E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The circadian variation in the relative contribution of intestinal uptake and renal elimination of levofloxacin |
De dag/nacht ritmes in de opname en afbraak van het antibioticum Levofloxacine. |
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E.1.1.1 | Medical condition in easily understood language |
Day/night rhythm in the uptake and elimination of levofloxacin |
De dag/nacht ritmes in de opname en afbraak van het antibioticum Levofloxacine. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
MedDRA Classification |
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 |
To evaluate diurnal variation of the pharmacokinetics of Levofloxacin |
Het doel van dit onderzoek is de opname van het antibioticum Levofloxacine in de darmen en de uitscheiding door de nieren in kaart te brengen. |
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E.2.2 | Secondary objectives of the trial |
To explore the daily variation in the magnitude of QT interval prolongation by Levofloxacin |
Het onderzoeken van de dagelijkse variatie van het effect van Levofloxacine op het QT interval. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Healthy male subjects (Caucasians), 18 to 50 years of age, inclusive. Health status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis.
2. Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum weight of 50 kg.
3. Regular bedtimes (between 23:00 and 24:00h) and wake-up times (between 07:00 and 08:00) from one week prior to the study.
4. Ability to communicate well with the investigator in the Dutch language.
5. Ability to participate and willing to give written informed consent and to comply with the study restrictions.
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1. Mannelijke vrijwilligers tussen de 18 en 50 jaar oud, inclusief;
2. Body mass index (BMI) tussen 18 en 30 kg/m2, inclusief;
3. Vermogen en bereidheid om schriftelijk toestemming te geven voor deelname;
4. Goede gezondheid, gebaseerd op resultaten van medische geschiedenis, lichamelijk onderzoek, vitale functies,
electrocardiogram (ECG), en laboratorische bloed en urine onderzoek;
5. Aderen zijn voldoende toegankelijk om bloed af te nemen zoals staat beschreven in het protocol. |
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E.4 | Principal exclusion criteria |
1. History of clinically significant haematologic, renal, hepatic, cardiovascular, neurologic, endocrinal, oncologic, pulmonary, immunologic, or psychiatric disorders;
2. Positive for hepatitis B, C or Human Immunodeficiency Virus (HIV);
3. Positive drug screen result (i.e. positive for cocaine, opiates, amphetamine, cannabis and/or benzodiazepines) at screening and before drug administration;
4. Positive alcohol breath test result at screening or before drug administration;
5. Systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg;
6. Any of the following findings in the resting ECG:
a. Screening or baseline ECG with QRS and/or T wave judged to be unfavourable for a consistently accurate QT measurement (e.g., neuromuscular artefact that cannot be readily eliminated, arrhythmias, indistinct QRS onset, low amplitude T wave, merged T- and U-waves, prominent U waves);
b. QTcB> 450 or < 300 msec at screening or baseline visit;
7. Use of prescription medication within 2 weeks prior to drug administration;
8. Use of over-the-counter medication (including homeopathic medicines and vitamins) within 3 days prior to Day 1. An exception is paracetamol (up to 4 g/day). Other exceptions will only be made if the rationale is discussed and clearly documented by the Investigator.
9. History of seizures or any disorder that predispose to seizures;
10. Personal or family history of congenital long QT syndrome or sudden death;
11. History of clinically significant allergies, including relevant drug hypersensitivity or allergy;
12. Presence or history of alcoholism or drug abuse;
13. Use of more than 21 units of alcohol per week;
14. Use of more than 8 units of caffeine per day;
15. Smoking (subjects had to be non-smokers for at least 90 days preceding Screening);
16. Transmeridian flights or shift work within a month prior to the start of the study;
17. Extreme morning and evening types (determined by the Horne-Ostberg Morningness/Eveningness Questionnaire).
18. Participation in another clinical trial within 3 months prior to the start of this study or more than 4 times a year;
19. Loss of blood over 500 mL within 3 months prior to screening;
20. Unsuitable to participate in the study for any reason in the opinion of the PI.
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1. Geschiedenis van klinisch significante hematologische, renale, hepatische, cardiovasculaire, neurologische, endocriene, oncologische, pulmonaire, immunologische, of psychiatrische aandoeningen;
2. Positieve test voor hepatitis B, C of Human Immunodeficiency Virus (HIV);
3. Positieve test voor drugs (d.w.z. positieve test op cocaine, opiaten, amfetamine, cannabis en/of
benzodiazepines) tijdens de keuring en voor toediening van onderzoeksmedicatie;
4. Positieve test voor alcohol in adem tijdens de keuring en voor toediening van onderzoeksmedicatie;
5. Systolische bloeddruk van meer dan 140 of minder dan 90mm Hg, en diastolische bloeddruk van meer dan 90 of minder dan 50 mm Hg;
6. Een van de volgende uitslagen in een ECG gemeten in rust (tijdens screening of baseline):
- QRS en/of T wave worden geacht niet te kunnen worden gebruikt om consequent een accurate lengte van het QT interval te berekenen;
- QTcB>450 of <300msec
7.Gebruik van voorgeschreven medicatie in de 14 dagen voor toediening van onderzoeksmedicatie;
8. Gebruik van zelfzorgmedicatie (inclusief homeopatische medicatie en vitamines) in de 3 dagen voor Dag 1. Een uitzondering is paracetamol (max 4g per dag). Andere uitzonderingen worden alleen gemaakt na overleg met, en documentatie door, de PI
9. Geschiedenis van epileptische aanvallen of aandoeningen die de kans hierop vergroten;
10. Persoonlijke of familiegeschiedenis van aangeboren lang QT syndroom of plotse hartdood;
11. Geschiedenis van klinisch significante allergieën, inclusief relevante medicijn overgevoeligheid of allergie;
12. Thans bekend met of geschiedenis van alcohol of drugsmisbruik;
13. Gebruik van meer dan 21 eenheden alcohol per week;
14. Gebruik van meer dan 8 eenheden caffeine per dag;
15. Roken (deelnemers mogen niet hebben gerookt voor ten minste 90 dagen voorafgaande aan de keuring;
16. Transmeridiane vluchten of werk in ploegendiensten/nachtdiensten in een maand voor de start van de studie;
17. Extreme ochtend- of avondmensen (vastgesteld dmv de Horne-Ostberg Morningness/Eveningness Questionnaire;
18. Deelname aan een ander klinisch onderzoek in de 3 maanden voorafgaand aan studiestart of meer dan 4 keer per jaar;
19. Bloedverlies van meer dan 500 mL in de 3 maanden voorafgaande aan keuring;
20. Niet geschikt om deel te nemen aan het onderzoek om welke reden dan ook volgens de onderzoeker.
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E.5 End points |
E.5.1 | Primary end point(s) |
The main PK parameters (Cmax, Tmax, t1/2, Vd, fu, CL and F) will be determined at each of the 6 experimental time points in order to establish their variation during the 24hr period.
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De volgende farmacokinetische parameters worden bepaald:
- Cmax, Tmax, halveringstijd, distributievolume en klaring van Levofloxacine
Voor elke parameter zal het circadiane profiel bepaald worden per vrijwilliger. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Levofloxacin blood samples are taken on each of the six study days at t=0, 30, 60, 90, 120, 150, 180, 240, 300, 360, 480, 600, 720min after administration |
Levofloxacine bloed monsters worden genomen op elke van de zes studiedagen op t=0, 30, 60, 90, 120, 150, 180, 240, 300, 360, 480, 600, 720min na toediening |
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E.5.2 | Secondary end point(s) |
The effect of levofloxacin on QT-interval will be determined at each of the 6 experimental time points in order to establish their variation during the 24hr period. |
Het effect van Levofloxacine op het QT interval wordt bepaald op de 6 toedieningstijden om de variatie hiervan gedurende de dag/nacht |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
ECGs are recorded at t=0, 30, 60, 90, 120, 150, 180, 240, 360, 480, 720min |
ECGs worden gemaakt op t=0, 30, 60, 90, 120, 150, 180, 240, 360, 480, 720min |
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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 | No |
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 | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Toediening op verschillende kloktijden |
Administration at different clock times |
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E.8.2.4 | Number of treatment arms in the trial | 6 |
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 | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |