Golimumab Trough Levels in Patients With Ulcerative Colitis

Ulcerative Colitis Clinical Trial

— GLMLEVEL  

Official title:

Association of Golimumab Trough Levels With Endoscopic and Histologic Healing in Patients With Ulcerative Colitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03773445
• Other study ID #: CTS-GOL-2018-01
• Status: Completed
• Start date: March 1, 2019
• Est. completion date: September 30, 2021

Study information

• Verified date: April 2022
• Source: Hospital San Carlos, Madrid
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Proactive therapeutic drug monitoring of Anti-TNFs with drug titration to a therapeutic window is associated with favorable long-term therapeutic outcomes in IBD and may be superior to reactive therapeutic drug monitoring. Moreover, many exposure-response relationship studies have shown that higher serum anti-TNF drug concentrations are associated with better clinical outcomes in IBD, suggesting that it is maybe time to go from a 'treat-to-target' to a 'treat-to trough' therapeutic approach. In this scenario, there are very limited data regarding therapeutic drug monitoring with golimumab in UC and even no data regarding a therapeutic window to target for important objectives outcomes like mucosal healing and histological remission.

Description:

Tumor necrosis factor (TNF)-α antagonists have changed the goals of ulcerative colitis (UC) treatment, with the focus now on preventing disease progression rather than just controlling symptoms. Anti-TNF agents have shown ability to achieve clinical remission and mucosal healing in UC. However, histological remission represents a target distinct from endoscopic healing in UC, and seems a better predictor of clinical outcomes. Moreover, histological remission and not mucosal healing has been associated with a reduced risk of colorectal cancer in UC. Infliximab was reported to induce histological remission in a significant proportion of UC patients. More recently, adalimumab was able to achieve histological remission in nearly one-third of anti-TNF naïve patients with moderately to severely active UC. Reactive therapeutic drug monitoring of anti-TNF agents may help to identify mechanisms for loss of response and to guide selection of optimal intervention in individual patients and has been shown to be cost-effective compared with empiric dose escalation. Proactive therapeutic drug monitoring showed that anti-TNF trough levels are correlated with clinical response, clinical remission and mucosal healing in patients with inflammatory bowel disease (IBD). Conversely, inadequate serum drug concentrations and antidrug antibodies are associated with poor clinical outcomes. Recently, a study demonstrated that infliximab trough concentrations during maintenance therapy are associated with endoscopic and histologic healing in patients with UC. Golimumab, a subcutaneously administered fully human antibody to TNF, induces clinical response and remission in patients with moderately to severely active UC. In patients who responded to induction therapy, golimumab doses administered every 4 weeks as a maintenance regimen was effective in maintaining clinical response through 1 year. Available data on golimumab drug monitoring and exposure-response relationship in UC patients are from the PURSUIT trials. A positive association between golimumab levels and efficacy outcomes, including mucosal healing, was confirmed during both induction and maintenance portions of the PURSUIT studies. Real life data regarding golimumab concentrations and clinical outcomes are lacking, with only a small observational study published. Besides, there are no data regarding the ability of golimumab to achieve histological remission in UC patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: September 30, 2021
• Est. primary completion date: September 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age greater than or equal to 18 years.
• Patients with a diagnosis of ulcerative colitis at least 12 months prior to the start of the study.
• Patients previously treated with golimumab for ulcerative colitis prescribed according to the usual clinical practice of each center and who have received at least 5 maintenance doses according to the guidelines accepted in the technical file.
• Sign of informed consent.

Exclusion Criteria:

• Patients with Crohn's disease or colitis pending classification
• Alterations in the coagulation that contraindicate the taking of biopsies
• Patients with moderate-severe heart failure (grades III / IV NYHA)
• Patients with tuberculosis or other serious infections such as septicemia, abscesses and opportunistic infections
• Psychiatric illness that discourages participation in the study
• Patients with a history of hypersensitivity to golimumab, to other murine proteins or to any of the excipients included in the golimumab data sheet
• Withdrawal of the informed consent by the patient
• Any other condition that in the opinion of the investigator discourages the participation of the subject in the study.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

Diagnostic Test:
• Golimumab trough levels
Golimumab trough levels taken immediately before the administration of the next subcutaneous dose of golimumab
• Antibodies to golimumab
Antibodies to golimumab taken immediately before the administration of the next subcutaneous dose of golimumab
• Histology
Histology of colonic biopsies using the Geboes Index
• Colonoscopy
Colonoscopy to evaluate the endoscopic activity by a Mayo endoscopic subscore

Locations

Country	Name	City	State
Spain	Hospital Universitario Fundación Alcorcón	Alcorcón	Madrid
Spain	Hospital Universitario Fuenlabrada	Fuenlabrada	Madrid
Spain	Hospital 12 de Octubre	Madrid
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Gregorio Marañón	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Puerta de Hierro	Majadahonda	Madrid
Spain	Complejo Hospitalario de Navarra	Pamplona	Navarra
Spain	Hospital Infanta Sofia	San Sebastián De Los Reyes	Madrid
Spain	Hospital Clínico Universitario de Valencia	Valencia
Spain	Hospital Universitario La Fe	Valencia

Sponsors (13)

Lead Sponsor

Collaborator

Hospital San Carlos, Madrid

Complejo Hospitalario de Navarra, Gregorio Marañón Hospital, Hospital Clínico Universitario de Valencia, Hospital Infanta Sofia, Hospital Universitario 12 de Octubre, Hospital Universitario de Fuenlabrada, Hospital Universitario Fundación Alcorcón, Hospital Universitario La Fe, Hospital Universitario La Paz, Hospital Universitario Ramon y Cajal, Merck Sharp & Dohme Corp., Puerta de Hierro University Hospital

Country where clinical trial is conducted

Spain, 

References & Publications (25)

Adedokun OJ, Sandborn WJ, Feagan BG, Rutgeerts P, Xu Z, Marano CW, Johanns J, Zhou H, Davis HM, Cornillie F, Reinisch W. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology. 2014 D — View Citation

Adedokun OJ, Xu Z, Marano CW, Strauss R, Zhang H, Johanns J, Zhou H, Davis HM, Reinisch W, Feagan BG, Rutgeerts P, Sandborn WJ. Pharmacokinetics and Exposure-response Relationship of Golimumab in Patients with Moderately-to-Severely Active Ulcerative Coli — View Citation

Bryant RV, Burger DC, Delo J, Walsh AJ, Thomas S, von Herbay A, Buchel OC, White L, Brain O, Keshav S, Warren BF, Travis SP. Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 year — View Citation

Cornillie F, Hanauer SB, Diamond RH, Wang J, Tang KL, Xu Z, Rutgeerts P, Vermeire S. Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysi — View Citation

Detrez I, Dreesen E, Van Stappen T, de Vries A, Brouwers E, Van Assche G, Vermeire S, Ferrante M, Gils A. Variability in Golimumab Exposure: A 'Real-Life' Observational Study in Active Ulcerative Colitis. J Crohns Colitis. 2016 May;10(5):575-81. doi: 10.1 — View Citation

Fernández-Blanco JI, Fernández-Díaz G, Cara C, Vera MI, Olivares D, Taxonera C. Adalimumab for Induction of Histological Remission in Moderately to Severely Active Ulcerative Colitis. Dig Dis Sci. 2018 Mar;63(3):731-737. doi: 10.1007/s10620-018-4935-5. Ep — View Citation

Gupta RB, Harpaz N, Itzkowitz S, Hossain S, Matula S, Kornbluth A, Bodian C, Ullman T. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology. 2007 Oct;133(4):1099-105; quiz — View Citation

Korelitz BI, Sultan K, Kothari M, Arapos L, Schneider J, Panagopoulos G. Histological healing favors lower risk of colon carcinoma in extensive ulcerative colitis. World J Gastroenterol. 2014 May 7;20(17):4980-6. doi: 10.3748/wjg.v20.i17.4980. — View Citation

Magro F, Lopes SI, Lopes J, Portela F, Cotter J, Lopes S, Moreira MJ, Lago P, Peixe P, Albuquerque A, Rodrigues S, Silva MR, Monteiro P, Lopes C, Monteiro L, Macedo G, Veloso L, Camila C, Afonso J, Geboes K, Carneiro F; Portuguese IBD group [GEDII]. Histo — View Citation

Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease. Clin Gastroenterol Hepatol. 2006 Oct;4(10):1248-54. Epub 2006 Aug 22. — View Citation

Papamichael K, Rakowsky S, Rivera C, Cheifetz AS, Osterman MT. Infliximab trough concentrations during maintenance therapy are associated with endoscopic and histologic healing in ulcerative colitis. Aliment Pharmacol Ther. 2018 Feb;47(4):478-484. doi: 10 — View Citation

Paul S, Del Tedesco E, Marotte H, Rinaudo-Gaujous M, Moreau A, Phelip JM, Genin C, Peyrin-Biroulet L, Roblin X. Therapeutic drug monitoring of infliximab and mucosal healing in inflammatory bowel disease: a prospective study. Inflamm Bowel Dis. 2013 Nov;1 — View Citation

Rosenberg L, Nanda KS, Zenlea T, Gifford A, Lawlor GO, Falchuk KR, Wolf JL, Cheifetz AS, Goldsmith JD, Moss AC. Histologic markers of inflammation in patients with ulcerative colitis in clinical remission. Clin Gastroenterol Hepatol. 2013 Aug;11(8):991-6. — View Citation

Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl — View Citation

Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M, Williams C, Price A, Talbot I, Forbes A. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004 Feb;126(2):451-9. — View Citation

Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, Adedokun OJ, Guzzo C, Colombel JF, Reinisch W, Gibson PR, Collins J, Järnerot G, Hibi T, Rutgeerts P; PURSUIT-SC Study Group. Subcutaneous golimumab induces clinical response and remission i — View Citation

Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, Adedokun OJ, Guzzo C, Colombel JF, Reinisch W, Gibson PR, Collins J, Järnerot G, Rutgeerts P; PURSUIT-Maintenance Study Group. Subcutaneous golimumab maintains clinical response in patients — View Citation

Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D'Haens G, Wolf DC, Kron M, Tighe MB, Lazar A, Thakkar RB. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012 Feb;142(2):25 — View Citation

Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010 Jan;59(1):49-54. doi: 10.1136/gut.2009.183095. — View Citation

Steenholdt C, Brynskov J, Thomsen OØ, Munck LK, Fallingborg J, Christensen LA, Pedersen G, Kjeldsen J, Jacobsen BA, Oxholm AS, Kjellberg J, Bendtzen K, Ainsworth MA. Individualised therapy is more cost-effective than dose intensification in patients with — View Citation

Vande Casteele N, Ferrante M, Van Assche G, Ballet V, Compernolle G, Van Steen K, Simoens S, Rutgeerts P, Gils A, Vermeire S. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015 Jun;148(7): — View Citation

Vande Casteele N, Khanna R, Levesque BG, Stitt L, Zou GY, Singh S, Lockton S, Hauenstein S, Ohrmund L, Greenberg GR, Rutgeerts PJ, Gils A, Sandborn WJ, Vermeire S, Feagan BG. The relationship between infliximab concentrations, antibodies to infliximab and — View Citation

Velayos FS, Kahn JG, Sandborn WJ, Feagan BG. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn's disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol. 2013 Jun;11(6):654-66. doi: 10.1016 — View Citation

Wiernicka A, Szymanska S, Cielecka-Kuszyk J, Dadalski M, Kierkus J. Histological healing after infliximab induction therapy in children with ulcerative colitis. World J Gastroenterol. 2015 Oct 7;21(37):10654-61. doi: 10.3748/wjg.v21.i37.10654. — View Citation

Zenlea T, Yee EU, Rosenberg L, Boyle M, Nanda KS, Wolf JL, Falchuk KR, Cheifetz AS, Goldsmith JD, Moss AC. Histology Grade Is Independently Associated With Relapse Risk in Patients With Ulcerative Colitis in Clinical Remission: A Prospective Study. Am J G — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Correlation between Golimumab trough levels and Endoscopic remission	defined as a Mayo endoscopic subscore of 0	Cross-Sectional: 15 days before or after the extraction of levels
Primary	Correlation between Golimumab trough levels and Endoscopic healing	defined as a Mayo endoscopic subscore of 0 or 1	Cross-Sectional: 15 days before or after the extraction of levels
Primary	Correlation between Golimumab trough levels and Histological remission	defined as a Geboes index =3.0	Cross-Sectional: 15 days before or after the extraction of levels
Secondary	Correlation between Golimumab trough levels and Clinical remission	defined as a total Mayo score =2 with no individual subscore exceeding 1 point	Cross-Sectional: 15 days before or after the extraction of levels
Secondary	Correlation between Golimumab trough levels and Clinical response	defined as a decrease from baseline in the total Mayo score of at least 3-points	Cross-Sectional: 15 days before or after the extraction of levels
Secondary	Receiver operating characteristic curve analysis	Thresholds of golimumab levels for outcomes 1 to 5 will be determined using the receiver operating characteristic curve analysis.	Cross-Sectional: 15 days before or after the extraction of levels
Secondary	C-reactive protein and fecal calprotectin.	Correlation between Golimumab trough levels with C-reactive protein and fecal calprotectin.	Cross-Sectional: 15 days before or after the extraction of levels
Secondary	Histological remission	Proportion of patients with Histological remission defined as a Geboes index =3.0	Cross-Sectional: 15 days before or after the extraction of levels