Cardiac Safety Evaluation of P03277
Sponsor
Guerbet (Industry)
Overall Status
Completed
CT.gov ID
NCT03657264
Collaborator
(none)
48
1
4
9.5
5
Study Details
Study Description
Brief Summary
The study is a Phase I, Single center, Randomized, Cross-over Double-blind Placebo-controlled and Open-label Positive-controlled (moxifloxacin) in healthy volunteers.
The primary objective is to assess the cardiac safety after administration of P03277 to 48 healthy volunteers at dose of 0.1 mmol/kg (anticipated clinical dose) and 0.3 mmol/kg (supra-clinical dose) by evaluating the QT and QTc intervals.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
Each subjects will be administered with 4 products (P03277 at the 2 different doses, placebo and moxifloxacin) in a 4*4 cross over sequence balanced for first order carry over effect. Twelve subjects will be assigned to each sequence (6 males and 6 females). The volunteers will be enrolled sequentially by cohort of 8 subjects.
ECG measurements will be compared with ECG parameters collected after administration of placebo (Nacl 0.9%). The test sensitivity will be assessed using a positive control (moxifloxacin 400 mg per os) known to induce delays in QT intervals.
Study Design
Study Type:
Interventional
Actual Enrollment
:
48 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Intervention Model Description:
Williams design for a 4*4 cross overWilliams design for a 4*4 cross over
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Diagnostic
Official Title:
Thorough QT/QTc Study to Assess the Electrocardiographic Safety of a New Gadolinium-based Contrast Agent P03277 in Healthy Volunteers
Actual Study Start Date
:
Aug 21, 2017
Actual Primary Completion Date
:
Jun 7, 2018
Actual Study Completion Date
:
Jun 7, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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). |
Drug: P03277 0.1 mmol/kg
Single intravenous bolus injection at 2 mL/sec
Other Names:
Drug: Moxifloxacin 400mg
One tablet per os
Drug: NaCl 0.9%
Single intravenous bolus injection at 2 mL/sec
Drug: P03277 0.3 mmol/kg
Single intravenous bolus injection at 2 mL/sec
Other Names:
|
| Experimental: 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). |
Drug: P03277 0.1 mmol/kg
Single intravenous bolus injection at 2 mL/sec
Other Names:
Drug: Moxifloxacin 400mg
One tablet per os
Drug: NaCl 0.9%
Single intravenous bolus injection at 2 mL/sec
Drug: P03277 0.3 mmol/kg
Single intravenous bolus injection at 2 mL/sec
Other Names:
|
| Experimental: 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). |
Drug: P03277 0.1 mmol/kg
Single intravenous bolus injection at 2 mL/sec
Other Names:
Drug: Moxifloxacin 400mg
One tablet per os
Drug: NaCl 0.9%
Single intravenous bolus injection at 2 mL/sec
Drug: P03277 0.3 mmol/kg
Single intravenous bolus injection at 2 mL/sec
Other Names:
|
| Experimental: 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). |
Drug: P03277 0.1 mmol/kg
Single intravenous bolus injection at 2 mL/sec
Other Names:
Drug: Moxifloxacin 400mg
One tablet per os
Drug: NaCl 0.9%
Single intravenous bolus injection at 2 mL/sec
Drug: P03277 0.3 mmol/kg
Single intravenous bolus injection at 2 mL/sec
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) [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.]
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.
Secondary Outcome Measures
- Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) [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.]
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.
- Predicted Value of ∆∆QTc at Cmax [from 1 hour before any administration until 24 hours post-administration.]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 59 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:
-
Subject assessed as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination)
-
Subject with a Body Mass Index (BMI) > 19 kg/m² and < 28 kg/m² and a weight at least of 40 kg for female and 50 kg for male and at maximum of 100 kg
Exclusion Criteria:
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Clinical Pharmacology unit, SGS-Life Science Service | Antwerpen | Belgium | 2060 |
Sponsors and Collaborators
- Guerbet
Investigators
- Principal Investigator: Frederic Vanhoutte, MD, SGS Clinical Pharmacology Unit
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Guerbet
ClinicalTrials.gov Identifier:
NCT03657264
Other Study ID Numbers:
- GDX-44-006
First Posted:
Sep 5, 2018
Last Update Posted:
Jul 18, 2022
Last Verified:
Mar 1, 2022
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Guerbet
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Sequence 1 | Sequence 2 | Sequence 3 | Sequence 4 |
|---|---|---|---|---|
| Arm/Group Description | 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). | 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). | 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). | 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). |
| Period Title: Overall Study | ||||
| STARTED | 12 | 12 | 12 | 12 |
| COMPLETED | 12 | 12 | 12 | 12 |
| NOT COMPLETED | 0 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Sequence 1 | Sequence 2 | Sequence 3 | Sequence 4 | Total |
|---|---|---|---|---|---|
| Arm/Group Description | 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). | 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). | 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). | 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). | Total of all reporting groups |
| Overall Participants | 12 | 12 | 12 | 12 | 48 |
| Age (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
35.8
(13.5)
|
41.9
(11.1)
|
44.8
(11.1)
|
39.8
(10.2)
|
40.5
(11.6)
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
6
50%
|
6
50%
|
6
50%
|
6
50%
|
24
50%
|
| Male |
6
50%
|
6
50%
|
6
50%
|
6
50%
|
24
50%
|
| Race (NIH/OMB) (Count of Participants) | |||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
1
8.3%
|
0
0%
|
0
0%
|
0
0%
|
1
2.1%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
11
91.7%
|
12
100%
|
12
100%
|
12
100%
|
47
97.9%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Weight (kg) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [kg] |
76.3
(10.4)
|
77.6
(11.1)
|
75.9
(8.3)
|
71.3
(9.8)
|
75.3
(9.9)
|
Outcome Measures
| Title | Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) |
|---|---|
| Description | 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. |
| Time Frame | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The primary analysis was performed using the per protocol set which included subjects who had no major protocol deviations throughout their whole study period. |
| Arm/Group Title | P03277 0.1 mmol/kg | P03277 0.3 mmol/kg | Placebo |
|---|---|---|---|
| Arm/Group Description | All subjects who received P03277 at 0.1 mmol/kg. | All subjects who received P03277 at 0.3 mmol/kg. | All subjects who received placebo. |
| Measure Participants | 47 | 47 | 47 |
| 5 min |
0.97
(0.88)
|
5.05
(0.89)
|
0.24
(0.89)
|
| 10 min |
-0.11
(0.86)
|
1.34
(0.86)
|
-0.59
(0.86)
|
| 20 min |
-1.25
(0.88)
|
-1.20
(0.88)
|
-1.41
(0.88)
|
| 30 min |
-1.06
(0.79)
|
-1.26
(0.79)
|
-1.69
(0.79)
|
| 1 hour |
-2.72
(0.92)
|
-2.44
(0.92)
|
-2.90
(0.92)
|
| 1.5 hours |
-3.08
(0.89)
|
-4.64
(0.89)
|
-3.53
(0.89)
|
| 2 hours |
-2.08
(0.99)
|
-3.22
(0.99)
|
-2.05
(0.99)
|
| 3 hours |
2.34
(0.98)
|
-1.38
(0.98)
|
-0.05
(0.98)
|
| 4 hours |
0.61
(0.97)
|
-0.51
(0.97)
|
0.33
(0.97)
|
| 8 hours |
-2.55
(1.17)
|
-5.59
(1.17)
|
-3.66
(1.17)
|
| 24 hours |
-3.18
(0.92)
|
-3.28
(0.92)
|
-3.49
(0.93)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 5 min | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.73 | |
| Confidence Interval |
(2-Sided) 90% -1.23 to 2.69 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.18 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 10 min | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.48 | |
| Confidence Interval |
(2-Sided) 90% -1.32 to 2.29 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.09 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 20 min | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.16 | |
| Confidence Interval |
(2-Sided) 90% -1.76 to 2.08 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.16 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 30 min | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.63 | |
| Confidence Interval |
(2-Sided) 90% -1.09 to 2.35 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.04 |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 1 hour | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.18 | |
| Confidence Interval |
(2-Sided) 90% -1.88 to 2.25 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.25 |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 1.5 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.45 | |
| Confidence Interval |
(2-Sided) 90% -1.47 to 2.37 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.16 |
|
| Estimation Comments | ||
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 2 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | -0.03 | |
| Confidence Interval |
(2-Sided) 90% -1.99 to 1.92 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.18 |
|
| Estimation Comments | ||
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 3 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 2.39 | |
| Confidence Interval |
(2-Sided) 90% 0.35 to 4.43 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.23 |
|
| Estimation Comments | ||
Statistical Analysis 9
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 4 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.27 | |
| Confidence Interval |
(2-Sided) 90% -1.57 to 2.12 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.11 |
|
| Estimation Comments | ||
Statistical Analysis 10
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 8 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 1.11 | |
| Confidence Interval |
(2-Sided) 90% -1.15 to 3.37 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.36 |
|
| Estimation Comments | ||
Statistical Analysis 11
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 24 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.31 | |
| Confidence Interval |
(2-Sided) 90% -1.52 to 2.14 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.10 |
|
| Estimation Comments | ||
Statistical Analysis 12
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 5 min | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 4.81 | |
| Confidence Interval |
(2-Sided) 90% 2.84 to 6.78 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.19 |
|
| Estimation Comments | ||
Statistical Analysis 13
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 10 min | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 1.93 | |
| Confidence Interval |
(2-Sided) 90% 0.12 to 3.73 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.09 |
|
| Estimation Comments | ||
Statistical Analysis 14
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 20 min | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.20 | |
| Confidence Interval |
(2-Sided) 90% -1.71 to 2.12 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.16 |
|
| Estimation Comments | ||
Statistical Analysis 15
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 30 min | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.43 | |
| Confidence Interval |
(2-Sided) 90% -1.29 to 2.15 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.04 |
|
| Estimation Comments | ||
Statistical Analysis 16
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 1 hour | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.47 | |
| Confidence Interval |
(2-Sided) 90% -1.60 to 2.53 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.25 |
|
| Estimation Comments | ||
Statistical Analysis 17
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 1.5 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | -1.11 | |
| Confidence Interval |
(2-Sided) 90% -3.03 to 0.81 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.16 |
|
| Estimation Comments | ||
Statistical Analysis 18
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 2 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | -1.17 | |
| Confidence Interval |
(2-Sided) 90% -3.13 to 0.78 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.18 |
|
| Estimation Comments | ||
Statistical Analysis 19
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 3 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | -1.33 | |
| Confidence Interval |
(2-Sided) 90% -3.36 to 0.71 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.23 |
|
| Estimation Comments | ||
Statistical Analysis 20
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 4 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | -0.85 | |
| Confidence Interval |
(2-Sided) 90% -2.69 to 1.00 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.11 |
|
| Estimation Comments | ||
Statistical Analysis 21
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 8 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | -1.94 | |
| Confidence Interval |
(2-Sided) 90% -4.19 to 0.32 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.36 |
|
| Estimation Comments | ||
Statistical Analysis 22
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.3 mmol/kg, Placebo |
|---|---|---|
| Comments | For the timepoint 24 hours | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | The upper limit of the 90% confidence interval was expected lower to the margin of 10 milliseconds for all tests. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 0.21 | |
| Confidence Interval |
(2-Sided) 90% -1.62 to 2.04 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.11 |
|
| Estimation Comments | ||
| Title | Change-from-baseline Mean Effect of Moxifloxacin on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) |
|---|---|
| Description | 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. |
| Time Frame | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis of secondary criteria was performed using the full analysis set which included all randomized subjects. |
| Arm/Group Title | Positive Control (Moxifloxacin) | Placebo |
|---|---|---|
| Arm/Group Description | All subjects who received moxifloxacin. | All subjects who received placebo. |
| Measure Participants | 48 | 48 |
| 1 hour |
1.73
(0.91)
|
-2.89
(0.91)
|
| 1.5 hours |
6.13
(0.88)
|
-3.27
(0.88)
|
| 2 hours |
8.60
(0.97)
|
-1.95
(0.97)
|
| 3 hours |
10.50
(0.97)
|
0.17
(0.97)
|
| 4 hours |
11.28
(0.95)
|
0.63
(0.95)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, P03277 0.3 mmol/kg |
|---|---|---|
| Comments | For the timepoint 1 hour | |
| Type of Statistical Test | Superiority | |
| Comments | The lower limit of the adjusted confidence interval was expected upper to the margin of 5 milliseconds. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 4.62 | |
| Confidence Interval |
(2-Sided) 90% 2.58 to 6.66 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.23 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, P03277 0.3 mmol/kg |
|---|---|---|
| Comments | For the timepoint 1.5 hours | |
| Type of Statistical Test | Superiority | |
| Comments | The lower limit of the adjusted confidence interval was expected upper to the margin of 5 milliseconds. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 9.40 | |
| Confidence Interval |
(2-Sided) 90% 7.14 to 11.66 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.14 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, P03277 0.3 mmol/kg |
|---|---|---|
| Comments | For the timepoint 2 hours | |
| Type of Statistical Test | Superiority | |
| Comments | The lower limit of the adjusted confidence interval was expected upper to the margin of 5 milliseconds. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 10.55 | |
| Confidence Interval |
(2-Sided) 90% 7.92 to 13.17 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.16 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, P03277 0.3 mmol/kg |
|---|---|---|
| Comments | For the timepoint 3 hours | |
| Type of Statistical Test | Superiority | |
| Comments | The lower limit of the adjusted confidence interval was expected upper to the margin of 5 milliseconds. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 10.33 | |
| Confidence Interval |
(2-Sided) 90% 7.70 to 12.95 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.22 |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | P03277 0.1 mmol/kg, P03277 0.3 mmol/kg |
|---|---|---|
| Comments | For the timepoint 4 hours | |
| Type of Statistical Test | Superiority | |
| Comments | The lower limit of the adjusted confidence interval was expected upper to the margin of 5 milliseconds. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares Mean Difference |
| Estimated Value | 10.65 | |
| Confidence Interval |
(2-Sided) 90% 8.05 to 13.25 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.10 |
|
| Estimation Comments | ||
| Title | Predicted Value of ∆∆QTc at Cmax |
|---|---|
| Description | 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. |
| Time Frame | from 1 hour before any administration until 24 hours post-administration. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | P03277 0.1 mmol/kg | P03277 0.3 mmol/kg |
|---|---|---|
| Arm/Group Description | All subjects who received P03277 at 0.1 mmol/kg. | All subjects who received P03277 at 0.3 mmol/kg. |
| Measure Participants | 48 | 48 |
| Number (90% Confidence Interval) [milliseconds] |
0.41
|
2.23
|
Adverse Events
| Time Frame | From informed consent signature until the end of the confinement period, i.e. a period ranging from 32 to 41 days. | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||
| Arm/Group Title | P03277 0.1 mmol/kg | P03277 0.3 mmol/kg | Positive Control (Moxifloxacin) | Placebo | ||||
| Arm/Group Description | All subjects who received P03277 at 0.1 mmol/kg. | All subjects who received P03277 at 0.3 mmol/kg. | All subjects who received Moxifloxacin. | All subjects who received placebo. | ||||
All Cause Mortality |
||||||||
| P03277 0.1 mmol/kg | P03277 0.3 mmol/kg | Positive Control (Moxifloxacin) | Placebo | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/48 (0%) | 0/48 (0%) | 0/48 (0%) | 0/48 (0%) | ||||
Serious Adverse Events |
||||||||
| P03277 0.1 mmol/kg | P03277 0.3 mmol/kg | Positive Control (Moxifloxacin) | Placebo | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/48 (0%) | 0/48 (0%) | 0/48 (0%) | 0/48 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| P03277 0.1 mmol/kg | P03277 0.3 mmol/kg | Positive Control (Moxifloxacin) | Placebo | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 25/48 (52.1%) | 22/48 (45.8%) | 16/48 (33.3%) | 22/48 (45.8%) | ||||
| Cardiac disorders | ||||||||
| Palpitations | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Ear and labyrinth disorders | ||||||||
| Ear pain | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Eye disorders | ||||||||
| Conjunctival hyperaemia | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Gastrointestinal disorders | ||||||||
| Diarrhoea | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 3/48 (6.3%) | 3 | 2/48 (4.2%) | 2 |
| Nausea | 0/48 (0%) | 0 | 2/48 (4.2%) | 2 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Abdominal pain | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Abdominal pain upper | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Aphthous ulcer | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Lip dry | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| General disorders | ||||||||
| Application site irritation | 6/48 (12.5%) | 7 | 7/48 (14.6%) | 8 | 5/48 (10.4%) | 5 | 6/48 (12.5%) | 6 |
| Injection site haematoma | 4/48 (8.3%) | 4 | 3/48 (6.3%) | 3 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Injection site erythema | 2/48 (4.2%) | 2 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Catheter site haematoma | 1/48 (2.1%) | 1 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Injection site inflammation | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Injection site rash | 1/48 (2.1%) | 1 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Injection site reaction | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 |
| Catheter site erythema | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Catheter site pain | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Catheter site related reaction | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Catheter site swelling | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Feeling hot | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Influenza like illness | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Injection site discomfort | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Injection site extravasation | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Injection site pain | 2/48 (4.2%) | 2 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 4/48 (8.3%) | 4 |
| Asthenia | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Back pain | 0/48 (0%) | 0 | 2/48 (4.2%) | 2 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Musculoskeletal stiffness | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Nervous system disorders | ||||||||
| Headache | 6/48 (12.5%) | 6 | 5/48 (10.4%) | 6 | 4/48 (8.3%) | 4 | 4/48 (8.3%) | 4 |
| Dysgeusia | 1/48 (2.1%) | 1 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 2/48 (4.2%) | 2 |
| Dizziness | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 2/48 (4.2%) | 2 | 0/48 (0%) | 0 |
| Paraesthesia | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 |
| Psychiatric disorders | ||||||||
| Nightmare | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Reproductive system and breast disorders | ||||||||
| Vulvovaginal discomfort | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Oropharyngeal pain | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 |
| Dyspnoea | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Throat tightness | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 | 0/48 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||
| Dry skin | 0/48 (0%) | 0 | 0/48 (0%) | 0 | 1/48 (2.1%) | 1 | 0/48 (0%) | 0 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Jing Hao, MD |
|---|---|
| Organization | Guerbet |
| Phone | +33145915000 |
| jing.hao@guerbet.com |
Responsible Party:
Guerbet
ClinicalTrials.gov Identifier:
NCT03657264
Other Study ID Numbers:
- GDX-44-006
First Posted:
Sep 5, 2018
Last Update Posted:
Jul 18, 2022
Last Verified:
Mar 1, 2022