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

NCT01323582 | Terminated Phase 2 Results

• 1 other identifier: 645-2008
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

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.

Conditions

Gastroparesis

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Time in Minutes for 50% of the Ingested Meal to Empty the Stomach With a Standardized Breath Test: Half the of the Week 11 Value (Period 2) Less Half the of the Week 4 Value (Period 1). This Estimates the Effect Size.

  Patients will be given a standardized meal enriched with a labeled material and the breath samples are then collected and analyzed. The estimated time to empty 50% (t 1/2) of the accumulated contents is recorded. Because the difference is RX-B -RX A in one group and RX A -RX B in the other, the difference between these two estimates twice the effect size. Hence the Half is applied, as is standard in the two sample method for crossover studies.

  Weeks 4 and 11 (end of periods)

• Gastroparesis Cardinal Symptom Index (GCSI) Score

  This is a Validated instrument for measuring symptom severity in patients with gastroparesis. This scoring is based on a Likert Scale from (0-5) with zero being no symptoms and five being very severe symptoms on 9 subscales, making the overall score range from 0-45. The higher the score, the more severe patient's symptoms. Reference for GCSI: Revicki DA, REntz AM, Dubois D, et al. Development and validation of a patient-assessed gastroparesis symptoms severity measure: the Gastroparesis Cardinal Symptom Index. Ailment Pharm Ther 2003; 18: 141:50. Because the difference is RX-B -RX A in one group and RX A -RX B in the other, the difference between these two estimates twice the effect size. Hence the Half is applied, as is standard in the two sample method for crossover studies.

  Weeks 4 and 11 (end of periods)

Secondary Outcomes (6)

• NDI Score

  Weeks 4 and 11 (end of periods)

• TLAG (Time From Ingestion of Meal to Start of Gastric Emptying)

  Weeks 4 and 11 (end of periods)

• Change in Time to 50% Gastric Emptying: Post Test Less Baseline Pooled Over Orderings

  Baseline and end of treatment period

• Change in Time to 50% Emptying: Post Test Less Baseline Pooled Over Orderings

  at baseline before initiation of the treatment and after completion of each treatment period.

• Gastroparesis Cardinal Symptom Index (GCSI) Score Change From Baseline to Post Treatment

  Baseline and end of treatment period

Study Arms (2)

erythromycin

ACTIVE COMPARATOR

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

Drug: Erythromycin

Azithromycin

EXPERIMENTAL

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.

Drug: Azithromycin

Interventions

Erythromycin DRUG

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

Also known as: Erythromycin ethylsuccinate

erythromycin

Azithromycin 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.

Azithromycin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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).

Sponsors & Collaborators

• University of Florida: lead
• Metabolic Solutions Inc.: collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32610, United States

Location

Related Publications (15)

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  PMID: 9824125 BACKGROUND

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• Choi MG, Camilleri M, Burton DD, Zinsmeister AR, Forstrom LA, Nair KS. [13C]octanoic acid breath test for gastric emptying of solids: accuracy, reproducibility, and comparison with scintigraphy. Gastroenterology. 1997 Apr;112(4):1155-62. doi: 10.1016/s0016-5085(97)70126-4.

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  PMID: 8817107 BACKGROUND

• Bromer MQ, Kantor SB, Wagner DA, Knight LC, Maurer AH, Parkman HP. Simultaneous measurement of gastric emptying with a simple muffin meal using [13C]octanoate breath test and scintigraphy in normal subjects and patients with dyspeptic symptoms. Dig Dis Sci. 2002 Jul;47(7):1657-63. doi: 10.1023/a:1015856211261.

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  BACKGROUND

• Ware JE Jr, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey: Manual and Interpretation Guide. Boston, MA: The Health Institute, New England Medical Center, 1993.

  BACKGROUND

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  PMID: 10102954 BACKGROUND

MeSH Terms

Conditions

Gastroparesis

Interventions

Erythromycin; Erythromycin Ethylsuccinate; Azithromycin

Condition Hierarchy (Ancestors)

Stomach Diseases; Gastrointestinal Diseases; Digestive System Diseases; Paralysis; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Macrolides; Polyketides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Baharak Moshiree MD
• Organization: University of Florida

bmoshiree@med.miami.edu

305-243-2515

Study Officials

• Baharak Moshiree, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2011
• First Posted: March 25, 2011
• Study Start: February 1, 2009
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: December 5, 2014
• Results First Posted: December 5, 2014

Record last verified: 2014-12

Locations

US (1)