Safety and Pharmacokinetics of Oral Controlled-ileocolonic-release Nicotinamide (CICR-NAM)

A Phase I, Double-blind, Randomised, Placebo-controlled, Single-ascending and Multiple-ascending Dose Trial 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

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.

Study Overview

• Status: Completed
• Conditions: Safety Issues; Pharmacokinetic
• Intervention / Treatment: Drug: controlled-ileocolonic-release nicotinamide (SAD/MAD/MD); Drug: Immediate-release nicotinamide (SAD); Drug: Placebo controlled-ileocolonic-release nicotinamide (SAD/MAD); Drug: Placebo Immediate-release nicotinamide (SAD)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Kiel, Germany
    • University Medical Center Schleswig-Holstein

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: healthy subjects; healthy subjects (single-ascending and multiple-ascending doses)	Drug: controlled-ileocolonic-release nicotinamide (SAD/MAD/MD); single- and multiple-ascending dose (SAD/MAD) or multiple dose (MD); Other Names: CICR-NAM (SAD/MAD/MD); Drug: Immediate-release nicotinamide (SAD); single-ascending dose (SAD); Other Names: ImR-NAM (SAD); Drug: Placebo controlled-ileocolonic-release nicotinamide (SAD/MAD); single- and multiple-ascending dose (SAD/MAD); Other Names: no active substance; Drug: Placebo Immediate-release nicotinamide (SAD); single-ascending dose (SAD); Other Names: no active substance
Experimental: IBD-patients; inflammatory bowel disease patients (multiple dose)	Drug: controlled-ileocolonic-release nicotinamide (SAD/MAD/MD); single- and multiple-ascending dose (SAD/MAD) or multiple dose (MD); Other Names: CICR-NAM (SAD/MAD/MD)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-Emergent Adverse Events [Safety and Tolerability]	Adverse Events (AEs) during treatment period	up to 60 days
Treatment-Emergent Serious Adverse Events [Safety and Tolerability]	Serious Adverse Events (SAEs) during treatment period	up to 60 days
Haemoglobin	Haemoglobin (Hb) in %	up to 60 days
White blood cells	White blood cell (WBC) count as x10^9/l	up to 60 days
Blood creatinine	Blood Creatinine in mmol/L	up to 60 days
Blood urea	Urea in mmol/L	up to 60 days
Blood uric acid	Uric acid in mmol/L	up to 60 days
Glomerular filtration rate	Glomerular filtration rate (GFR, automatically calculated by the laboratory based on creatinine values) GFR in ml/min/1.73m2	up to 60 days
Blood ALT	Alanine transaminase (ALT) in U/l	up to 60 days
Blood AST	Aspartate transaminase (AST) in U/l	up to 60 days
Blood GGT	Gamma glutamyl transferase (GGT) in U/l	up to 60 days

Collaborators and Investigators

• Sponsor: University Hospital Schleswig-Holstein
• Investigators: Principal Investigator: Susanna Nikolaus, Prof. Dr., University Medical Center Schleswig-Holstein, Campus Kiel

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2020
• Primary Completion (Actual): March 30, 2022
• Study Completion (Actual): March 30, 2022

Study Registration Dates

• First Submitted: August 19, 2021
• First Submitted That Met QC Criteria: February 16, 2022
• First Posted (Actual): February 28, 2022

Study Record Updates

• Last Update Posted (Actual): November 8, 2022
• Last Update Submitted That Met QC Criteria: November 5, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Inflammatory Bowel Disease; Nicotinamide
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: CICR-NAM; 2020-002815-23 (EudraCT Number); DRKS00023384 (Registry Identifier: DRKS - German Clinical Trials Register)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No