Safety and Immunogenicity of V114 in Preterm Infants: A Pooled Analysis of Four Phase Three Studies.

BACKGROUND: Risk of invasive pneumococcal disease is 3-fold higher in preterm versus full-term infants. V114 is a 15-valent pneumococcal conjugate vaccine (PCV) containing the 13 serotypes in PCV13 plus 2 unique serotypes, 22F and 33F. A pooled subgroup analysis was performed in preterm infants (<37 weeks gestational age) enrolled in 4 pediatric phase 3 studies evaluating the safety and immunogenicity of different 4-dose regimens of V114 or PCV13. METHODS: Healthy preterm infants were randomized 1:1 to receive V114/PCV13 in the 4 studies. Safety was evaluated as the proportion of participants with adverse events (AEs) following receipt of PCV. Serotype-specific antipneumococcal immunoglobulin G (IgG) geometric mean concentrations, IgG response rates and opsonophagocytic activity geometric mean titers were measured at 30 days postdose 3, pretoddler dose and 30 days postdose 4. RESULTS: V114 and PCV13 were administered to 174 and 180 participants, respectively. Mean gestational age was 35.4 weeks (range: 27 - <37 weeks). Proportions of participants with AEs were comparable between vaccination groups; most AEs experienced were of short duration (≤3 days) and mild-to-moderate intensity. V114-elicited IgG geometric mean concentrations, IgG response rates and opsonophagocytic activity geometric mean titers were generally comparable to PCV13 for the 13 shared serotypes and higher for serotypes 22F and 33F at 30 days postdose 3 and postdose 4. CONCLUSIONS: In preterm infants, V114 was well tolerated and induced comparable immune responses to PCV13 for the 13 shared serotypes and higher immune responses to serotypes 22F and 33F. Results support the use of V114 in preterm infants.

A Phase 3, Randomized, Double-Blind, Comparator-Controlled Study to Evaluate Safety, Tolerability, and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Allogeneic Hematopoietic Cell Transplant Recipients (PNEU-STEM).

BACKGROUND: Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk of pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. METHODS: Participants received 3 doses of V114 or PCV13 (Prevnar 13; Wyeth LLC) in 1-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAX 23 or a fourth dose of PCV (if they experienced chronic graft vs host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. RESULTS: A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at day 90. CONCLUSIONS: V114 was well tolerated in allo-HCT recipients, with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and was higher for V114 serotypes 22F and 33F. Study results support the use of V114 in allo-HCT recipients. Clinical Trials Registration. clinicaltrials.gov (NCT03565900) and European Union at EudraCT 2018-000066-11.

Safety and Tolerability of V114 Pneumococcal Vaccine in Infants: A Phase 3 Study.

BACKGROUND AND OBJECTIVES: Disease caused by Streptococcus pneumoniae is associated with considerable morbidity and mortality in children. Pneumococcal conjugate vaccines (PCVs) are well tolerated and effective at reducing pneumococcal disease caused by vaccine serotypes. VAXNEUVANCE (V114) is a 15-valent PCV containing 13 serotypes in Prevnar 13 (PCV13), plus serotypes 22F and 33F. This large phase 3 study evaluated safety and tolerability of V114 in infants. METHODS: In total, 2409 infants were randomized to receive V114 or PCV13 at 2, 4, 6, and 12 to 15 months of age. Safety was evaluated as the proportion of participants with adverse events (AEs). Solicited and unsolicited injection-site and systemic AEs were collected for 14 days after each study vaccination, and serious AEs up to 6 months after the last PCV dose. RESULTS: The proportions of participants with injection-site, systemic, vaccine-related, and serious AEs were generally comparable between recipients of V114 and PCV13. The most frequently reported AEs were solicited, with irritability and somnolence being the most frequent in both groups. Although the incidence of some AEs was higher in the V114 group, the between-group differences were small. The majority of experienced AEs were of mild-to-moderate intensity and lasted ≤3 days. There were 2 vaccine-related serious AEs of pyrexia in the V114 group, and 2 nonvaccine-related deaths, 1 in each group. No participant discontinued study vaccine because of AEs. CONCLUSIONS: V114 is well tolerated and has a generally comparable safety profile to that of PCV13. These study results support routine use of V114 in infants.

SGLT2 Inhibitors and the Risk of Hospitalization for Fournier's Gangrene: A Nested Case-Control Study.

INTRODUCTION: Based on post-marketing surveillance, concern has been raised that sodium-glucose cotransporter 2 inhibitors (SGLT2i) may increase the risk of necrotizing fasciitis of the perineum (Fournier's gangrene, FG). As a result of the low incidence of FG, data from clinical trials may be insufficient to robustly assess this issue because of the relatively limited numbers of participants. Real-world evidence may help clarify the association between SGLT2i and FG in the type 2 diabetes (T2D) population. METHODS: A nested case-control study was performed using Truven Health MarketScan™ databases. Each patient with T2D hospitalized for FG between 1 April 2013 (when the first SGLT2i was available) and 31 March 2018 (latest available data) was matched (on the basis of sex, age, and cohort entry date) with six controls from the same cohort. The adjusted odds ratio (OR) of hospitalization for FG was estimated for patients receiving SGLT2i compared with those receiving two or more non-SGLT2i antihyperglycemic agents (AHAs) or insulin alone using conditional logistic regression. RESULTS: The cohort included 1,897,935 patients, with 216 hospitalized for FG (incidence rate, 5.2 events per 100,000 person-years). Patients with FG ranged from 23 to 79 years of age; 201 (93.1%) were men. Among the 216 FG cases, 9 (4.2%) were current SGLT2i users; among the 1296 matched controls, 100 (7.7%) were current SGLT2i users. Approximately 93% of SGLT2i were used in combination. The adjusted OR of FG in patients treated with SGLT2i compared with patients treated with two or more non-SGLT2i AHAs or insulin alone was 0.55 [95% CI 0.25-1.18]. CONCLUSION: The study did not find that treatment with SGLT2i, as compared with treatment with two or more non-SGLT2i AHAs or insulin alone, was statistically significantly associated with an increased risk of hospitalization for FG. Additional studies are needed to corroborate the findings.

Perioperative management of a patient with a nonresectable pheochromocytoma.

OBJECTIVE: To describe the clinical course of a patient with a nonresectable pheochromocytoma during urgent hip surgery. METHODS: To describe the clinical management and postoperative outcome of the patient and review the relevant literature. RESULTS: An 85-year-old male with a nonresectable pheochromocytoma required urgent hip surgery following a traumatic hip fracture. He was perioperatively managed with phenoxybenzamine, metyrosine, and metoprolol to avoid potential pheochromocytoma-related complications. He remained hemodynamically stable and recovered from the surgery without complications. CONCLUSIONS: This case illustrates the successful management of a patient requiring urgent surgery in the setting of a nonresectable pheochromocytoma, which is rarely described in the literature.

Effects of metformin and leuprolide acetate on insulin resistance and testosterone levels in nondiabetic postmenopausal women: a randomized, placebo-controlled trial.

OBJECTIVE: To determine whether insulin sensitizers lower androgen levels and whether androgen suppression improves insulin resistance in nondiabetic postmenopausal women. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Clinical and Translational Research Center of a university hospital. PATIENT(S): Thirty-five postmenopausal women aged 50-79 years with insulin resistance and higher T levels. INTERVENTION(S): Subjects were randomized to metformin plus leuprolide acetate (LA) placebo, LA plus metformin placebo, or LA placebo plus metformin placebo in a 1:1:1 fashion during a 12-week period. MAIN OUTCOME MEASURE(S): Insulin sensitivity (M) assessed by euglycemic-hyperinsulinemic clamp and free T by equilibrium dialysis. RESULT(S): In those randomized to metformin, free T decreased by 19% compared with placebo, along with an expected improvement in M. Total T also decreased significantly, whereas sex hormone-binding globulin (SHBG) did not change. In those randomized to LA, the percent change in M was not different from placebo, despite a 48% relative decrease in free T levels. CONCLUSION(S): These data are the first to establish a causal link between insulin resistance and T in postmenopausal women. They confirm that treatment of insulin resistance decreases T production in this population and demonstrate that pharmacologic lowering of T does not affect insulin resistance.

Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease.

CONTEXT: Early postmenopausal women with higher testosterone (T) levels have increased insulin resistance (IR) and cardiovascular risk factors, but whether this translates into increased cardiovascular disease later in life is unknown. OBJECTIVE: The objective of the study was to determine whether higher T levels are associated with IR, the metabolic syndrome (MetSyn), and coronary heart disease (CHD) in elderly women. DESIGN: Total T and free T by equilibrium dialysis were measured using ultrasensitive assays in 344 women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to examine the associations between total and free T and IR, MetSyn, and CHD. RESULTS: There was a stepwise increase in the homeostasis model assessment of insulin resistance with increasing total (P = 0.0.003) and free T (P = 0.02) level and a corresponding decrease in Quantitative Insulin Sensitivity Check Index (P < 0.001 and P = 0.002, respectively). In adjusted models, higher levels of both total and free T were strongly associated with abdominal obesity and high fasting glucose, the two MetSyn components most strongly linked to IR. After adjustment, women in the top quartile of total T levels had a 3-fold greater odds of MetSyn (odds ratio 3.15, 95% confidence interval 1.57-6.35) than those in the bottom quartile and a 3-fold greater odds of CHD (odds ratio 2.95, 95% confidence interval 1.2-7.3) than those in second quartile, whereas free T was not significantly associated with MetSyn or CHD. CONCLUSIONS: Higher levels of T are associated with IR, MetSyn, and CHD in elderly women. Whether T is a marker or mediator of cardiovascular disease in this population merits further investigation.