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Phase 4 Study to Evaluate the Efficacy and Safety of Vedolizumab in the Treatment of Chronic Pouchitis (EARNEST)

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ClinicalTrials.gov Identifier: NCT02790138
Recruitment Status : Recruiting
First Posted : June 3, 2016
Last Update Posted : October 12, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:
The purpose of this study is to assess the efficacy and safety of vedolizumab intravenous (IV) in participants with a proctocolectomy and ileal pouch anal anastomosis for ulcerative colitis (UC) who have developed chronic or recurrent pouchitis, or require continuous antibiotic treatment.

Condition or disease Intervention/treatment Phase
Colitis, Ulcerative Drug: Vedolizumab Drug: Ciprofloxacin Drug: Vedolizumab Placebo Phase 4

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

All participants will receive an intravenous infusion at Weeks 0, 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 12, 2016
Estimated Primary Completion Date : March 9, 2019
Estimated Study Completion Date : March 9, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Vedolizumab 300 mg
Vedolizumab 300 mg, intravenous (IV) infusion, once at Weeks 0, 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.
Drug: Vedolizumab
Vedolizumab IV infusion
Other Names:
  • Entyvio
  • MLN0002 IV
  • Kynteles

Drug: Ciprofloxacin
Ciprofloxacin Tablets

Placebo Comparator: Placebo
Vedolizumab placebo-matching IV infusion, once at Weeks 0, 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.
Drug: Ciprofloxacin
Ciprofloxacin Tablets

Drug: Vedolizumab Placebo
Vedolizumab placebo-matching IV infusion




Primary Outcome Measures :
  1. Percentage of Participants with Chronic or Recurrent Pouchitis Achieving Clinically Relevant Remission after 14 Weeks of Treatment [ Time Frame: Week 14 ]
    Clinically relevant remission is defined as a modified pouchitis disease activity index (mPDAI) score <5 and a reduction of overall score by ≥2 points from Baseline. The mPDAI scale was developed as an objective, and quantitative criteria for pouch inflammation after ileal pouch anal anastomosis (IPAA). The 12-point overall score is calculated from 2 separate 6-point scales based on clinical symptoms (0 to 6), endoscopic findings (0 to 6). A cutoff of 5 differentiates participants with pouchitis (mPDAI ≥5) from participants without pouchitis (mPDAI <5).


Secondary Outcome Measures :
  1. Percentage of Participants Achieving mPDAI Score <5 and a Reduction of Overall Score by ≥2 Points From Baseline after 34 Weeks of Treatment [ Time Frame: Week 34 ]
  2. Percentage of Participants Achieving PDAI score <7 and a Reduction of Overall Score by ≥3 Points from Baseline PDAI Score after 14 Weeks of Treatment and after 34 Weeks of Treatment [ Time Frame: Weeks 14 and 34 ]
    PDAI is an objective and quantitative criteria for pouch inflammation after IPAA. The 18-point overall score is calculated from 3 separate 6-point scales based on clinical symptoms (0 to 6), endoscopic findings (0 to 6) and histologic changes (0 to 6). The PDAI incorporates histologic features of acute inflammation, along with symptom and inflammation on endoscopy, and establishes a cut-off of 7 for differentiation between 'pouchitis' (≥7 points) and 'no pouchitis' (<7 points).

  3. Time to Remission [ Time Frame: Baseline up to Week 34 ]
    Remission is defined as a PDAI score <7 and a decrease in PDAI score of ≥3 points from Baseline.

  4. Percentage of Participants Achieving a Partial Response after 14 and 34 Weeks of Treatment [ Time Frame: Weeks 14 and 34 ]
    Partial response is defined as a reduction in mPDAI score by ≥2 points from Baseline.

  5. Change in PDAI Endoscopic Subscore at Weeks 14 and 34 Compared to Baseline [ Time Frame: Baseline, Weeks 14 and 34 ]
    PDAI endoscopic subscore includes edema, granularity, friability, loss of vascular pattern, mucous exudates and ulcerations. Each item is scored on a scale of 0 to 1. A PDAI endoscopic subscore is calculated by summing the scores from each endoscopic finding. Total score ranges from 0 to 6. Maximum score indicates greater severity of the disease.

  6. Change in PDAI Histologic Subscore at Weeks 14 and 34 Compared to Baseline [ Time Frame: Baseline, Weeks 14 and 34 ]
    PDAI histologic subscore includes polymorphic nuclear leukocyte infiltration (mild=1; moderate + crypt abscess=2 and severe + crypt abscess=3) and ulceration per low power field (mean). A PDAI histologic subscore is calculated by summing the scores from each finding. Total score ranges from 0 to 6. Maximum score indicates greater severity of the disease.

  7. Change in Total PDAI Score at Weeks 14 and 34 Compared to Baseline [ Time Frame: Baseline, Weeks 14 and 34 ]
  8. Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Weeks 14, 22 and 34 Compared to Baseline [ Time Frame: Baseline, Weeks 14, 22 and 34 ]
    The IBDQ is an instrument used to assess quality of life in adult participants with inflammatory bowel disease (IBD). It includes 32 questions on 4 domains of Health-Related Quality-of-Life (HRQOL): Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic Function (5 items). Participants are asked to recall symptoms and quality of life from the last 2 weeks and rate each item on a 7-point Likert scale (1=worst to 7=best). A total IBDQ score is calculated by summing the scores from each domain; the total IBDQ score ranges from 32 to 224, with lower scores reflecting worse HRQOL.

  9. Change in Cleveland Global Quality of Life (CGQL) at Weeks 14, 22 and 34 Compared to Baseline [ Time Frame: Baseline, Weeks 14, 22 and 34 ]
    The CGQL (Fazio score) is a quality-of-life indicator specifically for participants with ileal pouch-anal anastomosis. Participants rate 3 items (current quality of life, current quality of health, and current energy level), each on a scale of 0 to 10 (0=worst; 10=best). The scores are added, and the final CGQL utility score is obtained by dividing this result by 30.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 subject 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 (eg, 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 (eg, 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 subject is immunodeficient (eg, 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 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 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 (eg, >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:
    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 (eg, 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02790138


Contacts
Contact: Takeda Study Registration Call Center +1-877-825-3327 medicalinformation@tpna.com

  Show 42 Study Locations
Sponsors and Collaborators
Takeda
Investigators
Study Director: Medical Director Clinical Science Takeda

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02790138     History of Changes
Other Study ID Numbers: Vedolizumab-4004
U1111-1171-0918 ( Registry Identifier: WHO )
2015-003472-78 ( EudraCT Number )
First Posted: June 3, 2016    Key Record Dates
Last Update Posted: October 12, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda:
Drug Therapy

Additional relevant MeSH terms:
Pouchitis
Colitis, Ulcerative
Colitis
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Inflammatory Bowel Diseases
Colonic Diseases
Intestinal Diseases
Ileitis
Enteritis
Ileal Diseases
Ciprofloxacin
Vedolizumab
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Gastrointestinal Agents