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.

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

Hypoglycemia

Evidence of Previous Gastric Surgery

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.

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.

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.

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 was analyzed using a visual analogue scale (1, very hungry to 10, not hungry), administered 120 minutes following ingestion of mixed meal.

Dumping score was calculated using changes in pulse and hematocrit. Higher scores indicate more severe dumping. Scores ranged from -196 to 186.

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.

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).

Joslin Diabetes Center

Participants in this study were asked to complete 4 study visits. Study visit 1 was a 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. At study visit 2, a baseline mixed meal tolerance test was performed. Glucose, hormonal responses, and satiety were assessed. Glucose and symptom log was reviewed. Pramlintide was prescribed, with instructions for titration from minimal to maximal dose (15 to 120 µg). During treatment, the participants kept a record of all hypoglycemic symptoms and blood glucose measurements at those times.

Study visit 3 occured at week 4 of treatment and focused on evaluation of symptoms and side effects. Participants again completed a food and glucose diary for 3 days. During study visit 4 (week 8 of treatment), participants underwent a repeat mixed meal tolerance test.

Pramlintide: See description above (arm description).

Pramlintide (Symlin)

Participants in this study completed 4 study visits. Study visit 1 was a screening visit. Participants kept 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 were performed. Glucose, hormonal responses, and satiety were assessed. Glucose and symptom log was reviewed. Pramlintide was prescribed, with instructions for titration from minimal to maximal dose (15 to 120 µg). During treatment, the participants kept a record of all hypoglycemic symptoms and blood glucose measurements at those times.

Study visit 3 occurred at week 4 of treatment and focused on evaluation of symptoms and side effects. Participants again completed a food and glucose diary for 3 days. During study visit 4 (week 8 of treatment), participants underwent a repeat mixed meal tolerance test.

Pramlintide: See description above (arm description).

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Pre-operative BMI

Current BMI

Onset of hypoglycemia (years since) surgery

Time Since RYGB (years)

Preoperative history of diabetes mellitus (DM) or gestational DM

Family history of DM in first-degree relative

Possible hypoglycemia symptoms present preoperatively (self-report)

Hypoglycemia frequency (self-report) - Daily or more

Hypoglycemia frequency (self-report) - Weekly or more (but not daily)

Hypoglycemia frequency (self-report) - Monthly or more (but not weekly)

Systolic Blood Pressure Supine

Diastolic Blood Pressure Supine

Cholesterol (mg/dL)

Triglycerides (mg/dl)

HDL (mg/dl)

Current therapy with acarbose

Current therapy with diazoxide

Current therapy with octreotide

Current therapy - medical nutrition therapy alone

Analysis is based upon 14 participants who completed the protocol.

Mary Elizabeth Patti, MD

Mixed meal #1 performed prior to initiation of pramlintide treatment.

Baseline (Prior to Pramlintide Treatment) Mixed Meal #1

Mixed meal #2 performed after 1 dose of pramlintide given 15 minutes prior to the mixed meal, at maximum tolerated dose achieved during the outpatient stage.

Pramlintide - Mixed Meal #2

Analysis was for the 14 participants who completed all study visits.

Plasma Glucose Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Glucose

Stage 1 of sequential design. Participant CGM data at baseline, prior to initiation of treatment with pramlintide TID.

Baseline (Prior to Treatment With Pramlintide) CGM #1

Stage 2 of sequential design. Participant CGM data during treatment with pramlintide TID.

Pramlintide CGM #2

Analysis was for the participants with available CGM data who completed all study visits in this sequential design. Note that the number of participants analyzed for CGM related outcomes differs from the number of participants analyzed in the other outcomes due to incomplete CGM data.

Continuous Glucose Monitoring Maximum Sensor Glucose Values Prior to (Baseline) and During Pramlintide Therapy.

Continuous Glucose Monitoring Minimum Sensor Glucose Prior to (Baseline) and During Pramlintide Therapy.

Hypoglycemia - Percentage of Time Sensor Glucose Levels < 70 mg/dL Prior to (Baseline) and During Pramlintide Therapy.

Plasma Insulin Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Insulin

Satiety Score During Mixed Meal Testing at 120 Minutes

Dumping Score During Mixed Meal Testing at Baseline and During Treatment With Pramlintide

Number of Days With Minimum Sensor Glucose < 54 mg/dL as Measured by Continuous Glucose Monitoring.

Nadir Plasma Glucose Levels During Mixed Meal Testing at Baseline and During Treatment With Pramlintide

Time to Nadir Plasma Glucose During Mixed Meal Testing at Baseline and During 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)

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

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Trial Timing

What is this trial about?

What are the participation requirements?