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

Primary Purpose

Renal Impairment

Status

Not yet recruiting

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

TNO155

About this trial

This is an interventional diagnostic trial for Renal Impairment focused on measuring TNO155, renal Impairment, SHP2

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Group 1

Group 2

Group 3

Group 4

Arm Description

Healthy control participants with normal renal function

Mild renal impairment

Moderate renal impairment

Severe renal impairment

Outcomes

Primary Outcome Measures

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.

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 infinity (AUCinf) of TNO155

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

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

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

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

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

Elimination half-life (T1/2) of TNO155

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

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

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

Apparent plasma clearance (CL/F) of TNO155

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

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.

Secondary Outcome Measures

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.

Unbound Cmax (Cmax,u) of TNO155

Cmax,u will be calculated based on the unbound fraction of TNO155 in plasma.

Unbound AUClast (AUClast,u) of TNO155

AUClast,u will be calculated based on the unbound fraction of TNO155 in plasma.

Unbound AUCinf (AUCinf,u) of TNO155

AUCinf,u will be calculated based on the unbound fraction of TNO155 in plasma

Unbound CL/F (CL/F,u) of TNO155

CL/F,u will be calculated based on the unbound fraction of TNO155 in plasma.

Renal clearance (CLr) of TNO155

CLr will be calculated based on urinary excretion data of TNO155.

Apparent non-renal clearance (CLNR/F) of TNO155

CLNR/F will be calculated based on urinary excretion data of TNO155.

Fraction of dose excreted in urine (fe) of TNO155

Fe will be calculated based on urinary excretion data of TNO155.

Full Information

NCT ID

NCT05541159

First Posted

September 12, 2022

Last Updated

July 27, 2023

Sponsor

Novartis Pharmaceuticals

Collaborators

Pharmaceutical Research Associates

1. Study Identification

Unique Protocol Identification Number

NCT05541159

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Not yet recruiting

Study Start Date

February 15, 2024 (Anticipated)

Primary Completion Date

June 12, 2024 (Anticipated)

Study Completion Date

June 12, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

Collaborators

Pharmaceutical Research Associates

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Renal Impairment

Keywords

TNO155, renal Impairment, SHP2

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Model Description

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 determined at the screening visit. Healthy participants who were identified and enrolled as matching partners for a renal impairment group in Part I can serve as matching partners for participants in renal impairment group (Group 4) 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 renal impairment as well as healthy control participants Part II: will include participants with severe renal impairment, if allowed after results of interim analysis (IA) obtained for mild and moderate groups.

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

48 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Group 1

Arm Type

Experimental

Arm Description

Healthy control participants with normal renal function

Arm Title

Group 2

Arm Type

Experimental

Arm Description

Mild renal impairment

Arm Title

Group 3

Arm Type

Experimental

Arm Description

Moderate renal impairment

Arm Title

Group 4

Arm Type

Experimental

Arm Description

Severe renal impairment

Intervention Type

Drug

Intervention Name(s)

TNO155

Intervention Description

Single oral dose of TNO155 on Day 1

Primary Outcome Measure Information:

Title

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

Description

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

Time Frame

Up to 240 hours post single dose

Title

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

Description

Time Frame

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

Title

AUC from time zero to infinity (AUCinf) of TNO155

Description

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

Time Frame

Up to 240 hours post single dose

Title

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

Description

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

Time Frame

Up to 240 hours post single dose

Title

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

Description

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

Time Frame

Up to 240 hours post single dose

Title

Elimination half-life (T1/2) of TNO155

Description

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

Time Frame

Up to 240 hours post single dose

Title

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

Description

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

Time Frame

Up to 240 hours post single dose

Title

Apparent plasma clearance (CL/F) of TNO155

Description

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

Time Frame

Up to 240 hours post single dose

Title

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

Description

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

Time Frame

Up to 240 hours post single dose

Secondary Outcome Measure Information:

Title

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

Description

Incidence of AEs and SAEs, including changes in vital signs, electrocardiograms (ECGs) and laboratory results qualifying and reported as AEs.

Time Frame

Up to 30 days post single dose

Title

Unbound Cmax (Cmax,u) of TNO155

Description

Cmax,u will be calculated based on the unbound fraction of TNO155 in plasma.

Time Frame

Up to 240 hours post single dose

Title

Unbound AUClast (AUClast,u) of TNO155

Description

AUClast,u will be calculated based on the unbound fraction of TNO155 in plasma.

Time Frame

Up to 240 hours post single dose

Title

Unbound AUCinf (AUCinf,u) of TNO155

Description

AUCinf,u will be calculated based on the unbound fraction of TNO155 in plasma

Time Frame

Up to 240 hours post single dose

Title

Unbound CL/F (CL/F,u) of TNO155

Description

CL/F,u will be calculated based on the unbound fraction of TNO155 in plasma.

Time Frame

Up to 240 hours post single dose

Title

Renal clearance (CLr) of TNO155

Description

CLr will be calculated based on urinary excretion data of TNO155.

Time Frame

Up to 240 hours post single dose

Title

Apparent non-renal clearance (CLNR/F) of TNO155

Description

CLNR/F will be calculated based on urinary excretion data of TNO155.

Time Frame

Up to 240 hours post single dose

Title

Fraction of dose excreted in urine (fe) of TNO155

Description

Fe will be calculated based on urinary excretion data of TNO155.

Time Frame

Up to 240 hours post single dose

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Novartis Pharmaceuticals

Phone

1-888-669-6682

novartis.email@novartis.com

First Name & Middle Initial & Last Name or Official Title & Degree

Novartis Pharmaceuticals

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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