A Phase 1b Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Doses of JNJ-64565111 in Participants With Type 2 Diabetes Mellitus

An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.

Maximum observed serum concentration (Cmax) of JNJ-64565111 will be assessed.

Actual sampling time to reach maximum observed serum concentration (Tmax) of JNJ-64565111 will be assessed.

The AUC (0-last) of JNJ-64565111 is the area under the serum concentration-time curve from time zero to last quantifiable time.

Average concentration over the dosing interval tau at steady state of JNJ-64565111 (defined as area under the serum concentration time curve observed during a dosing interval (tau) at steady state) will be calculated as AUC(0- T)/T.

Minimum observed serum concentration (Cmin) of JNJ-64565111 will be assessed.

Accumulation ratio of JNJ-64565111, calculated as AUC(0-T), Day 22 / AUC(0-T), Day 1 will be assessed after last dose.

The AUC (0-T) of JNJ-64565111 is the measure of the serum drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption.

Apparent terminal elimination half-life of JNJ-64565111, calculated as 0.693/apparent terminal elimination rate constant (Lambda[z]).

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after subcutaneous (SC) dose (apparent SC clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F will be calculated as CL/F = Dose/AUC [0-infinity].

Apparent volume of distribution of JNJ-64565111 is based on the terminal phase following subcutaneous administration calculated as Vd/F = Dose/ apparent terminal elimination rate constant (Lambda[z])*AUC [0-infinity].

Terminal rate constant of JNJ-64565111 is defined as the fraction of drug that is eliminated per unit of time (fraction/hour).

Immunogenicity will be measured by evaluating serum samples collected from participants. Serum samples will be screened for antibodies binding to JNJ-64565111. The titer of confirmed positive samples will be reported.

Body weight will be measured using a calibrated scale at each time a participant is weighed. Calibration must be documented in a calibration log.

Change from baseline in fasting plasma glucose (FPG) will be assessed.

Change from baseline in HbA1c will be assessed.

Fasting plasma lipids were measured to determine the total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL cholesterol, very low-density lipoprotein cholesterol (VLDL-C), triglycerides and free fatty acids to understand the potential impact of study drug on cardiovascular disease risk.

Mean plasma glucose defined as the total and/or incremental (that is, baseline-subtracted) area under the concentration (AUC) time curve over 0 to 24 hours, divided by 24.

MMTT-Stimulated 6-Hour C-peptide AUC is the mean area under the C-peptide level-time curve over the 6-hour period divided by the duration after a mixed-meal tolerance test.

MMTT-Stimulated 6-Hour total and/or incremental plasma glucose AUC is the mean area under the total and/or incremental plasma glucose level-time curve over the 6-hour period divided by the duration after a mixed-meal tolerance test.

MMTT-Stimulated 6-Hour Insulin AUC is the mean area under the insulin level-time curve over the 6-hour period divided by the duration after a mixed-meal tolerance test.

MMTT-Stimulated 6-Hour Glucagon AUC is the mean area under the glucagon level-time curve over the 6-hour period divided by the duration after a mixed-meal tolerance test.

Blood Pressure will be assessed by 24-hour ambulatory blood pressure and heart rate monitoring (ABPM) device by periodic measurements performed at 1 hour intervals for the first 14 hours, then at 2-hour intervals for the remaining 10 hours (that is, 19 measurements in total).

Heart rate measurements will be assessed with a completely automated (ambulatory blood pressure and heart rate monitoring) device.

Body Mass Index (BMI) is calculated by dividing the body weight (in kilogram) by the square of height (in meters).

Insulin secretion will be assessed by the insulinogenic index (Insulin 30-Insulin 0)/(Glucose 30-Glucose 0), by measuring the ratio of insulin to glucose. The insulinogenic index is frequently used as a measure of beta cell function.

HOMA is used to quantify insulin resistance and beta-cell function from basal (fasting) glucose and insulin (or C-peptide) concentrations. HOMA-B will be calculated by 20*I/(G-3.5) where I is fasting plasma insulin (micro units/per milliliter [uU/mL]) and G is fasting plasma glucose (millimoles per liter [mmol/L]).

The Matsuda index represents a composite of both hepatic and peripheral tissue sensitivity to insulin. Insulin sensitivity by Matsuda Index will be calculated by (10,000/square root of [fasting glucose * fasting insulin] * [mean glucose * mean insulin during oral glucose tolerance test [OGTT]).

Insulin sensitivity will be assessed by Homeostasis Model Assessment (HOMA-%S) where HOMA-%S is 100/HOMA-Insulin Resistance [IR]. The HOMA-IR is the product of the blood Glucose and Insulin levels, divided by a constant. HOMA-IR is expressed as the following: HOMA-IR = fasting serum insulin (uU/mL) * fasting plasma glucose (mmol/L) / 22.5.