Glucagon Ready to Use (RTU) in Subjects With Hyperinsulinemic Hypoglycemia After Bariatric Surgery

Study Overview
=================
Brief Summary
-----------------
This is a double-blind, placebo-controlled Phase 2 study to assess the efficacy, safety and tolerability of Glucagon RTU when administered to subjects with a history of bariatric surgery during episodes of post-postprandial hypoglycemia. Twelve eligible subjects will be randomly assigned to receive Glucagon RTU or placebo at the first of two clinical research center (CRC) visits, followed by the other treatment at the second CRC visit. Subjects will be randomly assigned to either Glucagon RTU or Placebo for the duration of a 12-week Outpatient Stage. A follow-up safety assessment visit will occur 14 to 28 days after a subject's last dose of study drug.

Official Title
-----------------
A Phase 2, Interventional, Randomized, Double-Blind, Placebo-Controlled Pilot Study of Glucagon RTU in Subjects Who Experience Hyperinsulinemic Hypoglycemia After Bariatric Surgery

Conditions
-----------------
Hyperinsulinemic Hypoglycemia

Intervention / Treatment
-----------------
* Drug: Glucagon RTU
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female Aged 18 to 75 years of age, inclusive Symptoms of hypoglycemia that developed after bariatric surgery (Roux-en-Y gastric bypass [RYGB] only) in the absence of antidiabetic medications History of bariatric surgery (RYGB only), at least 6 months prior to screening Whipple's triad Ability to both experience and recognize hypoglycemic awareness. Documented glucose levels < 54 mg/dL when experiencing symptoms suggestive of hypoglycemia Relief of hypoglycemia symptoms when the glucose is raised to normal Diagnosis of post-bariatric hypoglycemia (PBH) by a physician, requiring intervention such as intake of oral carbohydrates. This diagnosis includes documentation of endogenous hyperinsulinism in the presence of low plasma glucose. In subjects with medical history of diabetes, medical documentation of postoperative remission of diabetes mellitus (fasting glucose < 110 mg/dL), and HbA1c < 6% (or 42 mmol/mL) with all previous antidiabetic medication discontinued for at least 6 months before screening. Body mass index (BMI) ≤ 40 kg/m2 Willingness to follow all study procedures, including attending all clinic visits and self-administering blinded study drug at home for 12 weeks Understands the study procedures, alternative treatment available, and risks involved with the study, and he/she voluntarily agrees to participate by giving written informed consent Women of childbearing potential must have a negative urine pregnancy test and agree to use contraception and refrain from breast-feeding during the study and for at least 15 days after participating in the study. Exclusion Criteria: Documented hypoglycemia occurring in the fasting state (> 12 hours fast) within 12 months of study entry Hypoglycemic unawareness as evidenced by a Gold Scale score > 4 at screening Early Dumping Syndrome Known insulinoma or adrenal insufficiency Active treatment with any insulin/insulin secretagogues, or other diabetes medications except for acarbose and glucagon-like peptide 1 (GLP-1) analogues Chronic kidney disease Stage 4 or 5 or an estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m2 at screening Hepatic disease, including serum alanine aminotransferase or aspartate aminotransferase ≥ 3 times the upper limit of normal (ULN); hepatic synthetic insufficiency as defined as serum albumin < 3.0 g/dL Congestive heart failure, New York Heart Association Class III or IV History of myocardial infarction, unstable angina, or revascularization within 6 months prior to screening. History of a cerebrovascular accident within 6 months prior to screening or with major neurological deficits Seizure disorder (other than with suspected or documented hypoglycemia). Active malignancy, except for basal or squamous cell skin cancers Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease) Major surgical operation within 30 days prior to screening Hematocrit ≤ 30% Bleeding disorder, treatment with warfarin, or platelet count < 50,000 /mm3 Active alcohol abuse or substance abuse (per investigator assessment) Current chronic administration of oral or parenteral corticosteroids, however topical, intraarticular, and inhaled corticosteroids are allowed Use of an investigational drug within 15 days or 5 half-lives, whichever is longer, prior to screening Member of a special vulnerable populations such as pregnant women, prisoners, institutionalized or incarcerated individuals, or others who may be considered vulnerable Any other medical condition or finding that in the opinion of the investigator or sponsor, would compromise the safety of the subject or compromise the integrity of the study data

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: A randomized, placebo-controlled, double-blind, two-treatment, 2-period, crossover in-patient phase followed by a placebo-controlled, double-blind, parallel two-treatment outpatient stage..
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glucagon RTU (glucagon injection)<br>Glucagon Ready-to-Use (RTU); 60 μL injection (0.3 mg glucagon) | Drug: Glucagon RTU<br>* Glucagon RTU is a sterile subcutaneous injectable non-aqueous solution formulation supplied in a vial and administered via syringe.<br>* Other names: glucagon;|
| Placebo Comparator: Placebo<br>Non-active vehicle for Glucagon RTU; 60 μL injection | Other: Placebo<br>* The placebo is a non-active version of Glucagon RTU formulation, containing the same solvent and excipients (i.e., vehicle).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood glucose recovery: CRC | Number of subjects with blood glucose > 70 mg/dL | At 15 minutes following administration of study drug | 
| Blood glucose recovery: Out-patient | Frequency of blood glucose > 70 mg/dL | At 15 minutes following administration of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic Recovery: CRC | Change from Baseline in Hypoglycemia Symptoms | At 15, 30, and 60 minutes following administration of study drug | 
| Incidence of severe hypoglycemia: CRC | Number of subjects requiring external assistance to treat hypoglycemia | At 0-240 minutes following administration of study drug | 
| Incidence of severe hypoglycemia: Out-patient | Frequency of external assistance to treat postprandial hypoglycemia | During 12 weeks of out-patient treatment | 
| Incidence of serious hypoglycemia: CRC | Number of subjects with blood glucose < 54 mg/dL | At 0-240 minutes following administration of study drug | 
| Incidence of serious hypoglycemia: Out-patient | Frequency of postprandial blood glucose < 54 mg/dL | During 12 weeks of out-patient treatment | 
| Hypoglycemia Fear Scale | Change from Baseline in Hypoglycemia Fear Scale (HFS-2) Scores. The HFS-2 consists of two domains, Behavior, which has 15 questions, and Worry, which has 18 questions. Each question is assessed on a 5-point scale from 0=Never to 4=Almost Always. Lower scores indicate less fear of hypoglycemia, while higher scores indicate a greater level of fear. | During 12 weeks of out-patient treatment | 
| EuroQol Health Questionnaire (EQ-5D) | Change from Baseline in EQ-5D Score. This is a health assessment questionnaire with three domains. The first two domains of pain/discomfort and anxiety/depression are scored on a 5-point scale from 1=no pain/discomfort; not anxious or depressed to 5=extreme pain or discomfort; extremely anxious or depressed. For these two domains, lower scores indicate less pain/discomfort or anxiety/depression, while higher scores indicate increasing levels of pain/discomfort or anxiety/depression. The third domain of Health is assessed with a series of 5 visual analog scales, each scored from 0-100. On these VAS scales, high scores indicate better health, while low scores indicate worse health. | During 12 weeks of out-patient treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
glucagon, post-bariatric hypoglycemia