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Trial registered on ANZCTR


Registration number
ACTRN12621000023853
Ethics application status
Approved
Date submitted
2/11/2020
Date registered
14/01/2021
Date last updated
14/01/2021
Date data sharing statement initially provided
14/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Prospective Randomised Controlled Trial of Adults with Perianal Fistulising Crohn’s Disease and Optimised Therapeutic Infliximab Levels: PROACTIVE Trial
Scientific title
A Prospective Randomised Controlled Trial investigating the effect of optimised therapeutic infliximab levels guided by proactive therapeutic drug monitoring on fistula healing in adults with perianal fistulising Crohn's Disease: PROACTIVE Trial
Secondary ID [1] 302673 0
None
Universal Trial Number (UTN)
U1111-1260-5977
Trial acronym
PROACTIVE
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Perianal fistulising Crohn's Disease 319592 0
Condition category
Condition code
Oral and Gastrointestinal 317531 317531 0 0
Crohn's disease
Oral and Gastrointestinal 317532 317532 0 0
Inflammatory bowel disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will consist of two phases relating to infliximab therapy: induction (weeks 0-12) and maintenance (weeks 14-54). Blood will be collected for TLI (trough level infliximab) and anti-infliximab antibody titres immediately prior to each infliximab infusion.

In the proactive therapeutic monitoring (TDM) arm, the intervention will be prospective adjustments of infliximab dosing based on TLIs during induction and maintenance.

Patients in the proactive TDM arm will receive infliximab 5 mg/kg at weeks 0 and 2. Thereafter, infliximab doses will be modified based on the TLI at the preceding infusion, with dose-modification if they have TLIs below the target levels.

Induction Phase: Proactive TDM arm
If patients have TLIs < 25 µg/mL at week 2, they will receive infliximab 10 mg/kg at week 6. If patients have TLIs greater than or equal to 25 µg/mL at week 2, they will receive infliximab 5 mg/kg at week 6.
If patients have TLIs < 20 µg/mL at week 6, they will receive an additional infliximab 5 mg/kg dose at week 10. Patients who have TLIs greater than or equal to 20 µg/mL at week 6 will not receive an additional infliximab dose at week 10. Patients who have TLIs < 20 µg/mL at week 6 will be committed to dose escalation throughout maintenance therapy, as described below.

Maintenance Phase: Proactive TDM arm
Patients in the proactive TDM arm will have infliximab doses adjusted every treatment cycle based on the TLIs at the preceding infusion. The target TLI during maintenance will be greater than or equal to 10 µg/mL.
Patents in the proactive TDM arm with TLIs greater than or equal to 20 µg/mL at week 6 will receive infliximab 5 mg/kg at week 14. They will begin infliximab maintenance therapy at 5 mg/kg every 8 weeks, if they have TLIs greater than or equal to 10 µg/mL at week 14 (next infusion to occur at week 22) or 5 mg/kg every 6 weeks if they have TLIs < 10 µg/mL at week 14 (next infusion to occur at week 20).
Patients in the proactive TDM arm with TLIs < 20 µg/mL at week 6 will receive infliximab 5 mg/kg at week 14. They will begin infliximab maintenance therapy at 5 mg/kg every 6 weeks if they have TLIs greater than or equal to 10 µg/mL at week 14 (next infusion to occur at week 20) or 5 mg/kg every 4 weeks if they have TLIs < 10 µg/mL at week 14 (next infusion to occur at week 18).
Thereafter, patients in the proactive TDM arm will have dose modification in a stepwise fashion based on the TLIs at the preceding infusion, with dose modification if TLI < 10 µg/mL. Patients receiving infliximab 5 mg/kg every 8 weeks with TLIs < 10 µg/mL will have future infliximab infusion intervals shortened to 5 mg/kg every 6 weeks. Patients receiving infliximab 5 mg/kg every 6 weeks with TLIs < 10 µg/mL will have future infliximab infusion intervals shortened to 5 mg/kg every 4 weeks. Patients receiving infliximab 5 mg/kg every 4 weeks with TLIs < 10 µg/mL will have a dose increase for future infliximab infusions to 10 mg/kg every 4 weeks. As it takes 3 cycles to reach steady-state after doubling a dose of infliximab, the subsequent TLI will be performed 12 weeks later. This represents the maximal number of dose adjustments. Patients whose TLIs remain < 10 µg/mL after the maximal dose adjustments will continue to receive 10 mg/kg infusions every 4 weeks and will continue in the arm to which they were randomised until week 54 or early exit due to treatment failure, and the outcomes will be analysed in a sensitivity analysis at week 54.

All patients will be followed for 54 weeks from commencement of infliximab dosing.
Intervention code [1] 318958 0
Treatment: Drugs
Comparator / control treatment
Induction phase.
In the standard care arm, patients will receive infliximab 5 mg/kg at weeks 0, 2, and 6. No additional infliximab doses will be received.

Maintenance phase
In the standard care arm, patients will receive infliximab 5 mg/kg at week 14 and then 5mg/kg every 8 weeks. No additional infliximab doses will be received.

All patients will be followed for 54 weeks from commencement of infliximab dosing.
Control group
Active

Outcomes
Primary outcome [1] 325566 0
The proportion (%) of patients who achieve fistula healing, where fistula healing is defined as no further fistula drainage despite gentle finger compression as determined by physical examination on two consecutive visits.
Timepoint [1] 325566 0
Week 32 post initial induction dose of infliximab
Secondary outcome [1] 388400 0
The proportion of patients who achieve fistula closure, where fistula closure is defined as the closure of all external fistula openings, as determined by physical examination on two consecutive visits
Timepoint [1] 388400 0
Week 32, week 54 post initial induction dose of infliximab
Secondary outcome [2] 388401 0
The proportion of patients who achieve radiological fistula healing, where radiological fistula healing on pelvic magnetic resonance imaging (MRI) as defined as a van Assche Index score of 0 (when scoring the ‘number of fistula tracts’, assigning 0 points to each fistula track with hypo-intensity on T2-weighted fat suppression images)
Timepoint [2] 388401 0
Weeks 32 and 54 post initial induction dose of infliximab
Secondary outcome [3] 388402 0
The proportion of patients who achieve radiological fistula healing, where radiological fistula healing on pelvic magnetic resonance imaging (MRI) as defined as a Magnetic Resonance Novel Index for Fistula Imaging in Crohn’s Disease score of 0.
Timepoint [3] 388402 0
Weeks 32 and 54 post initial induction dose of infliximab
Secondary outcome [4] 388403 0
Patient-reported outcomes using the validated health-related quality of life tool, Inflammatory Bowel Disease Questionnaire-32
Timepoint [4] 388403 0
Weeks 12, 32 and 54 post initial induction dose of infliximab
Secondary outcome [5] 389569 0
Patient-reported outcomes using the validated health-related quality of life tool, Depression Anxiety and Stress Scale 21
Timepoint [5] 389569 0
Weeks 12, 32 and 54 post initial induction dose of infliximab
Secondary outcome [6] 389570 0
Patient-reported outcomes using validated sexual dysfunction measuring tool, the Inflammatory Bowel Disease-Specific Female Sexual Dysfunction Scale for female patents or the Inflammatory Bowel Disease-Specific Male Sexual Dysfunction Scale for male patients
Timepoint [6] 389570 0
Weeks 12, 32 and 54 post initial induction dose of infliximab
Secondary outcome [7] 389571 0
Time to treatment failure, defined as recurrence of a previously healed draining fistula, development of a new fistula, development of a perianal abscess requiring surgical incision and drainage, or discontinuation of study due to perceived lack of efficacy or loss to follow up; as determined from the patient's electronic medical record
Timepoint [7] 389571 0
Time (weeks) from initial induction dose of infliximab

Eligibility
Key inclusion criteria
Adult patients aged 18-80 years
Patients with complex perianal fistulising Crohn's disease (cpfCD) who have single or multiple externally draining perianal fistulas who are eligible for initiation of infliximab as per Pharmaceutical Benefits Scheme criteria. This incorporates patients with confirmed cpfCD treated by a gastroenterologist or a consultant physician in either internal or general medicine specialising in gastroenterology; with Crohn’s disease confirmed by standard clinical, endoscopic or radiological assessment; and who have an externally draining perianal fistula.
Patients unexposed to infliximab within 12 months of study inclusion
Patients with previous infliximab exposure > 12 months prior to study inclusion are eligible provided they were infliximab responsive at the time of cessation or non-responsive with below target maintenance infliximab trough level (< 10 µg/mL), and if anti-infliximab antibodies were present, titres were low (=< 60 ng/mL, using Ridascreen assay).
Patients previously treated with adalimumab, if non-responsive with below target trough adalimumab levels (< 5 µg/mL), with or without detectable anti-adalimumab antibody titres.
Patients with cpfCD and concurrent luminal disease or patients with isolated perianal fistulising Crohn’s disease without luminal disease. Isolated cpfCD will be defined as perianal fistulas with typical histological features of Crohn’s disease
Patients with or without a seton in situ
Patients with concurrent or previous therapies for Crohn’s disease including 5-aminosalicylic acids, thiopurines, methotrexate and corticosteroids
Patients who have previously trialled non-anti-TNF biologic or small molecule agents
Patients with controlled perianal sepsis on colorectal surgeon review
Patients who are able to understand and willing to sign the informed consent as approved by the Human Research Ethics Committee. Patients must have read and understood the Patient Information and Consent Form, must fully understand the requirements of the study, and must be willing to comply with all study visits and assessments
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Presence of a current diverting ileostomy or colostomy
Patients likely to undergo faecal stream diversion surgery in the next 3 months
Rectovaginal fistula or rectovesical fistulae
Uncontrolled perianal sepsis, as determined by colorectal surgeon review
Past failure to infliximab therapy with target maintenance infliximab trough level (>= 10µg/mL)
Usual Pharmaceutical Benefits Scheme exclusions to infliximab therapy including active systemic infections, untreated latent tuberculosis, malignancy in the last 5 years with the exception of non-melanoma skin cancer, untreated Clostridium difficile infection, moderate to severe heart failure, known systemic lupus erythematosus or connective tissue disorder, and autoimmune demyelinating conditions
Conditions interfering with treatment compliance
Pregnancy or expected pregnancy in the next 54 weeks; breast-feeding
Participants who cannot read or understand the Patient Information and Consent Form may not be enrolled in the study by a guardian or any other individual

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)
Patients will be randomised 1:1 to either the proactive TDM arm or standard care arm by the research coordinator at the primary site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using the randomisation module on the secured Research electronic data capture (REDCap) platform. Block randomisation will be used and randomisation will be stratified by prior anti-tumour necrosis-alpha exposure and smoking status.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Power Calculation
Fifty-eight patients per arm will be required to detect a difference of 25% in the proportions of patients meeting the primary outcome; assuming 50% of the standard care arm achieve the primary outcome compared to 75% in the proactive TDM arm, with a 2-tailed comparison with an alpha of 0.05 and 80% power. Using similar parameters, this will also be sufficient to determine differences between the two groups using Kaplan-Meier analyses for the secondary outcomes.

As not all patients entering the induction study will meet the continuation criteria for entering the maintenance study, over-enrolment in the induction arm is needed. Data released by the Australian Pharmaceutical Benefits Scheme shows that 93.9% of patients receiving infliximab for cpfCD are eligible for maintenance therapy. Therefore, we plan to enrol 138 patients, to allow for the 130 to enter the maintenance phase. We then anticipate a 10% drop-out rate during maintenance as based on previous clinical trials in order to have 116 complete the trial after anticipated drop-out.

Statistical Analyses

Primary objective
Data will be analysed according to both the intention-to-treat and per-protocol analysis. Patients who terminate the study early for any reason will be regarded as treatment failures and included in the intention-to-treat analysis but excluded in per protocol analyses. The primary analysis will assess the effect of the intervention on the clinical healing of perianal fistulae at week 32 by directly calculating relative risks and their 95% confidence interval. Relative risks will be calculated using log binomial regression.

Secondary objectives
Secondary analyses will assess the effect of the intervention on the secondary outcomes. If the secondary outcomes are binary, relative risks will be calculated as above. Continuous secondary outcomes will be analysed by means of analysis of variance if they are normally distributed and by means of nonparametric tests if their distribution is not normal. Secondary outcomes that include time to an event will be analysed by survival analysis. Potential outcomes to adjust for include gender, concurrent medical therapies, and duration since Crohn’s disease diagnosis. Future modelling will be used to estimate indirect costs using productivity-adjusted life years. Multiple imputation will be used to address missing data. Data relating to adverse events will be evaluated in exploratory analyses incorporating all participants.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2021
Actual
Date of last participant enrolment
Anticipated
30/04/2024
Actual
Date of last data collection
Anticipated
30/04/2025
Actual
Sample size
Target
138
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 17923 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 17924 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [3] 17925 0
Concord Repatriation Hospital - Concord
Recruitment hospital [4] 17926 0
St George Hospital - Kogarah
Recruitment hospital [5] 17927 0
Blacktown Hospital - Blacktown
Recruitment hospital [6] 17928 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [7] 17929 0
Wollongong Hospital - Wollongong
Recruitment hospital [8] 17930 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [9] 17931 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [10] 17932 0
Box Hill Hospital - Box Hill
Recruitment hospital [11] 17933 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [12] 17934 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [13] 17935 0
The Alfred - Melbourne
Recruitment hospital [14] 17936 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [15] 17937 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [16] 17938 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [17] 17939 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [18] 17940 0
Gold Coast University Hospital - Southport
Recruitment hospital [19] 17941 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [20] 17942 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [21] 17943 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [22] 17944 0
The Canberra Hospital - Garran
Recruitment hospital [23] 17945 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [24] 17946 0
St John of God Hospital, Subiaco - Subiaco
Recruitment postcode(s) [1] 31786 0
2170 - Liverpool
Recruitment postcode(s) [2] 31787 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 31788 0
2139 - Concord
Recruitment postcode(s) [4] 31789 0
2217 - Kogarah
Recruitment postcode(s) [5] 31790 0
2148 - Blacktown
Recruitment postcode(s) [6] 31791 0
2050 - Camperdown
Recruitment postcode(s) [7] 31792 0
2500 - Wollongong
Recruitment postcode(s) [8] 31793 0
2065 - St Leonards
Recruitment postcode(s) [9] 31794 0
3168 - Clayton
Recruitment postcode(s) [10] 31795 0
3128 - Box Hill
Recruitment postcode(s) [11] 31796 0
3065 - Fitzroy
Recruitment postcode(s) [12] 31797 0
3084 - Heidelberg
Recruitment postcode(s) [13] 31798 0
3004 - Melbourne
Recruitment postcode(s) [14] 31799 0
3050 - Parkville
Recruitment postcode(s) [15] 31800 0
4029 - Herston
Recruitment postcode(s) [16] 31801 0
4101 - South Brisbane
Recruitment postcode(s) [17] 31802 0
4575 - Birtinya
Recruitment postcode(s) [18] 31803 0
4215 - Southport
Recruitment postcode(s) [19] 31804 0
5000 - Adelaide
Recruitment postcode(s) [20] 31805 0
5042 - Bedford Park
Recruitment postcode(s) [21] 31806 0
5011 - Woodville
Recruitment postcode(s) [22] 31807 0
2605 - Garran
Recruitment postcode(s) [23] 31808 0
6150 - Murdoch
Recruitment postcode(s) [24] 31809 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 307378 0
Self funded/Unfunded
Name [1] 307378 0
Country [1] 307378 0
Primary sponsor type
Individual
Name
Associate Professor Susan Connor
Address
Department of Gastroenterology & Hepatology
Clinic E (123), Level 1
Liverpool Hospital
Corner of Elizabeth and Goulburn Streets
Liverpool NSW 2170
Country
Australia
Secondary sponsor category [1] 307684 0
Individual
Name [1] 307684 0
Dr Nik Ding
Address [1] 307684 0
Department of Gastroenterology & Hepatology
Building D - Daly Wing, Level 4 - D47
St Vincent’s Hospital Melbourne
41 Victoria Parade
Fitzroy VIC 3065
Country [1] 307684 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307227 0
South Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 307227 0
Ethics committee country [1] 307227 0
Australia
Date submitted for ethics approval [1] 307227 0
Approval date [1] 307227 0
30/03/2020
Ethics approval number [1] 307227 0
2020/ETH00492

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106474 0
A/Prof Susan Connor
Address 106474 0
Gastroenterology and Liver
Clinic E (123), Level 1
Liverpool Hospital
Corner of Elizabeth and Goulburn Streets
LIVERPOOL NSW 2170
Country 106474 0
Australia
Phone 106474 0
+61 2 8738 4085
Fax 106474 0
Email 106474 0
Susan.Connor1@health.nsw.gov.au
Contact person for public queries
Name 106475 0
Bonita Gu
Address 106475 0
Gastroenterology and Liver
Clinic E (123), Level 1
Liverpool Hospital
Corner of Elizabeth and Goulburn Streets
LIVERPOOL NSW 2170
Country 106475 0
Australia
Phone 106475 0
+61 2 8738 4085
Fax 106475 0
Email 106475 0
bonita.gu@health.nsw.gov.au
Contact person for scientific queries
Name 106476 0
Bonita Gu
Address 106476 0
Gastroenterology and Liver
Clinic E (123), Level 1
Liverpool Hospital
Corner of Elizabeth and Goulburn Streets
LIVERPOOL NSW 2170
Country 106476 0
Australia
Phone 106476 0
+61 2 8738 4085
Fax 106476 0
Email 106476 0
bonita.gu@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans to share individual patient data currently


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9586Study protocol    Study protocol will be published on BMJ Open



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseProspective randomised controlled trial of adults with perianal fistulising Crohn's disease and optimised therapeutic infliximab levels: PROACTIVE trial study protocol.2021https://dx.doi.org/10.1136/bmjopen-2020-043921
N.B. These documents automatically identified may not have been verified by the study sponsor.