Trial Outcomes & Findings for Pharmacokinetics of BAF312 in Patients With Hepatic Impairment (NCT NCT01565902)

Results Overview

The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

40 participants

Primary outcome timeframe

pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.

Results posted on

2020-12-29

Participant Flow

Up to forty-eight subjects were planned to be enrolled in four groups. A total of 40 subjects were enrolled and completed the study. All subjects were included in the safety and PK analysis. However, only 38 subjects were included for primary PK analysis based on matched pair analysis

To potentially reduce the number of healthy subjects exposed to BAF312, study allowed for multiple matching of subjects with hepatic impairment to healthy subjects. During the study, 2 healthy subjects were not matched to any of the subjects with hepatic impairment due to a retrospective identification of a better matching partner

Participant milestones

Participant milestones
Measure	Mild Hepatically Impaired Treatment with a single oral dose of 0.25 mg BAF312	Moderate Hepatically Impaired Treatment with a single oral dose of 0.25 mg BAF312	Severe Hepatically Impaired Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects Treatment with a single oral dose of 0.25 mg BAF312
Overall Study STARTED	8	8	8	16
Overall Study COMPLETED	8	8	8	16
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pharmacokinetics of BAF312 in Patients With Hepatic Impairment

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Mild Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Moderate Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Severe Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects n=16 Participants Treatment with a single oral dose of 0.25 mg BAF312	Total n=40 Participants Total of all reporting groups
Age, Continuous	53.9 Years STANDARD_DEVIATION 6.20 • n=5 Participants	47.8 Years STANDARD_DEVIATION 6.30 • n=7 Participants	51.8 Years STANDARD_DEVIATION 3.41 • n=5 Participants	50.1 Years STANDARD_DEVIATION 5.50 • n=4 Participants	50.7 Years STANDARD_DEVIATION 5.65 • n=21 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	6 Participants n=4 Participants	14 Participants n=21 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	6 Participants n=7 Participants	4 Participants n=5 Participants	10 Participants n=4 Participants	26 Participants n=21 Participants

PRIMARY outcome

Timeframe: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.

Population: The PK analysis set consists of all completed subjects with quantifiable pharmacokinetic (PK) measurements. To reduce the number of healthy subjects exposed to BAF312, study allowed matching of subjects with hepatic impairment to healthy subjects. A healthy subject served as matching partner for up to 3 subjects with hepatic impairment

The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.

Outcome measures

Outcome measures
Measure	Mild Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Moderate Hepatically Impaired n=7 Participants Treatment with a single oral dose of 0.25 mg BAF312	Severe Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Mild n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Moderate n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Severe n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312
Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)	68.3 h*ng/mL Standard Deviation 24.5	53.9 h*ng/mL Standard Deviation 7.57	73.7 h*ng/mL Standard Deviation 25.4	64.2 h*ng/mL Standard Deviation 20.8	63.2 h*ng/mL Standard Deviation 18.6	64.9 h*ng/mL Standard Deviation 23.6

PRIMARY outcome

Timeframe: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.

Population: The PK analysis set consists of all completed subjects with quantifiable pharmacokinetic (PK) measurements. To reduce the number of healthy subjects exposed to BAF312, study allowed matching of subjects with hepatic impairment to healthy subjects. A healthy subject served as matching partner for up to 3 subjects with hepatic impairment

The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.

Outcome measures

Outcome measures
Measure	Mild Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Moderate Hepatically Impaired n=7 Participants Treatment with a single oral dose of 0.25 mg BAF312	Severe Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Mild n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Moderate n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Severe n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312
Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)	66.8 h*ng/mL Standard Deviation 24.4	52.3 h*ng/mL Standard Deviation 7.51	71.6 h*ng/mL Standard Deviation 24.5	62.5 h*ng/mL Standard Deviation 20.9	61.7 h*ng/mL Standard Deviation 18.7	63.4 h*ng/mL Standard Deviation 23.6

PRIMARY outcome

Timeframe: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose

Population: The PK analysis set consists of all completed subjects with quantifiable pharmacokinetic (PK) measurements. To reduce the number of healthy subjects exposed to BAF312, study allowed matching of subjects with hepatic impairment to healthy subjects. A healthy subject served as matching partner for up to 3 subjects with hepatic impairment

The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose

Outcome measures

Outcome measures
Measure	Mild Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Moderate Hepatically Impaired n=7 Participants Treatment with a single oral dose of 0.25 mg BAF312	Severe Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Mild n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Moderate n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Severe n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312
Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax)	2.03 (ng/mL) Standard Deviation 0.532	1.54 (ng/mL) Standard Deviation 0.191	1.58 (ng/mL) Standard Deviation 0.304	1.74 (ng/mL) Standard Deviation 0.439	1.80 (ng/mL) Standard Deviation 0.417	1.94 (ng/mL) Standard Deviation 0.603

SECONDARY outcome

Timeframe: Day -1 to 22

Population: The safety analysis set consists of all subjects that received study drug and with no protocol deviations with relevant impact on safety.

Physical examination, vital signs, body temperature, standard safety laboratory evaluations (hematology, clinical chemistry, coagulation, Hepatitis B and C and HIV serology, α-fetoprotein \[in hepatically impaired subjects only\], pregnancy test, alcohol and drug screen), standard 12-lead electrocardiogram , cardiac monitoring, 24-h Holter ECG, suicidality assessment (C-SSRS), (serious) adverse event monitoring.

Outcome measures

Outcome measures
Measure	Mild Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Moderate Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Severe Hepatically Impaired n=8 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Mild n=16 Participants Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Moderate Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects - Severe Treatment with a single oral dose of 0.25 mg BAF312
Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 At least one AE	0 Participants	1 Participants	1 Participants	1 Participants	—	—
Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 Serious Adverse Events	0 Participants	0 Participants	0 Participants	0 Participants	—	—
Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 Death	0 Participants	0 Participants	0 Participants	0 Participants	—	—

Adverse Events

Moderate Hepatically Impaired

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Severe Hepatically Impaired

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Matched Healthy Subjects

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Mild Hepatically Impaired

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Moderate Hepatically Impaired n=8 participants at risk Treatment with a single oral dose of 0.25 mg BAF312	Severe Hepatically Impaired n=8 participants at risk Treatment with a single oral dose of 0.25 mg BAF312	Matched Healthy Subjects n=16 participants at risk Treatment with a single oral dose of 0.25 mg BAF312	Mild Hepatically Impaired n=8 participants at risk Treatment with a single oral dose of 0.25 mg BAF312
Cardiac disorders Atrioventricular block first degree	0.00% 0/8	12.5% 1/8	0.00% 0/16	0.00% 0/8
Infections and infestations Tonsillitis	12.5% 1/8	0.00% 0/8	0.00% 0/16	0.00% 0/8
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/8	0.00% 0/8	6.2% 1/16	0.00% 0/8

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee 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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety
Publication restrictions are in place

Restriction type: OTHER