Pharmacokinetic, Safety Issues
Conditions
Keywords
Nicotinic Acid, Prediabetes
Brief 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.
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.
Interventions
DRUGcontrolled-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.
DRUGimmediate-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.
DRUGPlacebo 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.
DRUGPlacebo 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.
Sponsors
University Hospital Schleswig-Holstein
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Masking description
Double (Participant, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-Emergent Adverse Events [Safety and Tolerability] | up to 60 days | Adverse Events (AEs) during treatment period |
| Treatment-Emergent Serious Adverse Events [Safety and Tolerability] | up to 60 days | Serious Adverse Events (SAEs) during treatment period |
| Haemoglobin | up to 60 days | Haemoglobin (Hb) in % |
| White blood cells | up to 60 days | White blood cell (WBC) count as x10\^9/l |
| Blood creatinine | up to 60 days | Blood Creatinine in mmol/L |
| Blood urea | up to 60 days | Urea in mmol/L |
| Blood uric acid | up to 60 days | Uric acid in mmol/L |
| Glomerular filtration rate | up to 60 days | Glomerular filtration rate (GFR, automatically calculated by the laboratory based on creatinine values) GFR in ml/min/1.73m2 |
| Blood ALT | up to 60 days | Alanine transaminase (ALT) in U/l |
| Blood AST | up to 60 days | Aspartate transaminase (AST) in U/l |
| Blood GGT | up to 60 days | Gamma glutamyl transferase (GGT) in U/l |
Countries
Germany
Outcome results
None listed