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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

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ClinicalTrials.gov Identifier: NCT03235219
Recruitment Status : Completed
First Posted : August 1, 2017
Last Update Posted : April 12, 2018
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Drug: JNJ-64565111 Drug: Placebo Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 39 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : August 1, 2017
Actual Primary Completion Date : February 19, 2018
Actual Study Completion Date : February 19, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1 to 4: JNJ-64565111 or Placebo
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.
Drug: JNJ-64565111
Participants will receive JNJ-64565111 subcutaneously in the abdomen on Days 1, 8, 15 and 22.
Other Name: Oxyntomodulin

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

Experimental: Cohort 5: JNJ-64565111 (Repeat or Lower Dose) or Placebo
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.
Drug: JNJ-64565111
Participants will receive JNJ-64565111 subcutaneously in the abdomen on Days 1, 8, 15 and 22.
Other Name: Oxyntomodulin

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




Primary Outcome Measures :
  1. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Up to Day 72 ]
    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 :
  1. Maximum Observed Serum Concentration (Cmax) [ 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. ]
    Maximum observed serum concentration (Cmax) of JNJ-64565111 will be assessed.

  2. Time to Reach Maximum Observed Plasma Concentration (Tmax) [ 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 ]
    Actual sampling time to reach maximum observed serum concentration (Tmax) of JNJ-64565111 will be assessed.

  3. Area Under Concentration-Time Curve From Time Zero to the Last Quantifiable Time (AUC [0-last]) [ Time Frame: First Dose: Predose (Day 1), and at 8, 24, 48, 72 and 120 hours post-dose (PD) ]
    The AUC (0-last) of JNJ-64565111 is the area under the serum concentration-time curve from time zero to last quantifiable time.

  4. Average Concentration Over the Dosing Interval Tau (T) at Steady State (Caverage,ss) [ Time Frame: Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD ]
    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.

  5. Minimum Observed Serum Concentration (Cmin) [ Time Frame: Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD ]
    Minimum observed serum concentration (Cmin) of JNJ-64565111 will be assessed.

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

  7. Area Under Curve over the dosing interval AUC (0-T) [ Time Frame: Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168 hours PD ]
    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.

  8. Apparent Terminal Elimination Half-life (t1/2term) [ Time Frame: Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD ]
    Apparent terminal elimination half-life of JNJ-64565111, calculated as 0.693/apparent terminal elimination rate constant (Lambda[z]).

  9. Apparent Clearance (CL/F) [ Time Frame: Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD ]
    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].

  10. Apparent Volume of Distribution (V/F) [ Time Frame: Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD ]
    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].

  11. Terminal Rate Constant (Kel) [ Time Frame: Fourth Dose: Predose (Day 22), and at 72, 96, 144, 168, 312, 480, 720, and 1200 hours PD ]
    Terminal rate constant of JNJ-64565111 is defined as the fraction of drug that is eliminated per unit of time (fraction/hour).

  12. Number of Participants With Anti-JNJ-64565111 Antibodies as Measure of Immunogenicity [ 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. ]
    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.

  13. Change From Baseline in Body Weight [ Time Frame: Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72 ]
    Body weight will be measured using a calibrated scale at each time a participant is weighed. Calibration must be documented in a calibration log.

  14. Change From Baseline in Fasting Plasma Glucose (FPG) [ Time Frame: Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72 ]
    Change from baseline in fasting plasma glucose (FPG) will be assessed.

  15. Change From Baseline in Hemoglobin A1c (HbA1c) [ Time Frame: Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72 ]
    Change from baseline in HbA1c will be assessed.

  16. Change From Baseline in Fasting Lipids [ Time Frame: Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72 ]
    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.

  17. Change From Baseline for 24-hour Mean Plasma Glucose [ Time Frame: Baseline, Day 26 ]
    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.

  18. Change From Baseline in C-peptide Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT) [ Time Frame: Baseline, Day 26 ]
    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.

  19. 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) [ Time Frame: Baseline, Day 26 ]
    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.

  20. Change From Baseline in Insulin Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT) [ Time Frame: Baseline, Day 26 ]
    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.

  21. Change From Baseline in Glucagon Area Under the Curve (AUC) Calculated From a 6-Hour Mixed Meal Tolerance Test (MMTT) [ Time Frame: Baseline, Day 26 ]
    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.

  22. Change From Baseline in 24-hour Blood Pressure [ Time Frame: Baseline and Day 28 ]
    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).

  23. Change From Baseline in 24-hour Heart Rate [ Time Frame: Baseline and Day 28 ]
    Heart rate measurements will be assessed with a completely automated (ambulatory blood pressure and heart rate monitoring) device.

  24. Change From Baseline in Body Mass Index (BMI) [ Time Frame: Baseline, Days 8, 15, 22, 28, 29, 35, 42, 52, and 72 ]
    Body Mass Index (BMI) is calculated by dividing the body weight (in kilogram) by the square of height (in meters).

  25. Change From Baseline Insulin Secretion as Assessed by the Insulinogenic Index [ Time Frame: Baseline, Day 26 ]
    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.

  26. Change from Baseline in Insulin Secretion as Assessed by Homeostasis Model Assessment of Beta Cell Function (HOMA-%B) [ Time Frame: Baseline, Day 26 ]
    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]).

  27. Change From Baseline in Insulin Sensitivity as Assessed by Matsuda Index [ Time Frame: Baseline, Day 26 ]
    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]).

  28. Change From Baseline in Insulin Sensitivity as Assessed by Homeostasis Model Assessment for Insulin Sensitivity (HOMA-%S) [ Time Frame: Baseline, Day 26 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03235219


Locations
United States, California
ProSciento, Inc.
Chula Vista, California, United States, 91911
United States, Florida
Advanced Pharma CR, LLC
Miami, Florida, United States, 33147
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT03235219     History of Changes
Other Study ID Numbers: CR108339
64565111EDI1002 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: August 1, 2017    Key Record Dates
Last Update Posted: April 12, 2018
Last Verified: April 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases