Tom Loeys

Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes

Aim:  To assess the addition of sitagliptin to ongoing metformin therapy in patients with type 2 diabetes who were inadequately controlled [haemoglobin A1c (HbA1c) 7–11%] on metformin monotherapy.

A causal proportional hazards estimator for the effect of treatment actually received in a randomized trial with all-or-nothing compliance.

Survival data from randomized trials are most often analyzed in a proportional hazards (PH) framework that follows the intention-to-treat (ITT) principle. When not all the patients on the experimental arm actually receive the assigned treatment, the ITT-estimator mixes its effect on treatment compliers with its absence of effect on noncompliers. The structural accelerated failure time (SAFT) models of Robins and Tsiatis are designed to consistently estimate causal effects on the treated, without direct assumptions about the compliance selection mechanism. The traditional PH-model, however, has not yet led to such causal interpretation. In this article, we examine a PH-model of treatment effect on the treated subgroup. While potential treatment compliance is unobserved in the control arm, we derive an estimating equation for the Compliers PROPortional Hazards Effect of Treatment (C-PROPHET). The jackknife is used for bias correction and variance estimation. The method is applied to data from a recently finished clinical trial in cancer patients with liver metastases.

Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial.

(Headache 2011;51:73‐84)

Protection against exercise-induced bronchoconstriction two hours after a single oral dose of montelukast

The objective of this double-blind cross-over study was to evaluate montelukast for the prevention of exercise-induced bronchoconstriction (EIB). Sixty-two patients with EIB (post-exercise decrease in forced expiratory volume in 1 second (FEV1) ≥ 20% at pre-randomization) were randomized to montelukast 10 mg or placebo, followed by exercise-challenge 2, 12, and 24 hours postdose. The primary endpoint was the maximum percent-fall in FEV1 (from pre-exercise FEV1) during 60 minutes after exercise-challenge at 2 hours postdose. This endpoint was improved after montelukast (mean ± SD = 11.7% ± 10.8) versus placebo (17.5% ± 13.8) (p ≤ 0.001); numerically greater improvements were seen at 12 hours and 24 hours. A quicker time to recovery after challenge (p ≤ 0.001) and a smaller area under the curve for percent-fall in FEV1 during 60 minutes after challenge (p ≤ 0.01) were seen with montelukast at 2 hours. At this timepoint, more patients taking montelukast (45/54) than taking placebo (37/54) were protected against EIB (p = 0.039). We concluded that montelukast provided significant protection against EIB at 2 hours after a single dose.

Evaluation of the effect of perioperative rofecoxib treatment on pain control and clinical outcomes in patients recovering from gynecologic abdominal surgery : A randomized, double-blind, placebo-controlled clinical study

Background and Objectives: In this randomized, placebo-controlled, double-blind study, the efficacy and safety of rofecoxib* 50 mg was evaluated in patients undergoing major abdominal gynecologic surgery. Methods: Patients were randomized to receive rofecoxib 50 mg (n = 81) or placebo (n = 83) ∼2 hours before total abdominal hysterectomy or myomectomy and once daily over the ensuing 4 days. Clinical measurements included average daily opioid use over the 5-day period (primary endpoint), pain intensity on movement, and opioid-related side effects. Results: Patients receiving rofecoxib required 32% less (P = .001) intravenous and oral opioids to relieve their postoperative pain from days 1 to 5 (primary endpoint), used 21% less (P = .011) on day 1, and 42% less (P < .001) from days 2 to 5. The rofecoxib group experienced less pain upon movement (P < .001), less sedation (P = .007), and a 24% reduction in the rate of antiemetic intake (P = .037) over the first 72 hours postsurgery. Earlier mean times to first flatus (−10.1 hours, P = .001), first bowel movement (−14.1 hours, P = .037), and time to hospital discharge (−10.9 hours; 95% confidence interval, −17.1 to −4.7) occurred in the rofecoxib group. There were no significant intergroup differences in blood loss, wound healing, or overall adverse experiences. Conclusions: Compared with placebo, perioperative administration of rofecoxib 50 mg provided significant opioid sparing, significantly better pain control, improved clinical outcomes, and was well tolerated.

Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children

OBJECTIVES To evaluate the effect of montelukast, 5 mg, or inhaled salmeterol, 50 microg, added to inhaled fluticasone in reducing the maximum percentage decrease in forced expiratory volume in 1 second (FEV1) after a standardized exercise challenge and response to rescue bronchodilation with albuterol in children aged 6 to 14 years with persistent asthma and exercise-induced bronchoconstriction (EIB). METHODS Randomized, double-blind, double-dummy, multicenter, 2-period, 4-week, crossover study conducted between December 22, 2005 and November 14, 2008 at 30 centers in Europe, Asia, Mexico, and South America. Patients with asthma receiving inhaled corticosteroids demonstrated an FEV1 of 70% or higher of the predicted value and EIB (defined as a decrease in FEV1 > or = 15% compared with preexercise baseline FEV1 on 2 occasions before randomization). Standardized exercise challenges were performed at baseline (prerandomization) and at the end of each active treatment period. RESULTS Of 154 patients randomized, 145 completed the study. Montelukast, compared with salmeterol, significantly reduced the mean maximum percentage decrease in FEV1 (10.6% vs 13.8%; P = .009), mean area under the curve for the first 20 minutes after exercise (116.0% x min vs 168.8% x min; P = .006), and median time to recovery (6.0 vs 11.1 minutes; P = .04). Response to albuterol rescue after exercise challenge was significantly greater (P < .001) with montelukast. Montelukast and salmeterol were generally well tolerated. CONCLUSIONS Attenuation and response of EIB to albuterol rescue after exercise challenge were significantly better with montelukast than with salmeterol after 4 weeks of treatment.

Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients: a comparison of the GOALLS and STATT studies

SUMMARY Background: Asians are thought to be more responsive to the lipid-lowering effects of statins than non-Asians although there are no head-to-head trials that examine this perception. Objective: To compare the results of the GOALLS and STATT studies that used similar titrate-to-goal protocols with 20 mg up to 80 mg simvastatin in Asian and non-Asian coronary heart disease (CHD) patients. Methods: GOALLS (N = 198; included non-Asians and Asians) and STATT (N = 133; included Asians only) were both multi-center, open-label 14-week studies in CHD patients with serum low density lipoprotein cholesterol (LDL-C) levels 115 mg/dL–180 mg/dL and triglycerides (TG) levels ≤ 400 mg/dL. Simvastatin was titrated from 20 mg/day up to 80 mg/day in order to achieve the National Cholesterol Education Program (NCEP) LDL-C target ≤ 100 mg/dL. The primary efficacy variable was the percentage of patients attaining the NCEP LDL-C target at Week 14. Secondary endpoints included proportion of patients achieving the European Society of Cardiology/European Atherosclerosis Society/European Society of Hypertension (European) LDL-C target ≤ 115 mg/dL at Week 14 and percentage change in lipid parameters. Safety and tolerability were assessed by monitoring adverse experiences and safety laboratory tests. Fifteen Asian patients were part of the GOALLS cohort and their data were compared separately with results of non-Asians from GOALLS and Asians from the STATT study. Results: After 14 weeks of simvastatin treatment, 87.1% of GOALLS non-Asians, 85.7% of GOALLS Asians, and 78.2% of STATT patients attained the NCEP LDL-C target. At Week 14, 94.4%, 92.9%, and 91.7% of the GOALLS non-Asians, GOALLS Asians, and STATT patients achieved the European LDL-C target, respectively. The average treatment doses to attain NCEP and European targets were comparable among groups. The percentage reductions in lipid parameters from baseline to week 14 were similar among groups except, changes in high density lipoprotein cholesterol and apolipoprotein A-I favored Asian subjects. There was also a greater reduction in TG in the STATT study, but this was not consistent with TG reductions experienced by Asians in the GOALLS study. In both studies, simvastatin was generally well tolerated by all patients across the dosage range of 20 mg–80 mg. No cases of rhabdomyolysis or myopathy were reported in either study. Conclusions: A great majority of CHD patients is able to achieve LDL-C treatment goals (up to 90%) on simvastatin regardless of racial background. Simvastatin treatment at doses of 20 mg–80 mg is well-tolerated in Asian and non-Asian CHD patients. This side-by-side comparison provides evidence that Asian and non-Asian CHD populations respond similarly to comparable doses of simvastatin.