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

Primary Purpose

Ulcerative Colitis

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Vedolizumab
Placebo
Sponsored by
Millennium Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ulcerative Colitis

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm Type

    Placebo Comparator

    Experimental

    Experimental

    Experimental

    Arm Label

    Placebo

    Vedolizumab 2 mg/kg

    Vedolizumab 6 mg/kg

    Vedolizumab 10 mg/kg

    Arm Description

    Vedolizumab-matching placebo, intravenous (IV), infusion on Days 1, 15, 29 and 85.

    Vedolizumab, 2 mg/kg, IV infusion on Days 1, 15, 29 and 85.

    Vedolizumab 6 mg/kg, IV infusion on Days 1, 15, 29 and 85.

    Vedolizumab 10 mg/kg, IV infusion on Days 1, 15, 29 and 85.

    Outcomes

    Primary Outcome Measures

    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.
    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.
    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.
    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
    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.
    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.
    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.
    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.
    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.

    Secondary Outcome Measures

    Full Information

    First Posted
    August 5, 2010
    Last Updated
    June 19, 2014
    Sponsor
    Millennium Pharmaceuticals, Inc.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01177228
    Brief Title
    Study of Vedolizumab Following Multiple Intravenous Doses in Patients With Ulcerative Colitis
    Official Title
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    June 2014
    Overall Recruitment Status
    Completed
    Study Start Date
    May 2007 (undefined)
    Primary Completion Date
    June 2008 (Actual)
    Study Completion Date
    September 2008 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Millennium Pharmaceuticals, Inc.

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Ulcerative Colitis

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    47 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    Vedolizumab-matching placebo, intravenous (IV), infusion on Days 1, 15, 29 and 85.
    Arm Title
    Vedolizumab 2 mg/kg
    Arm Type
    Experimental
    Arm Description
    Vedolizumab, 2 mg/kg, IV infusion on Days 1, 15, 29 and 85.
    Arm Title
    Vedolizumab 6 mg/kg
    Arm Type
    Experimental
    Arm Description
    Vedolizumab 6 mg/kg, IV infusion on Days 1, 15, 29 and 85.
    Arm Title
    Vedolizumab 10 mg/kg
    Arm Type
    Experimental
    Arm Description
    Vedolizumab 10 mg/kg, IV infusion on Days 1, 15, 29 and 85.
    Intervention Type
    Drug
    Intervention Name(s)
    Vedolizumab
    Other Intervention Name(s)
    Entyvio, MLN0002, MLN02, LDP-02
    Intervention Description
    Vedolizumab for intravenous infusion
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Placebo intravenous infusion
    Primary Outcome Measure Information:
    Title
    Number of Participants With Adverse Events
    Description
    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
    Title
    Cmax: Maximum Observed Plasma Concentration of Vedolizumab on Days 1 and 85
    Description
    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.
    Title
    Cmin: Minimum Observed Plasma Concentration of Vedolizumab
    Description
    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.
    Title
    Area Under the Plasma Concentration-Time Curve (AUC) for Vedolizumab
    Description
    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
    Time Frame
    Days 0-14, Days 85-99, Days 85-141
    Title
    Terminal Phase Elimination Half-life (t½) of Vedolizumab
    Description
    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
    Title
    Maximum Drug Effect (Emax) of Vedolizumab as Measured by Percent Inhibition of the Act-1 Marker
    Description
    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
    Title
    Maximum Drug Effect (Emax) as Measured by Inhibition of the MAdCAM-1-Fc Marker
    Description
    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
    Title
    Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the ACT-1 Marker
    Description
    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
    Title
    Area Under the Drug Effect Time Curve [AUEC(0-last)] as Measured by Inhibition of the MAdCAM-1-Fc Marker
    Description
    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

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    70 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Medical Monitor
    Organizational Affiliation
    Millennium Pharmaceuticals, Inc.
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    26893500
    Citation
    Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D'Haens G, Panaccione R, Loftus EV Jr, Sankoh S, Fox I, Parikh A, Milch C, Abhyankar B, Feagan BG. The safety of vedolizumab for ulcerative colitis and Crohn's disease. Gut. 2017 May;66(5):839-851. doi: 10.1136/gutjnl-2015-311079. Epub 2016 Feb 18.
    Results Reference
    derived
    PubMed Identifier
    25996351
    Citation
    Rosario M, Dirks NL, Gastonguay MR, Fasanmade AA, Wyant T, Parikh A, Sandborn WJ, Feagan BG, Reinisch W, Fox I. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease. Aliment Pharmacol Ther. 2015 Jul;42(2):188-202. doi: 10.1111/apt.13243. Epub 2015 May 20. Erratum In: Aliment Pharmacol Ther. 2015 Nov;42(9):1135.
    Results Reference
    derived

    Learn more about this trial

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

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