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This open-label study will assess the effects of hepatic impairment on the pharmacokinetics of a single oral dose of aleglitazar in subjects with mild or moderate hepatic impairment (Child-Pugh class A or B) and in matched control subjects with normal hepatic function. Subjects will receive a single oral dose of aleglitazar, with assessment of the pharmacokinetics of aleglitazar on Days 1-5. Anticipated duration of study for each enrolled subject is approximately 6 weeks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Mild impairment | Experimental |
| |
| Moderate impairment | Experimental |
| |
| Normal HF | Experimental |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| aleglitazar | Drug | single oral dose |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Aleglitazar | AUCinf was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Maximum Plasma Concentration (Cmax) of Aleglitazar | Cmax was obtained directly from the concentration-time data. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| AUCinf of M1 (RO4408754) and M6 (RO4583746) | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. AUCinf was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Trials | Hoffmann-La Roche | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Orlando | Florida | 32809 | United States | |||
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A total of 38 participants with normal hepatic function, or with mild or moderate hepatic impairment were enrolled from 30 September 2010 to 05 August 2011 at 2 study sites in the U. S.
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| ID | Title | Description |
|---|---|---|
| FG000 | Normal Hepatic Function | Participants with normal hepatic function received a single oral dose of aleglitazar 150 microgram (mcg) tablet |
| FG001 | Mild Hepatic Impairment | Participants with mild hepatic impairment received a single oral dose of aleglitazar 150 mcg tablet |
| FG002 | Moderate Hepatic Impairment | Participants with moderate hepatic impairment received a single oral dose of aleglitazar 150 mcg tablet |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Normal Hepatic Function | Participants with normal hepatic function received a single oral dose of aleglitazar 150 microgram (mcg) tablet |
| BG001 | Mild Hepatic Impairment | Participants with mild hepatic impairment received a single oral dose of aleglitazar 150 mcg tablet |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Aleglitazar | AUCinf was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | The pharmacokinetics (PK) analysis population consisted of all participants who received the study drug and adhered to the protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours (h)*nanogram (ng)/milliliter (mL) | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
|
Up to 6 weeks
SAEs and other AEs were collected in the safety population, which was defined as all enrolled participants who received the single dose of the study drug, whether prematurely withdrawn from the study or not.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Normal Hepatic Function | Participants with normal hepatic function received a single oral dose of aleglitazar 150 microgram (mcg) tablet |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ascites | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Roche Trial Information Hotline | F. Hoffmann-La Roche AG | +41 61 6878333 | global.trial_information@roche.com |
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| ID | Term |
|---|---|
| C542437 | aleglitazar |
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| Cmax of M1 and M6 | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. Cmax was obtained directly from the concentration-time data. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Post-dose (AUC0-48) of Aleglitazar, M1, and M6 | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. AUC0-48 was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Area Under the Plasma Concentration-time Curve From 0 to the Last Quantifiable Time-point Post-dose (AUClast) of Aleglitazar, M1, and M6 | AUClast was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Apparent Total Body Clearance (CL/F) of Aleglitazar | CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Renal Clearance (CLR) of Aleglitazar, M1, and M6 | CLR was calculated as Ae0-48/AUC0-48, where Ae0-48 as amount excreted in urine from time 0 to 48 hours post-dose and AUC0-48 represents area under the concentration-time curve of the analyte in plasma over the time interval from zero to the 48 hours post-dose. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72, and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
| Apparent Non-renal Clearance (CLNR/F) of Aleglitazar | Plasma and urine samples were collected for this PK parameter. CLNR/F was estimated as CL/F, based on the approximated formula of CLNR/F = (CL-CLR)/F with CLR of aleglitazar being equal to zero. CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. CLR was calculated as Ae0-48/AUC0-48, where Ae0-48 as amount excreted in urine from time zero to 48 hours post-dose and AUC0-48 represents area under the concentration-time curve of the analyte in plasma over the time interval from zero to the 48 hours post-dose. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
| Time of Maximum Plasma Concentration (Tmax) of Aleglitazar, M1, and M6 | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. Tmax was measured as time to reach the maximum concentration in the plasma after post-dose. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Apparent Terminal Half-life (t½) of Aleglitazar, M1, and M6 | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. T1/2 is the time required for a given drug concentration in the plasma to decrease by 50%. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Elimination Rate Constant (Kel) of Aleglitazar | The kel is fraction of a substance that is removed per unit time measured at any particular instant. It was calculated using at least 3 concentration-time points and ideally covered more than 2 half-lives. | 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
| Apparent Volume of Distribution (Vz/F) of Aleglitazar | Vz/F is the apparent volume of distribution during terminal phase after non-intravenous administration. It was calculated as CL/F/kel, where CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity and kel as constant elimination rate of aleglitazar. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
| Amount Excreted in Urine From Time 0 to 48 Hours Post-dose (Ae0-48) of Aleglitazar, M1, and M6 | The cumulative amount excreted in urine Ae0-48 over the entire collection interval of 48 hours was calculated by adding the Ae of the intervals 0-4, 4-8, 8-12, 12-24, and 24-48 hours, where Ae was calculated by multiplying the urine volume within the collection interval by the associated drug concentration. | 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
| Fraction of Drug Excreted in Urine From Time 0 to 48 Hours Post-dose (fe0-48) of Aleglitazar | fe0-48 was calculated as Ae0-48/dose. The cumulative amount excreted in urine Ae0-48 over the entire collection interval of 48 hours was calculated by adding the Ae of the intervals 0-4, 4-8, 8-12, 12-24, and 24-48 hours. Ae was calculated by multiplying the urine volume within the collection interval by the associated drug concentration. | 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
| Mean of Fraction of Unbound Aleglitazar (fu) | fu was calculated using the mean of the 2-hour (reflecting Cmax) and 24-hour (reflecting Ctrough) values for each participant or, if the result of only one time-point was available, fu was the result of the available time-point. Ctrough) is a measured concentration at the end of a dosing interval at steady state. | 2 and 24 hours post-dose |
| Area Under the Unbound Plasma Concentration-time Curve of Aleglitazar From Time 0 to Infinity (AUCu,Inf) | AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. It was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. It was assessed using an analysis of variance model on the log-transformed values of AUCinf of aleglitazar with hepatic impairment group as factor. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Maximum Unbound Plasma Concentration (Cmax,u) of Aleglitazar | Cmax was obtained directly from the concentration-time data. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Area Under the Unbound Plasma Concentration-time Curve of Aleglitazar From 0 to the Last Quantifiable Time-point Post-dose (AUCu,Last) | Plasma samples were collected for this PK parameter. AUClast represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero 0 to the last quantifiable time-point post-dose. It was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. AUClast was extrapolated to AUCinf by adding the ratio of Clast/kel to the AUClast, where Clast was the last observed concentration and kel was elimination rate constant. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Area Under the Unbound Plasma Concentration-time Curve of Aleglitazar From Time 0 to 48 Hours Post-dose (AUCu,0-48) | AUClast represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero to the 48 hours post-dose. It was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
| Apparent Unbound Volume of Distribution (Vz/Fu) of Aleglitazar | VzF/u is an apparent volume of Unbound distribution during terminal phase after non-intravenous administration. It was calculated as CL/F/kel, where CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity and kel as constant elimination rate of aleglitazar. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
| Apparent Unbound Total Body Clearance (CL/Fu) of Aleglitazar | CL/F is an apparent total clearance of the drug from plasma after oral administration. It was calculated as dose/AUCinf. AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
| Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), Death, and Study Discontinuation | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. | Up to 6 weeks |
| Number of Participants With Low and High Electrocardiograms (ECGs) Parameter Values | The ECG evaluations were performed after participants were at rest and in supine position for at least 5 minutes before recording and remain resting and supine during the recordings. ECGs parameters included heart rate (HR), RR interval, PR interval, QRS duration, QT interval, QTcB, and QTcF intervals. The normal ranges of ECG parameter values were: HR as 40-100 beats per minute, RR as 600-1500 milliseconds (msec), PR as 120-200 msec, QRS as 80-120 msec, QT as 200-500 msec, QTcB as 350-450 msec, and QTcF as 350-450 msec. Data was reported as the number of participants who had low level values (values less than the normal range) and high level values (values more than the normal range). | Screening (Days -28 to -2), baseline (Day -1), Days 1 to 5, and follow-up visit (Day 10) |
| Number of Participants With Low and High Vital Signs Values | Vital signs were assessed after participants had rested in a supine position for no less than 5 minutes. Vital signs included systolic blood pressure, diastolic blood pressure, pulse rate, and oral body temperature. The normal ranges of vital signs were: systolic blood pressure as 90-140 millimeter of Hg (mm Hg), diastolic blood pressure as 50-90 mm Hg, pulse rate as 45-100 beats per minute, and oral body temperature as 36.3-37.5 degree Celsius. Data was reported as the number of participants who had low level values (values less than the normal range) and high level values (values more than the normal range). | Days -28 to -2, Day -1, Days 1 to 5, and Day 10 for blood pressure and pulse rate; and Days -28 to -2, Day -1, and Day 10 for oral body temperature |
| Number of Participants With Marked Abnormalities in Clinical Laboratory Parameters | Laboratory parameters included hematology, coagulation, biochemistry, and urinalysis. A marked abnormality was defined as a test result which was outside of the marked abnormality range. Data was reported as the number of participants who had low level values (values less than the normal range) and high level values (values more than the normal range). | Up to 6 weeks |
| Knoxville |
| Tennessee |
| 37920 |
| United States |
| BG002 | Moderate Hepatic Impairment | Participants with moderate hepatic impairment received a single oral dose of aleglitazar 150 mcg tablet |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
Participants with mild hepatic impairment received a single oral dose of aleglitazar 150 mcg tablet |
| OG002 | Moderate Hepatic Impairment | Participants with moderate hepatic impairment received a single oral dose of aleglitazar 150 mcg tablet |
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| Secondary | AUCinf of M1 (RO4408754) and M6 (RO4583746) | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. AUCinf was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Primary | Maximum Plasma Concentration (Cmax) of Aleglitazar | Cmax was obtained directly from the concentration-time data. | The pharmacokinetics (PK) analysis population consisted of all participants who received the study drug and adhered to the protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Cmax of M1 and M6 | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. Cmax was obtained directly from the concentration-time data. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Post-dose (AUC0-48) of Aleglitazar, M1, and M6 | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. AUC0-48 was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Area Under the Plasma Concentration-time Curve From 0 to the Last Quantifiable Time-point Post-dose (AUClast) of Aleglitazar, M1, and M6 | AUClast was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Apparent Total Body Clearance (CL/F) of Aleglitazar | CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Renal Clearance (CLR) of Aleglitazar, M1, and M6 | CLR was calculated as Ae0-48/AUC0-48, where Ae0-48 as amount excreted in urine from time 0 to 48 hours post-dose and AUC0-48 represents area under the concentration-time curve of the analyte in plasma over the time interval from zero to the 48 hours post-dose. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72, and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
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| Secondary | Apparent Non-renal Clearance (CLNR/F) of Aleglitazar | Plasma and urine samples were collected for this PK parameter. CLNR/F was estimated as CL/F, based on the approximated formula of CLNR/F = (CL-CLR)/F with CLR of aleglitazar being equal to zero. CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. CLR was calculated as Ae0-48/AUC0-48, where Ae0-48 as amount excreted in urine from time zero to 48 hours post-dose and AUC0-48 represents area under the concentration-time curve of the analyte in plasma over the time interval from zero to the 48 hours post-dose. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
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| Secondary | Time of Maximum Plasma Concentration (Tmax) of Aleglitazar, M1, and M6 | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. Tmax was measured as time to reach the maximum concentration in the plasma after post-dose. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. | Posted | Mean | Full Range | h | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Apparent Terminal Half-life (t½) of Aleglitazar, M1, and M6 | M1 and M6 are pharmacologically inactive metabolites of aleglitazar. T1/2 is the time required for a given drug concentration in the plasma to decrease by 50%. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Elimination Rate Constant (Kel) of Aleglitazar | The kel is fraction of a substance that is removed per unit time measured at any particular instant. It was calculated using at least 3 concentration-time points and ideally covered more than 2 half-lives. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | 1/h | 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
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| Secondary | Apparent Volume of Distribution (Vz/F) of Aleglitazar | Vz/F is the apparent volume of distribution during terminal phase after non-intravenous administration. It was calculated as CL/F/kel, where CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity and kel as constant elimination rate of aleglitazar. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | L | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
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| Secondary | Amount Excreted in Urine From Time 0 to 48 Hours Post-dose (Ae0-48) of Aleglitazar, M1, and M6 | The cumulative amount excreted in urine Ae0-48 over the entire collection interval of 48 hours was calculated by adding the Ae of the intervals 0-4, 4-8, 8-12, 12-24, and 24-48 hours, where Ae was calculated by multiplying the urine volume within the collection interval by the associated drug concentration. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | mcg | 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
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| Secondary | Fraction of Drug Excreted in Urine From Time 0 to 48 Hours Post-dose (fe0-48) of Aleglitazar | fe0-48 was calculated as Ae0-48/dose. The cumulative amount excreted in urine Ae0-48 over the entire collection interval of 48 hours was calculated by adding the Ae of the intervals 0-4, 4-8, 8-12, 12-24, and 24-48 hours. Ae was calculated by multiplying the urine volume within the collection interval by the associated drug concentration. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. Only participants with data available for specific study drug/metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | mcg | 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
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| Secondary | Mean of Fraction of Unbound Aleglitazar (fu) | fu was calculated using the mean of the 2-hour (reflecting Cmax) and 24-hour (reflecting Ctrough) values for each participant or, if the result of only one time-point was available, fu was the result of the available time-point. Ctrough) is a measured concentration at the end of a dosing interval at steady state. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. Only participants with data available for specific study drug/metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Percentage | 2 and 24 hours post-dose |
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| Secondary | Area Under the Unbound Plasma Concentration-time Curve of Aleglitazar From Time 0 to Infinity (AUCu,Inf) | AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. It was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. It was assessed using an analysis of variance model on the log-transformed values of AUCinf of aleglitazar with hepatic impairment group as factor. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. Only participants with data available for specific study drug/metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Maximum Unbound Plasma Concentration (Cmax,u) of Aleglitazar | Cmax was obtained directly from the concentration-time data. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. Only participants with data available for specific study drug/metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Area Under the Unbound Plasma Concentration-time Curve of Aleglitazar From 0 to the Last Quantifiable Time-point Post-dose (AUCu,Last) | Plasma samples were collected for this PK parameter. AUClast represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero 0 to the last quantifiable time-point post-dose. It was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. AUClast was extrapolated to AUCinf by adding the ratio of Clast/kel to the AUClast, where Clast was the last observed concentration and kel was elimination rate constant. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. Only participants with data available for specific study drug/metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Area Under the Unbound Plasma Concentration-time Curve of Aleglitazar From Time 0 to 48 Hours Post-dose (AUCu,0-48) | AUClast represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero to the 48 hours post-dose. It was calculated by non-compartmental analysis using the linear trapezoidal rule, using relative actual time values. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. Only participants with data available for specific study drug/metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose |
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| Secondary | Apparent Unbound Volume of Distribution (Vz/Fu) of Aleglitazar | VzF/u is an apparent volume of Unbound distribution during terminal phase after non-intravenous administration. It was calculated as CL/F/kel, where CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity and kel as constant elimination rate of aleglitazar. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific metabolite were analyzed. Only participants with data available for specific study drug/metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | L | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
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| Secondary | Apparent Unbound Total Body Clearance (CL/Fu) of Aleglitazar | CL/F is an apparent total clearance of the drug from plasma after oral administration. It was calculated as dose/AUCinf. AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity. | The PK analysis population consisted of all participants who received the study drug and adhered to the protocol. Only participants with data available for specific study drug/metabolite were analyzed. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 15, 24, 36, 48, 72 and 96 hours post-dose for plasma; 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose for urine |
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| Secondary | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), Death, and Study Discontinuation | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. | The safety analysis consisted of all participants who had received the single dose of the study drug (aleglitazar), whether prematurely withdrawn from the study or not. | Posted | Number | participants | Up to 6 weeks |
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| Secondary | Number of Participants With Low and High Electrocardiograms (ECGs) Parameter Values | The ECG evaluations were performed after participants were at rest and in supine position for at least 5 minutes before recording and remain resting and supine during the recordings. ECGs parameters included heart rate (HR), RR interval, PR interval, QRS duration, QT interval, QTcB, and QTcF intervals. The normal ranges of ECG parameter values were: HR as 40-100 beats per minute, RR as 600-1500 milliseconds (msec), PR as 120-200 msec, QRS as 80-120 msec, QT as 200-500 msec, QTcB as 350-450 msec, and QTcF as 350-450 msec. Data was reported as the number of participants who had low level values (values less than the normal range) and high level values (values more than the normal range). | The safety analysis consisted of all participants who had received the single dose of the study drug (aleglitazar), whether prematurely withdrawn from the study or not. | Posted | Number | participants | Screening (Days -28 to -2), baseline (Day -1), Days 1 to 5, and follow-up visit (Day 10) |
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| Secondary | Number of Participants With Low and High Vital Signs Values | Vital signs were assessed after participants had rested in a supine position for no less than 5 minutes. Vital signs included systolic blood pressure, diastolic blood pressure, pulse rate, and oral body temperature. The normal ranges of vital signs were: systolic blood pressure as 90-140 millimeter of Hg (mm Hg), diastolic blood pressure as 50-90 mm Hg, pulse rate as 45-100 beats per minute, and oral body temperature as 36.3-37.5 degree Celsius. Data was reported as the number of participants who had low level values (values less than the normal range) and high level values (values more than the normal range). | The safety analysis consisted of all participants who had received the single dose of the study drug (aleglitazar), whether prematurely withdrawn from the study or not. | Posted | Number | participants | Days -28 to -2, Day -1, Days 1 to 5, and Day 10 for blood pressure and pulse rate; and Days -28 to -2, Day -1, and Day 10 for oral body temperature |
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| Secondary | Number of Participants With Marked Abnormalities in Clinical Laboratory Parameters | Laboratory parameters included hematology, coagulation, biochemistry, and urinalysis. A marked abnormality was defined as a test result which was outside of the marked abnormality range. Data was reported as the number of participants who had low level values (values less than the normal range) and high level values (values more than the normal range). | The safety analysis consisted of all participants who had received the single dose of the study drug (aleglitazar), whether prematurely withdrawn from the study or not. | Posted | Number | participants | Up to 6 weeks |
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| 0 |
| 18 |
| 3 |
| 18 |
| EG001 | Mild Hepatic Impairment | Participants with mild hepatic impairment received a single oral dose of aleglitazar 150 mcg tablet | 0 | 10 | 0 | 10 |
| EG002 | Moderate Hepatic Impairment | Participants with moderate hepatic impairment received a single oral dose of aleglitazar 150 mcg tablet | 1 | 10 | 1 | 10 |
| Diarrhoea | Gastrointestinal disorders | MedDRA (14.1) | Non-systematic Assessment |
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| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA (14.1) | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (14.1) | Non-systematic Assessment |
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| Nasal decongestion therapy | Surgical and medical procedures | MedDRA (14.1) | Non-systematic Assessment |
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The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
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This statistical analysis consisted of all evaluable hepatic impaired participants for whom at least one evaluable matching healthy participant was available. One Participant with moderate hepatic impairment was not included in the statistical analysis of the PK parameters as there was no appropriate participant with normal hepatic function match.
| Geometric Least-Squares Mean Ratio |
| 1.0782 |
| 2-Sided |
| 90 |
| 0.8941 |
| 1.3002 |
| No |
| Superiority or Other |
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| M6 (n = 18, 10, 9) |
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| M6 (n= 18, 10, 10) |
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| M1 (n = 18, 9, 9) |
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| M6 (n = 18, 10, 9) |
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| M6 |
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| M6 (n = 18, 10, 9) |
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| M1 (n = 18, 10, 10) |
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| M6 (n = 18, 10, 10) |
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This statistical analysis consisted of all evaluable hepatic impaired participants for whom at least one evaluable matching healthy participant was available. One participant with moderate hepatic impairment was not included in the statistical analysis of the PK parameters as there was no appropriate participant with normal hepatic function match.
| Geometric Least-Squares Mean Ratio |
| 1.5587 |
| 2-Sided |
| 90 |
| 1.2165 |
| 1.9971 |
| No |
| Superiority or Other |
This statistical analysis consisted of all evaluable hepatic impaired participants for whom at least one evaluable matching healthy participant was available. One participant with moderate hepatic impairment was not included in the statistical analysis of the PK parameters as there was no appropriate participant with normal hepatic function match.
| GeometricLeast-Squares Mean Ratio |
| 1.2254 |
| 2-Sided |
| 90 |
| 0.9836 |
| 1.5266 |
| No |
| Superiority or Other |
| Title | Measurements |
|---|---|
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| Death |
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| Study discontinuation |
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| Title | Measurements |
|---|---|
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| RR - high |
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| RR - low |
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| PR - high |
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| PR - low |
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| QRS - high |
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| QRS - low |
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| QT - high |
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| QT - low |
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| QTcB - high |
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| QTcB - low |
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| QTcF - high |
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| QTcF - low |
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| Diastolic blood pressure - high |
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| Diastolic blood pressure - low |
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| Pulse rate - high |
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| Pulse rate - low |
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| Oral body temperature - high |
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| Oral body temperature - low |
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| Title | Measurements |
|---|---|
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| Phosphate - high |
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| Blood - high |
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| Glucose - high |
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| Protein - high |
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