Ulcerative Colitis
Conditions
Brief summary
There are fewer therapeutic options for patients with active ulcerative colitis (UC) compared to patients with active Crohn's disease (CD) and the investigators are facing a persistent unmet need for additional effective and affordable therapies for patients with UC. Methotrexate (MTX) 25 mg once weekly administered subcutaneously (sq) or intramuscularly (im) is an efficient therapy to induce and maintain steroid free remission in patients with CD. To evaluate the efficacy of a similar approach in patients with active ulcerative colitis the investigators conduct a double-blind, placebo controlled, randomized, multicenter, parallel group trial to investigate the safety and efficacy of 25 mg MTX applied subcutaneously once weekly in patients with active UC, who either failed 5-ASA therapy, or are steroid dependent or are intolerant or not responding to azathioprine/6-mercaptopurine therapy or have no response/ lost response to infliximab prior to the study inclusion. The study is designed as a drug withdrawal trial and includes two periods, the Induction Period (week 0-16) and the Maintenance Period (week 17-48). In the open label Induction Period every patient will receive a steroid taper, MTX 25 mg sq once weekly + daily folic acid 1 mg tablets for the induction of clinical response or remission. Patients responding to the open label MTX therapy and being off steroids between week 12-16 will be randomized at week 16 1:1 to Placebo sq once weekly + daily folic acid 1 mg tablets + 2.4 g mesalamine or to MTX 25 mg sq once weekly + daily folic acid 1 mg tablets+ 2.4 g mesalamine. The Specific Aims of the trial are: i) To evaluate the safety and tolerability of 25 mg MTX applied sq once weekly over a time period of 48 weeks; ii) To evaluate the relapse-free survival of MTX maintenance therapy compared to placebo over a time period of 32 weeks; iii) To evaluate the efficacy of MTX over a time period of 16 weeks to induce steroid free remission; iiii) To establish a DNA, plasma and serum library to enable the evaluation of clinical and pharmacogenomic models to predict the response to MTX therapy in patients with UC. With 25-30 participating centers actively enrolling, the investigators anticipate to complete enrollment for this study in a time period of 3 years. Completion of this trial will define the therapeutic value of MTX in UC, potentially changing the current therapeutic strategy in UC.
Interventions
DRUGMethotrexate
Induction period (week 1-16) (Open label): 25 mg MTX sq once weekly + Steroid taper + 1 mg folic acid daily Maintenance period (week 17-48) (Randomization): 25 mg MTX sq once weekly + 1 mg folic acid daily + 2.4 g mesalamine or Placebo sq once weekly + 1 mg folic acid daily + 2.4 g mesalamine
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent. * Man or woman between 18 and 70 years of age. * UC diagnosed by routine clinical, radiographic, endoscopic, and pathological criteria. * Active UC with a Mayo score of 6 to 12 points and moderate-to severe active disease on sigmoidoscopy (Mayo endoscopic subscore of at least 2) and at least ONE of the following criteria: * Steroid dependent UC \* * Primary failure or loss of response to an anti-TNF (infliximab, adalimumab, golimumab) in the past * Primary failure or loss of response to vedolizumab in the past * Intolerance/failure of azathioprine/6-MP therapy in the past * Failure of 5-ASA therapy * Steroid dependence is defined as a clinical response to treatment with prednisone 40 to 60 mg/day and relapse within 30 days after prednisone treatment was completed or as a requirement for a daily dosage of not less than 10 mg of prednisone and impossibility of weaning the patient off steroid without clinical relapses (two attempts to discontinue the medication within the preceding six months of the start of the study).
Exclusion criteria
* Failure to respond to 40 mg of prednisone or higher/day in the last 2 weeks before inclusion * Concomitant use of azathioprine (AZA) or 6-mercaptopurine (6-MP) must be discontinued at least 2 weeks before inclusion into the study (Week 0 visit) * Anti-TNF therapy in the 2 weeks before the Week 0 visit * Failure of cyclosporine therapy in the previous 6 months prior to Screening visit * Patients with serum albumin \< 2.5 g/dl at baseline * Low serum folate defined as decrease of \>10% below normal range * Patients with WBC\< 3.0 x109th/L at baseline * Patients with platelet count \< 100 x109th/L * Patients with an underlying infection with C. difficile at Screening visit * Patients with pre-existing hepatic disease * Patients with known non-alcoholic fatty liver disease (NAFLD) * Patients with known Hepatitis B or Hepatitis C * Patients with pre-existing renal dysfunction (creatinine \>1.5 mg/dl). * Patients with a pre-existing chronic lung disease other than well controlled asthma * Patients with interstitial lung disease of unknown cause * Patients with a BMI \>35 * Known previous or concurrent malignancy (other than that considered surgically cured, with no evidence for recurrence for 5 years - basal cell does not exclude) * Existing pregnancy, lactation, or planned pregnancy\* (men and women) within the next 12 months. (\*Methotrexate should not be used for at least 3 months before planned pregnancy for men and women and should not be used during pregnancy or breast feeding) * High alcohol consumption (more than seven drinks per week) * Non - steroidal inflammatory medications (NSAIDs) as long-term treatment, defined as use for at least 4 days a week each month * Continuous treatment with one of the following drugs: * Probenecid, * Trimethoprim/sulfamethoxazole * Sulfasalazine * Acitretin * Streptozocin * Non-use of appropriate contraceptives in females of childbearing potential (e.g. condoms, intrauterine device {IUD}, hormonal contraception, or other means considered adequate by the responsible investigator) or in males with a child-fathering potential (condoms, or other means considered adequate by the responsible investigator during treatment * Participation in another clinical trial within the last 30 days, simultaneous participation in another clinical trial, or previous participation in this trial * Well-founded doubt about the patient's cooperation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relapse Free Survival Week 17-48 | 48 weeks | Relapse-free survival: Total week 48 Mayo score not exceeding 2 points, with all individual subscores not exceeding 1 point and relapse free survival defined by a numerical stable Mayo score throughout 32 weeks of maintenance therapy without increase of 3 or more points in the partial Mayo clinic score (excluding sigmoidoscopy) compared to the partial Mayo score of the individual patient at randomization at week 16 and no steroid use or other immunosuppressive medication throughout the 32 week maintenance period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mucosal Healing at Week 48. | 48 weeks | Mucosal healing is defined as an absolute Mayo subscore for endoscopy of 0 or 1 |
| Relapse of Disease Between Week 17-48 | 48 weeks | Relapse of disease in the Maintenance period as defined as an increase of 3 or more points in the partial Mayo clinic score (excluding sigmoidoscopy) with an absolute clinical Mayo score ≥ 4 or need for retreatment with steroids. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Calprotectin Levels <250 mcg/g Stool in Patients in Response or in Remission at Week 16 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening | 16 weeks | Steroid free clinical remission as defined as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point or steroid free clinical response defined as a reduction from baseline in the clinical Mayo score of ≥ 2 points and at least 25%, with an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0-1 point and a clinical Mayo score ≤5 and stool calprotectin levels \<250 mcg/g stool at week 16 of the induction period in the subgroup of patients with calprotectin \>250mcg/g stool at screening. |
| Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 48 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening | 48 weeks | Steroid free clinical remission as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point and stool calprotectin levels of ≤ 50mcg at week 48 of the induction period in the subgroup of patients with calprotectin ≥ 250mcg/g stool at screening. |
| Calprotectin Levels <250 mcg/g Stool in Patients in Response or in Remission at Week 48 With Calprotectin Levels > 250 mcg/g Stool at Screening | 48 weeks | Steroid free clinical remission as defined as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point or steroid free clinical response defined as a reduction from baseline in the clinical Mayo score of ≥ 2 points and at least 25%, with an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0-1 point and a clinical Mayo score ≤5 and stool calprotectin levels \<250 mcg/g stool at week 32 of the maintenance period in the subgroup of patients with calprotectin ≥ 250mcg/g stool at screening. |
| Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 16 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening | 16 weeks | Steroid free clinical remission as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point and stool calprotectin levels of ≤ 50mcg at week 16 of the induction period in the subgroup of patients with calprotectin ≥ 250mcg/g stool at screening. |
Countries
United States
Participant flow
Recruitment details
256 patients were assessed for eligibility between February 2012 and May 2016 at 37 sites across the US. 76 met exclusion criteria and one patient withdrew consent during screening.
Participants by arm
| Arm | Count |
|---|---|
| Induction Period (Week 1-16) Steroid taper for 12 weeks and 25 mg MTX sq once weekly + 1 mg folic acid daily | 179 |
| Total | 179 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Induction Period (week1-16) | Adverse Event | 16 | 0 | 0 |
| Induction Period (week1-16) | Lack of Efficacy | 70 | 0 | 0 |
| Induction Period (week1-16) | Withdrawal by Subject | 9 | 0 | 0 |
| Maintenance Period Week | Adverse Event | 0 | 5 | 2 |
| Maintenance Period Week | Lack of Efficacy | 0 | 22 | 22 |
| Maintenance Period Week | Lost to Follow-up | 0 | 1 | 0 |
| Maintenance Period Week | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Induction Period (Week 1-16) |
|---|---|
| Age, Continuous | 42 years |
| Calprotectin week 0 (Induction period) or week 16 (Maintenance period) | 612 mg/kg STANDARD_DEVIATION 524 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 169 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 155 Participants |
| Region of Enrollment United States | 179 Participants |
| Sex: Female, Male Female | 69 Participants |
| Sex: Female, Male Male | 110 Participants |
| Site of disease Left colon | 86 Participants |
| Site of disease Pancolitis | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 179 | 0 / 44 | 0 / 40 |
| other Total, other adverse events | 69 / 179 | 41 / 44 | 30 / 40 |
| serious Total, serious adverse events | 15 / 179 | 0 / 44 | 1 / 40 |
Outcome results
Primary
Relapse Free Survival Week 17-48
Relapse-free survival: Total week 48 Mayo score not exceeding 2 points, with all individual subscores not exceeding 1 point and relapse free survival defined by a numerical stable Mayo score throughout 32 weeks of maintenance therapy without increase of 3 or more points in the partial Mayo clinic score (excluding sigmoidoscopy) compared to the partial Mayo score of the individual patient at randomization at week 16 and no steroid use or other immunosuppressive medication throughout the 32 week maintenance period.
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate Maintenance (Week 17-48) | Relapse Free Survival Week 17-48 | 12 Participants |
| Placebo Maintenance (Week 17-48) | Relapse Free Survival Week 17-48 | 12 Participants |
Secondary
Mucosal Healing at Week 48.
Mucosal healing is defined as an absolute Mayo subscore for endoscopy of 0 or 1
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate Maintenance (Week 17-48) | Mucosal Healing at Week 48. | 12 Participants |
| Placebo Maintenance (Week 17-48) | Mucosal Healing at Week 48. | 12 Participants |
Secondary
Relapse of Disease Between Week 17-48
Relapse of disease in the Maintenance period as defined as an increase of 3 or more points in the partial Mayo clinic score (excluding sigmoidoscopy) with an absolute clinical Mayo score ≥ 4 or need for retreatment with steroids.
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate Maintenance (Week 17-48) | Relapse of Disease Between Week 17-48 | 29 Participants |
| Placebo Maintenance (Week 17-48) | Relapse of Disease Between Week 17-48 | 25 Participants |
Other Pre-specified
Calprotectin Levels <250 mcg/g Stool in Patients in Response or in Remission at Week 16 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening
Steroid free clinical remission as defined as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point or steroid free clinical response defined as a reduction from baseline in the clinical Mayo score of ≥ 2 points and at least 25%, with an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0-1 point and a clinical Mayo score ≤5 and stool calprotectin levels \<250 mcg/g stool at week 16 of the induction period in the subgroup of patients with calprotectin \>250mcg/g stool at screening.
Time frame: 16 weeks
Population: 134 /179 (75%) patients had a calprotectin value ≥ 250 mcg/g stool at screening.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate Maintenance (Week 17-48) | Calprotectin Levels <250 mcg/g Stool in Patients in Response or in Remission at Week 16 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening | 56 Participants |
Other Pre-specified
Calprotectin Levels <250 mcg/g Stool in Patients in Response or in Remission at Week 48 With Calprotectin Levels > 250 mcg/g Stool at Screening
Steroid free clinical remission as defined as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point or steroid free clinical response defined as a reduction from baseline in the clinical Mayo score of ≥ 2 points and at least 25%, with an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0-1 point and a clinical Mayo score ≤5 and stool calprotectin levels \<250 mcg/g stool at week 32 of the maintenance period in the subgroup of patients with calprotectin ≥ 250mcg/g stool at screening.
Time frame: 48 weeks
Population: 33/44 patient in the Methotrexate Maintenance group and 32/40 patients in the Placebo Maintenance group met the criteria of calprotectin ≥ 250 mcg/g stool at screening
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate Maintenance (Week 17-48) | Calprotectin Levels <250 mcg/g Stool in Patients in Response or in Remission at Week 48 With Calprotectin Levels > 250 mcg/g Stool at Screening | 10 Participants |
| Placebo Maintenance (Week 17-48) | Calprotectin Levels <250 mcg/g Stool in Patients in Response or in Remission at Week 48 With Calprotectin Levels > 250 mcg/g Stool at Screening | 8 Participants |
Other Pre-specified
Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 16 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening
Steroid free clinical remission as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point and stool calprotectin levels of ≤ 50mcg at week 16 of the induction period in the subgroup of patients with calprotectin ≥ 250mcg/g stool at screening.
Time frame: 16 weeks
Population: 134 /179 (75%) patients had a calprotectin value ≥ 250 mcg/g stool at screening.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate Maintenance (Week 17-48) | Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 16 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening | 10 Participants |
Other Pre-specified
Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 48 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening
Steroid free clinical remission as a Mayo score of ≤ 2 points with no individual subscore exceeding 1 point and stool calprotectin levels of ≤ 50mcg at week 48 of the induction period in the subgroup of patients with calprotectin ≥ 250mcg/g stool at screening.
Time frame: 48 weeks
Population: 33/44 patient in the Methotrexate Maintenance group and 32/40 patients in the Placebo Maintenance group met the criteria of calprotectin ≥ 250 mcg/g stool at screening
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methotrexate Maintenance (Week 17-48) | Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 48 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening | 2 Participants |
| Placebo Maintenance (Week 17-48) | Calprotectin Levels < 50 mcg/g Stool in Patients in Remission at Week 48 With Calprotectin Levels ≥ 250 mcg/g Stool at Screening | 2 Participants |