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Pharmacokinetic Study of Icenticaftor in Participants With Hepatic Impairment

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ClinicalTrials.gov Identifier: NCT04587622
Recruitment Status : Recruiting
First Posted : October 14, 2020
Last Update Posted : March 18, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hepatic Failure Drug: Icenticaftor Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 30, 2020
Estimated Primary Completion Date : September 24, 2021
Estimated Study Completion Date : September 24, 2021

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 Name: 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 Name: 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 Name: 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 Name: QBW251




Primary Outcome Measures :
  1. Maximum observed icenticaftor plasma concentration (Cmax) after single oral dose [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-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).

  2. Area under the plasma concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of icenticaftor after single oral dose [ Time Frame: 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 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.

  3. Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of icenticaftor after single oral dose [ Time Frame: 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 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.

  4. Time to reach maximum icenticaftor plasma concentration (Tmax) after single oral dose [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-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).

  5. Apparent plasma clearance (CL/F) of icenticaftor after single oral dose [ Time Frame: 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 icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher).

  6. Apparent volume of distribution during terminal phase (Vz/F) of icenticaftor after single oral dose [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose ]
    Vz/F of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher).

  7. Elimination half-life (T1/2) of icenticaftor after single oral dose [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-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.


Secondary Outcome Measures :
  1. Plasma protein binding free fraction (unbound fraction [fu]) of icenticaftor [ Time Frame: 3 hours post-dose ]
    The free fraction in plasma fu of icenticaftor will be evaluated at 3 hours post-dose using equilibrium dialysis method.

  2. Cmax of unbound icenticaftor (Cmax,u) [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose ]
    Icenticaftor Cmax,u will be calculated as Cmax*fu.

  3. AUClast of unbound icenticaftor (AUClast,u) [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose ]
    Icenticaftor AUClast,u will be calculated as AUClast*fu.

  4. AUCinf of unbound icenticaftor (AUCinf,u) [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose ]
    Icenticaftor AUCinf,u will be calculated as AUCinf*fu.

  5. CL/F of unbound icenticaftor (CL/F,u) [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose ]
    Icenticaftor CL/F,u will be calculated as CL/F/fu.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04587622


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals

Locations
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United States, Florida
Novartis Investigative Site Recruiting
Miami, Florida, United States, 33014-3616
Novartis Investigative Site Active, not recruiting
Orlando, Florida, United States, 32809
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04587622    
Other Study ID Numbers: CQBW251A2104
First Posted: October 14, 2020    Key Record Dates
Last Update Posted: March 18, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Hepatic impairment
Child-Pugh classification
Icenticaftor
QBW251
Additional relevant MeSH terms:
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Liver Failure
Hepatic Insufficiency
Liver Diseases
Digestive System Diseases