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slow enrolment of patients and new insights
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Moxifloxacin | Experimental | Moxifloxacinin escalating dose |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| up to 21 days |
| Bound area under the plasma concentration-time curve (AUC0-24h) relative to the minimal inhibitory concentration (MIC) |
| 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. | 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 | 7 days post dosage |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jos GW Kosterink, PharmD, PhD | Univeristy Medical Center Groningen | Study Chair |
| Jan-Willem C Alffenaar, PharmD, PhD | University Medical Center Groningen | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Medical Center Groningen | Groningen | Netherlands |
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| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
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| ID | Term |
|---|---|
| D000077266 | Moxifloxacin |
| ID | Term |
|---|---|
| D024841 | Fluoroquinolones |
| D042462 | 4-Quinolones |
| D015363 | Quinolones |
| D011804 | Quinolines |
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% 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 |
| Correlation between MFX concentration (mg/L) and QT interval (msec) | Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 400 mg (i.e. 7 days post dosage) moxifloxacin | 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. | 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. | 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) | 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) | Correlation between MFX concentration (mg/L) and QT interval (msec) after administration of 800 mg (i.e. 21 days post dosage) moxifloxacin | 21 days post dosage |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |