A Phase II/III, Randomised, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Oral Controlled-Ileocolonic-Release Nicotinamide (CICR-NAM) for Induction and Maintenance Therapy in Patients with Mild to Moderately Active Ulcerative Colitis
Overview
- Phase
- Phase 2
- Intervention
- Low-Dose CICR-NAM
- Conditions
- Ulcerative Colitis, Unspecified
- Sponsor
- University Hospital Schleswig-Holstein
- Enrollment
- 459
- Locations
- 1
- Primary Endpoint
- Symptomatic remission
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
Double-blind, randomised, placebo-controlled phase II / III trial evaluating efficacy and safety of two different doses (2 g/d or 3 g/d) of oral controlled-ileocolonic-release nicotinamide (CICR-NAM) compared to placebo in patients with ulcerative colitis (UC).
The intended therapeutic use of CICR-NAM is to improve intestinal inflammation in adults with UC by topically increasing nicotinamide supply in the ileocolonic region and thus favourably influencing the composition of intestinal microbiota
Detailed Description
ORNATUS 1 is a double-blind randomised trial evaluating the efficacy and safety of CICR-NAM in patients with mild to moderately active UC. The trial includes a 12-week induction period and a 40-week maintenance period. Patients will be randomised 1:1:1 placebo vs. 2 g/d CICR-NAM vs. 3 g/d CICR-NAM prior to induction treatment and will remain in the allocated dose level in the maintenance period, which results in a 52-week treatment in a treat-through design. An optional open label arm with 3 g/d CICR-NAM will be implemented for patients that have completed the induction period and show worsening of disease activity at the end of the induction period.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and female patients with UC and 18 to 80 years of age (at the time of signing the informed consent).
- •Ability to understand and comply with the protocol.
- •Signed written informed consent.
- •Disease-specific:
- •Documented diagnosis of UC, with a minimum disease duration of 3 months prior to screening and ≥ 1 relapse, clinically defined using established criteria within the last 12 months.
- •Histology supportive for the diagnosis of UC.
- •Mild to moderate disease activity (at screening): modified Mayo score (mMS) 4-7 RB ≥ 1, endoscopic score ES ≥1 and SF ≥
- •RHI \> 4 (at screening endoscopy).
- •Disease extent \>15 cm from the anal verge (at screening endoscopy).
- •Elevated level(s) of C-reactive protein (CRP) and/or faecal calprotectin during the screening period (levels above the reference range, measured by local laboratories).
Exclusion Criteria
- •General health and UC:
- •Diagnosis of CD, microscopic colitis, ischaemic colitis, radiation colitis or indeterminate colitis.
- •Infectious colitis, diverticulitis or segmental colitis associated with diverticulosis (SCAD) within the last 6 months before screening.
- •Current or past diagnosis of complex fistulae, intra-abdominal or peritoneal abscesses, strictures with obstructive symptoms.
- •Severe UC disease activity (modified Mayo score \>7).
- •Severe extraintestinal manifestations of UC requiring special treatment.
- •Steroid-dependent or steroid-refractory UC.
- •Foreseeable need for hospitalisation.
- •Previous colonic surgery, except for appendectomy.
- •Stools positive for enteric pathogens; Clostridium difficile toxin (CDT)-positive infection; indications for other relevant infections including cytomegalovirus colitis, each at screening.
Arms & Interventions
Low-Dose (2 g/d CICR-NAM (blinded))
To maintain blinding for patients and investigators in the induction and maintenance treatment, all patients self-administer 6 tablets per day. In the low-dose arm, subjects receive 4 tablets of verum CICR-NAM and 2 tablets of placebo CICR-NAM per day, resulting in a total daily intake of 2 g/d CICR-NAM
Intervention: Low-Dose CICR-NAM
High-Dose (3 g/d CICR-NAM (blinded))
To maintain blinding for patients and investigators in the induction and maintenance treatment, all patients self-administer 6 tablets per day. In the high-dose arm, subjects receive 6 tablets of verum CICR-NAM and 0 tablets of placebo CICR-NAM per day, resulting in a total daily intake of 3 g/d CICR-NAM
Intervention: High-Dose CICR-NAM
Placebo (0 g/d CICR-NAM (blinded))
To maintain blinding for patients and investigators in the induction and maintenance treatment, all patients self-administer 6 tablets per day. For the placebo arm, subjects receive 0 tablets of verum CICR-NAM and 6 tablets of placebo CICR-NAM per day, resulting in a total daily intake of 0 g/d CICR-NAM
Intervention: 0 g/d CICR-NAM (blinded)
Open-Label (3 g/d CICR-NAM (blinded))
Patients that have completed the induction period and show worsening of disease activity at the end of the induction period will be allowed to switch to the open-label arm to receive 6 tablets of verum CICR-NAM of 0 tablets of placebo CICR-NAM per day, resulting in a total daily intake of 3 g/d CICR-NAM
Intervention: Open-Label
Outcomes
Primary Outcomes
Symptomatic remission
Time Frame: Baseline - Week 12
The proportion of subjects that show symptomatic remission. Symptomatic remission is achieved if: Mayo SF = 0 or 1 (and SF no greater than baseline) and Mayo RB = 0 as well as a reduction from Mayo ES = 2 or 3 at baseline by at least one point or a reduction from Mayo ES = 1 at baseline to Mayo ES = 0 or, in case of a constant Mayo ES = 1 from baseline, an objective second marker of improvement (histologic improvement to RHI ≤ 4)
Clinical remission
Time Frame: Baseline - Week 52
The proportion of subjects that show clincial remission. Clinical remission is achieved if: Mayo SF = 0 (or SF = 1 with a ≥ 1-point decrease from baseline), Mayo RB = 0, and Mayo ES ≤ 1 (excluding friability) (for constant Mayo ES = 1 from baseline, histologic improvement to RHI ≤ 4)