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

Primary Purpose

Diabetes Mellitus, Type 2

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

JNJ-64565111

Placebo

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 2

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Diagnosis of type 2 diabetes mellitus (T2DM) at least 3 months prior to Screening
Hemoglobin A1c (HbA1c) greater than or equal to (>=) 7.0 percent (%) and lesser than or equal to (<=)9.5% at Screening
On a stable treatment regimen for at least 3 months prior to Screening of (1) diet and exercise, and/or (2) metformin monotherapy (at a dose of at least 1,000 milligram (mg) per day)
Body mass index (BMI) ranging from 25 to 40 kilogram per square meter (kg/m^2) (inclusive), weighing between 75 and 130 kg (inclusive)
A woman must have a negative highly sensitive serum beta-human chorionic gonadotropin (beta- hCG) at Screening and Day -2
Blood pressure (measured after the participant is sitting/ resting quietly for 5 minutes) between 90 and 140 millimeter of mercury (mmHg) systolic, inclusive, and between 60 and 100 mmHg diastolic, inclusive at Screening (sitting) and Day -2 (supine). If the average of the first triplicate blood pressure assessment is out of range, up to 2 repeated triplicate assessments are permitted

Exclusion Criteria:

History or current diagnosis of acute or chronic pancreatitis
Familial or personal history of multiple endocrine neoplasia type 2,familial/non-familial medullary thyroid carcinoma
Donated blood or blood products or lost a significant amount of blood (>500 milliliter [mL]) within 3 months before the first administration of study drug
History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease, or tests positive for HBsAg or anti-HCV at Screening
History of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV at Screening

Sites / Locations

ProSciento, Inc.
Advanced Pharma CR, LLC

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Cohort 1 to 4: JNJ-64565111 or Placebo

Cohort 5: JNJ-64565111 (Repeat or Lower Dose) or Placebo

Arm Description

Participants in cohort 1 to 4 in a ratio of 4:1 will receive a dose of JNJ-64565111 or placebo subcutaneously on Days 1, 8, 15 and 22. Cohort 1, 2 and 3 will be dosed in parallel. Dosing for subsequent cohort 4 will be escalated based on review by the Sponsor and Principal Investigator of blinded safety, tolerability, pharmacokinetic, and (all available) pharmacodynamic data collected up to Day 29, but will not exceed from well-tolerated dose.

Participants in ratio of 4:1 will receive a dose of JNJ-64565111 or placebo subcutaneously on Days 1, 8, 15 and 22, and may be modified. The dose can be repeated or lower than a dose previously assessed as well tolerated.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events as a Measure of Safety and Tolerability

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.

Secondary Outcome Measures

Maximum Observed Serum Concentration (Cmax)

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

Time to Reach Maximum Observed Plasma Concentration (Tmax)

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

Area Under Concentration-Time Curve From Time Zero to the Last Quantifiable Time (AUC [0-last])

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 (T) at Steady State (Caverage,ss)

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)

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

Accumulation Ratio

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

Area Under Curve over the dosing interval AUC (0-T)

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 (t1/2term)

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

Apparent Clearance (CL/F)

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 (V/F)

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 (Kel)

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

Number of Participants With Anti-JNJ-64565111 Antibodies as Measure of Immunogenicity

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.

Change From Baseline in Body Weight

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)

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

Change From Baseline in Hemoglobin A1c (HbA1c)

Change from baseline in HbA1c will be assessed.

Change From Baseline in Fasting Lipids

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.

Change From Baseline for 24-hour Mean Plasma Glucose

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.

Change From Baseline in C-peptide Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT)

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.

Change From Baseline in Total and/or Incremental Plasma Glucose Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT)

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.

Change From Baseline in Insulin Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT)

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.

Change From Baseline in Glucagon Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT)

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.

Change From Baseline in 24-hour Blood Pressure

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).

Change From Baseline in 24-hour Heart Rate

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

Change From Baseline in Body Mass Index (BMI)

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

Change From Baseline Insulin Secretion as Assessed by the Insulinogenic Index

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.

Change from Baseline in Insulin Secretion as Assessed by Homeostasis Model Assessment of Beta Cell Function (HOMA-%B)

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]).

Change From Baseline in Insulin Sensitivity as Assessed by Matsuda Index

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]).

Change From Baseline in Insulin Sensitivity as Assessed by Homeostasis Model Assessment for Insulin Sensitivity (HOMA-%S)

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.

Full Information

NCT ID

NCT03235219

First Posted

July 28, 2017

Last Updated

April 13, 2023

Sponsor

Janssen Research & Development, LLC

1. Study Identification

Unique Protocol Identification Number

NCT03235219

Brief Title

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

Official Title

A Double-Blind, Randomized, Placebo-Controlled, Multiple Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-64565111 in Men and Women With Type 2 Diabetes Mellitus

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Completed

Study Start Date

August 1, 2017 (Actual)

Primary Completion Date

February 19, 2018 (Actual)

Study Completion Date

February 19, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Janssen Research & Development, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this Phase 1b study is to assess the safety and tolerability of JNJ-64565111 in adult men and women (of non-child bearing potential) with Type 2 Diabetes Mellitus.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus, Type 2

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

39 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1 to 4: JNJ-64565111 or Placebo

Arm Type

Experimental

Arm Description

Arm Title

Cohort 5: JNJ-64565111 (Repeat or Lower Dose) or Placebo

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

JNJ-64565111

Other Intervention Name(s)

Oxyntomodulin

Intervention Description

Participants will receive JNJ-64565111 subcutaneously in the abdomen on Days 1, 8, 15 and 22.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Participants will receive placebo subcutaneously in the abdomen on Days 1, 8, 15 and 22.

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events as a Measure of Safety and Tolerability

Description

Time Frame

Up to Day 72

Secondary Outcome Measure Information:

Title

Maximum Observed Serum Concentration (Cmax)

Description

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

Time Frame

First Dose: Predose (Day 1), and at 8, 24, 48, 72 and 120 hours post-dose (PD); Fourth Dose: predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD.

Title

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Description

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

Time Frame

First Dose: Predose (Day 1), and at 8, 24, 48, 72 and 120 hours post-dose (PD); Fourth Dose: predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD

Title

Area Under Concentration-Time Curve From Time Zero to the Last Quantifiable Time (AUC [0-last])

Description

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

Time Frame

First Dose: Predose (Day 1), and at 8, 24, 48, 72 and 120 hours post-dose (PD)

Title

Average Concentration Over the Dosing Interval Tau (T) at Steady State (Caverage,ss)

Description

Time Frame

Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD

Title

Minimum Observed Serum Concentration (Cmin)

Description

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

Time Frame

Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD

Title

Accumulation Ratio

Description

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

Time Frame

First Dose: Predose (Day 1), and at 8, 24, 48, 72 and 120 hours post-dose (PD); Fourth Dose: predose (Day 22), and at 72, 96, 144, 168 hours PD

Title

Area Under Curve over the dosing interval AUC (0-T)

Description

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.

Time Frame

Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168 hours PD

Title

Apparent Terminal Elimination Half-life (t1/2term)

Description

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

Time Frame

Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD

Title

Apparent Clearance (CL/F)

Description

Time Frame

Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD

Title

Apparent Volume of Distribution (V/F)

Description

Time Frame

Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD

Title

Terminal Rate Constant (Kel)

Description

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

Time Frame

Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD

Title

Number of Participants With Anti-JNJ-64565111 Antibodies as Measure of Immunogenicity

Description

Time Frame

First Dose: Predose (Day 1); Second Dose: predose (Day 8) Third Dose: predose (Day 15); Fourth Dose: predose (Day 22), 144, 480, 720, and 1200 hours post-dose.

Title

Change From Baseline in Body Weight

Description

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

Time Frame

Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72

Title

Change From Baseline in Fasting Plasma Glucose (FPG)

Description

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

Time Frame

Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72

Title

Change From Baseline in Hemoglobin A1c (HbA1c)

Description

Change from baseline in HbA1c will be assessed.

Time Frame

Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72

Title

Change From Baseline in Fasting Lipids

Description

Time Frame

Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72

Title

Change From Baseline for 24-hour Mean Plasma Glucose

Description

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.

Time Frame

Baseline, Day 26

Title

Change From Baseline in C-peptide Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT)

Description

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.

Time Frame

Baseline, Day 26

Title

Change From Baseline in Total and/or Incremental Plasma Glucose Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT)

Description

Time Frame

Baseline, Day 26

Title

Change From Baseline in Insulin Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT)

Description

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.

Time Frame

Baseline, Day 26

Title

Change From Baseline in Glucagon Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT)

Description

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.

Time Frame

Baseline, Day 26

Title

Change From Baseline in 24-hour Blood Pressure

Description

Time Frame

Baseline and Day 28

Title

Change From Baseline in 24-hour Heart Rate

Description

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

Time Frame

Baseline and Day 28

Title

Change From Baseline in Body Mass Index (BMI)

Description

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

Time Frame

Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72

Title

Change From Baseline Insulin Secretion as Assessed by the Insulinogenic Index

Description

Time Frame

Baseline, Day 26

Title

Change from Baseline in Insulin Secretion as Assessed by Homeostasis Model Assessment of Beta Cell Function (HOMA-%B)

Description

Time Frame

Baseline, Day 26

Title

Change From Baseline in Insulin Sensitivity as Assessed by Matsuda Index

Description

Time Frame

Baseline, Day 26

Title

Change From Baseline in Insulin Sensitivity as Assessed by Homeostasis Model Assessment for Insulin Sensitivity (HOMA-%S)

Description

Time Frame

Baseline, Day 26

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diagnosis of type 2 diabetes mellitus (T2DM) at least 3 months prior to Screening Hemoglobin A1c (HbA1c) greater than or equal to (>=) 7.0 percent (%) and lesser than or equal to (<=)9.5% at Screening On a stable treatment regimen for at least 3 months prior to Screening of (1) diet and exercise, and/or (2) metformin monotherapy (at a dose of at least 1,000 milligram (mg) per day) Body mass index (BMI) ranging from 25 to 40 kilogram per square meter (kg/m^2) (inclusive), weighing between 75 and 130 kg (inclusive) A woman must have a negative highly sensitive serum beta-human chorionic gonadotropin (beta- hCG) at Screening and Day -2 Blood pressure (measured after the participant is sitting/ resting quietly for 5 minutes) between 90 and 140 millimeter of mercury (mmHg) systolic, inclusive, and between 60 and 100 mmHg diastolic, inclusive at Screening (sitting) and Day -2 (supine). If the average of the first triplicate blood pressure assessment is out of range, up to 2 repeated triplicate assessments are permitted Exclusion Criteria: History or current diagnosis of acute or chronic pancreatitis Familial or personal history of multiple endocrine neoplasia type 2,familial/non-familial medullary thyroid carcinoma Donated blood or blood products or lost a significant amount of blood (>500 milliliter [mL]) within 3 months before the first administration of study drug History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease, or tests positive for HBsAg or anti-HCV at Screening History of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV at Screening

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Janssen Research & Development, LLC Clinical Trial

Organizational Affiliation

Janssen Research & Development, LLC

Official's Role

Study Director

Facility Information:

Facility Name

ProSciento, Inc.

City

Chula Vista

State/Province

California

ZIP/Postal Code

91911

Country

United States

Facility Name

Advanced Pharma CR, LLC

City

Miami

State/Province

Florida

ZIP/Postal Code

33147

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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