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Study of the Ability of Clarithromycin to Induce Oxidative Stress (CLAROX)

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ClinicalTrials.gov Identifier: NCT00707330
Recruitment Status : Completed
First Posted : June 30, 2008
Last Update Posted : August 11, 2008
Sponsor:
Information provided by:
Rigshospitalet, Denmark

Brief Summary:
The purpose of the study is to examine whether Klacid® (Clarithromycin) will induce oxidative stress (stress from oxygen) in healthy subjects. This is done by measuring the content of a particular substance in the urine sample, which is released when the body is exposed to oxidative stress. In addition, there will also be taken blood samples, which is analysed for another substance that is indicative of oxidative stress.

Condition or disease Intervention/treatment Phase
Oxidative Stress Drug: Clarithromycin Phase 1

Detailed Description:

The purpose of the study is to examine whether Klacid® induce oxidative stress in healthy subjects.

Many studies have shown that atherosclerosis can cause acute myocardial infarction (AMI). The development of atherosclerosis is exacerbated by simultaneous infection with Chlamydophila pneumoniae, and its accompanying inflammation. There has been shown a positive association between Chlamydophila pneumoniae antibodies and the incidence of cardiovascular complications, suggesting that Chlamydophila pneumoniae could exacerbate the development of atherosclerosis [1]. It has therefore been tried to treat atherosclerotic AMI- patients prophylactically with macrolide antibiotics (which is used to treat Chlamydia infections), to halt development of the atherosclerosis and the accompanying risk of a new acute myocardial infarction.

Two minor studies have demonstrated a positive effect of macrolide-treatment, why a major Danish study of Clarithromycin was implemented [2-4]. Clarithromycin treatment was tested against placebo in 4373 atherosclerotic patients who had had an AMI. It appeared that the use of clarithromycin led to an increased cardiovascular mortality, which could not be explained [4]. The finding of the study suggests that clarithromycin cannot be used for secondary prophylaxis of cardiovascular complications, but whether clarithromycin can be used for primary prophylaxis is not known.

It has been shown that oxidative stress can participate in the development of cardiovascular complications [5], and it could be such an oxidative stress that had led to the increased mortality in the above study. Especially because a recent american study found evidence that bactericidal antibiotics induce oxidative stress in bacteria, leading to cell death [6]. This oxidative stress contributes significantly to the impact of the bactericidal antibiotics, which was thought to be primarily attributed to their specific drug/target interactions. The same study also examined erythromycin, from which clarithromycin is a derivate. Erythromycin showed no induction of oxidative stress, but clarithromycin is twice as effective as erythromycin, which could be due to oxidative stress caused by clarithromycin.

This study seeks to clarify a possible mechanism for clarithromycin, by an examination on healthy volunteers without atherosclerosis.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Screening
Official Title: A Randomized, Single Blinded, Open-Label Crossover-Study of the Possible Induction of Oxidative Stress by Clarithromycin in Healthy Subjects
Study Start Date : May 2008
Actual Primary Completion Date : July 2008
Actual Study Completion Date : July 2008

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1
Subjects randomised to this arm will first be treated with Clarithromycin for a week, then have a 2-week washout, and finally one week of no treatment
Drug: Clarithromycin
Prolonged release tablet, 500 mg, 1 tablet a day for a week
Other Names:
  • Klacid Uno
  • ATC: J01FA09

Active Comparator: 2
Subjects randomised to this arm will first receive one week of no treatment, then have a 2-week washout, and finally be treated with Clarithromycin for a week
Drug: Clarithromycin
Prolonged release tablet, 500 mg, 1 tablet a day for a week
Other Names:
  • Klacid Uno
  • ATC: J01FA09




Primary Outcome Measures :
  1. Amount of 8-oxo-deoxyguanine in 24 hour-urine measured in nmol/mmol creatinine [ Time Frame: End of study (July-August 2008) ]
  2. Amount of Malondialdehyde in plasma [ Time Frame: End of study (July-August 2008) ]

Secondary Outcome Measures :
  1. Amount of Total Vitamin C (Ascorbic acid) in plasma [ Time Frame: End of study (July-August 2008) ]
  2. Caffeine-metabolite ratio in 24 hour-urine [ Time Frame: End of Study (July-August 2008) ]


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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Caucasian
  • Non-smoker
  • Body mass index (BMI) must be ≥18 and ≤ 30
  • Blood pressure must be within the following limits:
  • Systolic blood pressure (110 mmHg > X < 140 mmHg)
  • Diastolic blood pressure (60 mmHg > Y < 90 mmHg)
  • Normal lipid plasma levels:
  • Total cholesterol (≤ 6,0 mmol/l)
  • HDL-cholesterol (≥ 0,9 mmol/l)
  • LDL-cholesterol (≤ 4,5 mmol/l)
  • Triglycerides (0,5-2,2 mmol/l)

Exclusion Criteria:

  • Smokers
  • CRP: > 10 mg/l
  • Prolonged QT interval (defined as QTc > 450 msec.)
  • Severe renal insufficiency (Cpl (creatinine) > 0100 mmol/l)
  • Hereditary galactose intolerance
  • A special form of hereditary lactase deficiency (Lapp Lactase deficiency)
  • Glucose/galactose malabsorption
  • Use of medicines and herbal remedies that affect/is affected by Clarithromycin, or lead to QT prolongation, for example, cisapride, pimozide, terfenadine, ergotamine, dihydroergotamine, fluconazole, ritonavir, carbamazepine, kinidin, disopyramide, lovastatin, simvastatin, warfarin, acenocoumarol, sildenafil, Tadalafil, vardenafil, theophylline, tolterodine, triazolo benzodiazepins, omeprazole, colchinine, digoxin, zidovudine, phenytoin, valproat, atazanavir, itraconazole, saquinavir
  • Inborn condition with prolonged QT interval
  • The following disorders:
  • Coronary artery disease
  • Former cardiac arrhythmias
  • Severe heart insufficiency
  • Non-compensated hypokalemia (defined as Cpl (K) < 3.2 mmol/ l) and/or hypomagnesemia (defined as Cpl (Mg) < 0.67 mmol/l)
  • Bradycardia ( < 50 bpm)
  • Known allergy to clarithromycin or other macrolides
  • Narcotic
  • Eating food supplements

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00707330


Locations
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Denmark
Department of Clinical Pharmacology Q, Rigshospitalet, Blegdamsvej 9
Kopenhagen O, Denmark, 2100
Sponsors and Collaborators
Rigshospitalet, Denmark
Investigators
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Principal Investigator: Henrik E Poulsen, dr. med. Head of Department, Department of Clinical Pharmacology, Rigshospitalet

Publications:
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Responsible Party: Henrik Enghusen Poulsen, professor, dr. med., overlæge, Head of Department of Clinical Parmacology
ClinicalTrials.gov Identifier: NCT00707330     History of Changes
Other Study ID Numbers: 3-12-1-18-15-23
EudraCT 2008-001299-61
VEK H-D-2008-026
DKMA 2612-3720
Datatilsynet 2008-41-2030
First Posted: June 30, 2008    Key Record Dates
Last Update Posted: August 11, 2008
Last Verified: August 2008

Keywords provided by Rigshospitalet, Denmark:
oxidative stress
8-oxo-deoxyguanine
8-oxodG
clarithromycin
malondialdehyde
mda
vitamine C
ascorbic acid

Additional relevant MeSH terms:
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Clarithromycin
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors