TOFACITINIB vs TOFACITINIB WITH MESALAMINE IN ULCERATIVE COLITIS

TOFACITINIB COMPARED TO TOFACITINIB WITH MESALAMINE FOR MAINTENANCE OF REMISSION IN ULCERATIVE COLITIS: A RANDOMIZED CONTROLLED TRIAL

All the trials using tofacitinib for maintenance of remission in UC have allowed the use of concomitant therapies except glucocorticoids. Mesalamine, a drug used in mild-to-moderate UC is often continued in patients receiving other drugs for maintenance. In this study, we plan to compare the effect of withdrawing mesalamine and continuing monotherapy with tofacitinib versus continuing dual therapy with tofacitinib and mesalamine. We hypothesize that the continuation of tofacitinib monotherapy after withdrawing mesalamine will be as efficacious and safe as continuation of the combination in remission maintenance in UC.

Study Overview

• Status: Not yet recruiting
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: Tofacitinib; Drug: Tofacitinib plus mesalamine

Detailed Description

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of bowel having a relapsing and remitting course. It has two major forms: ulcerative colitis (UC) and Crohn's disease (CD). Other less common forms include microcytic colitis, primary collagenous colitis and lymphocytic colitis. Ulcerative colitis is a form of IBD in which there is continuous involvement of the colon with the inflammation initiating from the rectum and then progressively involving variable lengths of the large intestine. Both genetic predisposition and environmental factors play a role. A dysregulated immune response, gut microbiota and epithelial barrier defects are implicated in the pathogenesis of UC.

The usual presentation is bloody diarrhoea. Diagnosis is based on clinical, endoscopic and histological findings. The aim of treatment in ulcerative colitis is to induce clinical, biochemical and endoscopic remission and to maintain it on a long-term. Various treatment options include 5-ASA, glucocorticoids, thiopurines, biologicals and small molecules. 5-ASA is used both in inducing and maintaining remission in UC. As per the American Gastroenterology Association (AGA) guidelines, 5-ASA is used as the first line agent for inducing remission in mild to moderate UC (1). It has also been extensively evaluated in the maintenance of remission (2). In an initial multicentre study, 264 subjects with UC in remission for 1 month were randomized into a mesalamine and a placebo arm. Endoscopic remission at 6 months was the primary endpoint defining treatment success. In both the intention-to-treat and per protocol analyses, mesalamine was significantly better than placebo for remission maintenance the end of 6 months. Since then, several studies have demonstrated the efficacy of different preparations of mesalamine in maintaining remission in ulcerative colitis.

Tofacitinib has also been studied in the OCTAVE trials for both induction and maintenance of remission in UC. In the OCTAVE induction 1 and 2 trials, tofacitinib was compared to placebo for induction of remission in moderate-to-severe UC and it was found to be better than placebo. Various meta-analyses also confirmed the same. The OCTAVE sustain proved tofacitinib to be better than placebo in maintaining UC in remission at both the studied doses (10 mg twice daily and 5 mg twice daily). All the trials using tofacitinib for maintenance of remission in UC have allowed the use of concomitant therapies except glucocorticoids. Mesalamine, a drug used in mild-to-moderate UC is often continued in patients receiving other drugs for maintenance. Recent guidelines have emphasised the importance of low-cost healthcare as there is increasing pressure on healthcare budgets worldwide (3). A study in the United Kingdom suggested that mesalamine accounts for up to 25% of the total healthcare costs in UC, with an average annual maintenance prescription estimated to be £740 or €850 (4). While mesalamine is safe and well-tolerated, it has rare but serious idiosyncratic adverse effects including pancreatitis. Around 3% of patients even report a paradoxical worsening of diarrhoea (5). The negative impact of polypharmacy must also be taken into consideration, with non-compliance often linked to higher pill burdens (6). In fact, the burden of a more complex medication regimen has been associated with poorer outcomes in both UC with real-world compliance as low as 50% (7). Furthermore, compliance to topical 5-ASA therapy is even worse than oral therapy (8). Thus, there is a clear need to explore the withdrawal of 5-ASA from the UC treatment regimen.

Two studies have evaluated the outcomes of withdrawal of oral 5-ASA in patients concomitantly treated with immunomodulators. Both studies showed no difference in relapse rates between patients with ulcerative colitis receiving either azathioprine monotherapy or combination of azathioprine and oral 5-ASA therapy with better compliance in azathioprine monotherapy group (9, 10). No randomized controlled trial (RCT) has yet evaluated the withdrawal of 5-ASA in patients treated with either biologic therapy or tofacitinib. However, a recent cohort study from two national population-based databases (from the United States and Denmark) showed no increase in the risk of adverse clinical events after withdrawing oral 5-ASA within 90 days of initiating anti-TNF therapy compared to those who continued 5-ASA (11). No RCT or prospective study has evaluated the outcome of 5-ASA withdrawal in patients receiving tofacitinib therapy. Indirect evidence from subgroup analysis of RCTs suggests that concomitant 5-ASA therapy does not increase the likelihood of maintaining clinical remission after escalation to tofacitinib (12).

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Beenal Dhooria, MD; Phone Number: +917798152446; Email: braavobeenal@gmail.com
• Study Contact Backup: Name: Saroj K Sinha, MD, DM; Email: sarojksinha@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed cases of UC by endoscopy and biopsy
• Patients in clinical remission for at least 3 months on Tofacitinib and mesalamine

Exclusion Criteria:

• Incomplete evaluation
• Uncertain diagnosis
• Active disease
• Subjects with Crohn's disease, microscopic colitis and collegenous colitis or IBD-U
• Unwilling to participate in study
• Pregnant and lactating women or those who are planning pregnancy in the forthcoming 2 years
• Patients with any suspected or proven malignancy
• Subjects with severe comorbidities
• Prior history of venous thromboembolism.
• Subjects undergoing major surgery
• Myocardial infarction within previous 3 months
• Heart failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tofacitinib; Mesalamine will be withdrawn while tofacitinib will be continued during maintenance of remission of the disease	Drug: Tofacitinib; Tofacitinib alone will be continued at a dose of 11 mg once a day
Active Comparator: Tofacitinib plus mesalamine; Both mesalamine and tofacitinib will be continued during maintenance of remission of the disease	Drug: Tofacitinib plus mesalamine; Both tofacitinib 11 mg once a day and mesalamine will be continued

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to relapse of colitis	Relapse of ulcerative colitis will be diagnosed based on the study subject's clinical findings	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum biomarker C-reactive protein	Changes in the level of serum biomarker C-reactive protein	12 months
Serum biomarker calprotectin	Changes in the level of serum biomarker calprotectin	12 months
Physician global assessment	The physician will assess the overall clinical condition of the subject on a visual analog scale from 0 to 100	12 months
Adverse effects	The adverse effects of the study drugs (venous thromboembolism, nasopharyngitis, diarrhea) and any other patient-reported adverse effects	12 months

Collaborators and Investigators

• Sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: October 2, 2024
• First Submitted That Met QC Criteria: October 2, 2024
• First Posted (Actual): October 3, 2024

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: October 2, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Protein Kinase Inhibitors; Janus Kinase Inhibitors; Tofacitinib; Mesalamine
• Other Study ID Numbers: TOME

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized data will be shared after publication on reasonable request.
• IPD Sharing Time Frame: After publication...for 2 years
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No