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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Renal Impairment

Intervention / Treatment
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* Drug: LIK066


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 78 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on 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. | Baseline , Day 7 | 
| Maximum Observed Plasma Concentration (Cmax) for LIK066 | 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. | 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) | 
| Time to Reach the Maximum Plasma Concentration (Tmax) for LIK066 | 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. | 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) | 
| Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for LIK066 | 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. | 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) | 
| Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for LIK066 on Day 7 | 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. | 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) | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for LIK066 on Day 1 | 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. | 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) | 
| Terminal Elimination Half-life (T1/2) for LIK066 on Day 7 | 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. | 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) | 
| Apparent Systemic (or Total Body) Clearance From Plasma Following Extravascular Administration (CL/F) for LIK066 on Day 1 | 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. | 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) | 
| Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) for LIK066 on Day 1 | 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. | 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) | 
| Renal Clearance From Plasma (CLr) for LIK066 | 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. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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decreased kidney function, kidney disease, urinary glucose excretion, renal function, sodium-glucose co-transporter, pharmacokinetics, decreased renal function, UGE