Clinical trial NCT01903252: TP05 for the Treatment of Mild to Moderate Active Ulcerative Colitis (UC)
Official title: A Randomised, Active-Controlled, Double-Blind and Open Label Extensions Study to Evaluate the Efficacy, Long-Term Safety and Tolerability of TP05 3.2g/Day for the Treatment of Active Ulcerative Colitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Ulcerative Colitis
Keywords: UC
Lead sponsor: Tillotts Pharma AG
Sponsor class: INDUSTRY
First posted: 2013-07-19
Enrollment: 817
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Period 1: Clinical and Endoscopic Remission
timeFrame: Week 8
measure: Period 2: Clinical Response, Open-Label Extended Induction
timeFrame: Week 16
measure: Period 3: Clinical Remission
timeFrame: Week 38
Secondary outcomes:
measure: Period 1: Endoscopic Remission
timeFrame: Week 8
measure: Period 1: Endoscopic Response
timeFrame: Week 8
measure: Period 1: Clinical Remission
timeFrame: Week 8
measure: Period 1: Rectal Bleeding Sub-score of 0
timeFrame: Week 8
measure: Period 1: Clinical and Endoscopic Response
timeFrame: Week 8
measure: Period 1: Clinical Remission
timeFrame: Week 12
measure: Period 1: Clinical Response
timeFrame: Week 12
measure: Period 1: Rectal Bleeding Score of 0
timeFrame: Week 12
measure: Period 1: Clinical Remission at Both Week 8 and 12
timeFrame: Week 8 and week 12
measure: Period 1: Clinical Response at Both Week 8 and Week 12
timeFrame: Week 8 and Week 12
measure: Period 1: Change in Mayo Score From Baseline
timeFrame: Baseline and Week 8
measure: Period 1: Change in Partial Mayo Score From Baseline
timeFrame: Baseline and Week 8
measure: Period 1: Change in Stool Frequency Score
timeFrame: Baseline and Week 8
measure: Period 1: Change in Rectal Bleeding Score From Baseline
timeFrame: Baseline and Week 8
measure: Period 1: Change in Physician Global Assessment Score From Baseline
timeFrame: Baseline and Week 8
measure: Period 1: Change in Endoscopic Score From Baseline
timeFrame: Baseline and Week 8
measure: Period 2: Clinical Remission
timeFrame: Week 16
measure: Period 2: Rectal Bleeding Sub-score of 0
timeFrame: Week 16
measure: Period 2: Stool Frequency 0
timeFrame: Week 16
measure: Period 2: Urgency
timeFrame: Week 16
measure: Period 2: UC-Related Complications
timeFrame: Week 16
measure: Period 3: Clinical Response
timeFrame: Week 38
measure: Period 3: Clinical and Endoscopic Remission
timeFrame: Week 38
measure: Period 3: Clinical and Endoscopic Response
timeFrame: Week 38
measure: Period 3: Endoscopic Remission
timeFrame: Week 38
measure: Period 3: Endoscopic Response
timeFrame: Week 38
measure: Period 3: Rectal Bleeding Sub Score of 0
timeFrame: Week 38
measure: Period 3: Stool Frequency Sub-score 0
timeFrame: Week 38
measure: Period 3: No Urgency
timeFrame: Week 38
measure: Period 3: UC-Related Complications
timeFrame: Week 38
Other outcomes:
Locations:
city: Rheinfelden
country: Switzerland
facility: Tillotts Pharma AG
state: Baslerstrasse 15
Study officials:
affiliation: Alimentiv Inc.
name: Geert R D'Haens, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ma C, Jeyarajah J, Guizzetti L, Parker CE, Singh S, Dulai PS, D'Haens GR, Sandborn WJ, Feagan BG, Jairath V. Modeling Endoscopic Improvement after Induction Treatment With Mesalamine in Patients With Mild-to-Moderate Ulcerative Colitis. Clin Gastroenterol Hepatol. 2022 Feb;20(2):447-454.e1. doi: 10.1016/j.cgh.2020.11.040. Epub 2020 Dec 3.
citation: Ma C, Sandborn WJ, D'Haens GR, Zou G, Stitt LW, Singh S, Ananthakrishnan AN, Dulai PS, Khanna R, Jairath V, Feagan BG. Discordance Between Patient-Reported Outcomes and Mucosal Inflammation in Patients With Mild to Moderate Ulcerative Colitis. Clin Gastroenterol Hepatol. 2020 Jul;18(8):1760-1768.e1. doi: 10.1016/j.cgh.2019.09.021. Epub 2019 Sep 20.
citation: D'Haens GR, Sandborn WJ, Zou G, Stitt LW, Rutgeerts PJ, Gilgen D, Jairath V, Hindryckx P, Shackelton LM, Vandervoort MK, Parker CE, Muller C, Pai RK, Levchenko O, Marakhouski Y, Horynski M, Mikhailova E, Kharchenko N, Pimanov S, Feagan BG. Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis. Aliment Pharmacol Ther. 2017 Aug;46(3):292-302. doi: 10.1111/apt.14164. Epub 2017 Jun 1.