Pharmacokinetic Study of Icenticaftor in Participants With Hepatic Impairment

A Phase 1, Open-label, Single-dose, Parallel-group Study to Evaluate the Systemic Pharmacokinetics of Icenticaftor in Participants With Mild, Moderate, or Severe Hepatic Impairment Compared to Matched Healthy Control Participants

The primary purpose of this study is to evaluate the effect of hepatic impairment on the systemic pharmacokinetics, safety, and tolerability of icenticaftor in participants with varying degrees of hepatic impairment.

Study Overview

• Status: Completed
• Conditions: Hepatic Failure
• Intervention / Treatment: Drug: Icenticaftor

Detailed Description

This is a Phase 1, multi-center study with parallel groups. The study employs a single-dose, open-label design in subjects with mild, moderate, or severe hepatic impairment along with matched healthy control subjects with normal hepatic function. Subjects with normal hepatic function will be matched with subjects with hepatic impairment for gender, age (± 10 years), body weight (± 15%), and smoking status (smoker or non-smoker).

Up to a total of 48 participants will be enrolled in this study (approximately 8 in each mild [Child-Pugh A], moderate [Child-Pugh B], severe hepatic impairment [Child-Pugh C] groups), and up to 24 healthy control subjects). Each participant will receive a single oral dose of 300 mg of icenticaftor (QBW251) on Day 1 under fasting conditions.

The study is comprised of an up to 28-day screening period (Days -28 to -1), a baseline evaluation (Day -1) prior to treatment on Day 1, and a follow-up period of 7 days for pharmacokinetics (PK) sample collection (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose). A safety follow-up contact will be done 30 days after administration of the study drug.

The primary purpose of this study is to evaluate the effect of hepatic impairment on the systemic PK, safety, and tolerability of icenticaftor in participants with varying degrees of hepatic impairment.

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

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33014-3616
      • Novartis Investigative Site
    • Orlando, Florida, United States, 32809
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

All Participants:

Inclusion Criteria:

• Male and non-child bearing potential female participants, 18 to 75 years of age (inclusive) at Screening.
• Participants must weigh at least 50.0 kg and must have a body mass index (BMI) within the range of 18.0 to 38.0 kg/m2, inclusive, at Screening.
• Must be a non-smoker or agree to smoke no more than 5 cigarettes (or equivalent) per day from Screening until the End of Study. Participants must maintain the same smoking status throughout the study (i.e. smoker or non smoker).

Exclusion Criteria:

• Use of other investigational drugs within 5 half-lives prior to dosing of study treatment, or within 30 days, whichever is longer; or longer if required by local regulations.
• Are taking medications prohibited to be taken with the study treatment
• Known history of, or current clinically significant arrhythmias. Have clinically significant ECG abnormality or history of long-QT syndrome or whose QT interval corrected by Fridericia's formula (QTcF) is prolonged (> 480 msec) at Screening. Participants having myocardial infarction ≥ 5 years ago are eligible to participate.
• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection.

Healthy Participants:

• Each participant must match in age (± 10 years), gender, weight (± 15%), and smoking status to participants in Group 2, 3, or 4.
• Seated vital signs must be within the following ranges at Screening and Baseline:
• Body temperature, 35.0 to 37.5°C, inclusive.
• Systolic blood pressure, 89 to 149 mmHg, inclusive.
• Diastolic blood pressure, 50 to 89 mmHg, inclusive.
• Pulse rate, 40 to 90 bpm, inclusive.
• Participants must be in good health as determined by medical history, physical examination, ECG, and clinical laboratory tests at Screening.

Exclusion Criteria:

• Liver disease or liver injury as indicated by abnormal liver function tests.
• Chronic infection with HBV or HCV.
• History or presence of impaired renal function.

Hepatic Impairment Participants:

Inclusion Criteria:

• Seated vital signs must be within the following ranges at Screening and Baseline:
• Body temperature, 35.0 to 37.5°C, inclusive.
• Systolic blood pressure, 89 to 159 mmHg, inclusive.
• Diastolic blood pressure, 50 to 99 mmHg, inclusive.
• Pulse rate, 50 to 99 bpm, inclusive.
• Hepatic impairment as defined by the Child-Pugh classification for severity of liver disease

Exclusion Criteria:

• Have severe complications of liver disease within the preceding 3 months of Screening.
• Emergency room visit or hospitalization due to liver disease within the preceding 3 months of Screening.
• Have received liver transplant at any time in the past.
• Have encephalopathy Grade 3 or worse within 28 days prior to dosing of study treatment.
• Have acute hepatitis B (HBV) or hepatitis C (HCV) infection.
• Clinically significant abnormal findings in physical examination or clinical laboratory evaluations not consistent with known liver disease.

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1 - Healthy subjects with normal hepatic function; Healthy subjects with normal hepatic function - Control	Drug: Icenticaftor; Single oral dose of 300 mg of icenticaftor (QBW251); Other Names: QBW251
Experimental: Group 2 - Mild Hepatic Impairment; Mild hepatic impairment: Child-Pugh A (Score 5-6)	Drug: Icenticaftor; Single oral dose of 300 mg of icenticaftor (QBW251); Other Names: QBW251
Experimental: Group 3 - Moderate Hepatic Impairment; Moderate hepatic impairment: Child-Pugh B (Score 7-9)	Drug: Icenticaftor; Single oral dose of 300 mg of icenticaftor (QBW251); Other Names: QBW251
Experimental: Group 4 - Severe Hepatic Impairment; Severe hepatic impairment: Child-Pugh C (Score 10-15)	Drug: Icenticaftor; Single oral dose of 300 mg of icenticaftor (QBW251); Other Names: QBW251

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed icenticaftor plasma concentration (Cmax) after single oral dose	Icenticaftor plasma concentrations will be determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Cmax of icenticaftor will be determined with Phoenix WinNonlin (Version 6.4 or higher).	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
Area under the plasma concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of icenticaftor after single oral dose	AUClast of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher). The linear trapezoidal rule will be used for AUClast calculation.	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of icenticaftor after single oral dose	AUCinf of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher). The linear trapezoidal rule will be used for AUCinf calculation.	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
Time to reach maximum icenticaftor plasma concentration (Tmax) after single oral dose	Icenticaftor plasma concentrations will be determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Tmax of icenticaftor will be determined with Phoenix WinNonlin (Version 6.4 or higher).	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
Apparent plasma clearance (CL/F) of icenticaftor after single oral dose	CL/F of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher).	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
Apparent volume of distribution during terminal phase (Vz/F) of icenticaftor after single oral dose	Vz/F of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher).	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
Elimination half-life (T1/2) of icenticaftor after single oral dose	T1/2 of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher). Regression analysis of the terminal plasma elimination phase will be used for T1/2 calculation.	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma protein binding free fraction (unbound fraction [fu]) of icenticaftor	The free fraction in plasma fu of icenticaftor will be evaluated at 3 hours post-dose using equilibrium dialysis method.	3 hours post-dose
Cmax of unbound icenticaftor (Cmax,u)	Icenticaftor Cmax,u will be calculated as Cmax*fu.	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
AUClast of unbound icenticaftor (AUClast,u)	Icenticaftor AUClast,u will be calculated as AUClast*fu.	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
AUCinf of unbound icenticaftor (AUCinf,u)	Icenticaftor AUCinf,u will be calculated as AUCinf*fu.	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
CL/F of unbound icenticaftor (CL/F,u)	Icenticaftor CL/F,u will be calculated as CL/F/fu.	pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CQBW251A2104 from the Novartis Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2020
• Primary Completion (Actual): September 15, 2022
• Study Completion (Actual): September 15, 2022

Study Registration Dates

• First Submitted: September 29, 2020
• First Submitted That Met QC Criteria: October 13, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Actual): August 21, 2023
• Last Update Submitted That Met QC Criteria: August 17, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Hepatic impairment; Child-Pugh classification; QBW251; Icenticaftor
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency
• Other Study ID Numbers: CQBW251A2104

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No