving study treatment participants were evaluated by clinic staff for signs of PML using a PML symptom checklist. | through Day 637 | 
| Number of Participants With Human Anti-human Antibodies (HAHA) |  | Samples collected prior to dosing on Days 1, 43, 155, 267, 379, 491, and 637. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentration of Vedolizumab Before Dosing | Vedolizumab serum concentrations were measured from serum samples collected for pharmacokinetic (PK) analysis within 2 hours prior to dosing. The original protocol specified that PK parameters, including but not limited to minimum plasma concentration (Cmin), were to be estimated; however, due to intrapatient dose modification with Amendment 1, it was no longer feasible to perform a full PK parameter estimation. The summaries of pre-infusion data (i.e., trough levels) are presented at time points where at least 50% of participants had quantifiable vedolizumab concentrations, using a value of 0 for results below a measurable range. This provides information on the pharmacokinetic behavior of vedolizumab when administered as long-term therapy. | Days 43, 99, 155 and 267, predose | 
| Saturation of Receptors by Vedolizumab Before Dosing on Days 1, 43, 99, 155 and 267 by ACT-1 Assay | 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 percentage of cells bearing α4β7 that were not saturated with vedolizumab at the time of sampling. | Days 43, 99, 155 and 267, predose | 
| Saturation of Receptors by Vedolizumab Before Dosing Using the MAdCAM-1-Fc Assay | 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 address in 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 at time points where at least 50% of participants in the analysis set had non-missing results. MAdCAM-1-Fc is a fusion of human MAdCAM-1 with parts of a mouse monoclonal antibody. The assay measures the percentage of cells bearing α4β7 that were not saturated with vedolizumab at the time of sampling. | Days 43, 99, 155 and 267, predose |