ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12622001458729

Ethics application status

Approved

Date submitted

28/10/2022

Date registered

17/11/2022

Date last updated

29/09/2024

Date data sharing statement initially provided

17/11/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

Switching from Dose-Intensified intravenous to SubCutaneoUS infliximab in Inflammatory Bowel Disease: a randomised controlled trial - DISCUS-IBD

Scientific title

Switching from Dose-Intensified intravenous to SubCutaneoUS infliximab in Inflammatory Bowel Disease: a randomised controlled trial - DISCUS-IBD

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1284-2633

Trial acronym

DISCUS-IBD

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Inflammatory bowel disease

Crohn's disease

Ulcerative colitis

Condition category

Condition code

Oral and Gastrointestinal

Inflammatory bowel disease

Oral and Gastrointestinal

Crohn's disease

Oral and Gastrointestinal

Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The interventional arm will receive subcutaneous (SC) infliximab and the dosing will be stratified according to prior intravenous (IV) infliximab dosing regimen.

120 mg SC infliximab 2-weekly - patients previously receiving IV infliximab at doses of 5-7.5 mg/kg 4- or 6-weekly and 7.5-10 mg/kg 6- or 8-weekly
240 mg SC infliximab 2-weekly - patients previously receiving IV infliximab 10 mg/kg 4-weekly

The duration of administration will be 48 weeks.

Patients receiving a dose of 120 mg SC infliximab 2-weekly that meet relapse criteria at weeks 12, 24, 36, or at any time point during the study, will be escalated to a maximum of SC infliximab 240 mg 2-weekly. Criteria for dose-escalation include one of the following three:
- Modified Harvey Bradshaw Index (HBI) >/=5 in Crohn's disease (CD) patients, partial Mayo Score >/=2 in ulcerative colitis (UC) patients AND objective evidence of active disease (defined as C-reactive protein [CRP] >5mg/L OR faecal calprotectin [FCP] > 250 µg/g)
- Need for corticosteroids, new immunomodulator or switch in biologic therapy
- IBD-related hospitalisation or surgery

Self-reported adherence with prescribed medications will be surveyed 12-weekly throughout the 48-week study.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

The control arm will continue to receive their existing regimen of dose-intensified IV infliximab. The duration of administration will be 48 weeks.

Patients in the IV arm that experience a disease flare at weeks 12, 24, 36 or at any time point during the study can undergo one further infliximab intensification at the discretion of the treating clinical team. Criteria for further dose-escalation include one of the following three:
- Modified Harvey Bradshaw Index (HBI) >/=5 in Crohn's disease (CD) patients, partial Mayo Score >/=2 in ulcerative colitis (UC) patients AND objective evidence of active disease (defined as C-reactive protein [CRP] >5mg/L OR faecal calprotectin [FCP] > 250 µg/g)
- Need for corticosteroids, new immunomodulator or switch in biologic therapy
- IBD-related hospitalisation or surgery.

The maximum dose of IV infliximab is 10mg/kg 4-weekly and patients failing this dose will be withdrawn from the study

Control group

Active

Outcomes

Primary outcome [1]

Rate of disease relapse in each group, defined as one of: 1. Clinical (either modified HBI >/=5 in CD or partial Mayo Score >/=2 in UC) AND objective evidence of active disease (either CRP >5mg/L, or FCP >250 µg/g) 2. Need for corticosteroids, immunomodulator or switch in biologic therapy. 3. Need for IBD-related hospitalisation or surgery.

Patients meeting any of the relapse criteria are permitted one dose-escalation in their subcutaneous or intravenous infliximab. The maximum subcutaneous dose is 240 mg 2-weekly and the maximum IV dose is 10 mg/kg 4-weekly.

Patients receiving escalation will be recorded as meeting the primary endpoint (relapse) whilst still remaining in the study to 48 weeks to measure response to dose-intensification. The above criteria will be measured using 12-weekly blood tests, faecal tests and clinical surveys to inform primary and secondary outcomes.

Timepoint [1]

Week 48 from the time of receiving their first dose of either IV or SC infliximab within the study

Secondary outcome [1]

Change in serum infliximab drug levels in each group measured on 12-weekly blood tests

Timepoint [1]

Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [2]

Rates of clinical relapse in each group, defined as: modified HBI >/=5 in CD patients, partial Mayo Score >/=2 in UC patients measured on clinical surveys.

Timepoint [2]

Week 24 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [3]

Rates of biochemical disease relapse in each group, defined as: CRP >5 mg/L, or FCP >250 µg/g post-first dose of either IV or SC infliximab within the study. CRP and FCP measured on 12-weekly blood and faecal tests.

Timepoint [3]

Week 24 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [4]

Rate of dose-intensification due to clinical and biochemical relapse in each group post-first dose of either IV or SC infliximab within the study collected on a study-specific database.

Timepoint [4]

Week 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [5]

Change in faecal calprotectin in each group measure on 12-weekly faecal tests.

Timepoint [5]

Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [6]

Change in CRP in each group measured on 12-weekly blood tests.

Timepoint [6]

Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [7]

Antibodies to infliximab in each group measured on 12-weekly blood tests.

Timepoint [7]

Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [8]

Adverse events in each group (including infusion or injection site reaction, hypersensitivity, rash, lymphopenia, infection) using a study-specific questionnaire 12-weekly.

Timepoint [8]

Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [9]

Patient satisfaction (Likert scale satisfaction survey) questionnaire.

Timepoint [9]

Week 0, 24 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [10]

Composite adherence (number of missed doses, number of rescheduled doses) and any impact of COVID-19 on adherence (yes/no). Collected on 12-weekly surveys designed specifically for this study.

Timepoint [10]

Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [11]

Success of further dose-intensification in each group as measured by an increment in drug levels and rate of recapture of clinical and biochemical response (defined as achieving the same remission parameters required to qualify for study enrolment) collected on 12-weekly blood tests, faecal tests and either the partial Mayo score or HBI, as appropriate.

Timepoint [11]

Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.

Secondary outcome [12]

Health-related quality of life (Inflammatory Bowel Disease Questionnaire - IBD-Q)

Timepoint [12]

Week 0, 24 and 48 post-first dose of either IV or SC infliximab within the study.

Eligibility

Key inclusion criteria

Adult luminal CD or UC patients on maintenance escalated IV infliximab in clinical steroid-free remission for at least 6 months and biochemical remission at study entry, defined as:
- Modified HBI <5 for CD and partial Mayo score <2 for UC) AND
- CRP <5 mg/L AND FCP <250 µg/g

Minimum age

18 Years

Maximum age

85 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- Patients with recent IV infliximab dose change (within 3 months)
- Patients with perianal CD in the absence of luminal CD
- Pregnancy or planning pregnancy within 12 months
- Actively breastfeeding
- Weight <40 kg or >120 kg

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation concealment via central computerised randomisation by the primary, coordinating site (The Alfred Hospital) with subsequent notification via telephone or email

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

1:1 central computerised randomisation stratified for disease type (CD/UC), immunomodulator use (yes/no) and weight (<80kg / >/=80kg)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 3 / Phase 4

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

A non-inferiority study will be performed, aiming to achieve statistical power of 90% at a significance of p <0.05. The pre-specified non-inferiority margin is 15%, consistent with other similar studies. Assumptions for rates of relapse were 24% in the SC group and 16% in the IV group. On this basis, a sample size of 52 patients per group is required, i.e. 104 patients in total. Allowing for >10% drop out rate, the planned sample size is 120 patients.

Normally distributed continuous data will be presented as mean and standard deviation (SD) and compared using the Student’s t-test or ANOVA with Tukey correction for paired, longitudinal drug levels, clinical activity and biomarkers. Non-normally distributed continuous data will be presented as the median and interquartile range (IQR) and compared using the Wilcoxon signed rank-sum test or Friedman test with Dunn’s correction for paired, serial drug levels, clinical activity and biomarkers. Categorical data will be presented as number and percent, with comparison using Chi-squared or Fisher’s exact test, as appropriate. Multivariate analysis for predictors of relapse will be undertaken using logistic regression. Multilevel linear modelling will also be performed to look at patient and disease characteristics that predict change in serial drug level data both between and within participants in both groups. Kaplan-Meier survival curves with log-rank tests of difference will compare the failure rate between the two groups and a Cox proportional-hazards model will be used to identify the association of baseline independent variables with failure rate over the study period. An interim-analysis will be performed when 60 patients reach week 24. Recruitment and data collection will continue whilst data is analysed to ensure that there are no significant safety concerns between the two groups and that the recruitment and randomisation processes are functioning correctly. SPSS Version 28 will be used for all analysis. Statistical significance will be determined as a p value < 0.05.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

15/02/2023

Actual

6/03/2023

Date of last participant enrolment

Anticipated

31/12/2025

Actual

Date of last data collection

Anticipated

31/12/2026

Actual

Sample size

Target

120

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,SA,WA,VIC

Recruitment hospital [1]

The Alfred - Melbourne

Recruitment hospital [2]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [3]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [4]

The Northern Hospital - Epping

Recruitment hospital [5]

St Vincent's Private Hospital - Fitzroy

Recruitment hospital [6]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [7]

Liverpool Hospital - Liverpool

Recruitment hospital [8]

Mater Hospital Brisbane - South Brisbane

Recruitment hospital [9]

The Queen Elizabeth Hospital - Woodville

Recruitment postcode(s) [1]

3004 - Melbourne

Recruitment postcode(s) [2]

3084 - Heidelberg

Recruitment postcode(s) [3]

3168 - Clayton

Recruitment postcode(s) [4]

3076 - Epping

Recruitment postcode(s) [5]

3065 - Fitzroy

Recruitment postcode(s) [6]

6150 - Murdoch

Recruitment postcode(s) [7]

2170 - Liverpool

Recruitment postcode(s) [8]

4101 - South Brisbane

Recruitment postcode(s) [9]

5011 - Woodville

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Celltrion Healthcare Australia

Address [1]

Celltrion Healthcare Australia Pty Ltd
Suite 13.03/31 Market St, St Martins Tower
Sydney, NSW, 2000, Australia

Country [1]

Australia

Primary sponsor type

Hospital

Name

The Alfred Hospital

Address

The Alfred Hospital
55 Commercial Road
Melbourne, 3004, VIC

Country

Australia

Secondary sponsor category [1]

Individual

Name [1]

Dr. Robert Little

Address [1]

Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC

Country [1]

Australia

Secondary sponsor category [2]

Individual

Name [2]

A/Prof Miles Sparrow, Director IBD Service

Address [2]

Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC

Country [2]

Australia

Other collaborator category [1]

Individual

Name [1]

A/Prof Mark Ward

Address [1]

Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Alfred Hospital Ethics Committee

Ethics committee address [1]

The Alfred Hospital
55 Commercial Road
Melbourne, VIC, 3004

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/10/2022

Approval date [1]

13/02/2023

Ethics approval number [1]

Summary

Brief summary

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is an incurable, chronic illness. Patients with IBD often require long term immune suppressing medications. Infliximab is a biologic medication that achieves and maintains remission in the majority of IBD patients. However, between 30 and 50% of patients require higher doses of infliximab than that which is registered in Australia. Infliximab is traditionally administered intravenously (IV). However, a new infliximab formulation administered directly beneath the skin (subcutaneous tissue), appears to be equally effective to IV infliximab. Subcutaneous medications are preferred by the majority of patients given greater flexibility and convenience. Emerging evidence demonstrates that, in patients receiving dose-intensified IV infliximab, switching to subcutaneous infliximab maintains remission in the vast majority of patients.

This study aims to confirm that patients with Crohn’s disease and ulcerative colitis receiving dose-intensified IV infliximab can switch to subcutaneous infliximab and maintain clinical and biochemical (blood and stool test) remission and adequate drug levels.

We will perform a multicentre, randomised non-inferiority trial. We will recruit 120 adults with IBD in remission receiving stable dose-intensified IV infliximab. Participants will be randomly allocated to continue their current regimen or to switch to subcutaneous infliximab. Clinical and biochemical activity as well as drug levels will be measured every 12 weeks until study conclusion at week 48. The primary outcome is rate of relapse between the two groups at week 48. Relapse is defined as composite clinical and objective activity OR need for corticosteroids, immunomodulator or switch in therapy OR need for IBD-related hospitalisation/surgery. Patients meeting the first clinical and biochemical relapse criterion are permitted one dose-escalation in their subcutaneous or IV infliximab. They will be recorded as meeting the primary endpoint whilst still remaining in the study to 48 weeks to measure response to further dose-intensification. Secondary endpoints will include changes in infliximab drug levels, anti-infliximab antibodies, economic impact, patient satisfaction and the change in clinical and biochemical markers of disease activity throughout the study.

Trial website

Trial related presentations / publications

Public notes

We anticipate that the results of this study will make a number of contributions to the scientific literature in IBD. As opposed to IV biologics, subcutaneous administration allows greater flexibility, convenience and less utilisation of healthcare resources. The anticipated practical advantages of subcutaneous infliximab are compounded by the requirement for rapid resource reallocation during ongoing waves of the COVID-19 pandemic.

Contacts

Principal investigator

Name

Dr Robert Little

Address

Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC

Country

Australia

Phone

+61 03 9076 2223

Fax

[email protected]

Contact person for public queries

Name

Jo McKenzie

Address

Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC

Country

Australia

Phone

+61 03 9076 2223

Fax

[email protected]

Contact person for scientific queries

Name

Robert Little

Address

Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC

Country

Australia

Phone

+61 03 9076 2223

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Patients are de-identified upon enrolment. All data analyses are undertaken using this de-identified code and therefore only aggregate de-identified data will be available.

What supporting documents are/will be available?

Doc. No.	Type	Other Details
17498	Study protocol	Study protocol will be made available upon reasona... [More Details]
17499	Statistical analysis plan	Statistical analysis plan will be made available u... [More Details]
17500	Informed consent form	A Master Patient Information Sheet Consent Form wi... [More Details]
17501	Ethical approval	Receipt of ethical approval will be made available... [More Details]

Results publications and other study-related documents

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No additional documents have been identified.

Trial Review

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