Pharmacokinetics and Safety of Moxifloxacin

NCT01329250 | Terminated Phase 4 DMC

• 1 other identifier: MFX468
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberculosis

Keywords

Tuberculosis; Moxifloxacin; Pharmacokinetics; Safety

Outcome Measures

Primary Outcomes (13)

• Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC)

  % 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

  7 days post dosage

• Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis

  % 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

  % 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

• Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance

  % 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

  7 days post dosage

• % of patients having adverse effects, including QT interval prolongation, hypersensitive reactions, diarrhoea, vomiting and hepatic or renal injury

  * 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

  up to 21 days

• Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC)

  % 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

• Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC)

  % 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

  21 days post dosage

• Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis

  % 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

  % 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.

  21 days post dosage

• Bound AUC0-24h/Mutant Prevention Concentration (MPC) ratio

  % 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

  % 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

  % 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

  14 days 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

  % 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

  21 days post dosage

Secondary Outcomes (8)

• 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.

  7 days post dosage

• Correlation between MFX concentration (mg/L) and QT interval (msec)

  7 days post dosage

• Correlation of drug exposure (AUC) and adverse effects

  up to 21 days

• Correlation between the genetic risk score and MFX induced QT prolongation

  up to 21 days

• 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.

  14 days post dosage

Study Arms (1)

Moxifloxacin

EXPERIMENTAL

Moxifloxacinin escalating dose

Drug: Moxifloxacin

Interventions

Moxifloxacin DRUG

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.

Also known as: MFX

Moxifloxacin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (1)

University Medical Center Groningen

Groningen, Netherlands

Location

MeSH Terms

Conditions

Tuberculosis

Interventions

Moxifloxacin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Jos GW Kosterink, PharmD, PhD

  Univeristy Medical Center Groningen

  STUDY CHAIR

• Jan-Willem C Alffenaar, PharmD, PhD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PharmD, PhD

Study Record Dates

• First Submitted: March 8, 2011
• First Posted: April 5, 2011
• Study Start: May 1, 2011
• Primary Completion: June 1, 2015
• Study Completion: August 1, 2016
• Last Updated: November 18, 2016

Record last verified: 2016-11

Locations

NL (1)