Relationship Between Gastric Emptying and Glycemic Variability in Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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With this study, the investigators hoped to learn if the rate at which food empties from the stomach affects blood sugar values. Using data from this study, we hope to improve our ability to control blood sugars in individuals with type 1 diabetes mellitus.

Detailed Description
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The study comprised 3 outpatient visits over a period of 11 days. Safety lab test were performed at the screening visit. At each visit, GE was evaluated by 13C-spirulina breath tests. Phase 1: After the baseline assessment (GE1), the second and third GE tests were performed during treatment with intravenous (GE2) and oral erythromycin (GE3) or placebo. Subject arrived fasting at each study visit. Prior to gastric emptying study, there was placement of an intravenous line. Subject continued to take insulin and other medications as usual. Subjects were required to do finger-stick glucose readings 4 times a day or as instructed by their physician. Subjects were provided with a log sheet to keep track of meal times, insulin dosing and times, glucose readings, and activities. Continuous glucose monitoring (CGM) and gastric emptying were evaluated for the duration of the study (11 days) and thrice respectively. GE was evaluated at baseline (GE1) and after randomized to intravenous saline, erythromycin (2 mg/kg) or erythromycin (3 mg/kg). Phase 2: Thereafter, patients were randomized to erythromycin ethyl succinate suspension (250 mg tid) or placebo for a total period of 7 days. GE3 was preferably performed on day 7, after oral erythromycin or placebo was started. An EKG was performed at baseline to identify (and exclude) patients who have contraindications to erythromycin. An EKG was also repeated at the end of the study, i.e., on GE3 for safety. No change to insulin (apart from those that patients do with their self management skills) or other medications was made during this research study.

Official Title
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Relationship Between Gastric Emptying and Glycemic Variability in Type 1 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Erythromycin lactobionate
* Drug: Placebo IV
* Drug: [13C]-Spirulina
* Drug: Erythromycin Ethylsuccinate Suspension
* Drug: Placebo Suspension


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or non-pregnant non-breastfeeding female volunteers with type 1 diabetes mellitus (T1 DM) undergoing a clinically-indicated continuous glucose monitoring (CGM) study (Women of childbearing potential may be enrolled if they use contraceptives throughout the length of the study). Able to provide written informed consent before participating in the study Able to communicate adequately with the investigator and to comply with the requirements for the entire study. Glycated hemoglobin (A1c) < 8.5 % Exclusion Criteria: Severe nausea or vomiting precluding study assessments Use of medications that alter GI motility e.g., narcotics, medications with significant anticholinergic effects, CYP-450 3A4 inhibitors, antibiotics (other than the experimental drug erythromycin), pramlintide or GLP-1 based therapy. Subjects using metoclopramide or erythromycin will be enrolled but these medications will be held for 7 days before CGM1 and GE1 Pancreas transplantation Contraindications to erythromycin: i.e., 1) concomitant therapy with astemizole, cisapride, pimozide, or terfenadine; 2) hypersensitivity to erythromycin or any component of the product; Corrected QT interval on EKG >460 msec Known family history of sudden death or congenital QT prolongation Serum potassium and magnesium levels outside of normal range at screening or visit 1 Patients with moderate or severe renal insufficiency, i.e., subjects with an eGFR < 60 mL/min/1.73 m^2) Patients who are allergic to eggs, wheat or milk or unwilling to consume these products.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erythromycin lactobionate IV 2 mg/kg<br>During the second visit, erythromycin was given as an initial bolus of 0.5 mg/kg over 10 min immediately before the meal. The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points. Thereafter, an infusion of 1.5 mg/kg was given over the next 50 min with the same infusion pump. | Drug: Erythromycin lactobionate<br>* In Phase 1 of the study, during the second visit, erythromycin was given as an initial bolus of 0.5 mg/kg over 10 min immediately before the meal. Thereafter, an infusion of 1.5 or 2.5 mg/kg was given over the next 50 min with the same infusion pump. The goal of testing 2 different doses was not to assess dose-related effects but to compare glycemic indices against a spectrum of gastric emptying rates.<br>* Other names: Erythrocin™ Lactobionate-IV;Drug: [13C]-Spirulina<br>* The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points.<br>* Other names: Gastric Emptying Breath Test (GEBT);|
| Active Comparator: Erythromycin lactobionate IV 3 mg/kg<br>During the second visit, erythromycin was given as an initial bolus of 0.5 mg/kg over 10 min immediately before the meal. The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points.Thereafter, an infusion of 1.5 mg/kg was given over the next 50 min with the same infusion pump. | Drug: Erythromycin lactobionate<br>* In Phase 1 of the study, during the second visit, erythromycin was given as an initial bolus of 0.5 mg/kg over 10 min immediately before the meal. Thereafter, an infusion of 1.5 or 2.5 mg/kg was given over the next 50 min with the same infusion pump. The goal of testing 2 different doses was not to assess dose-related effects but to compare glycemic indices against a spectrum of gastric emptying rates.<br>* Other names: Erythrocin™ Lactobionate-IV;Drug: [13C]-Spirulina<br>* The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points.<br>* Other names: Gastric Emptying Breath Test (GEBT);|
| Placebo Comparator: Placebo IV<br>Saline was given as an initial bolus over 10 min immediately before the meal. The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points. Thereafter, an infusion of saline was given over the next 50 min with the same infusion pump. | Drug: Placebo IV<br>* In Phase 1 of the study, during the second visit, saline was given as an initial bolus over 10 min immediately before the meal. Thereafter, an infusion of saline was given over the next 50 min with the same infusion pump.<br>* Other names: Saline;Drug: [13C]-Spirulina<br>* The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points.<br>* Other names: Gastric Emptying Breath Test (GEBT);|
| Experimental: Erythromycin Ethylsuccinate Suspension<br>In Phase 2 of the study, subjects randomized to this arm will receive Erythromycin Ethylsuccinate Suspension 250 mg tid orally for a total period of 7 days. The GEBT was performed approximately on day 7. The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points. | Drug: [13C]-Spirulina<br>* The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points.<br>* Other names: Gastric Emptying Breath Test (GEBT);Drug: Erythromycin Ethylsuccinate Suspension<br>* In Phase 2 of the study, subjects randomized to this arm will receive Erythromycin Ethylsuccinate Suspension 250 mg tid orally for a total period of 7 days.<br>* Other names: E.E.S.;|
| Placebo Comparator: Placebo Suspension<br>In Phase 2 of the study, subjects randomized to this arm will receive an oral placebo prepared to mimic the Erythromycin Ethylsuccinate Suspension for a total period of 7 days. The GEBT was performed approximately on day 7. The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points. | Drug: [13C]-Spirulina<br>* The subject consumed the test meal containing 13C-Spirulina in no more than 10 minutes. Breath samples were collected at baseline obtained upon completion of the meal and at 15, 30, 45, 60, 90, 120, 150, 180, and 240 minute time points.<br>* Other names: Gastric Emptying Breath Test (GEBT);Drug: Placebo Suspension<br>* In Phase 2 of the study, subjects randomized to this arm will receive an oral placebo prepared to mimic the Erythromycin Ethylsuccinate Suspension for a total period of 7 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship between gastric emptying and glycemia | GE was measured by 13C spirulina GEBT. Glycemia was measured with continuous glucose monitoring. | 11 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with delayed gastric emptying |  | 11 days |