A Multiple Dose, Randomized, Placebo-controlled, Dose-escalating Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered MD-18 for healthy subjects with overweight or obesity
This study will be conducted as a single center study, at the Sheba Medical Center, Israel. Escalating daily doses of MD-18 or placebo will be administered subcutaneously to each subject over a 4-week period with a 7-day follow-up period. 54 patients will be enrolled across 7 cohorts. Each of the cohorts will enroll 4 active and two placebo subjects, except for the final cohort. Cohort 7 will be comprised of obese subjects and will enroll 12 active and 6 placebo subjects. Starting dose has been determined from the SAD study (CG MD-18-01). Cohorts will receive 74 mg MD-18 three times weekly, (starting dose), 114 mg three times weekly, 227 mg three times weekly, 302 mg once weekly, 302 mg three times weekly or 302 mg daily using 4:2 (active:placebo) randomization; all doses refer to the MD-18 salt. A total of 36 subjects will receive active therapy across seven cohorts (24 in the first six cohorts and 12 in the seventh cohort) and 18 subjects will receive placebo. The study will be conducted on an outpatient basis, with visits performed as shown in the schedule of events.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
54
Sheba Medical Center
Ramat Gan, Please Select, Israel
RECRUITINGTo determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of Adverse events.
All adverse events, exacerbations of concomitant illnesses, or events known to be related to underlying disease processes or concomitant medications are to be recorded on the case report form throughout the study. Should there be more than 2 subjects receiving MD-18 with an adverse event grade 4 or 5 that is at least possibly related to MD-18, the study will be put on immediate hold and the data will be reviewed by the site Principal Investigator (PI) and the company Chief Medical Officer (CMO) before proceeding.
Time frame: Through study completion, an average of 8 months
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of body temperature.
Body temperature measurements in Celsius (°C) will be conllected at the visits specified in the study protocol's Schedule of Events. If any clinically significant findings or machine/equipment errors occur, the measurement will be repeated. Any confirmed clinically significant result will be recorded as adverse events (AEs).
Time frame: During the following study visits: Screening, Day 1,7,14,21,28 and 35) and at the study visits of the 8 weeks study extension period on days 42,56,70,84 and 92 (Only for subjects that have agreed to participate from Cohort 7)
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of Serum chemistry.
Collection of blood samples for serum chemistry
Time frame: During the screening visit, Day 1, 7,28,35 and at the study visits of Day 56,84 and 92 at the 8 weeks study extension period (Only for subjects that have agreed to participate from Cohort 7).
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of body weight
Body weight (in kilograms) will be measured. To ensure consistency and accuracy, all subjects will be measured while wearing only undergarments or light clothing, without shoes. A calibrated scale will be used consistently throughout the study. In addition, weight measurements along with the screening height measurement will be combined to report BMI in kg/m\^2
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Time frame: During each study visit and at the study visits of the 8 weeks study extension period (Only for subjects that have agreed to participate from Cohort 7)
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of Electrocardiogram examination.
12-lead triplicate ECGs will be obtained. The ECG machine will automatically calculate the following: Heart rate ( refers to the number of contractions of the heart per minute) PR interval (PR interval is the time from the beginning of the P wave (atrial depolarization) to the beginning of the QRS complex. QRS complex (represents the depolarization of ventricles And the beginning of systole and ventricular contraction). QT interval (is the time from the beginning of the QRS complex, representing ventricular depolarization, to the end of the T wave, resulting from ventricular repolarization). QTc interval (is the QT interval corrected for heart rate).
Time frame: at screening (visit 1; Day -7) and days 7, 28 and 35. On Day 92 (for the 8 weeks extension period Only for subjects that have agreed to participate from Cohort 7).
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of respiration rate
Respiration rate in breaths per minute will be collected at the visits specified in the study protocol's Schedule of Events. If any clinically significant findings or machine/equipment errors occur, the measurement will be repeated. Any confirmed clinically significant result will be recorded as adverse events.
Time frame: During the following study visits: Screening, Day 1,7,14,21,28 and 35) and at the study visits of the 8 weeks study extension period on days 42,56,70,84 and 92 (Only for subjects that have agreed to participate from Cohort 7)
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of heart rate
Heart rate in beats per minute will be collected at the visits specified in the study protocol's Schedule of Events. If any clinically significant findings or machine/equipment errors occur, the measurement will be repeated. Any confirmed clinically significant result will be recorded as adverse events.
Time frame: During the following study visits: Screening, Day 1,7,14,21,28 and 35) and at the study visits of the 8 weeks study extension period on days 42,56,70,84 and 92 (Only for subjects that have agreed to participate from Cohort 7)
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of systolic and diastolic blood pressure
Systolic and diastolic blood pressure in millimeters of mercury (mmHg) will be collected at the visits specified in the study protocol's Schedule of Events. If any clinically significant findings or machine/equipment errors occur, the measurement will be repeated. Any confirmed clinically significant result will be recorded as adverse events.
Time frame: During the following study visits: Screening, Day 1,7,14,21,28 and 35) and at the study visits of the 8 weeks study extension period on days 42,56,70,84 and 92 (Only for subjects that have agreed to participate from Cohort 7)
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of Hematology blood test
Collection of Hematology blood test
Time frame: During the screening visit, Day 1, 7,28,35 and at the study visits of Day 56,84 and 92 at the 8 weeks study extension period (Only for subjects that have agreed to participate from Cohort 7).
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of coagulation panel
Collection of blood samples for coagulation panel.
Time frame: During the screening visit, Day 1, 7,28,35 and at the study visits of Day 56,84 and 92 at the 8 weeks study extension period (Only for subjects that have agreed to participate from Cohort 7).
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of Urine analysis
Collection of urine samples for Urine analysis
Time frame: During the screening visit, Day 1, 7,28,35 and at the study visits of Day 56,84 and 92 at the 8 weeks study extension period (Only for subjects that have agreed to participate from Cohort 7).
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of height
Height (in centimeters) will be collected only at the screening visit and will be combined with the body weight measurements in order to calculate the body mass index (BMI) in kg/m2. A calibrated scale will be used consistently throughout the study.
Time frame: At the study screening visit (Day -28 to day -1 Pre-Treatment)
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of pharmacokinetic for Area Under the Curve (AUC) analysis
Plasma samples will be collected for the pharmacokinetic analysis of Area Under the Curve (AUC) for various time intervals: AUC0-1h, AUC0-2h, AUC0-4h, AUC0-12h, AUC0-24h, and AUCinf. Pharmacokinetic parameters will be summarized using descriptive statistics at each scheduled assessment time point.
Time frame: Before dose administration and at 0.5, 1, 2, 4, and 8 hours after dose administration on Days 1 and 28 of each dose level.
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of pharmacokinetic for Maximum concentration of MD-18 (Cmax) analysis
Plasma samples will be collected for the pharmacokinetic analysis of Maximum concentration of MD-18 (Cmax).
Time frame: Before dose administration and at 0.5, 1, 2, 4, and 8 hours after dose administration on Days 1 and 28 of each dose level.
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of pharmacokinetic for Minimum concentration of MD-18 between doses (Cmin) analysis
Plasma samples will be collected for the pharmacokinetic analysis of inimum concentration of MD-18 between doses (Cmin). Pharmacokinetic parameters will be summarized using descriptive statistics at each scheduled assessment time point.
Time frame: Before dose administration and at 0.5, 1, 2, 4, and 8 hours after dose administration on Days 1 and 28 of each dose level.
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of Plasma samples for the pharmacokinetics analysis of Time to reach maximum concentration
Plasma samples will be collected for the pharmacokinetic analysis of Time to reach maximum concentration of MD-18 (Tmax). Pharmacokinetic parameters will be summarized using descriptive statistics at each scheduled assessment time point.
Time frame: Before dose administration and at 0.5, 1, 2, 4, and 8 hours after dose administration on Days 1 and 28 of each dose level.
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of pharmacokinetic for the analysis of Half-life (t½)
Plasma samples will be collected for the pharmacokinetic analysis of the study drug MD-18 Half-life (t½). Pharmacokinetic parameters will be summarized using descriptive statistics at each scheduled assessment time point.
Time frame: Before dose administration and at 0.5, 1, 2, 4, and 8 hours after dose administration on Days 1 and 28 of each dose level.
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of Plasma samples for pharmacokinetics analysis of clearance rate (CL/F)
Plasma samples will be collected for the pharmacokinetic analysis of the study drug MD-18 clearance rate (CL/F). Pharmacokinetic parameters will be summarized using descriptive statistics at each scheduled assessment time point.
Time frame: Before dose administration and at 0.5, 1, 2, 4, and 8 hours after dose administration on Days 1 and 28 of each dose level.
To determine the safety and tolerability multiple subcutaneous doses of MD-18 in overweight or obese but otherwise healthy subjects, as assessed by the collection of Plasma samples for the pharmacokinetics analysis of volume of distribution (V/F)
Plasma samples will be collected for the pharmacokinetic analysis of the study drug MD-18 volume of distribution (V/F). Pharmacokinetic parameters will be summarized using descriptive statistics at each scheduled assessment time point.
Time frame: Before dose administration and at 0.5, 1, 2, 4, and 8 hours after dose administration on Days 1 and 28 of each dose level.