Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine.

BACKGROUND: Active immunization with the BNT162b2 vaccine (Pfizer-BioNTech) has been a critical mitigation tool against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (Covid-19) pandemic. In light of reports of waning protection occurring 6 months after the primary two-dose vaccine series, data are needed on the safety and efficacy of offering a third (booster) dose in persons 16 years of age or older. METHODS: In this ongoing, placebo-controlled, randomized, phase 3 trial, we assigned participants who had received two 30-µg doses of the BNT162b2 vaccine at least 6 months earlier to be injected with a third dose of the BNT162b2 vaccine or with placebo. We assessed vaccine safety and efficacy against Covid-19 starting 7 days after the third dose. RESULTS: A total of 5081 participants received a third BNT162b2 dose and 5044 received placebo. The median interval between dose 2 and dose 3 was 10.8 months in the vaccine group and 10.7 months in the placebo group; the median follow-up was 2.5 months. Local and systemic reactogenicity events from the third dose were generally of low grade. No new safety signals were identified, and no cases of myocarditis or pericarditis were reported. Among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated, Covid-19 with onset at least 7 days after dose 3 was observed in 6 participants in the vaccine group and in 123 participants in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% confidence interval, 89.5 to 98.3). CONCLUSIONS: A third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against Covid-19 as compared with two doses of the BNT162b2 vaccine during a median follow-up of 2.5 months. (Funded by BioNTech and Pfizer; C4591031 ClinicalTrials.gov number, NCT04955626.).

Evaluation of Accuracy and Safety of the Next-Generation Up to 180-Day Long-Term Implantable Eversense Continuous Glucose Monitoring System: The PROMISE Study.

Background: Use of continuous glucose monitoring (CGM) systems is being rapidly adopted as standard of care for insulin-requiring patients with diabetes. The PROMISE study (NCT03808376) evaluated the accuracy and safety of the next-generation implantable Eversense CGM system for up to 180 days. Methods: This was a prospective multicenter study involving 181 subjects with diabetes at 8 USA sites. All subjects were inserted with a primary sensor. Ninety-six subjects had a second sensor, either an identical sensor or a modified sensor (sacrificial boronic acid [SBA]), inserted in their other arm (53 and 43 subjects, respectively). Accuracy was evaluated by comparing CGM to YSI 2300 glucose analyzer (Yellow Springs Instrument [YSI]) values during 10 clinic visits (day 1-180). Confirmed event detection rates, calibration stability, sensor survival, and serious adverse events (SAEs) were evaluated. Results: For primary sensors, the percent CGM readings within 20%/20% of YSI values was 92.9%; overall mean absolute relative difference (MARD) was 9.1%. The confirmed alert detection rate at 70 mg/dL was 93% and at 180 mg/dL was 99%. The median percentage of time for one calibration per day was 56%. Sixty-five percent of the primary sensors survived to 180 days. For the SBA sensors, the percent CGM readings within 20%/20% of YSI values was 93.9%; overall MARD was 8.5%. The confirmed alert detection rate at 70 mg/dL was 94% and at 180 mg/dL was 99%. The median percentage of time for one calibration per day was 63%. Ninety percent of the SBA sensors survived to 180 days. No device- or insertion/removal procedure-related SAEs were reported. Conclusion: These data show the next-generation Eversense CGM system had sustained accuracy and safety up to 180 days, with an improved calibration scheme and survival, using the primary or SBA sensors.

Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial.

Hyperglucagonemia contributes to hyperglycemia in patients with type 1 diabetes (T1D); however, novel therapeutics that block glucagon action could improve glycemic control. This phase 2 study evaluated the safety and efficacy of volagidemab, an antagonistic monoclonal glucagon receptor (GCGR) antibody, as an adjunct to insulin therapy in adults with T1D. The primary endpoint was change in daily insulin use at week 12. Secondary endpoints included changes in hemoglobin A1c (HbA1c) at week 13, in average daily blood glucose concentration and time within target range as assessed by continuous blood glucose monitoring (CGM) and seven-point glucose profile at week 12, incidence of hypoglycemic events, the proportion of subjects who achieve HbA1c reduction of ≥0.4%, volagidemab drug concentrations and incidence of anti-drug antibodies. Eligible participants (n = 79) were randomized to receive weekly subcutaneous injections of placebo, 35 mg volagidemab or 70 mg volagidemab. Volagidemab produced a reduction in total daily insulin use at week 12 (35 mg volagidemab: -7.59 units (U) (95% confidence interval (CI) -11.79, -3.39; P = 0.040 versus placebo); 70 mg volagidemab: -6.64 U (95% CI -10.99, -2.29; P = 0.084 versus placebo); placebo: -1.27 U (95% CI -5.4, 2.9)) without meeting the prespecified significance level (P < 0.025). At week 13, the placebo-corrected reduction in HbA1c percentage was -0.53 (95% CI -0.89 to -0.17, nominal P = 0.004) in the 35 mg volagidemab group and -0.49 (95% CI -0.85 to -0.12, nominal P = 0.010) in the 70 mg volagidemab group. No increase in hypoglycemia was observed with volagidemab therapy; however, increases in serum transaminases, low-density lipoprotein (LDL)-cholesterol and blood pressure were observed. Although the primary endpoint did not meet the prespecified significance level, we believe that the observed reduction in HbA1c and tolerable safety profile provide a rationale for further randomized studies to define the long-term efficacy and safety of volagidemab in patients with T1D.

Clinical Impact of ITCA 650, a Novel Drug-Device GLP-1 Receptor Agonist, in Uncontrolled Type 2 Diabetes and Very High Baseline HbA1c: The FREEDOM-1 HBL (High Baseline) Study.

OBJECTIVE: ITCA 650 is a subdermal osmotic mini-pump that continuously delivers exenatide subcutaneously for 3-6 months. The efficacy, safety, and tolerability of ITCA 650 added to diet and exercise alone or combined with metformin, sulfonylurea, or thiazolidinedione monotherapy or a combination of these drugs was evaluated in poorly controlled patients with type 2 diabetes (T2D) who were ineligible for participation in a placebo-controlled study (FREEDOM-1) because of severe hyperglycemia (HbA1c >10% [86 mmol/mol]). RESEARCH DESIGN AND METHODS: This 39-week, open-label, phase 3 trial enrolled patients aged 18-80 years with HbA1c >10% to ≤12% (86-108 mmol/mol) and BMI 25-45 kg/m2. Patients received ITCA 650 20 µg/day for 13 weeks, then 60 µg/day for 26 weeks. The primary end point was change in HbA1c at week 39. RESULTS: Sixty patients were enrolled. At baseline, mean HbA1c was 10.8% (94.7 mmol/mol) and mean (± SD) duration of diabetes was 8.6 (± 5.3) years. At week 39, there was a mean reduction in HbA1c of -2.8% (-30.3 mmol/mol; P < 0.001 vs. baseline) and in body weight of -1.2 kg (P = 0.105), and 25% of patients achieved HbA1c <7% (53 mmol/mol). A reduction in HbA1c of ≥1% (≥10.9 mmol/mol) occurred in 90% of patients. The most common adverse events were nausea, vomiting, diarrhea, and headache. Gastrointestinal adverse events were generally transient and subsided over time; only 4 patients (6.7%) discontinued for gastrointestinal events. CONCLUSIONS: Treatment with ITCA 650, the first injection-free glucagon-like peptide 1 receptor agonist, resulted in significant improvements in glycemic control in poorly controlled long-standing T2D patients with a high baseline HbA1c >10%.

A Prospective Multicenter Evaluation of the Accuracy of a Novel Implanted Continuous Glucose Sensor: PRECISE II.

BACKGROUND: Persistent use of real-time continuous glucose monitoring (CGM) improves diabetes control in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D). METHODS: PRECISE II was a nonrandomized, blinded, prospective, single-arm, multicenter study that evaluated the accuracy and safety of the implantable Eversense CGM system among adult participants with T1D and T2D (NCT02647905). The primary endpoint was the mean absolute relative difference (MARD) between paired Eversense and Yellow Springs Instrument (YSI) reference measurements through 90 days postinsertion for reference glucose values from 40 to 400 mg/dL. Additional endpoints included Clarke Error Grid analysis and sensor longevity. The primary safety endpoint was the incidence of device-related or sensor insertion/removal procedure-related serious adverse events (SAEs) through 90 days postinsertion. RESULTS: Ninety participants received the CGM system. The overall MARD value against reference glucose values was 8.8% (95% confidence interval: 8.1%-9.3%), which was significantly lower than the prespecified 20% performance goal for accuracy (P < 0.0001). Ninety-three percent of CGM values were within 20/20% of reference values over the total glucose range of 40-400 mg/dL. Clarke Error Grid analysis showed 99.3% of samples in the clinically acceptable error zones A (92.8%) and B (6.5%). Ninety-one percent of sensors were functional through day 90. One related SAE (1.1%) occurred during the study for removal of a sensor. CONCLUSIONS: The PRECISE II trial demonstrated that the Eversense CGM system provided accurate glucose readings through the intended 90-day sensor life with a favorable safety profile.

Glycemic Effect and Safety of a Systemic, Partial Glucokinase Activator, PF-04937319, in Patients With Type 2 Diabetes Mellitus Inadequately Controlled on Metformin-A Randomized, Crossover, Active-Controlled Study.

Glucokinase enhances glucose conversion to glucose-6-phosphate, causing glucose-stimulated insulin secretion from pancreatic ß cells and increased hepatic glucose uptake. PF-04937319 is a partial glucokinase activator designed to maintain efficacy with reduced hypoglycemia risk. In this randomized, double-blind, double-dummy, 3-period crossover phase 1b study, patients aged 18-70 years with type 2 diabetes mellitus and on metformin received once-daily PF-04937319 (300 mg), split-dose PF-04937319 (150+100 mg; breakfast+lunch), or sitagliptin (100 mg once daily). The primary end point was day 14 weighted mean daily glucose (WMDG) change from period-specific baseline. Secondary end points included change from baseline in fasting plasma glucose, premeal C-peptide and insulin, and safety, including hypoglycemia frequency. Mean decrease from baseline in observed WMDG (mg/dL) was greater for PF-04937319 (split-dose, -31.24; once daily, -31.33) versus sitagliptin (-19.24). Using the integrated glucose red-cell HbA1c model, the observed WMDG effect with both PF-04937319 dosing regimens was projected to yield a clinically superior effect on mean glycated hemoglobin (HbA1c ; split-dose, -0.88%; once daily, -0.94%) compared with sitagliptin (-0.63%). There was no difference in premeal C-peptide or insulin levels, and although the effect on WMDG with both PF-04937319 regimens was similar, the split-dose regimen appeared to offer some advantage in safety and tolerability.

Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial.

PURPOSE: To determine whether a combination of L-methylfolate, methylcobalamin, and pyridoxal-5'-phosphate (LMF-MC-PLP [Metanx; Pamlab LLC, Covington, La]) improves sensory neuropathy. RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled trial involved 214 patients with type 2 diabetes and neuropathy (baseline vibration perception threshold [VPT]: 25-45 volts), who were randomly assigned to 24 weeks of treatment with either L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg or placebo. The primary end point was effect on VPT. Secondary end points included Neuropathy Total Symptom Score (NTSS-6) and Short Form 36 (SF-36), as well as plasma levels of folate, vitamins B(6) and B(12), methylmalonic acid (MMA), and homocysteine. RESULTS: There was no significant effect on VPT. However, patients receiving LMF-MC-PLP consistently reported symptomatic relief, with clinically significant improvement in NTSS-6 scores at week 16 (P=.013 vs placebo) and week 24 (P=.033). Improvement in NTSS scores was related to baseline MMA and inversely related to baseline PLP and metformin use. Quality-of-life measures also improved. Homocysteine decreased by 2.7±3.0 µmol/L with LMF-MC-PLP versus an increase of 0.5±2.4 µmol/L with placebo (P=.0001). Adverse events were infrequent, with no single event occurring in ≥2% of subjects. CONCLUSIONS: LMF-MC-PLP appears to be a safe and effective therapy for alleviation of peripheral neuropathy symptoms, at least in the short term. Additional long-term studies should be conducted, as the trial duration may have been too short to show an effect on VPT. In addition, further research on the effects in patients with cobalamin deficiency would be useful.