Efficacy and Safety of Oral Controlled-Ileocolonic-Release Nicotinamide (CICR-NAM) in Patients With Mild to Moderately Active Ulcerative Colitis

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.

Inclusion criteria

General:

• 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 ≥ 1.
• 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).
• Full colonoscopy with no signs of malignancy either during screening or within one year before screening.

Medication:

• In the case of no oral 5-ASA therapy within the last 2 weeks before entry into screening with informed consent, any prior oral 5-ASA therapy is permitted and the patient is not allowed to receive 5-ASA during the study. In the case of oral 5-ASA therapy within 2 weeks before entry into screening with informed consent, the 5-ASA therapy should have been ongoing for > 3 months, should not be increased ≥ 4 weeks before screening endoscopy and should remain stable for ≥ 1 week before screening endoscopy at the maximum dose according to label or lower. This 5-ASA baseline medication must be kept stable in the induction period and may be reduced (but not increased again) in the maintenance period. In cases in which 5-ASA is dosed higher than the approved dose, the dose will be adjusted to the maximum approved dose at the time of randomization.

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.
• Current or history of colon carcinoma, high grade colonic dysplasia or other malignancies except for completely resected basal cell carcinoma and squamous cell carcinoma of the skin.
• Moderate to severe anaemia (haemoglobin <9 g/dL) at screening.
• Moderate to severe renal impairment (glomerular filtration rate <60) at screening.
• Relevant bleeding or thrombotic disorders.
• Alcohol or drug abuse within the last 2 years.

Medications:

• Rectal topical 5-ASA and/or rectal budesonide therapy (enemas, foams or suppositories) ≤ 2 weeks prior to screening endoscopy (up to 3 single doses allowed).
• Use of oral corticosteroids and/or oral budesonide ≤ 4 weeks prior to screening endoscopy.
• Previous use of immunosuppressants, Janus kinase inhibitors, sphingoside-1-phosphate receptor modulators or biologics.
• Use of antibiotics for the treatment of UC or probiotic medication within 6 weeks prior to screening endoscopy.
• Any need of parenteral therapies for the therapy of UC (except iron infusions).
• Known hypersensitivity towards any component of the CICR-NAM or placebo tablets.

Regulatory requirements

• Participation in a clinical trial within 4 weeks prior to screening for this trial or intake of an investigational medicinal product (IMP) within the last 8 weeks or 5 half-lives (whichever is longer) prior to screening (or longer if necessary in the investigator's discretion).
• Patients under legal supervision or guardianship, including patients, who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• Patients who are dependent on the investigator or the sponsor.

Other:

• Pregnant or breastfeeding women.
• Women of childbearing potential (WoCBP) not using highly effective contraception till at least 1 month after last dosing of IMP.
• Male participants with female partners of childbearing potential who are not willing to use a highly effective contraception till at least 1 month after last dosing of IMP.
• Indications that the patient may be unable to comply with the trial procedures, e.g. language barriers precluding adequate understanding or cooperation.
• Any circumstances or medical conditions which could contradict a trial participation and lead the investigator to assess the patient as unsuitable for trial participation for any other reason.