Clinical trial NCT01329250: Pharmacokinetics and Safety of Moxifloxacin
Official title: Pharmacokinetics and Safety of Moxifloxacin; a Dose Escalation in Patients With Tuberculosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Tuberculosis
Keywords: Tuberculosis
Moxifloxacin
Pharmacokinetics
Safety
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2011-04-05
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC)
timeFrame: 7 days post dosage
measure: Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis
timeFrame: 7 days post dosage
measure: Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio
timeFrame: 7 days post dosage
measure: Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance
timeFrame: 7 days post dosage
measure: % of patients having adverse effects, including QT interval prolongation, hypersensitive reactions, diarrhoea, vomiting and hepatic or renal injury
timeFrame: up to 21 days
measure: Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC)
timeFrame: 14 days post dosage
measure: Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC)
timeFrame: 21 days post dosage
measure: Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis
timeFrame: 14 days post dosage
measure: Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis
timeFrame: 21 days post dosage
measure: Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio
timeFrame: 14 post dosage
measure: Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio
timeFrame: 21 post dosage
measure: Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance
timeFrame: 14 days post dosage
measure: Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance
timeFrame: 21 days post dosage
Secondary outcomes:
measure: 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.
timeFrame: 7 days post dosage
measure: Correlation between MFX concentration (mg/L) and QT interval (msec)
timeFrame: 7 days post dosage
measure: Correlation of drug exposure (AUC) and adverse effects
timeFrame: up to 21 days
measure: Correlation between the genetic risk score and MFX induced QT prolongation
timeFrame: up to 21 days
measure: 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.
timeFrame: 14 days post dosage
measure: 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.
timeFrame: 21 days post dosage
measure: Correlation between MFX concentration (mg/L) and QT interval (msec)
timeFrame: 14 days post dosage
measure: Correlation between MFX concentration (mg/L) and QT interval (msec)
timeFrame: 21 days post dosage
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: Univeristy Medical Center Groningen
name: Jos GW Kosterink, PharmD, PhD
role: STUDY_CHAIR
affiliation: University Medical Center Groningen
name: Jan-Willem C Alffenaar, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References: