Official Title: “A Randomized, Single Blinded, Open-Label Crossover-Study of the Possible Induction of Oxidative Stress by Clarithromycin in Healthy Subjects”

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.

Study Type: Interventional

Study Design: Screening, Randomized, Open Label, Crossover Assignment, Pharmacodynamics Study

Study Primary Completion Date: July 2008

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.

Intervention(s) in this Clinical Trial

• Drug: Clarithromycin
  • Prolonged release tablet, 500 mg, 1 tablet a day for a week

Arms, Groups and Cohorts in this Clinical Trial

• 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
• 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

Primary Measures

• Amount of 8-oxo-deoxyguanine in 24 hour-urine measured in nmol/mmol creatinine
  • Time Frame: End of study (July-August 2008)
    Safety Issue?: No
• Amount of Malondialdehyde in plasma
  • Time Frame: End of study (July-August 2008)
    Safety Issue?: No

Secondary Measures

• Amount of Total Vitamin C (Ascorbic acid) in plasma
  • Time Frame: End of study (July-August 2008)
    Safety Issue?: No
• Caffeine-metabolite ratio in 24 hour-urine
  • Time Frame: End of Study (July-August 2008)
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Male

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 35 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Rigshospitalet, Denmark

Overall Clinical Trial Officials and Contacts

Henrik E Poulsen, dr. med. Principal Investigator Head of Department, Department of Clinical Pharmacology, Rigshospitalet  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00707330

Study ID Number: 3-12-1-18-15-23

ClinicalTrials.gov Identifier: NCT00707330

Health Authority: Denmark: Danish Medicines Agency