Crohn's DiseasePhase 4WITHDRAWNCT01802593
Comparison of 2 Immunomodulator Withdrawal Schemes for Infliximab Monotherapy in Active Pediatric Crohn's Disease After Thiopurine Failure
A Phase 4 study testing AZATHIOPRINE or METHOTREXATE in people with Crohn's Disease, run by Prof. Arie Levine at 1 site in Israel.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 6 to 18 years
- Conditions the study is for
- Crohn's Disease
- What is being tested?
- AZATHIOPRINE or METHOTREXATE
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteIsrael
- Study dates
- Feb 2013to Dec 2015
- Phase
- Phase 4
- Are there results?
- None posted in the registry
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 6 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Crohns disease
- Age: 6 - 18 years ( inclusive)
- Active disease PCDAI >10, or any steroid dependence despite thiopurine use for >10 weeks.
- Naïve to biologics
- Informed consent
- CRP ≥0.6 mg/dl
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- Neg. TB-Test, negative HBV- S Ag
- Use of IMM at present or in past for at least 10 weeks ( for Withdraw only).
- Negative stool culture, parasites and clostridium toxin current flare
- Patients receiving corticosteroids may be included if the disease is active and CRP elevated.
- All other treatments such as 5ASA , , must be discontinued immediately after the first IFX infusion.
- Patients may receive an antihistamine prior to any infusion.Use of corticosteroid pretreatment is allowed only during the first two infusions (single infusion on day of infliximab), or if an infusion reaction has occurred.
- Partial enteral nutrition, accounting for less than 50% of daily required calories, may be supplied as needed.
- Patients receiving antibiotics must cease use of antibiotics within the 14 days of receiving the first infusion.
- ESR >20 can be alternative if the CRP <0.6.
- Negative stool culture, parasites and clostridium toxin current flare will examined only if the patient has diarrhea.
- Patients may be enrolled directly in to the Predict study , in which case duration of IMM is irrelevant , but patients must have received an IMM until week 2 as in the withdraw
Who cannot join
- Intolerance to thiopurines/methotrexate
- Pregnancy
- Contraindication for any of the drugs.
- Leukopenia <4000 or absolute neutrophil count below 1200 on two consecutive tests during screening.
- Hepatocellular Liver disease ( ALT > 60 ) or cirrhosis.
- Renal Failure
Show all 20Show fewer
- Prior idiosyncratic side effects with thiopurines ( pancreatitis etc).
- Current abscess ( < 14 days of antibiotics) or perforation of the bowel( <14 days antibiotics).
- Small bowel obstruction within the last 3 months
- Fixed non inflammatory stricture with predilatation with symptoms related to stricture
- Complicated or heavily draining perianal fistula ( indolent non draining or scant draining fistula are not exclusion criteria)
- Prior treatment with infliximab
- Previous malignancy
- Toxic Megacolon
- Sepsis
- Surgery related to Crohn's disease in previous 8 weeks.
- Positive Hepatitis B surface antigen or evidence for TB.
- Current bacterial infection
- IBD unclassified
- 1. Prior surgery or post operative recurrence are not exclusion criteria.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase 4, Open Label Multicenter Randomized Controlled Trial. Comparison of 2 Immunomodulator Withdrawal Schemes for Infliximab Monotherapy in Active Pediatric Crohn's Disease After Immunomodulator Failure
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.
Read the 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 immunosuppressive therapies, and the risks of co-therapy. Monotherapy 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.
In a parallel study , using the same data base, We also hypothesize that low trough levels at week 14 ( parallel study) will predict LOR- This study, called Predict Study; Prediction of Loss of Response to Infliximab in Crohn's Disease Based on Week 14 Trough Levels.will enable open label enrolment of patients receiving infliximab with an immunomodulator, but will not require randomization, and patients may be allocated to group one or group 2 at the physicians or patients discretion.
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.
- Conditions
- Crohn's Disease
- Being tested
- AZATHIOPRINE or METHOTREXATE
- Keywords
- Pediatric, Crohn's disease, Infliximab, Thiopurine
- Medical subject headings
- Crohn Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZATHIOPRINE or METHOTREXATEDrug
Also called 6 MERCAPTOPURINE
Patients should continue azathioprine or 6 MP or methotrexate at their previous doses for 6 months IMM therapy 26 weeks
AZATHIOPRINE or METHOTREXATEDrug
Also called 6 MERCAPTOPURINE
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
| Study group | Role | What they receive |
|---|---|---|
| Immunomodulator therapy 26 weeks | Experimental | IFX 5mg/kg for 76 weeks, continuing immunomodulator for 6 months from first infusion Receives: Drug: AZATHIOPRINE or METHOTREXATE |
| Immunomodulator therapy 2 weeks | Experimental | IFX 5mg/kg induction for 76 weeks, discontinuing immunomodulator on day of second infusion( after 14 days). Receives: Drug: AZATHIOPRINE or METHOTREXATE |
What is being measured
The primary outcome is the main question the study is designed to answer.
Complete or partial LAR (lack of remission)
- 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.
Measured: 76 weeks
Secondary outcomes (6)
Mean trough level
Measured: 14 and 52 weeks
Sustained steroid free remission
Measured: 52 and 76 weeks
Presence of ATI
Measured: 52 weeks
Corticosteroid free remission
Measured: 14 weeks
Hospitalizations for LOR (loss of response) or failure to obtain remission
Measured: Up to 76 weeks
Medication associated adverse events
Measured: Up to 76 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Mar 2013 (estimated)
- Study startFeb 2013
- Primary completionDec 2015
- Study completionDec 2015
Why it stopped: lack of budget and failure to reach milestones
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Crohn's DiseaseStudies of the same condition, open and under way.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Prof. Arie Levine
- Sponsor type
- Other government
- Responsible party
- Sponsor-investigator, Prof. Arie Levine, Wolfson Medical Center
- Investigators
- Arie Levine, MD, Study chair, Pediatric Gastroenterology and Nutrition Unit, The E. Wolfson MC, Tel-Aviv University, Holon, IsraelDan Turner, MD, PhD, Study director, Pediatric Gastroenterology and Nutrition Unit, The Hebrew University of Jerusalem, Shaare Zedek MC, Jerusalem, IsraelRaanan Shamir, MD, Principal investigator, Schneider Childrens HospitalMichal Kori, MD, Principal investigator, Kaplan Medical CenterMichael Wilshanski, MD, Principal investigator, Hadassah Medical OrganizationRon Shaoul, MD, Principal investigator, Meyer Childrens Hospital Rambam, Haifa, IsraelShlomi Cohen, MD, Principal investigator, Tel Aviv Medical CenterBatia Weiss, MD, Principal investigator, Sheba Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01802593
- Sponsor's protocol ID
- 0169-12-WOMC
- Acronym
- WITHDRAW
- Status last verified
- Dec 2015
- First submitted
- 24 Dec 2012
- Last updated
- 22 Dec 2015
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 22 Dec 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 4, Open Label Multicenter Randomized Controlled Trial. Comparison of 2 Immunomodulator Withdrawal Schemes for Infliximab Monotherapy in Active Pediatric Crohn's Disease After Immunomodulator Failure
- ClinicalTrials.gov ID
- NCT01802593
- Acronym / sponsor ID
- WITHDRAW / 0169-12-WOMC
- Conditions
- Crohn's Disease
- Keywords
- Pediatric, Crohn's disease, Infliximab, Thiopurine
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: lack of budget and failure to reach milestones
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Prof. Arie LevineOther government
- Study start
- Feb 2013
- Primary completion
- Dec 2015 (actual)
- Study completion
- Dec 2015 (actual)
- First posted
- 1 Mar 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 immunosuppressive therapies, and the risks of co-therapy. Monotherapy 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.
In a parallel study , using the same data base, We also hypothesize that low trough levels at week 14 ( parallel study) will predict LOR- This study, called Predict Study; Prediction of Loss of Response to Infliximab in Crohn's Disease Based on Week 14 Trough Levels.will enable open label enrolment of patients receiving infliximab with an immunomodulator, but will not require randomization, and patients may be allocated to group one or group 2 at the physicians or patients discretion.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Immunomodulator therapy 26 weeks | Experimental | Drug: AZATHIOPRINE or METHOTREXATEIFX 5mg/kg for 76 weeks, continuing immunomodulator for 6 months from first infusion |
| Immunomodulator therapy 2 weeks | Experimental | Drug: AZATHIOPRINE or METHOTREXATEIFX 5mg/kg induction for 76 weeks, discontinuing immunomodulator on day of second infusion( after 14 days). |
Who may qualify
- Ages
- 6 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (17 listed)
- Crohns disease
- Age: 6 - 18 years ( inclusive)
- Active disease PCDAI >10, or any steroid dependence despite thiopurine use for >10 weeks.
- Naïve to biologics
- Informed consent
Key exclusion criteria (20 listed)
- Intolerance to thiopurines/methotrexate
- Pregnancy
- Contraindication for any of the drugs.
- Leukopenia <4000 or absolute neutrophil count below 1200 on two consecutive tests during screening.
- Hepatocellular Liver disease ( ALT > 60 ) or cirrhosis.
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 |
|---|---|---|
| AZATHIOPRINE or METHOTREXATEAlso: 6 MERCAPTOPURINEPatients should continue azathioprine or 6 MP or methotrexate at their previous doses for 6 months IMM therapy 26 weeks | Drug | Immunomodulator therapy 26 weeks |
| AZATHIOPRINE or METHOTREXATEAlso: 6 MERCAPTOPURINEPatients 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 | Drug | Immunomodulator therapy 2 weeks |
Primary outcome
Complete or partial LAR (lack of remission)
Time frame: 76 weeks
* 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.
6 secondary outcomes
Mean trough level
Time frame: 14 and 52 weeks
Sustained steroid free remission
Time frame: 52 and 76 weeks
Presence of ATI
Time frame: 52 weeks
Corticosteroid free remission
Time frame: 14 weeks
Hospitalizations for LOR (loss of response) or failure to obtain remission
Time frame: Up to 76 weeks
Medication associated adverse events
Time frame: Up to 76 weeks
Results and safety
The study was stopped early (reason given: lack of budget and failure to reach milestones). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Dec 2015.
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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.
Arie Levine, MD study chair
Pediatric Gastroenterology and Nutrition Unit, The E. Wolfson MC, Tel-Aviv University, Holon, Israel
Dan Turner, MD, PhD study director
Pediatric Gastroenterology and Nutrition Unit, The Hebrew University of Jerusalem, Shaare Zedek MC, Jerusalem, Israel
Raanan Shamir, MD principal investigator
Schneider Childrens Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing AZATHIOPRINE or METHOTREXATE in people with Crohn's Disease, run by Prof. Arie Levine at 1 site in Israel.
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 17 inclusion and 20 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 22 Dec 2015. 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 Israel. 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. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: lack of budget and failure to reach milestones). Results are not available in the source record.
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?
Complete or partial LAR (lack of remission) (time frame: 76 weeks). 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 22 Dec 2015.