Endovenous Corticosteroid Pulses in Moderate Ulcerative Colitis

Ulcerative Colitis Clinical Trial

— CECUM  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02921555
• Other study ID #: CECUM
• Status: Completed
• Phase: Phase 4
• Start date: October 11, 2018
• Est. completion date: November 7, 2022

Study information

• Verified date: February 2023
• Source: Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 75
• Est. completion date: November 7, 2022
• Est. primary completion date: November 7, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

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)
• 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)

Locations

Country	Name	City	State
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Universitario Cruces	Baracaldo	Vizcaya
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitario Reina Sofia	Córdoba
Spain	Hospital de Galdakao	Galdakao	Bilbao
Spain	Hospital Universitari Dr. Josep Trueta	Girona
Spain	Hospital 12 de Octubre	Madrid
Spain	Hospital De La Princesa	Madrid
Spain	Hospital Gregorio Marañon	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	hospital Puerta de Hierro-Majadahonda	Majadahonda	Madrid
Spain	Althaia, xarxa assistencial universitaria de Manresa	Manresa	Barcelona
Spain	Hospital Universitario de Ourense	Orense	Ourense
Spain	Hospital Universitario Central de Asturias	Oviedo	Astúrias
Spain	Consorci Corporació Sanitària Parc Taulí	Sabadell	Barcelona
Spain	Hospital Moisès Broggi	Sant Joan Despí	Barcelona
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria
Spain	Complejo Hospitalario Universitario Santiago de Compostela	Santiago de Compostela	A Coruña
Spain	Consorci Hospitalari de Terrassa	Terrassa	Barcelona
Spain	Mútua de Terrassa	Terrassa
Spain	Hospital Clínico de Valencia	Valencia
Spain	Hospital de Manises	Valencia
Spain	Hospital Universitari La Fe	Valencia
Spain	Hospital Universitario General de Valencia	Valencia
Spain	Hospital Universitario Río Hortega	Valladolid
Spain	Hospital Álvaro Cunqueiro	Vigo	Pontevedra

Sponsors (1)

Lead Sponsor	Collaborator
Grupo Espanol de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa

Country where clinical trial is conducted

Spain, 

References & Publications (15)

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. — View Citation

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. — View Citation

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. — View Citation

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;: — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Ponticelli C, Glassock RJ, Moroni G. Induction and maintenance therapy in proliferative lupus nephritis. J Nephrol. 2010 Jan-Feb;23(1):9-16. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Biological response		at week 8 and 54 from baseline
Secondary	Rate of adverse events		2 years
Secondary	Rate of serious adverse events		2 years
Secondary	Proportion of patients with clinical recurrence		2 years
Secondary	Time to clinical relapse		2 years
Secondary	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
Secondary	Time to corticodependency		2 years
Secondary	Number of participants with surgery events	assessed by disease activity index (DAI) and simple activity index	2 years
Secondary	Proportion of patients with corticodependency criteria	Relapse during dose reduction of prednisolone or within 3 months after the discontinuation of steroid treatment.	2 years