Pharmacokinetics of BAF312 in Patients With Hepatic Impairment

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01565902
• Collaborator: (none)
• Enrollment: 40
• Locations: 3
• Arms: 4
• Duration (Months): 17
• Patients Per Site: 13.3
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This study will investigate the pharmacokinetics of BAF312 in patients with mild, moderate and severe hepatic impairment compared to healthy control subjects.

Condition or Disease	Intervention/Treatment	Phase
Hepatic Impairment	Drug: BAF312	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Single-dose, Open-label, Parallel-group Study to Assess the Pharmacokinetics of BAF312 in Subjects With Mild, Moderate and Severe Hepatic Impairment Compared to Healthy Control Subjects.
• Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mild hepatically impaired Treatment with a single oral dose of 0.25 mg BAF312	Drug: BAF312; Treatment with a single oral dose of 0.25 mg BAF312
Experimental: Moderate hepatically impaired Treatment with a single oral dose of 0.25 mg BAF312	Drug: BAF312; Treatment with a single oral dose of 0.25 mg BAF312
Experimental: Severe hepatically impaired Treatment with a single oral dose of 0.25 mg BAF312	Drug: BAF312; Treatment with a single oral dose of 0.25 mg BAF312
Experimental: Matched healthy subjects Treatment with a single oral dose of 0.25 mg BAF312	Drug: BAF312; Treatment with a single oral dose of 0.25 mg BAF312

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) [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.]

   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.

2. 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) [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.]

   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.

3. Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) [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]

   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

Secondary Outcome Measures

1. 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 [Day -1 to 22]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

All subjects:

• Male and female Caucasian subjects 18 to 70 years of age

• At least 50 kg and body mass index (BMI) within 18-35 kg/m2.

• CYP2C9 wild-type (CYP2C9*1 homozygous carriers)

Hepatic impairment:

• Subjects must have either mild, moderate or severe hepatic impairment

Exclusion Criteria:

All subjects

• Hepatic impairment due to non-liver disease.

• Use of other investigational drugs within certain timelines

• Donation or loss of 400 mL or more of blood or plasma within eight (8) weeks prior to initial dosing

• History of cardiac rhythm abnormalities or cardiac rhythm abnormalities identified in the 24-h Holter ECG recording including episodes of bradycardia (HR < 50 bpm) during waking hours and/or arrhythmic episodes; subjects with history or presence of ventricular rhythm disturbances (ventricular extra-systoles >100/24h, or higher grade), or supraventricular arrhythmias (other than occasional supraventricular ectopic beats with a maximum of 5 subsequent ectopic beats per event) or subjects with conduction disturbances (higher than AV-block grade 1) or bradycardia or tachycardia.

• History of cardiac catheter ablation.

• Women of child-bearing potential

• History of malignancy of any organ system

• Recent and/or recurrent history of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease)

• History or presence of symptomatic postural hypotension or syncope.

• Total WBC or lymphocyte counts which falls outside the 1.5-fold local laboratory normal range or platelet count < 30,000/μL at screening or baseline.

• Clinically significant infection or recent vaccination with live-attenuated vaccines.

• History or presence of hepatitis B or C and/or positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result at screening.

• History or presence of coronary heart disease (stable or unstable), myocardial infarction, myocarditis, cardiomyopathy, heart failure NYHA II - IV.

Hepatic impairment:

• History or presence of any non-controlled and clinically significant disease that could affect the study outcome or that would place the patient at undue risk.

• Any surgical or medical condition other than hepatic impairment which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the safety of the study subject in case of participation in the study.

• Treatment with certain drugs

Healthy subjects:

• History or presence of any clinically significant disease of any major system organ class including (but not limited to) cardiovascular, metabolic, renal, neurological or psychiatric diseases.

• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, drugs, or which may jeopardize the subject in case of participation in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Balatonfured		Hungary	8230
2	Novartis Investigative Site	Budapest		Hungary	1076
3	Novartis Investigative Site	Moscow		Russian Federation	115419

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Publication from the International Journal of Clinical Pharmacology and Therapeutics
• Results for CBAF312A2122 can be found on the Novartis Clinical Trial Results Website

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01565902
• Other Study ID Numbers: CBAF312A2122; 2012-000562-37
• First Posted: Mar 29, 2012
• Last Update Posted: Dec 29, 2020
• Last Verified: Feb 1, 2018

• Keywords provided by Novartis Pharmaceuticals: BAF312; Pharmacokinetics; Hepatic impairment
• Additional relevant MeSH terms: Liver Diseases; Siponimod

Study Results

Participant Flow

Recruitment Details	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
Pre-assignment Detail	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

Arm/Group Title	Mild Hepatically Impaired	Moderate Hepatically Impaired	Severe Hepatically Impaired	Matched Healthy Subjects
Arm/Group Description	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312
Period Title: Overall Study
STARTED	8	8	8	16
COMPLETED	8	8	8	16
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Mild Hepatically Impaired	Moderate Hepatically Impaired	Severe Hepatically Impaired	Matched Healthy Subjects	Total
Arm/Group Description	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Total of all reporting groups
Overall Participants	8	8	8	16	40
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.9 (6.20)	47.8 (6.30)	51.8 (3.41)	50.1 (5.50)	50.7 (5.65)
Sex: Female, Male (Count of Participants)
Female	2 25%	2 25%	4 50%	6 37.5%	14 35%
Male	6 75%	6 75%	4 50%	10 62.5%	26 65%

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)
Description	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.
Time Frame	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 Measure Data

Analysis Population Description

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

Arm/Group Title	Mild Hepatically Impaired	Moderate Hepatically Impaired	Severe Hepatically Impaired	Matched Healthy Subjects - Mild	Matched Healthy Subjects - Moderate	Matched Healthy Subjects - Severe
Arm/Group Description	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312
Measure Participants	8	7	8	8	8	8
Mean (Standard Deviation) [h*ng/mL]	68.3 (24.5)	53.9 (7.57)	73.7 (25.4)	64.2 (20.8)	63.2 (18.6)	64.9 (23.6)

2. Primary Outcome

Title	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)
Description	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.
Time Frame	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 Measure Data

Analysis Population Description

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

Arm/Group Title	Mild Hepatically Impaired	Moderate Hepatically Impaired	Severe Hepatically Impaired	Matched Healthy Subjects - Mild	Matched Healthy Subjects - Moderate	Matched Healthy Subjects - Severe
Arm/Group Description	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312
Measure Participants	8	7	8	8	8	8
Mean (Standard Deviation) [h*ng/mL]	66.8 (24.4)	52.3 (7.51)	71.6 (24.5)	62.5 (20.9)	61.7 (18.7)	63.4 (23.6)

3. Primary Outcome

Title	Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax)
Description	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
Time Frame	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 Measure Data

Analysis Population Description

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

Arm/Group Title	Mild Hepatically Impaired	Moderate Hepatically Impaired	Severe Hepatically Impaired	Matched Healthy Subjects - Mild	Matched Healthy Subjects - Moderate	Matched Healthy Subjects - Severe
Arm/Group Description	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312
Measure Participants	8	7	8	8	8	8
Mean (Standard Deviation) [(ng/mL)]	2.03 (0.532)	1.54 (0.191)	1.58 (0.304)	1.74 (0.439)	1.80 (0.417)	1.94 (0.603)

4. Secondary Outcome

Title	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
Description	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.
Time Frame	Day -1 to 22

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Mild Hepatically Impaired	Moderate Hepatically Impaired	Severe Hepatically Impaired	Matched Healthy Subjects
Arm/Group Description	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312	Treatment with a single oral dose of 0.25 mg BAF312
Measure Participants	8	8	8	16
At least one AE	0 0%	1 12.5%	1 12.5%	1 6.3%
Serious Adverse Events	0 0%	0 0%	0 0%	0 0%
Death	0 0%	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	Moderate Hepatically Impaired		Severe Hepatically Impaired		Matched Healthy Subjects		Mild Hepatically Impaired
Arm/Group Description	Treatment with a single oral dose of 0.25 mg BAF312		Treatment with a single oral dose of 0.25 mg BAF312		Treatment with a single oral dose of 0.25 mg BAF312		Treatment with a single oral dose of 0.25 mg BAF312
All Cause Mortality
	Moderate Hepatically Impaired		Severe Hepatically Impaired		Matched Healthy Subjects		Mild Hepatically Impaired
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Moderate Hepatically Impaired		Severe Hepatically Impaired		Matched Healthy Subjects		Mild Hepatically Impaired
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/16 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Moderate Hepatically Impaired		Severe Hepatically Impaired		Matched Healthy Subjects		Mild Hepatically Impaired
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)		1/8 (12.5%)		1/16 (6.3%)		0/8 (0%)
Cardiac disorders
Atrioventricular block first degree	0/8 (0%)		1/8 (12.5%)		0/16 (0%)		0/8 (0%)
Infections and infestations
Tonsillitis	1/8 (12.5%)		0/8 (0%)		0/16 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/8 (0%)		0/8 (0%)		1/16 (6.3%)		0/8 (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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety