Endovenous Corticosteroid Pulses in Moderate Ulcerative Colitis (CECUM)

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

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.

Study Overview

• Status: Completed
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: Methylprednisolone; Drug: Prednisone

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.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Alicante, Spain
    • Hospital General Universitario de Alicante
  • Barcelona, Spain
    • Hospital del Mar
  • Barcelona, Spain
    • Hospital de la Santa Creu i Sant Pau
  • Córdoba, Spain, 14004
    • Hospital Universitario Reina Sofia
  • Girona, Spain, 17007
    • Hospital Universitari Dr. Josep Trueta
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain
    • Hospital 12 de Octubre
  • Madrid, Spain, 28007
    • Hospital Gregorio Marañón
  • Madrid, Spain, 28006
    • Hospital de La Princesa
  • Madrid, Spain
    • Hospital Universitario Ramon y Cajal
  • Terrassa, Spain, 08227
    • Mutua de Terrassa
  • Valencia, Spain, 46010
    • Hospital Clinico de Valencia
  • Valencia, Spain
    • Hospital Universitari La Fe
  • Valencia, Spain
    • Hospital de Manises
  • Valencia, Spain, 46010
    • Hospital Universitario General de Valencia
  • Valladolid, Spain, 47012
    • Hospital Universitario Río Hortega
  • A Coruña
    • Santiago de Compostela, A Coruña, Spain
      • Complejo Hospitalario Universitario Santiago de Compostela
  • Astúrias
    • Oviedo, Astúrias, Spain, 33011
      • Hospital Universitario Central de Asturias
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Germans Trias i Pujol
    • Manresa, Barcelona, Spain, 08243
      • ALTHAIA, Xarxa Assistencial Universitària de Manresa
    • Sabadell, Barcelona, Spain, 08208
      • Consorci Corporacio Sanitaria Parc Tauli
    • Sant Joan Despí, Barcelona, Spain, 08970
      • Hospital Moisés Broggi
    • Terrassa, Barcelona, Spain, 08227
      • Consorci Hospitalari de Terrassa
  • Bilbao
    • Galdakao, Bilbao, Spain
      • Hospital de Galdakao
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Hospital Universitario Marques de Valdecilla
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Puerta de Hierro-Majadahonda
  • Ourense
    • Orense, Ourense, Spain, 32005
      • Hospital Universitario de Ourense
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36312
      • Hospital Álvaro Cunqueiro
  • Vizcaya
    • Baracaldo, Vizcaya, Spain, 48903
      • Hospital Universitario Cruces

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: methylprednisolone & prednisone; Intravenous bolus of methylprednisolone followed by a decreasing conventional course of oral prednisone	Drug: 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); Other Names: Urbason; Drug: 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); Other Names: URbason
Active Comparator: prednisone; A decreasing conventional course of oral prednisone	Drug: 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); Other Names: URbason

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
• Investigators: Principal Investigator: Eugeni Domènech, MD, PhD, Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa

Publications and helpful links

General Publications

• Sood A, Midha V, Sood N, Awasthi G. A prospective, open-label trial assessing dexamethasone pulse therapy in moderate to severe ulcerative colitis. J Clin Gastroenterol. 2002 Oct;35(4):328-31. doi: 10.1097/00004836-200210000-00009.
• Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, D'Haens G, D'Hoore A, Mantzaris G, Novacek G, Oresland T, Reinisch W, Sans M, Stange E, Vermeire S, Travis S, Van Assche G. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis. 2012 Dec;6(10):991-1030. doi: 10.1016/j.crohns.2012.09.002. Epub 2012 Oct 3. No abstract available. Erratum In: J Crohns Colitis. 2022 Aug 16;:
• BARON JH, CONNELL AM, KANAGHINIS TG, LENNARD-JONES JE, JONES AF. Out-patient treatment of ulcerative colitis. Comparison between three doses of oral prednisone. Br Med J. 1962 Aug 18;2(5302):441-3. doi: 10.1136/bmj.2.5302.441. No abstract available.
• Hawthorne AB, Record CO, Holdsworth CD, Giaffer MH, Burke DA, Keech ML, Hawkey CJ. Double blind trial of oral fluticasone propionate v prednisolone in the treatment of active ulcerative colitis. Gut. 1993 Jan;34(1):125-8. doi: 10.1136/gut.34.1.125.
• Sood A, Midha V, Sood N, Kaushal V, Awasthi G. Methylprednisolone acetate versus oral prednisolone in moderately active ulcerative colitis. Indian J Gastroenterol. 2002 Jan-Feb;21(1):11-3.
• Ardizzone S, Cassinotti A, Duca P, Mazzali C, Penati C, Manes G, Marmo R, Massari A, Molteni P, Maconi G, Porro GB. Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis. Clin Gastroenterol Hepatol. 2011 Jun;9(6):483-489.e3. doi: 10.1016/j.cgh.2010.12.028. Epub 2010 Dec 31.
• Elliott PR, Powell-Tuck J, Gillespie PE, Laidlow JM, Lennard-Jones JE, English J, Chakraborty J, Marks V. Prednisolone absorption in acute colitis. Gut. 1980 Jan;21(1):49-51. doi: 10.1136/gut.21.1.49.
• Garcia-Planella E, Manosa M, Van Domselaar M, Gordillo J, Zabana Y, Cabre E, Lopez San Roman A, Domenech E. Long-term outcome of ulcerative colitis in patients who achieve clinical remission with a first course of corticosteroids. Dig Liver Dis. 2012 Mar;44(3):206-10. doi: 10.1016/j.dld.2011.10.004. Epub 2011 Nov 11.
• Rhodes JM, Robinson R, Beales I, Pugh S, Dickinson R, Dronfield M, Speirs CJ, Wilkinson P, Wilkinson SP. Clinical trial: oral prednisolone metasulfobenzoate (Predocol) vs. oral prednisolone for active ulcerative colitis. Aliment Pharmacol Ther. 2008 Feb 1;27(3):228-40. doi: 10.1111/j.1365-2036.2007.03569.x. Epub 2007 Nov 6.
• Berghouse LM, Elliott PR, Lennard-Jones JE, English J, Marks V. Plasma prednisolone levels during intravenous therapy in acute colitis. Gut. 1982 Nov;23(11):980-83. doi: 10.1136/gut.23.11.980.
• Llao J, Naves JE, Ruiz-Cerulla A, Marin L, Manosa M, Rodriguez-Alonso L, Cabre E, Garcia-Planella E, Guardiola J, Domenech E. Intravenous corticosteroids in moderately active ulcerative colitis refractory to oral corticosteroids. J Crohns Colitis. 2014 Nov;8(11):1523-8. doi: 10.1016/j.crohns.2014.06.010. Epub 2014 Jul 22.
• Ponticelli C, Glassock RJ, Moroni G. Induction and maintenance therapy in proliferative lupus nephritis. J Nephrol. 2010 Jan-Feb;23(1):9-16.
• Oshitani N, Kamata N, Ooiso R, Kawashima D, Inagawa M, Sogawa M, Iimuro M, Jinno Y, Watanabe K, Higuchi K, Matsumoto T, Arakawa T. Outpatient treatment of moderately severe active ulcerative colitis with pulsed steroid therapy and conventional steroid therapy. Dig Dis Sci. 2003 May;48(5):1002-5. doi: 10.1023/a:1023076318751.
• Nagata S, Shimizu T, Kudo T, Tomomasa T, Tajiri H, Yoden A, Kagimoto S, Tahara T, Ushijima K, Uchida K, Kobayashi A. Efficacy and safety of pulse steroid therapy in Japanese pediatric patients with ulcerative colitis: a survey of the Japanese Society for Pediatric Inflammatory Bowel Disease. Digestion. 2010;81(3):188-92. doi: 10.1159/000255379. Epub 2010 Jan 19.
• Kudo T, Nagata S, Ohtani K, Fujii T, Wada M, Haruna H, Shoji H, Ohtsuka Y, Shimizu T, Yamashiro Y. Pulse steroids as induction therapy for children with ulcerative colitis. Pediatr Int. 2011 Dec;53(6):974-9. doi: 10.1111/j.1442-200X.2011.03405.x.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2018
• Primary Completion (Actual): November 7, 2022
• Study Completion (Actual): November 7, 2022

Study Registration Dates

• First Submitted: September 22, 2016
• First Submitted That Met QC Criteria: September 29, 2016
• First Posted (Estimate): October 3, 2016

Study Record Updates

• Last Update Posted (Estimate): February 23, 2023
• Last Update Submitted That Met QC Criteria: February 22, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: RCT (randomized controlled trial)
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Prednisone
• Other Study ID Numbers: CECUM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No