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

Primary Purpose

Renal Impairment

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

LIK066

About this trial

This is an interventional treatment trial for Renal Impairment focused on measuring renal function, sodium-glucose co-transporter, pharmacokinetics, decreased renal function, decreased kidney function, kidney disease, urinary glucose excretion, UGE

Eligibility Criteria

18 Years - 78 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Mild

Moderate A

Moderate B

Severe

Normal

Arm 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.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT03131479

First Posted

April 17, 2017

Last Updated

December 9, 2020

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT03131479

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2019

Overall Recruitment Status

Completed

Study Start Date

April 28, 2017 (Actual)

Primary Completion Date

January 16, 2018 (Actual)

Study Completion Date

January 16, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Renal Impairment

Keywords

renal function, sodium-glucose co-transporter, pharmacokinetics, decreased renal function, decreased kidney function, kidney disease, urinary glucose excretion, UGE

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Non-Randomized

Enrollment

53 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Mild

Arm Type

Experimental

Arm Description

Patients with mild renal impairment (Group 1) received LIK066 50 mg qd before breakfast for 7 days.

Arm Title

Moderate A

Arm Type

Experimental

Arm Description

Patients with moderate renal impairment grade A (Group 2) received LIK066 50 mg qd before breakfast for 7 days.

Arm Title

Moderate B

Arm Type

Experimental

Arm Description

Patients with moderate renal impairment grade B (Group 3) received LIK066 50 mg qd before breakfast for 7 days.

Arm Title

Severe

Arm Type

Experimental

Arm Description

Patients with severe renal impairment (Group 4) received LIK066 50 mg qd before breakfast for 7 days.

Arm Title

Normal

Arm Type

Experimental

Arm Description

Patients with normal renal function (Group 5) received LIK066 50 mg qd before breakfast for 7 days.

Intervention Type

Drug

Intervention Name(s)

LIK066

Intervention Description

LIK066 50 mg tablets taken orally once daily before breakfast for 7 days.

Primary Outcome Measure Information:

Title

Change From Baseline in 24-hour Urinary Glucose Excretion (UGE) on Day 7

Description

Time Frame

Baseline , Day 7

Title

Maximum Observed Plasma Concentration (Cmax) for LIK066

Description

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)

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)

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)

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)

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)

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)

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)

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)

Title

Renal Clearance From Plasma (CLr) for LIK066

Description

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)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

78 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Orlando

State/Province

Florida

ZIP/Postal Code

32809

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

IPD Sharing URL

https://www.clinicalstudydatarequest.com

Links:

URL

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=371

Description

A Plain Language Trial Summary is available on novartisclinicatrials.com

Learn more about this trial

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

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