Comparison of Two Macrolides, Azithromycin and Erythromycin, for Symptomatic Treatment of Gastroparesis

NCT ID: NCT01323582

Last Updated: 2014-12-05

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-02-28
• Study Completion Date: 2012-12-31

Brief Summary

Erythromycin is effectively used in the treatment of Gastroparesis (GP) patients. In susceptible patients however, it has been associated with sudden cardiac death due to prolongation of QT intervals and subsequent cardiac risks through its interaction some other drugs. Azithromycin (AZI) is a macrolide antibiotic but does not have the mentioned druf interactions , has fewer gastrointestinal side effects, and fewer risks of QT prolongation and cardiac arrhythmias. Consequently, AZI avoids drawbacks of dosing with erythromycin and may be preferred as a prokinetic agent in patients on other concomitant medications.

We hope to demonstrate the effectiveness of Azithromycin (AZI) as compared to Erythromycin in the treatment of Gastroparesis (GP), and later, form the framework for larger randomized-controlled parallel studies to investigate use of AZI for treatment of GP.

Our novel hypothesis is to determine whether AZI can be used to treat GP.

Detailed Description

Gastroparesis (GP) is a chronic gastrointestinal motility disorder resulting from delayed transit of gastric contents from the stomach into the duodenum in the absence of mechanical outlet obstruction. The symptoms of GP are variable but include early satiety, bloating, nausea, vomiting, and epigastric abdominal pain. Although the true prevalence of the disorder is unknown, symptoms suggestive of GP are present in 7-15% of the population with an estimated one-third of diabetic patients in tertiary care settings having abnormal gastric emptying studies. Yet, despite the significant healthcare and economic costs due to frequent hospitalization in these patients, treatment of GP is difficult due to the lack of available treatment options and the often potential side effects of available prokinetic agents, including cardiac side effects such as QT prolongation, sudden cardiac death, and torsade de pointes.

One such medication used for treatment of GP is erythromycin. Erythromycin has its drawbacks. Several reports of cardiac arrhythmias associated with use of either oral or intravenous (IV) Erythromycin have been reported. This finding sparked our interest in another macrolide, Azithromycin (AZI), which does not have the drug-drug interactions as seen with erythromycin and is not metabolized by the CYP3A inhibitors, therefore having fewer cardiac side effects.

In This study our primary goal is to determine whether AZI can be used to treat GP.

Conditions

Gastroparesis

Keywords

Gastroparesis; Gastroparesis Treatment; Gastric Emptying; Prokinetic Agents; Macrolides; Erythromycin; Azithromycin; Erythromycin Cardiac Side-effects; Erythromycin drug interactions; AZI

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

erythromycin

200mg/5ml elixir administered orally three times a day half an hour prior to meals.

Group Type: ACTIVE_COMPARATOR

Erythromycin

Intervention Type: DRUG

200mg/5ml elixir administered orally three times a day half an hour prior to meals.

Azithromycin

The dose of Azithromycin was determined based on our dose response curve obtained on 10 healthy subjects who were given three different doses of Azithromycin, 50 mg, 100 mg and 133 mg and underwent breath testing to determine the gastric emptying half-time. These doses were determined based on a maximum safe dosage per day of Azithromycin of 400 mg given the medication would then be administered three times daily before meals. The appearance of the medication (azithromycin) and administration period was then identical to that of Erythromycin, i.e. 5ml elixir administered orally three times a day half an hour prior to meals. The total daily dosage of Azithromycin was determined after obtaining the dose- response analysis.

Group Type: EXPERIMENTAL

Azithromycin

Intervention Type: DRUG

The dose of Azithromycin given was determined based on the following study on 10 healthy subjects. In random order, each of ten healthy subjects underwent OBT studies following administration of AZI, at doses of 50mg, 100mg, and 133mg. The T½ and Tlag was then compared for the three doses by a randomized block analysis using Analysis of Variance followed by Tukey's multiple comparison. Results: The T½ for each of the respective doses of AZI (50mg, 100mg, and 133mg) was 129 ± 27, 128 ± 31, and 128 ± 16 minutes (p = 0.98). This data suggested that AZI at doses of 50mg, 100mg and 133 mg have fairly similar activity in its effects on gastric emptying in healthy subjects. Based on this analysis , we decided to use a dose of 50 mg/5 ml for administered TID prior to meals.

Interventions

Erythromycin

200mg/5ml elixir administered orally three times a day half an hour prior to meals.

Intervention Type: DRUG

Azithromycin

The dose of Azithromycin given was determined based on the following study on 10 healthy subjects. In random order, each of ten healthy subjects underwent OBT studies following administration of AZI, at doses of 50mg, 100mg, and 133mg. The T½ and Tlag was then compared for the three doses by a randomized block analysis using Analysis of Variance followed by Tukey's multiple comparison. Results: The T½ for each of the respective doses of AZI (50mg, 100mg, and 133mg) was 129 ± 27, 128 ± 31, and 128 ± 16 minutes (p = 0.98). This data suggested that AZI at doses of 50mg, 100mg and 133 mg have fairly similar activity in its effects on gastric emptying in healthy subjects. Based on this analysis , we decided to use a dose of 50 mg/5 ml for administered TID prior to meals.

Intervention Type: DRUG

Other Intervention Names

Erythromycin ethylsuccinate

Eligibility Criteria

Inclusion Criteria

• presenting to gastroenterology motility specialty clinics at the University of Florida (UF), who meet the clinical and radiologic diagnostic criteria for diagnosis of GP

Exclusion Criteria

• Any history of mechanical obstruction
• Gastrointestinal malignancy
• Current use of prokinetics such as cisapride, pimozide, or anticholinergic medication which cannot be discontinued 72 hrs prior to study
• Abnormal upper endoscopy with finding of erosions or ulcerations
• Helicobacter pylori infection in past 6 months
• Recent abdominal surgery < 6 months
• Cardiac history with EKG finding of QTC > 450 done on a screening test
• Detected renal or hepatic dysfunction described as a GFR <10 ml/min and ALT/AST values > 2 times the normal level in our laboratory
• Allergy to macrolide antibiotics
• Psychiatric history other than anxiety or depression
• Predominant symptoms of irritable bowel syndrome such as constipation or diarrhea
• Uncontrolled diabetes with fasting blood glucose levels > 180 mg/dL, due to effect of hyperglycemia on gastric emptying. For patients with diabetes, blood glucose levels will be recorded in a patient diary.
• Pregnant or nursing females
• Any history of myasthenia gravis
• Current use of Coumadin, lovastatin, simvastatin Nelfinavir, theophylline, digoxin, ergotamine/dihydroergotamine products, benzodiazepines, and sildenafil (this will be discontinued for the duration of the clinical trial if subject is on this medication).
• History of elevated liver function studies or CPKs.
• Pregnancy : A urine pregnancy test will be performed at the beginning of each treatment period and only subjects who are not pregnant will be enrolled for the study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Metabolic Solutions Inc.

INDUSTRY

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Baharak Moshiree, MD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

University of Florida

Gainesville, Florida, United States

Countries

United States

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Other Identifiers

645-2008

Identifier Type: -

Identifier Source: org_study_id