Calprotectin-Directed Humira® Maintenance Therapy (CADHUM)

Study Overview
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Brief Summary
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This is a study that invites adults with Crohn's disease and have been responding well to Adalimumab (Humira ®) for at least 6 months. Patients frequently discontinue maintenance medications in Crohn's disease, particularly when in remission. Patients want to know that they truly need to take a medication, yet they don't want to have flares. The purpose of this study is to see that if we monitor the patient, along with looking at changes in their stool samples, we can safely stop the maintenance medication Adalimumab for up to 48 weeks, or add as-needed dosing only, and keep them in remission.

Detailed Description
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Patients frequently discontinue maintenance medications in Crohn's disease, particularly when in remission. Patients want to know that they truly need to take a medication, yet they don't want to have flares. As a biomarker, fecal calprotectin < 167 has a 100% negative predictive value for flare within the next 12 weeks (Gisbert, 2009). Adalimumab has low antigenicity, and can be safely stopped and restarted later with good clinical effect (Colombel, 2007). Patients want intermittent therapy, if it can be delivered in a timely fashion when pre-clinical inflammation starts, in order to avoid clinically-significant flares. This study will combine monitoring for pre-clinical inflammation with fecal calprotectin and as-needed dosing with Adalimumab to maintain remission in patients who have obtained remission with Adalimumab. This will be compared to two comparator arms: standard maintenance therapy and complete cessation of therapy (Step-Down approach).

Official Title
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Calprotectin-Directed Humira® Maintenance Therapy, a Double-blind, Double-dummy, Randomized Controlled Trial in Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: Adalimumab
* Drug: Adalimumab PRN
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women 18 years of age or older at the time of informed consent. Crohn's disease confirmed by endoscopy with biopsies. On maintenance Adalimumab at a dose of 40 mg SC q 2 weeks without concomitant immunosuppressive therapy. Must be in clinical remission (CDAI <150) at the baseline/randomization (Week 0) visit and biologic remission (both CRP <0.8 and FCP <167)at Week 0. Prior medication for Crohn's disease may include one of the following and must have been stopped with wash out periods: Methotrexate, Azathioprine, 6-Mercaptopurine, Tacrolimus, Steroids. Negative for TB, Hepatitis B-negative, and negative stool for Clostridium difficile. Exclusion Criteria Unable to consent for themselves. Are prisoners, students or employees of the investigators, or mentally incapacitated. Are unwilling to complete this 48 week study, provide stool samples throughout, or unwilling to undergo multiple venipunctures. Have a current infection with Clostridium difficile, clinically-significant intestinal stricture, history of allergy, or adverse reaction, to Adalimumab, history of sensitivity to latex. Are currently using steroids or systemic immunomodulators (MTX, AZA, 6-MP, or Tacrolimus), or have used another biologic medication in the past 12 weeks other than Adalimumab, or have current or past use of Kineret® (Anakinra) or Tysabri® (natalizumab). Have received any live bacterial or viral vaccinations ≤ 12 weeks prior to Week 0 and must not receive 12 months after study as well as BCG vaccination Are known to have congestive heart failure. Have a history of, or ongoing chronic or recurrent infectious disease, including but not limited to chronic renal, chest infection (i.e. bronchiectasis) or urinary tract infection (i.e. recurrent pyelonephritis) or open, draining, or infected skin wounds or ulcers. Have evidence of current clinically active and important infection. Have or ever had a non-tuberculous mycobacterium infection or serious opportunistic infection (i.e. cytomegalovirus, Pneumocystis carinii, aspergillosis). Are known to be infected with HIV, Hepatitis B, or Hepatitis C. Have severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof. Have a known history of lymphoproliferative disease including lymphoma. Have a history of certain malignancies within five years of screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo/Step-Down<br>1 syringe of placebo SC q 2 weeks. | Drug: Placebo<br>* 1 syringe of placebo SC q 2 weeks, with additional placebo loading of 3 syringes/1 syringe at Weeks 0/2, 12/14, 24/26, and 36/38 Weeks.<br>|
| Active Comparator: PRNLOAD Arm<br>160 mg/80 mg Adalimumab at Weeks 0 and 2, followed by 1 syringe SC placebo q 2 weeks (except at Weeks 12/14, 24/26, and 36/38) | Drug: Adalimumab PRN<br>* 160 mg/80 mg Adalimumab at Weeks 0 and 2, followed by 1 syringe SC placebo q 2 weeks (except at Weeks 12/14, 24/26, and 36/38), with PRNLOADing of 160 mg/80 mg Adalimumab at Weeks 12/14, 24/26, or 36/38 if most recent FCP is ≥167 mcg/gram of stool, Or, placebo loading of 4 syringes/2 syringes at Weeks 12/14, 24/26, and 36/38 if most recent FCP is < 167 mcg/gram of stool.<br>* Other names: Humira;|
| Active Comparator: Maintenance Arm<br>Adalimumab 40 mg q 2 weeks. | Drug: Adalimumab<br>* Adalimumab 40 mg q 2 weeks, with placebo loading of 3 syringes/1 syringe at Weeks 0/2, 12/14, 24/26, and 36/38<br>* Other names: Humira;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Time in Remission (PTIR) in PRNLOAD vs. Placebo arms | Determine whether adding as-needed q 12 weeks Adalimumab re-loading (160 mg/80 mg) when FCP ≥167 mcg/gram of stool can improve the maintenance of remission in Crohn's disease patients who stop Adalimumab therapy (PRNLOAD Arm) compared to the placebo arm. Endpoint: Percent time in remission (q 4 week evaluation for 48 weeks). | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Time in Remission MAINT vs. PRNLOAD | Compare the percent of monitoring visits in which the subject is in remission in each arm between the MAINT and PRNLOAD arms. | 48 weeks | 
| Percent Time in Remission MAINT vs. PBO | Compare the percent of monitoring visits in which the subject is in remission in each arm between the MAINT and PBO arms. | 48 weeks. | 
| Strict Biologic Remission Rates | Percent of visits with strict biologic remission (FCP <50 and CRP <0.5) with 3 comparisons: PRNLOAD vs. PBO, MAINT vs. PRNLOAD, MAINT vs. PBO | 48 weeks | 
| Subject acceptability | Measure subject acceptability of repeated stool sampling. | 48 weeks | 
| Subject preference | Measure subject preference for the MAINT versus PRNLOAD regimen. | 48 weeks | 
| Equivalence of Percent Time in Remission | Compare percent time in remission (CDAI <150) over 48 weeks, evaluation every 4 weeks across 3 arms (chi square test). | 48 weeks | 
| Comparison of Average CDAI | Compare average CDAI over 48 weeks, evaluation every 4 weeks across 3 arms (ANOVA). | 48 weeks | 
| Comparison of average IBDQ | Compare average IBDQ over 48 weeks, evaluation every 4 weeks across 3 arms (ANOVA). | 48 weeks | 
| Comparison of average FCP | Compare average FCP over 48 weeks, evaluation every 12 weeks across 3 arms (ANOVA). | 48 weeks | 
| Comparison of average CRP | Compare average CRP over 48 weeks, evaluation every 12 weeks across 3 arms (ANOVA). | 48 weeks | 
| Comparison of Rates of Hospitalization | Comparison of Rates of Hospitalization across all 3 arms - hospital admissions per patient over 48 weeks (ANOVA). | 48 Weeks | 
| Comparison of Rates of Emergency Department visits | Comparison of Rates of Emergency Department visits across all 3 arms - hospital admissions per patient over 48 weeks (ANOVA). | 48 Weeks | 
| Comparison of Rates of Physician visits | Comparison of Rates of Physician visits across all 3 arms - hospital admissions per patient over 48 weeks (ANOVA). | 48 Weeks | 
| Comparison of mg prednisone prescribed | Comparison of average milligrams of prednisone prescribed across all 3 arms - over 48 weeks (ANOVA). | 48 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's Disease, Crohn's, Crohns, Inflammatory Bowel Disease, IBD, Humira, Adalimumab, Adalimumab injection, Higgins, Calprotectin, biomarkers, Gastroenterology, University of Michigan, U of M