Clinical trial NCT02445911: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of KQ-791 in Diabetes Mellitus
Official title: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Oral Doses of KQ-791 in Subjects With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Kaneq Bioscience Limited
Sponsor class: OTHER
First posted: 2015-05-15
Enrollment: 81
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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

Primary outcomes:
measure: Difference in the Change From Baseline in Fasting Blood Glucose Between KQ-791 and Placebo
timeFrame: Baseline to Day 29
measure: Number of Participants With One or More Treatment-Emergent Adverse Events
timeFrame: Baseline to Day 29
Secondary outcomes:
measure: Change From Baseline in the Quantitative Insulin Sensitivity Check Index (QUICKI)
timeFrame: Baseline to Day 29
measure: Change From Baseline in the Insulin Sensitivity Index (ISI)
timeFrame: Baseline to Day 29
measure: Change From Baseline in Beta Cell Function
timeFrame: Baseline to Day 29
measure: Change From Baseline in Disposition Index
timeFrame: Baseline to Day 29
measure: Change From Baseline in the Hepatic Insulin Resistance Index
timeFrame: Baseline to Day 29
measure: Change From Baseline in 7-point Average Blood Glucose
timeFrame: Baseline to Day 29
measure: Change From Baseline in Postprandial Glucose
timeFrame: Baseline to Day 29
measure: Change From Baseline in HbA1c
timeFrame: Baseline to Day 29
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 24-hours Post-Dose (AUC0-24)
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose
measure: Time of the Maximum Measured Plasma Concentration (Tmax)
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose
measure: Area Under the Plasma Concentration Versus Time Curve (AUCtau)
timeFrame: 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
measure: Maximum Observed Plasma Concentration at Steady-state (Cmax_ss)
timeFrame: 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
measure: Time of the Maximum Measured Plasma Concentration at Steady-state (Tmax_ss)
timeFrame: 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
measure: Apparent Terminal Elimination Half-life (t1/2)
timeFrame: 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
measure: Accumulation Index (AI)
timeFrame: 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
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Celerion
state: Arizona
city: Miami
country: United States
facility: Clinical Pharmacology of Miami, Inc.
state: Florida
city: Orlando
country: United States
facility: Orlando Clinical Research Center
state: Florida
city: Lincoln
country: United States
facility: Celerion
state: Nebraska
Study officials:
affiliation: Kaneq Bioscience
name: Email: daniel.bouthillier@Kaneq.ca
role: STUDY_DIRECTOR
References: