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
- Conditions
- This is a phase I clinical trial which includes only healthy subjects and subjects with prediabetes.
- Registration Number
- DRKS00030865
- Lead Sponsor
- niversitätsklinikum Schleswig-Holstein, Campus Kiel
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- All
- Target Recruitment
- 66
Healthy subjects (SAD and MAD parts):
2. Healthy subjects without relevant medical conditions; the following criteria have to be fulfilled at screening and baseline assessment:
(a) heart rate: heart rate of 45 to 99 bpm (heart rate <50 and =45 bpm is acceptable in case of normal thyroid function and no signs of diseases associated with bradycardia),
(b) blood pressure: diastolic blood pressure of 65 to 89 mmHg and systolic blood pressure of 100 to 139 mmHg, (c) Electrocardiogram (ECG): QTcF interval of 370 to 430 ms (males) or 370 to 460 ms (females) (first-degree atrioventricular (AV) block is acceptable if heart rate complies with the inclusion criteria and is not interpreted as a sign of cardiac dysfunction/disease),
(d) relevant hepatic parameters that do not exceed the upper limit of normal (ULN*): alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (AP) and bilirubin (except in case of Gilbert’s disease),
(e) relevant renal parameters that do not exceed ULN*: creatinine and estimated glomerular filtration rate (GFR) (in clinical context with creatinine) and
(f) relevant blood count parameters that do not exceed ULN*:
haemoglobin, platelet count and white blood cell count.
*The upper limit of normal is defined by age- and sex-specific
reference limits according to local laboratory routine.
3. Ability to understand and comply with the protocol
4. Signed written Informed Consent
5. A body mass index (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 long-term, heavy smoking (>10 pack-years)
Subjects with prediabetes (MD-PreD part):
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 (based on evaluation of medical history and screening assessments) 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 long-term, heavy smoking (>10 pack-years).
Healthy subjects and subjects with PreD
1. Clinically relevant abnormal findings in medical history or screening assessments which, in the opinion of the Investigator, may put the subject at risk when participating in the study or provide difficulties in interpreting the study data
2. Current or history of malignancy except for completely resected basal cell carcinoma and squamous cell carcinoma of the skin
3. History of severe allergy or anaphylactic reactions
4. Known hypersensitivity to any component of the NA or placebo
formulations
5. Participation in a clinical study within 4 weeks prior to enrolment in this study or intake of an IMP within the last 8 weeks or 5 half-lives (whichever is longer) prior to the first dose of IMP (or longer if necessary, as judged by the Investigator)
6. Use of any prescribed or over-the-counter medication, food supplements or herbal preparations within 2 weeks prior to the first dose of IMP. Paracetamol, topical allergy medicines and oral contraceptives according to label are allowed
7. Use of antibiotics (systemic or gut-acting [non-absorbed]) within
8 weeks prior to the first dose of IMP
8. Alcohol or drug abuse within the last 2 years
9. Blood donation or major blood loss (= 500 mL) within the last 3 months prior to the first dose of IMP
10. Pregnant or breastfeeding women
11. Women of childbearing potential (WoCBP) not using highly effective contraception till at least 1 month after last dosing of IMP
12. Male participants with female partners of childbearing potential not willing to use a condom during intercourse and to have their female partners use a highly effective contraception till at least 1 month after last dosing of IMP
13. Legal incapacity
14. Indications that the subject may be unable to comply with the study procedures, e.g. language barriers precluding adequate understanding or cooperation
15. Any circumstances which could contradict a study participation and lead the Investigator to assess the subject as unsuitable for study participation for any other reason
16. Findings in the screening ileocolonoscopy which could interfere with the assessment of local tolerability or require therapeutic or preventive intervention like polypectomy (only in the highest MAD dose group)
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Safety evaluation based on AEs, SAEs, laboratory assessments (haematology, clinical chemistry), physical examination, vital signs, ECG, and local tolerability assessed by ile-ocolonoscopy with serial biopsies (only in the highest MAD dose group)
- Secondary Outcome Measures
Name Time Method • Pharmacokinetics of NA and its main metabolites Nicotinamide (NAM), N-methylnicotinamide (NMN), N-methyl-2-pyridone-5-carboxamide (2-Py) and Nicotinuric Acid NUA in plasma <br>• Relative bioavailability of CIR-NA compared to ImR-NA <br>• Dose-depending bioavailability of CIR-NA after single doses and multiple doses <br>• Comparison of PK and bioavailability of CIR-NA in healthy subjects and in subjects with prediabetes. <br>• Changes in urine concentrations of NA and its main metabolites NAM, NMN, 2-Py and NUA