Ulcerative Colitis
Conditions
Keywords
RCT (randomized controlled trial)
Brief summary
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
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.
Interventions
DRUGMethylprednisolone
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)
DRUGPrednisone
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)
Sponsors
Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Endoscopic and Clincal Remission | Change from baseline at week 8 | The percentage of patients with steroid-free, endoscopic remission, with no rescue therapies. It has been measured by Mayo endoscopic subscore (MES). MES= 0 (no friability and granularity and intact vascular pattern). MES= 1 (mild erythema or decreased vascular pattern). MES= 2 (marked erythema, absent vascular pattern, friability, and erosions). MES= 3 (spontaneous bleeding and ulceration) |
| Percentage of Participants With Endoscopic and Clinical Remission | Change from baseline at week 54 | The proportions of patients with steroid-free, endoscopic remission, with no rescue therapies. It has been measured by Mayo endoscopic subscore (MES). MES= 0 (no friability and granularity and intact vascular pattern). MES= 1 (mild erythema or decreased vascular pattern). MES= 2 (marked erythema, absent vascular pattern, friability, and erosions). MES= 3 (spontaneous bleeding and ulceration) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Clinical Remission | Change from baseline at week 8. | It was measured as a decrease in the Mayo index score from baseline of at least 3 points; and a decrease of at least 30% in the rectal bleeding variable of at least 1 point or with an absolute value of 0 or 1. The Mayo index score is composed of four parts: rectal bleeding, stool frequency, physician assessment, and endoscopy appearance. Each part is rated from 0 to 3, giving a total score of 0 to 12. A score of 3 to 5 points indicates mildly active disease, a score of 6 to 10 points indicates moderately active disease, and a score of 11 to 12 points indicates severely active disease. |
| Number of Participants With Adverse Events | 12 months | Adverse events (AEs) were collected during the study, from informed consent until the last visit. |
| Number of Participants With Serious Adverse Events | 12 months | Serious Adverse Events (SAEs) were defined as any adverse event or adverse drug reaction that resulted in death, is life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, or caused a congenital anomaly/birth defect. |
| Levels of C-reactive Protein | Baseline | Clinical assessments included the analytical laboratory test. Blood samples were taken for haematology, and C-reactive protein (mg/L) levels were measured. |
| Levels of Serum Albumin | Baseline | Clinical assessments included the analytical laboratory test. Blood samples were taken for haematology, and Serum albumin determination. |
| Levels of Faecal Calprotectin | Baseline | Faecal samples were collected at baseline, frozen and stored at -20 Celsius degrees (ºC) for central measurement of faecal calprotectin (FC). |
Countries
Spain
Contacts
PRINCIPAL_INVESTIGATOREugeni Domènech, MD, PhD
Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Methylprednisolone & Prednisone Intravenous bolus of methylprednisolone followed by a decreasing conventional course of oral prednisone
Methylprednisolone : 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)
Prednisone: 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) | 36 |
| Prednisone A decreasing conventional course of oral prednisone
Prednisone: 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) | 39 |
| Total | 75 |
Baseline characteristics
| Characteristic | Methylprednisolone & Prednisone | Total | Prednisone |
|---|---|---|---|
| Active smokers | 2 Participants | 3 Participants | 1 Participants |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 10 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 65 Participants | 35 Participants |
| Age, Continuous | 47 years | 49 years | 50 years |
| Extensive ulcerative colitis | 21 Participants | 38 Participants | 17 Participants |
| Familial inflammatory bowel disease | 5 Participants | 9 Participants | 4 Participants |
| Number of patients with Mayo Complete score at baseline | 12 participants | 21 participants | 9 participants |
| Oral mesalazine at inclusion | 28 Participants | 59 Participants | 31 Participants |
| Race/Ethnicity, Customized Not responded | 36 Participants | 75 Participants | 39 Participants |
| Region of Enrollment Spain | 36 participants | 75 participants | 39 participants |
| Severe endoscopic activity | 11 Participants | 22 Participants | 11 Participants |
| Sex: Female, Male Female | 16 Participants | 34 Participants | 18 Participants |
| Sex: Female, Male Male | 20 Participants | 41 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 39 |
| other Total, other adverse events | 25 / 36 | 21 / 39 |
| serious Total, serious adverse events | 1 / 36 | 6 / 39 |
Outcome results
Primary
Percentage of Participants With Endoscopic and Clincal Remission
The percentage of patients with steroid-free, endoscopic remission, with no rescue therapies. It has been measured by Mayo endoscopic subscore (MES). MES= 0 (no friability and granularity and intact vascular pattern). MES= 1 (mild erythema or decreased vascular pattern). MES= 2 (marked erythema, absent vascular pattern, friability, and erosions). MES= 3 (spontaneous bleeding and ulceration)
Time frame: Change from baseline at week 8
Population: All patients participating in the study had to undergo an endoscopic assessment of at least \>25cm from the anal verge at baseline and after 8 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methylprednisolone & Prednisone | Percentage of Participants With Endoscopic and Clincal Remission | 11 participants |
| Prednisone | Percentage of Participants With Endoscopic and Clincal Remission | 10 participants |
p-value: 0.05Chi-squared
p-value: 0.05Chi-squared
Primary
Percentage of Participants With Endoscopic and Clinical Remission
The proportions of patients with steroid-free, endoscopic remission, with no rescue therapies. It has been measured by Mayo endoscopic subscore (MES). MES= 0 (no friability and granularity and intact vascular pattern). MES= 1 (mild erythema or decreased vascular pattern). MES= 2 (marked erythema, absent vascular pattern, friability, and erosions). MES= 3 (spontaneous bleeding and ulceration)
Time frame: Change from baseline at week 54
Population: All patients participating in the study had to undergo an endoscopic assessment of at least \>25cm from the anal verge at baseline and after 54 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methylprednisolone & Prednisone | Percentage of Participants With Endoscopic and Clinical Remission | 31 Percentage of participants |
| Prednisone | Percentage of Participants With Endoscopic and Clinical Remission | 36 Percentage of participants |
Secondary
Levels of C-reactive Protein
Clinical assessments included the analytical laboratory test. Blood samples were taken for haematology, and C-reactive protein (mg/L) levels were measured.
Time frame: Baseline
Population: Laboratory assessments were conducted at baseline, and blood samples were collected for C-reactive protein determination.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methylprednisolone & Prednisone | Levels of C-reactive Protein | 8 mg/L |
| Prednisone | Levels of C-reactive Protein | 11 mg/L |
Secondary
Levels of Faecal Calprotectin
Faecal samples were collected at baseline, frozen and stored at -20 Celsius degrees (ºC) for central measurement of faecal calprotectin (FC).
Time frame: Baseline
Population: FC concentration was measured using the quantitative, chemiluminescent, sandwich immunoassay Calprotectin (LIASON® DiaSorin, Italy), with a measuring range of 5-8,000 mg/g.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methylprednisolone & Prednisone | Levels of Faecal Calprotectin | 1,230 mg/g |
| Prednisone | Levels of Faecal Calprotectin | 1,710 mg/g |
Secondary
Levels of Serum Albumin
Clinical assessments included the analytical laboratory test. Blood samples were taken for haematology, and Serum albumin determination.
Time frame: Baseline
Population: Analytical laboratory test at baseline were performed in all participants at baseline. Blood samples were taken for haematology, and Serum albumin was determined.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Methylprednisolone & Prednisone | Levels of Serum Albumin | 41 g/L |
| Prednisone | Levels of Serum Albumin | 40 g/L |
Secondary
Number of Participants With Adverse Events
Adverse events (AEs) were collected during the study, from informed consent until the last visit.
Time frame: 12 months
Population: Information on adverse events (AEs) were collected at all study visits via spontaneous patient reporting and patient interviews at each visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methylprednisolone & Prednisone | Number of Participants With Adverse Events | 25 Participants |
| Prednisone | Number of Participants With Adverse Events | 21 Participants |
Secondary
Number of Participants With Serious Adverse Events
Serious Adverse Events (SAEs) were defined as any adverse event or adverse drug reaction that resulted in death, is life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, or caused a congenital anomaly/birth defect.
Time frame: 12 months
Population: Information on adverse events (AEs) were collected at all study visits via spontaneous patient reporting and patient interviews at each visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methylprednisolone & Prednisone | Number of Participants With Serious Adverse Events | 1 Participants |
| Prednisone | Number of Participants With Serious Adverse Events | 6 Participants |
Secondary
Percentage of Patients With Clinical Remission
It was measured as a decrease in the Mayo index score from baseline of at least 3 points; and a decrease of at least 30% in the rectal bleeding variable of at least 1 point or with an absolute value of 0 or 1. The Mayo index score is composed of four parts: rectal bleeding, stool frequency, physician assessment, and endoscopy appearance. Each part is rated from 0 to 3, giving a total score of 0 to 12. A score of 3 to 5 points indicates mildly active disease, a score of 6 to 10 points indicates moderately active disease, and a score of 11 to 12 points indicates severely active disease.
Time frame: Change from baseline at week 8.
Population: All patients participating in the study had to undergo a clinical assessment at baseline and after 8 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methylprednisolone & Prednisone | Percentage of Patients With Clinical Remission | 36 percentage of participants |
| Prednisone | Percentage of Patients With Clinical Remission | 39 percentage of participants |