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

NCT01177228 | Completed Phase 2 Results

• 2 other identifiers: C13002U1111-1156-8540
• Study Type: interventional
• Target: 47
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Ulcerative Colitis

Outcome Measures

Primary Outcomes (9)

• 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: 1. 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 2. 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) 3. 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

Study Arms (4)

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Vedolizumab 2 mg/kg

EXPERIMENTAL

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

Drug: Vedolizumab

Vedolizumab 6 mg/kg

EXPERIMENTAL

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

Drug: Vedolizumab

Vedolizumab 10 mg/kg

EXPERIMENTAL

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

Drug: Vedolizumab

Interventions

Vedolizumab DRUG

Vedolizumab for intravenous infusion

Also known as: Entyvio, MLN0002, MLN02, LDP-02

Vedolizumab 10 mg/kg; Vedolizumab 2 mg/kg; Vedolizumab 6 mg/kg

Placebo DRUG

Placebo intravenous infusion

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Related Publications (2)

• 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.

  PMID: 26893500 DERIVED

• 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.

  PMID: 25996351 DERIVED

MeSH Terms

Conditions

Colitis, Ulcerative

Interventions

vedolizumab; LDP-02

Condition Hierarchy (Ancestors)

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Inflammatory Bowel Diseases; Colonic Diseases; Intestinal Diseases

Results Point of Contact

• Title: Medical Director
• Organization: Millennium Pharmaceuticals Inc

clinicaltrialregistry@tpna.com

1-800-778-2860

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2010
• First Posted: August 6, 2010
• Study Start: May 1, 2007
• Primary Completion: June 1, 2008
• Study Completion: September 1, 2008
• Last Updated: July 18, 2014
• Results First Posted: July 18, 2014

Record last verified: 2014-06