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

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

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.

Study Overview

• Status: Completed
• Conditions: Safety Issues; Pharmacokinetic
• Intervention / Treatment: Drug: controlled-ileal-release nicotinic acid (SAD/ MAD/MD) single- and multiple-ascending dose (SAD/MAD) or multiple dose (MD); Drug: immediate-release nicotinic acid (SAD); Drug: Placebo controlled-ileal-release nicotinic acid (SAD/MAD); Drug: Placebo immediate-release nicotinic acid (SAD)

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • University Medical Center Schleswig-Holstein, Campus Kiel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

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 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

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 multipleascending doses (SAD/MAD)	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.; Other Names: CIR-NA (SAD/MAD/MD); Drug: 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.; Other Names: ImR-NA (SAD); Drug: 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.; Other Names: no active substance (SAD/MAD); Drug: 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.; Other Names: no active substance (SAD)
Experimental: subjects with prediabetes; multiple dose (MD)	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.; Other Names: CIR-NA (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 19, 2022
• Primary Completion (Actual): November 12, 2024
• Study Completion (Actual): November 12, 2024

Study Registration Dates

• First Submitted: April 17, 2024
• First Submitted That Met QC Criteria: April 19, 2024
• First Posted (Actual): April 22, 2024

Study Record Updates

• Last Update Posted (Estimated): November 27, 2024
• Last Update Submitted That Met QC Criteria: November 25, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Prediabetes; Nicotinic Acid
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Hyperglycemia; Prediabetic State; Glucose Intolerance; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Micronutrients; Vitamin B Complex; Vitamins; Vasodilator Agents; Hypolipidemic Agents; Lipid Regulating Agents; Niacin; Niacinamide; Nicotinic Acids
• Other Study ID Numbers: CIR-NA I

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