Comparison of a ready-to-use liquid glucagon injection administered by autoinjector to glucagon emergency kit for the symptomatic relief of severe hypoglycemia: two randomized crossover non-inferiority studies.

INTRODUCTION: To prevent medical sequelae of severe hypoglycemic emergencies, prompt and reliable rescue intervention is critically important. A ready-to-use, liquid stable glucagon, administered subcutaneously by glucagon autoinjector (GAI), Gvoke HypoPen (glucagon injection; Xeris Pharmaceuticals), was evaluated for rescue treatment of severe hypoglycemia. RESEARCH DESIGN AND METHODS: Two phase III, randomized, controlled, blinded, non-inferiority crossover studies were conducted in 161 adults with type 1 diabetes to compare 1 mg doses of GAI versus glucagon emergency kit (GEK) for treating insulin-induced severe hypoglycemia. Efficacy was evaluated as either a return of plasma glucose to >70 mg/dL (3.9 mmol/L) or increase ≥20 mg/dL (1.1 mmol/L) from a baseline glucose of <50 mg/dL (2.9 mmol/L), within 30 min of dosing. RESULTS: For successful plasma glucose recovery within 30 min, treatment with GAI was non-inferior to GEK. Treatment with GAI was non-inferior to GEK for a plasma glucose >70 mg/dL (3.9 mmol/L) or neuroglycopenic symptom relief within 30 min. From administration of glucagon, the mean time to achieve plasma glucose >70 mg/dL (3.9 mmol/L) or increase ≥20 mg/dL (1.1 mmol/L) was 13.8±5.6 min for GAI and 10.0±3.6 min for GEK. This mean time does not account for the significantly shorter (p<0.0001) drug preparation and administration time for GAI (27.3±19.7 s) versus GEK (97.2±45.1 s). The incidence of treatment emergent adverse events was comparable in both groups. CONCLUSIONS: A ready-to-use GAI was non-inferior to GEK, with a similar tolerability profile. GAI is an effective, safe, and well-tolerated rescue treatment for severe hypoglycemia and is a viable alternative to GEK. TRIAL REGISTRATION NUMBERS: NCT02656069 and NCT03439072.

A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Postbariatric Hypoglycemia.

BACKGROUND: Postbariatric hypoglycemia (PBH) can threaten safety and reduce quality of life. Current therapies are incompletely effective. METHODS: Patients with PBH were enrolled in a double-blind, placebo-controlled, crossover trial to evaluate a closed-loop glucose-responsive automated glucagon delivery system designed to reduce severe hypoglycemia. A hypoglycemia detection and mitigation algorithm was embedded in the artificial pancreas system connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with liquid investigational glucagon (Xeris) or placebo (vehicle). Sensor/plasma glucose responses to mixed meal were assessed during 2 study visits. The system delivered up to 2 doses of study drug (300/150 µg glucagon or equal-volume vehicle) if triggered by the algorithm. Rescue dextrose was given for plasma glucose <55 mg/dL or neuroglycopenia. RESULTS: Twelve participants (11 females/1 male, age 52 ± 2, 8 ± 1 years postsurgery, mean ± SEM) completed all visits. Predictive hypoglycemia alerts prompted automated drug delivery postmeal, when sensor glucose was 114 ± 7 vs 121 ± 5 mg/dL (P = .39). Seven participants required rescue glucose after vehicle but not glucagon (P = .008). Five participants had severe hypoglycemia (<55 mg/dL) after vehicle but not glucagon (P = .03). Nadir plasma glucose was higher with glucagon vs vehicle (67 ± 3 vs 59 ± 2 mg/dL, P = .004). Plasma glucagon rose after glucagon delivery (1231 ± 187 vs 16 ± 1 pg/mL at 30 minutes, P = .001). No rebound hyperglycemia occurred. Transient infusion site discomfort was reported with both glucagon (n = 11/12) and vehicle (n = 10/12). No other adverse events were observed. CONCLUSION: A CGM-guided closed-loop rescue system can detect imminent hypoglycemia and deliver glucagon, reducing severe hypoglycemia in PBH. CLINICAL TRIALS REGISTRATION: NCT03255629.

Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes.

OBJECTIVE: Patients with type 1 diabetes who do aerobic exercise often experience a drop in blood glucose concentration that can result in hypoglycemia. Current approaches to prevent exercise-induced hypoglycemia include reduction in insulin dose or ingestion of carbohydrates, but these strategies may still result in hypoglycemia or hyperglycemia. We sought to determine whether mini-dose glucagon (MDG) given subcutaneously before exercise could prevent subsequent glucose lowering and to compare the glycemic response to current approaches for mitigating exercise-associated hypoglycemia. RESEARCH DESIGN AND METHODS: We conducted a four-session, randomized crossover trial involving 15 adults with type 1 diabetes treated with continuous subcutaneous insulin infusion who exercised fasting in the morning at ∼55% VO2max for 45 min under conditions of no intervention (control), 50% basal insulin reduction, 40-g oral glucose tablets, or 150-µg subcutaneous glucagon (MDG). RESULTS: During exercise and early recovery from exercise, plasma glucose increased slightly with MDG compared with a decrease with control and insulin reduction and a greater increase with glucose tablets (P < 0.001). Insulin levels were not different among sessions, whereas glucagon increased with MDG administration (P < 0.001). Hypoglycemia (plasma glucose <70 mg/dL) was experienced by six subjects during control, five subjects during insulin reduction, and none with glucose tablets or MDG; five subjects experienced hyperglycemia (plasma glucose ≥250 mg/dL) with glucose tablets and one with MDG. CONCLUSIONS: MDG may be more effective than insulin reduction for preventing exercise-induced hypoglycemia and may result in less postintervention hyperglycemia than ingestion of carbohydrate.

Design and Clinical Evaluation of a Novel Low-Glucose Prediction Algorithm with Mini-Dose Stable Glucagon Delivery in Post-Bariatric Hypoglycemia.

BACKGROUND: Postbariatric hypoglycemia (PBH) is a complication of bariatric surgery with limited therapeutic options. We developed an event-based system to predict and detect hypoglycemia based on continuous glucose monitor (CGM) data and recommend delivery of minidose liquid glucagon. METHODS: We performed an iterative development clinical study employing a novel glucagon delivery system: a Dexcom CGM connected to a Windows tablet running a hypoglycemia prediction algorithm and an Omnipod pump filled with an investigational stable liquid glucagon formulation. Meal tolerance testing was performed in seven participants with PBH and history of neuroglycopenia. Glucagon was administered when hypoglycemia was predicted. Primary outcome measures included the safety and feasibility of this system to predict and prevent severe hypoglycemia. Secondary outcomes included hypoglycemia prediction by the prediction algorithm, minimization of time below hypoglycemia threshold using glucagon, and prevention of rebound hyperglycemia. RESULTS: The hypoglycemia prediction algorithm alerted for impending hypoglycemia in the postmeal state, prompting delivery of glucagon (150 µg). After observations of initial incomplete efficacy to prevent hypoglycemia in the first two participants, system modifications were implemented: addition of PBH-specific detection algorithm, increased glucagon dose (300 µg), and a second glucagon dose if needed. These modifications, together with rescue carbohydrates provided to some participants, contributed to progressive improvements in glucose time above the hypoglycemia threshold (75 mg/dL). CONCLUSIONS: Preliminary results indicate that our event-based automatic monitoring algorithm successfully predicted likely hypoglycemia. Minidose glucagon therapy was well tolerated, without prolonged or severe hypoglycemia, and without rebound hyperglycemia.

Efficacy and Safety of Mini-Dose Glucagon for Treatment of Nonsevere Hypoglycemia in Adults With Type 1 Diabetes.

Context: Standard treatment of hypoglycemia is oral carbohydrate, but it often results in hyperglycemia and entails extra caloric intake. Objective: To evaluate low-dose glucagon to treat mild hypoglycemia in ambulatory adults with type 1 diabetes (T1D). Design: Randomized crossover trial (two 3-week periods). Setting: Five U.S. diabetes clinics. Patients: Twenty adults with T1D using an insulin pump and continuous glucose monitor (CGM) and experiencing frequent mild hypoglycemia. Intervention: Nonaqueous mini-dose glucagon (MDG) (150 µg) to treat nonsevere hypoglycemia. Main Outcome Measures: Successful treatment was defined as blood glucose (BG) ≥50 mg/dL 15 minutes and ≥70 mg/dL 30 minutes after intervention, on the study meter. Two authors, blinded to treatment arm, independently judged each event as a clinical success or failure. Results: Sixteen participants (mean age 39 years, 75% female, mean diabetes duration 23 years, mean hemoglobin A1c 7.2%) had 118 analyzable events with initial BG of 50 to 69 mg/dL. Successful treatment criteria were met for 58 (94%) of 62 events during the MDG period and 53 (95%) of 56 events during the glucose tablets (TABS) period (adjusted P = 0.99). Clinical assessments of success for these events were 97% and 96%, respectively. CGM-measured time in range did not differ between treatment groups during the 2 hours after events, but TABS resulted in higher maximum glucose (116 vs 102 mg/dL; P = 0.01) over the first hour. Conclusions: Low-dose glucagon can successfully treat mild hypoglycemia and may be a useful alternative to treatment with oral carbohydrate when trying to avoid unnecessary caloric intake.

Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects.

BACKGROUND: There is currently no stable liquid form of glucagon commercially available. The aim of this study is to assess the speed of absorption and onset of action of G-Pump™ glucagon at 3 doses as compared to GlucaGen®, all delivered subcutaneously via an OmniPod®. METHODS: Nineteen adult subjects with type 1 diabetes participated in this Phase 2, randomized, double-blind, cross-over, pharmacokinetic/pharmacodynamic study. Subjects were given 0.3, 1.2, and 2.0 µg/kg each of G-Pump glucagon and GlucaGen via an OmniPod. RESULTS: G-Pump glucagon effectively increased blood glucose levels in a dose-dependent fashion with a glucose Cmax of 183, 200, and 210 mg/dL at doses of 0.3, 1.2, and 2.0 µg/kg, respectively (P = ns vs GlucaGen). Mean increases in blood glucose from baseline were 29.2, 52.9, and 77.7 mg/dL for G-Pump doses of 0.3, 1.2, and 2.0 µg/kg, respectively. There were no statistically significant differences between treatments in the glucose T50%-early or glucagon T50%-early with one exception. The glucagon T50%-early was greater following G-Pump treatment at the 2.0 µg/kg dose (13.9 ± 4.7 min) compared with GlucaGen treatment at the 2.0 µg/kg dose (11.0 ± 3.1 min, P = .018). There was more pain and erythema at the infusion site with G-Pump as compared to GlucaGen. No serious adverse events were reported, and no unexpected safety issues were observed. CONCLUSIONS: G-Pump glucagon is a novel, stable glucagon formulation with similar PK/PD properties as GlucaGen, but was associated with more pain and infusion site reactions as the dose increased, as compared to GlucaGen.

Nonaqueous, Mini-Dose Glucagon for Treatment of Mild Hypoglycemia in Adults With Type 1 Diabetes: A Dose-Seeking Study.

OBJECTIVE: To evaluate mini-dose glucagon in adults with type 1 diabetes using a stable, liquid, ready-to-use preparation. RESEARCH DESIGN AND METHODS: Twelve adults with type 1 diabetes receiving treatment with insulin pumps received subcutaneous doses of 75, 150, and 300 µg of nonaqueous glucagon. Plasma glucose, glucagon, and insulin concentrations were measured. At 180 min, subjects received insulin followed in ~60 min by a second identical dose of glucagon. RESULTS: Mean (±SE) fasting glucose concentrations (mg/dL) were 110 ± 7, 110 ± 10, and 109 ± 9 for the 75-, 150-, and 300-µg doses, respectively, increasing maximally at 60 min by 33, 64, and 95 mg/dL (all P < 0.001). The post-insulin administration glucose concentrations were 70 ± 2, 74 ± 5, and 70 ± 2 mg/dL, respectively, with maximal increases of 19, 24, and 43 mg/dL post-glucagon administration (P < 0.02) at 45-60 min. CONCLUSIONS: Subcutaneous, nonaqueous, ready-to-use G-Pen Mini glucagon may provide an alternative to oral carbohydrates for the management of anticipated, impending, or mild hypoglycemia in adults with type 1 diabetes.

Low-dose oral interferon alpha as prophylaxis against viral respiratory illness: a double-blind, parallel controlled trial during an influenza pandemic year.

BACKGROUND AND OBJECTIVE: Interferon alpha (IFNα) is a known antiviral agent. A double-blind, placebo-controlled clinical trial was conducted investigating the use of low-dose oral interferon alpha for preventing acute viral respiratory illnesses. METHODS: Two hundred healthy adults aged 18-75 years were enrolled and completed weekly health data questionnaires to monitor for symptoms and impact of respiratory illness. Serum samples were tested for antibodies against influenza and other common respiratory viruses. RESULTS: Low-dose oral IFNα prophylaxis did not reduce the incidence or impact of acute respiratory illness (ARI) or the impact of illness on daily activities. Post hoc analysis of participant subgroups, however, identified significant reductions in the incidence of ARI reported by males, those aged 50 years or more and those who received the 2009 seasonal influenza vaccine. Interferon alpha prophylaxis had a significant impact on the reporting of moderate-to-severe feverishness by the study population. Seropositive participants in the IFN group were more likely to report asymptomatic or mild symptoms compared with those in the placebo group who were more likely to report stronger symptoms. CONCLUSIONS: Low-dose oral IFNα prophylaxis was not effective in limiting the overall incidence of ARI in our study population. However, there was evidence that prophylaxis reduced the severity of symptoms and had a beneficial effect in some subpopulations, including those who received the 2009 seasonal trivalent influenza vaccination.

Oromucosal Administration of Interferon to Humans.

The prevailing dogma is that, to be systemically effective, interferon-alpha (IFNα) must be administered in sufficiently high doses to yield functional blood concentrations. Such an approach to IFNa therapy has proven effective in some instances, but high-dose parenteral IFNα therapy has the disadvantage of causing significant adverse events. Mounting evidence suggests that IFNα delivered into the oral cavity in low doses interacts with the oral mucosa in a unique manner to induce systemic host defense mechanisms without IFNα actually entering the circulation, thus reducing the potential for toxic side effects. A better understanding of the applications and potential benefits of this treatment modality are under active investigation. This paper provides a review of the relevant literature on the clinical use of the oromucosal route of administration of interferon, with an emphasis on the treatment of influenza.

Treatment of primary Sjögren's syndrome with low-dose human interferon alfa administered by the oromucosal route: combined phase III results.

OBJECTIVE: This study tested the safety and efficacy of human interferon (IFN) alfa for treatment of salivary hypofunction and dry mouth symptoms in primary Sjögren's syndrome patients. METHODS: Combined results are reported from 2 phase III clinical trials in which a total of 497 subjects with primary Sjögren's syndrome received 150 international units of human IFN alfa or matching placebo 3 times per day for 24 weeks by the oromucosal route. RESULTS: Subjects given IFN alfa had a significantly (P = 0.01) greater mean increase in unstimulated whole saliva (UWS) flow, compared with subjects given placebo. In IFN alfa patients, increases in UWS correlated positively and significantly with improvements noted in 7 of 8 symptoms associated with oral and ocular dryness. The coprimary endpoints of stimulated whole saliva flow and oral dryness were not significantly improved in the IFN alfa group relative to placebo. No significant differences were found between the groups with respect to overall adverse event incidence or severity. CONCLUSION: IFN alfa given at low dosage by the oromucosal route can significantly increase UWS flow in patients with primary Sjögren's syndrome, without causing significant adverse events.

A third study on the use of orally administered anhydrous crystalline maltose for relief of dry mouth in primary Sjögren's syndrome.

OBJECTIVES: To examine the safety and efficacy of anhydrous crystalline maltose for treatment of dry mouth and other symptoms of dryness in patients with primary Sjögren's syndrome. DESIGN: Anhydrous crystalline maltose was delivered orally as a 200-mg lozenge given three times daily over a 24-week period to a total of 100 subjects. All participants had prominent complaints of persistent dry mouth associated with primary Sjögren's syndrome. Patients were examined at baseline and every 6 weeks of treatment. SETTINGS: Patients were seen in outpatient clinics at a total of 27 sites within the United States. OUTCOME MEASURES: Unstimulated whole saliva output, a measure of basal salivary gland function, was determined at each visit. Symptoms associated with oral and ocular dryness were assessed at the same time with the use of 100-mm visual analogue scales. Safety was assessed by physical examination and laboratory studies. RESULTS: During this clinical trial, a majority of evaluable subjects (39/76) demonstrated an increase in unstimulated whole saliva output, and the treatment exhibited an excellent safety profile. The anhydrous crystalline maltose treatment led to significant improvement in several subjective measures of oral and ocular comfort. CONCLUSIONS: In this study, anhydrous crystalline maltose lozenges administered three times daily for 24 weeks improved salivary output and decreased complaints of dry mouth and eyes in patients with primary Sjögren's syndrome. Side-effects were minimal, and treatment was without significant adverse events. These results are similar to the benefits observed in two prior studies reported by the authors. This safe and simple intervention appears to provide clinical benefit to primary Sjögren's syndrome patients with distressing dry mouth symptoms.