Pharmacodynamics and Pharmacokinetics of Different Glucose Bead Formulations in Obese Healthy Subjects

Overview

The goal of this clinical study was to assess pharmacodynamics (PD) and pharmacokinetics (PK) of different Glucose beads formulations in obese healthy subjects under fasting condition. The study was designed in 2 parts. Part 1 (single-dose) of the study was randomized, open label, five-treatment, five-period, five-sequence, crossover and single-centric. Treatment arms were three dosages of a coated Glucose beads formulation (47% w/w glucose/bead; 8 g \[T1\], 12 g \[T2\] and 16 g glucose \[T3\]), one uncoated Glucose beads formulation (47% w/w glucose/bead; 12 g glucose \[T4\]) and one coated Glucose beads formulation (60% w/w glucose/bead;12 g glucose \[T5\]). Part 2 (multiple-dose) of the study was open label, one-treatment, one-period and single-centric. Treatment arm was coated Glucose beads formulation (12 g glucose \[T2\]).

Twenty healthy obese subjects were planned for this study. Eligible subjects fulfilling the inclusion/ exclusion criteria and who had willing to give their informed consent were enrolled for screening examination and, if found eligible, enrolled in the study. Before each hospitalization, on day -1, subjects with Real-Time Reverse Transcription-Polymerase Chain Reaction (rRT-PCR) tested negative for the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus were hospitalized. At the hospitalization examination physical examinations (weight), vital signs, pregnancy test for female subjects, alcohol breath test, as well as a check of adverse events, inclusion and exclusion criteria and restrictions were performed. Subjects were admitted to the clinical site at least 13 hours prior to the administration of investigational product in each treatment period. During each treatment period the hospitalization period in the clinical unit was 13 hours before and up to 11 hours after investigational product administration. Part 1: Single dose After an overnight fasting of at least 10 hours the subjects was administered either 8 g glucose (T1), 12 g glucose (T2), 16 g glucose (T3) of the coated Glucose beads formulation (47%), the uncoated Glucose beads formulation (T4) containing 12 g glucose (47%) or the coated Glucose beads formulation (60% w/w glucose/bead; 12 g glucose \[T5\]) starting at 8:00 (time 0; administration time was staggered beginning at 8:00 for the first group of subjects) in sitting position. 17 blood samples was drawn for determination of glucagon-like polypeptide 1 (GLP-1) levels at the prescribed times pre-dose (-1.0 h, -0.5 and 0.0 h \[within 5 minutes\]) and 0.5, 1.0, 1.5. 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0. 5.5, 6.0, 8.0 and 10.0 hours after investigational product administration. A fraction of one pre-dose sample (-1.0 h) before investigational product administration in treatment period I was also used to determine circulating concentration of microRNA (miRNA) 1983. One additional blood sample was drawn pre-dose (-1.0 h) before investigational product administration in treatment period I for determination of adiponectin level. Fractions of the blood samples was also used to determine circulating concentrations of 13 diabetes and obesity related hormones and inflammatory proteins (amylin c-peptide, ghrelin, gastric inhibitory polypeptide \[GIP\], GLP-1, glucagon, interleukin-6 \[IL-6\], insulin, leptin, monocyte chemoattractant protein-1 \[MCP-1\], pancreatic polypeptide \[PP\], peptide tyrosine tyrosine \[PYY\], tumor necrosis factor alpha \[TNFa\]) with formulation T3 (16 g glucose). Part 2: Multiple dose After an overnight fasting of at least 10 hours, the subjects were administered the new developed Glucose beads formulation containing 12 g glucose starting at 8:00 (time 0: administration time was be staggered beginning at 8.00 for the first group of subjects) in sitting position for the 3 days. Standard meals were provided 0.5 h (morning meal), 4.5 h (mid-day meal) and 10 h (evening meal) after investigational product administration. Blood samples were drawn for determination of GLP-1 levels before (-1.0 h, -0.5 h and 0 h \[within 5 minutes\]) each investigational product administration (total 9 samples) on each day. Venous blood glucose measurement was performed before each investigational product administration (total 3 samples). On Day 4, after an overnight fasting of at least 10 hours the subjects were administered the Glucose beads formulation containing 12 g glucose starting at 8:00 (time 0; administration time was staggered beginning at 8:00 for the first group of subjects) in sitting position. 17 blood samples were drawn for determination of GLP-1 levels at the prescribed times pre-dose (-1.0 h, -0.5 h and 0 h \[within 5 minutes\]) and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0 and 10.0 hours after investigational product administration. A fraction of one blood sample (10.0 h) was also used to determine circulating concentrations of miRNA1983. One additional blood sample was drawn (10.0 h) for determination of adiponectin level. Fractions of the blood samples was also used to determine circulating concentrations of 13 diabetes and obesity related hormones and inflammatory proteins (amylin c-peptide, ghrelin, GIP, GLP-1, glucagon, IL-6, insulin, leptin, MCP-1, PP, PYY, TNFa). Follow-up Within 7 days after last blood sampling in the last treatment period, 12-lead ECG, clinical routine laboratory parameters, vital signs (blood pressure, heart rate, body temperature) and physical examination were repeated. Furthermore questioning for subjective well-being and questioning of adverse events was performed. Wash-out periods Wash-out periods of at least 3 days separated the five treatment periods. A wash-out period of at least 3 days separated part 1 (single dose) and part 2 (multiple dose) of the study.