Comparison of 2 Immunomodulator Withdrawal Schemes for Inflixiamb Monotherapy in Active Pediatric Crohn's Disease After Thiopurine Failure (WITHDRAW)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Wolfson Medical Center
Information provided by (Responsible Party):
Prof. Arie Levine, Wolfson Medical Center Identifier:
First received: December 24, 2012
Last updated: April 8, 2014
Last verified: April 2014

The goal of the present study is to evaluate the best regimen for infliximab monotherapy, and to evaluate if limited combination therapy with IFX and an Immunomodulator for the first 6 months of therapy, in prior Immunomodulator failures, is superior to monotherapy with Immunomodulator cessation from the second infusion, in preventing loss of remission to IFX.

Condition Intervention Phase
Crohn's Disease
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 4,Open Lable Multicenter Randomized Controlled Trial. Comparison of 2 Immunomodulator Withdrawal Schemes for Inflixiamb Monotherapy in Active Pediatric Crohn's Disease After Immunomodulator Failure

Resource links provided by NLM:

Further study details as provided by Wolfson Medical Center:

Primary Outcome Measures:
  • Complete or partial LAR (lack of remission) [ Time Frame: 76 weeks ] [ Designated as safety issue: No ]
    • Complete LAR- Patient failing to achieve remission after first 3 scheduled doses , or absence of remission 7 days after an infliximab infusion in a patient who had achieved remission after any previous infusion, and unresponsive to dose escalation or dose interval change, or relapse occurring less than 4 weeks after last infusion
    • Partial LAR- Relapse 4-8 weeks after previous infusion, with requirement for dose escalation or shortening of infliximab schedule, and remission with change in dosing or interval.

Secondary Outcome Measures:
  • Mean trough level [ Time Frame: 14 and 52 weeks ] [ Designated as safety issue: No ]
  • Sustained steroid free remission [ Time Frame: 52 and 76 weeks ] [ Designated as safety issue: No ]
  • Presence of ATI [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
  • Corticosteroid free remission [ Time Frame: 14 weeks ] [ Designated as safety issue: No ]
  • Hospitalizations for LOR (loss of response) or failure to obtain remission [ Time Frame: Up to 76 weeks ] [ Designated as safety issue: No ]
  • Medication associated adverse events [ Time Frame: Up to 76 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 90
Study Start Date: February 2013
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Immunomodulator therapy 26 weeks
IFX 5mg/kg for 76 weeks, continuing immunomodulator for 6 months from first infusion
Patients should continue azathioprine or 6 MP or methotrexate at their previous doses for 6 months IMM therapy 26 weeks
Experimental: Immunomodulator therapy 2 weeks
IFX 5mg/kg induction for 76 weeks, discontinuing immunomodulator on day of second infusion( after 14 days).

Patients should continue the same dose of azathioprine or 6 MP or methotrexate until the day of the second infusion (week 2)

Thiopurine therapy 2 weeks


Detailed Description:

Background: Current data from studies and registries involving pediatric Crohn's disease indicate that 50-80% of children will receive an immunomodulator (IMM) as a maintenance therapy within 12 months of diagnosis, and between 60-80% by 18 months. The common use of IMM early in the disease also leads to a high proportion of patients with active disease despite IMM (IMMfailure).

Infliximab has become a standard of care in North America, Europe and Israel, and is recommended at present for steroid dependent or refractory patients, fistulizing disease, active disease despite an immunomodulator.

Infliximab was originally prescribed as an add on therapy to IMM, because of concerns regarding IFX side effects and loss of response due to development of antibodies to infliximab (ATIs). An early study clearly showed an advantage in long term remission with thiopurine co administration.However, subsequent studies in adults with CD showed that with scheduled IFX treatment, AZA could be safely discontinued after the first 6 months of therapy , lowering the risks associated with dual immuno-suppressive therapies, and the risks of co-therapy. Mono-therapy subsequently became the recommended method of treatment with IFX, despite a decrease in trough levels among those who discontinued IMM.

IFX mono-therapy became the method of choice for treatment in pediatric CD, though this strategy has been called into question due to frequent loss of response to IFX requiring dose escalation of IFX or decreased intervals of IFX. This loss of response has been attributed to development of ATIs and low trough levels of IFX, which can develop after the first infusions. Low trough levels of infliximab at 14 weeks were predictive of LOR. The second reason for questioning IFX mono-therapy is a trial that compared mono-therapy to combined AZA+IFX therapy in adults with moderate to severe thiopurine naïve disease. This study clearly showed improved long term remission rates and mucosal healing in an unselected cohort of patients with combination therapy. Conversely, mono-therapy was associated with low levels of sustained mucosal healing, which is troublesome. Lastly, some excellent results obtained in a pediatric cohort treated with combined therapy, along with the relatively low risk of HTSCL, has left pediatric gastroenterologists at a loss; Should we recommend primary mono-therapy , or use IMM for a limited period of time before discontinuing therapy ? When should the IMM be discontinued, after the first infusion or after several months? There are no controlled data in pediatric IBD to answer this pressing question.

There is also a movement towards increased use of methotrexate instead of thiopurines as immunomodulators because of concerns about neoplasia.

Recent studies have shown that by adding an immunomodulator to a biologic after LOR, trough levels can be improved and ATIs or ADAs decreased, suggesting that IMM may inhibit antibody formation.

The investigators hypothesize that by continuing IMM with IFX for the first 6 months, the investigators will detect a benefit . The investigators hypothesize that early cessation of an IMM will increase the risk of LOR (Loss of response), decrease trough levels at 14 weeks, and be associated with lower rates of corticosteroid free sustained remission by one year.

Methods: It is a prospective open label phase 4 RCT in pediatric patients with active CD, defined by the Porto criteria, despite >10 weeks of prior treatment with an immunomodulator (thiopurines/Methotrexate) ,requiring infliximab, involving 2 arms, and intention to treat analysis after the first infusion.


Ages Eligible for Study:   6 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Crohns disease
  2. Age: 6 - 18 years ( inclusive)
  3. Active disease PCDAI >10, or any steroid dependence despite thiopurine use for >10 weeks.
  4. Naïve to biologics
  5. Informed consent
  6. CRP ≥0.6 mg/dl
  7. Neg. TB-Test, negative HBV- S Ag
  8. Use of IMM at present or in past for at least 10 weeks
  9. Negative stool culture, parasites and clostridium toxin current flare

Exclusion Criteria:

  1. Intolerance to thiopurines/methotrexate
  2. Pregnancy
  3. Contraindication for any of the drugs.
  4. Leukopenia <4000 or absolute neutrophil count below 1200 on two consecutive tests during screening.
  5. Hepatocellular Liver disease ( ALT > 60 ) or cirrhosis.
  6. Renal Failure
  7. Prior idiosyncratic side effects with thiopurines ( pancreatitis etc).
  8. Current abscess ( < 14 days of antibiotics) or perforation of the bowel( <14 days antibiotics).
  9. Small bowel obstruction within the last 3 months
  10. Fixed non inflammatory stricture with predilatation with symptoms related to stricture
  11. Complicated or heavily draining perianal fistula ( indolent non draining or scant draining fistula are not exclusion criteria)
  12. Prior treatment with infliximab
  13. Previous malignancy
  14. Toxic Megacolon
  15. Sepsis
  16. Surgery related to Crohn's disease in previous 8 weeks.
  17. Positive Hepatitis B surface antigen or evidence for TB.
  18. Current bacterial infection
  19. IBD unclassified
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01802593

Contact: Arie Levine Levine, MD 972-3-5028808

The E. Wolfson.Medical Center Recruiting
Holon, Israel, 58100
Contact: Arie Levine, MD    972-3-5028808   
Principal Investigator: Arie Levine, MD         
Sponsors and Collaborators
Prof. Arie Levine
Study Chair: Arie Levine, MD Pediatric Gastroenterology and Nutrition Unit, The E. Wolfson MC, Tel-Aviv University, Holon, Israel
Study Director: Dan Turner, MD, PhD Pediatric Gastroenterology and Nutrition Unit, The Hebrew University of Jerusalem, Shaare Zedek MC, Jerusalem, Israel
Principal Investigator: Raanan Shamir, MD Schneider Childrens Hospital
Principal Investigator: Michal Kori, MD Kaplan Medical Center
Principal Investigator: Michael Wilshanski, MD Hadassah Medical Center
Principal Investigator: Ron Shaoul, MD Meyer Childrens Hospital Rambam, Haifa, Israel
Principal Investigator: Shlomi Cohen, MD Tel Aviv Medical Center
Principal Investigator: Batia Weiss, MD Sheba Medical Center
Principal Investigator: Sarit Peleg, MD Afula Hospital
Principal Investigator: Baruch Yerushalmi, MD Soroka Medical Center
Principal Investigator: Efrat Broide, MD Asaf Harofe Medical Center
Principal Investigator: Avi On, MD Poriah Hospital
Principal Investigator: Hussein Chemali, MD Nazheret Hospital
Principal Investigator: Aharon Lerner, MD Carmel Hospital
  More Information

No publications provided

Responsible Party: Prof. Arie Levine, Director, Pediatric Gastroenterology and Nutrition unit., Wolfson Medical Center Identifier: NCT01802593     History of Changes
Other Study ID Numbers: 0169-12-WOMC
Study First Received: December 24, 2012
Last Updated: April 8, 2014
Health Authority: Israel: Ministry of Health

Keywords provided by Wolfson Medical Center:
Crohn's disease

Additional relevant MeSH terms:
Crohn Disease
Digestive System Diseases
Gastrointestinal Diseases
Inflammatory Bowel Diseases
Intestinal Diseases
Adjuvants, Immunologic
Immunologic Factors
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses processed this record on October 23, 2014