UCDCRC/15/007

University College Dublin

Catherine McAuley Centre, Nelson Street, Dublin 7, Dublin 7, Ireland, D07 A8NN

Gráinne O'Reilly. Director of Research Clinical Trials., UCD, +353 17166603, grainne.oreilly1@ucd.ie

Gráinne O'Reilly. Director of Research Clinical Trials., UCD, +353 17166603, grainne.oreilly1@ucd.ie

No

No

No

Final

13 Sep 2024

Yes

10 Jul 2023

Yes

10 Jul 2023

Yes

To ascertain if use of intensive monitoring of fecal calprotectin (FCP) and drug levels of Golimumab (GLM) (during maintenance) to guide dose intensification improves rates of Patient continuous clinical response (pCCR) and reduces disease activity in UC, relative to standard dosing of GLM according to the Summary of product characteristics (SmPC)

Ethics approval was obtained prior to commencement of the trial. Ethical approval was obtained from each participating site before site initiation.This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki,in accordance with Good Clinical Practice (GCP), as defined by the International Conference on Harmonisation (ICH) and in accordance with the ethical principles underlying European Union Directive 2001/20/EC and 2005/28/EC. Written informed consent for enrollment of each study subject was obtained as per local requirements and as approved by the ethics committee for the site.

01 Feb 2016

No

Yes

Ireland: 97

97

97

0

0

0

0

0

0

94

3

0

Baseline period (overall period)

Randomised - controlled

Yes

Golimumab

Injection

Subcutaneous use

Loading dosage at WK 0 & 2 as per protocol (200mgs week 0 and 100mgs at week 2). Following loading dose- Drug levels and FCP dictate dosage given (see published protocol doi: 10.1136/bmjgast-2017-000174 )

Golimumab

Injection

Subcutaneous use

Loading dosage at WK 0 & 2 as per protocol (200mgs week 0 and 100mgs at week 2). As per SmPC- weight based dosing >80kgs 100mgs every 4 weeks <80kgs 50mgs every 4 weeks. Golimumab is solution for injection supplied in a single use pre-filled pen called SmartJect.

Intervention arm

SmPC arm

Intervention arm

SmPC arm

Patient Continuous Clinical Response (pCCR) at week 46, defined as the absence of clinical flare ( an increase in modified partial Mayo score of 2 points value with accompanying requirement for treatment intervention) from WK 14 through to WK 46. An increase in MPMS of 2 points or more will be determined if such an increase happens from any visit from week 14 onwards to any subsequent visit. Primary analysis is conducted on the Full Analysis Set using a conservative non-responder imputation approach to handle missing data. • Subjects missing week 14 or 46 data are categorized as non-responders, including those discontinued due to disease worsening • Subjects who do not complete GLM treatment per protocol are considered non-responders • Since data on MPMS across all visits is used in determination of pCCR, only data actually collected will be used i.e. missing data between weeks 14 and 46 will be ignored Descriptive data are reported below are also based on this categorization

Primary

The primary endpoint is evaluated from week 14 to week 46.

Analysis is conducted on the Full Analysis Set, including randomised patients having the studied disease, having taken at least one dose of study treatment after inclusion and with at least one evaluation of the primary criteria. This primary analysis is conducted using non-responder imputation, where those with missing data at weeks 14 or 46 and those who don't complete per protocol GLM treatment are considered non-responders.

SmPC arm v Intervention arm

95

Pre-specified

7.9

2-sided

Sensitivity analysis 1 involves a variation in how subjects are categorized as achieving the primary endpoint or not. Here, subjects who do not meet criteria for Week 14 clinical response will be classified as failing to meet pCCR. This analysis will determine the impact on trial results of any subjectivity in the decision to allow subjects to continue past Week 14. Analysis are conducted in the same manner as for the primary analysis.

Intervention arm v SmPC arm

95

Post-hoc

4

2-sided

This analysis is based on a logistic regression model of the primary endpoint (calculated using non-responder imputation) with adjustment for covariates including disease duration, ever smoked, age, gender, BMI, total mayo score at screening, prior use of anti-TNFa therapy and prior use of immunomodulators. The unadjusted odds ratio (model without predictors) is 1.39 (95% CI: 0.61, 3.16) while shown below is the adjusted odds ratio

Intervention arm v SmPC arm

95

Pre-specified

1.29

2-sided

This analysis is an exploratory subgroup analysis carried out on subjects in the FAS-M analysis set. These are subjects who met the criteria for Week 14 Clinical Response (using the definition used to classify subjects in the main analysis of Week 14 Clinical Response). Analysis includes 26 subjects in the SmPC arm and 27 subjects in the Intervention arm.

Intervention arm v SmPC arm

95

Post-hoc

8.8

2-sided

Week 14 Clinical Response is defined as • A decrease from BL in partial Mayo score by ≥30% or a decrease of 3 points. Or • A decrease from BL in modified partial Mayo of 2 points or a decrease of ≥30% from baseline. The Partial Mayo Score (PMS) is only collected at the screening visit and hence the value collected at screening is the baseline for PMS. The Modified Partial Mayo Score is collected both at screening and baseline. Thus, the value collected at baseline be used as the reference value in determination of Week 14 Clinical Response. However, the screening value will be used as the reference value where a value is not recorded at baseline. • In the primary analysis of Week 14 Clinical Response, a non-responder imputation (NRI) approach will be taken to handle missing data at Week 14. Subjects missing data on either the PMS or MPMS scores will be deemed non-responders at Week 14, regardless of the reason for missingness.

Secondary

Baseline to Week 14

The effect of the intervention on Week 14 Clinical Response will be estimated as a difference in proportions with a 95% confidence interval. Two-sided, two-proportion Z test with continuity correction will test for a difference in proportions between treatment arms. A non-responder imputation (NRI) approach will be taken to handle missing data at Week 14. Subjects discontinued from GLM treatment by week 14 and subjects missing data on either the PMS or MPMS scores will be deemed non-responders

Intervention arm v SmPC arm

95

Pre-specified

-1.4

2-sided

Secondary

Defined as a Mayo endoscopic subscore of 0 or 1 at Week 46.

Non-responder imputation (NRI) is used to handle missing data at Week 46. Subjects missing data on the endoscopic subscore of the Mayo Score at Week 46 will be deemed NOT to meet the endpoint of mucosal healing at week 46, regardless of the reason for missingness. Furthermore, subjects who discontinued per protocol GLM treatment will be considered as not meeting this endpoint. With this assumption, 17/49 in the intervention group and 14/46 subjects in the SmPC group meet the endpoint

Intervention arm v SmPC arm

95

Pre-specified

4.3

2-sided

Subjects with Total Mayo Score > 5 at week 46 will be recorded as meeting this endpoint, while those with Total Mayo Score <=5 will be considered as not meeting the endpoint.

Secondary

Week 46

A non-responder imputation (NRI) approach is taken to handle missing data at Week 46. Subjects missing data on Total Mayo Score at Week 46 will be deemed to meet the endpoint of moderate-severe UC, regardless of the reason for missingness. Subjects discontinued from per protocol GLM treatment will (conservatively) be assumed to meet the endpoint. These assumptions result in 30/46 (65.2%) of subjects in the SmPC arm and 29/49 (59.2%) of subjects in the intervention arm meeting the endpoint

Intervention arm v SmPC arm

95

Pre-specified

-6

2-sided

Clinical Remission at Week 46 is defined as a Total Mayo Score <= 2 pts with no individual subscore >1.

Secondary

Week 46

A non-responder imputation (NRI) approach will be taken to handle missing data at Week 46. Subjects missing data on Total Mayo Score or on any of its subscores at Week 46 will be deemed as not achieving Clinical Remission, regardless of the reason for missingness. Furthermore, subjects with data on Total Mayo Score but discontinued from GLM treatment will be categorized as failing to meet this endpoint.

Intervention arm v SmPC arm

95

Pre-specified

6.7

2-sided

Corticosteroid free remission at Week 46 is defined as a Total Mayo Score <= 2 pts with no individual subscore >1 with no concomitant steroids. Note that all subjects who met the definition of Clinical Remission at Week 46 were off concomitant steroids - hence results are the same as for Clinical Remission at Week 46.

Secondary

Week 46

A non-responder imputation (NRI) approach will be taken to handle missing data at Week 46. Subjects missing data on Total Mayo Score or on any of its subscores at Week 46 will be deemed as not achieving Clinical Remission, regardless of the reason for missingness. Furthermore, subjects with data on Total Mayo Score but discontinued from per protocol GLM treatment will be categorized as failing to meet this endpoint.

Intervention arm v SmPC arm

95

Pre-specified

6.7

2-sided

A Dublin score is calculated as a product of the Endoscopic Mayo Score and the Extent Score (E1-3) of the Montreal Classification of Disease. Higher scores indicate more severe disease. There were 18 complete cases in the intervention group, with a median change in Dublin score of -0.3 (IQR: -4, -0.5) and 15 complete cases in the SmPC arm with a median change in Dublin score of -2.0 (IQR: -4,-1). For the treatment group comparison below, baseline values were carried forward to replace missing values on change from screening to week 46 in Dublin score.

Secondary

Change from screening to Week 46

For the analysis of this endpoint, the change in Dublin Score from screening to week 46 will be calculated and compared between treatment groups. For subjects with missing Dublin Score at week 46, a last observation carried forward approach will be taken, whereby the subject’s Dublin score will be assumed to be equal to the value recorded at screening. Analysis includes a Mann Whitney U test for a difference in the change scores (calculated with LOCF) between treatment arm.

Intervention arm v SmPC arm

95

Pre-specified

From randomisation to end of 46 week follow-up

26.1

Intervention group (Safety Set)

SmPC arm (Safety Set)