Endovenous Corticosteroid Pulses in Moderate Ulcerative Colitis

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of high-dose corticosteroid pulses added to conventional oral corticosteroid course for moderate flares of ulcerative colitis.

Detailed Description
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Oral corticosteroids (CS) are the treatment of choice for moderate flares of ulcerative colitis (UC) in patients who are on 5-aminosalicylic acid (5ASA) maintenance therapy. However, the efficacy of oral CS is limited, with up to 50% of remission rate in the available randomized controlled trials (RCTs). By the other hand, uncompleted disease remission after CS use, that is, clinical but not endoscopic remission, has been associated with a higher risk of hospitalizations and need for immunomodulator or colectomy in UC. Uncontrolled data suggests that intravenous CS (IV CS) may increase the remission rate and also reduce the proportion of patients developing steroid-dependency after the index course of CS. The hypothesis of this study is that the addition of a 3-day high-dose IV CS pulses schedule administered in the outpatient infusion unit, added to a conventional oral CS course increases the endoscopic remission rate and reduces the 1-year proportion of patients developing steroid-dependency. This is a randomized, phase IV, open-label, multicenter, controlled study. The planned number of patients to be included is 148, distributed in two treatment arms (with or without initial high-dose CS pulse), and stratified regarding disease onset and mesalazine use. The main end-point will be the proportion of patients with steroid-free, clinical and endoscopic remission at 8 and 54 weeks, with no rescue therapies. The demonstration of a higher efficacy of the proposed treatment schedule would impact on a lower requirement for conventional immunosuppressive therapy (thiopurines) and biological agents, reduced hospitalizations and surgery. Moreover, this treatment regimen allows an outpatient management of moderate flares. Baseline characteristics will be analyzed by descriptive statistical analysis by conventional methods. Categorical variables will be compared using Mann-Whitney test and continuous variables by Student T test. In order to evaluate the primary endpoint a Chi square test will be performed to compare the proportions of patients in both study groups that achieved clinical and endoscopic steroid-free remission at 8 weeks and is maintained without steroids or salvage therapy and with no rescue therapy up to 54 weeks. Per protocol (PP) and intention-to-treat (IT) analysis will be made The Per Protocol analysis will include all participants who did adequately adhere to the protocol, in particular those who did received the total amount of the intervention. Missing outcomes data will be treated as non-response imputation (NRI). The intention-to treat-analysis will only include all randomized patients in the analysis, all retained in the group to which they were allocated, except those patients with missing outcomes that did not completed treatment regimen due to SAE criteria or treatment failure. In order to evaluate the secondary endpoints a Chi square test and a Student T test will be performed for both study groups. Cumulative probabilities of relapse, steroid dependency and surgery will be evaluated in both groups by Kaplan-Meiery, and compared by using log-rank test. Finally, association analysis of early clinical response, clinical and endoscopic remission at week 8 and week 8 and 54 will be performed by chi-square test and Student T test; those variables that reach a Pvalue ≤ 0.1 will be included in the logistic regression analysis.

Official Title
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Efficacy of High-dose Corticosteroid Pulses Added to Conventional Oral Corticosteroid Course for Moderate Flares of Ulcerative Colitis.

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Methylprednisolone
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ulcerative colitis diagnosis by Lennard-Jones criteria ≥18 years Left or extended extent of disease Moderate flares of ulcerative colitis according to disease activity index (DAI) No maintenance therapy or 5ASA treatment The patient is available to understand study procedures and to sign the inform consent form Inform Consent Form Exclusion Criteria: Previous or current thiopurines, methotrexate or biological treatment Administration of systemic corticoids the last 6 months Acute or moderate systemic infection Diabetes mellitus or arterial hypertension Pregnancy or breastfeeding Allergic reactions associated to corticosteroids therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: methylprednisolone & prednisone<br>Intravenous bolus of methylprednisolone followed by a decreasing conventional course of oral prednisone | Drug: Methylprednisolone<br>* Intravenous bolus of methylprednisolone 0.5g/day for 3 consecutive days followed by a decreasing conventional course of oral prednisone (week1; 60mg/d, w2; 50mg/d, w3;40mg/d, w4; 30mg/d, w5; 20mg/d, w6; 15mg/d, w7; 10mg/d, w8; 5 mg/d, w9; 0mg/d)<br>* Other names: Urbason;Drug: Prednisone<br>* Conventional course of oral prednisone (week1; 60mg/d, w2; 50mg/d, w3;40mg/d, w4; 30mg/d, w5; 20mg/d, w6; 15mg/d, w7; 10mg/d, w8; 5 mg/d, w9; 0mg/d)<br>* Other names: URbason;|
| Active Comparator: prednisone<br>A decreasing conventional course of oral prednisone | Drug: Prednisone<br>* Conventional course of oral prednisone (week1; 60mg/d, w2; 50mg/d, w3;40mg/d, w4; 30mg/d, w5; 20mg/d, w6; 15mg/d, w7; 10mg/d, w8; 5 mg/d, w9; 0mg/d)<br>* Other names: URbason;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Remission | The proportions of patients with steroid-free, clinical and endoscopic remission, with no rescue therapies. It will be measured as Mayo index score ≤ 2 points with any single variable >1. | Change from baseline, at 8 and 54 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | It will be measured as a decrease in Mayo index score of at least 3 points and at least 30% decrease of the rectal bleeding variable of at least 1 point or with an absolute value of 0 or 1. | at week 8 and 54 from baseline | 
| Biological response |  | at week 8 and 54 from baseline | 
| Rate of adverse events |  | 2 years | 
| Rate of serious adverse events |  | 2 years | 
| Proportion of patients with clinical recurrence |  | 2 years | 
| Time to clinical relapse |  | 2 years | 
| Risk of hospitalization | The risk of hospitalization will be measured by SAE criteria: Death Life-threatening Hospitalization (initial or prolonged) Disability or Permanent Damage Congenital Anomaly/Birth Defect Required Intervention to Prevent Permanent Impairment or Damage (Devices) Other Serious (Important Medical Events) | 2 years | 
| Time to corticodependency |  | 2 years | 
| Number of participants with surgery events | assessed by disease activity index (DAI) and simple activity index | 2 years | 
| Proportion of patients with corticodependency criteria | Relapse during dose reduction of prednisolone or within 3 months after the discontinuation of steroid treatment. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RCT (randomized controlled trial)