Hypoglycemia, Evidence of Previous Gastric Surgery
Conditions
Keywords
Hypoglycemia, Gastric bypass surgery
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.
Interventions
DRUGPramlintide
See description above (arm description).
Sponsors
Bristol-Myers Squibb
Joslin Diabetes Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants in this study were asked to complete 4 study visits. Arm/Phase 1: Baseline: Study V1 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 V2, a baseline mixed meal tolerance test (MMTT) was performed. Glucose, hormonal responses, and satiety were assessed. Glucose and symptom logs were reviewed. Arm / Phase 2: Pramlintide treatment Pramlintide was prescribed at the end of visit 2 (following MMTT), 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 MMTT.
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. | — |
| 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. | — |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants with post-bariatric hypoglycemia (PBH) following gastric bypass were recruited from outpatient clinics at Joslin Diabetes Center, Boston, Massachusetts for an open label study of pramlintide efficacy over 8 weeks.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Concommitant medical issues | 2 |
| Overall Study | Did not receive study drug at visit 4 prior to mixed meal testing | 1 |
| Overall Study | Underwent reversal of Roux-en-Y gastric bypass (RYGB) | 2 |
Baseline characteristics
| Characteristic | Pramlintide (Symlin) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age, Continuous | 60.2 years STANDARD_DEVIATION 8.7 |
| Cholesterol (mg/dL) | 169.6 mg/dL STANDARD_DEVIATION 18.2 |
| Current BMI | 29.6 kg/m^2 STANDARD_DEVIATION 4.3 |
| Current therapy - medical nutrition therapy alone | 6 Participants |
| Current therapy with acarbose | 8 Participants |
| Current therapy with diazoxide | 0 Participants |
| Current therapy with octreotide | 1 Participants |
| Diastolic Blood Pressure Supine | 67.8 mmHg STANDARD_DEVIATION 10.3 |
| Family history of DM in first-degree relative | 6 Participants |
| HDL (mg/dl) | 64.6 mg/dL STANDARD_DEVIATION 10.1 |
| Hypoglycemia frequency (self-report) - Daily or more | 1 Participants |
| Hypoglycemia frequency (self-report) - Monthly or more (but not weekly) | 1 Participants |
| Hypoglycemia frequency (self-report) - Weekly or more (but not daily) | 7 Participants |
| Onset of hypoglycemia (years since) surgery | 2.9 years STANDARD_DEVIATION 2.9 |
| Possible hypoglycemia symptoms present preoperatively (self-report) | 2 Participants |
| Pre-operative BMI | 46.8 kg/m^2 STANDARD_DEVIATION 6.2 |
| Preoperative history of diabetes mellitus (DM) or gestational DM | 3 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 2 Participants |
| Systolic Blood Pressure Supine | 119.1 mmHg STANDARD_DEVIATION 12.5 |
| Time Since RYGB (years) | 6.2 years STANDARD_DEVIATION 2.7 |
| Triglycerides (mg/dl) | 75.2 mg/dL STANDARD_DEVIATION 20.2 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 22 |
| other Total, other adverse events | 9 / 22 |
| serious Total, serious adverse events | 1 / 22 |
Outcome results
Primary
Plasma Glucose Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Glucose
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.
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.
Population: Analysis was for the 14 participants who completed all study visits.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Plasma Glucose Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Glucose | 2828 mg*min/dL | Standard Deviation 3255 |
| Pramlintide - Mixed Meal #2 | Plasma Glucose Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Glucose | 2893 mg*min/dL | Standard Deviation 2770 |
p-value: 0.9Wilcoxon (Mann-Whitney)
Secondary
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)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Continuous Glucose Monitoring Maximum Sensor Glucose Values Prior to (Baseline) and During Pramlintide Therapy. | 172 mg/dL | Standard Deviation 50.98 |
| Pramlintide - Mixed Meal #2 | Continuous Glucose Monitoring Maximum Sensor Glucose Values Prior to (Baseline) and During Pramlintide Therapy. | 188 mg/dL | Standard Deviation 43.6 |
p-value: 0.08t-test, 2 sided
Secondary
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)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Continuous Glucose Monitoring Minimum Sensor Glucose Prior to (Baseline) and During Pramlintide Therapy. | 54 mg/dL | Standard Deviation 14.68 |
| Pramlintide - Mixed Meal #2 | Continuous Glucose Monitoring Minimum Sensor Glucose Prior to (Baseline) and During Pramlintide Therapy. | 56.6 mg/dL | Standard Deviation 11.44 |
p-value: =0.20492t-test, 2 sided
Secondary
Dumping Score During Mixed Meal Testing at Baseline and During 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 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Dumping Score During Mixed Meal Testing at Baseline and During Treatment With Pramlintide | 28.89 dumping score | Standard Deviation 101.81 |
| Pramlintide - Mixed Meal #2 | Dumping Score During Mixed Meal Testing at Baseline and During Treatment With Pramlintide | 72.04 dumping score | Standard Deviation 70.93 |
p-value: 0.37t-test, 2 sided
Secondary
Hypoglycemia - Percentage of Time Sensor Glucose Levels < 70 mg/dL Prior to (Baseline) and During Pramlintide Therapy.
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.
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)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Hypoglycemia - Percentage of Time Sensor Glucose Levels < 70 mg/dL Prior to (Baseline) and During Pramlintide Therapy. | 8.85 percent time sensor glucose less than 70 | Standard Deviation 9.23 |
| Pramlintide - Mixed Meal #2 | Hypoglycemia - Percentage of Time Sensor Glucose Levels < 70 mg/dL Prior to (Baseline) and During Pramlintide Therapy. | 5.60 percent time sensor glucose less than 70 | Standard Deviation 5.32 |
p-value: 0.2655t-test, 2 sided
Secondary
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Nadir Plasma Glucose Levels During Mixed Meal Testing at Baseline and During Treatment With Pramlintide | 67.18 mg/dL | Standard Deviation 17.14 |
| Pramlintide - Mixed Meal #2 | Nadir Plasma Glucose Levels During Mixed Meal Testing at Baseline and During Treatment With Pramlintide | 69.9 mg/dL | Standard Deviation 14.8 |
p-value: 0.412t-test, 2 sided
Secondary
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)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Number of Days With Minimum Sensor Glucose < 54 mg/dL as Measured by Continuous Glucose Monitoring. | 1.31 days | Standard Deviation 1.49 |
| Pramlintide - Mixed Meal #2 | Number of Days With Minimum Sensor Glucose < 54 mg/dL as Measured by Continuous Glucose Monitoring. | 0.56 days | Standard Deviation 0.73 |
p-value: 0.14t-test, 2 sided
Secondary
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Number of Participants Requiring Rescue Treatment for Severe Hypoglycemia During Mixed Meal Testing (Visit 2 Baseline vs. Visit 4 Post-pramlintide Dosing) | 6 number of participants |
| Pramlintide - Mixed Meal #2 | Number of Participants Requiring Rescue Treatment for Severe Hypoglycemia During Mixed Meal Testing (Visit 2 Baseline vs. Visit 4 Post-pramlintide Dosing) | 4 number of participants |
p-value: 0.69Fisher Exact
Secondary
Plasma Insulin Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Insulin
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.
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Plasma Insulin Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Insulin | 3393 uIU*min/mL | Standard Deviation 2155 |
| Pramlintide - Mixed Meal #2 | Plasma Insulin Levels in Response to Mixed Meal Testing - Area Under the Curve for Plasma Insulin | 3501 uIU*min/mL | Standard Deviation 2683 |
p-value: 0.64Wilcoxon (Mann-Whitney)
Secondary
Satiety Score During Mixed Meal Testing at 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.
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Satiety Score During Mixed Meal Testing at 120 Minutes | 4.57 satiety score | Standard Deviation 3.05 |
| Pramlintide - Mixed Meal #2 | Satiety Score During Mixed Meal Testing at 120 Minutes | 5.43 satiety score | Standard Deviation 2.51 |
p-value: 0.597t-test, 2 sided
Secondary
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline (Prior to Pramlintide Treatment) Mixed Meal #1 | Time to Nadir Plasma Glucose During Mixed Meal Testing at Baseline and During Treatment With Pramlintide | 64.29 minutes | Standard Deviation 40.52 |
| Pramlintide - Mixed Meal #2 | Time to Nadir Plasma Glucose During Mixed Meal Testing at Baseline and During Treatment With Pramlintide | 66.43 minutes | Standard Deviation 48.77 |
p-value: 0.89t-test, 2 sided