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Cardiac Safety Evaluation of P03277

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ClinicalTrials.gov Identifier: NCT03657264
Recruitment Status : Completed
First Posted : September 5, 2018
Results First Posted : August 22, 2019
Last Update Posted : August 22, 2019
Sponsor:
Information provided by (Responsible Party):
Guerbet

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
Healthy Volunteers Drug: P03277 0.1 mmol/kg Drug: Moxifloxacin 400mg Drug: NaCl 0.9% Drug: P03277 0.3 mmol/kg 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Williams 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 : August 21, 2017
Actual Primary Completion Date : June 7, 2018
Actual Study Completion Date : June 7, 2018

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 Name: Gadopiclenol

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 Name: Gadopiclenol

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 Name: Gadopiclenol

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 Name: Gadopiclenol

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 Name: Gadopiclenol

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 Name: Gadopiclenol

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 Name: Gadopiclenol

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 Name: Gadopiclenol




Primary Outcome Measures :
  1. Change-from-baseline Mean Effect of P03277 on QT Interval Expressed as QTc According to Fridericia's Formula (∆QTcF) [ 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. ]

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

  2. Predicted Value of ∆∆QTc at Cmax [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 59 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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:

-


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03657264


Locations
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Belgium
Clinical Pharmacology unit, SGS-Life Science Service
Antwerpen, Belgium, 2060
Sponsors and Collaborators
Guerbet
Investigators
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Principal Investigator: Frederic Vanhoutte, MD SGS Clinical Pharmacology Unit
  Study Documents (Full-Text)

Documents provided by Guerbet:
Statistical Analysis Plan  [PDF] July 24, 2018
Study Protocol  [PDF] September 27, 2017


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Responsible Party: Guerbet
ClinicalTrials.gov Identifier: NCT03657264     History of Changes
Other Study ID Numbers: GDX-44-006
First Posted: September 5, 2018    Key Record Dates
Results First Posted: August 22, 2019
Last Update Posted: August 22, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Guerbet:
Gadolinium-based contrast agent
Cardiac safety
ECG
Gadopiclenol
Additional relevant MeSH terms:
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Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs