Evaluation of Safety and Pharmacokinetics of Oral Controlled-ileal-release Nicotinic Acid (CIR-NA) Compared to Immediate-release Nicotinic Acid and Placebo in Healthy Subjects and Subjects With Prediabetes

Safety Issues Clinical Trial

Official title:

A Phase I, Double-blind, Randomised, Placebo-controlled, Single-ascending and Multiple-ascending Dose Trial to Evaluate the Safety and Pharmacokinetics of Oral Controlled-ileal-release Nicotinic Acid (CIR-NA) Compared to Immediate-release Nicotinic Acid and Placebo in Healthy Subjects and Subjects With Prediabetes

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06378125
• Other study ID #: CIR-NA I
• Status: Recruiting
• Phase: Phase 1
• Start date: December 19, 2022
• Est. completion date: June 1, 2025

Study information

• Verified date: April 2024
• Source: University Hospital Schleswig-Holstein
• Contact: Corinna Geisler, PhD
• Phone: +4943150022446
• Email: corinna.geisler[@]uksh.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A double-blind, randomised, placebo-controlled, single-ascending and multiple-ascending dose trial to evaluate the safety and pharmacokinetics of oral controlled-ileal-release nicotinic acid (CIR-NA) compared to immediate-release nicotinic acid and placebo in healthy subjects and subjects with prediabetes.

Description:

Recently, administration of one form of vitamin B3, Nicotinamide (NAM), has been shown to improve the host-microbiome interaction in a mouse model, especially when administered in a controlled-release formulation targeting the ileocolic region. Thus, NAM and also the other form of vitamin B3, Nicotinicacid (NA), were identified as promising candidates for a gut-targeted microbiome intervention. As the upper gastrointestinal tract efficiently absorbs amino acids and vitamins, simply increasing the NA and/or NAM content in human food would not be expected to deliver these molecules in sufficient amounts into the lower ileum and colon, where most of the microbiota are located. Moreover, adverse effects such as flushing or gastrointestinal symptoms can occur under high and immediately systemically available dosage of NA. Therefore, the novel CIR-NA formulation will be applied to deliver NA to the lower ileum and colon to tar-get the gut microbiome, while largely avoiding systemic exposure, as the terminal ileum and colon have a much lower absorptive capacity than the stomach and upper small intestine. Both in the single- and multiple-ascending (SAD/MAD) part of the study, CIR-NA or placebo tablets will be self-administered orally, with daily doses of 100 mg (1 tablet), 200 mg (2 tablets), 500 mg (5 tablets) or 1,000 mg CIR-NA (10 tablets) or the corresponding amounts of placebo tablets. In the SAD part, an additional dose of 2,000 mg CIR-NA or placebo (20 tablets) will be self-administered.After completion of the SAD and the 200 mg MAD part in healthy subjects, an additional mul-tiple dose part (200 mg/d CIR-NA) in subjects with PreD (MD-PreD part) will start in parallel to the further dose groups of the MAD part.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: June 1, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Main inclusion and exclusion criteria

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

1. Male and female subjects aged 18 to 65 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-Part (subjects with prediabetes):

1. Male and female subjects aged 18 to 65 years.

2. Previously diagnosed prediabetes with confirmation via the HbA1c level (5.7 to < 6.5%) at the screening visit.

3. Subjects without relevant medical conditions and without clinically significant impairment of renal or hepatic function.

4. Ability to understand and comply with the protocol.

5. Signed written Informed Consent.

6. A body mass index of 25 to 40 kg/m², both inclusive .

7. Non-smoker or light smoker (average of <7 cigarettes per week) and no history of longterm, heavy smoking (>10 pack-years). Exclusion criteria for the SAD, MAD and MD part with healthy subjects and subjects with

prediabetes:

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

Related Conditions & MeSH terms

• Glucose Intolerance
• Pharmacokinetic
• Prediabetic State
• Safety Issues

Intervention

Drug:
• controlled-ileal-release nicotinic acid (SAD/ MAD/MD) single- and multiple-ascending dose (SAD/MAD) or multiple dose (MD)
A double-blind, randomised, placebo-controlled, single-ascending and multiple-ascending dose trial to evaluate the safety and pharmacokinetics of oral controlled-ileal-release nicotinic acid (CIR-NA) compared to immediate-release nicotinic acid and placebo in healthy subjects and subjects with prediabetes.
• immediate-release nicotinic acid (SAD)
A double-blind, randomised, placebo-controlled, single-ascending and multiple-ascending dose trial to evaluate the safety and pharmacokinetics of oral controlled-ileal-release nicotinic acid (CIR-NA) compared to immediate-release nicotinic acid and placebo in healthy subjects and subjects with prediabetes.
• Placebo controlled-ileal-release nicotinic acid (SAD/MAD)
A double-blind, randomised, placebo-controlled, single-ascending and multiple-ascending dose trial to evaluate the safety and pharmacokinetics of oral controlled-ileal-release nicotinic acid (CIR-NA) compared to immediate-release nicotinic acid and placebo in healthy subjects and subjects with prediabetes.
• Placebo immediate-release nicotinic acid (SAD)
A double-blind, randomised, placebo-controlled, single-ascending and multiple-ascending dose trial to evaluate the safety and pharmacokinetics of oral controlled-ileal-release nicotinic acid (CIR-NA) compared to immediate-release nicotinic acid and placebo in healthy subjects and subjects with prediabetes.

Locations

Country	Name	City	State
Germany	University Medical Center Schleswig-Holstein, Campus Kiel	Kiel	Schleswig-Holstein

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Schleswig-Holstein

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment-Emergent Adverse Events [Safety and Tolerability]	Adverse Events (AEs) during treatment period	up to 60 days
Primary	Treatment-Emergent Serious Adverse Events [Safety and Tolerability]	Serious Adverse Events (SAEs) during treatment period	up to 60 days
Primary	Haemoglobin	Haemoglobin (Hb) in %	up to 60 days
Primary	White blood cells	White blood cell (WBC) count as x10^9/l	up to 60 days
Primary	Blood creatinine	Blood Creatinine in mmol/L	up to 60 days
Primary	Blood urea	Urea in mmol/L	up to 60 days
Primary	Blood uric acid	Uric acid in mmol/L	up to 60 days
Primary	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
Primary	Blood ALT	Alanine transaminase (ALT) in U/l	up to 60 days
Primary	Blood AST	Aspartate transaminase (AST) in U/l	up to 60 days
Primary	Blood GGT	Gamma glutamyl transferase (GGT) in U/l	up to 60 days