Clinical trial NCT02790138: A Study to Evaluate the Efficacy and Safety of Vedolizumab in the Treatment of Chronic Pouchitis
Official title: A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to Evaluate the Efficacy and Safety of Entyvio (Vedolizumab IV) in the Treatment of Chronic Pouchitis (EARNEST)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pouchitis
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2016-06-03
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the efficacy of vedolizumab intravenous (IV) and placebo in terms of the percentage of participants with chronic or recurrent pouchitis achieving clinically relevant remission.

Detailed description: Vedolizumab is being tested to treat people who have chronic pouchitis. This study will look at the healing of inflammation of ileal pouch in people who take vedolizumab as compared to those receiving a matching placebo. The study will enroll approximately 110 patients. Participants will be randomly assigned to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Vedolizumab 300 mg IV
* Placebo IV

All participants will receive an intravenous infusion at Day 1, Weeks 2, 6, 14, 22, and 30 along with concomitant antibiotic treatment with ciprofloxacin 500 mg twice daily through Week 4.

This multicenter trial will be conducted in North America and Europe. The overall time to participate in treatment and efficacy assessment of this study is 34 weeks. Participants will make multiple visits to the clinic, plus a final visit 18 weeks after the last dose of study drug for a safety follow-up assessment (up to Week 48). Participants will also participate in a long-term follow-up, by phone after the last dose of study drug up to Week 56.

Eligibility criteria: Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. Has a history of ileal pouch anal anastomosis (IPAA) for ulcerative colitis (UC) completed at least 1 year prior to the Day 1 (Randomization) Visit.
4. Has pouchitis that is chronic or recurrent, defined by an modified pouchitis disease activity index (mPDAI) score ≥5 assessed as average from 3 days immediately prior to the Baseline endoscopy and a minimum endoscopic subscore of 2 (outside the staple or suture line) with either (a) ≥3 recurrent episodes within 1 year prior to the Screening Period treated with ≥2 weeks of antibiotic or other prescription therapy, or (b) requiring maintenance antibiotic therapy taken continuously for ≥4 weeks immediately prior to the Baseline Endoscopy Visit.
5. Agrees to take ciprofloxacin (500 mg twice daily) on Day 1 and through Week 4, regardless of the previous treatment and to stop any previous antibiotic therapy on Day 1 of the study (additional courses of antibiotics will be allowed, as needed, for flares after Week 14).
6. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use a barrier method of contraception (e.g., condom with spermicide) from signing of informed consent throughout the duration of the study and for 18 weeks after last dose. The female partner of a male participant should also be advised to use a highly effective method of contraception.
7. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use a highly effective method of contraception from signing of informed consent throughout the duration of the study and for 18 weeks after last dose.

Exclusion Criteria:

Gastrointestinal Exclusion Criteria

1. Has Crohn's disease (CD), or CD of the pouch.
2. Has irritable pouch syndrome (IPS).
3. Has isolated or predominant cuffitis.
4. Has mechanical complications of the pouch (e.g., pouch stricture or pouch fistula).
5. Currently requires or has a planned surgical intervention for UC during the study.
6. Has diverting stoma.

Infectious Disease Exclusion Criteria 1. Has evidence of an active infection (e.g., sepsis, cytomegalovirus, or listeriosis) during Screening.

2. Has active or latent tuberculosis (TB), regardless of treatment history, as evidenced by any of the following:

1. A diagnostic TB test performed within 30 days of Screening or during the Screening Period that is positive, as defined by:

   1. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests. OR
   2. A tuberculin skin test reaction ≥10 mm (≥5 mm in participants receiving the equivalent of \>15 mg/day prednisone).

      OR
2. Chest X-ray within 3 months prior to Day 1 that is suspicious for pulmonary TB, and a positive or 2 successive indeterminate QuantiFERON test within 30 days prior to Screening or during the Screening Period.

   3. Has chronic hepatitis B virus (HBV) infection\* or chronic hepatitis C virus (HCV) infection\*\* or a known history of human immunodeficiency virus (HIV) infection (or is found to be seropositive at Screening) or participant is immunodeficient (e.g., due to organ transplantation, history of common variable immunodeficiency, etc).

   \* Participants who are positive for hepatitis B virus surface antigen (HBsAg) will be excluded. For participants who are negative for HBsAg but are positive for either surface antibodies and/or core antibodies, HBV Deoxyribonucleic acid (DNA) polymerase chain reaction will be performed and if any test result meets or exceeds detection sensitivity, the participant will be excluded.
   * If participant is HCV antibody positive, then a viral load test will be performed. If the viral load test is positive then the participant will be excluded.

     4. Has evidence of active infection with Clostridium (C) difficile during Screening (to be confirmed by laboratory test)

   General Exclusion Criteria
   1. Has any prior exposure to vedolizumab, natalizumab, efalizumab, rituximab, etrolizumab, or anti-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) therapy.
   2. Has a history of hypersensitivity or allergies to vedolizumab or its components.
   3. Has allergies to and/or contraindications for ciprofloxacin, a history of tendon disorders related to quinolone administration and/or glucose-6-phosphate dehydrogenase (G6PD) deficiency. Further conditions requiring precautions for use of ciprofloxacin have to be considered based on local prescribing information.
   4. Is taking, has taken, or is required to take any excluded medications.
   5. Has received any investigational or approved biologic or biosimilar agent within 60 days prior to Randomization.
   6. Has received an investigational nonbiologic therapy within 30 days prior to Randomization.
   7. Has received an approved nonbiologic therapy (including 5-aminosalicylate \[5-ASA\], corticosteroid, azathioprine, 6-mercaptopurine \[6-MP\], etc.) in an investigational protocol within 30 days prior to Randomization.
   8. Has received any live vaccinations within 30 days prior to randomization.
   9. Has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist at Screening.
   10. Has had a kidney, heart, or lung transplant.
   11. Has a history of malignancy, except for the following: adequately-treated non-metastatic basal cell skin cancer; squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to the Screening visit; and history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to Screening. Participants with a remote history of malignancy (e.g., \>10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy received and must be discussed with the sponsor on a case-by-case basis prior to enrollment.
   12. Has a history of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, demyelinating, or neurodegenerative disease.
   13. Has conditions, which in the opinion of the investigator, may interfere with the participant's ability to comply with the study procedures.
   14. Has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal (GI), genitourinary, hematological, coagulation, immunological, endocrine/metabolic, neurologic, or other medical disorder that, in the opinion of the investigator, would confound the study results or compromise participant safety.
   15. Has any of the following laboratory abnormalities during the Screening Period:

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   1. Hemoglobin level \<8 g/dL.
   2. White blood cell (WBC) count \<3 × 10\^9/L.
   3. Lymphocyte count \<0.5 × 10\^9/L.
   4. Platelet count \<100 × 10\^9/L or \>1200 × 10\^9/L.
   5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 × the upper limit of normal (ULN).
   6. Alkaline phosphatase \>3 × ULN.
   7. Serum creatinine \>2 × ULN.

   16. If female, the participant is pregnant or lactating or intending to become pregnant or nurse before, during, or within 18 weeks after the last dose of study medication; or intending to donate ova during such time period.

   17. If male, the participant intends to donate sperm or father a child during the course of this study or for 18 weeks after the last dose of study medication.

   18. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.

   19. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to Screening.

Primary outcomes:
measure: Percentage of Participants With Chronic or Recurrent Pouchitis Achieving Clinically Relevant Remission at Week 14
timeFrame: Week 14
Secondary outcomes:
measure: Percentage of Participants With Chronic or Recurrent Pouchitis Achieving Clinically Relevant Remission at Week 34
timeFrame: Week 34
measure: Percentage of Participants Achieving Pouchitis Disease Activity Index (PDAI) Remission at Weeks 14 and 34
timeFrame: Weeks 14 and 34
measure: Time to PDAI Remission
timeFrame: Baseline up to Week 34
measure: Percentage of Participants Achieving a Partial mPDAI Response at Weeks 14 and 34
timeFrame: Weeks 14 and 34
measure: Change From Baseline in PDAI Endoscopic Inflammation Subscore at Weeks 14 and 34
timeFrame: Baseline up to Weeks 14 and 34
measure: Change From Baseline in PDAI Acute Histologic Inflammation Subscore at Weeks 14 and 34
timeFrame: Baseline up to Weeks 14 and 34
measure: Change From Baseline in Total PDAI Score at Weeks 14 and 34
timeFrame: Baseline up to Weeks 14 and 34
measure: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Weeks 14, 22, and 34
timeFrame: Baseline up to Weeks 14, 22, and 34
measure: Change From Baseline in Cleveland Global Quality of Life (CGQL) at Weeks 14, 22, and 34
timeFrame: Baseline up to Weeks 14, 22, and 34
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Evanston
country: United States
facility: Northshore University HealthSystem
state: Illinois
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Chapel Hill
country: United States
facility: University of North Carolina GI
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas HealthCare System Digestive Health
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Southlake
country: United States
facility: Texas Digestive Disease Consultants
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Leuven
country: Belgium
facility: UZ Leuven - University Hospital Gasthuisberg
city: Vancouver
country: Canada
facility: GIRI (GI Research Institute)
state: British Columbia
city: Ottawa
country: Canada
facility: Ottawa Hospital - General Campus
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Rennes cedex 9
country: France
facility: CHU de Rennes - Hopital de Pontchaillou
city: Saint-Priest en Jarez
country: France
facility: CHU Saint Etienne - Hopital Nord
city: Toulouse cedex 9
country: France
facility: CHU de Toulouse - Hopital Rangueil
city: Vandoeuvre les Nancy
country: France
facility: CHRU Nancy Hopital de Brabois
city: Berlin
country: Germany
facility: Charite Universitatsmedizin Berlin -Campus Virchow Klinikum
city: Hamburg
country: Germany
facility: Asklepios Hospital Hamburg - West
city: Heidelberg
country: Germany
facility: Praxis fuer Gastroenterologie, Drs. Ehehalt/ Helmstaedter
city: Jena
country: Germany
facility: Universitatsklinikum Jena
city: Mannheim
country: Germany
facility: Klinikum Mannheim GmbH Universitaetsklinikum
city: Bologna
country: Italy
facility: Azienda Ospedaliera S. Orsola-Malpighi
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Rome
country: Italy
facility: Policlinico Gemelli
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas IRCCS
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Doctor Negrin
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico La Fe
city: Harrow
country: United Kingdom
facility: St. Mark's Hospital
city: London
country: United Kingdom
facility: Royal London Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: