TP05 for the Treatment of Mild to Moderate Active Ulcerative Colitis (UC)

Phase 3CompletedNCT01903252

Tillotts Pharma AG817 enrolled

Overview

The purpose of this research study was to compare the medication TP05 to the medication Asacol™ for the treatment of ulcerative colitis (UC) and to assess the safety and tolerability of TP05. This study investigated whether TP05 is as good as (non-inferior to) Asacol™(1). (1)The trademark Asacol™ is registered in over 55 countries as Asacol™ and as Octasa™, Fivasa™, Lixacol™, Asacolon™ in the United Kingdom, France, Spain and Ireland, respectively. The rights to Asacol, including the rights to the trademark, are owned by Tillotts Pharma AG in various countries except for the following: Switzerland, USA, United Kingdom, Canada, Italy, Belgium, the Netherlands and Luxembourg.

This is a Phase 3, randomised, double-blind, active-controlled, multi-centre, non-inferiority trial evaluating the safety and efficacy of 3.2 g of TP05/day compared to 3.2 g/day of Asacol™ with an open label extension to assess the long-term safety and tolerability of TP05 administered over a 26 week period. A total of 817 subjects with mildly to moderately active UC were evaluated. Eligible subjects were randomly assigned in a 1:1 ratio to receive 3.2 g/day of TP05 (administered once daily(OD)) or 3.2 g/day of Asacol™. The primary efficacy outcome was assessed at Week 8. All subjects who respond to TP05/Asacol™ (response or remission) continued receiving blinded study treatment for up to 12 weeks. After that, subjects could enroll in an Open Label Extension (OLE) for 26 weeks duration to receive TP05. Subjects failing to respond to study drug at the Week 8 visit could enroll in the OLE at week 8 and received 4.8 g/day of TP05.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

817

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Induction phase - Main criteria for inclusion include: 1. Male or non-pregnant, non-lactating females, 18 years of age or older. Females of child bearing potential must have a negative serum pregnancy test prior to randomisation, and must use a hormonal (oral, implantable or injectable) or barrier method of birth control throughout the study. Females unable to bear children must have documentation of such in the source records (i.e., tubal ligation, hysterectomy, or post-menopausal \[defined as a minimum of one year since the last menstrual period\]). 2. Documented diagnosis of UC with disease extending at least 15 cm from the anal verge. 3. Active UC defined by: * a. Mayo score of ≥ 5 * b. Sigmoidoscopy component score ≥ 2 confirmed by central review and * c. Rectal bleeding component score ≥ 1 4. Ability of the subject to participate fully in all aspects of this clinical trial. 5. Written informed consent must be obtained and documented. Induction Phase - Main criteria for exclusion include: Subjects who exhibit any of the following conditions are to be excluded from the study: (1) Severe UC defined by the following criteria: 6 bloody stools daily with one or more of the following: * a. oral temperature \> 37.8 degrees C or \> 100.0 degrees F * b. pulse \> 90 beats/min * c. haemoglobin \< 10 g/dL (2) Treatment with oral mesalamine at a dose of \> 2.4 g/day within 4 weeks prior to randomisation. (3) Treatment with topical therapy (mesalamine or corticosteroids) within 2 weeks prior to randomisation (4) Treatment with systemic or rectal steroids within 4 weeks prior to randomisation. (5) Treatment with immunosuppressants within 6 weeks prior to randomisation. (6) Treatment with infliximab or other biologics within 3 months prior to randomisation. (7) Treatment with antibiotics within 7 days prior to randomisation. (8) Treatment with probiotics within 7 days prior to randomisation. (9) Treatment with anti-diarrhoeal treatment within 7 days prior to randomisation. (10) Treatment with nicotine patch within 7 days prior to randomisation. (11) Received any investigational drug within 30 days prior to randomisation. (12) History of colectomy or partial colectomy. (13) History of definite dysplasia in colonic biopsies. (14) Crohn's disease. (15) Immediate or significant risk of toxic megacolon. (16) Known bleeding disorders. (17) Hypersensitivity to salicylates, aspirin, sulfasalazine or mesalazine. (18) Serum creatinine \> 1.5 times the upper limit of the normal range. (19) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin or alkaline phosphatase \> 2 times the upper limit of the normal range. (20) Serious underlying disease other than UC which in the opinion of the investigator may interfere with the subject's ability to fully participate in the study. (21) History of alcohol or drug abuse which in the opinion of the investigator may interfere with the subject's ability to comply with the study procedures. (22) Stools positive for Clostridium difficile toxin. (23) Pregnant or lactating women. (24) Prior enrolment in the study. OLE - Main criteria for inclusion include: 1. Attendance at the Week 8 visit and completion of disease activity assessments prior to enrolment in OLE at Week 12 (responders or remitters) or Week 8 (non-responders). 2. At least 75% compliance with study medication in the induction phase. OLE - Main criteria for exclusion include: (1) Withdrawal from the induction phase prior to the Week 8 visit.

Outcomes

Primary Outcomes

Period 1: Clinical and Endoscopic Remission

Mayo Score of \<= 2 points with no individual sub-score \> 1

Time frame: Week 8

Period 2: Clinical Response, Open-Label Extended Induction

A decrease in the PMCS of ≥ 2 points and ≥ 30% from baseline, with a decrease in the rectal bleeding sub-score of ≥ 1 point or absolute rectal bleeding sub-score of 1 or 0.

Time frame: Week 16

Period 3: Clinical Remission

Clinical Remission was defined as a score of 0 points for both stool frequency and rectal bleeding on the Partial Mayo Clinic Score (PMCS)

Time frame: Week 38

Secondary Outcomes

Period 1: Endoscopic Remission

Endoscopic remission was defined as a Mayo endoscopy subscore of 0

Time frame: Week 8

Period 1: Endoscopic Response

Endoscopic response was define as a reduction in the Mayo endoscopic sub score of at least one.

Time frame: Week 8

Period 1: Clinical Remission

Clinical Remission was defined as a score of 0 points for both stool frequency and rectal bleeding on the Partial Mayo Clinic Score (PMCS)

Time frame: Week 8

Period 1: Rectal Bleeding Sub-score of 0

Rectal bleeding sub-score of 0 was defined as a sub score on the rectal bleeding component of the Mayo score

Time frame: Week 8

Period 1: Clinical and Endoscopic Response

Clinical and Endoscopic Response was defined as a decrease in the Mayo score of ≥3 points from baseline and a reduction of ≥ 30% from baseline with either an accompanying decrease in the rectal bleeding sub-score of at least 1 point or an absolute rectal bleeding sub-score of 0 or 1 at the Week 8 visit. If a subject withdrew from the study prior to Week 8 or their response status was not evaluable due to incomplete and/or invalid data, the subject was considered a non-responder.

Time frame: Week 8

Period 1: Clinical Remission

Clinical Remission was defined as a score of 0 points for both stool frequency and rectal bleeding on the Partial Mayo Clinic Score (PMCS)

Time frame: Week 12

Period 1: Clinical Response

A decrease in the PMCS of ≥ 2 points and ≥ 30% from baseline, with a decrease in the rectal bleeding sub-score of ≥ 1 point or absolute rectal bleeding sub-score of 1 or 0.

Time frame: Week 12

Period 1: Rectal Bleeding Score of 0

Rectal bleeding sub-score of 0 was defined as a sub score on the rectal bleeding component of the Mayo score

Time frame: Week 12

Period 1: Clinical Remission at Both Week 8 and 12

Clinical Remission was defined as a score of 0 points for both stool frequency and rectal bleeding on the Partial Mayo Clinic Score (PMCS)

Time frame: Week 8 and week 12

Period 1: Clinical Response at Both Week 8 and Week 12

A decrease in the Partial Mayo Score of ≥ 2 points and ≥ 30% from baseline, with a decrease in the rectal bleeding sub-score of ≥ 1 point or absolute rectal bleeding sub-score of 1 or 0.

Time frame: Week 8 and Week 12

Period 1: Change in Mayo Score From Baseline

Between-Group Difference of Mayo Score, Change from Baseline The changes from baseline to week 8 values in Mayo scores are compared between the two treatment groups. The Mayo scoring system is a well-established tool for assessing UC disease activity. The Mayo score is the sum of 4 component sub-scores, each scored on a scale ranging from 0 representing no pathology to 3 for severe disease. The 4 component sub-scores consist of, 1) stool frequency, 2) rectal bleeding, 3) flexible sigmoidoscopy scores, and 4) physician's global assessment. A Mayo score of 0 indicates no pathology and a score of 12, severe disease. Change from Baseline is calculated Baseline-score minus week 8-score. A larger change in Mayo score from baseline when patients experienced acute disease, indicates improvement and treatment success.