Clinical trial NCT05737927: Pharmacodynamics and Pharmacokinetics of Different Glucose Bead Formulations in Obese Healthy Subjects
Official title: Pharmacodynamics and Pharmacokinetics of Different Coated and Uncoated Formulations of Glucose Beads After Single and Multiple Dose Administration Under Fasting Conditions in Obese Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Obese
Lead sponsor: Aphaia Pharma US LLC
Sponsor class: INDUSTRY
Collaborators: name: NovaClin Medical Research Center S.R.L
name: ACC GmbH Analytical Clinical Concepts
name: SC Bioclinica SA
name: Galephar Pharmaceutical Research (PR), Inc.
First posted: 2023-02-21
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Part 1: randomised, open label, five-treatment, five-period, five-sequence, crossover, at one study site

Part 2: open label, one-treatment, one-period, at one study site
Primary purpose: TREATMENT

Brief summary: 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 \[T2\]).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Healthy obese, Caucasian, male and female subjects 18 - 55 years of age
* Body mass index within the range of \> 30.0 kg/m2
* Waist circumference: men \> 102 cm
* women \> 88 cm
* Female subjects of childbearing potential agree to undergo pregnancy tests and to use an appropriate method of contraception (i.e. oral contraceptive steroids, intrauterine device, barrier method)
* Findings within the range of clinical acceptability in medical history (or the clinical investigator considers the deviation to be irrelevant for the purpose of the study)
* Findings within the range of clinical acceptability in physical examination (or the clinical investigator considers the deviation to be irrelevant for the purpose of the study)
* Laboratory values within the normal range (or the clinical investigator considers the deviation to be irrelevant for the purpose of the study)
* Normal ECG or abnormalities which the clinical investigator does not consider a disqualification for participation in the study
* Normal vital signs (normal blood pressure and heart rate measured under stabilised conditions at screening visit after at least 5 minutes of rest in sitting position) or abnormalities which the clinical investigator does not consider a disqualification for participation in the study
* Normal GI function, or abnormalities which the clinical investigator does not consider a disqualification for participation in the study
* Willingness to undergo screening and follow-up examinations (i.e. physical examinations and laboratory investigations before and after the treatment periods)
* Ability to comprehend subject information and willingness to sign the informed consent

Exclusion Criteria:

* Gastrointestinal, hepatic and renal diseases and/or pathological findings, which might interfere with pharmacokinetics and pharmacodynamics of the investigational product
* Established diagnosis of type-1 or type-2 diabetes mellitus
* Treatment with insulin, insulin secretagogues (sulfonylurea derivatives, glinides, GLP-1 agonists (exenatide, lixisenatide, glutides), or thiazolidinediones (glitazones)
* Unexplained rise in blood glucose
* Treatment for constipation (including but not limited to lactulose or any other form of stool softeners, laxatives) or diarrhea (including but not limited to pectins, loperamide etc.) or any other medication known to interfere with gastrointestinal transit time, such as e.g. metoclopramide, opioids, or gastric potential of hydrogen (pH) (including but not limited to antacids, H2-receptor antagonists, prazoles)
* History of hypersensitivity to the investigational product or any related drugs or to any of the excipients
* History or presence of any clinically significant cardiovascular, pulmonary, hepatobiliary, renal, hematological, gastrointestinal, endocrinologic, immunologic, dermatologic, neurological, psychiatric, metabolic, musculoskeletal, or malignant disease, which the clinical investigator does not consider a disqualification for participation in the study
* Known heart failure (Grade I to IV of New York Heart Association classification)
* Significant renal disease, including nephritic syndrome, chronic renal failure (defined as creatinine clearance \< 60 mL/min and serum creatinine \>180 μmol/L)
* Unexplained serum creatine phosphokinase (CPK) \> 3-times the upper limit of normal (ULN).
* Subjects with a reason for CPK elevation may have the measurement repeated prior to randomization; a CPK retest \> 3-times ULN leads to exclusion.
* Clinically significant abnormal laboratory values
* Clinically significant ECG findings
* Clinically significant vital signs
* Clinically significant illness or surgery within 4 weeks prior to dosing
* Less than 14 days after last acute disease
* Volunteers liable to orthostatic dysregulation, fainting, or blackouts
* History of, or current compulsive alcohol abuse (more than a total of 10 drinks weekly whereby one drink corresponds to 500 ml beer, 200 ml wine or 50 g spirits); or regular exposure to other substances of abuse
* Donation or loss of blood equal to or exceeding 500 ml during 90 days before the first administration of investigational product
* Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) and hepatitis C-virus (HCV)
* Participation in another study with an experimental drug within at least 3 months (or within five elimination half-lives of the previous experimental drug, whichever is longer) before the first administration of investigational product
* Any use of drug, prescribed or over the counter (OTC) (inclusive herbal remedies), within 2 weeks (or within six elimination half-lives of this medication, whichever is longer) prior to the first administration of investigational product except if this will not affect the outcome of the study in the opinion of the clinical investigator
* Pregnant women (positive pregnancy test)
* Lactating women
* Failure to provide informed consent
* Unwillingness or inability to comply with the study protocol or study-related procedures (e.g. difficulty to stay fasting, consume the standard meals, or swallow the beads formulations; difficult venous access)
* Positive result of rRT-PCR test to detect infection with the new SARS-CoV-2 coronavirus

Primary outcomes:
measure: GLP-1
timeFrame: Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Day 1-3:- pre-dose (-1.0 hour, -0.5 hour and 0 hour). Day 4:- Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Day 1-3:- pre-dose (-1.0 hour, -0.5 hour and 0 hour). Day 4:- Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
measure: GLP-1
timeFrame: Day 1-3:- pre-dose (-1.0 hour, -0.5 hour and 0 hour). Day 4:- Pre-dose (-1.0 hour, -0.5 hour and 0 hour [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.
Secondary outcomes:
measure: Glucose levels
timeFrame: Pre-dose (-1.0 hour, 0 hour [within 5 minutes]) and 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0 and 10.0 hours after investigational product administration.
measure: Glucose levels
timeFrame: Pre-dose (-1.0 hour, 0 hour [within 5 minutes]) and 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0 and 10.0 hours after investigational product administration.
measure: Glucose levels
timeFrame: Day 1- Day 3:- Pre-dose (3 samples). Day 4:- Pre-dose (-1.0 hour, 0 hour [within 5 minutes]) and 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0 and 10.0 hours after investigational product administration.
measure: Glucose levels
timeFrame: Day 1- Day 3:- Pre-dose (3 samples). Day 4:- Pre-dose (-1.0 hour, 0 hour [within 5 minutes]) and 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0 and 10.0 hours after investigational product administration.
measure: Visual analogue scale appetite
timeFrame: Pre-dose (0 hour) and 2, 3, 4, 5, 6, 8 and 10 hours after investigational product administration.
measure: Visual analogue scale stomach rumbles
timeFrame: Pre-dose (0 hour) and 2, 3, 4, 5, 6, 8 and 10 hours after investigational product administration.
Other outcomes:
Locations:
city: Timisoara
country: Romania
facility: NovaClin Medical Research Center S.R.L
Study officials:
affiliation: NovaClin Medical Research Center S.R.L
name: Carmen Vizman
role: PRINCIPAL_INVESTIGATOR
References: