- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01329250
Pharmacokinetics and Safety of Moxifloxacin (MFX468)
Pharmacokinetics and Safety of Moxifloxacin; a Dose Escalation in Patients With Tuberculosis
Study Overview
Detailed Description
Moxifloxacin (MFX) is a fluoroquinolone with a high in vitro and in vivo bactericidal activity against Mycobacterium tuberculosis. A daily dose of 600-800 mg MFX should be considered for optimal killing of the involved mycobacteria and suppression of drug resistance, which is higher than the currently used dose of 400 mg once daily. In general, safety data to support switching to the suggested higher dose are limited.
For this purpose, twenty tuberculosis patients will start on a standard dose of MFX 400 mg once daily. After 8 days the dose will be increased to 600 mg once daily and on the 15th day of treatment, the dose of MFX will be escalated to 800 mg. In patients who have been treated with rifampicin (RIF) in the past three weeks prior to start of MFX treatment an additional washout period of 3 weeks to reduce the rifampicin induced enzymatic activity will precede the dose escalation.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
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Groningen, Netherlands
- University Medical Center Groningen
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients with TB, with Mycobacterium tuberculosis (or M. africanum) by culture
- Starting treatment with MFX in a dose of 400 mg as part of their TB treatment
Exclusion Criteria:
- Contra-indication for MFX
- Baseline QTc-interval > 450 msec
- History of resuscitation
- History of ventricular tachycardia (including Torsades de Pointes)
- Family history of sudden cardiac death or Torsades de Pointes
- Additional risk factors for Torsades de Pointes (including known heart failure, Left ventricular hypertrophy)
- Use of concomitant treatment with QT/QTc prolonging drugs (including anti-dysrhythmics class IA and III, antipsychotics, tricyclic antidepressants or the antihistaminic drug terfenadine)
- Abnormal electrolytes (K, Mg, Na, Ca)
- Abnormal cardiac repolarisation on screening/baseline ECG
- History of adverse events to fluoroquinolones
- HIV co-infection
- RIF treatment during last 3 weeks before start of the study. After a washout period of 3 weeks the patient can be included.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Moxifloxacin
Moxifloxacinin escalating dose
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Patients will start on a standard dose of MFX 400 mg once daily.
After 8 days the dose will be increased to 600 mg once daily and on the 15th day of treatment, the dose of MFX will be escalated to 800 mg.
In patients who have been treated with rifampicin (RIF) in the past three weeks prior to start of MFX treatment an additional washout period of 3 weeks to reduce the rifampicin induced enzymatic activity will precede the dose escalation.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC)
Time Frame: 7 days post dosage
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% of patients who will reach an AUC0-24h/MIC ratio of at least 100 after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin
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7 days post dosage
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Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis
Time Frame: 7 days post dosage
|
% of patients who will reach an unbound AUC0-24h/MIC ratio of at least 60 after administration of 400 mg (i.e. 7 day post dosage) moxifloxacin.
|
7 days post dosage
|
Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio
Time Frame: 7 days post dosage
|
% of patients who will reach an adequate AUC0-24h/MPC ratio of at least 93 after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin
|
7 days post dosage
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Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance
Time Frame: 7 days post dosage
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% of patients who will reach an unbound AUC0-24h/MPC ratio of at least 53 after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin
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7 days post dosage
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% of patients having adverse effects, including QT interval prolongation, hypersensitive reactions, diarrhoea, vomiting and hepatic or renal injury
Time Frame: up to 21 days
|
|
up to 21 days
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Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC)
Time Frame: 14 days post dosage
|
% of patients who will reach an AUC0-24h/MIC ratio of at least 100 after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin
|
14 days post dosage
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Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC)
Time Frame: 21 days post dosage
|
% of patients who will reach an AUC0-24h/MIC ratio of at least 100 after administration of 800 mg (i.e.
21 days post dosage) moxifloxacin
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21 days post dosage
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Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis
Time Frame: 14 days post dosage
|
% of patients who will reach an unbound AUC0-24h/MIC ratio of at least 60 after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin.
|
14 days post dosage
|
Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis
Time Frame: 21 days post dosage
|
% of patients who will reach an unbound AUC0-24h/MIC ratio of at least 60 after administration of 800 mg (21 days post dosage) moxifloxacin.
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21 days post dosage
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Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio
Time Frame: 14 post dosage
|
% of patients who will reach an adequate AUC0-24h/MPC ratio of at least 93 after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin
|
14 post dosage
|
Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio
Time Frame: 21 post dosage
|
% of patients who will reach an adequate AUC0-24h/MPC ratio of at least 93 after administration of 800 mg (i.e.
21 days post dosage) moxifloxacin
|
21 post dosage
|
Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance
Time Frame: 14 days post dosage
|
% of patients who will reach an unbound AUC0-24h/MPC ratio of at least 53 after administration of 600 mg (i.e. 14 days post dosage) and moxifloxacin
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14 days post dosage
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Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance
Time Frame: 21 days post dosage
|
% of patients who will reach an unbound AUC0-24h/MPC ratio of at least 53 after administration of 800 mg (i.e.
21 days post dosage) moxifloxacin
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21 days post dosage
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Evaluation of the predictive performance of the limited sampling strategies based on a pharmacokinetic population model to calculate AUC0-24h. Several limited sampling points will be evaluated.
Time Frame: 7 days post dosage
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Several limited sampling strategies to predict moxifloxacin AUC0-24h, based on limited sampling points, will be evaluated after administration of 400 mg (i.e. 7 days post dosage)moxifloxacin
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7 days post dosage
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Correlation between MFX concentration (mg/L) and QT interval (msec)
Time Frame: 7 days post dosage
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Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin
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7 days post dosage
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Correlation of drug exposure (AUC) and adverse effects
Time Frame: up to 21 days
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up to 21 days
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Correlation between the genetic risk score and MFX induced QT prolongation
Time Frame: up to 21 days
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up to 21 days
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Evaluation of the predictive performance of the limited sampling strategies based on a pharmacokinetic population model to calculate AUC0-24h. Several limited sampling points will be evaluated.
Time Frame: 14 days post dosage
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Several limited sampling strategies to predict moxifloxacin AUC0-24h, based on limited sampling points, will be evaluated after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin
|
14 days post dosage
|
Evaluation of the predictive performance of the limited sampling strategies based on a pharmacokinetic population model to calculate AUC0-24h. Several limited sampling points will be evaluated.
Time Frame: 21 days post dosage
|
Several limited sampling strategies to predict moxifloxacin AUC0-24h, based on limited sampling points, will be evaluated after administration of 800 mg (i.e.
21 days post dosage) moxifloxacin
|
21 days post dosage
|
Correlation between MFX concentration (mg/L) and QT interval (msec)
Time Frame: 14 days post dosage
|
Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin
|
14 days post dosage
|
Correlation between MFX concentration (mg/L) and QT interval (msec)
Time Frame: 21 days post dosage
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Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 800 mg (i.e.
21 days post dosage) moxifloxacin
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21 days post dosage
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Collaborators and Investigators
Investigators
- Study Chair: Jos GW Kosterink, PharmD, PhD, Univeristy Medical Center Groningen
- Principal Investigator: Jan-Willem C Alffenaar, PharmD, PhD, University Medical Center Groningen
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Infections
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Tuberculosis
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antineoplastic Agents
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Anti-Bacterial Agents
- Moxifloxacin
Other Study ID Numbers
- MFX468
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