Calprotectin-Directed Humira® Maintenance Therapy (CADHUM)

Phase 3

Withdrawn

• Conditions: Crohn's Disease
• Interventions: Drug: Placebo; Drug: Adalimumab PRN; Drug: Adalimumab

• Registration Number: NCT01674413
• Lead Sponsor: Peter Higgins

Brief Summary

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

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).

Study Timeline

• Study First Submitted: 2012-08-16
• Study First Submitted QC: 2012-08-27
• Study First Posted: 2012-08-28
• Study Start: 2013-10
• Primary Completion: 2016-03
• Study Completion: 2016-03
• Status Verified: 2017-05
• Last Update Submitted: 2017-05-23
• Last Update Posted: 2017-05-24

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Men or women 18 years of age or older at the time of informed consent.
2. Crohn's disease confirmed by endoscopy with biopsies.
3. On maintenance Adalimumab at a dose of 40 mg SC q 2 weeks without concomitant immunosuppressive therapy.
4. 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.
5. 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.
6. Negative for TB, Hepatitis B-negative, and negative stool for Clostridium difficile.

Exclusion Criteria

1. Unable to consent for themselves.
2. Are prisoners, students or employees of the investigators, or mentally incapacitated.
3. Are unwilling to complete this 48 week study, provide stool samples throughout, or unwilling to undergo multiple venipunctures.
4. Have a current infection with Clostridium difficile, clinically-significant intestinal stricture, history of allergy, or adverse reaction, to Adalimumab, history of sensitivity to latex.
5. 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).
6. 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
7. Are known to have congestive heart failure.
8. 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.
9. Have evidence of current clinically active and important infection.
10. Have or ever had a non-tuberculous mycobacterium infection or serious opportunistic infection (i.e. cytomegalovirus, Pneumocystis carinii, aspergillosis).
11. Are known to be infected with HIV, Hepatitis B, or Hepatitis C.
12. Have severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof.
13. Have a known history of lymphoproliferative disease including lymphoma. Have a history of certain malignancies within five years of screening.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo/Step-Down	Placebo	1 syringe of placebo SC q 2 weeks.
PRNLOAD Arm	Adalimumab PRN	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)
Maintenance Arm	Adalimumab	Adalimumab 40 mg q 2 weeks.

Primary Outcome Measures

Name	Time	Method
Percent Time in Remission (PTIR) in PRNLOAD vs. Placebo arms	48 weeks	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).

Secondary Outcome Measures

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

Trial Locations

Locations (1)

University of Michigan Health System; 🇺🇸 Ann Arbor, Michigan, United States