Cardiac Safety Evaluation of P03277 | NCT03657264

Cardiac Safety Evaluation of P03277 | NCT03657264 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Sequence 1	Experimental	The sequence of administration is: P/ScD/PC/CD Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os).	Drug: P03277 0.1 mmol/kg Drug: Moxifloxacin 400mg Drug: NaCl 0.9% Drug: P03277 0.3 mmol/kg
Sequence 2	Experimental	The sequence of administration is: CD/PC/ScD/P Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os).	Drug: P03277 0.1 mmol/kg Drug: Moxifloxacin 400mg Drug: NaCl 0.9% Drug: P03277 0.3 mmol/kg
Sequence 3	Experimental	The sequence of administration is: ScD/CD/P/PC Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os).	Drug: P03277 0.1 mmol/kg Drug: Moxifloxacin 400mg Drug: NaCl 0.9% Drug: P03277 0.3 mmol/kg
Sequence 4	Experimental	The sequence of administration is: PC/P/CD/ScD Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os).

Name	Type	Description	Arm Group Labels	Other Names
P03277 0.1 mmol/kg	Drug	Single intravenous bolus injection at 2 mL/sec	Sequence 1 Sequence 2 Sequence 3 Sequence 4

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF)	Each subject was monitored with a 12-lead Holter electrocardiogram (ECG). The study had to show that both 0.1 and 0.3 mmol/kg doses of P03277 do not increase the QT interval corrected by Fridericia formula (QTcF). The study is successful if the difference between each of the two doses of P03277 and placebo for the largest mean change from baseline for the QTcF is lower than 10 milliseconds. The baseline was defined as the mean of the 3 triplicates ECG measured within 1 hour before each product administration.	from 1 hour before any administration until 24 hours post-administration at the following timepoints: -1 hour, 5 min, 10 min, 20 min, 30 min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 hours.

Secondary Outcomes

Measure	Description	Time Frame
Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF)	Each subject was monitored with a 12-lead Holter electrocardiogram (ECG). The assay sensitivity was assessed through this outcome. The difference between the positive control (moxifloxacin) and placebo for the largest mean change from baseline for the QTcF had to be greater than 5 milliseconds for at least one time point. The baseline was defined as the mean of the 3 triplicates ECG measured within 1 hour before each product administration.

Contacts/Locations Module

Name	Affiliation	Role
Frederic Vanhoutte, MD	SGS Clinical Pharmacology Unit	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Clinical Pharmacology unit, SGS-Life Science Service		Antwerp		2060	Belgium

Arm/Group Information

ID	Title	Description
FG000	Sequence 1	The sequence of administration is: P/ScD/PC/CD Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os).
FG001	Sequence 2	The sequence of administration is: CD/PC/ScD/P Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os).
FG002	Sequence 3	The sequence of administration is: ScD/CD/P/PC Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os).
FG003	Sequence 4	The sequence of administration is: PC/P/CD/ScD Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os).

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG00012 subjects FG00112 subjects FG00212 subjects FG00312 subjects
COMPLETED		FG00012 subjects FG00112 subjects FG00212 subjects FG00312 subjects
NOT COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0030 subjects

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Sequence 1	The sequence of administration is: P/ScD/PC/CD Where: P = Placebo (Nacl 0.9%) CD = P03277 tested at 0.1 mmol/kg ScD = P03277 tested at 0.3 mmol/kg PC = Positive control (moxifloxacin 400 mg - per os).
BG001	Sequence 2

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF)

Each subject was monitored with a 12-lead Holter electrocardiogram (ECG). The study had to show that both 0.1 and 0.3 mmol/kg doses of P03277 do not increase the QT interval corrected by Fridericia formula (QTcF).

The study is successful if the difference between each of the two doses of P03277 and placebo for the largest mean change from baseline for the QTcF is lower than 10 milliseconds. The baseline was defined as the mean of the 3 triplicates ECG measured within 1 hour before each product administration.

The primary analysis was performed using the per protocol set which included subjects who had no major protocol deviations throughout their whole study period.

Posted

Least Squares Mean

Standard Error

milliseconds

from 1 hour before any administration until 24 hours post-administration at the following timepoints: -1 hour, 5 min, 10 min, 20 min, 30 min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 8 hours, 24 hours.

ID	Title	Description

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	P03277 0.1 mmol/kg	All subjects who received P03277 at 0.1 mmol/kg.	0

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Application site irritation	General disorders	MedDRA 21.0	Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Jing Hao, MD	Guerbet	+33145915000		jing.hao@guerbet.com

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Aug 31, 2018	Nov 4, 2021	Prot_002.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Jul 24, 2018	Nov 4, 2021	SAP_003.pdf

Intervention Browse Module

ID	Term
C000656634	gadopiclenol
D000077266	Moxifloxacin
D012965	Sodium Chloride

ID	Term
D024841	Fluoroquinolones
D042462	4-Quinolones
D015363	Quinolones
D011804	Quinolines

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG0020 BG0030 BG0040
Asian	BG0001 BG0010 BG0020 BG0030 BG004
Native Hawaiian or Other Pacific Islander	BG0000 BG0010 BG0020 BG0030 BG004
Black or African American	BG0000 BG0010 BG0020 BG0030 BG004
White	BG00011 BG00112 BG00212 BG00312 BG004
More than one race	BG0000 BG0010 BG0020 BG0030 BG004
Unknown or Not Reported	BG0000 BG0010 BG0020 BG0030 BG004

Title

Denominators

Categories

5 min

Title	Measurements
	OG0000.97± 0.88 OG0015.05± 0.89 OG0020.24± 0.89

10 min

Title	Measurements
	OG000-0.11± 0.86 OG0011.34± 0.86 OG002-0.59± 0.86

20 min

Title	Measurements
	OG000-1.25± 0.88 OG001-1.20± 0.88 OG002-1.41± 0.88

30 min

Title	Measurements
	OG000-1.06± 0.79 OG001-1.26± 0.79 OG002-1.69± 0.79

1 hour

Title	Measurements
	OG000-2.72± 0.92 OG001-2.44± 0.92 OG002-2.90± 0.92

1.5 hours

Title	Measurements
	OG000-3.08± 0.89 OG001-4.64± 0.89 OG002-3.53± 0.89

2 hours

Title	Measurements
	OG000-2.08± 0.99 OG001-3.22± 0.99 OG002-2.05± 0.99

3 hours

Title	Measurements
	OG0002.34± 0.98 OG001-1.38± 0.98 OG002-0.05± 0.98

4 hours

Title	Measurements
	OG0000.61± 0.97 OG001-0.51± 0.97 OG0020.33± 0.97

8 hours

Title	Measurements
	OG000-2.55± 1.17 OG001-5.59± 1.17 OG002-3.66± 1.17

24 hours

Title	Measurements
	OG000-3.18± 0.92 OG001-3.28± 0.92 OG002-3.49± 0.93

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Non-Inferiority Type	Non-Inferiority Comment
OG000 OG002	For the timepoint 5 min	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.73	Standard Error of the Mean	1.18	2-Sided	90	-1.23	2.69	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 10 min	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.48	Standard Error of the Mean	1.09	2-Sided	90	-1.32	2.29	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 20 min	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.16	Standard Error of the Mean	1.16	2-Sided	90	-1.76	2.08	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 30 min	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.63	Standard Error of the Mean	1.04	2-Sided	90	-1.09	2.35	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 1 hour	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.18	Standard Error of the Mean	1.25	2-Sided	90	-1.88	2.25	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 1.5 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.45	Standard Error of the Mean	1.16	2-Sided	90	-1.47	2.37	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 2 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	-0.03	Standard Error of the Mean	1.18	2-Sided	90	-1.99	1.92	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 3 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	2.39	Standard Error of the Mean	1.23	2-Sided	90	0.35	4.43	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 4 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.27	Standard Error of the Mean	1.11	2-Sided	90	-1.57	2.12	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 8 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	1.11	Standard Error of the Mean	1.36	2-Sided	90	-1.15	3.37	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG000 OG002	For the timepoint 24 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.31	Standard Error of the Mean	1.10	2-Sided	90	-1.52	2.14	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 5 min	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	4.81	Standard Error of the Mean	1.19	2-Sided	90	2.84	6.78	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 10 min	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	1.93	Standard Error of the Mean	1.09	2-Sided	90	0.12	3.73	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 20 min	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.20	Standard Error of the Mean	1.16	2-Sided	90	-1.71	2.12	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 30 min	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.43	Standard Error of the Mean	1.04	2-Sided	90	-1.29	2.15	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 1 hour	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.47	Standard Error of the Mean	1.25	2-Sided	90	-1.60	2.53	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 1.5 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	-1.11	Standard Error of the Mean	1.16	2-Sided	90	-3.03	0.81	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 2 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	-1.17	Standard Error of the Mean	1.18	2-Sided	90	-3.13	0.78	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 3 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	-1.33	Standard Error of the Mean	1.23	2-Sided	90	-3.36	0.71	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 4 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	-0.85	Standard Error of the Mean	1.11	2-Sided	90	-2.69	1.00	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 8 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	-1.94	Standard Error of the Mean	1.36	2-Sided	90	-4.19	0.32	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.
OG001 OG002	For the timepoint 24 hours	ANCOVA	Each timepoint was tested through a separate model.	p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	0.21	Standard Error of the Mean	1.11	2-Sided	90	-1.62	2.04	Non-Inferiority	The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests.

Secondary

Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF)

Each subject was monitored with a 12-lead Holter electrocardiogram (ECG). The assay sensitivity was assessed through this outcome. The difference between the positive control (moxifloxacin) and placebo for the largest mean change from baseline for the QTcF had to be greater than 5 milliseconds for at least one time point. The baseline was defined as the mean of the 3 triplicates ECG measured within 1 hour before each product administration.

Analysis of secondary criteria was performed using the full analysis set which included all randomized subjects.

Posted

Least Squares Mean

Standard Error

milliseconds

from 1 hour before any administration until 4 hours post-administration at the following timepoints: -1 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours.

ID	Title	Description
OG000	Positive Control (Moxifloxacin)	All subjects who received moxifloxacin.
OG001	Placebo	All subjects who received placebo.

Units	Counts
Participants	OG00048 OG00148

Title

Denominators

Categories

1 hour

Title	Measurements
	OG0001.73± 0.91 OG001-2.89± 0.91

1.5 hours

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	For the timepoint 1 hour	ANCOVA	As multiple timepoints were examined separately, the overall type I error rate needed to be adjusted.		p-value is not shown, as this is a non-inferiority study.	Least Squares Mean Difference	4.62	Standard Error of the Mean	1.23	2-Sided	90	2.58	6.66					Superiority	The lower limit of the adjusted confidence interval was expected upper to the margin of 5 milliseconds.

Secondary

Predicted Value of ∆∆QTc at Cmax

Concentration-response relationship was investigated between ∆QTc and P03277 concentrations using a mixed model approach. Plasma concentration of P03277 was measured at the same timepoints as ECG measurements.

Posted

Number

90% Confidence Interval

milliseconds

from 1 hour before any administration until 24 hours post-administration.

ID	Title	Description
OG000	P03277 0.1 mmol/kg	All subjects who received P03277 at 0.1 mmol/kg.
OG001	P03277 0.3 mmol/kg	All subjects who received P03277 at 0.3 mmol/kg.

Units	Counts
Participants	OG00048 OG00148

Title

Denominators

Categories

Title	Measurements
	OG0000.41(-0.08 to 0.90) OG0012.23(1.19 to 3.26)