Double-blind, randomised, placebo-controlled phase I trial with single-ascending and multiple-ascending dose to evaluate safety and pharmacokinetics of oral controlled-ileocolonic-release nicotinamide (CICR-NAM) compared to immediate-release nicotinamide and placebo in healthy subjects and in patients with inflammatory bowel diseases.

Nicotinamide (NAM) has been implicated in the restoration and maintenance of a healthy gut microbiome. Conventional NAM formulations are designed for systemic NAM supplementation and therefore release NAM in the stomach and upper small intestine for maximum absorption. In contrast, the novel CICR-NAM tablets (controlled-ileocolonic-release nicotinamide) start releasing in the lower small intestine for topical delivery of NAM to the microbiota and the mucosa in the ileum and colon, also leading to a reduced systemic exposure. This clinical Phase I trial investigates the safety and tolerability of CICR-NAM in single- and multiple-ascending doses (1, 2 and 4 g). At the beginning of the trial, single-dose pharmacokinetics (PK) of 1 g of conventional immediate-release NAM and CICR-NAM are compared. At the end of the trial, patients with inflammatory bowel diseases (IBD) receive a medium multiple dose (2 g for 4 weeks) to compare their exposure, PK and safety data with those of healthy subjects at the same dose level.

Main inclusion and exclusion criteria

Inclusion criteria for the SAD and MAD parts with healthy subjects:

1. Male and female subjects aged 18 to 75 years.
2. Healthy subjects without relevant medical conditions.
3. Ability to understand and comply with the protocol.
4. Signed written Informed Consent.
5. A BMI of 18.5 to 29.99 kg/m².
6. Non-smoker or light smoker (average of <7 cigarettes per week) and no history of longterm, heavy smoking (>10 pack-years).

Inclusion criteria for the MD-IBD part:

1. Male and female patients with IBD and 18 to 75 years of age.
2. Ability to understand and comply with the protocol.
3. Signed written Informed Consent.
4. Documented diagnosis of relapsing ileal, ileocolonic or colonic Crohn disease or relapsing ulcerative colitis.
5. Concomitant therapy (background medication) for inflammatory bowel disease: none or stable 8 weeks before baseline.
6. No signs of malignancy.

Exclusion criteria for the SAD and MAD part with healthy subjects:

1. Pre-existing relevant medical conditions.
2. Clinically relevant abnormal findings in medical history or screening assessments.
3. Participation in a clinical study.
4. Use of any prescribed or over-the-counter medication, food supplements or herbal preparations.
5. Use of antibiotics (systemic or gut-acting [non-absorbed]).
6. Pregnant or breastfeeding women or women of childbearing potential and male participants with female partners of childbearing age not using highly effective contraception till at least 1 month after last dosing of investigational medicinal product (IMP).
7. Legal incapacity.
8. Indications that the patient may be unable to comply with the study procedures, e.g. language barriers precluding adequate understanding or cooperation

Exclusion criteria for the MD-IBD part:

1. Diagnosis of indeterminate colitis, microscopic colitis, ischaemic colitis, infectious colitis, radiation colitis or diverticular disease (except for diverticles accompanying CD).
2. Current or past diagnosis of complex fistulae or intra-abdominal or peritoneal abscesses.
3. Strictures with obstructive symptoms.
4. Pregnant or breastfeeding women or women of childbearing potential and male participants with female partners of childbearing age not using highly effective contraception till at least 1 month after last dosing of investigational medicinal product (IMP).
5. Legal incapacity.
6. Indications that the patient may be unable to comply with the study procedures, e.g. language barriers precluding adequate understanding or cooperation