Don Johns

A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus.

OBJECTIVE The goal of this study was to compare the effects of 2 doses of pioglitazone hydrochloride (a thiazolidinedione insulin sensitizer) with placebo on glycated hemoglobin (HbA(1c)), insulin sensitivity, and lipid profiles in patients with type 2 diabetes mellitus who had suboptimal glycemic control and mild dyslipidemia. METHODS Patients with type 2 diabetes mellitus (HbA(1c) >/=6.5% and </=9.8%) who had not previously received insulin or oral antihyperglycemic medications (OAMs) were randomized to treatment with placebo, pioglitazone 30 mg QD, or pioglitazone 45 mg QD in double-blind fashion for 16 weeks at 41 centers in Canada and Spain. RESULTS A total of 297 patients were randomized (99 in each group). Overall, 286 (96.3%) were white. Mean (SD) age was 58.4 (10.9) years (range, 24-85 years), mean (SD) body mass index was 31.4 (4.8) kg/m(2), mean (SD) duration of type 2 diabetes mellitus was 20.0 (37.4) months, and 30.6% of patients were receiving medication for dyslipidemia. Treatment with pioglitazone 30 or 45 mg QD for 16 weeks reduced mean HbA(1c) by 0.8% and 0.9% from baseline, respectively (both P < 0.001 vs baseline and placebo). A reduction in HbA(1c) of 0.2% was observed in the placebo group (P = 0.025). In patients with medium (>/=7% to <8%) or high (>/=8% to </=9.8%) baseline HbA(1c), both doses of pioglitazone significantly reduced HbA(1c) (both P < 0.001 vs placebo). Pioglitazone 30 and 45 mg significantly reduced fasting serum insulin versus placebo (P = 0.008 and P = 0.006, respectively) and increased insulin sensitivity by Homeostasis Model Assessment versus placebo (P = 0.039 and P = 0.001, respectively). Relative to placebo, pioglitazone 30 and 45 mg significantly increased high-density lipoprotein cholesterol (HDL-C [P = 0.028 and P < 0.001, respectively]) and lowered the atherogenic index of plasma (P = 0.018 and P < 0.001, respectively). Pioglitazone 45 mg also significantly reduced serum triglycerides, apolipoprotein B, and total cholesterol:HDL-C ratio versus placebo (P = 0.007, P = 0.015, and P = 0.005, respectively). Pioglitazone 30 and 45 mg were associated with a significant reduction in serum alanine aminotransferase relative to placebo (P = 0.036 and P = 0.005, respectively). Pioglitazone appeared to be safe and was well tolerated. CONCLUSIONS In the present study, pioglitazone 30 and 45 mg produced significant improvements in HbA(1c), insulin sensitivity, and lipid profile in OAM-naive patients with type 2 diabetes mellitus with suboptimal glycemic control and mild dyslipidemia.

Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea

AIMS To evaluate the efficacy of exenatide in Asian patients with type 2 diabetes (T2D) inadequately controlled with oral agents. METHODS Patients taking metformin (MET) alone or with a sulphonylurea (SU) were randomly assigned to exenatide 5 microg then 10 microg twice-daily for 4 and 12 weeks, respectively, or placebo. The primary endpoint was baseline to endpoint HbA(1c) change. RESULTS 466 patients (age 54+/-9 years, weight 68.7+/-11.2 kg, BMI 26.3+/-3.3 kg/m(2), and HbA(1c) 8.3+/-1.1%; mean+/-S.D.) were enrolled in the full analysis set. Endpoint HbA(1c) reduction (mean [95% CI]) with exenatide was superior to placebo (-1.2 [-1.3, -1.1]% vs. -0.4 [-0.5, -0.2]%, p<0.001). More exenatide- than placebo-treated patients achieved HbA(1c) <or=7% (48% vs. 17%, p<0.001). At endpoint, weight reduction was greater with exenatide (-1.2 [-1.5, -0.9]kg) than placebo (-0.1 [-0.3, 0.2]kg), p<0.001. Nausea, generally mild-to-moderate, was the most common adverse event with exenatide (25% vs. 1% with placebo). The incidence of symptomatic hypoglycaemia with exenatide and placebo were 36% and 9%, respectively (p<0.001). Hypoglycaemia rates (events/patient-year) for patients taking exenatide with MET or MET and SU were 1.8 (0.9, 3.7) and 4.7 (3.5, 6.5), respectively. CONCLUSION Exenatide treatment improved glycaemic control in Asian patients with T2D and had a similar safety profile as in non-Asian patients.

Effects of pioglitazone and glimepiride on glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, parallel-group trial

BACKGROUND Pioglitazone and glimepiride improve glycemic control in patients with type 2 diabetes mellitus by different mechanisms. Pioglitazone is a thiazolidinedione that reduces insulin resistance, and glimepiride is a sulfonylurea insulin secretagogue. OBJECTIVE The goals of this study were to compare changes in measures of glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes who received pioglitazone or glimepiride for 1 year. METHODS This was a multicenter, 52-week, double-blind, parallel-group trial. Patients were randomized to receive monotherapy with either glimepiride (2 mg QD initially) or pioglitazone (15 mg QD initially). Doses were titrated (maximal doses: pioglitazone 45 mg, glimepiride 8 mg) to achieve glycemic targets (fasting blood glucose < or =7 mmol/L and 1-hour postprandial blood glucose < or =10 mmol/L). Insulin sensitivity (primary end point) was evaluated in terms of the Homeostasis Model Assessment for Insulin Sensitivity (HOMA-S), the Quantitative Insulin Sensitivity Check Index (QUICKI), and fasting serum insulin (FSI) concentrations. Glycemic control was evaluated in terms of glycosylated hemoglobin (HbA(1c)) values and fasting plasma glucose (FPG) concentrations. Patients were encouraged to maintain their individual diet and exercise regimens throughout the study. RESULTS Two hundred forty-four patients (125 women, 119 men; all but 1 Hispanic) were randomized to receive pioglitazone (n = 121) or glimepiride (n = 123). In the intent-to-treat sample, pioglitazone and glimepirede produced comparable reductions in HbA(1c) from baseline to the end of the study (-0.78% and -0.68%, respectively). The pioglitazone group had significantly higher HbA(1c) values compared with the glimepiride group after 12 weeks of therapy (8.66% vs 7.80%; P = 0.007) but had significantly lower values after 52 weeks (7.46% vs 7.77%; P = 0.027). Pioglitazone significantly reduced FPG compared with glimepiride (-0.6 vs 0.6 mmol/L; P = 0.01). Pioglitazone therapy was associated with significant increases in insulin sensitivity (reduced insulin resistance), whereas glimepiride had no effect. HOMA-S values changed 18.0% for pioglitazone and -7.9% for glimepiride (P < 0.001), QUICKI values changed a respective 0.013 and -0.007 (P < 0.001), and FSI values were -21.1 and 15.1 pmol/L (P< 0.001). Both drugs were well tolerated, with pioglitazone associated with more peripheral edema (number of treatment-emergent cases: 35/121[28.9%] vs 17/123 [13.8%]; P = 0.005) and fewer hypoglycemic episodes (19 [15.7%] vs 38 [30.9%]; P = 0.024). The incidence of weight gain was not significantly different between treatment groups. CONCLUSIONS These data suggest that long-term treatment with pioglitazone enhances insulin sensitivity relative to glimepiride in Mexican patients with type 2 diabetes and that pioglitazone may have a more sustained antihyperglycemic effect.

Reduced Daily Risk of Glycemic Variability: Comparison of Exenatide with Insulin Glargine

BACKGROUND Conventional methods describing daily glycemic variability (i.e., standard deviation and coefficient of variation) do not express risk. Low and High Blood Glucose Indices (LBGI and HBGI, respectively) and Average Daily Risk Range (ADRR) are parameters derived from self-monitored blood glucose (SMBG) data that quantify risk of glycemic excursions and temporal aspects of variability. In the present study, variability parameters were used to assess effects of exenatide and insulin glargine on risk of acute blood glucose extremes. METHODS New (LBGI, HBGI, and ADRR) and conventional variability analyses were applied retrospectively to SMBG data from patients with type 2 diabetes suboptimally controlled with metformin and a sulfonylurea plus exenatide or insulin glargine as a next therapeutic step. Exenatide- (n = 282) and insulin glargine-treated (n = 267) patients were well matched. RESULTS Exenatide treatment reduced ADRR overall (exenatide, mean +/- SEM, 16.33 +/- 0.45; insulin glargine, 18.54 +/- 0.49; P = 0.001). Seventy-seven percent of exenatide-treated patients were at low risk for glucose variability compared with 62% of glargine-treated patients (P = 0.00023). LBGI for exenatide remained minimal for all categories and significantly lower than glargine for all comparisons, and HBGI for exenatide remained low or moderate for all categories and significantly lower than glargine after the morning and evening meals. Reduced variability in exenatide-treated patients was shown by conventional methods but provided no indications of risk. CONCLUSIONS Average glycemic control was similar for both treatment groups. However, exenatide treatment minimized risk for glycemic variability and extremes to a greater degree than insulin glargine treatment.

Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes

Background: Miyazaki etal, demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n = 23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity. The Homeostasis Model Assessment-Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations. Study aim: To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (∼1000). Research design and methods: Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study. We evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI. Results: PIO 15, 30 and 45 mg enhanced HOMA-S compared with baseline (56.9-63.6%, p = 0.0298); (53.7-64.7%, p = 0.0008); (59.0-75.9%, p < 0.0001), respectively. Only the 45 mg dose showed a difference from placebo (p = 0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p = 0.0026); (0.287-0.299, p = 0.0001); (0.290-0.306, p = 0.0001), respectively. Both the 30 and 45mg doses were different from placebo for QUICKI (p = 0.0005, p < 0.0001). PIO 15 and 30mg plus SU enhanced HOMA-S compared with baseline (58.4–.7%, p = 0.0007; 53.2–68.4%, p < 0.0001) and placebo plus SU (p = 0.0129, p < 0.0001, respectively). Likewise, PIO 15 and 30 mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p = 0.0001; 0.287-0.305, p = 0.0001, respectively). Both doses had different effects from placebo plus SU (p = 0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2–82.2%, p < 0.0001) and placebo plus MET (p = 0.0002).

Use of predictive probabilities in phase II and phase III clinical trials.

Predictive probability is particularly useful in aiding a decision-making process related to drug development. This is especially true for decisions occurring as the result of interim analyses of clinical trials. Examples of clinical trial applications of Bayesian predictive probability and the use of the beta-binomial distribution are described.

Quantifying the effect of exenatide and insulin glargine on postprandial glucose excursions in patients with type 2 diabetes

ABSTRACT In this report, we quantify the effects of exenatide and glargine on the relative contributions of fasting and postprandial glucose (PPG) excursion to overall hyperglycemia based on self-monitored blood glucose. After 26 weeks of treatment, insulin glargine reduced fasting glucose to a greater extent than exenatide without significant effect on PPG excursion. The principal effect of exenatide on hyperglycemia was mitigating the rise in PPG with moderate improvement on fasting glucose. These findings may be limited by the fact that glucose measurements were collected through self-monitoring with six time points measured during the daytime, the meals were not standardized and the exact time for glucose measurements was unknown.

Loracarbef Versus Clarithromycin in Children with Acute Otitis Media with Effusion

Two multicenter, randomized, single-masked, parallel-group studies compared loracarbef and clarithromycin with regard to efficacy, tolerability, and patient acceptance. Three hundred thirty-four children aged 6 months to 3 years with acute otitis media with effusion received loracarbef (15 mg/kg) or clarithromycin (7.5 mg/kg) orally twice daily for 10 days. Patients were assessed for the presence of the diagnostic signs and symptoms of otitis media with effusion by physical examination and pneumatic otoscopy at 48 hours pretreatment, 3 to 5 days after initiation of treatment, 0 to 3 days after the final dose (posttreatment), and 14 to 21 days later (termination). Symptoms were assigned numeric values. Symptomatic response was assessed at the posttherapy and termination visits. Tolerability was determined by assessing adverse events, and a patient acceptance survey was completed by each patients caregiver. The combined results of these 2 studies showed that the efficacy and tolerability of loracarbef were comparable to those of clarithromycin. Adverse events were reported by 46.4% of loracarbef patients and 41.0% of clarithromycin patients, with no statistically significant difference between groups. In the intent-to-treat analysis, 57.9% of loracarbef patients were cured at the termination of the study, compared with 55.7% of clarithromycin patients. Improvement was seen in 4.1% of loracarbef patients and 2.7% of clarithromycin patients. Results of the patient acceptance survey showed a clear preference for loracarbef over clarithromycin. Difficulties with administration of treatment were reported by 36.3% of clarithromycin caregivers, compared with 7.8% of loracarbef caregivers (P < 0.001). A desire to stop treatment was reported by 23.8% of clarithromycin caregivers, compared with 7.8% of loracarbef caregivers (P < 0.001). Taste and texture issues were most frequently cited as reasons for nonacceptance.

Cefaclor advanced formulation 750 mg twice daily versus clarithromycin 500 mg twice daily in the treatment of acute maxillary sinusitis

Abstract This multicenter, open-label, randomized, parallel-treatment, outpatient study compared the therapeutic equivalence and safety of cefaclor advanced formulation (AT) with those of clarithromycin in the treatment of acute maxillary sinusitis. Eligible patients were randomly allocated to receive cefaclor AT 750 mg twice daily for 10 days (n = 64) or clarithromycin 500 mg twice daily for 10 days (n = 65). A medical history was recorded, a physical examination was performed, and sinusitis diagnostic criteria (maxillofacial pain or tenderness, purulent rhinorrhea, headache, and fever) were assessed ≤24 hours before administration of the first dose of study medication (pretherapy). Assessments of symptomatic response, clinical response, and adverse events were performed 3 to 5 days after the end of therapy or at the time of early discontinuation (post therapy) and 10 to 14 days after the end of therapy (follow-up). Symptomatic responses of maxillofacial pain or tenderness, purulent rhinorrhea, and headache were scored on a 4-point scale (0 = absent, 1 = mild, 2 = moderate, and 3 = severe); clinical response was defined as cure, improvement, relapse, failure, or indeterminate. Treatment with cefaclor AF or clarithromycin almost eliminated maxillofacial pain and tenderness, purulent rhinorrhea, and headache. Mean symptom scores post therapy and at follow-up ranged from 0.1 to 0.3 in the cefaclor AF group and from 0.0 to 0.2 in the clarithromycin group. The incidence of treatment success was identical in the 2 treatment groups: 58 patients (91%) in the cefaclor AF group and 59 patients (91%) in the clarithromycin group were cured or improved post therapy. Twenty patients (31%) in the cefaclor AF group and 19 patients (29%) in the clarithromycin group experienced adverse events, none of which were serious. Discontinuations because of adverse events occurred in 4 patients in the clarithromycin group (gastrointestinal, 3; rash, 1) and 1 patient in the cefaclor AF group (rash); these differences were not statistically significant. In terms of clinical response and symptom score, cefaclor AF and clarithromycin were equally effective in the treatment of this group of patients with acute maxillary sinusitis.

DOUBLE-MASKED, RANDOMIZED, PARALLEL-GROUP COMPARISON OF CEFACLOR AF AND CEFACLOR IN THE TREATMENT OF ACUTE BACTERIAL SINUSITIS

Abstract A multicenter, randomized, double-masked, parallel-group study was conducted to compare the efficacy and safety of cefaclor AF (750 mg twice daily) and cefaclor (500 mg three times daily) in the treatment of 298 patients with acute bacterial sinusitis. Patients demonstrating a favorable clinical response 3 to 5 days posttherapy were reevaluated for relapse 10 to 14 days after therapy. At the posttherapy visit, there was a favorable clinical response (ie, cure/ improvement) in 91.8% of patients in the cefaclor AF group and in 92.9% of those in the cefaclor group. At the follow-up evaluation, only 1.8% of patients receiving cefaclor AF and 4.3% of those receiving cefaclor had relapsed. None of the between-group differences were statistically significant. The most common pathogens isolated were Streptococcus pneumoniae and Haemophilus influenzae . In patients with infections caused by S pneumoniae , 90.9% of those treated with cefaclor AF and 95.4% of those treated with cefaclor had a favorable clinical response at the posttherapy visit. In patients with infections caused by H influenzae , 90.9% of those treated with cefaclor AF and 77.8% of those treated with cefaclor had a favorable clinical response at the posttherapy visit. All patients infected by these pathogens were clinically cured at the follow-up visit. Both treatments were also highly effective in treating infections caused by Staphylococcus aureus, Moraxella catarrhalis , and Streptococcus pogenes . Both treatments were well tolerated, and there were no statistically significant differences between treatment groups in the frequency of adverse events. The only adverse events considered to be treatment related were diarrhea and abdominal pain. The results of this study demonstrate that the efficacy and safety of cefaclor AF are comparable with that of cefaclor in the treatment of patients with acute bacterial sinusitis