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

Phase 1

Completed

• Conditions: Renal Insufficiency; Healthy Volunteers
• Interventions: Drug: P03277

• Registration Number: NCT03657784
• Lead Sponsor: Guerbet

Brief Summary

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

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.

Study Timeline

• Study Start: 2017-10-13
• Study First Submitted: 2018-08-31
• Study First Submitted QC: 2018-08-31
• Study First Posted: 2018-09-05
• Status Verified: 2019-02
• Primary Completion: 2019-02-01
• Study Completion: 2019-08-23
• Last Update Submitted: 2019-10-21
• Last Update Posted: 2019-10-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1	P03277	P03277 will be administered to healthy volunteers with stable normal renal function defined with an absolute value of eGFR ≥ 90 mL/min.
Cohort 2	P03277	P03277 will be administered to patients with stable mild renal impairment defined with an absolute value of eGFR between 60 and 89 mL/min.
Cohort 3	P03277	P03277 will be administered to patients with stable moderate renal impairment defined with an absolute value of eGFR between 30 and 59 mL/min.
Cohort 4	P03277	P03277 will be administered to patients with stable severe renal impairment defined with an absolute value of eGFR between 15 and 29 mL/min.
Cohort 5	P03277	P03277 will be administered to patients with end-stage renal failure who requires 3 hemodialysis sessions per week.

Primary Outcome Measures

Name	Time	Method
AUC	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)	AUC: area under the plasma concentration curve. Blood samples will be collected.
Cmax	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: peak concentration. Blood samples will be collected.
t1/2	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: terminal half-life. Blood samples will be collected.
CLT	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: total clearance. Blood samples will be collected.
Ae	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	Ae: amount excreted. Urine samples will be collected.
Relative amount of eliminated P03277 in blood	Just before the start of the session and at 30, 90 minutes and 4 hours after the start of the session.	This outcome will be assessed for cohort 5 only. Venous blood samples will be collected at each session of hemodialysis.
Clearance of P03277	Just before the start of the session and at 30 and 90 minutes after the start of the session.	This outcome will be assessed for cohort 5 only and at the first hemodialysis only. Arterial and venous blood samples will be collected.
Dialysis clearance of P03277	Just before the start of the session and at 30, 90 minutes and 4 hours after the start of the session.	This outcome will be assessed for cohort 5 only. Venous blood and dialysate samples will be collected at each session of hemodialysis.

Secondary Outcome Measures

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

Trial Locations

Locations (2)

Republican Clinical Hospital, Arensia EM Unit; 🇲🇩 Chisinau, Moldova, Republic of

Arensia Phase I unit "Carol Davila" Nephrology Hospital; 🇷🇴 Bucharest, Romania