Pharmacokinetics, Dialysability and Safety of P03277 in Healthy Volunteers and in Patients With Impaired Renal Function

Study Overview
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Brief Summary
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This is an open-label, non-randomized, successive cohorts design, multicenter, single dose phase I study. The primary objectives are: to evaluate the pharmacokinetics (plasma and urine) profile of P03277 following single intravenous injection (0.1 mmol/kg body weight) in patients with mild to severe renal impairment and in healthy volunteers with normal renal function used as reference. to assess dialysability of P03277 following a single intravenous injection (0.1 mmol/kg body weight) in patients with end stage renal disease requiring hemodialysis.

Detailed Description
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A full range design including the different degrees of renal impairment and healthy volunteers used as reference has been chosen. Enrolment will be successive starting with both healthy volunteers (cohort 1) and patients with mild renal impairment (cohort 2), then patients with moderate renal impairment (cohort 3), then patients with severe renal impairment (cohort 4) to end with patients with end stage renal disease (cohort 5). Pharmacokinetics and safety profiles following the confinement period will be reviewed per each successive cohort by a Data Monitoring Committee before starting recruitment of patients in the next cohort. Cohorts 1 and 2 will be recruited in parallel and Data Monitoring Committee review will start after the completion of these first two cohorts.

Official Title
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Pharmacokinetics, Dialysability and Safety of P03277, a New Gadolinium-based Contrast Agent, in Healthy Volunteers and in Patients With Impaired Renal Function

Conditions
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Renal Insufficiency, Healthy Volunteers

Intervention / Treatment
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* Drug: P03277


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For all subjects: Subject being 18 years or older, able and willing to participate in the trial Subject in good enough health status as determined by investigator according to medical history, physical examination, vital signs, 12 lead ECG and laboratory tests at screening and inclusion For healthy volunteers / cohort 1: Healthy volunteer with stable normal renal function defined with an absolute value of eGFR ≥ 90 mL/min based on two eGFR assessments done at screening and inclusion, with a maximum tolerance of 15% between the 2 measurements For patients with renal impairment / cohorts 2 to 5: Cohort 2: patient with stable mild renal impairment defined with an absolute value of eGFR between 60 and 89 mL/min included based on two eGFR assessments done at screening and inclusion, with a maximum tolerance of 15% between the 2 measurements Cohort 3: patient with stable moderate renal impairment defined with an absolute value of eGFR between 30 and 59 mL/min included based on two eGFR assessments done at screening and inclusion, with a maximum tolerance of 15% between the 2 measurements Cohort 4: patient with stable severe renal impairment defined with an absolute value of eGFR between 15 and 29 mL/min included based on two eGFR assessments done at screening and inclusion, with a maximum tolerance of 15% between the 2 measurements Cohort 5: patient with end-stage renal failure who requires 3 hemodialysis sessions per week

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Successive cohorts design and single dose administration
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>P03277 will be administered to healthy volunteers with stable normal renal function defined with an absolute value of eGFR ≥ 90 mL/min. | Drug: P03277<br>* Single intravenous bolus injection at 0.1 mmol/kg body weight at a rate of 2 mL/second<br>* Other names: gadopiclenol;|
| Experimental: Cohort 2<br>P03277 will be administered to patients with stable mild renal impairment defined with an absolute value of eGFR between 60 and 89 mL/min. | Drug: P03277<br>* Single intravenous bolus injection at 0.1 mmol/kg body weight at a rate of 2 mL/second<br>* Other names: gadopiclenol;|
| Experimental: Cohort 3<br>P03277 will be administered to patients with stable moderate renal impairment defined with an absolute value of eGFR between 30 and 59 mL/min. | Drug: P03277<br>* Single intravenous bolus injection at 0.1 mmol/kg body weight at a rate of 2 mL/second<br>* Other names: gadopiclenol;|
| Experimental: Cohort 4<br>P03277 will be administered to patients with stable severe renal impairment defined with an absolute value of eGFR between 15 and 29 mL/min. | Drug: P03277<br>* Single intravenous bolus injection at 0.1 mmol/kg body weight at a rate of 2 mL/second<br>* Other names: gadopiclenol;|
| Experimental: Cohort 5<br>P03277 will be administered to patients with end-stage renal failure who requires 3 hemodialysis sessions per week. | Drug: P03277<br>* Single intravenous bolus injection at 0.1 mmol/kg body weight at a rate of 2 mL/second<br>* Other names: gadopiclenol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | AUC: area under the plasma concentration curve. Blood samples will be collected. | Prior to P03277 administration and at 2, 5, 10, 20, 30, 45 minutes and at 1, 2, 4, 6, 8, 12, 24 hours after administration for all cohorts. Additionally, after P03277 administration at 48 hours (cohorts 2-3-4), 72 hours (cohort 3) and 96 hours (cohort 4) | 
| Cmax | Cmax: peak concentration. Blood samples will be collected. | Prior to P03277 administration and at 2, 5, 10, 20, 30, 45 minutes and at 1, 2, 4, 6, 8, 12, 24 hours after administration for all cohorts. Additionally, after P03277 administration at 48 hours (cohorts 2-3-4), 72 hours (cohort 3) and 96 hours (cohort 4) | 
| t1/2 | t1/2: terminal half-life. Blood samples will be collected. | Prior to P03277 administration and at 2, 5, 10, 20, 30, 45 minutes and at 1, 2, 4, 6, 8, 12, 24 hours after administration for all cohorts. Additionally, after P03277 administration at 48 hours (cohorts 2-3-4), 72 hours (cohort 3) and 96 hours (cohort 4) | 
| CLT | CLT: total clearance. Blood samples will be collected. | Prior to P03277 administration and at 2, 5, 10, 20, 30, 45 minutes and at 1, 2, 4, 6, 8, 12, 24 hours after administration for all cohorts. Additionally, after P03277 administration at 48 hours (cohorts 2-3-4), 72 hours (cohort 3) and 96 hours (cohort 4) | 
| Ae | Ae: amount excreted. Urine samples will be collected. | Prior to P03277 administration and during the intervals 0-6, 6-24, 24-48 hours for all cohorts + during 48-72 and 72-96 hours intervals for cohorts 2-3-4, 96-120 hours interval for cohorts 3-4, 120-144 hours and 144-168 hours intervals for cohort 4 | 
| Relative amount of eliminated P03277 in blood | This outcome will be assessed for cohort 5 only. Venous blood samples will be collected at each session of hemodialysis. | Just before the start of the session and at 30, 90 minutes and 4 hours after the start of the session. | 
| Clearance of P03277 | This outcome will be assessed for cohort 5 only and at the first hemodialysis only. Arterial and venous blood samples will be collected. | Just before the start of the session and at 30 and 90 minutes after the start of the session. | 
| Dialysis clearance of P03277 | This outcome will be assessed for cohort 5 only. Venous blood and dialysate samples will be collected at each session of hemodialysis. | Just before the start of the session and at 30, 90 minutes and 4 hours after the start of the session. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P03277concentration in blood (long-term) | Blood samples will be collected. | At 1, 3 and 6 months after P03277 administration | 
| P03277 concentration in urine (long-term) | Urine samples will be collected. | At 1, 3 and 6 months after P03277 administration |