| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Physical Phenomena [G01] |
| 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 study the pharmacokinetics of gentamicin, tobramycin, vancomycin and ciprofloxacin in morbidly obese patients and compare with normal weight patients. |
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| E.2.2 | Secondary objectives of the trial |
| To assess the influence of covariates (such as total bodyweight, lean bodyweight, serum creatinine, metabolomics and GFR) on the pharmacokinetics of gentamicin, tobramycin, vancomycin and ciprofloxacin. To develop dosing recommendations for gentamicin, tobramycin, vancomycin and ciprofloxacin in (morbidly) obese individuals. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for (morbidly) obese participants:
- Indication for bariatric surgery (i.e. BMI > 40 kg/m2 or BMI > 35 kg/m2 with additional risk factors). Bariatric surgery includes the following: laparoscopic gastric bypass surgery or laparoscopic sleeve gastrectomy. We will equally stratify subjects to 4 weight groups: 100-120 kg, 120-145 kg, 145-170 kg and >170 kg;
- Participants between 18 - 60 years old;
- ASA physical classification of II or III;
- Participant is able and willing to sign the Informed Consent before screening evaluations.
Inclusion criteria for controls (normal weight participants):
- BMI between 18 and 25 kg/m2;
- Participants between 18 - 55 years old;
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| E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study:
- Renal insufficiency identified by eGFR < 60 ml/min/1.73m2. A recent serum creatinine (measured in the previous year) has to be known to assess this criterion. When not available, the patient’s own general practioner or pharmacy can be contacted for a recent serum creatinine. This is only done with oral consent from the patient. If not available, then serum creatinine is measured before the study drug is administered (see study procedures) with priority);
- Known allergy to the administered drug;
- Recent use of the study drug (up to 7 days before administration of the study drug);
- Treatment with the concerning study drug up to 7 days before administration of the study drug.
- Pregnancy or breastfeeding. This is an exclusion criteria for bariatric surgery as well (participants are informed by their surgeon and bariatric nurse). Women of childbearing potential using contraception are allowed to participate in the study.
Specific exclusion criteria for participants receiving an aminoglycoside or vancomycin:
- Participant who are treated with known nephro- or ototoxic drugs (immunosuppressants, antivirals, antineoplastic agents, ACE-inhibitors, lisdiuretics, aminoglycosides, vancomycin) up to 7 days before administration of the study drug. For NSAIDs, participants are not allowed to use a NSAID 24 hours before administration of the study drug (with the exception of meloxicam (72 hours), nabumeton (72 hours) or piroxicam 7 days).
Specific exclusion criteria for participants receiving ciprofloxacin IV:
- Known liver disease identified by liver function tests: ASAT, ALAT, prothrombin time, γ-GT, bilirubin, or alkaline phosphatase (ALP) (> 3 times upper limit of normal values)
- Known prolonged QT-interval or participants that use drugs that are known to prolong the QT-interval (based on the list published by CredibleMeds®, formerly known as AZCERT)
- Epilepsy
- Myasthenia gravis
- Porphyria cutanea tarda
- Psychoses in history
- Participants that use drugs that are known to be metabolized by CYP1A2 or CYP3A4
Additional exclusion criteria for participants receiving ciprofloxacin PO:
- Participants that use oral drugs that contain bivalent cations (calcium, magnesium, aluminum or iron), phosphate binders (sevelamer) or sucralphate, antacids or influence gastric emptying (see Appendix1) less than 6 hours before administration of ciprofloxacin.
For healthy volunteers a few extra prohibitions apply to participation (these are standard prohibitions employed in the CRCN):
- Water is allowed as desired except for one hour before and one hour after administration of study medication.
- From four hours after dosing until release of confinement, consumption of available beverages is free and meals are standardized in regard to consumption and time of administration.
- No history of alcohol or drugs abuse (up until one month before study drug administration).
- Subjects may not consume alcoholic beverages from 24 hours before until 48 hours after administration of study medication.
- Subjects may not use grapefruit containing food or juice, or St John’s worth, from 7 days before until the end of the study.
- Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the study period. Male subjects should also use contraceptive methods in order to avoid pregnancy of their partners during the study period.
- Subjects are to refrain from strenuous exercise of all types while at the clinical research centre and at the day prior to administration of study medication.
- Subjects are not allowed to lie down without permission from one hour before until 4 hours after dosing of oral ciprofloxacin because body position and posture may influence physiological characteristics such as dissolution and (the rate of) absorption of ciprofloxacin.
- Subjects are not allowed to smoke at the clinical research centre.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoint is clearance (Cl) of gentamicin, tobramycin, vancomycin or ciprofloxacin in obese participants versus normal weight participants. Other primary endpoints are volume of distribution (Vd) and oral bioavailability (F) for ciprofloxacin in obese participants versus normal weight participants. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 hours post infusion (48h in patients receiving vancomycin and 12h hours in patients receiving ciprofloxacin) |
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| E.5.2 | Secondary end point(s) |
Influence of covariates (total bodyweight, lean bodyweight, gender, length, age, creatinine, metabolomic profile, GFR) on primary parameters of interest (i.e. clearance and volume of distribution). The covariate history/duration of obesity means that we want to investigate the influence of the duration of obesity (measured as number of years that the patient is known to have obesity, and since what phase in life) on different PK-parameters.
Other study parameters:
GFR measured using creatinine concentration in urine collected over 24 hours in morbidly obese participants. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 24 hours post infusion (48h in patients receiving vancomycin and 12 hours in patients receiving ciprofloxacin) |
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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 | No |
| 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 | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Tested IMP's are also investigated in normal weight patients for comparison |
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| 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 |
| Tested IMP's are also investigated in normal weight patients for comparison |
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| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
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