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

A Phase 1, Open-label, Single-dose, Multi-center, Parallel Group Study to Evaluate the Pharmacokinetics of TNO155 in Participants With Mild, Moderate, or Severe Renal Impairment Compared to Matched Healthy Control Participants

The purpose of this Phase 1 study is to evaluate the effect of various degrees of renal 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 renal impairment

Study Overview

• Status: Withdrawn
• Conditions: Renal Impairment
• Intervention / Treatment: Drug: TNO155

Detailed Description

This is a study to evaluate the PK of TNO155 in participants with mild, moderate or severe renal impairment compared to matched healthy control participants with normal renal function. The study will be divided into 2 parts. Participants in the renal impairment groups will be staged by their respective degree of renal function (mild, moderate, or severe) according to the estimated glomerular filtration rate (eGFR) determined at the screening visit. Each renal impairment participant must be matched to a healthy control participant with respect to age (±10 years), body weight (±20%) and sex. Each participant in the healthy control group (Group 1) can be matched to one or more participants from any renal impairment group (Groups 2, 3, and 4).

On Day 1 morning, participants will receive a single oral dose of TNO155 .All participants will be domiciled from Day -1 until Day 11. All participants should have a poststudy safety follow-up contact conducted approximately 30 days after administration of study treatment. The study will be considered complete once all the participants have finished the required assessments, dropped out, or been lost to follow-up before completing the required assessments.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

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. Must be a non-smoker or and agree to remain a non-smoker from screening until the End of Study.

Group 1

•eGFR as determined by Chronic Kidney Disease Epidemiology Collaboration [CKD EPI] equation and conversion within normal range as determined by GFR 90 mL/min at screening and baseline.

Groups 2 to 4

• Participants with different levels of impaired renal function satisfying criteria for renal impairment as determined at screening by the eGFR at screening
• Participants must have documented stable renal disease without evidence of renal progressive disease

Exclusion Criteria:

All Participants

• Use of drugs (prescription, non-prescription and herbal remedies such as St John's wort), within 4 weeks prior to dosing until completion of the End of Study Visit.
• Participant has received a renal transplant at any time in the past and is on immunosuppressant therapy Left ventricular ejection fraction (LVEF) < 50% or below the institutional standard lower limit, at screening or baseline.
• Uncontrolled hypertension despite medical treatment at screening or baseline. Group 1
• Significant illness, which has not been resolved within 2 weeks prior to dosing of study treatment.
• History or presence of renal disease or kidney injury Groups 2, 3 and 4
• Severe albuminuria
• Other laboratory values grade 2 severity according to NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE)
• Participants undergoing any method of dialysis.
• Participants with renal impairment due to hepatic disease (hepatorenal syndrome).

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• 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 control participants with normal renal function	Drug: TNO155; Single oral dose of TNO155 on Day 1
Experimental: Group 2; Mild renal impairment	Drug: TNO155; Single oral dose of TNO155 on Day 1
Experimental: Group 3; Moderate renal impairment	Drug: TNO155; Single oral dose of TNO155 on Day 1
Experimental: Group 4; Severe renal impairment	Drug: TNO155; Single oral dose of TNO155 on Day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 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
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.	AUC from time zero to time "t" (AUC0-t) of TNO155

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Incidence of AEs and SAEs, including changes in vital signs, electrocardiograms (ECGs) and laboratory results qualifying and reported as AEs.	Up to 30 days post single dose
Unbound Cmax (Cmax,u) of TNO155	Cmax,u will be calculated based on the unbound fraction of TNO155 in plasma.	Up to 240 hours post single dose
Unbound AUClast (AUClast,u) of TNO155	AUClast,u will be calculated based on the unbound fraction of TNO155 in plasma.	Up to 240 hours post single dose
Unbound AUCinf (AUCinf,u) of TNO155	AUCinf,u will be calculated based on the unbound fraction of TNO155 in plasma	Up to 240 hours post single dose
Unbound CL/F (CL/F,u) of TNO155	CL/F,u will be calculated based on the unbound fraction of TNO155 in plasma.	Up to 240 hours post single dose
Renal clearance (CLr) of TNO155	CLr will be calculated based on urinary excretion data of TNO155.	Up to 240 hours post single dose
Apparent non-renal clearance (CLNR/F) of TNO155	CLNR/F will be calculated based on urinary excretion data of TNO155.	Up to 240 hours post single dose
Fraction of dose excreted in urine (fe) of TNO155	Fe will be calculated based on urinary excretion data of TNO155.	Up to 240 hours post single dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Pharmaceutical Research Associates
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Estimated): March 19, 2025
• Primary Completion (Estimated): July 15, 2025
• Study Completion (Estimated): July 15, 2025

Study Registration Dates

• First Submitted: September 12, 2022
• First Submitted That Met QC Criteria: September 12, 2022
• First Posted (Actual): September 15, 2022

Study Record Updates

• Last Update Posted (Actual): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: SHP2; TNO155; renal Impairment
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency
• Other Study ID Numbers: CTNO155A12105

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
• product manufactured in and exported from the U.S.: No