Crohn's DiseasePhase 4NCT02269358
Salvage Therapy With High/Low Methotrexate for Loss of Response to Infliximab Dose Escalation
A Phase 4 study testing 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 if addition of methotrexate can restore remission after loss of response to infliximab after dose escalation. another goal is to evaluate if low dose methotrexate can maintain remission achieved by regular dose methotrexate by 6 months. Read more about this study
- Who is it for?
- Ages 8 to 18 years
- Conditions the study is for
- Crohn's Disease
- What is being tested?
- METHOTREXATE
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteIsrael
- Study dates
- Jul 2015to 9 Oct 2018
- 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 8 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Informed consent
- Established diagnosis of Crohns disease.
- Age: 8 - 18 years ( inclusive)
- Active disease PCDAI >10 at least two weeks after infusion.
- On Infliximab with at least 3 prior infusions, and still active despite a decreased dose interval ( ≤ 6 weeks) or increased dose of infliximab (≥7.5 mg/kg /dose q 8 weeks).
- Comment: Patients who are on combination therapy with a stable thiopurine>8 weeks can also be included ( thiopurine will be stopped at enrollment).
- -
Who cannot join
- 1. Patients who are primary non responders after first two doses 2. Patients who have had to stop infliximab due to side effects. 3. Patients with known intolerance to methotrexate. 4. Elevated ALT >1.5 normal. 5. Pregnancy. 6. Patients who have insulin-dependent diabetes 7. Patients who have significantly impaired renal function 8. Current bacterial infection/ inflammation including Hepatitis B or C and Pneumonia.
- -
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase 4, Open Lable Non Randomized un Controlled Study. Salvage Therapy With High/Low Methotrexate for Loss of Response to Infliximab Dose Escalation
The goal of the present study is to evaluate if addition of methotrexate can restore remission after loss of response to infliximab after dose escalation.
another goal is to evaluate if low dose methotrexate can maintain remission achieved by regular dose methotrexate by 6 months.
Read the detailed description
Background: 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( up to 40% during the first year) (1). This loss of response has been attributed to development of ATIs and low trough levels of IFX, which can develop after the first infusions. This loss of response will often occur in patients with prior azathioprine exposure (2,3,4).
Currently , the first step during loss of response to infliximab in children is dose escalation either by decreasing the interval between infusions or doubling the dose. However, patients with persistent antibodies or high titers are likely to fail even with dose escalation. The Sonic trial clearly demonstrated that combination therapy with a thiopurine may be more effective than Anti TNF alpha monotherapy (2). Ben Horin et al demonstrated that antidrug antibodies can be reversed and improved anti TNF trough levels obtained by adding an immunomodulator to failed monotherapy due to an antidrug antibody (3).
We have previously shown that in patients with a previous loss of response to two biologics leading to cessation of both biologics can respond to reinduction with adalimumab and methotrexate . Among 12 patients (10 children and two adults) , 6 obtained complete remission. We subsequently lowered the does in several patients without loss of response, and tried stopping methotrexate in 3 patients. All 3 patients relapsed within months of complete cessation of methorexate.In this previous study we took two separate actions that restored response, re-induction and methotrexate therapy. In the current proposal we will take patients that are on escalated therapy and just add methotrexate, in order to evaluate if adding methotrexate once weekly can restore response after loss of response to infliximab after failed dose escalation.It is important to note that methotrexate does not increase the risk of malignancy as co-therapy as far as we know.
Methods: It is a prospective open label phase 4, non randomized uncontrolled study in a small cohort of patients to evaluate if addition of methotrexate can restore remission after loss of response to infliximab after dose escalation in paediatric patients.
- Conditions
- Crohn's Disease
- Being tested
- METHOTREXATE
- Medical subject headings
- Crohn Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
METHOTREXATEDrug
Also called Rheumatrex, Trexall
Infliximab therapy after escalation. SC methotrexate at 15 mg/m2 , not to exceed 25 mg/m2 per week for 4 weeks. Patients in remission after 4 weeks reduce their dose by halve. patients not in remission will continue the full dose until 12 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Addition of methotrexate | Experimental | Addition SC methotrexate at 15 mg/m2, not to exceed 25 mg/m2 . Patients in remission after 4 weeks will reduce their dose by halve. patients not in remission will continue the full dose until 12 weeks. Receives: Drug: METHOTREXATE |
What is being measured
The primary outcome is the main question the study is designed to answer.
remission
remission without additional therapy.
Measured: at 12 weeks
Secondary outcomes (3)
Remission
Measured: 6 months
Trough levels
Measured: week 12
ATIs
Measured: week 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2014 (estimated)
- Study startJul 2015
- Primary completion9 Oct 2018
- Study completion9 Oct 2018
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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 22 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, Israel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02269358
- Sponsor's protocol ID
- 0143-14-WOMC
- Status last verified
- Oct 2018
- First submitted
- 30 Sep 2014
- Last updated
- 18 Oct 2018
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 18 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 4, Open Lable Non Randomized un Controlled Study. Salvage Therapy With High/Low Methotrexate for Loss of Response to Infliximab Dose Escalation
- ClinicalTrials.gov ID
- NCT02269358
- Acronym / sponsor ID
- 0143-14-WOMC
- Conditions
- Crohn's Disease
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Prof. Arie LevineOther government
- Study start
- Jul 2015
- Primary completion
- 9 Oct 2018 (actual)
- Study completion
- 9 Oct 2018 (actual)
- First posted
- 21 Oct 2014 (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 if addition of methotrexate can restore remission after loss of response to infliximab after dose escalation.
another goal is to evaluate if low dose methotrexate can maintain remission achieved by regular dose methotrexate by 6 months.
Detailed description
Background: 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( up to 40% during the first year) (1). This loss of response has been attributed to development of ATIs and low trough levels of IFX, which can develop after the first infusions. This loss of response will often occur in patients with prior azathioprine exposure (2,3,4).
Currently , the first step during loss of response to infliximab in children is dose escalation either by decreasing the interval between infusions or doubling the dose. However, patients with persistent antibodies or high titers are likely to fail even with dose escalation. The Sonic trial clearly demonstrated that combination therapy with a thiopurine may be more effective than Anti TNF alpha monotherapy (2). Ben Horin et al demonstrated that antidrug antibodies can be reversed and improved anti TNF trough levels obtained by adding an immunomodulator to failed monotherapy due to an antidrug antibody (3).
We have previously shown that in patients with a previous loss of response to two biologics leading to cessation of both biologics can respond to reinduction with adalimumab and methotrexate . Among 12 patients (10 children and two adults) , 6 obtained complete remission. We subsequently lowered the does in several patients without loss of response, and tried stopping methotrexate in 3 patients. All 3 patients relapsed within months of complete cessation of methorexate.In this previous study we took two separate actions that restored response, re-induction and methotrexate therapy. In the current proposal we will take patients that are on escalated therapy and just add methotrexate, in order to evaluate if adding methotrexate once weekly can restore response after loss of response to infliximab after failed dose escalation.It is important to note that methotrexate does not increase the risk of malignancy as co-therapy as far as we know.
Methods: It is a prospective open label phase 4, non randomized uncontrolled study in a small cohort of patients to evaluate if addition of methotrexate can restore remission after loss of response to infliximab after dose escalation in paediatric patients.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Addition of methotrexate | Experimental | Drug: METHOTREXATEAddition SC methotrexate at 15 mg/m2, not to exceed 25 mg/m2 . Patients in remission after 4 weeks will reduce their dose by halve. patients not in remission will continue the full dose until 12 weeks. |
Who may qualify
- Ages
- 8 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (7 listed)
- Informed consent
- Established diagnosis of Crohns disease.
- Age: 8 - 18 years ( inclusive)
- Active disease PCDAI >10 at least two weeks after infusion.
- On Infliximab with at least 3 prior infusions, and still active despite a decreased dose interval ( ≤ 6 weeks) or increased dose of infliximab (≥7.5 mg/kg /dose q 8 weeks).
Key exclusion criteria (2 listed)
- 1. Patients who are primary non responders after first two doses 2. Patients who have had to stop infliximab due to side effects. 3. Patients with known intolerance to methotrexate. 4. Elevated ALT >1.5 normal. 5. Pregnancy. 6. Patients who have insulin-dependent diabetes 7. Patients who have significantly impaired renal function 8. Current bacterial infection/ inflammation including Hepatitis B or C and Pneumonia.
- -
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 |
|---|---|---|
| METHOTREXATEAlso: Rheumatrex, TrexallInfliximab therapy after escalation. SC methotrexate at 15 mg/m2 , not to exceed 25 mg/m2 per week for 4 weeks. Patients in remission after 4 weeks reduce their dose by halve. patients not in remission will continue the full dose until 12 weeks. | Drug | Addition of methotrexate |
Primary outcome
remission
Time frame: at 12 weeks
remission without additional therapy.
3 secondary outcomes
Remission
Time frame: 6 months
Trough levels
Time frame: week 12
ATIs
Time frame: week 12
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Oct 2018.
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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
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 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 7 inclusion and 2 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: finished, as of the sponsor's last update on 18 Oct 2018. 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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
remission (time frame: at 12 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 18 Oct 2018.