Pharmacokinetics of TNO155 in Participants With Mild, Moderate, or Severe Hepatic Impairment Compared to Matched Healthy Participants

NCT05490030 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: CTNO155A12106
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to evaluate the effect of various degrees of hepatic impairment on plasma pharmacokinetics (PK), safety and tolerability of TNO155. The results of this study will guide the Novartis recommendation regarding whether or not a dose adjustment may be needed when treating patients with hepatic impairment.

Conditions

Hepatic Impairment

Keywords

Hepatic; Impairment; TNO155; Phase 1; pharmacokinetics; safety; Tolerability; Child-Pug

Outcome Measures

Primary Outcomes (9)

• Area under the concentration-versus-time curve (AUC) from time zero to the last measurable plasma concentration (AUClast) of TNO155

  AUClast will be calculated based on TNO155 plasma concentrations and non-compartmental methods.

  Up to 240 hours post single dose

• AUC from time zero to time "t" (AUC0-t) of TNO155

  AUC0-t will be calculated as needed based on TNO155 plasma concentrations and non-compartmental methods. The definition of time "t" may be data-driven post-hoc to mitigate treatment bias due to within participant differences in Tlast between the treatments, or may be selected to allow between-study exposure comparisons that use a common time window.

  Up to 240 hours post single dose

• AUC from time zero to infinity (AUCinf) of TNO155

  AUCinf will be calculated based on TNO155 plasma concentrations and non-compartmental methods.

  Up to 240 hours post single dose

• Maximum (peak) observed plasma concentration (Cmax) of TNO155

  Cmax will be calculated based on TNO155 plasma concentrations and non-compartmental methods.

  Up to 240 hours post single dose

• Time to reach maximum observed plasma concentration (Tmax) of TNO155

  Tmax will be calculated based on TNO155 plasma concentrations and non-compartmental methods

  Up to 240 hours post single dose

• Elimination half-life (T1/2) of TNO155

  T1/2 will be calculated based on TNO155 plasma concentrations and non-compartmental methods.

  Up to 240 hours post single dose

• Sampling time of the last measurable plasma concentration (Tlast) of TNO155

  Tlast will be calculated based on TNO155 plasma concentrations and non-compartmental methods.

  Up to 240 hours post single dose

• Apparent plasma clearance (CL/F) of TNO155

  CL/F will be calculated based on TNO155 plasma concentrations and non-compartmental methods.

  Up to 240 hours post single dose

• Apparent volume of distribution during terminal phase (Vz/F) of TNO155

  Vz/F will be calculated based on TNO155 plasma concentrations and non-compartmental methods.

  Up to 240 hours post single dose

Secondary Outcomes (8)

• Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Up to 30 days post single dose

• Unbound Cmax (Cmax,u) of TNO155

  Up to 240 hours post single dose

• Unbound AUClast (AUClast,u) of TNO155

  Up to 240 hours post single dose

• Unbound AUCinf (AUCinf,u) of TNO155

  Up to 240 hours post single dose

• Unbound CL/F (CL/F,u) of TNO155

  Up to 240 hours post single dose

Study Arms (4)

Group 1 (control)

EXPERIMENTAL

Healthy control participants with normal hepatic function

Drug: TNO155

Group 2 (score 5-6)

EXPERIMENTAL

Mild hepatic impairment: Child-Pugh A

Drug: TNO155

Group 3 (score 7-9)

EXPERIMENTAL

Moderate hepatic impairment: Child-Pugh B

Drug: TNO155

Group 4 (score 10-15)

EXPERIMENTAL

Severe hepatic impairment: Child-Pugh C. This group may be opened if allowed by the results of the interim analysis of the Groups 1 to 3.

Drug: TNO155

Interventions

TNO155 DRUG

Single oral dose of TNO155 on Day 1

Group 1 (control); Group 2 (score 5-6); Group 3 (score 7-9); Group 4 (score 10-15)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All participants Participants must weigh at least 50 kg and no more than 120 kg and must have a body mass index (BMI) within the range of 18.0 to 38.0 kg/m2, inclusive, for healthy participants. For participants with hepatic impairment without overt ascites, the BMI should be within the range of 18.0 to 40.0 kg/m2. For participants with hepatic impairment with overt ascites, the BMI should be within the range of 18.0 to 45.0 kg/m2.
• Group 1
• Each healthy control participant must match in age (± 10 years), sex, body weight (± 20%), and smoking status to at least 1 hepatic impairment participant in Groups 2, 3 and/or 4.
• Groups 2 to 4 •Participants with mild, moderate or severe hepatic impairment must have a Child-Pugh score clinically determined at screening and confirmed unchanged at baseline calculated as per the Child-Pugh classification in line with the hepatic impairment status of each Group

You may not qualify if:

• All Participants
• Use of drugs (prescription, non-prescription and herbal remedies such as St John's wort) known to affect CYP3A or UGT1A3, including UGT1A3 inhibitors and inducers and strong and moderate CYP3A inhibitors and inducers, within 4 weeks prior to dosing until completion of the End of Study Visit.
• Acute or chronic hepatitis B or C infection or active infection requiring therapy that will not be completed before screening.
• Left ventricular ejection fraction (LVEF) \< 50% or below the institutional standard lower limit, whichever is higher, as determined by multiple gated acquisition (MUGA) scan or Trans-thoracic echocardiography (TTE) at screening or baseline.
• At screening, history of retinal vein occlusion (RVO) or presence of predisposing factors to RVO or central serous retinopathy, or any other clinically significant ophthalmologic abnormalities determined by an ophthalmologist.
• Group 1
• Any single parameter of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) exceeding 2.5 × upper limit of normal (ULN) or total bilirubin ≥ 1.5 ULN OR any elevation above ULN of more than 1 parameter of ALT, AST, GGT, ALP, or serum bilirubin at screening or baseline.
• Impaired renal function as indicated by clinically significantly abnormal creatinine or blood urea nitrogen and/or other urea values outside local laboratory ranges or abnormal urinary constituents at screening or baseline.
• Groups 2 and 3
• Severe complications of liver disease within the preceding 3 months prior to dosing.
• Hospitalization due to liver disease within the preceding 1 month prior to dosing.
• Participant has received liver transplant at any time in the past and is on immunosuppressant therapy.
• Participants requiring paracentesis more than every 3 weeks for the management of ascites are excluded.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• Pharmaceutical Research Associates: collaborator

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The study will be divided into 2 parts. Participants in the hepatic impairment groups will be staged by their respective degree of hepatic impairment according to the Child Pugh classification score determined at the screening visit and confirmed unchanged at the baseline visit. Healthy participants who were identified and enrolled as matching partners for a hepatic impairment group in Part I can serve as matching partners for participants in hepatic impairment group in Part II if they fulfilled the matching criteria. Otherwise, additional matched healthy participants will be enrolled. Part I: will include participants with mild and moderate levels of hepatic impairment as well as healthy control participants assigned to the groups Part II: will include participants with severe hepatic impairment.

Study Record Dates

• First Submitted: August 4, 2022
• First Posted: August 5, 2022
• Study Start: March 6, 2025
• Primary Completion: June 26, 2025
• Study Completion: June 26, 2025
• Last Updated: February 29, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share