Pharmacokinetics and Safety of Moxifloxacin (MFX468)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by University Medical Centre Groningen
Sponsor:
Information provided by (Responsible Party):
JWC Alffenaar, University Medical Centre Groningen
ClinicalTrials.gov Identifier:
NCT01329250
First received: March 8, 2011
Last updated: November 12, 2013
Last verified: November 2013

March 8, 2011
November 12, 2013
May 2011
May 2014   (final data collection date for primary outcome measure)
  • Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC) [ Time Frame: 7 days post dosage ] [ Designated as safety issue: Yes ]
    % 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
  • Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis [ Time Frame: 7 days post dosage ] [ Designated as safety issue: Yes ]
    % 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.
  • Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio [ Time Frame: 7 days post dosage ] [ Designated as safety issue: Yes ]
    % 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
  • 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 ] [ Designated as safety issue: Yes ]
    % 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
  • % of patients having adverse effects, including QT interval prolongation, hypersensitive reactions, diarrhoea, vomiting and hepatic or renal injury [ Time Frame: up to 21 days ] [ Designated as safety issue: Yes ]
    • QT interval in msec
    • Percentage of patients developing hepatic toxicity grade ≥ 2 or 3 Common Toxicity Criteria (CTC)
    • Percentage of patients developing renal toxicity grade ≥ 2 CTC
  • Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC) [ Time Frame: 14 days post dosage ] [ Designated as safety issue: Yes ]
    % 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
  • Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC) [ Time Frame: 21 days post dosage ] [ Designated as safety issue: Yes ]
    % 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
  • Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis [ Time Frame: 14 days post dosage ] [ Designated as safety issue: Yes ]
    % 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.
  • Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis [ Time Frame: 21 days post dosage ] [ Designated as safety issue: Yes ]
    % 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.
  • Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio [ Time Frame: 14 post dosage ] [ Designated as safety issue: Yes ]
    % 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
  • Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio [ Time Frame: 21 post dosage ] [ Designated as safety issue: Yes ]
    % 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
  • 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 ] [ Designated as safety issue: Yes ]
    % 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
  • 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 ] [ Designated as safety issue: Yes ]
    % 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
Same as current
Complete list of historical versions of study NCT01329250 on ClinicalTrials.gov Archive Site
  • 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 ] [ Designated as safety issue: No ]
    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
  • Correlation between MFX concentration (mg/L) and QT interval (msec) [ Time Frame: 7 days post dosage ] [ Designated as safety issue: Yes ]
    Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin
  • Correlation of drug exposure (AUC) and adverse effects [ Time Frame: up to 21 days ] [ Designated as safety issue: Yes ]
    • vomiting and diarrhoea
    • QT interval (msec)
  • Correlation between the genetic risk score and MFX induced QT prolongation [ Time Frame: up to 21 days ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]
    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
  • 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 ] [ Designated as safety issue: No ]
    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
  • Correlation between MFX concentration (mg/L) and QT interval (msec) [ Time Frame: 14 days post dosage ] [ Designated as safety issue: Yes ]
    Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 600 mg (i.e. 14 days post dosage) moxifloxacin
  • Correlation between MFX concentration (mg/L) and QT interval (msec) [ Time Frame: 21 days post dosage ] [ Designated as safety issue: Yes ]
    Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 800 mg (i.e. 21 days post dosage) moxifloxacin
Same as current
Not Provided
Not Provided
 
Pharmacokinetics and Safety of Moxifloxacin
Pharmacokinetics and Safety of Moxifloxacin; a Dose Escalation in Patients With Tuberculosis

The main objective of this prospective clinical trial is to compare pharmacokinetics and safety and tolerability of a standard dose (400 mg) with an escalated dose (600 mg; 800 mg) of moxifloxacin (MFX). This clinical trial will provide important safety information on MFX in a higher dosage in TB patients.

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.

Interventional
Phase 4
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Tuberculosis
Drug: Moxifloxacin
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.
Not Provided
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
20
September 2014
May 2014   (final data collection date for primary outcome measure)

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.
Both
18 Years and older
No
Netherlands
 
NCT01329250
MFX468
Yes
JWC Alffenaar, University Medical Centre Groningen
University Medical Centre Groningen
Not Provided
Study Chair: Jos GW Kosterink, PharmD, PhD Univeristy Medical Center Groningen
Principal Investigator: Jan-Willem C Alffenaar, PharmD, PhD University Medical Centre Groningen
University Medical Centre Groningen
November 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP