Clinical trial NCT03657784: Pharmacokinetics, Dialysability and Safety of P03277 in Healthy Volunteers and in Patients With Impaired Renal Function
Official title: Pharmacokinetics, Dialysability and Safety of P03277, a New Gadolinium-based Contrast Agent, in Healthy Volunteers and in Patients With Impaired Renal Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Insufficiency
Healthy Volunteers
Lead sponsor: Guerbet
Sponsor class: INDUSTRY
First posted: 2018-09-05
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Successive cohorts design and single dose administration
Primary purpose: DIAGNOSTIC

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.

Eligibility criteria: 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

Primary outcomes:
measure: AUC
timeFrame: 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)
measure: Cmax
timeFrame: 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)
measure: t1/2
timeFrame: 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)
measure: CLT
timeFrame: 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)
measure: Ae
timeFrame: 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
measure: Relative amount of eliminated P03277 in blood
timeFrame: Just before the start of the session and at 30, 90 minutes and 4 hours after the start of the session.
measure: Clearance of P03277
timeFrame: Just before the start of the session and at 30 and 90 minutes after the start of the session.
measure: Dialysis clearance of P03277
timeFrame: Just before the start of the session and at 30, 90 minutes and 4 hours after the start of the session.
Secondary outcomes:
measure: P03277concentration in blood (long-term)
timeFrame: At 1, 3 and 6 months after P03277 administration
measure: P03277 concentration in urine (long-term)
timeFrame: At 1, 3 and 6 months after P03277 administration
Other outcomes:
Locations:
city: Chisinau
country: Moldova, Republic of
facility: Republican Clinical Hospital, Arensia EM Unit
city: Bucharest
country: Romania
facility: Arensia Phase I unit "Carol Davila" Nephrology Hospital
Study officials:
affiliation: Arensia Phase I unit "Carol Davila" Nephrology Hospital
name: Penescu Mircea, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bradu A, Penescu M, Pitrou C, Hao J, Bourrinet P. Pharmacokinetics, Dialysability, and Safety of Gadopiclenol, a New Gadolinium-Based Contrast Agent, in Patients With Impaired Renal Function. Invest Radiol. 2021 Aug 1;56(8):486-493. doi: 10.1097/RLI.0000000000000764.