Study of PK/PD, Safety and Tolerability of LIK066 in Patients With Decreased Renal Function.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03131479
• Collaborator: (none)
• Enrollment: 53
• Location: 1
• Arms: 5
• Actual Duration (Months): 8.6
• Patients Per Site Per Month: 6.1

Study Details

Study Description

Brief Summary

The purpose of this trial was to evaluate whether the study drug, LIK066, causes glucose excretion in urine in patients with varying degrees of decreased kidney function and in subjects with normal kidney function. Blood samples were collected to measure the concentrations of LIK066 and to study the pharmacokinetics of LIK066. Pharmacokinetics is meant to study how LIK066 is absorbed, distributed and eliminated, in other words what the body does to the drug. The results of this study may be used to help determine whether LIK066 can be used to treat people with reduced kidney function and the proper dosing regimen.

Condition or Disease	Intervention/Treatment	Phase
Renal Impairment	Drug: LIK066	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: An Open-label, Parallel-group Study to Assess the Effect of LIK066 on Urinary Glucose Excretion, Pharmacokinetics, Safety and Tolerability Following Multiple Dose Administration in Patients With Decreased Renal Function Compared to Subjects With Normal Renal Function
• Actual Study Start Date: Apr 28, 2017
• Actual Primary Completion Date: Jan 16, 2018
• Actual Study Completion Date: Jan 16, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mild Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Drug: LIK066; LIK066 50 mg tablets taken orally once daily before breakfast for 7 days.
Experimental: Moderate A Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Drug: LIK066; LIK066 50 mg tablets taken orally once daily before breakfast for 7 days.
Experimental: Moderate B Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Drug: LIK066; LIK066 50 mg tablets taken orally once daily before breakfast for 7 days.
Experimental: Severe Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.	Drug: LIK066; LIK066 50 mg tablets taken orally once daily before breakfast for 7 days.
Experimental: Normal Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Drug: LIK066; LIK066 50 mg tablets taken orally once daily before breakfast for 7 days.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7 [Baseline , Day 7]

   Urine was collected over 24 h to measure Urinary Glucose Excretion (UGE) at baseline (Day -1), following a single dose (Day 1) and at the end of the 7-day treatment (Day 7) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function.

2. Maximum Observed Plasma Concentration (Cmax) for LIK066 [Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)]

   Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Cmax was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.

3. Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 [Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)]

   Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Tmax was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.

4. Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 [Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)]

   Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUCtau was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.

5. Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7 [Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)]

   Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUClast was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. AUClast is similar to AUCtau on Day 1 since the Tlast for Day 1 = 24hrs (tau = 24hrs); therefore AUClast is not reported for Day1, it is however reported for Day 7 since the Tlast is different from 24 hours. Only descriptive analysis done.

6. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1 [Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)]

   Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUCinf was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. AUCinf is a single dose parameter and therefore is presented on Day 1 only, after the first dose of LIK066. Only descriptive analysis done.

7. Terminal Elimination Half-life (T1/2) for LIK066 on Day 7 [Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)]

   Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. T1/2 was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. T1/2 is only reported at Day 7 only, since there was sampling out to ~5 half-lives after the Day 7 dose of LIK066. Only descriptive analysis done.

8. Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1 [Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)]

   Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. CL/F was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Since Day 7 represented steady state of LIK066 in the study, the appropriately calculated steady-state clearance parameter computed was CLss/F and was presented. Only descriptive analysis done.

9. Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1 [Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)]

   Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Vz/F was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.

10. Renal Clearance From Plasma (CLr) for LIK066 [Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)]

    Urine PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. CLr was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 78 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent must be obtained before any assessment is performed.

• Male and female subjects age 18-78 years, inclusive, with controlled health condition as determined by past medical history, physical examination, electrocardiogram and laboratory test at screening.

• patients with Type 2 diabetes, HbA1c <10% at screening.

• Body mass index (BMI) ≤ 50 kg/m^2 at screening.

Exclusion Criteria:

• Patients with Type 1 diabetes

• Evidence of clinically significant liver function test: ALT, AST, gamma-GT, alkaline phosphatase >3 X ULN; serum bilirubin > 1.5 X ULN.

• Patients undergoing any method of dialysis

• clinically significant GI disorder related to malabsorption or that may affect drug or glucose absorption.

• subjects who experienced ketoacidosis, lactic acidosis or hyperosmolar coma within 6 months of screening visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Orlando	Florida	United States	32809

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jan 11, 2017
• Statistical Analysis Plan - Feb 15, 2018

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03131479
• Other Study ID Numbers: CLIK066B2202; 2016-004770-18
• First Posted: Apr 27, 2017
• Last Update Posted: Jan 5, 2021
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: renal function; sodium-glucose co-transporter; pharmacokinetics; decreased renal function; decreased kidney function; kidney disease; urinary glucose excretion; UGE
• Additional relevant MeSH terms: Renal Insufficiency; Licogliflozin

Study Results

Participant Flow

Recruitment Details	This study was conducted at 1 centers in the United States.

Arm/Group Title	Mild	Moderate A	Moderate B	Severe	Normal
Arm/Group Description	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.
Period Title: Overall Study
STARTED	10	10	11	12	10
Safety Analysis Set (SS)	10	10	11	12	10
Pharmacokinetic Analysis Set (PAS)	10	10	11	12	10
Pharcodynamic Analysis Set (PD)	10	10	11	12	10
COMPLETED	10	10	10	10	10
NOT COMPLETED	0	0	1	2	0

Baseline Characteristics

Arm/Group Title	Mild	Moderate A	Moderate B	Severe	Normal	Total
Arm/Group Description	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Total of all reporting groups
Overall Participants	10	10	11	12	10	53
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.4 (9.03)	66.3 (8.10)	65.8 (9.10)	63.3 (12.66)	59.3 (8.17)	64.0 (9.66)
Sex: Female, Male (Count of Participants)
Female	6 60%	5 50%	8 72.7%	3 25%	6 60%	28 52.8%
Male	4 40%	5 50%	3 27.3%	9 75%	4 40%	25 47.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	1 10%	1 1.9%
Black or African American	3 30%	1 10%	3 27.3%	3 25%	4 40%	14 26.4%
White	7 70%	9 90%	8 72.7%	9 75%	5 50%	38 71.7%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
24-hour Urinary glucose excretion (UGE) (gram (g)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [gram (g)]	4.7 (9.96)	2.9 (6.27)	0.1 (0.12)	0.3 (0.77)	0.1 (0.07)	1.5 (5.25)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7
Description	Urine was collected over 24 h to measure Urinary Glucose Excretion (UGE) at baseline (Day -1), following a single dose (Day 1) and at the end of the 7-day treatment (Day 7) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function.
Time Frame	Baseline , Day 7

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Analysis Set (PD), which consisted of all participants with an observed PD value, was considered. Only patients with evaluable data at each time point were analyzed for that time point.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Mean (Standard Deviation) [gram (g)]	40.45 (21.93)	31.87 (13.79)	36.27 (19.51)	19.88 (18.66)	5.50 (3.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal, Mild
	Comments
	Type of Statistical Test	Equivalence
	Comments	Change from baseline was analyzed using a repeated measures model which included diabetic status, renal function, day and renal function*day and diabetic status*day as fixed factors and age, baseline body weight and baseline fasting plasma glucose as covariates.
Statistical Test of Hypothesis	p-Value	0.154
	Comments
	Method	Regression, Logistic
	Comments	An unstructured variance-covariance structure was used. Baseline is defined to be the measurement collected on Day -1.
Method of Estimation	Estimation Parameter	adjusted arithmetic mean difference
	Estimated Value	-9.21
	Confidence Interval	(2-Sided) 90%; -19.88 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Normal, Moderate A
	Comments
	Type of Statistical Test	Equivalence
	Comments	Change from baseline was analyzed using a repeated measures model which included diabetic status, renal function, day and renal function*day and diabetic status*day as fixed factors and age, baseline body weight and baseline fasting plasma glucose as covariates.
Statistical Test of Hypothesis	p-Value	0.343
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	adjusted arithmetic mean difference
	Estimated Value	-6.05
	Confidence Interval	(2-Sided) 90%; -16.65 to 4.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Normal, Moderate B
	Comments
	Type of Statistical Test	Equivalence
	Comments	Change from baseline was analyzed using a repeated measures model which included diabetic status, renal function, day and renal function*day and diabetic status*day as fixed factors and age, baseline body weight and baseline fasting plasma glucose as covariates.
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	adjusted arithmetic mean difference
	Estimated Value	-21.5
	Confidence Interval	(2-Sided) 90%; -31.79 to 4.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Normal, Severe
	Comments
	Type of Statistical Test	Equivalence
	Comments	Change from baseline was analyzed using a repeated measures model which included diabetic status, renal function, day and renal function*day and diabetic status*day as fixed factors and age, baseline body weight and baseline fasting plasma glucose as covariates.
Statistical Test of Hypothesis	p-Value	0.000
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	adjusted arithmetic mean difference
	Estimated Value	-35.6
	Confidence Interval	(2-Sided) 90%; -46.00 to -25.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) for LIK066
Description	Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Cmax was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time Frame	Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only patients with evaluable data at each time point were analyzed for that time point. Only descriptive analysis done.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Day 1	565 (176)	590 (176)	492 (142)	569 (147)	650 (199)
Day 7	650 (250)	678 (219)	686 (243)	743 (301)	800 (268)

3. Primary Outcome

Title	Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066
Description	Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Tmax was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time Frame	Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only patients with evaluable data at each time point were analyzed for that time point. Only descriptive analysis done.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Day 1	1.00	1.00	1.00	1.00	1.00
Day 7	1.00	1.03	1.00	1.00	1.00

4. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066
Description	Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUCtau was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time Frame	Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only patients with evaluable data at each time point were analyzed for that time point. Only descriptive analysis done.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Day 1	2830 (650)	3330 (563)	3120 (567)	3360 (886)	4150 (1040)
Day 7	3440 (790)	4170 (981)	4080 (1040)	4510 (1240)	6290 (2280)

5. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7
Description	Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUClast was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. AUClast is similar to AUCtau on Day 1 since the Tlast for Day 1 = 24hrs (tau = 24hrs); therefore AUClast is not reported for Day1, it is however reported for Day 7 since the Tlast is different from 24 hours. Only descriptive analysis done.
Time Frame	Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Mean (Standard Deviation) [hour*nanogram per milliliter (hr*ng/mL)]	4190 (1090)	5280 (1540)	5440 (1740)	6410 (2160)	9620 (3910)

6. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1
Description	Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. AUCinf was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. AUCinf is a single dose parameter and therefore is presented on Day 1 only, after the first dose of LIK066. Only descriptive analysis done.
Time Frame	Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Mean (Standard Deviation) [hour*nanogram per milliliter (hr*ng/mL)]	310 (688)	3610 (649)	3440 (551)	3520 (1000)	4450 (1480)

7. Primary Outcome

Title	Terminal Elimination Half-life (T1/2) for LIK066 on Day 7
Description	Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. T1/2 was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. T1/2 is only reported at Day 7 only, since there was sampling out to ~5 half-lives after the Day 7 dose of LIK066. Only descriptive analysis done.
Time Frame	Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Mean (Standard Deviation) [hour (hr)]	22.9 (20.3)	21.8 (10.8)	21.1 (9.25)	20.9 (8.91)	22.8 (9.52)

8. Primary Outcome

Title	Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1
Description	Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. CL/F was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Since Day 7 represented steady state of LIK066 in the study, the appropriately calculated steady-state clearance parameter computed was CLss/F and was presented. Only descriptive analysis done.
Time Frame	Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Mean (Standard Deviation) [Liter per hour (L/h)]	17.4 (4.20)	14.3 (2.59)	14.9 (2.55)	15.4 (4.87)	12.4 (4.53)

9. Primary Outcome

Title	Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1
Description	Plasma PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. Vz/F was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time Frame	Day 1 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only descriptive analysis done.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Mean (Standard Deviation) [Liter (L)]	160 (59.4)	140 (28.6)	164 (79.9)	176 (67.8)	134 (50.5)

10. Primary Outcome

Title	Renal Clearance From Plasma (CLr) for LIK066
Description	Urine PK samples were collected at Day 1 and Day 7 and assayed for LIK066 concentrations using validated liquid chromatography-tandem mass spectrometry assays (LC MS/MS). The method will have an LLOQ of at least 5 ng/mL for LIK066. Concentrations were expressed in mass per volume units and refered to LIK066 plasma concentrations. CLr was determined using the actual recorded sampling times and non-compartmental method(s) to assess the effect of a 7 day treatment with LIK066 in subjects with decreased renal function compared to those with normal renal function. Only descriptive analysis done.
Time Frame	Day 1 and Day 7 (0 hour predose and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least 1 valid PK concentration measurement, was considered. Only patients with evaluable data at each time point were analyzed for that time point. Only descriptive analysis done.

Arm/Group Title	Normal	Mild	Moderate A	Moderate B	Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.	Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.	Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.	Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
Measure Participants	10	10	10	11	12
Day 1	0.389 (0.179)	0.348 (0.141)	0.259 (0.114)	0.173 (0.0919)	0.0522 (0.0237)
Day 7	0.474 (0.275)	0.367 (0.0815)	0.294 (0.119)	0.174 (0.0636)	0.0694 (0.0461)

Adverse Events

Time Frame	Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 7 months
Arm/Group Title	Normal		Mild		Moderate A		Moderate B		Severe
Arm/Group Description	Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.		Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.		Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.		Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.		Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.
All Cause Mortality
	Normal		Mild		Moderate A		Moderate B		Severe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/11 (0%)		0/12 (0%)
Serious Adverse Events
	Normal		Mild		Moderate A		Moderate B		Severe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		1/11 (9.1%)		1/12 (8.3%)
Cardiac disorders
Acute left ventricular failure	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/11 (0%)		1/12 (8.3%)
Acute myocardial infarction	0/10 (0%)		0/10 (0%)		0/10 (0%)		1/11 (9.1%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Normal		Mild		Moderate A		Moderate B		Severe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/10 (90%)		10/10 (100%)		10/10 (100%)		11/11 (100%)		11/12 (91.7%)
Gastrointestinal disorders
Abdominal pain	2/10 (20%)		2/10 (20%)		1/10 (10%)		3/11 (27.3%)		3/12 (25%)
Diarrhoea	9/10 (90%)		10/10 (100%)		10/10 (100%)		10/11 (90.9%)		11/12 (91.7%)
Flatulence	7/10 (70%)		7/10 (70%)		6/10 (60%)		9/11 (81.8%)		7/12 (58.3%)
Nausea	0/10 (0%)		1/10 (10%)		0/10 (0%)		1/11 (9.1%)		1/12 (8.3%)
Vomiting	0/10 (0%)		0/10 (0%)		0/10 (0%)		1/11 (9.1%)		0/12 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/11 (0%)		1/12 (8.3%)
Metabolic acidosis	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/11 (0%)		1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/10 (0%)		0/10 (0%)		0/10 (0%)		1/11 (9.1%)		0/12 (0%)
Muscle spasms	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/11 (0%)		1/12 (8.3%)
Nervous system disorders
Dizziness	1/10 (10%)		0/10 (0%)		0/10 (0%)		1/11 (9.1%)		0/12 (0%)
Headache	0/10 (0%)		0/10 (0%)		0/10 (0%)		1/11 (9.1%)		1/12 (8.3%)
Tremor	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/11 (0%)		1/12 (8.3%)
Reproductive system and breast disorders
Vaginal haemorrhage	0/10 (0%)		0/10 (0%)		0/10 (0%)		1/11 (9.1%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.