Pharmacokinetics and Safety of Fevipiprant in Patients With Renal Impairment Compared to Matched Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
The aim of the study is to assess whether renal impairment could affect fevipiprant pharmacokinetics (PK) to the extent that dosage adjustment is appropriate for this patient population. The study also aims to determine the effect of dialysis on the fevipiprant pharmacokinetic profile as the procedure might remove a significant fraction of the drug.

Detailed Description
-----------------
The purpose of this study is to determine if the pharmacokinetic profile of fevipiprant is different in patients with renal impariment compared to healthy matched volunteers to an extent that would require an adjustment of the dosage. Data from this study will be used to guide enrollment criteria in future clinical trials and to support regulatory submission and labeling information

Official Title
-----------------
An Open-label, Single-dose, Parallel Group Study to Assess the Pharmacokinetics of Fevipiprant (QAW039) in Patients With End-stage Renal Disease on Hemodialysis and Optionally in Patients With Severe to Moderate and Mild Renal Impairment Compared to Matched Healthy Volunteers Including a Cross-over Assessment in End-stage Renal Disease Patients on the Effect of Dialysis on Fevipiprant Pharmacokinetics

Conditions
-----------------
Renal Insufficiency

Intervention / Treatment
-----------------
* Drug: QAW039
* Drug: QAW39A
* Drug: QAW39A2107
* Drug: QAW39A2107


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy subjects must satisfy the criteria for normal renal function as evidenced by normal Glomerular Filtration Rate (GFR): eGFR ≥ 90 mL/min/1.73m2; each healthy subject must match in age (+/- 10years), gender, smoking status, and weight (+/- 15%), a patient from the renail impaired patient groups: A body mass index (BMI) within the range of 18 - 36 kg/m2 ESRD patients on hemodialysis: an glomerulo filtration rat GFR of < 15 mL/min/1.73 m2 patients with severe renal impairment: GFR of< 30 mL/min/1.73m2 (without need of hemodialysis); patients with moderate renal impairment: 30 mL/min/1.73m2 ≤ eGFR < 60 mL/min/1.73m2; patients with mild impairment: 60 mL/min/1.73m2 ≤ eGFR < 90 mL/min/1.73m2 Exclusion Criteria: Pregnant or nursing (lactating) women History or evidence of any inherited bilirubin disease or disorder subjects participating in another study malignancies in the past Hemoglobin levels below 10 g/dL at screening HIV positiv Heavy smokers (≥20 cigarettes per day) Liver disease, as indicated by ALT, γ-GT, AST and alkaline phosphatase which should not exceed twice the upper limit of normal and should be stable (e.g. increased liver values known from previous patient records). Serum bilirubin > 27 μmol/L (1.6 mg/dL) Clinically significant ECG changes and/or arrhythmias Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>ESRD patients | Drug: QAW039<br>* 450 mg<br>* Other names: fevipiprant;|
| Experimental: Group 2<br>healthy volunteers | Drug: QAW39A<br>* 450 mg<br>* Other names: fevipiprant;|
| Experimental: Group 3<br>severe and moderate renal impaired patients | Drug: QAW39A2107<br>* 450 mg<br>* Other names: fevipiprant;|
| Experimental: Group 4<br>mild renal impaired patients | Drug: QAW39A2107<br>* 450 mg<br>* Other names: fevipiprant;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Plasma concentration of fevipiprant by AUClast | AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration | 68 hours post dose | 
| Pharmacokinetics: Plasma concentration of fevipiprant by AUCinf | AUCinf is the area under the plasma concentration-time curve from time zero to infinity | 68 hours post dose | 
| Pharmacokinetics: Plasma concentration of fevipiprant by Cmax | Cmax is the observed maximum plasma concentration following drug administration | 68 hours post dose | 
| Pharmacokinetics: Plasma contentration of fevipiprant by AUC0-68h | AUC0-68h is the area under the plasma concentration from time zero to time 68 hours of the last measured concentration above the limit of quantification after dosing | 68 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship between plasma pharmacokinetics of fevipiprant by AUClast and between eGFR as well as creatinine clearance | AUClast (the area under the plasma concentration time curve from time zero to the time of the last quantifiable concentration ) related to eGFR estimated by the Modification of Diet in Renal Disease (MDRD) formula, and Cockcroft-Gault (C-G) estimated creatinine clearance | 68 hours post dose | 
| Relationship between plasma pharmacokinetics of fevipiprant by AUCinf and between eGFR as well as creatinine clearance | AUCinf (the area under the plasma concentration time curve from time zero to infinity) related to eGFR estimated by the Modification of Diet in Renal Disease (MDRD) formula, and Cockcroft-Gault (C-G) estimated creatinine clearance | 68 hours post dose | 
| Relationship between plasma pharmacokinetics of fevipiprant by Cmax and between eGFR as well as creatinine clearance | Cmax (observed maximum plasma concentration following drug administration) related to eGFR estimated by the Modification of Diet in Renal Disease (MDRD) formula, and Cockcroft-Gault (C-G) estimated creatinine clearance | 68 hours post dose | 
| Pharmacokinetics of the metabolite CCN362 by AUClast | AUClast is the area under the plasma concentration time curve from time zero to the time of the last quantifiable concentration | 68 hours post dose | 
| Pharmacokinetics of the metabolite CCN362 by AUCinf | AUCinf is the area under the plasma concentration time curve from time zero to infinity | 68 hours post dose | 
| Pharmacokinetics of the metabolite CCN362 by Cmax | Cmax is the observed maximum plasma concentration following drug administration | 68 hours post dose | 
| Pharmacokinetics: plasma concentration of fevipiprant in patients with End Stage Renal Disease (ESRD) | Partial AUCs (AUCt1-t2) covering the time interval of dialysis, Cmax and total AUCs (AUC0-68h and/or AUCinf) will be compared | 68 hours post dose | 
| urinary excretion of fevipiprant and metabolite in patients with renal impairment compared to healthy controls | Renal clearance (CLr) and fraction of dose excreted in urine for fevipiprant and metabolite | 24 hours post dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
end stage renal disase ESRD, dialysis effect on pharmacokinetics PK, renal impairment