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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]

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

Condition category

Condition code

Oral and Gastrointestinal

Crohn's disease

Oral and Gastrointestinal

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]

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]

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]

Week 32 post initial induction dose of infliximab

Secondary outcome [1]

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]

Week 32, week 54 post initial induction dose of infliximab

Secondary outcome [2]

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]

Weeks 32 and 54 post initial induction dose of infliximab

Secondary outcome [3]

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]

Weeks 32 and 54 post initial induction dose of infliximab

Secondary outcome [4]

Patient-reported outcomes using the validated health-related quality of life tool, Inflammatory Bowel Disease Questionnaire-32

Timepoint [4]

Weeks 12, 32 and 54 post initial induction dose of infliximab

Secondary outcome [5]

Patient-reported outcomes using the validated health-related quality of life tool, Depression Anxiety and Stress Scale 21

Timepoint [5]

Weeks 12, 32 and 54 post initial induction dose of infliximab

Secondary outcome [6]

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]

Weeks 12, 32 and 54 post initial induction dose of infliximab

Secondary outcome [7]

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]

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?

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]

Liverpool Hospital - Liverpool

Recruitment hospital [2]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Recruitment hospital [3]

Concord Repatriation Hospital - Concord

Recruitment hospital [4]

St George Hospital - Kogarah

Recruitment hospital [5]

Blacktown Hospital - Blacktown

Recruitment hospital [6]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [7]

Wollongong Hospital - Wollongong

Recruitment hospital [8]

Royal North Shore Hospital - St Leonards

Recruitment hospital [9]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [10]

Box Hill Hospital - Box Hill

Recruitment hospital [11]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [12]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [13]

The Alfred - Melbourne

Recruitment hospital [14]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [15]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [16]

Mater Adult Hospital - South Brisbane

Recruitment hospital [17]

Sunshine Coast University Hospital - Birtinya

Recruitment hospital [18]

Gold Coast University Hospital - Southport

Recruitment hospital [19]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [20]

Flinders Medical Centre - Bedford Park

Recruitment hospital [21]

The Queen Elizabeth Hospital - Woodville

Recruitment hospital [22]

The Canberra Hospital - Garran

Recruitment hospital [23]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [24]

St John of God Hospital, Subiaco - Subiaco

Recruitment postcode(s) [1]

2170 - Liverpool

Recruitment postcode(s) [2]

2010 - Darlinghurst

Recruitment postcode(s) [3]

2139 - Concord

Recruitment postcode(s) [4]

2217 - Kogarah

Recruitment postcode(s) [5]

2148 - Blacktown

Recruitment postcode(s) [6]

2050 - Camperdown

Recruitment postcode(s) [7]

2500 - Wollongong

Recruitment postcode(s) [8]

2065 - St Leonards

Recruitment postcode(s) [9]

3168 - Clayton

Recruitment postcode(s) [10]

3128 - Box Hill

Recruitment postcode(s) [11]

3065 - Fitzroy

Recruitment postcode(s) [12]

3084 - Heidelberg

Recruitment postcode(s) [13]

3004 - Melbourne

Recruitment postcode(s) [14]

3050 - Parkville

Recruitment postcode(s) [15]

4029 - Herston

Recruitment postcode(s) [16]

4101 - South Brisbane

Recruitment postcode(s) [17]

4575 - Birtinya

Recruitment postcode(s) [18]

4215 - Southport

Recruitment postcode(s) [19]

5000 - Adelaide

Recruitment postcode(s) [20]

5042 - Bedford Park

Recruitment postcode(s) [21]

5011 - Woodville

Recruitment postcode(s) [22]

2605 - Garran

Recruitment postcode(s) [23]

6150 - Murdoch

Recruitment postcode(s) [24]

6008 - Subiaco

Funding & Sponsors

Funding source category [1]

Self funded/Unfunded

Name [1]

Address [1]

Country [1]

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]

Individual

Name [1]

Dr Nik Ding

Address [1]

Department of Gastroenterology & Hepatology
Building D - Daly Wing, Level 4 - D47
St Vincent’s Hospital Melbourne
41 Victoria Parade
Fitzroy VIC 3065

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

South Western Sydney Local Health District Human Research Ethics Committee

Ethics committee address [1]

South Western Sydney Local Health District Human Research Ethics Committee
Research Directorate
Locked Bag 7103
LIVERPOOL BC NSW 1871

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

30/03/2020

Ethics approval number [1]

2020/ETH00492

Summary

Brief summary

Crohn’s disease can be complicated by perianal fistulising Crohn’s disease, a highly morbid condition which can cause perianal pain, sepsis, and faecal incontinence. Infliximab is the most effective medical treatment for perianal fistulising Crohn’s disease. In patients who lose response to infliximab or relapse, therapeutic drug monitoring allows doctors to decide whether to increase the infliximab dose or to switch to another drug. Therapeutic drug monitoring is a process that involves measuring infliximab drug levels in the blood and measuring the presence of antibodies against infliximab. How therapeutic drug monitoring can be used to prevent a relapse and sustain Crohn’s disease remission is currently not clear.

This research project aims to analyse whether optimal dosing strategy of infliximab to achieve fistula healing in patients with complex perianal fistulising Crohn’s disease by comparing two treatment arms: the standard care arm and the proactive therapeutic drug monitoring arm. We will compare rates of fistula healing, fistula closure, healing as seen on magnetic resonance imaging (MRI), patient-reported outcomes and quality of life between the two groups. 

Patients will be screened for suitability for infliximab therapy by their gastroenterologist, who perform a number of examinations, tests and procedures, and will review your medical history. Eligible patients will be randomly allocated to either the proactive therapeutic drug monitoring arm or the standard care arm. Patients in the standard care arm will receive the standard dose of infliximab and patients in the proactive therapeutic drug monitoring arm will have infliximab dosing is adjusted based on the infliximab levels in their blood. Patients will be assessed for response based on their symptoms, physical examination of the perianal area, blood tests, imaging results including MRI and patient-reported outcomes including quality of life assessments. In both arms patients will be required to attend regularly for reviews, infliximab infusions and investigations. The maximum duration of this study will be approximately 54 weeks (1 year) from the time you decide to participate. At each study visit, patients will undergo a clinical evaluation, routine blood tests, blood collection for infliximab level testing, and/or a stool specimen collection for faecal testing.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Susan Connor

Address

Gastroenterology and Liver
Clinic E (123), Level 1
Liverpool Hospital
Corner of Elizabeth and Goulburn Streets
LIVERPOOL NSW 2170

Country

Australia

Phone

+61 2 8738 4085

Fax

[email protected]

Contact person for public queries

Name

Bonita Gu

Address

Gastroenterology and Liver
Clinic E (123), Level 1
Liverpool Hospital
Corner of Elizabeth and Goulburn Streets
LIVERPOOL NSW 2170

Country

Australia

Phone

+61 2 8738 4085

Fax

[email protected]

Contact person for scientific queries

Name

Bonita Gu

Address

Gastroenterology and Liver
Clinic E (123), Level 1
Liverpool Hospital
Corner of Elizabeth and Goulburn Streets
LIVERPOOL NSW 2170

Country

Australia

Phone

+61 2 8738 4085

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

There are no plans to share individual patient data currently

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
9586	Study 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

Source	Title	Year of Publication	DOI
Embase	Prospective randomised controlled trial of adults with perianal fistulising Crohn's disease and optimised therapeutic infliximab levels: PROACTIVE trial study protocol.	2021	https://dx.doi.org/10.1136/bmjopen-2020-043921

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

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