Trial Review

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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
22/04/2024
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] 308245 0
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 328023 0
Crohn's disease 328024 0
Ulcerative colitis 328025 0
Condition category
Condition code
Oral and Gastrointestinal 325084 325084 0 0
Inflammatory bowel disease
Oral and Gastrointestinal 325085 325085 0 0
Crohn's disease
Oral and Gastrointestinal 325086 325086 0 0
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] 324715 0
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] 332907 0
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] 332907 0
Week 48 from the time of receiving their first dose of either IV or SC infliximab within the study
Secondary outcome [1] 415123 0
Change in serum infliximab drug levels in each group measured on 12-weekly blood tests
Timepoint [1] 415123 0
Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [2] 415124 0
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] 415124 0
Week 24 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [3] 415125 0
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] 415125 0
Week 24 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [4] 415127 0
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] 415127 0
Week 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [5] 415131 0
Change in faecal calprotectin in each group measure on 12-weekly faecal tests.
Timepoint [5] 415131 0
Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [6] 415132 0
Change in CRP in each group measured on 12-weekly blood tests.
Timepoint [6] 415132 0
Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [7] 415133 0
Antibodies to infliximab in each group measured on 12-weekly blood tests.
Timepoint [7] 415133 0
Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [8] 415134 0
Adverse events in each group (including infusion or injection site reaction, hypersensitivity, rash, lymphopenia, infection) using a study-specific questionnaire 12-weekly.
Timepoint [8] 415134 0
Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [9] 415135 0
Patient satisfaction (Likert scale satisfaction survey) questionnaire.
Timepoint [9] 415135 0
Week 0, 24 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [10] 415144 0
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] 415144 0
Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [11] 415355 0
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] 415355 0
Week 12, 24, 36 and 48 post-first dose of either IV or SC infliximab within the study.
Secondary outcome [12] 415712 0
Health-related quality of life (Inflammatory Bowel Disease Questionnaire - IBD-Q)
Timepoint [12] 415712 0
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?
No
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
30/06/2025
Actual
Date of last data collection
Anticipated
1/06/2026
Actual
Sample size
Target
120
Accrual to date
25
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 23468 0
The Alfred - Melbourne
Recruitment hospital [2] 26461 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 26462 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 26463 0
The Northern Hospital - Epping
Recruitment postcode(s) [1] 38875 0
3004 - Melbourne
Recruitment postcode(s) [2] 42443 0
3076 - Epping
Recruitment postcode(s) [3] 42441 0
3084 - Heidelberg
Recruitment postcode(s) [4] 42442 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 312502 0
Commercial sector/Industry
Name [1] 312502 0
Celltrion Healthcare Australia
Country [1] 312502 0
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] 314090 0
Individual
Name [1] 314090 0
Dr. Robert Little
Address [1] 314090 0
Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC
Country [1] 314090 0
Australia
Secondary sponsor category [2] 314147 0
Individual
Name [2] 314147 0
A/Prof Miles Sparrow, Director IBD Service
Address [2] 314147 0
Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC
Country [2] 314147 0
Australia
Other collaborator category [1] 282470 0
Individual
Name [1] 282470 0
A/Prof Mark Ward
Address [1] 282470 0
Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC
Country [1] 282470 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311838 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 311838 0
The Alfred Hospital
55 Commercial Road
Melbourne, VIC, 3004
Ethics committee country [1] 311838 0
Australia
Date submitted for ethics approval [1] 311838 0
24/10/2022
Approval date [1] 311838 0
13/02/2023
Ethics approval number [1] 311838 0

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 122546 0
Dr Robert Little
Address 122546 0
Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC
Country 122546 0
Australia
Phone 122546 0
+61 03 9076 2223
Fax 122546 0
Email 122546 0
r.little@alfred.org.au
Contact person for public queries
Name 122547 0
Ms Jo McKenzie
Address 122547 0
Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC
Country 122547 0
Australia
Phone 122547 0
+61 03 9076 2223
Fax 122547 0
Email 122547 0
j.mckenzie@alfred.org.au
Contact person for scientific queries
Name 122548 0
Dr Robert Little
Address 122548 0
Gastroenterology Department, Ground Floor
The Alfred Centre, 99 Commercial Road
Melbourne, 3004, VIC
Country 122548 0
Australia
Phone 122548 0
+61 03 9076 2223
Fax 122548 0
Email 122548 0
r.little@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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.TypeCitationLinkEmailOther DetailsAttachment
17498Study protocol    Study protocol will be made available upon reasona... [More Details]
17499Statistical analysis plan    Statistical analysis plan will be made available u... [More Details]
17500Informed consent form    A Master Patient Information Sheet Consent Form wi... [More Details]
17501Ethical approval    Receipt of ethical approval will be made available... [More Details]



Results publications and other study-related documents

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