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

Phase 2

Completed

Conditions: Crohn's Disease
Ulcerative Colitis

Interventions: Drug: vedolizumab

Registration Number: NCT00619489

Lead Sponsor: Millennium Pharmaceuticals, Inc.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 72

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vedolizumab 6 mg/kg	vedolizumab	Participants received vedolizumab, 6 mg/kg, IV, on Days 1, 15 and 43, and thereafter once every 8 weeks for up to 78 weeks.
Vedolizumab 2 mg/kg	vedolizumab	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs)	From Day 1 to Day 637	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.
Number of Participants With Clinically Significant Laboratory Findings	through Day 637	Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are enzymes in the blood.
Number of Participants With Signs and Symptoms of Progressive Multifocal Leukoencephalopathy (PML)	through Day 637	At every visit, before receiving study treatment participants were evaluated by clinic staff for signs of PML using a PML symptom checklist.
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

Name	Time	Method
Serum Concentration of Vedolizumab Before Dosing	Days 43, 99, 155 and 267, predose	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.
Saturation of Receptors by Vedolizumab Before Dosing on Days 1, 43, 99, 155 and 267 by ACT-1 Assay	Days 43, 99, 155 and 267, predose	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.
Saturation of Receptors by Vedolizumab Before Dosing Using the MAdCAM-1-Fc Assay	Days 43, 99, 155 and 267, predose	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.