Pramlintide (Symlin) for the Treatment of Hypoglycemia Following Gastric Bypass Surgery

Phase 4

Completed

Conditions: Hypoglycemia
Evidence of Previous Gastric Surgery

Interventions: Drug: Pramlintide

Registration Number: NCT01841359

Lead Sponsor: Joslin Diabetes Center

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

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 & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Pramlintide	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).

Primary Outcome Measures

Name	Time	Method
Plasma Glucose Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Glucose	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.	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.

Secondary Outcome Measures

Name	Time	Method
Plasma Insulin Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Insulin	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.	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.
Satiety Score During Mixed Meal Testing at 120 Minutes	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.	Satiety was analyzed using a visual analogue scale (1, very hungry to 10, not hungry), administered 120 minutes following ingestion of mixed meal.
Continuous Glucose Monitoring Maximum Sensor Glucose Values Prior to (Baseline) and During Pramlintide Therapy.	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)
Number of Days With Minimum Sensor Glucose < 54 mg/dL as Measured by Continuous Glucose Monitoring.	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)
Nadir Plasma Glucose Levels During Mixed Meal Testing at Baseline and During Treatment With Pramlintide	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.
Continuous Glucose Monitoring Minimum Sensor Glucose Prior to (Baseline) and During Pramlintide Therapy.	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)
Hypoglycemia - Percentage of Time Sensor Glucose Levels < 70 mg/dL Prior to (Baseline) and During Pramlintide Therapy.	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)	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.
Dumping Score During Mixed Meal Testing at Baseline and During Treatment With Pramlintide	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.	Dumping score was calculated using changes in pulse and hematocrit. Higher scores indicate more severe dumping. Scores ranged from -196 to 186.
Time to Nadir Plasma Glucose During Mixed Meal Testing at Baseline and During Treatment With Pramlintide	Assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.
Number of Participants Requiring Rescue Treatment for Severe Hypoglycemia During Mixed Meal Testing (Visit 2 Baseline vs. Visit 4 Post-pramlintide Dosing)	Assessed on the two days of mixed meal testing: the first occurring at baseline; and the second following 8 weeks of treatment with pramlintide.