E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Inflammatory bowel disease: Crohn's disease and Ulcerative colitis |
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E.1.1.1 | Medical condition in easily understood language |
Inflammatory bowel disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011401 |
E.1.2 | Term | Crohn's disease |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045365 |
E.1.2 | Term | Ulcerative colitis |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare a regular dose of MTX to a lower dose of MTX to suppress immunogenicity and recapture clinical remission in patients who fail on anti-TNF therapy. |
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E.2.2 | Secondary objectives of the trial |
To find the optimal intracellular MTX concentration (measured in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs)) that suppresses immunogenicity, and to relate these findings to clinical and biochemical outcomes. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age ≥ 18 years (both men and women) - Confirmed diagnosis of CD or UC by endoscopy and histopathology - Maintenance therapy with IFX or ADL, with or without thiopurines (i.e. azathioprine or mercaptopurine) - Loss of response, defined by clinical parameters (i.e. HBI> 4 points (CD), SCCAI> 5 points (UC), and/or patients with actively draining perianal fistula (CD)) and/or with elevated inflammatory biomarkers (i.e. serum CRP > 5 mg/l and/or fecal calprotectin > 250 mg/kg)) - Detectable anti-drug antibodies (ADA) directed against IFX or ADL (>12 AE/ml) using a drug-sensitive assay
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E.4 | Principal exclusion criteria |
- Prior intolerance to MTX - Pregnancy or planned pregnancy in the coming year (men and women) - Patients with total bilirubin, alkaline phosphatase, gamma-glutamyl transferase, AST or ALT of more than 2 times the upper limit of normal - Subjects with evidence of or suspected liver disease, such as primary sclerosing cholangitis or cirrhosis
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E.5 End points |
E.5.1 | Primary end point(s) |
A composite primary endpoint will be used: i.e. percentage of patients with: • Complete disappearance of measurable ADA, AND • Measurable IFX or ADL serum concentrations within 6 months after starting MTX, AND • Clinical and biochemical remission (defined by HBI <4 (CD) or SCCAI <5 (UC), serum CRP <5 mg/l and fecal calprotectine <250 mg/kg)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 0, 2, 6, 10, 14, 18, 22, and 26. |
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E.5.2 | Secondary end point(s) |
- Association of intracellular MTX-polyglutamate (MTX-Glu1-5) concentrations in red blood cells (RBCs) with reduction of immunogenicity - Association of intracellular MTX-polyglutamate (MTX-Glu1-5) concentrations in peripheral blood mononuclear cell (PBMCs) with reduction of immunogenicity - Association of plasma MTX concentrations (extracellular concentrations) with reduction of immunogenicity - Correlation of MTX-Glu-1-5 levels between RBCs and PBMCs - Impact of HLA genotype on therapeutic effect of MTX - Time to disappearance of ADA after addition of MTX - Time to regained clinical and biochemical response after addition of MTX - Proportion of patients in clinical remission at 1, 2, 3 and 6 months (defined by Harvey Bradshaw Index (HBI) ≤ 4 points, Simple Clinical Colitis Activity Index (SCCAI) ≤ 5 points) - Evaluation of adverse events due to MTX treatment (using the PRO-CTCAE questionnaire) - Proportion of patients in biochemical remission at 1, 2, 3 and 6 months, defined by serum CRP level < 5 mg/l and fecal calprotectin levels < 250 mg/kg)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 0, 2, 6, 10, 14, 18, 22, and 26. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Same product, lower dose: Methotrexate in 7.5 mg subcuteanous |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |