E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10044755 |
E.1.2 | Term | Tuberculosis |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 of 600 and 800 mg MFX |
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E.2.2 | Secondary objectives of the trial |
*To evaluate limited sampling strategies based on a pharmacokinetic population model to predict MFX AUC0-24h
*To evaluate the correlation between MFX concentration (mg/L) and QT interval (msec)
*To evaluate a genetic risk score for the prediction of MFX induced QT prolongation
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacokinetics * Bound AUC0-24h/MIC ratio; the percentage of patients who will reach an AUC0-24h/MIC ratio of at least 100 after administration of different dosages (400; 600; 800 mg) * Unbound AUC0-24h/MIC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis; the percentage of patients who will reach an unbound AUC0-24h/MIC ratio of at least 60 after administration of different dosages (400; 600; 800 mg) * Bound AUC0-24h/MPC ratio; percentage of patients who will reach an adequate AUC0-24h/MPC ratio of at least 93 after administration of different dosages (400; 600; 800 mg) * Unbound AUC0-24h/MPC ratio as predictive parameter for efficacy of unbound MFX dose escalated treatment of tuberculosis and suppression of MFX resistance; percentage of patients who will reach an unbound AUC0-24h/MPC ratio of at least 53 after administration of different dosages (400; 600; 800 mg)
Safety Percentage 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 CTC * Percentage of patients developing renal toxicity grade ≥ 2 CTC
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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21 days after inclusion of the last subject undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |