Pharmacokinetics of BAF312 in Patients With Hepatic Impairment

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.

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

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: BAF312

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Hungary
  • Balatonfured, Hungary, 8230
    • Novartis Investigative Site
  • Budapest, Hungary, 1076
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 115419
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)	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.	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.
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)	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.	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.
Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax)	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	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

Outcome Measure	Measure Description	Time Frame
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	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.	Day -1 to 22

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: March 26, 2012
• First Submitted That Met QC Criteria: March 26, 2012
• First Posted (Estimate): March 29, 2012

Study Record Updates

• Last Update Posted (Actual): December 29, 2020
• Last Update Submitted That Met QC Criteria: December 6, 2020
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Hepatic impairment; BAF312
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Siponimod
• Other Study ID Numbers: CBAF312A2122; 2012-000562-37 (EudraCT Number)