The purpose of this study is to determine whether pramlintide (Symlin) will help to reduce the frequency and severity of hypoglycemia in individuals who have had gastric bypass surgery.
- Study Type: Interventional
- Study Design
- Allocation: N/A
- Intervention Model: Single Group Assignment
- Primary Purpose: Treatment
- Masking: None (Open Label)
- Study Primary Completion Date: July 2016
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. 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. 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 for comparison with the pre-treatment results.
- Drug: Pramlintide
- See description above (arm description).
Arms, Groups and Cohorts
- Other: Pramlintide (Symlin)
- Participants in this study will be asked to complete 4 study visits. Study visit 1 will be for screening. Eligible individuals who provide informed consent will be asked to keep a 3-day log of food intake, blood glucose (8 per day), as well as any hypoglycemic symptoms. At study visit 2, a baseline mixed meal tolerance test will be performed. Glucose, hormonal responses, and satiety will be assessed. Glucose and symptom log will be reviewed. Pramlintide will be prescribed, with instructions for titration from minimal to maximal dose (15 to 120 µg). During treatment, the participants will keep a record of all hypoglycemic symptoms and blood glucose measurements at those times. Study visit 3 will occur at week 4 of treatment and focus on evaluation of symptoms and side effects. Participants will again complete a food and glucose diary for 3 days. During study visit 4 (week 8 of treatment), participants will undergo a repeat mixed meal tolerance test.
Clinical Trial Outcome Measures
- Time Frame: 8 weeks
- The primary study endpoint will be 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 day, assessed by continuous glucose monitoring). Additional parameters assessed for clinical efficacy include other glucose parameters derived from both capillary glucose and symptom monitoring for 5 days 8 times daily (average blood glucose, minimum blood glucose, frequency of reported symptoms, and frequency of glucose values < 70 mg/dl) and continuous glucose monitoring (including minimum glucose, frequency of glucose values >140 mg/dl, and maximum glucose values) prior to and during pramlintide therapy.
- meal hormonal responses
- Time Frame: 8 weeks
- The secondary study endpoints will be assessment of pramlintide effects on mixed meal hormonal responses, including glucagon, insulin, and incretins. Additional comparisons will include measures of satiety and fasting and diet-induced thermogenesis and respiratory quotient. Pre- and post-treatment fasting values and postprandial values (peak values, area under curve) will be compared using a two-sided comparison of paired means.
Participating in This Clinical Trial
- 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 ALT and 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
Gender Eligibility: All
Minimum Age: 21 Years
Maximum Age: 65 Years
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Joslin Diabetes Center
- Bristol-Myers Squibb
- Provider of Information About this Clinical Study
- Overall Official(s)
- Mary E. Patti, MD, Principal Investigator, Joslin Diabetes Center
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. 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. 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.
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