- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01841359
Pramlintide (Symlin) for the Treatment of Hypoglycemia Following Gastric Bypass Surgery
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This study is an open-label short-term proof of concept study. The investigators will administer pramlintide to patients with severe post-prandial hypoglycemia following gastric bypass, in order to determine whether pramlintide is effective in reducing the frequency or severity of hypoglycemia. Pramlintide will be prescribed for 8 weeks. In order to assess the efficacy of pramlintide to prevent post-prandial hypoglycemia and hypoglycemic symptoms, the investigators will compare (a) blood glucose measurements and frequency of hypoglycemic symptoms, before and at the end of the drug intervention, using both capillary glucose monitoring and continuous glucose monitoring, and (b) glycemic, hormonal, and energetic responses to a three-hour mixed meal tolerance test.
The study will utilize an open label design to evaluate the efficacy of pramlintide in patients who have had gastric bypass and have severe postprandial hypoglycemia. The study will not be randomized or blinded. The investigators will recruit 26 participants from Joslin Diabetes Center.
Briefly, participants in this study will be asked to complete 4 study visits. The first visit will be for screening. They will then be asked to keep a 3-day log in which they record food intake (including estimated portion sizes), blood glucoses eight times daily, as well as any hypoglycemic symptoms, before they initiate treatment. Concurrently participants will wear a professional (blinded) continuous glucose monitoring (CGM) device for 3 days. At a second study visit, they will undergo a mixed meal tolerance test, which will serve as a baseline evaluation. Patterns of (a) glucose excursions (initial postprandial peak, subsequent postprandial fall and potential hypoglycemia), and (b) hormonal responses (insulin, C-peptide, glucagon, incretins) will be assessed. At the end of the mixed meal, satiety will be assessed using a visual analog scale. Baseline hypoglycemia frequency and severity will be assessed by reviewing patient glucose and hypoglycemia symptom log recorded prior to the visit.
At the completion of visit 2, pramlintide will be prescribed, with instructions for titration of the drug from minimal to maximal dose (see titration schedule below) to help reduce the incidence of side effects. During the treatment period, the participants will keep a record of all hypoglycemic symptoms and blood glucose measurements at those times.
There will be one follow-up visit (visit 3) in the middle of the treatment period for evaluation of symptoms and tolerance of medication. During the last (eighth) week of treatment, for comparison with pre-treatment glycemia, participants will again complete a food diary, and measure and record blood glucoses eight times daily for 3 days, while also wearing a professional (blinded) CGM. During that final week of the study, participants will also come to a fourth study visit, during which they will undergo a repeat mixed meal tolerance test, receiving a dose of pramlintide prior to the start of the mixed meal, for comparison with the pre-treatment (baseline) results.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Joslin Diabetes Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- severe hypoglycemic episodes post-gastric bypass surgery
- normal fasting glucose
- age 21 to 65
- hypoglycemia must not have responded to dietary intervention (low glycemic index, controlled carbohydrate portions) and a trial of acarbose therapy at the maximally tolerated dose
Exclusion Criteria:
- Hypoglycemia in the fasting state (greater than 12 hours fast)
- History of preoperative diabetes mellitus
- Use of medications that affect gastrointestinal motility (e.g., cisapride, metoclopramide)
- Impaired renal function (creatinine clearance < 20 ml/min or on dialysis
- Hepatic disease (defined as liver enzymes > 2 times upper normal limit for alanine transaminase (ALT) and aspartate aminotransferase (AST))
- Blood donation for 2 months prior to the study.
- Severe hypoglycemic unawareness, as defined by inability to recognize adrenergic or neuroglycopenic symptoms of hypoglycemia despite detailed education
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
No Intervention: Baseline
Baseline Arm/Phase 1, is comprised of study visits 1 and 2. Visit 1: Screening visit. Eligible individuals who provided informed consent were asked to keep a 3-day log of food intake, blood glucose (8 per day), as well as any hypoglycemic symptoms, concurrent with a 3 day period of blinded (masked) continuous glucose monitoring device wear. Visit 2: a baseline mixed meal tolerance test was performed. Glucose, hormonal responses, and satiety were assessed. Glucose and symptom logs were reviewed. |
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Experimental: Pramlintide
At the end of Visit 2 (following the baseline mixed meal tolerance test), pramlintide was prescribed, with instructions for titration from minimal to maximal dose (15 to 120 µg). During the treatment phase (8 weeks), the participants were asked to keep record of all hypoglycemic symptoms and blood glucose measurements.. Visit 3: (week 4 of treatment) focused on evaluation of symptoms and side effects. Participants again completed a food and glucose diary for 3 days with concurrent wear of a blinded (masked) continuous glucose monitoring device. Visit 4: (week 8 of treatment), participants received a dose of pramlintide 15 minutes prior to undergoing a repeat mixed meal tolerance test. (the dose administered was the maximally tolerated dose of pramlintide used during the 8 week outpatient treatment phase). |
See description above (arm description).
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Plasma Glucose Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Glucose
Time Frame: Levels assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Baseline and post-treatment with pramlintide mixed meal testing plasma glucose values, area under the curve (AUC), calculated with the trapezoidal method. Plasma glucose was measured at timepoints (minutes): -5 (baseline), 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes. |
Levels assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Continuous Glucose Monitoring Maximum Sensor Glucose Values Prior to (Baseline) and During Pramlintide Therapy.
Time Frame: During 8 week period of participation, V1-V2 (baseline CGM data over 3 days); V3-V4 (CGM data during treatment with three times per day (TID) pramlintide over 3 days)
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During 8 week period of participation, V1-V2 (baseline CGM data over 3 days); V3-V4 (CGM data during treatment with three times per day (TID) pramlintide over 3 days)
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Continuous Glucose Monitoring Minimum Sensor Glucose Prior to (Baseline) and During Pramlintide Therapy.
Time Frame: During 8 week period of participation, V1-V2 (baseline CGM data over 3 days); V3-V4 (CGM data during treatment with TID pramlintide over 3 days)
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During 8 week period of participation, V1-V2 (baseline CGM data over 3 days); V3-V4 (CGM data during treatment with TID pramlintide over 3 days)
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Hypoglycemia - Percentage of Time Sensor Glucose Levels < 70 mg/dL Prior to (Baseline) and During Pramlintide Therapy.
Time Frame: During 8 week period of participation, V1-V2 (baseline CGM data over 3 days); V3-V4 (CGM data during treatment with TID pramlintide over 3 days)
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Assessment of clinical response to pramlintide treatment, as indicated by paired comparison of the frequency of glucose values under 70 mg/dl (expressed as percentage of time) assessed by continuous glucose monitoring.
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During 8 week period of participation, V1-V2 (baseline CGM data over 3 days); V3-V4 (CGM data during treatment with TID pramlintide over 3 days)
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Plasma Insulin Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Insulin
Time Frame: Levels assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Pre- and post-treatment mixed meal testing plasma insulin levels area under the curve (AUC) was calculated with the trapezoidal method. Plasma insulin was measured at timepoints (minutes): -5 (baseline), 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes. |
Levels assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Satiety Score During Mixed Meal Testing at 120 Minutes
Time Frame: Levels assessed on the two days of mixed meal testing at the 120 min time point: the first occurring at baseline (prior to treatment with pramlintide), and the second following 8 weeks of treatment with pramlintide.
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Satiety was analyzed using a visual analogue scale (1, very hungry to 10, not hungry), administered 120 minutes following ingestion of mixed meal.
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Levels assessed on the two days of mixed meal testing at the 120 min time point: the first occurring at baseline (prior to treatment with pramlintide), and the second following 8 weeks of treatment with pramlintide.
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Dumping Score During Mixed Meal Testing at Baseline and During Treatment With Pramlintide
Time Frame: Levels assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Dumping score was calculated using changes in pulse and hematocrit.
Higher scores indicate more severe dumping.
Scores ranged from -196 to 186.
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Levels assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Number of Days With Minimum Sensor Glucose < 54 mg/dL as Measured by Continuous Glucose Monitoring.
Time Frame: During 8 week period of participation, V1-V2 (baseline CGM data over 3 days); V3-V4 (CGM data during treatment with TID pramlintide over 3 days)
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During 8 week period of participation, V1-V2 (baseline CGM data over 3 days); V3-V4 (CGM data during treatment with TID pramlintide over 3 days)
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Nadir Plasma Glucose Levels During Mixed Meal Testing at Baseline and During Treatment With Pramlintide
Time Frame: Levels assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Levels assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Time to Nadir Plasma Glucose During Mixed Meal Testing at Baseline and During Treatment With Pramlintide
Time Frame: Assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Number of Participants Requiring Rescue Treatment for Severe Hypoglycemia During Mixed Meal Testing (Visit 2 Baseline vs. Visit 4 Post-pramlintide Dosing)
Time Frame: Assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Mary E. Patti, MD, Joslin Diabetes Center
Publications and helpful links
General Publications
- Patti ME, Goldfine AB. Hypoglycaemia following gastric bypass surgery--diabetes remission in the extreme? Diabetologia. 2010 Nov;53(11):2276-9. doi: 10.1007/s00125-010-1884-8. Epub 2010 Aug 21.
- Goldfine AB, Mun EC, Devine E, Bernier R, Baz-Hecht M, Jones DB, Schneider BE, Holst JJ, Patti ME. Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol Metab. 2007 Dec;92(12):4678-85. doi: 10.1210/jc.2007-0918. Epub 2007 Sep 25.
- Patti ME, McMahon G, Mun EC, Bitton A, Holst JJ, Goldsmith J, Hanto DW, Callery M, Arky R, Nose V, Bonner-Weir S, Goldfine AB. Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia. 2005 Nov;48(11):2236-40. doi: 10.1007/s00125-005-1933-x. Epub 2005 Sep 30.
- Goldfine AB, Mun E, Patti ME. Hyperinsulinemic hypoglycemia following gastric bypass surgery for obesity. Current Opinion in Endocrinology and Diabetes 13: 419-24, 2006.
- Sheehan A, Goldfine A, Bajwa M, Wolfs D, Kozuka C, Piper J, Fowler K, Patti ME. Pramlintide for post-bariatric hypoglycaemia. Diabetes Obes Metab. 2022 Jun;24(6):1021-1028. doi: 10.1111/dom.14665. Epub 2022 Mar 9.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- Joslin 08-34
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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