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

• Sponsor: Kaneq Bioscience Limited (Other)
• Overall Status: Completed
• CT.gov ID: NCT02445911
• Collaborator: (none)
• Enrollment: 81
• Locations: 4
• Arms: 4
• Duration (Months): 8
• Patients Per Site: 20.3
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: KQ-791; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 81 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Oral Doses of KQ-791 in Subjects With Type 2 Diabetes
• Study Start Date: Jun 1, 2015
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: KQ-791 Dose 1 Single loading dose on day 1, followed by single doses on days 8, 15, 22, 29	Drug: KQ-791; Capsules administered orally
Experimental: KQ-791 Dose 2 Single loading dose on day 1, followed by a daily dose for 28 days	Drug: KQ-791; Capsules administered orally
Experimental: KQ-791 Dose 3 Single loading dose on day 1 or days 1-2, followed by a daily dose for 28 days	Drug: KQ-791; Capsules administered orally
Placebo Comparator: Placebo Multiple ascending doses matching KQ-791 dose	Drug: Placebo; Capsules administered orally

Outcome Measures

Primary Outcome Measures

1. Difference in the Change From Baseline in Fasting Blood Glucose Between KQ-791 and Placebo [Baseline to Day 29]

   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.

2. Number of Participants With One or More Treatment-Emergent Adverse Events [Baseline to Day 29]

Secondary Outcome Measures

1. Change From Baseline in the Quantitative Insulin Sensitivity Check Index (QUICKI) [Baseline to Day 29]

   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.

2. Change From Baseline in the Insulin Sensitivity Index (ISI) [Baseline to Day 29]

   Insulin sensitivity index (ISI) composite using Matsuda's whole body insulin sensitivity, ISI [composite] = 10000/√[(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.

3. Change From Baseline in Beta Cell Function [Baseline to Day 29]

   Evaluated as beta index = (Insulin Area Under the Effect Curve (AUEC) in MMTT/Glucose AUEC in MMTT)

4. Change From Baseline in Disposition Index [Baseline to Day 29]

   Disposition Index evaluated as beta index x ISI [composite]. Lower values of the disposition index suggests loss of function of beta cells.

5. Change From Baseline in the Hepatic Insulin Resistance Index [Baseline to Day 29]

   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

6. Change From Baseline in 7-point Average Blood Glucose [Baseline to Day 29]

   The 7-points measured were just prior to each meal and 90 minutes after the start of the meal and approximately bedtime.

7. Change From Baseline in Postprandial Glucose [Baseline to Day 29]

8. Change From Baseline in HbA1c [Baseline to Day 29]

9. 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]

10. Maximum Observed Plasma Concentration (Cmax) [Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose]

11. Time of the Maximum Measured Plasma Concentration (Tmax) [Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose]

12. 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]

13. 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]

14. 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]

15. 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]

16. Accumulation Index (AI) [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]

    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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Celerion	Tempe	Arizona	United States	85283
2	Clinical Pharmacology of Miami, Inc.	Miami	Florida	United States	33014
3	Orlando Clinical Research Center	Orlando	Florida	United States	32809
4	Celerion	Lincoln	Nebraska	United States	68502

Sponsors and Collaborators

• Kaneq Bioscience Limited

Investigators

• Study Director: Email: [e-mail], Kaneq Bioscience

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kaneq Bioscience Limited
• ClinicalTrials.gov Identifier: NCT02445911
• Other Study ID Numbers: KQ-791-02
• First Posted: May 15, 2015
• Last Update Posted: Nov 26, 2019
• Last Verified: Nov 1, 2019

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Period Title: Overall Study
STARTED	20	20	21	20
COMPLETED	20	20	21	20
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo	Total
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally	Total of all reporting groups
Overall Participants	20	20	21	20	81
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	17 85%	14 70%	20 95.2%	16 80%	67 82.7%
>=65 years	3 15%	6 30%	1 4.8%	4 20%	14 17.3%
Sex: Female, Male (Count of Participants)
Female	12 60%	10 50%	10 47.6%	10 50%	42 51.9%
Male	8 40%	10 50%	11 52.4%	10 50%	39 48.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	17 85%	19 95%	17 81%	16 80%	69 85.2%
Not Hispanic or Latino	3 15%	1 5%	4 19%	4 20%	12 14.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	3 15%	2 10%	2 9.5%	5 25%	12 14.8%
White	17 85%	18 90%	19 90.5%	15 75%	69 85.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	21 100%	20 100%	81 100%

Outcome Measures

1. Primary Outcome

Title	Difference in the Change From Baseline in Fasting Blood Glucose Between KQ-791 and Placebo
Description	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.
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) population incudes all 81 participants

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	20	21	20
Mean (Standard Deviation) [mg/dL milligrams per deciliters]	-3.28 (22.99)	-3.93 (30.63)	0.67 (30.82)	3.17 (23.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KQ-791 Dose 1, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least-squares Mean Difference
	Estimated Value	-6.78
	Confidence Interval	(2-Sided) 95%; -23.75 to 10.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least-squares means have baseline and site as covariates. Placebo was the reference group.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KQ-791 Dose 2, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least-squares Mean Difference
	Estimated Value	-2.97
	Confidence Interval	(2-Sided) 95%; -19.65 to 13.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least-squares means have baseline and site as covariates. Placebo was the reference group.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KQ-791 Dose 3, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least-squares Mean Difference
	Estimated Value	-5.05
	Confidence Interval	(2-Sided) 95%; -21.97 to 11.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least-squares means have baseline and site as covariates. Placebo was the reference group.

2. Primary Outcome

Title	Number of Participants With One or More Treatment-Emergent Adverse Events
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

PD population includes all 81 participants

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	20	21	20
Number [participants]	12 60%	12 60%	11 52.4%	14 70%

3. Secondary Outcome

Title	Change From Baseline in the Quantitative Insulin Sensitivity Check Index (QUICKI)
Description	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.
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

PD population includes all 81 participants

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	20	21	20
Mean (Standard Deviation) [units on a scale]	.0043 (.012)	.003 (.013)	.005 (.0125)	-.0012 (.0116)

4. Secondary Outcome

Title	Change From Baseline in the Insulin Sensitivity Index (ISI)
Description	Insulin sensitivity index (ISI) composite using Matsuda's whole body insulin sensitivity, ISI [composite] = 10000/√[(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.
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

Includes all subjects who receive at least one dose of study drug and have evaluable ISI data.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	19	21	20
Mean (Standard Deviation) [units on a scale]	.0043 (0.7345)	-.0585 (0.586)	0.145 (0.697)	-0.112 (0.669)

5. Secondary Outcome

Title	Change From Baseline in Beta Cell Function
Description	Evaluated as beta index = (Insulin Area Under the Effect Curve (AUEC) in MMTT/Glucose AUEC in MMTT)
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

PD population includes all 81 participants

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	20	21	20
Mean (Standard Deviation) [(hr*μIU/mL(hr*mg/dL))]	0.00098 (0.0866)	0.012 (0.0585)	0.0535 (0.1099)	0.0027 (0.0491)

6. Secondary Outcome

Title	Change From Baseline in Disposition Index
Description	Disposition Index evaluated as beta index x ISI [composite]. Lower values of the disposition index suggests loss of function of beta cells.
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

Includes all subjects who receive at least one dose of study drug and have evaluable data for disposition index.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	19	21	20
Mean (Standard Deviation) [Index]	0.022 (0.128)	0.023 (0.147)	0.084 (0.185)	0.008 (0.085)

7. Secondary Outcome

Title	Change From Baseline in the Hepatic Insulin Resistance Index
Description	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
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

PD population includes all 81 participants

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	20	21	20
Mean (Standard Deviation) [(hr*mg/dL)*(hr*μUI/mL)]	99.51 (495.81)	255.53 (484.27)	93.17 (462.25)	56.90 (482.72)

8. Secondary Outcome

Title	Change From Baseline in 7-point Average Blood Glucose
Description	The 7-points measured were just prior to each meal and 90 minutes after the start of the meal and approximately bedtime.
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

PD population includes all 81 participants

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	20	21	20
Mean (Standard Deviation) [mg/dL]	-5.04 (20.76)	0.35 (35.74)	-2.61 (38.66)	4.44 (27.91)

9. Secondary Outcome

Title	Change From Baseline in Postprandial Glucose
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

PD population includes all 81 participants

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	20	21	20
Mean (Standard Deviation) [hr*mg/dL]	-72.23 (281.62)	-0.086 (484.712)	-35.60 (524.57)	58.61 (381.88)

10. Secondary Outcome

Title	Change From Baseline in HbA1c
Time Frame	Baseline to Day 29

Outcome Measure Data

Analysis Population Description

Includes all subjects who receive at least one dose of study drug and have evaluable HbA1c data.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3	Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally	Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
Measure Participants	20	20	20	18
Mean (Standard Deviation) [Percentage of glycosylated hemoglobin]	-0.185 (0.3265)	0.025 (0.4303)	-0.315 (0.5174)	-0.0333 (0.3343)

11. Secondary Outcome

Title	Area Under the Plasma Concentration-Time Curve From Time Zero to 24-hours Post-Dose (AUC0-24)
Time Frame	Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Includes all randomized subjects who received at least 1 dose of KQ-791and had sufficient evaluable PK data to compute AUC0-24.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally
Measure Participants	20	20	21
Mean (Standard Deviation) [ng*hr/mL]	14372.2 (2882.69)	29011.2 (6030.57)	140990.4 (47460.96)

12. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax)
Time Frame	Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Includes all randomized subjects who received at least 1 dose of KQ-791and had sufficient evaluable PK data to compute Cmax.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally
Measure Participants	20	20	21
Mean (Standard Deviation) [ng/mL]	747.56 (163.768)	1484.74 (341.712)	7204.70 (2517.201)

13. Secondary Outcome

Title	Time of the Maximum Measured Plasma Concentration (Tmax)
Time Frame	Pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Includes all randomized subjects who received at least 1 dose of KQ-791and had sufficient evaluable PK data to compute Tmax.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally
Measure Participants	20	20	21
Mean (Standard Deviation) [hours]	4.60 (3.251)	5.05 (3.395)	9.42 (8.663)

14. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve (AUCtau)
Time Frame	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

Outcome Measure Data

Analysis Population Description

Includes all randomized subjects who received at least 1 dose of KQ-791and had sufficient evaluable PK data to compute AUCtau.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally
Measure Participants	20	20	21
Mean (Standard Deviation) [ng*hr/mL]	76863.5 (34469.47)	25754.9 (13130.00)	150681.0 (55372.30)

15. Secondary Outcome

Title	Maximum Observed Plasma Concentration at Steady-state (Cmax_ss)
Time Frame	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

Outcome Measure Data

Analysis Population Description

Includes all randomized subjects who received at least 1 dose of KQ-791and had sufficient evaluable PK data to compute Cmax_ss.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally
Measure Participants	20	20	21
Mean (Standard Deviation) [ng/mL]	657.82 (238.542)	1164.65 (568.489)	7221.37 (2672.180)

16. Secondary Outcome

Title	Time of the Maximum Measured Plasma Concentration at Steady-state (Tmax_ss)
Time Frame	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

Outcome Measure Data

Analysis Population Description

Includes all randomized subjects who received at least 1 dose of KQ-791and had sufficient evaluable PK data to compute Tmax_ss.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally
Measure Participants	20	20	21
Mean (Standard Deviation) [hours]	5.10 (5.00)	5.43 (5.69)	3.83 (3.40)

17. Secondary Outcome

Title	Apparent Terminal Elimination Half-life (t1/2)
Time Frame	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

Outcome Measure Data

Analysis Population Description

Includes all randomized subjects who received at least 1 dose of KQ-791and had sufficient evaluable PK data to compute t1/2.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally
Measure Participants	20	20	21
Mean (Standard Deviation) [hours]	201.095 (79.378)	184.386 (36.385)	178.018 (28.389)

18. Secondary Outcome

Title	Accumulation Index (AI)
Description	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)
Time Frame	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

Outcome Measure Data

Analysis Population Description

Includes all randomized subjects who received at least 1 dose of KQ-791and had sufficient evaluable PK data to compute AI.

Arm/Group Title	KQ-791 Dose 1	KQ-791 Dose 2	KQ-791 Dose 3
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally	Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally	Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally
Measure Participants	19	20	21
Mean (Standard Deviation) [1/h]	1.97 (0.537)	9.37 (4.934)	12.01 (6.507)

Adverse Events

Arm/Group Title	KQ-791 Dose 1		KQ-791 Dose 2		KQ-791 Dose 3		Placebo
Arm/Group Description	Single loading dose of 100 mg on day 1, followed by single 50 mg doses on days 8, 15, 22, 29 KQ-791: Capsules administered orally		Single loading dose of 250 mg on day 1, followed by a daily dose of 25 mg for 28 days KQ-791: Capsules administered orally		Single loading dose of 1500 mg on day 1, followed by a daily dose of 150 mg for 28 days KQ-791: Capsules administered orally		Multiple ascending doses matching KQ-791 dose Placebo: Capsules administered orally
All Cause Mortality
	KQ-791 Dose 1		KQ-791 Dose 2		KQ-791 Dose 3		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	KQ-791 Dose 1		KQ-791 Dose 2		KQ-791 Dose 3		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/21 (0%)		1/20 (5%)
Blood and lymphatic system disorders
Anaemia	0/20 (0%)	0	0/20 (0%)	0	0/21 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	KQ-791 Dose 1		KQ-791 Dose 2		KQ-791 Dose 3		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/20 (60%)		12/20 (60%)		11/21 (52.4%)		14/20 (70%)
Eye disorders
Conjunctival irritation	1/20 (5%)		0/20 (0%)		0/21 (0%)		0/20 (0%)
Dry eye	1/20 (5%)		0/20 (0%)		2/21 (9.5%)		0/20 (0%)
Ocular discomfort	1/20 (5%)		0/20 (0%)		0/21 (0%)		0/20 (0%)
Gastrointestinal disorders
Abdominal discomfort	2/20 (10%)		5/20 (25%)		4/21 (19%)		0/20 (0%)
Abdominal pain	1/20 (5%)		0/20 (0%)		0/21 (0%)		0/20 (0%)
Abdominal pain upper	0/20 (0%)		1/20 (5%)		0/21 (0%)		0/20 (0%)
Constipation	1/20 (5%)		2/20 (10%)		2/21 (9.5%)		2/20 (10%)
Diarrhoea	4/20 (20%)		3/20 (15%)		6/21 (28.6%)		6/20 (30%)
Dyspepsia	0/20 (0%)		0/20 (0%)		0/21 (0%)		2/20 (10%)
Eructation	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Faeces discoloured	0/20 (0%)		3/20 (15%)		5/21 (23.8%)		2/20 (10%)
Nausea	1/20 (5%)		2/20 (10%)		3/21 (14.3%)		1/20 (5%)
Retching	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Toothache	0/20 (0%)		0/20 (0%)		0/21 (0%)		1/20 (5%)
Vomiting	1/20 (5%)		0/20 (0%)		2/21 (9.5%)		1/20 (5%)
Duodenal ulcer	0/20 (0%)		0/20 (0%)		0/21 (0%)		1/20 (5%)
General disorders
Fatigue	0/20 (0%)		0/20 (0%)		0/21 (0%)		1/20 (5%)
Infections and infestations
Upper respiratory tract infection	0/20 (0%)		0/20 (0%)		0/21 (0%)		1/20 (5%)
Urinary tract infection	1/20 (5%)		0/20 (0%)		0/21 (0%)		0/20 (0%)
Injury, poisoning and procedural complications
Arthropod bite	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Investigations
Blood creatine phosphokinase increased	1/20 (5%)		1/20 (5%)		0/21 (0%)		0/20 (0%)
Glomuerular filtration rate decreased	0/20 (0%)		0/20 (0%)		0/21 (0%)		1/20 (5%)
Neutrophil count increased	0/20 (0%)		1/20 (5%)		0/21 (0%)		0/20 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	1/20 (5%)		0/20 (0%)		0/21 (0%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/20 (5%)		0/20 (0%)		0/21 (0%)		0/20 (0%)
Muscle twitching	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Myalgia	1/20 (5%)		0/20 (0%)		0/21 (0%)		0/20 (0%)
Pain in extremity	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Nervous system disorders
Dizziness	0/20 (0%)		1/20 (5%)		1/21 (4.8%)		0/20 (0%)
Headache	7/20 (35%)		5/20 (25%)		6/21 (28.6%)		4/20 (20%)
Psychiatric disorders
Confusional state	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Nervousness	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Restlessness	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/20 (0%)		0/20 (0%)		0/21 (0%)		1/20 (5%)
Dyspnoea	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Oropharyngeal pain	0/20 (0%)		0/20 (0%)		0/21 (0%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Eyelid oedema	2/20 (10%)		0/20 (0%)		0/21 (0%)		0/20 (0%)
Hyperhidrosis	0/20 (0%)		0/20 (0%)		1/21 (4.8%)		0/20 (0%)
Rash	1/20 (5%)		0/20 (0%)		0/21 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Written consent