COVET: Vedolizumab Monotherapy Vs Combination Therapy With Tacrolimus in UC

Sponsor
Medical College of Wisconsin (Other)
Overall Status
Terminated
CT.gov ID
NCT02954159
Collaborator
Takeda (Industry)
4
1
2
20.5
0.2

Study Details

Study Description

Brief Summary

The aim of this study is to assess if a combination therapy of tacrolimus and vedolizumab is superior to vedolizumab monotherapy for induction of remission in moderate to severe UC, and its effect on long and short-term outcomes including colectomy rate. Secondary aim of this study is to assess the safety of tacrolimus as an induction agent in patients with UC.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Phase III studies have shown that patients with UC who received vedolizumab had a higher rate of clinical response, clinical remission and mucosal healing when compared to placebo3. Nevertheless, while clinical response rate was almost 50%, the rate of clinical remission at 6 weeks was only 16.9. In comparison, in the ACT trials almost 40% of patients achieved remission at week 84. The delayed onset of action of vedolizumab monotherapy in patients with UC may lead to a higher colectomy rate and limit the use of vedolizumab in patients with active disease who require rapid induction of remission. Corticosteroids are used as a bridging agent to rapidly induce remission. However, steroid refractory or dependent disease and steroid intolerance are common. Furthermore, steroids have devastating side effects.

Tacrolimus inhibits the complexion of calcineurin with its respective cytoplasmic receptors cyclophilin and FK-binding protein 12 (FKBP-12), both of which regulate a calmodulin dependent-phosphatase. Tacrolimus has been found to be efficacious in the treatment of patients with moderate to severe UC. Unfortunately, because of the safety profile with long term use, the drug is mostly used as an induction agent.

While switching to vedolizumab from another drug that has not been efficacious or has lost effectiveness (or starting vedolizumab as a first agent) can be beneficious in the long term, patients need an induction agent in order to achieve remission in a short period of time. Tacrolimus is a widely used drug to prevent implant rejection after a transplant. Randomized controlled trials have shown that is highly effective with good response rates even after 2 weeks of therapy. In order to avoid side effects, tacrolimus is usually used for a limited amount of time (12-14 weeks), which is sufficient time to induce remission of disease. Unfortunately, as other inflammatory bowel diseases, UC recurs and patients also require a maintenance therapy. While tacrolimus has been used with good results as a long term agent, the ideal scenario is to avoid its long term use as there is still a potential for side effects and a need for a very strict close monitoring. This is why a long term maintenance agent is needed to keep the patient in remission. Until recently, no ideal agent was available for this purpose, as while anti-tumor necrosis factor agents (infliximab and adalimumab) have been approved for ulcerative colitis, its combination with another agent that induces systemic immunosuppression (in this case, tacrolimus) could potentially increase the risk of infections and/or malignancies. Because vedolizumab is gut selective, does not affect the entire immune system and post-marketing studies have confirmed its safety profile. This makes it a perfect combination agent to tacrolimus, theoretically decreasing the potential side effect while increasing its efficacy.

The hypothesis is that the addition of tacrolimus as an induction agent to a standard regimen of vedolizumab increases the efficacy of the drug, decreasing the rate of need for colectomy and other complications while quickly improving the patients' quality of life without significantly increasing the risk of adverse events.

Study Design

Study Type:
Interventional
Actual Enrollment :
4 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
Induction of Response and Remission of Vedolizumab Monotherapy Vs Combination Therapy With Tacrolimus in Patients With Moderately to Severely Active Ulcerative Colitis
Actual Study Start Date :
May 18, 2017
Actual Primary Completion Date :
Jan 31, 2019
Actual Study Completion Date :
Jan 31, 2019

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Treatment arm

vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily)

Drug: Tacrolimus
Oral tacrolimus tablet starting at 0.05mg/kg twice daily, with dose adjustments aiming for serum trough levels of 10-15 ng/ml during the first 2 weeks, and 5-10ng/ml subsequently.
Other Names:
  • Prograf
  • Drug: Vedolizumab
    Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care.
    Other Names:
  • Entyvio
  • Placebo Comparator: Placebo Arm

    vedolizumab at standard regimen with placebo.

    Drug: Vedolizumab
    Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care.
    Other Names:
  • Entyvio
  • Other: Placebo
    Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm.

    Outcome Measures

    Primary Outcome Measures

    1. Clinical Response [week 6]

      Steroid-free clinical response at week 6 after starting vedolizumab, defined as a reduction in the Mayo Clinic score of at least 3 points and a decrease of at least 30% from the baseline score, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1 while off steroids.

    Secondary Outcome Measures

    1. Clinical Response [week 14]

      Steroid-free clinical response at week 14 after starting vedolizumab.

    Other Outcome Measures

    1. Mayo UC Score [Screening, Week 2, 6, 8, 14, 30]

      total score on assessment

    2. Short Inflammatory Bowel Disease Questionnaire [Screening, Week 6, 14, 30]

      total score on assessment

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Patients aged 18 to 65 years with a confirmed diagnosis of UC.

    2. Diagnosis of UC established at least 6 months before enrollment or evidence of chronicity in colonic biopsies.

    3. Patients with UC disease extent beyond 15 cm (must involve at least the sigmoid colon)

    4. In female patients:

    • Post-menopausal for ≥1 year before screening, or

    • Surgically sterile, or

    • Agree to be on a contraceptive method from the screening visit through 4 weeks after discontinuing tacrolimus (or placebo), or

    • Completely abstain from heterosexual intercourse.

    1. In male patients:

    o Agreement not to father a child through 4 weeks after discontinuing tacrolimus (through contraception or abstinence).

    1. Moderate to severe UC
    • Mayo Clinic partial UC score of 6 to 12, with a baseline sigmoidoscopy sub-score of at least 2, and disease that extended 15 cm or more from the anal verge.

    • Steroid dependent patients (Appendix 1)

    • Steroid naïve or steroid responsive

    1. Patients are planned to start vedolizumab as part of their clinical care.

    2. 5-aminosalicilates (oral or topical) are permitted as long as the dose is stable for at least 2 weeks before screening.

    3. Patients with or without previous exposure to anti-TNF agents can be included. Patients with previous exposure to anti-TNF must be off infliximab for 8 weeks and off adalimumab for 4 weeks.

    4. Anti-diarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic diarrhea are not permitted.The patient must be off anti-diarrheal at the time of screening.

    5. Immunosupressants (thiopurines or methotrexate) must be stopped 4 weeks prior to starting the study medications.

    6. Patients with previous Clostridium Difficile infection can be included as long as they received a full course of therapy and have a negative Clostridium Difficile PCR test and are infection free for 60 days prior to screening.

    Exclusion Criteria:
    1. Positive stool test for parasites or stool culture for pathologic bacteria within 30 days prior to enrollment.

    2. Evidence or history of Clostridium Difficile infection within 60 days prior to enrollment.

    3. Active Cytomegalovirus (CMV) infection evidenced by a positive CMV PCR in serum and/or positive immunohistochemistry stain in colonic tissue.

    4. Uncontrolled hypertension.

    5. Chronic kidney disease (defined as a glomerular filtration rate < 60 mL/min, calculated using the Modification of Diet in Renal Disease (MDRD) formula)

    6. Chronic liver disease.

    7. A refractory electrolyte disorder (e.g. hypomagnesemia).

    8. Persistent hypomagnesemia that does not respond to oral magnesium supplementation defined as a value <1.3 mEq/L in two separate readings, despite the administration of oral magnesium [10 meq of slow-release magnesium chloride three times per day for 48 hours].

    9. Persistent hypophosphatemia defined as levels <2.2 mg/dL in two separate readings, 48 hours apart despite phosphate supplementation (sodium phosphate/potassium phosphate 500 mg up to three times daily for 48 hours).

    10. Creatinine values of 1.5 mg/dL in 2 separate readings.

    11. Established diagnosis of diabetes mellitus.

    12. Clinical or radiological evidence of megacolon.

    13. Intestinal perforation, or abdominal abscess within 3 months prior to enrollment.

    14. Active clinically significant bacterial infection (within 30 days of enrollment).

    15. Personal history of total or sub-total colectomy.

    16. Current Pregnancy or lactation.

    17. Unstable or uncontrolled medical disorder.

    18. Personal history of malignant neoplasm.

    19. Inability to give informed consent.

    20. History of alcohol or illicit drug abuse in the previous 6 months to enrollment.

    21. Patient that have received any experimental drug within 6 months prior to enrollment.

    22. Patients with previous exposure to vedolizumab, cyclosporine or tacrolimus.

    23. Personal history of congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation) excluding pharmacologic immunosuppressant.

    24. Any of the following laboratory abnormalities during the screening period:

    25. Hemoglobin level <9 g/dL

    26. WBC count <3 × 109/L

    27. Lymphocyte count <0.5 × 109/L

    28. Platelet count <100 × 109/L or >1200 × 109/L

    29. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the upper limit of normal (ULN)

    30. To avoid interactions, patients on medications that induce or inhibit the Cytochrome p450 family 3, subfamily A (CYP3A) will be excluded. CYP3A inducers and inhibitors are shown in Appendix 3

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Medical College of Wisconsin Milwaukee Wisconsin United States 53226

    Sponsors and Collaborators

    • Medical College of Wisconsin
    • Takeda

    Investigators

    • Principal Investigator: Andres J Yarur, MD, Medical College of Wisconsin

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Andres Yarur, Assistant Professor, Dept of Gastroenterology, Medical College of Wisconsin
    ClinicalTrials.gov Identifier:
    NCT02954159
    Other Study ID Numbers:
    • 2016-101742
    First Posted:
    Nov 3, 2016
    Last Update Posted:
    Sep 3, 2020
    Last Verified:
    Aug 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Treatment Arm Placebo Arm
    Arm/Group Description vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) Tacrolimus: Oral tacrolimus tablet starting at 0.05mg/kg twice daily, with dose adjustments aiming for serum trough levels of 10-15 ng/ml during the first 2 weeks, and 5-10ng/ml subsequently. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. vedolizumab at standard regimen with placebo. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. Placebo: Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm.
    Period Title: Overall Study
    STARTED 2 2
    COMPLETED 1 1
    NOT COMPLETED 1 1

    Baseline Characteristics

    Arm/Group Title Treatment Arm Placebo Arm Total
    Arm/Group Description vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) Tacrolimus: Oral tacrolimus tablet starting at 0.05mg/kg twice daily, with dose adjustments aiming for serum trough levels of 10-15 ng/ml during the first 2 weeks, and 5-10ng/ml subsequently. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. vedolizumab at standard regimen with placebo. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. Placebo: Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm. Total of all reporting groups
    Overall Participants 2 2 4
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    2
    100%
    2
    100%
    4
    100%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    1
    50%
    2
    100%
    3
    75%
    Male
    1
    50%
    0
    0%
    1
    25%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    1
    50%
    1
    25%
    Not Hispanic or Latino
    2
    100%
    1
    50%
    3
    75%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    White
    2
    100%
    2
    100%
    4
    100%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    2
    100%
    2
    100%
    4
    100%

    Outcome Measures

    1. Primary Outcome
    Title Clinical Response
    Description Steroid-free clinical response at week 6 after starting vedolizumab, defined as a reduction in the Mayo Clinic score of at least 3 points and a decrease of at least 30% from the baseline score, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1 while off steroids.
    Time Frame week 6

    Outcome Measure Data

    Analysis Population Description
    Data not collected
    Arm/Group Title Treatment Arm Placebo Arm
    Arm/Group Description vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) Tacrolimus: Oral tacrolimus tablet starting at 0.05mg/kg twice daily, with dose adjustments aiming for serum trough levels of 10-15 ng/ml during the first 2 weeks, and 5-10ng/ml subsequently. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. vedolizumab at standard regimen with placebo. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. Placebo: Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm.
    Measure Participants 0 0
    2. Secondary Outcome
    Title Clinical Response
    Description Steroid-free clinical response at week 14 after starting vedolizumab.
    Time Frame week 14

    Outcome Measure Data

    Analysis Population Description
    Data not collected
    Arm/Group Title Treatment Arm Placebo Arm
    Arm/Group Description vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) Tacrolimus: Oral tacrolimus tablet starting at 0.05mg/kg twice daily, with dose adjustments aiming for serum trough levels of 10-15 ng/ml during the first 2 weeks, and 5-10ng/ml subsequently. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. vedolizumab at standard regimen with placebo. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. Placebo: Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm.
    Measure Participants 0 0
    3. Other Pre-specified Outcome
    Title Mayo UC Score
    Description total score on assessment
    Time Frame Screening, Week 2, 6, 8, 14, 30

    Outcome Measure Data

    Analysis Population Description
    Data not collected
    Arm/Group Title Treatment Arm Placebo Arm
    Arm/Group Description vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) Tacrolimus: Oral tacrolimus tablet starting at 0.05mg/kg twice daily, with dose adjustments aiming for serum trough levels of 10-15 ng/ml during the first 2 weeks, and 5-10ng/ml subsequently. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. vedolizumab at standard regimen with placebo. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. Placebo: Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm.
    Measure Participants 0 0
    4. Other Pre-specified Outcome
    Title Short Inflammatory Bowel Disease Questionnaire
    Description total score on assessment
    Time Frame Screening, Week 6, 14, 30

    Outcome Measure Data

    Analysis Population Description
    Data not collected
    Arm/Group Title Treatment Arm Placebo Arm
    Arm/Group Description vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) Tacrolimus: Oral tacrolimus tablet starting at 0.05mg/kg twice daily, with dose adjustments aiming for serum trough levels of 10-15 ng/ml during the first 2 weeks, and 5-10ng/ml subsequently. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. vedolizumab at standard regimen with placebo. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. Placebo: Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm.
    Measure Participants 0 0

    Adverse Events

    Time Frame 20 months, 13 days
    Adverse Event Reporting Description
    Arm/Group Title Treatment Arm Placebo Arm
    Arm/Group Description vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) Tacrolimus: Oral tacrolimus tablet starting at 0.05mg/kg twice daily, with dose adjustments aiming for serum trough levels of 10-15 ng/ml during the first 2 weeks, and 5-10ng/ml subsequently. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. vedolizumab at standard regimen with placebo. Vedolizumab: Intravenous Vedolizumab 300 mg at week 0, 2 and 6 followed by the same dose every 8 weeks. This drug will be given as per standard of care. Placebo: Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm.
    All Cause Mortality
    Treatment Arm Placebo Arm
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/2 (0%) 0/2 (0%)
    Serious Adverse Events
    Treatment Arm Placebo Arm
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/2 (50%) 0/2 (0%)
    Gastrointestinal disorders
    Increase in severity of UC symptoms 1/2 (50%) 1 0/2 (0%) 0
    Other (Not Including Serious) Adverse Events
    Treatment Arm Placebo Arm
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/2 (100%) 2/2 (100%)
    Endocrine disorders
    clinically significant low phosphorus 1/2 (50%) 1 0/2 (0%) 0
    clinically significant low magnesium 1/2 (50%) 1 0/2 (0%) 0
    Gastrointestinal disorders
    Nausea 0/2 (0%) 0 1/2 (50%) 1
    Emesis 0/2 (0%) 0 1/2 (50%) 1
    increased diarrhea 1/2 (50%) 1 0/2 (0%) 0
    increase in severity of UC symptoms 1/2 (50%) 1 0/2 (0%) 0
    General disorders
    increased pain 1/2 (50%) 1 0/2 (0%) 0
    Nervous system disorders
    Intermittent tremor 0/2 (0%) 0 1/2 (50%) 1
    Renal and urinary disorders
    clinically significant elevated creatinine 1/2 (50%) 1 0/2 (0%) 0
    Skin and subcutaneous tissue disorders
    rash 0/2 (0%) 0 0/2 (0%) 0

    Limitations/Caveats

    Study was stopped due to lack of enrollment. 4 subjects were enrolled. A Amendment was needed sooner to lessen patient burden/time or increase patient compensation.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Andres Yarur, MD; Principal Investigator
    Organization Medical College Of Wisconsin
    Phone 414-955-6858
    Email ayarur@mcw.edu
    Responsible Party:
    Andres Yarur, Assistant Professor, Dept of Gastroenterology, Medical College of Wisconsin
    ClinicalTrials.gov Identifier:
    NCT02954159
    Other Study ID Numbers:
    • 2016-101742
    First Posted:
    Nov 3, 2016
    Last Update Posted:
    Sep 3, 2020
    Last Verified:
    Aug 1, 2020