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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
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Anti-TNF treatment (infliximab (IFX), adalimumab (ADA)) has become standard therapy for refractory pediatric and adult Crohn's disease (CD) patients, and is used for the induction (primary response) and maintenance of remission. When effective, clinical and endoscopic remission is reached within weeks. However, primary non-response is observed in 20% of pediatric patients, and in 40% of adult CD patients, suggesting a more robust acute response to anti-TNF therapy in children as compared to adults.During maintenance treatment, 60 - 80% of patients have secondary loss of response, necessitating dose adjustments to maintain clinical response. Anti-TNF treatment is also increasingly used in ulcerative colitis (UC), and has been shown to induce remission in active disease. For UC, the comparison between the efficacy in children versus adults is more difficult to report as studies in children are scarce. Anti-TNF treatment is associated with rare but potentially fatal side effects, infusion reactions, and is an expensive treatment. To avoid overtreatment it is necessary to early identify non-responders to treatment, and therefore it is important to develop predictive biomarkers of treatment response.
Crohn's disease (CD) is a lifelong disease that may present during childhood in 20 - 25% of patients. There seems to be a worldwide trend towards increasing incidence rates of CD, especially in children. Patients with CD suffer from diarrhea, abdominal pain, nausea, malaise, and chronic malnutrition, in children often accompanied by growth failure and pubertal delay. CD is characterized by a transmural, granulomatous inflammation, involving any part of the gastrointestinal tract in a discontinuous manner.
Increased concentrations of tumor necrosis factor-α (TNFα) are found in the mucosa of CD patients , suggesting that TNF-α plays a pivotal role in the cytokine cascade of the inflammatory process. This key role of TNF-α has led to the development of biologic therapy based on the administration of monoclonal antibodies which bind and inactivate TNF-α. Infliximab (IFX, Remicade®) is a chimeric monoclonal antibody (75% human, 25% murine), while adalimumab (ADA, Humira®) is a fully human monoclonal antibody. Both antibodies bind with high affinity and specificity to soluble and membrane-bound TNF-α.
Anti-TNF drugs have become an important treatment strategy for CD patients who do not respond to or are intolerant of treatment with immunosuppressants (azathioprine, methotrexate) and corticosteroids. Anti-TNF induction therapy can induce complete clinical remission within weeks, often accompanied by mucosal healing. Interestingly, response to initial anti-TNF treatment is higher in pediatric CD patients (about 80%) than in adult CD patients (about 60%). Anti-TNF drugs do not cure CD: after their impressive initial effects, repeated infusions every 8 weeks or repeated subcutaneous injections every 2 weeks are necessary, while there is great concern about the long-term risks (infections, auto-immune disease, malignancy). Anti-TNF treatment is also increasingly used in ulcerative colitis, and has been shown to induce remission in active disease. For UC, the comparison between the efficacy in children versus adults is more difficult to report as studies in children are scarce. There are likely multiple host factors that influence the inter-individual variation in initial treatment response, such as disease phenotype, immune phenotype, and genetic background.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pediatric IBD patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab |
| |
| Adult IBD patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Infliximab | Biological | Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Pre-treatment Serum Level of Endogenous Anti-TNF in Relation to Primary Clinical Response or Non-response | Pre-treatment serum level of endogenous anti-TNF are measured and analyzed in relation to primary clinical response or non-response | 8 weeks |
| RNA Expression Profiles in Relation to Clinical Endpoints | Changes in week 0 and week 8 RNA expression profiles were evaluated in relation to the overall population and by study arm, i.e. either pediatric IBD or adult IBD. | 8 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Clinical Endpoints of Interest. | Clinical endpoints of Interest were the following:
|
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Inclusion Criteria:
Exclusion Criteria:
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Pediatric and adult IBD patients from the Department of Pediatric Gastroenterology of Erasmus MC-Sophia Children's Hospital and from the Department of Gastroenterology of Erasmus MC respectively.
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| Name | Affiliation | Role |
|---|---|---|
| J C Escher, MD, PhD | Erasmus Medical Center - Sophia Children's Hospital | Principal Investigator |
| C J van der Woude, MD, PhD | Erasmus Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Erasmus Medical Center | Rotterdam | 3015 GJ | Netherlands |
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| ID | Title | Description |
|---|---|---|
| FG000 | Pediatric IBD Patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab Infliximab: Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6. Adalimumab: ADA is administered as subcutaneous injections every other week.In children (age below 18 years), remission induction in anti-TNF naïve patients will be achieved by an initial loading dose of 80 mg, followed by 40 mg 2 weeks later. |
| FG001 | Adult IBD Patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab Infliximab: Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6. Adalimumab: ADA is administered as subcutaneous injections every other week. In adults, remission is induced by 160 mg at week 0, followed by 80 mg at week 2 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline Until Week 6 |
|
| ||||||||||||||||||||||||
| Week 6 Until Week 8 |
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| Week 8 Until Week 14 |
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| Week 14 Until Week 22 |
| |||||||||||||||||||||||||
| Week 22 Until Week 52 |
| |||||||||||||||||||||||||
| Week 52 Until Week 78 |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Pediatric IBD Patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab Infliximab: Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6. Adalimumab: ADA is administered as subcutaneous injections every other week.In children (age below 18 years), remission induction in anti-TNF naïve patients will be achieved by an initial loading dose of 80 mg, followed by 40 mg 2 weeks later. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Pre-treatment Serum Level of Endogenous Anti-TNF in Relation to Primary Clinical Response or Non-response | Pre-treatment serum level of endogenous anti-TNF are measured and analyzed in relation to primary clinical response or non-response | The pre-treatment serum levels of endogenous anti-TNF were zero in all 11 adult patients in whom endogenous anti-TNF was measured. Therefore, pre-treatment serum level of endogenous anti-TNF could not be fully analyzed in relation to primary clinical response or non-response. | Posted | Number | endogenous anti-TNF serum level (µg/mL) | 8 weeks |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Pediatric IBD Patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab Infliximab: Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6. Adalimumab: ADA is administered as subcutaneous injections every other week.In children (age below 18 years), remission induction in anti-TNF naïve patients will be achieved by an initial loading dose of 80 mg, followed by 40 mg 2 weeks later. In adults, remission is induced by 160 mg at week 0, followed by 80 mg at week 2 |
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Further analysis of clinical endpoints in relation to (clinical) biomarkers will be done by Mixed Model Analysis
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Professor J.C. Escher | Erasmus University Medical Centre - Sophia Childrens Hospital | +31107036076 | j.escher@erasmusmc.nl |
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| ID | Term |
|---|---|
| D015212 | Inflammatory Bowel Diseases |
| ID | Term |
|---|---|
| D005759 | Gastroenteritis |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
| D007410 | Intestinal Diseases |
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| ID | Term |
|---|---|
| D000069285 | Infliximab |
| D000068879 | Adalimumab |
| ID | Term |
|---|---|
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
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whole blood, gastrointestinal tract biopsies,buccal epithelium
|
| Adalimumab | Biological | ADA is administered as subcutaneous injections every other week.In children (age below 18 years), remission induction in anti-TNF naïve patients will be achieved by an initial loading dose of 80 mg, followed by 40 mg 2 weeks later. In adults, remission is induced by 160 mg at week 0, followed by 80 mg at week 2 |
|
|
| Duration of study (start anti-TNF until 1 year after start of anti-TNF) |
| Anti-TNF Treatment Specific Outcomes | Anti-TNF treatment specific outcomes that were considered were:
| Duration of study (start anti-TNF until 1 year after start of anti-TNF) |
| Number of Participants With Concommitant Treatment | Number of participants with concommitant treatment during the study was assessed. Concomitant treatment was defined as:
| Duration of study (start anti-TNF until 1 year after start of anti-TNF) |
| COMPLETED |
|
| NOT COMPLETED |
|
|
| Therapy Escalation | Therapy escalation defined as either increasing anti-TNF dose or shortening interval between doses |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| Therapy Escalation | Therapy escalation defined as either increasing anti-TNF dose or shortening interval between doses |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| Therapy Escalation | Therapy escalation defined as either increasing anti-TNF dose or shortening interval between doses |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| NOT COMPLETED |
|
|
| BG001 | Adult IBD Patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab Infliximab: Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6. Adalimumab: ADA is administered as subcutaneous injections every other week. In adults, remission is induced by 160 mg at week 0, followed by 80 mg at week 2 |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Diagnosis Crohn's Disease | Count of Participants | Participants |
|
| Disease Duration at start of anti-TNF | Median | Inter-Quartile Range | years |
|
| Number of participants on Infliximab at start | Count of Participants | Participants |
|
| OG001 | Adult IBD Patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab Infliximab: Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6. Adalimumab: ADA is administered as subcutaneous injections every other week.In children (age below 18 years), remission induction in anti-TNF naïve patients will be achieved by an initial loading dose of 80 mg, followed by 40 mg 2 weeks later. In adults, remission is induced by 160 mg at week 0, followed by 80 mg at week 2 |
|
|
| Primary | RNA Expression Profiles in Relation to Clinical Endpoints | Changes in week 0 and week 8 RNA expression profiles were evaluated in relation to the overall population and by study arm, i.e. either pediatric IBD or adult IBD. | Changes in week 0 and week 8 RNA expression profiles were analyzed within a subgroup of 29 patients (15 children and 14 adults) on infliximab treatment with samples taken at both week 0 and week 8. The number of genes with a 1.5 fold change (FDR value ≤ 0.05; paired t-test) from week 0 to week 8 were assessed for pediatric IBD or adult IBD patients. | Posted | Number | Genes with 1.5 fold change (FDR value ≤ | 8 weeks | RNA expression profile samples | RNA expression profile samples |
|
|
|
|
| Secondary | Number of Participants With Clinical Endpoints of Interest. | Clinical endpoints of Interest were the following:
| Posted | Count of Participants | Participants | Duration of study (start anti-TNF until 1 year after start of anti-TNF) |
|
|
|
|
| Secondary | Anti-TNF Treatment Specific Outcomes | Anti-TNF treatment specific outcomes that were considered were:
| Posted | Count of Participants | Participants | Duration of study (start anti-TNF until 1 year after start of anti-TNF) |
|
|
|
|
| Secondary | Number of Participants With Concommitant Treatment | Number of participants with concommitant treatment during the study was assessed. Concomitant treatment was defined as:
| Posted | Count of Participants | Participants | Duration of study (start anti-TNF until 1 year after start of anti-TNF) |
|
|
|
| 0 |
| 24 |
| 0 |
| 24 |
| 0 |
| 24 |
| EG001 | Adult IBD Patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab Infliximab: Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6. Adalimumab: ADA is administered as subcutaneous injections every other week.In children (age below 18 years), remission induction in anti-TNF naïve patients will be achieved by an initial loading dose of 80 mg, followed by 40 mg 2 weeks later. In adults, remission is induced by 160 mg at week 0, followed by 80 mg at week 2 | 0 | 21 | 0 | 21 | 0 | 21 |
| EG002 | Overall | Overall combined data for pediatric and adult IBD patients | 0 | 45 | 0 | 45 | 0 | 45 |
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| D001798 |
| Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D061067 | Antibodies, Monoclonal, Humanized |
| Title | Measurements |
|---|---|
|
| Response at week 8 |
|
| Continued anti-TNF after 12 months |
|
| Continued anti-TNF after 18 months |
|
|
| Interval shortening |
|
| Antibodies to infliximab Development |
|
| Infliximab serum trough level ≤ 3 mg/ml at week 14 |
|
|