Safety of a C1-inhibitor concentrate in pregnant women with hereditary angioedema.

BACKGROUND: Increased estrogen levels during pregnancy can exacerbate hereditary angioedema (HAE), yet disease and treatment ramifications remain poorly studied in pregnant women. OBJECTIVE: Data from the international Berinert Patient Registry were used to evaluate outcomes of pregnancies exposed to plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) during routine HAE management. METHODS: This observational registry, conducted between 2010 and 2014 at 30 U.S. and 7 European sites, gathered data on 318 subjects and 15,000 pnfC1-INH infusions. Whenever possible, the subjects who used pnfC1-INH during pregnancy were followed up to term to assess neonatal outcomes and to collect maternal adverse events (AE) that occurred up to 1 month after pnfC1-INH administration. RESULTS: The registry data base included 11 pregnancies in 10 subjects who used pnfC1-INH for HAE attack treatment and/or prophylaxis (>261 doses during pregnancy). Eight pregnancies concluded in the birth of a healthy baby. Of the remaining three pregnancies: one was voluntarily terminated at 9 weeks of gestation; a second ended as a first-trimester spontaneous abortion 1 week after the subject's most recent pnfC1-INH infusion and was considered unrelated to pnf-C1INH treatment; and the third occurred in a subject who exited the registry approximately 2 months before her due date, with no further follow up. As assessed for 30 days after each pnfC1-INH infusion, there were no AEs that were considered related to pnfC1-INH therapy. CONCLUSION: Administration of pnfC1-INH during pregnancy was generally safe and not associated with any treatment-related AEs. In all registry pregnancies followed up to term, the birth of a healthy baby was reported.

Efficacy and safety of an intravenous C1-inhibitor concentrate for long-term prophylaxis in hereditary angioedema.

BACKGROUND: The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. OBJECTIVE: This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). METHODS: The international registry (2010-2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. RESULTS: The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500-3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH-treated attack of 72.0 hours (range, 0.0-166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH-treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). CONCLUSION: In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration.

Assessment of inhibitory antibodies in patients with hereditary angioedema treated with plasma-derived C1 inhibitor.

BACKGROUND: Limited data are available regarding C1 inhibitor (C1-INH) administration and anti-C1-INH antibodies. OBJECTIVE: To assess the incidence of antibody formation during treatment with pasteurized, nanofiltered plasma-derived C1-INH (pnfC1-INH) in patients with hereditary angioedema with C1-INH deficiency (C1-INH-HAE) and the comparative efficacy of pnfC1-INH in patients with and without antibodies. METHODS: In this multicenter, open-label study, patients with C1-INH-HAE (≥12 years of age) were given 20 IU/kg of pnfC1-INH per HAE attack that required treatment and followed up for 9 months. Blood samples were taken at baseline (day of first attack) and months 3, 6, and 9 and analyzed for inhibitory anti-C1-INH antibody (iC1-INH-Ab) and noninhibitory anti-C1-INH antibodies (niC1-INH-Abs). RESULTS: The study included 46 patients (69.6% female; mean age, 38.9 years; all white) who received 221 on-site pnfC1-INH infusions; most patients received 6 or fewer infusions. No patient tested positive (titer ≥1:50) for iC1-INH-Ab at any time during the study. Thirteen patients (28.2%) had detectable niC1-INH-Abs in 1 or more samples. Nine patients (19.6%) had detectable niC1-INH-Abs at baseline; 3 of these had no detectable antibodies after baseline. Of 10 patients (21.7%) with 1 or more detectable result for niC1-INH-Abs after baseline, 6 had detectable niC1-INH-Abs at baseline. Mean times to symptom relief onset and complete symptom resolution per patient were similar for those with or without anti-niC1-INH-Abs. CONCLUSION: Administration of pnfC1-INH was not associated with iC1-INH-Ab formation in this population. Noninhibitory antibodies were detected in some patients but fluctuated during the study independently of pnfC1-INH administration and appeared to have no effect on pnfC1-INH efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01467947.

Use of a C1 Inhibitor Concentrate in Adults ≥65 Years of Age with Hereditary Angioedema: Findings from the International Berinert® (C1-INH) Registry.

BACKGROUND: Treatment of hereditary angioedema (HAE) in 'older adults' (those aged ≥65 years) has not been well studied. The international Berinert Patient Registry collected data on the use of intravenous plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH; Berinert®/CSL Behring) in patients of any age, including many older adults. METHODS: This observational registry, conducted from 2010 to 2014 at 30 US and seven European sites, gathered prospective (post-enrollment) and retrospective (pre-enrollment) usage and adverse event (AE) data on subjects treated with pnfC1-INH. RESULTS: The registry documented 1701 pnfC1-INH infusions in 27 older adults. A total of 1511 HAE attacks treated with pnfC1-INH administration were reported among 25 of the 27 (92.6 %) older adults. Among the older adults, mean (standard deviation [SD]) (8.8 [4.1] IU/kg) and median (6.4 IU/kg) pnfC1-INH doses were lower than those reported for 252 'younger adults' (those aged <65 years: 12.9 [6.2], 12.5 IU/kg, respectively). A total of 19 AEs occurred in 8 of 23 (34.8 %) older adults with prospective data, for rates of 0.83 events per subject and 0.02 events per infusion, similar to corresponding rates in younger adults (0.91 and 0.03, respectively). None of the AEs were considered related to pnfC1-INH, and all but two events (prostatectomy, gastrointestinal bleeding) were mild or moderate in severity. Administration of pnfC1-INH outside of a healthcare setting was reported for 1609 infusions in 16 older adults, representing 94.6 % of all pnfC1-INH infusions in this age group. There were no recorded instances of difficulty with self-administration of intravenous pnfC1-INH. CONCLUSIONS: These findings suggest a high degree of safety with intravenous pnfC1-INH use in older adults with HAE, regardless of administration setting. Trial Registration Clinicaltrials.gov NCT01108848.

Safety and Usage of C1-Inhibitor in Hereditary Angioedema: Berinert Registry Data.

BACKGROUND: The plasma-derived, highly purified, nanofiltered C1-inhibitor concentrate (Berinert; "pnfC1-INH") is approved in the United States for treating hereditary angioedema (HAE) attacks and in many European countries for attack treatment and short-term prophylaxis. OBJECTIVE: The objective of this study was to describe safety and usage patterns of pnfC1-INH. METHODS: A multicenter, observational, registry was conducted between 2010 and 2014 at 30 United States and 7 European sites to obtain both prospective (occurring after enrollment) and retrospective (occurring before enrollment) safety and usage data on subjects receiving pnfC1-INH for any reason. RESULTS: Of 343 enrolled patients, 318 received 1 or more doses of pnfC1-INH for HAE attacks (11,848 infusions) or for prophylaxis (3142 infusions), comprising the safety population. Median dosages per infusion were 10.8 IU/kg (attack treatment) and 16.6 IU/kg (prophylaxis). Approximately 95% of infusions were administered outside of a health care setting. No adverse events (AEs) were reported in retrospective data. Among prospective data (n = 296 subjects; 9148 infusions), 252 AEs were reported in 85 (28.7%) subjects (rate of 0.03 events/infusion); 9 events were considered related to pnfC1-INH. Two thromboembolic events were reported in subjects with thrombotic risk factors. No patient was noted to have undergone viral testing for suspected blood-borne infection during registry participation. CONCLUSIONS: The findings from this large, international patient registry documented widespread implementation of pnfC1-INH self-administration outside of a health care setting consistent with current HAE guidelines. These real-world data revealed pnfC1-INH usage for a variety of reasons in patients with HAE and showed a high level of safety regardless of administration setting or reason for use.

Effect of reversal of neuromuscular blockade with sugammadex versus usual care on bleeding risk in a randomized study of surgical patients.

BACKGROUND: Previous studies show a prolongation of activated partial thromboplastin time and prothrombin time in healthy volunteers after treatment with sugammadex. The authors investigated the effect of sugammadex on postsurgical bleeding and coagulation variables. METHODS: This randomized, double-blind trial enrolled patients receiving thromboprophylaxis and undergoing hip or knee joint replacement or hip fracture surgery. Patients received sugammadex 4 mg/kg or usual care (neostigmine or spontaneous recovery) for reversal of rocuronium- or vecuronium-induced neuromuscular blockade. The Cochran-Mantel-Haenszel method, stratified by thromboprophylaxis and renal status, was used to estimate relative risk and 95% confidence interval (CI) of bleeding events with sugammadex versus usual care. Safety was further evaluated by prespecified endpoints and adverse event reporting. RESULTS: Of 1,198 patients randomized, 1,184 were treated (sugammadex n = 596, usual care n = 588). Bleeding events within 24 h (classified by an independent, blinded Adjudication Committee) were reported in 17 (2.9%) sugammadex and 24 (4.1%) usual care patients (relative risk [95% CI], 0.70 [0.38 to 1.29]). Compared with usual care, increases of 5.5% in activated partial thromboplastin time (P < 0.001) and 3.0% in prothrombin time (P < 0.001) from baseline with sugammadex occurred 10 min after administration and resolved within 60 min. There were no significant differences between sugammadex and usual care for other blood loss measures (transfusion, 24-h drain volume, drop in hemoglobin, and anemia), or risk of venous thromboembolism, and no cases of anaphylaxis. CONCLUSION: Sugammadex produced limited, transient (<1 h) increases in activated partial thromboplastin time and prothrombin time but was not associated with increased risk of bleeding versus usual care.

Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo-controlled 54-week trial in patients with type 2 diabetes.

BACKGROUND: New therapeutic approaches are needed to improve glycemic control in patients with type 2 diabetes (T2D), a progressive disorder that often requires combination therapy. The present study assessed the efficacy and safety of sitagliptin as add-on therapy to metformin and rosiglitazone in patients with T2D. METHODS: The present study was a randomized double-blind placebo-controlled parallel-group 54-week study conducted at 41 sites across North and South America, Europe, and Asia in 278 patients with HbA1c ranging from ≥7.5% to ≤11.0% despite ongoing combination therapy with metformin (≥1500 mg/day) and rosiglitazone (≥4 mg/day). Patients were randomized (2:1) to receive sitagliptin 100 mg or placebo once daily. The main outcome measure was change from baseline in HbA1c at Week 18. RESULTS: Mean baseline HbA1c was 8.8%. The mean placebo-adjusted change from baseline in HbA1c with sitagliptin treatment was -0.7% (P < 0.001) at Week 18 and -0.8% (P < 0.001) at Week 54. There were also significant (P < 0.001) reductions in 2-h post-meal glucose and fasting plasma glucose compared with placebo at Weeks 18 and 54. Significantly higher proportions of sitagliptin- than placebo-treated patients had HbA1c<7.0% at Weeks 18 (22% vs 9%; P = 0.003) and 54 (26% vs 14%; P = 0.015). Changes in body weight and the rates of adverse events overall, hypoglycemia, and gastrointestinal adverse events were similar in the sitagliptin and placebo groups during the 54-week study. CONCLUSIONS: In patients with T2D, the addition of sitagliptin for 54 weeks to ongoing therapy with metformin and rosiglitazone improved glycemic control and was generally well tolerated compared with placebo.

Lower risk of hypoglycemia with sitagliptin compared to glipizide when either is added to metformin therapy: a pre-specified analysis adjusting for the most recently measured HbA(1c) value.

BACKGROUND: In a previously-published study, adding sitagliptin or glipizide to ongoing metformin therapy provided similar HbA(1c) improvement (both groups, -0.7%) after 52 weeks in patients with type 2 diabetes (T2DM). Significantly fewer patients experienced symptomatic hypoglycemia with sitagliptin (5% of 588 patients) compared to glipizide (32% of 584 patients). Glycemic efficacy and patient characteristics may influence hypoglycemic events. The present analysis evaluated the risk of hypoglycemia with sitagliptin or glipizide after adjusting for the most recently measured HbA(1c) value. METHODS: Data for this analysis were from the aforementioned 52-week, randomized, double-blind, active-controlled study. The primary endpoint was confirmed hypoglycemia (i.e., symptomatic hypoglycemia confirmed with a concurrent fingerstick glucose ≤70 mg/dL [3.9 mmol/L]); the secondary endpoint was severe hypoglycemia (requiring medical or non-medical assistance or symptoms of neuroglycopenia). Complementary log-log regression random effects models with terms for treatment, most recently measured HbA(1c) value, time (i.e., days since randomization), gender, and age (< or ≥65 years) were used to assess adjusted subject-specific treatment effects. RESULTS: Over the full range of HbA(1c) levels and follow-up time, the risk of confirmed hypoglycemic events was lower with sitagliptin compared with glipizide (31 vs. 448 events; adjusted hazard ratio [HR] = 0.05 [95% CI: 0.03, 0.09], p < 0.001). The risk was also lower with sitagliptin in the younger (HR = 0.06 [95% CI: 0.03, 0.12], p < 0.001) and older (HR = 0.02 [0.01, 0.08], p < 0.001) age groups compared with glipizide. For severe hypoglycemia events (2 vs. 22), the risk was lower with sitagliptin (HR = 0.08 [95% CI: 0.01, 0.47]; p = 0.005). LIMITATIONS: The actual time between the HbA(1c) measurement and the hypoglycemic event was variable and not controlled for in the analysis. CONCLUSION: In pre-specified analyses adjusting for the most recently measured HbA(1c) value, there was a substantial reduction in risk for confirmed hypoglycemia with sitagliptin compared to glipizide when added to ongoing metformin therapy in patients with T2DM. The risk of confirmed hypoglycemia was very low in younger and older patients treated with sitagliptin.

Sitagliptin more effectively achieves a composite endpoint for A1C reduction, lack of hypoglycemia and no body weight gain compared with glipizide.

Sitagliptin and glipizide added to metformin provided similar degrees of glycemic efficacy in patients with type 2 diabetes with inadequate glycemic control on metformin monotherapy at 1 year; however, significantly more patients in the sitagliptin group achieved an A1C reduction of >0.5% without hypoglycemia and without an increase in body weight.

Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Type 2 diabetes in the elderly is an important and insufficiently studied public health problem. This study evaluated sitagliptin monotherapy in patients with type 2 diabetes aged ≥ 65 years. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group study conducted at 52 sites in the United States. Patients were treated with once-daily sitagliptin (100 or 50 mg, depending on renal function) or placebo for 24 weeks. Key endpoints included change from baseline in glycated hemoglobin (HbA(1c)), 2-hour post-meal glucose (2-h PMG) and fasting plasma glucose (FPG) at week 24, and average blood glucose on treatment days 3 and 7. CLINICAL TRIAL REGISTRATION: NCT00305604. RESULTS: Among randomized patients (N = 206), mean age was 72 years and mean baseline HbA(1c) was 7.8%. At week 24, HbA(1c) decreased by 0.7%, 2-h PMG by 61 mg/dL, and FPG by 27 mg/dL in sitagliptin-treated patients compared with placebo (all p < 0.001). On day 3 of treatment, mean average blood glucose was decreased from baseline by 20.4 mg/dL in sitagliptin-treated patients compared with placebo (p < 0.001). In subgroups defined by baseline HbA(1c) <8.0% (n = 132), ≥ 8.0% to <9.0% (n = 42), and ≥ 9.0% (n = 18), the placebo-adjusted reductions in HbA(1c) with sitagliptin treatment were 0.5%, 0.9%, and 1.6%, respectively. Patients in the sitagliptin and placebo groups had similar rates of adverse events overall (46.1% and 52.9%, respectively); serious adverse events were reported in 6.9% and 13.5%, respectively. No adverse events of hypoglycemia were reported. Potential study limitations include a relatively small number of patients with more severe hyperglycemia (HbA(1c) ≥ 9.0%) and the exclusion of patients with severe renal insufficiency. CONCLUSION: In this study, sitagliptin treatment significantly and rapidly improved glycemic measures and was well tolerated in patients aged ≥ 65 years with type 2 diabetes.

Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes.

BACKGROUND: In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies. METHODS: The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea +/- metformin, insulin +/- metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea +/- metformin, insulin +/- metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events. RESULTS: Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events. CONCLUSIONS: In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.

Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study.

OBJECTIVE: To assess the 54-week efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control (HbA(1c) 7.5-11%) on diet and exercise. METHODS AND MATERIALS: This was multinational study conducted at 140 clinical sites in 18 countries. Following an initial 24-week, double-blind, placebo-controlled period, patients entered a double-blind continuation period for an additional 30 weeks. Following the week 24 evaluation, patients remained on their previously assigned active, oral treatments: sitagliptin 50 mg b.i.d. + metformin 1000 mg b.i.d. (S100 + M2000), sitagliptin 50 mg b.i.d. + metformin 500 mg b.i.d. (S100 + M1000), metformin 1000 mg b.i.d. (M2000), metformin 500 mg b.i.d. (M1000), and sitagliptin 100 mg q.d. (S100). Patients initially randomized to placebo were switched to M2000 (designated PBO/M2000) at week 24. This report summarizes the overall safety and tolerability data for the 54-week study and presents efficacy results for patients randomized to continuous treatments who entered the 30-week continuation period. RESULTS: Of the 1091 randomized patients, 906 completed the 24-week placebo-controlled phase and 885 patients continued into the 30-week continuation period (S100 + M2000 n = 161, S100+M1000 n = 160, M2000 n = 153, M1000 n = 147, S100 n = 141, PBO/M2000 n = 123). At baseline, patients included in the efficacy analysis had mean age of 54 years, mean BMI of 32 kg/m(2), mean HbA(1c) of 8.7% (8.5-8.8% across groups), and mean duration of type 2 diabetes of 4 years. At week 54, in the all-patients-treated analysis of continuing patients, least-squares (LS) mean changes in HbA(1c) from baseline were -1.8% (S100 + M2000), -1.4% (S100 + M1000), -1.3% (M2000), -1.0% (M1000), and -0.8% (S100). The proportions of continuing patients with an HbA(1c) < 7% at week 54 were 67% (S100 + M2000), 48% (S100 + M1000), 44% (M2000), 25% (M1000), and 23% (S100). For the patients completing treatment through week 54, LS mean changes in HbA(1c) from baseline were -1.9% (S100 + M2000), -1.7% (S100 + M1000), -1.6% (M2000), -1.2% (M1000), and -1.4% (S100). Glycemic response was generally durable over time across treatments. All treatments improved measures of beta-cell function (e.g., HOMA-beta, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1-3%) across treatment groups. The incidence of gastrointestinal adverse experiences with the co-administration of sitagliptin and metformin was similar to that observed with metformin alone. LIMITATIONS: The patient population evaluated in the 54-week efficacy analysis was a population of patients who entered the continuation period without receiving glycemic rescue therapy in the 24-week placebo-controlled period. Because the baseline HbA(1c) inclusion criteria ranged from 7.5 to 11% and the glycemic rescue criterion was an HbA(1c) > 8% after week 24, there was a greater likelihood of glycemic rescue in the monotherapy groups; this led to more missing data in the continuation all-patients-treated population(CAPT) analysis and fewer patients contributing to the completers analysis in the monotherapy groups. CONCLUSIONS: In this study, initial treatment with sitagliptin, metformin, or the combination therapy of sitagliptin and metformin provided substantial and durable glycemic control, improved markers of beta-cell function, and was generally well-tolerated over 54 weeks in patients with type 2 diabetes.

Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis.

BACKGROUND: Sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, is the first in a new class of oral antihyperglycemic agents (AHAs) for the treatment of patients with type 2 diabetes. Type 2 diabetes is a life-long disease requiring chronic treatment and management. Therefore, robust assessment of the long-term safety and tolerability of newer therapeutic agents is of importance. The purpose of this analysis was to assess the safety and tolerability of sitagliptin by pooling 12 large, double-blind, Phase IIb and III studies up to 2 years in duration. METHODS: This analysis included 6139 patients with type 2 diabetes receiving either sitagliptin 100 mg/day (N = 3415) or a comparator agent (placebo or an active comparator) (N = 2724; non-exposed group). The 12 studies from which this pooled population was drawn represent the double-blind, randomized, Phase IIB and III studies that included patients treated with the clinical dose of sitagliptin (100 mg/day) for at least 18 weeks up to 2 years and that were available in a single safety database as of November 2007. These 12 studies assessed sitagliptin as monotherapy, initial combination therapy with metformin, or add-on combination therapy with other oral AHAs (metformin, pioglitazone, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone). Patients in the non-exposed group were taking placebo, pioglitazone, metformin, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. This safety analysis used patient-level data from each study to evaluate clinical and laboratory adverse experiences. RESULTS: For clinical adverse experiences, the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups. The incidence rates of specific adverse experiences were also generally similar in the two groups, with the exception of an increased incidence rate of hypoglycemia observed in the non-exposed group. The incidence rates of drug-related adverse experiences overall and discontinuations due to drug-related adverse experiences were higher in the non-exposed group, primarily due to the increased incidence rate of hypoglycemia in this group. For cardiac- and ischemia-related adverse experiences (including serious events), there were no meaningful between-group differences. No meaningful differences between groups in laboratory adverse experiences, either summary measures or specific adverse experiences, were observed. CONCLUSION: In patients with type 2 diabetes, sitagliptin 100 mg/day was well tolerated in clinical trials up to 2 years in duration.

Efficacy of montelukast for treating perennial allergic rhinitis.

Perennial allergic rhinitis (PAR) is a chronic inflammatory nasal condition in individuals exposed year-round to allergens. This was a double-blind study of 15- to 85-year-old patients randomly allocated to montelukast, 10 mg (n=630), placebo (n=613), or the positive control cetirizine, 10 mg (n=122) for 6 weeks. The primary efficacy end point was change from baseline in Daytime Nasal Symptoms Score (DNSS; mean of congestion, rhinorrhea, sneezing, and itching scores, rated daily by patients [scale: 0=none to 3=severe]) averaged during the initial 4 weeks (primary analysis) or entire 6 weeks of treatment. Also assessed were combined post hoc results of primary end point data from this study and another similarly designed study (Patel P, et al. Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis, Ann Allergy Asthma Immunol 95:551, 2005). Over 4 weeks, montelukast showed numerical improvement over placebo in DNSS (least-squares mean difference of -0.04 [95% confidence interval (CI}, -0.09, 0.01]); the difference between cetirizine and placebo was significant: -0.10 (95% CI, -0.19, -0.01). However, when averaged over 6 weeks, neither active treatment was significantly different from placebo. The Rhinoconjunctivitis Quality-of-Life score was significantly improved by montelukast (p < 0.05), but not by cetirizine, during 4 and 6 weeks. The treatment effect of montelukast, but not cetirizine, generally remained consistent through the 6 weeks of treatment. In pooled data, montelukast consistently improved DNSS versus placebo during all 6 weeks of treatment (-0.07 [95% CI, -0.10, -0.041). In conclusion, montelukast produced numerical improvement in daytime nasal symptoms and significant improvement in quality of life. In a pooled post hoc analysis, montelukast provided consistent improvement in daytime nasal symptoms over 6 weeks, supportive of an overall benefit in PAR.

Placebo-controlled study of montelukast and budesonide on short-term growth in prepubertal asthmatic children.

BACKGROUND: Inhaled corticosteroids and anti-leukotriene agents are widely used in the treatment of pediatric asthma. Although data on the effect of corticosteroids on growth are available, there are few such data on anti-leukotriene agents. The aim of this study was to assess the influence of montelukast on short-term lower leg growth rate (LLGR) in prepubertal children with asthma. METHODS: Forty-two boys (6- to 12-year old) and 29 girls (6- to 11-year old) with mild asthma were randomized to 1 of 2 crossover arms, with two treatment sequences per arm: montelukast 5 mg once daily/placebo or inhaled dry powder budesonide 200 microg twice daily/placebo. Budesonide was used as a positive control to ensure that the method was sensitive enough to detect a suppression of LLGR. The 3-week double-blind treatment period was followed by a 3-week washout. Primary outcome was LLGR over the 3-week treatment, measured by knemometry. RESULTS: Ninety-four percent of patients completed the study. Mean LLGR was similar between patients receiving montelukast and placebo treatments: mean difference, -0.02 mm/week [95% confidence interval -0.14, 0.11]. Mean LLGR in patients receiving budesonide was significantly less than for those receiving placebo (difference of -0.16 mm/week [-0.25, -0.06], P = 0.002). Mean LLGR was similar for patients taking placebo in the two arms (0.43 and 0.44 mm/week). CONCLUSION: Montelukast 5 mg did not significantly affect short-term LLGR in prepubertal children.

Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control on diet and exercise. RESEARCH DESIGN AND METHODS: In a 24-week, randomized, double-blind, placebo-controlled, parallel-group study, 1,091 patients with type 2 diabetes and A1C 7.5-11% were randomized to one of six daily treatments: sitagliptin 100 mg/metformin 1,000 mg (S100/M1000 group), sitagliptin 100 mg/metformin 2,000 mg (S100/M2000 group), metformin 1,000 mg (M1000 group), metformin 2,000 mg (M2000 group) (all as divided doses administered twice daily [b.i.d.]), sitagliptin 100 mg q.d. (S100 group), or placebo. Patients who had an A1C >11% or a fasting glucose value >280 mg/dl after the run-in period were not eligible to be randomized; these patients could participate in an open-label substudy and were treated with S100/M2000 for 24 weeks. RESULTS: The mean baseline A1C was 8.8% in the randomized patients. The placebo-subtracted A1C change from baseline was -2.07% (S100/M2000), -1.57% (S100/M1000), -1.30% (M2000), -0.99% (M1000), and -0.83% (S100) (P < 0.001 for comparisons versus placebo and for coadministration versus respective monotherapies). The proportion of patients achieving an A1C <7% and <6.5% was 66 and 44%, respectively, in the S100/M2000 group (P < 0.001 vs. S100 or M2000). For the open-label cohort (n = 117; baseline A1C 11.2%) treated with S100/M2000, the within-group mean A1C change from baseline was -2.9%. The incidence of hypoglycemia was low (0.5-2.2%) across active treatment groups and not significantly different from that in the placebo group (0.6%). The incidence of gastrointestinal adverse experiences was similar for coadministration therapies compared with their respective metformin monotherapy. CONCLUSIONS: The initial combination of sitagliptin and metformin provided substantial and additive glycemic improvement and was generally well tolerated in patients with type 2 diabetes.

Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes.

OBJECTIVE: To examine the efficacy and safety of once-daily oral sitagliptin as monotherapy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled study, 741 patients (baseline HbA(1c) [A1C] 8.0%) were randomized to sitagliptin 100 or 200 mg or placebo for 24 weeks. RESULTS: Sitagliptin 100 and 200 mg produced significant (P < 0.001) placebo-subtracted reductions in A1C (-0.79 and -0.94%, respectively) and fasting plasma glucose (-1.0 mmol/l [-17.1 mg/dl] and -1.2 mmol/l [-21.3 mg/dl], respectively). Patients with baseline A1C >or=9% had greater reductions in placebo-subtracted A1C with sitagliptin 100 and 200 mg (-1.52 and -1.50%, respectively) than those with baseline A1C <8% (-0.57 and -0.65%) or >or=8 to <9.0% (-0.80 and -1.13%, respectively). In a meal tolerance test, sitagliptin 100 and 200 mg significantly decreased 2-h postprandial glucose (PPG) (placebo-subtracted PPG -2.6 mmol/l [-46.7 mg/dl] and -3.0 mmol/l [-54.1 mg/dl], respectively). Results for the above key efficacy parameters were not significantly different between sitagliptin doses. Homeostasis model assessment of beta-cell function and proinsulin-to-insulin ratio improved with sitagliptin. The incidence of hypoglycemia was similar, and overall gastrointestinal adverse experiences were slightly higher with sitagliptin. No meaningful body weight changes from baseline were observed with sitagliptin 100 (-0.2 kg) or 200 mg (-0.1 kg). The body weight change with placebo (-1.1 kg) was significantly (P < 0.01) different from that observed with sitagliptin. CONCLUSIONS: In this 24-week study, once-daily sitagliptin monotherapy improved glycemic control in the fasting and postprandial states, improved measures of beta-cell function, and was well tolerated in patients with type 2 diabetes.