Ulcerative ColitisPhase 3COVETNCT02954159
Vedolizumab Monotherapy Vs Combination Therapy With Tacrolimus in UC
A Phase 3 study testing Tacrolimus and Vedolizumab in people with Ulcerative Colitis, run by Medical College of Wisconsin at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Ulcerative Colitis
- What is being tested?
- Tacrolimus and Vedolizumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 4 participants
- Where
- 1 siteUnited States
- Study dates
- 18 May 2017to 31 Jan 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients aged 18 to 65 years with a confirmed diagnosis of UC.
- Diagnosis of UC established at least 6 months before enrollment or evidence of chronicity in colonic biopsies.
- Patients with UC disease extent beyond 15 cm (must involve at least the sigmoid colon)
- In female patients:
- Post-menopausal for ≥1 year before screening, or
- Surgically sterile, or
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- 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.
- In male patients:
- o Agreement not to father a child through 4 weeks after discontinuing tacrolimus (through contraception or abstinence).
- 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
- Patients are planned to start vedolizumab as part of their clinical care.
- 5-aminosalicilates (oral or topical) are permitted as long as the dose is stable for at least 2 weeks before screening.
- 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.
- 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.
- Immunosupressants (thiopurines or methotrexate) must be stopped 4 weeks prior to starting the study medications.
- 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.
Who cannot join
- Positive stool test for parasites or stool culture for pathologic bacteria within 30 days prior to enrollment.
- Evidence or history of Clostridium Difficile infection within 60 days prior to enrollment.
- Active Cytomegalovirus (CMV) infection evidenced by a positive CMV PCR in serum and/or positive immunohistochemistry stain in colonic tissue.
- Uncontrolled hypertension.
- Chronic kidney disease (defined as a glomerular filtration rate < 60 mL/min, calculated using the Modification of Diet in Renal Disease (MDRD) formula)
- Chronic liver disease.
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- A refractory electrolyte disorder (e.g. hypomagnesemia).
- 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].
- 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).
- Creatinine values of 1.5 mg/dL in 2 separate readings.
- Established diagnosis of diabetes mellitus.
- Clinical or radiological evidence of megacolon.
- Intestinal perforation, or abdominal abscess within 3 months prior to enrollment.
- Active clinically significant bacterial infection (within 30 days of enrollment).
- Personal history of total or sub-total colectomy.
- Current Pregnancy or lactation.
- Unstable or uncontrolled medical disorder.
- Personal history of malignant neoplasm.
- Inability to give informed consent.
- History of alcohol or illicit drug abuse in the previous 6 months to enrollment.
- Patient that have received any experimental drug within 6 months prior to enrollment.
- Patients with previous exposure to vedolizumab, cyclosporine or tacrolimus.
- Personal history of congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation) excluding pharmacologic immunosuppressant.
- Any of the following laboratory abnormalities during the screening period:
- Hemoglobin level <9 g/dL
- WBC count <3 × 109/L
- Lymphocyte count <0.5 × 109/L
- Platelet count <100 × 109/L or >1200 × 109/L
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the upper limit of normal (ULN)
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
About this study
Official title: Induction of Response and Remission of Vedolizumab Monotherapy Vs Combination Therapy With Tacrolimus in Patients With Moderately to Severely Active Ulcerative Colitis
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.
Read the 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.
- Conditions
- Ulcerative Colitis
- Being tested
- Tacrolimus, Vedolizumab, Placebo
- Medical subject headings
- Colitis, Ulcerative
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TacrolimusDrug
Also called Prograf
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.
VedolizumabDrug
Also called Entyvio
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.
PlaceboOther
Patients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm.
| Study group | Role | What they receive |
|---|---|---|
| Treatment arm | Active comparator | vedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) Receives: Drug: Tacrolimus; Drug: Vedolizumab |
| Placebo Arm | Placebo comparator | vedolizumab at standard regimen with placebo. Receives: Drug: Vedolizumab; Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical Response
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.
Measured: week 6
Secondary outcomes (1)
Clinical Response
Steroid-free clinical response at week 14 after starting vedolizumab.
Measured: week 14
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Nov 2016 (estimated)
- Study start18 May 2017
- Primary completion31 Jan 2019
- Study completion31 Jan 2019
Why it stopped: insufficient enrollment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Ulcerative ColitisStudies of the same condition, open and under way.
- More trials run by Medical College of WisconsinThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical College of Wisconsin
- Sponsor type
- University, hospital or other
- Collaborators
- Takeda
- Responsible party
- Principal investigator, Andres Yarur, Medical College of Wisconsin
- Investigators
- Andres J Yarur, MD, Principal investigator, Medical College of Wisconsin
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02954159
- Sponsor's protocol ID
- 2016-101742
- Other IDs
- 2016
- Acronym
- COVET
- Status last verified
- Aug 2020
- First submitted
- 14 Oct 2016
- Last updated
- 3 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Induction of Response and Remission of Vedolizumab Monotherapy Vs Combination Therapy With Tacrolimus in Patients With Moderately to Severely Active Ulcerative Colitis
- ClinicalTrials.gov ID
- NCT02954159
- Acronym / sponsor ID
- COVET / 2016-101742
- Conditions
- Ulcerative Colitis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: insufficient enrollment
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Medical College of WisconsinUniversity, hospital or other
- Collaborators
- Takeda
- Study start
- 18 May 2017 (actual)
- Primary completion
- 31 Jan 2019 (actual)
- Study completion
- 31 Jan 2019 (actual)
- First posted
- 3 Nov 2016 (estimated)
- Results
- Posted 3 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment arm | Active comparator | Drug: Tacrolimus, Drug: Vedolizumabvedolizumab at standard regimen with concomitant induction treatment of tacrolimus (starting 0.05 mg per Kg twice daily) |
| Placebo Arm | Placebo comparator | Drug: Vedolizumab, Other: Placebovedolizumab at standard regimen with placebo. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- Patients aged 18 to 65 years with a confirmed diagnosis of UC.
- Diagnosis of UC established at least 6 months before enrollment or evidence of chronicity in colonic biopsies.
- Patients with UC disease extent beyond 15 cm (must involve at least the sigmoid colon)
- In female patients:
- In male patients:
Key exclusion criteria (30 listed)
- Positive stool test for parasites or stool culture for pathologic bacteria within 30 days prior to enrollment.
- Evidence or history of Clostridium Difficile infection within 60 days prior to enrollment.
- Active Cytomegalovirus (CMV) infection evidenced by a positive CMV PCR in serum and/or positive immunohistochemistry stain in colonic tissue.
- Uncontrolled hypertension.
- Chronic kidney disease (defined as a glomerular filtration rate < 60 mL/min, calculated using the Modification of Diet in Renal Disease (MDRD) formula)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TacrolimusAlso: PrografOral 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. | Drug | Treatment arm |
| VedolizumabAlso: EntyvioIntravenous 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. | Drug | Placebo Arm, Treatment arm |
| PlaceboPatients will be randomized 1:1 in Treatment arm (receive Tacrolimus) and Placebo Arm. | Other | Placebo Arm |
Primary outcome
Clinical Response
Time frame: 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.
1 secondary outcome
Clinical Response
Time frame: week 14
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andres J Yarur, MD principal investigator
Medical College of Wisconsin
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tacrolimus and Vedolizumab in people with Ulcerative Colitis, run by Medical College of Wisconsin at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 3 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical Response (time frame: week 6). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2020.