Not Yet RecruitingPhase 4ACTRN12621000023853

A Prospective Randomised Controlled Trial of Adults with Perianal Fistulising Crohn’s Disease and Optimised Therapeutic Infliximab Levels: PROACTIVE Trial

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

Sponsor

Associate Professor Susan Connor

Enrollment

138 participants

Start Date

May 1, 2021

Study Type

Interventional

Conditions

Perianal fistulising Crohn's Disease

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.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 80 Yearss

Inclusion Criteria11

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

Exclusion Criteria9

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

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Interventions

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.