Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of KQ-791 in Diabetes Mellitus

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Oral Doses of KQ-791 in Subjects With Type 2 Diabetes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02445911
• Other study ID #: KQ-791-02
• Status: Completed
• Phase: Phase 1
• Start date: June 2015
• Est. completion date: February 2016

Study information

• Verified date: November 2019
• Source: Kaneq Bioscience Limited
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will consist of multiple ascending oral doses in up to 3 groups, for 29 days.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 81
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Have a diagnosis of Type 2 Diabetes Mellitus (T2DM)

• Be an adult between the ages of 18 (19 for Lincoln site) and 70 years

• Female participants must be of non-childbearing potential, and must be either 1) postmenopausal with amenorrhea for at least 1 year prior to the first dose and Follicle Stimulating Hormone (FSH) serum levels consistent with postmenopausal status, or 2) have undergone one of the following sterilization procedures at least 6 months prior to the first dose:

• hysteroscopic sterilization

• bilateral tubal ligation or bilateral salpingectomy

• hysterectomy

• bilateral oophorectomy

• Non-vasectomized males must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 100 days beyond the last dose of study drug. (No restrictions are required for a vasectomized male provided his vasectomy has been performed 4 months or more prior to first dosing. A male who has been vasectomized less than 4 months prior to first dosing must follow the same restrictions as a non-vasectomized male)

• Males must agree to not donate sperm during the study and for 100 days following the last dose

• Have an HbA1c value between 7.0-10.0%

• Be on a stable treatment regimen of metformin, with or without diet/exercise, for at least 8 weeks

• Weigh 60 kilograms (kg) or more at screening and have a body mass index (BMI) greater than or equal to (=) 25.0 and less than or equal to (=) 40.0 kilograms/meters squared (kg/m2)

• Have laboratory test results within the normal range for T2DM population, or with abnormalities deemed clinically insignificant. Urine protein levels must be within normal limits

• Absence of active diabetic retinopathy (Stage 2 or greater by the International Clinical Disease Severity Scale for Diabetic Retinopathy)

• Are willing to comply with specific dietary restrictions (that is, [i] able to fast overnight for at least 8-12 hours on several days and [ii] able to consume the standard meals provided during specified confinement days)

• Have given written consent to allow collection of samples for Peripheral Blood Mononuclear Cells (PBMC) analysis and for possible biomarkers/safety analysis

• Have given written informed consent approved by the institutional review board (IRB) governing the site

Exclusion Criteria:

• Are currently enrolled in a clinical trial involving an investigational product or off-label use of a drug or device, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study

• Participated (defined as the last dose of study drug) within 30 days prior to dosing in a clinical trial involving an investigational product or non-approved use of a drug with a short half-life or within 5 half-lives of an investigational product with a half-life longer than 6 days

• - Have a (QTcF) greater than (>) 450 milliseconds (msec), or clinical significant hypokalemia, a family history of long QT syndrome or any abnormality in the 12-lead Electrocardiogram (ECG)

• Abnormal blood pressure (sitting) defined as diastolic blood pressure > 95 or less than (<) 50 millimeter of mercury (mmHg) and/or systolic blood pressure > 160 or < 90 mmHg

• Have a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs

• Show evidence of regular use of known drugs of abuse and/or positive findings on urinary drug screening

• Evidence of human immunodeficiency virus (HIV) infection, hepatitis B, hepatitis C and/or positive results at screening for the respective antibodies for HIV, hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV)

• Have anemia that would interfere with the trial or have donated =500 mL of blood within 56 days before the first dose or have donated plasma within 7 days before the first dose or provided any blood donation within last 30 days

• Have an average weekly alcohol intake that exceeds 14 units per week (males) and 7 units per week (females) [1 unit = 12 ounces (oz) or 360 mL of beer, 5 oz or 150 mL of wine, or 1.5 oz or 45 mL of distilled spirits] or are unwilling to stop alcohol consumption 48 hours prior to the first dosing and throughout the study

• Consume more than 10 cigarettes per day or the equivalent or are unable or unwilling to adhere to restricted smoking policies

• Have had >1 episode of documented severe hypoglycemia within last 6 months or are currently diagnosed as having hypoglycemia unawareness

• Have any of the following clinical laboratory test results:

• estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (impaired renal function)

• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 1.5 times (x) the upper limit of normal (ULN)

• triglycerides (TG) > 500 milligrams/deciliter (mg/dL)

• Have used insulin or other glycemic control medications, except metformin, for diabetic control within 3 months

• Intend to use non-steroidal anti-inflammatory drugs (except aspirin) and drugs known to prolong QT interval, herbal products, or vitamin supplements that change glucose levels. The following medications are allowed for participants:

• drugs for treatment of hypertension or lipid disorders (except bile acid resins, niacin or fish oils), platelet inhibitors, and on stable dose for 12 weeks prior to first dose

• thyroid replacement therapy, proton pump inhibitors, antidepressants, antihistamines, regularly taken over-the-counter (OTC) and anti-emetics that do not cause a corrected QT interval (QTc) prolongation, provided such drugs are not specifically excluded

• hormonal replacement therapy

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• KQ-791
Capsules administered orally
• Placebo
Capsules administered orally

Locations

Country	Name	City	State
United States	Celerion	Lincoln	Nebraska
United States	Clinical Pharmacology of Miami, Inc.	Miami	Florida
United States	Orlando Clinical Research Center	Orlando	Florida
United States	Celerion	Tempe	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Kaneq Bioscience Limited

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in the Change From Baseline in Fasting Blood Glucose Between KQ-791 and Placebo	Data table is change from baseline in Fasting Blood Glucose. Statistical Analysis includes results for difference in Change from baseline in Fasting Blood Glucose Between KQ-791 and Placebo.	Baseline to Day 29
Primary	Number of Participants With One or More Treatment-Emergent Adverse Events		Baseline to Day 29
Secondary	Change From Baseline in the Quantitative Insulin Sensitivity Check Index (QUICKI)	QUICKI = 1/(log FPG + log FPI) where FPG = fasting plasma glucose (mg/dL); FPI = fasting plasma insulin (estimated based on fasting serum insulin; (µIU/mL)). Lower numbers reflect greater insulin resistance.	Baseline to Day 29
Secondary	Change From Baseline in the Insulin Sensitivity Index (ISI)	Insulin sensitivity index (ISI) composite using Matsuda's whole body insulin sensitivity, ISI [composite] = 10000/v[(FPG x FPI)x(Mean Glucose 0-120min in MMTT x Mean Insulin 0-120 min in MMTT)] where MMTT is a mixed meal tolerance test, Hour 0=just prior dosing. Lower values indicate greater insulin resistance.	Baseline to Day 29
Secondary	Change From Baseline in Beta Cell Function	Evaluated as beta index = (Insulin Area Under the Effect Curve (AUEC) in MMTT/Glucose AUEC in MMTT)	Baseline to Day 29
Secondary	Change From Baseline in Disposition Index	Disposition Index evaluated as beta index x ISI [composite]. Lower values of the disposition index suggests loss of function of beta cells.	Baseline to Day 29
Secondary	Change From Baseline in the Hepatic Insulin Resistance Index	Hepatic Insulin Resistance Index will be evaluated as Glucose AUEC from zero to 30 minutes (AUEC0-30min) in MMTT x Insulin AUEC0-30 min in MMTT	Baseline to Day 29
Secondary	Change From Baseline in 7-point Average Blood Glucose	The 7-points measured were just prior to each meal and 90 minutes after the start of the meal and approximately bedtime.	Baseline to Day 29
Secondary	Change From Baseline in Postprandial Glucose		Baseline to Day 29
Secondary	Change From Baseline in HbA1c		Baseline to Day 29
Secondary	Area Under the Plasma Concentration-Time Curve From Time Zero to 24-hours Post-Dose (AUC0-24)		Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose
Secondary	Maximum Observed Plasma Concentration (Cmax)		Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose
Secondary	Time of the Maximum Measured Plasma Concentration (Tmax)		Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose
Secondary	Area Under the Plasma Concentration Versus Time Curve (AUCtau)		Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose; Day 3, 8, 15, 22, 29, and up to 24 hours post-dose on Day 29
Secondary	Maximum Observed Plasma Concentration at Steady-state (Cmax_ss)		Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose; Day 3, 8, 15, 22, 29, and up to 24 hours post-dose on Day 29
Secondary	Time of the Maximum Measured Plasma Concentration at Steady-state (Tmax_ss)		Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose; Day 3, 8, 15, 22, 29, and up to 24 hours post-dose on Day 29
Secondary	Apparent Terminal Elimination Half-life (t1/2)		Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose; Day 3, 8, 15, 22, 29, and up to 24 hours post-dose on Day 29
Secondary	Accumulation Index (AI)	Based on AUC (RacAUC), where RacAUC is the ratio of AUC during a dosing interval following the last dose over the loading dose (first dose)	Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose; Day 3, 8, 15, 22, 29, and up to 24 hours post-dose on Day 29