Gastroparesis
Conditions
Keywords
Gastroparesis, Gastroparesis Treatment, Gastric Emptying, Prokinetic Agents, Macrolides, Erythromycin, Azithromycin, Erythromycin Cardiac Side-effects, Erythromycin drug interactions, AZI
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.
Interventions
DRUGErythromycin
200mg/5ml elixir administered orally three times a day half an hour prior to meals.
DRUGAzithromycin
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.
Sponsors
Metabolic Solutions Inc.
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Weeks 4 and 11 (end of periods) | 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. |
| Gastroparesis Cardinal Symptom Index (GCSI) Score | Weeks 4 and 11 (end of periods) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Time to 50% Gastric Emptying: Post Test Less Baseline Pooled Over Orderings | Baseline and end of treatment period | 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 reaching 50% of the accumulated contents is recorded. |
| 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. | 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 reaching 50% of the accumulated contents is recorded. |
| NDI Score | Weeks 4 and 11 (end of periods) | Nepean Dyspepsia Index (NDI) is a measure of symptom status and quality of life in functional dyspepsia. This scale is scored using each subscale (Tension, interference with daily activities), Eating/drinking, Knowledge/control, work/study) and adding up the items for each of the five subscale score (2-10). Total score range would be 10-50). For the NDI, a lower number is better meaning the symptom is not effecting quality of life and a higher score closer to 50 is worse meaning it is effecting patients quality of life. Reference: Talley NJ, Verlinden M, Jones M. Quality of life in functional dyspepsia: responsiveness of the Nepean Dyspepsia Index and developement of a new 10-iten short form. Aliment Pharmacol Ther 2001: 15: 207-216. 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. |
| Does GCSI Score Improve (Lower) on Treatment, Pooling the AZ Patients Over Their Treatment Periods? Endpoint is Difference in Post-test Less Baseline | Baseline and end of treatment period | 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 symptom 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 are. The scale is reported in the references. This is a calculation taken with GCSI score at end of treatment minus baseline. Negative value reflects this change. |
| Gastroparesis Cardinal Symptom Index (GCSI) Score Change From Baseline to Post Treatment | Baseline and end of treatment period | 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 symptom 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 are. The scale is reported in the references. The change was calculated by measuring the end of treatment minus baseline GCSI score. Negative value reflects this change. |
| TLAG (Time From Ingestion of Meal to Start of Gastric Emptying) | Weeks 4 and 11 (end of periods) | This is defined as the time from ingestion of the meal to the beginning of the emptying process in minutes. 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Erythromycin First Then Azithromycin Erythromycin is given for 4 weeks (1-4), there is a 3 week washout (5-7), then Azithromycin is given for 4 weeks (Weeks 8-11). | 12 |
| Azithromycin Then Erythromycin Azithromycin is given for 4 weeks (1-4), there is a 3 week washout (5-7), then Erythromycin is given for 4 weeks (Weeks 8-11). | 14 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Weeks 1-4 (First Period) | Withdrawal by Subject | 2 | 2 |
| Weeks 5-7 (Washout) | Withdrawal by Subject | 0 | 1 |
| Weeks 8-11 (Period 2) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Erythromycin First Then Azithromycin | Azithromycin Then Erythromycin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 13 Participants | 25 Participants |
| Age, Continuous | 46.1 years STANDARD_DEVIATION 12.7 | 48.5 years STANDARD_DEVIATION 11.7 | 47.4 years STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 12 participants | 14 participants | 26 participants |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 23 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 26 | 3 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 |
Outcome results
Primary
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.
Time frame: Weeks 4 and 11 (end of periods)
Population: One subject did not complete this part of analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin First Then Azithromycin | Gastroparesis Cardinal Symptom Index (GCSI) Score | -1.6 units on a scale | Standard Deviation 5.2 |
| Azithromycin Then Erythromycin | Gastroparesis Cardinal Symptom Index (GCSI) Score | -2.9 units on a scale | Standard Deviation 7 |
Comparison: Study planned to accrue 50 subjects, but due to difficult recruitment was not able to meet its objective.p-value: 0.6595% CI: [-4.8, 7.5]t-test, 2 sided
Primary
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.
Time frame: Weeks 4 and 11 (end of periods)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin First Then Azithromycin | 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. | -1.6 Minutes | Standard Deviation 32.3 |
| Azithromycin Then Erythromycin | 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. | -5.2 Minutes | Standard Deviation 17.9 |
Comparison: Study planned to accrue 50 subjects, but due to difficult recruitment was not able to meet its objective.p-value: 0.7695% CI: [-21.5, 28.6]t-test, 2 sided
Secondary
Change in Time to 50% Emptying: Post Test Less Baseline Pooled Over Orderings
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 reaching 50% of the accumulated contents is recorded.
Time frame: at baseline before initiation of the treatment and after completion of each treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin First Then Azithromycin | Change in Time to 50% Emptying: Post Test Less Baseline Pooled Over Orderings | -15.0 minutes | Standard Deviation 31 |
p-value: 0.03495% CI: [-28.7, -1.26]t-test, 2 sided
Secondary
Change in Time to 50% Gastric Emptying: Post Test Less Baseline Pooled Over Orderings
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 reaching 50% of the accumulated contents is recorded.
Time frame: Baseline and end of treatment period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin First Then Azithromycin | Change in Time to 50% Gastric Emptying: Post Test Less Baseline Pooled Over Orderings | -11.8 Minutes | Standard Deviation 40.8 |
p-value: 0.2195% CI: [-30.9, 7.3]t-test, 2 sided
Secondary
Does GCSI Score Improve (Lower) on Treatment, Pooling the AZ Patients Over Their Treatment Periods? Endpoint is Difference in Post-test Less Baseline
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 symptom 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 are. The scale is reported in the references. This is a calculation taken with GCSI score at end of treatment minus baseline. Negative value reflects this change.
Time frame: Baseline and end of treatment period
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Erythromycin First Then Azithromycin | Does GCSI Score Improve (Lower) on Treatment, Pooling the AZ Patients Over Their Treatment Periods? Endpoint is Difference in Post-test Less Baseline | -6.40 units on a scale | Standard Deviation 10.3 |
p-value: 0.008395% CI: [-10.97, -1.83]t-test, 2 sided
Secondary
Gastroparesis Cardinal Symptom Index (GCSI) Score Change From Baseline to Post Treatment
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 symptom 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 are. The scale is reported in the references. The change was calculated by measuring the end of treatment minus baseline GCSI score. Negative value reflects this change.
Time frame: Baseline and end of treatment period
Population: One subject did not complete this part of analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin First Then Azithromycin | Gastroparesis Cardinal Symptom Index (GCSI) Score Change From Baseline to Post Treatment | -5.32 units on a scale | Standard Deviation 8.64 |
p-value: 0.01595% CI: [-9.48, -1.16]t-test, 2 sided
Secondary
NDI Score
Nepean Dyspepsia Index (NDI) is a measure of symptom status and quality of life in functional dyspepsia. This scale is scored using each subscale (Tension, interference with daily activities), Eating/drinking, Knowledge/control, work/study) and adding up the items for each of the five subscale score (2-10). Total score range would be 10-50). For the NDI, a lower number is better meaning the symptom is not effecting quality of life and a higher score closer to 50 is worse meaning it is effecting patients quality of life. Reference: Talley NJ, Verlinden M, Jones M. Quality of life in functional dyspepsia: responsiveness of the Nepean Dyspepsia Index and developement of a new 10-iten short form. Aliment Pharmacol Ther 2001: 15: 207-216. 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.
Time frame: Weeks 4 and 11 (end of periods)
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Erythromycin First Then Azithromycin | NDI Score | 1.65 units on a scale | Standard Deviation 5.6 |
| Azithromycin Then Erythromycin | NDI Score | 1.30 units on a scale | Standard Deviation 4.6 |
Comparison: Half of the period 2 minus period 1 differences were used, since the difference between these two derived means is an unbiased estimate of the effect size.p-value: 0.8895% CI: [-4.58, 5.19]t-test, 2 sided
Secondary
TLAG (Time From Ingestion of Meal to Start of Gastric Emptying)
This is defined as the time from ingestion of the meal to the beginning of the emptying process in minutes. 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.
Time frame: Weeks 4 and 11 (end of periods)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythromycin First Then Azithromycin | TLAG (Time From Ingestion of Meal to Start of Gastric Emptying) | -1.71 Minutes | Standard Deviation 16.2 |
| Azithromycin Then Erythromycin | TLAG (Time From Ingestion of Meal to Start of Gastric Emptying) | -0.22 Minutes | Standard Deviation 8.2 |
p-value: 0.895% CI: [-13.9, 10.9]t-test, 2 sided