Association of Golimumab Trough Levels With Endoscopic and Histologic Healing in Patients With Ulcerative Colitis
Conditions: Ulcerative Colitis
Sponsor: Hospital San Carlos, Madrid

 
 
Association of Golimumab Trough Levels 
With Endoscopic and Histologic Healing in 
Patients With Ulcerative Colitis 
(GLMLEVEL) 
Protocol ID: CTS-GOL-2018-01 
 
 
 
 
 
 
 
 
 
 
 
Version 2 
November 15th 2018 
 
 

1. IDENTIFICATION OF THE PROTOCOL 
Protocol code: CTS-GOL-2018-01 
Acronym: GLMLEVEL 
Version 2: November 15th, 2018 
 
2. TITLE 
Association of Golimumab Trough Levels With Endoscopic and Histologic 
Healing in Patients With Ulcerative Colitis 
 
3. IDENTIFICATION OF THE SPONSOR 
Inflammatory Bowel Disease (IBD) Unit of the Hospital Clinico San Carlos. 
 
4. RELEVANT ASPECTS ON THE FUNDING OF THE STUDY 
The study will be carry out with the funds of the IBD Unit dedicated to research. 
There is no compensation planned for researchers or for patients. 
 
5. MAIN RESEARCHERS 
Hidden 
 
6. REFERENCE IRB/ETHICS COMMITTEE 
The IRB that will act as reference will be the Hospital Clínico San Carlos Ethics 
Committee. 
 
7. SITES WHERE THE STUDY WILL BE CARRIED OUT 
Hospital Clínico San Carlos, Madrid; Hospital Ramón y Cajal, Madrid; Hospital 
Gregorio Marañón, Madrid; Hospital 12 de Octubre, Madrid; Hospital Puerta de 
Hierro, Madrid; Hospital La Paz, Madrid; Hospital Universitario de Fuenlabrada, 
Madrid; Hospital Fundación Alcorcón, Madrid; Hospital Infanta Sofía, Madrid; 
Hospital La Fe, Valencia; Hospital Clínico Valencia, Valencia; Hospital 
Complejo Universitario de Navarra, Navarra 
 

8. JUSTIFICATION AND OBJECTIVES OF THE STUDY 
 
8.1 BACKGROUND 
Antagonists of tumor necrosis factor (anti-TNF) -α have changed the treatment of 
ulcerative colitis (UC) in order to prevent the progression of the disease instead 
of simply controlling the symptoms. Anti-TNF agents have demonstrated the 
ability to achieve clinical remission and mucosal healing in UC [1-3]. However, 
histologic remission represents a different objective of endoscopic healing in UC 
and seems to be a better predictor of clinical outcomes [4-6]. In addition, 
histologic remission and not mucosal healing has been associated with a lower 
risk of colorectal cancer in patients with UC [7-9]. It has been reported that 
infliximab, an anti-TNF, induces histological remission in a significant proportion 
of patients with UC [10,11]. More recently, adalimumab achieved histologic 
remission in almost one third of patients who had not received prior treatment 
with another anti-TNF and who had moderate to severe active UC [12]. 
 
8.2 JUSTIFICATION 
The therapeutic monitoring of anti-TNF agents can help to identify mechanisms 
for the loss of response and find an optimal and individualized treatment, and has 
also proved to be cost-effective compared to the empirical intensification of doses 
[13,14]. Proactive drug monitoring showed that trough anti-TNF levels correlate 
with clinical response, clinical remission and mucosal healing in patients with 
inflammatory bowel disease (IBD) [15-19]. In contrast, inadequate concentrations 
of trough drug and anti-drug antibodies are associated with poorer clinical 
outcomes [20,21]. Recently, a study in patients with UC correlates the 
concentrations of infliximab needed during maintenance therapy with endoscopic 
and histological healing [22]. 
Golimumab, a fully humanized TNF antibody administered subcutaneously, 
induces response and clinical remission in patients with active UC of moderate 
to severe [3]. In patients who responded to induction therapy, the doses of 
golimumab administered every 4 weeks as a maintenance regimen were effective 
in maintaining the clinical response for 1 year [23]. The available data on 
golimumab monitoring and the exposure-response relationship in patients with 
UC come from the PURSUIT trials [24]. A positive association between 
golimumab levels and efficacy results, including mucosal healing, is confirmed 
during the induction and maintenance phases of the PURSUIT studies. 
A real-life study demonstrates the effectiveness and safety of golimumab in 
patients with UC [25]. However, we do not have sufficient data in real life about 
golimumab valley concentrations in patients in maintenance with this drug, and 
its correlation with clinical results. The available data come from an observational 
study with a limited number of patients [26]. In addition, there are no published 

data on the ability of golimumab to achieve histological remission in patients with 
UC. 
 
8.3 HYPOTHESIS 
Several exposure-response studies have shown that trough concentrations of 
adequate anti-TNF drugs are associated with better clinical outcomes in IBD. 
Drug levels and anti-drug antibodies are very relevant to our understanding of the 
mechanisms of primary or secondary loss of response to anti-TNF agents, and 
can help to guide therapeutic decisions. In this regard, determining golimumab 
levels during maintenance treatment may be clinically relevant in order to predict 
the efficacy of golimumab. 
 
8.4 OBJECTIVES 
The objective of this study is to investigate in clinical practice the association of 
trough concentrations of golimumab during maintenance treatment in patients 
with UC, with outcomes that include clinical and biological response, mucosal 
healing and histological remission. 
 
9. DESCRIPTION AND DESIGN OF THE STUDY 
9.1 Study design. 
Multicenter, non-interventional, cross-sectional study. 
Target population: Eligible patients will include patients of at least 18 years old 
with moderate to severe UC who are previously in maintenance therapy with 
golimumab according to usual clinical practice and have received the induction 
regimen with the drug according to the guidelines accepted in the technical file, 
followed by maintenance treatment for at least 6 months from the first dose of the 
drug. 
The study population will include all consecutive patients who meet these criteria 
and in whom a scheduled colonoscopy is performed according to clinical practice 
and at the discretion of the responsible physician for one of the following reasons: 
1. UC flare requiring endoscopic evaluation 
2. To evaluate the effects of the drug on the target mucous healing, in a treat-to-
target strategy 
3. In case of long-term remission with intention to discontinue the drug 
4. Screening for prevention of colorectal cancer according to protocol (> 8 years 
of illness) 
 

9.2 Procedures 
If they agree to participate, patients will sign an informed consent and a 
scheduled colonoscopy will be performed, and the following procedures will be 
carried out: 
1. The demographic and clinical characteristics, the concomitant treatment and 
the dosage of golimumab will be recorded in the corresponding Case Report 
Form (CRF). 
2. Samples will be taken for valley trough levels immediately before the 
administration of the subcutaneous dose of golimumab closest to the 
colonoscopy. Venous blood samples will be taken in BD Vacutainer trough tubes, 
and will be processed immediately or within 4 hours after extraction. Serum 
samples will be obtained after centrifugation at 2330 g for 10 minutes at room 
temperature, and finally 4 separate aliquots will be frozen at -20 °C. Golimumab 
concentrations will be determined centrally in the main center using commercially 
available drug-sensitive enzyme-linked immunosorbent assays (ELISA) kits: 
Promonitor (Progenika Biopharma, Spain) and Lisa-Tracker Anti-Infliximab 
(Theradiag, France). Twp aliquots will be reserved to give the opportunity to 
perform a sensitivity analysis using another tests, if necessary. 
3. Anti-golimumab antibodies will be evaluated by a drug-sensitive enzyme-linked 
immunosorbent assay (ELISA) by kits from the same manufactures. 
4. The 9-point partial Mayo score, which uses the results reported by patients in 
addition to the Physician Global assessment (PGA), will be recorded by the 
responsible physician on the day of extraction of the levels. 
5. Quality of life is assessed through SIBDQ-9 questionnaire on the day of 
extraction of the levels. 
7. Samples of C-reactive protein and fecal calprotectin  will be obtained on the 
day of extraction of the levels. 
8. Colonoscopy with local reading (to evaluate the endoscopic activity by a Mayo 
endoscopic subscore) sub-score will be performed between 15 days before and 
15 days after the extraction of trough levels and other procedures of the study. 
9. Histology: during colonoscopy, two rectal biopsies (called R-biopsy) and two 
sigmoid biopsies (called S-biopsy) will be taken for histological examination. In 
patients who have maximum endoscopic activity beyond sigma, two additional 
biopsies of this area will be taken. In order not to break the blind of pathologists, 
in these patients only biopsies of the rectum (called R-biopsy) and biopsies of the 
area with the highest endoscopic involvement (called S-Biopsy -replace sigma 
biopsy-) were remitted for histological evaluation. 
The specimens will be fixed in neutrally buffered formalin [4%] and will be mailed 
to the central pathologist (Hospital Clinico San Carlos) blinded for patient disease 
status and endoscopic score. Biopsies were centrally evaluated by two 
independent gastrointestinal pathologist using the Geboes index. In case of 

disagreement between pathologists biopsies were evaluated by a third senior 
specialized gastrointestinal pathologist. The biopsy with the maximum 
histological activity will be selected for the analysis of the histological score. 
The Geboes index is composed by six grades (each with subgrade), which 
corresponds to an increase in the degrees of inflammation in the mucosa. Grade 
0 indicates structural (architectural) change, grade 1 chronic inflammatory 
infiltrate, degree infiltrated in eosinophil lamina (2A) or neutrophils (2B), grade 3 
neutrophils in epithelium, grade 4 destruction of crypts, and grade 5 erosions or 
ulcers. Within each grade, the highest subgrade scores reflect a more severe 
histological alteration.  
 
9.2 Duration of the study 
One year is estimated for the inclusion of the total number of patients. 
 
9.3 Outcomes 
9.3.1 Primary 
1- Correlation between Golimumab trough levels and Endoscopic remission: 
defined as an endoscopic Mayo sub-score of 0. 
2- Correlation between Golimumab trough levels and Endoscopic healing: 
defined as an endoscopic Mayo sub-score of 0 or 1. 
3- Correlation between Golimumab trough levels and Histological remission: 
defined as a Geboes index ≤3.0. 
9.3.2 Secondary 
4- Correlation between Golimumab trough levels and Clinical remission: defined 
as a total Mayo score of ≤2 without any individual sub-score greater than 1 point. 
5- Correlation between Golimumab trough levels and Clinical response: defined 
as a decrease from the beginning to the evaluation point of at least 3 points in 
the total Mayo score (only if baseline endoscopy is available before induction). 
6. Thresholds of golimumab trough levels for outcomes 1 to 5 will be determined 
using the receiver-operating-characteristic curve [ROC] analysis. 
7. Correlation between Golimumab trough levels with C-reactive protein and fecal 
calprotectin. 
8. Proportion of patients with Histological remission defined as a Geboes index 
≤3.0. 
 
 
 

9.4 Treatment 
The study is observational, does not prefix the start of the treatment or its 
maintenance. 
We believe that the study does not induce prescription because patients are 
already receiving the drug. 
The treatment will be discontinued according to the investigator's criteria due to 
adverse effect or loss of secondary response. 
 
10. SELECTION OF PATIENTS 
10.1 Criteria for the inclusion of patients 
 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 who have previously been 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. 
 
10.2 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. 
 
10.3 Sample size 
Since this is a pilot study, no hypothesis will be established about the results to 
be obtained and, therefore, no statistical estimation of the sample size will be 

made, which will be established in 100 patients with UC considering it as a 
realistic number, suitable to draw conclusions from the results. 
 
10.4 Recruitment period 
 Start, January 2019. End, October 2019. 
 
4. DATA COLLECTION. 
The Case Report Form (annex 9.1) will include all the variables of interest. It will 
be prepared in paper format, and once all the variables have been agreed, an 
encrypted computer application (Excel) with limited access will be designed as 
an alternative, in which the patient data will be collected. 
 
5. STATISTICAL ANALYSIS. 
The results of golimumab levels will be summarized as median and interquartile 
range (IQR) and the qualitative data will be shown as numbers and percentages. 
The trough concentrations of golimumab in serum will also be classified in 
quartiles. Golimumab levels will be compared between patients who achieve or 
do not the specified efficacy results, using a two-sided Wilcoxon-Mann-Whitney 
test. Endoscopic and histologic healing / remission rates will be compared in 
golimumab concentration quartiles using a chi-square test (linear-linear 
association). The associations between golimumab levels and efficacy outcomes, 
including patient characteristics, will be evaluated using the multivariable logistic 
regression model. The thresholds of golimumab levels for efficacy results will be 
determined using the receiver-operating-characteristic curve [ROC] analysis. 
 
6. ADVERSE EVENTS 
The research team will monitor the possible adverse effects that may arise 
throughout the study, including the time of appearance, duration, intensity, 
course, outcome and causality. 
According to the ICH guideline E2A "Clinical Safety Data Management; 
Definitions and Standards for Expedited Reporting" of 04.10.99, an adverse event 
is defined as any unwanted medical event that occurs to a patient or research 
subject to which a pharmaceutical product is being administered and that does 
not necessarily have to be related to the product administered. The administration 
of any drug during the study is not predetermined. 
In accordance with order SAS/3470/2009 concerning the guidelines on 
observational post-authorization studies carried out with medicinal products for 
human use, the suspicion of serious adverse reactions detected during the 
course of the study will be notified to the contact point designated by the 

competent body in the field of pharmacovigilance of the Autonomous Community 
where the health professional who reports the case performs its activity, within a 
maximum period of 15 calendar days since the suspected adverse reaction was 
known through the submission of a yellow card to the corresponding regional 
pharmacovigilance center, indicating in observations, the name and code of the 
study from which the AEMPS already comes, using the "on-line" upload through 
the SINAEM portal of the AEMPS, following the instructions published by the 
AEMPS. 
 
7. ETHICAL ASPECTS. 
7.1. Declaration of Helsinki. 
The study will be carried out strictly following the international ethical 
recommendations for research and clinical trials in humans included in the 
Declaration of Helsinki of 1964 and its successive updates. 
 
7.2 Information to the patient and obtaining consent. 
It is the responsibility of the researcher to explain to the patients, verbally and in 
writing in an intelligible language, the objectives and requirements of the study. 
These explanations will include complete information about the nature, objective, 
possible risks and benefits of the study. You will be allowed to ask the questions 
that you consider appropriate and you will be given some time to consider your 
decision. Patients must be explicitly informed of their complete freedom to 
withdraw at any time during the study. The researcher must obtain written or 
verbal informed consent from each of the participants before a witness, before its 
inclusion. 
The Patient Information and Informed Consent models are included in Annex 9.3. 
Each patient will keep a copy of both documents. 
The forms with the Informed Consent will be kept by the researcher in the study 
file. If modifications are made according to local requirements, the new version 
must be approved by the study Sponsor and by the Hospital Ethics Committee. 
 
 
 

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