scholarly journals 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

2021 ◽  
Vol 9 (1) ◽  
pp. e002137
Author(s):  
Mark P Christiansen ◽  
Martin Cummins ◽  
Steven Prestrelski ◽  
Nicole C Close ◽  
Anh Nguyen ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Symptom Relief ◽  
Severe Hypoglycemia ◽  
Phase Iii ◽  
Tolerability Profile ◽  
Drug Preparation ◽  
Link Type ◽  
Rescue Treatment ◽  
Glucagon Injection ◽  
Mean Time

IntroductionTo 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 methodsTwo 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.ResultsFor 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.ConclusionsA 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 numbersNCT02656069 and NCT03439072.

129-LB: Evaluation of Attitudes towards Two Glucagon Delivery Devices for Rescue Treatment of Severe Hypoglycemia

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 129-LB
Author(s):  
SANJAY K. BAJPAI ◽  
JANELLE CAMBRON-MELLOTT ◽  
NEDINA K. RAIBULET ◽  
EUGENIA Y. PECK ◽  
JIAT LING POON ◽  
...  
Keyword(s):  
Severe Hypoglycemia ◽  
Rescue Treatment

scholarly journals Direct Chemical Measurement of the λ of the Lumped Constant of the [14C]Deoxyglucose Method in Rat Brain: Effects of Arterial Plasma Glucose Level on the Distribution Spaces of [14C]Deoxyglucose and Glucose and on λ

1989 ◽  
Vol 9 (3) ◽  
pp. 304-314 ◽  
Author(s):  
Kentaro Mori ◽  
Nancy Cruz ◽  
Gerald Dienel ◽  
Thomas Nelson ◽  
Louis Sokoloff
Keyword(s):  
Plasma Glucose ◽  
Glucose Concentration ◽  
Severe Hypoglycemia ◽  
Plasma Glucose Concentration ◽  
Operational Equation ◽  
Chemical Measurements ◽  
Lumped Constant ◽  
Dg Method ◽  
Arterial Plasma ◽  
Distribution Spaces

The lumped constant in the operational equation of the 2-[14C]deoxyglucose (DG) method contains the factor λ that represents the ratio of the steady-state tissue distribution spaces for [14C]DG and glucose. The lumped constant has been shown to vary with arterial plasma glucose concentration. Predictions based mainly on theoretical grounds have suggested that disproportionate changes in the distribution spaces for [14C]DG and glucose and in the value of λ are responsible for these variations in the lumped constant. The influence of arterial plasma glucose concentration on the distribution spaces for DG and glucose and on λ were, therefore, determined in the present studies by direct chemical measurements. The brain was maintained in steady states of delivery and metabolism of DG and glucose by programmed intravenous infusions of both hexoses designed to produce and maintain constant arterial concentrations. Hexose concentrations were assayed in acid extracts of arterial plasma and freeze-blown brain. Graded hyperglycemia up to 28 m M produced progressive decreases in the distribution spaces of both hexoses from their normoglycemic values (e.g., ∼ – 20% for glucose and – 50% for DG at 28 m M). In contrast, graded hypoglycemia progressively reduced the distribution space for glucose and increased the space for [14C]DG. The values for λ were comparatively stable in normoglycemic and hyperglycemic conditions but rose sharply (e.g., as much as 9–10-fold at 2 m M) in severe hypoglycemia.

scholarly journals MRI and Dose Selection in a Phase II Trial of Baricitinib with Conventional Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis

2019 ◽  
Vol 46 (8) ◽  
pp. 887-895 ◽  
Author(s):  
Charles Peterfy ◽  
Julie DiCarlo ◽  
Paul Emery ◽  
Mark C. Genovese ◽  
Edward C. Keystone ◽  
...  
Keyword(s):  
Bone Erosion ◽  
Joint Damage ◽  
Phase Iii ◽  
Cartilage Loss ◽  
Dose Selection ◽  
Mri Findings ◽  
Clinical Trial Registration ◽  
Treatment Groups ◽  
Link Type ◽  
Registration Number

Objective.Magnetic resonance imaging (MRI) was used in a phase IIb study of baricitinib in patients with RA to support dose selection for the phase III program.Methods.Three hundred one patients with active RA who were taking stable methotrexate were randomized 2:1:1:1:1 to placebo or once-daily baricitinib (1, 2, 4, or 8 mg) for up to 24 weeks. One hundred fifty-four patients with definitive radiographic erosion had MRI of the hand/wrist at baseline and at weeks 12 and 24. Two expert radiologists, blinded to treatment and visit order, scored images for synovitis, osteitis, bone erosion, and cartilage loss. Combined inflammation (osteitis + 3× synovitis score) and total joint damage (erosion + 2.5× cartilage loss score) scores were calculated. Treatment groups were compared using ANCOVA adjusting for baseline scores.Results.Mean changes from baseline to Week 12 for synovitis were −0.10, −1.50, and −1.60 for patients treated with placebo, baricitinib 4 mg, and baricitinib 8 mg, respectively (p = 0.003 vs placebo for baricitinib 4 and 8 mg). Mean changes for osteitis were 0.00, −3.20, and −2.10 (p = 0.001 vs placebo for baricitinib 4 mg and p = 0.037 for 8 mg), respectively. Mean changes for bone erosion were 0.90, 0.10, and 0.40 (p = 0.089 for 4 mg and p = 0.275 for 8 mg), respectively, in these treatment groups.Conclusion.MRI findings in this subgroup of patients suggest suppression of synovitis, osteitis, and combined inflammation by baricitinib 4 and 8 mg. This corroborates previously demonstrated clinical efficacy of baricitinib and increases confidence that baricitinib 4 mg could reduce the radiographic progression in phase III studies. [Clinical trial registration number (www.ClinicalTrials.gov): NCT01185353]

scholarly journals A randomized trial evaluating the safety profile of sugammadex in high surgical risk ASA physical class 3 or 4 participants

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
W. Joseph Herring ◽  
Yuki Mukai ◽  
Aobo Wang ◽  
Jeannine Lutkiewicz ◽  
John F. Lombard ◽  
...  
Keyword(s):  
Sinus Tachycardia ◽  
Sinus Bradycardia ◽  
Neuromuscular Block ◽  
Tolerability Profile ◽  
Double Blind ◽  
Link Type ◽  
Cardiac Arrythmias ◽  
Deep Neuromuscular Block ◽  
American Society ◽  
The Impact

Abstract Background The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest. Methods Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias. Results Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m2, age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study. Conclusions Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants. Trial registration ClinicalTrials.gov Identifier: NCT03346057.

scholarly journals Subcutaneous Abatacept for the Treatment of Rheumatoid Arthritis: Longterm Data from the ACQUIRE Trial

2014 ◽  
Vol 41 (4) ◽  
pp. 629-639 ◽  
Author(s):  
Mark C. Genovese ◽  
César Pacheco Tena ◽  
Arturo Covarrubias ◽  
Gustavo Leon ◽  
Eduardo Mysler ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Severe Disease ◽  
Incidence Rates ◽  
Phase Iii ◽  
Inadequate Response ◽  
Open Label ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Link Type

Objective.Assess longterm tolerability, safety, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate-refractory patients with rheumatoid arthritis (RA).Methods.The phase III, multinational Abatacept Comparison of Sub[QU]cutaneous Versus Intravenous in Inadequate Responders to MethotrexatE (ACQUIRE) trial comprised a 6-month, randomized, double-blind (DB) period, in which patients received intravenous (IV) or SC ABA, plus MTX, followed by an open-label, longterm extension (LTE), in which patients received SC ABA, 125 mg/week. Safety and efficacy from the LTE (∼3.5 yrs of exposure) are reported.Results.Patients who completed the DB period (1372/1385, 99.1%) entered the LTE; 1134 patients (82.7%) kept taking the treatment at time of reporting. Mean (SD) was 31.9 months (6.8); median (range) exposure was 33.0 (8–44) months. Patients entering the LTE had longstanding, moderate-to-severe disease [mean 7.6 (7.9) yrs and DAS28 (C-reactive protein) 6.2 (0.9)]. Incidence rates (events/100 patient-yrs) were reported for serious adverse events (8.76, 95% CI 7.71, 9.95), infections (44.80, 95% CI 41.76, 48.01), serious infections (1.72, 95% CI 1.30, 2.27), malignancies (1.19, 95% CI 0.86, 1.66), and autoimmune events (1.31, 95% CI 0.95, 1.79). Twenty-seven patients (2%) experienced injection-site reactions; all except 1 were mild. American College of Rheumatology 20, 50, and 70 responses achieved during the DB period were maintained through the LTE, and on Day 981 were 80.2% (95% CI 77.2, 83.2), 63.5% (95% CI 58.2, 68.9), and 39.5% (95% CI 34.0, 44.9) for patients who kept taking SC ABA, and 80.0% (95% CI 77.0, 83.0), 63.2% (95% CI 57.8, 68.7), and 39.2% (95% CI 33.7, 44.7) for those who switched from IV to SC ABA.Conclusion.These findings support SC ABA as a well-tolerated and efficacious longterm treatment for patients with RA and inadequate response to MTX (ClinicalTrials.gov identifier NCT00559585).

scholarly journals Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment

2018 ◽  
Vol 46 (1) ◽  
pp. 7-18 ◽  
Author(s):  
Josef S. Smolen ◽  
Mark C. Genovese ◽  
Tsutomu Takeuchi ◽  
David L. Hyslop ◽  
William L. Macias ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Safety Profile ◽  
Active Rheumatoid Arthritis ◽  
Prolonged Exposure ◽  
Janus Kinase ◽  
Phase Iii ◽  
Integrated Analysis ◽  
Drug Discontinuation ◽  
Adverse Cardiovascular Event ◽  
Link Type

Objective.Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated baricitinib’s safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)].Methods.The “all-bari-RA” group included patients who received any baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 (“placebo-4 mg” dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data (“2 mg-4 mg–extended”). The uncommon events description used the non-controlled all-bari-RA.Results.There were 3492 patients who received baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure.Conclusion.In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers:NCT01185353,NCT00902486,NCT01469013,NCT01710358,NCT01721044,NCT01721057,NCT01711359, andNCT01885078atclinicaltrials.gov.

NASAL GLUCAGON DELIVERY IS MORE SUCCESSFUL THAN INJECTABLE DELIVERY: A SIMULATED SEVERE HYPOGLYCEMIA RESCUE

2020 ◽  
Vol 26 (4) ◽  
pp. 407-415
Author(s):  
Julie A. Settles ◽  
Gregg Francis Gerety ◽  
Erik Spaepen ◽  
Jeffrey Gideon Suico ◽  
Christopher J. Child
Keyword(s):  
Success Rate ◽  
High Stress ◽  
Real Life ◽  
Severe Hypoglycemia ◽  
High Fidelity ◽  
Success Rates ◽  
Dose Delivery ◽  
Mean Time

Objective: A severe hypoglycemia (SH) episode is an acute, high-stress moment for the caregivers of persons with diabetes (PWD). We compared the success rates of nasal glucagon (NG) and injectable glucagon (IG) administration for PWD-trained and untrained users in treating simulated SH episodes. Methods: Thirty-two PWD-trained users and 33 untrained users administered NG and IG to high-fidelity manikins simulating treatment of an SH emergency. Simulation rooms resembled common locations with typical diabetic supplies and stressor elements mimicking real-life SH environments. Success rate and time to administer glucagon were measured. Results: Of all the PWD-trained and untrained users, 58/64 (90.6%) could successfully deliver NG, while 5/63 (7.9%) could successfully deliver IG. For NG simulations, 28/31 (90.3%) PWD-trained users and 30/33 (90.9%) untrained users could successfully administer the dose (mean time 47.3 seconds and 44.5 seconds, respectively). For IG simulations, 5/32 (15.6%) PWD-trained users successfully injected IG (mean time 81.8 seconds), whereas none (0/31 [0%]) of the untrained users were successful. Reasons for unsuccessful administration of NG included oral administration and incomplete pushing of the device plunger. For IG, inability to perform reconstitution steps, partial dose delivery, and injection at an inappropriate site were the causes for failure. Conclusion: With or without training, the success rate for administering NG was 90.6%, whereas it was only 7.9% for IG. NG was easily and quickly administered even by untrained users, whereas training was necessary for successful administration of IG. NG may expand the community of caregivers who can help PWD during an SH episode. Abbreviations: IG = injectable glucagon; NG = nasal glucagon; PWD = person with diabetes; SH = severe hypoglycemia; T1D = type 1 diabetes; T2D = type 2 diabetes

PP126 MEA In Italy: Correlation Between Time To Payment By Result And Time To Off Treatment Curve

2017 ◽  
Vol 33 (S1) ◽  
pp. 131-132
Author(s):  
Gabriele Vittoria ◽  
Antonio Fascì ◽  
Matteo Ferrario ◽  
Giovanni Giuliani
Keyword(s):  
Clinical Trials ◽  
Treatment Failure ◽  
Median Time ◽  
Real Life ◽  
Standard Of Care ◽  
Phase Iii ◽  
Experimental Drug ◽  
The Mean ◽  
Line Of Therapy ◽  
Mean Time

INTRODUCTION:Payment by result agreements have been quite widely used in Italy to provide access for high costs oncologic drugs and minimize uncertainties of real life benefits (1). The aim of this analysis was to overview the Roche experience in terms of Payment by Result (Pbr) in oncology and investigate the relation between timing for the evaluation of treatment failures and observed Time to Off Treatment (TTOT) from Phase III clinical trials (2).METHODS:A retrospective analysis of the Roche payment by results schemes in place in Italy was conducted. For each drug included in the analysis it was collected: (i) the negotiated timing to assess the treatment failure for payment by result, (ii) the median time to off treatment curve observed in clinical trials for the experimental drug, (iii) the median time to off treatment observed in clinical trials for the control arm. The mean ratios between timing to assess the treatment failure for payment by result and the time to off treatment observed for the experimental drug or the median time to off treatment observed in the control arm were calculated to identify potential correlations. High level of correlation was expected if ratio was close to 1 (±.2).RESULTS:Roche products or different indications of the same product were identified as candidates for the analysis from 2008 to 2016. The timing for the evaluation of treatment failures for Pbr varies between 2 and 9 months, depending on the type of tumor and line of therapy. The mean Time to Payment By Result (TTPbr) / Control arm Time To Off Treatment (cTTOT) ratio was 1.16 (±.37) while the mean Time to Payment By Result (TTPbr) / Experimental arm Time To Off Treatment (eTTOT) ratio was .71 (±.13). Data analysis according to different time periods shows that the mean TTPbr/cTTOT and TTPbr/eTTOT for drugs negotiated from 2008 to 2015 were respectively 1.07 and 1.39 whereas for drugs negotiated in 2016 were respectively and .63 and 1.CONCLUSIONS:Good level of correlation between TTPbr and cTTOT was found. This finding is in line with the methodology used by Italian Medicines Agency so far, leveraging the cTTOT as the most appropriate proxy to assess any incremental effect of a new drug compared to the previous Standard of Care. The analysis over time of TTPbr shows that in the first years of payment by result negotiation TTPbr is more correlated to the cTTOT whereas in the last years is moving closer to the experimental one.

Hypoglycemia in Dogs and Recovery After Intracisternal Administration of Glucose

1957 ◽  
Vol 191 (2) ◽  
pp. 367-370 ◽  
Author(s):  
Miles L. Doyle ◽  
Norman S. Olsen
Keyword(s):  
Cerebrospinal Fluid ◽  
Electrical Activity ◽  
Plasma Glucose ◽  
General Circulation ◽  
Severe Hypoglycemia ◽  
Brain Electrical Activity ◽  
Arterial Blood ◽  
Serial Sampling ◽  
The Brain

A standardized procedure for the production of hypoglycemia in dogs has been developed. The degree of hypoglycemia may be determined by the correlation of electroencephalographic tracings and levels of plasma constituents. During severe hypoglycemia glucose was injected either by the intravenous or intracisternal route. In the former group the brain electrical activity returned to normal within 1 minute, whereas, the latter group required 6–10 minutes. Serial sampling of arterial blood in the animals which had been given glucose directly into the cerebrospinal fluid showed that relatively large increases in plasma glucose preceded the return to normal electrical activity of the brain. It is concluded that glucose does not pass directly from the cerebrospinal fluid into the cerebral tissues but rather is transported to the general circulation before entering the brain.

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