Olga Kuznetsova

Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia.

Background:  Improving lipids beyond low‐density lipoprotein cholesterol (LDL‐C) lowering with statin monotherapy may further reduce cardiovascular risk. Niacin has complementary lipid‐modifying efficacy to statins and cardiovascular benefit, but is underutilised because of flushing, mediated primarily by prostaglandin D2 (PGD2). Laropiprant (LRPT), a PGD2 receptor (DP1) antagonist that reduces niacin‐induced flushing has been combined with extended‐release niacin (ERN) into a fixed‐dose tablet.

Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study

BACKGROUND Antileukotrienes and inhaled corticosteroids are asthma controller agents widely used in the treatment of pediatric asthma. OBJECTIVE To evaluate the effects of montelukast and beclomethasone on linear growth in prepubertal asthmatic children for 1 year. METHODS This was a 30-center study of boys (6.4-9.4 years old) and girls (6.4-8.4 years old) at Tanner stage I with mild, persistent asthma. After a placebo run-in period, 360 patients were randomized in equal ratios to double-blind, double-dummy treatment with 5 mg of montelukast, 200 microg of beclomethasone twice daily (positive control), or placebo for 56 weeks; 90% of the patients completed the study. The primary end point was linear growth velocity, measured using a stadiometer. RESULTS Linear growth rates were similar between the montelukast and placebo groups; the mean difference for the year was 0.03 cm. The mean growth rate with beclomethasone was significantly less than with placebo (-0.78 cm) or montelukast (0.81 cm) (P < .001 for both). Median percentage of days with beta-agonist use was greater with placebo (14.58%) vs montelukast (10.55%) or beclomethasone (6.65%) (P < .05 for all). More patients used oral corticosteroid rescue with placebo (34.7%) than with montelukast (25.0%) or beclomethasone (23.5%). An imbalance in bone marker levels was seen with beclomethasone but not with montelukast. CONCLUSION In prepubertal asthmatic children, montelukast did not affect linear growth, whereas the growth rate with beclomethasone was significantly decreased during 1 year of treatment.

Hypophosphatemic Effect of Niacin in Patients without Renal Failure: A Randomized Trial

BACKGROUND AND OBJECTIVES Niacin administration lowers the marked hyperphosphatemia that is characteristic of renal failure. We examined whether niacin administration also reduces serum phosphorus concentrations in patients who have dyslipidemia and are free of advanced renal disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a post hoc data analysis of serum phosphorus concentrations that had been determined serially (at baseline and weeks 4, 8, 12, 18, and 24) among 1547 patients who had dyslipidemia and were randomly assigned in a 3:2:1 ratio to treatment with extended release niacin (ERN; 1 g/d for 4 weeks and dose advanced to 2 g/d for 20 weeks) combined with the selective prostaglandin D2 receptor subtype 1 inhibitor laropiprant (L; n = 761), ERN alone (n = 518), or placebo (n = 268). RESULTS Repeated measures analysis revealed that ERN-L treatment resulted in a net mean (95% confidence interval) serum phosphorus change comparing ERN-L with placebo treatment of -0.13 mmol/L (-0.15 to -0.13 mmol/L; -0.41 mg/dl [-0.46 to -0.37 mg/dl]). These results were consistent across the subgroups defined by estimated GFR of <60 or > or =60 ml/min per 1.73 m(2), a serum phosphorus of >1.13 mmol/L (3.5 mg/dl) versus < or =1.13 mmol/L (3.5 mg/dl), the presence of clinical diabetes, or concomitant statin use. CONCLUSIONS We have provided definitive evidence that once-daily ERN-L treatment causes a sustained 0.13-mmol/L (0.4-mg/dl) reduction in serum phosphorus concentrations, approximately 10% from baseline, which is unaffected by estimated GFR ranging from 30 to > or =90 ml/min per 1.73 m(2) (i.e., stages 1 through 3 chronic kidney disease).

Preserving the allocation ratio at every allocation with biased coin randomization and minimization in studies with unequal allocation.

The demand for unequal allocation in clinical trials is growing. Most commonly, the unequal allocation is achieved through permuted block randomization. However, other allocation procedures might be required to better approximate the allocation ratio in small samples, reduce the selection bias in open-label studies, or balance on baseline covariates. When these allocation procedures are generalized to unequal allocation, special care is to be taken to preserve the allocation ratio at every allocation step. This paper offers a way to expand the biased coin randomization to unequal allocation that preserves the allocation ratio at every allocation. The suggested expansion works with biased coin randomization that balances only on treatment group totals and with covariate-adaptive procedures that use a random biased coin element at every allocation. Balancing properties of the allocation ratio preserving biased coin randomization and minimization are described through simulations. It is demonstrated that these procedures are asymptotically protected against the shift in the rerandomization distribution identified for some examples of minimization with 1:2 allocation. The asymptotic shift in the rerandomization distribution of the difference in treatment means for an arbitrary unequal allocation procedure is explicitly derived in the paper.

Safety of extended-release niacin/laropiprant in patients with dyslipidemia

OBJECTIVE To evaluate the safety profile of extended-release niacin/laropiprant (ERN/LRPT), pooling data from studies in the clinical development program. METHODS Data were pooled from three active- or placebo-controlled phase 3 studies and three 1-year extensions of phase 2 studies that ranged from 12 to 52 weeks (N = 4747): ERN/LRPT = 2548; ERN or Niaspan® (ERN-NSP = 1268); or simvastatin or placebo (SIMVA-PBO = 931). RESULTS The safety and tolerability profile for ERN/LRPT was similar to that of ERN-NSP, except for fewer flushing-related adverse experiences and discontinuations with ERN/LRPT than ERN-NSP. The incidence of consecutive ≥3× the upper limit of normal increases in alanine aminotransferase and/or aspartate aminotransferase was numerically (but not statistically) greater with ERN/LRPT (1.0%) than ERN-NSP (0.5%) and similar to SIMVA-PBO (0.9%). Elevations were reversible with therapy discontinuation and not associated with clinical hepatotoxicity. There was no evidence that ERN/LRPT administered alone or concurrently with a statin had adverse effects on muscle. ERN/LRPT and ERN-NSP produced small median increases in fasting blood glucose levels (∼4 mg/dL) after 24 weeks of treatment, consistent with known effects of niacin. CONCLUSION The favorable safety and tolerability profile of ERN/LRPT for up to 1 year supports the use of LRPT to achieve improved therapeutic dosing of niacin, an agent with comprehensive lipid-modifying efficacy and shown to reduce cardiovascular risk.

Blood pressure-lowering effects of extended-release niacin alone and extended-release niacin/laropiprant combination: A post hoc analysis of a 24-week, placebo-controlled trial in dyslipidemic patients

BACKGROUND Dyslipidemia and high blood pressure are both major cardiovascular disease risk factors. Niacin is an effective lipid-altering agent that has been reported to reduce the risk of cardiovascular disease. However, the more widespread use of niacin is limited, mainly due to the occurrence of flushing. Laropiprant (LRPT) is a selective antagonist of prostaglandin D(2) receptor subtype 1 that reduces extended-release niacin (ERN)-induced flushing without affecting its beneficial lipid effects. While the lipid effects of ERN are well known, the blood pressure effects are unclear. OBJECTIVE The aim of this analysis was to examine the blood pressure effects of ERN and ERN/LRPT. METHODS This was a post hoc analysis of a 24-week, worldwide, multicenter, double-blind, randomized, placebo-controlled, parallel, Phase III, previously published study of dyslipidemic patients, which examined the effect of ERN and ERN/LRPT on systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS A total of 1613 men and women, aged 21 to 85 years, with primary hypercholesterolemia or mixed dyslipidemia (66% on statins), were included in the original analysis. ERN alone, or in combination with LRPT, was associated with significant reductions in SBP and DBP at 24 weeks from baseline. The placebo-adjusted mean changes from baseline at week 24 in SBP were -2.2 and -3.1 mm Hg for the ERN and ERN/LRPT groups, respectively (P < 0.05 and P < 0.001). Similar changes in DBP were observed; -2.7 and -2.5 mm Hg in the ERN and ERN/ LRPT groups, respectively (both, P < 0.001). CONCLUSION This post hoc analysis of a 24-week trial found that ERN alone, or in combination with LRPT, was associated with significant placebo-adjusted reductions from baseline in blood pressure in these hyperlipidemic hypertensive or normotensive subjects.

An oral selective M3 cholinergic receptor antagonist in COPD

Cholinergic antagonists have been used since the early 1900s as bronchodilators for chronic obstructive pulmonary disease (COPD). The present study investigated whether an oral muscarinic M3-selective anticholinergic agent (OrM3) would provide an improved therapeutic advantage compared with an inhaled anticholinergic agent in patients with COPD. A 6-week, multicentre, randomised, placebo- and active-controlled, parallel-group study was performed at 56 sites in the USA. In total, 412 male and female patients (aged 35–86 yrs) with a clinical history consistent with COPD were randomised to receive OrM3 0.5, 2, 3 or 4 mg orally once daily, ipratropium bromide 36 μg by inhalation four times daily or placebo. OrM3 demonstrated a significant dose-related improvement in serial forced expiratory volume in one second and a trend for dose-related improvement in patient-reported symptoms compared with placebo. However, at a dose that provided efficacy less than that of ipratropium, the incidence of dose-related, mechanism-based side-effects for OrM3 exceeded those observed for ipratropium. In patients with chronic obstructive pulmonary disease, the oral M3-selective agent did not offer a therapeutic advantage over inhaled ipratropium. These results do not support the hypothesis that high selectivity for muscarinic M3 receptors over airway neuronal M2 receptors will represent a more effective therapy than current inhaled anticholinergics in obstructive airway disease.

Expansion of the modified Zelen's approach randomization and dynamic randomization with partial block supplies at the centers to unequal allocation

Modified Zelens approach is a randomization technique useful in multi-center trials where balance in treatment assignments within a center is desired. It has great balancing properties in a study with equal allocation to several treatment arms. This technique can also be used in studies with unequal allocation, where it would provide an allocation ratio close to the targeted one within centers as well as across centers. However, the implementation of the modified Zelens approach for unequal allocation involves more than just imposing a constraint on within-center imbalance in treatment assignments, as is the case with equal allocation. Failure to account for this might provide a potential for accidental bias and (even in a double-blind study) selection and evaluation bias. The naive expansion of the modified Zelens approach to unequal allocation can also lead to a shift in the re-randomization distribution of the between-group difference in treatment means. This paper will explain why and will offer an easy way to expand the modified Zelens approach to unequal allocation that allows one to avoid these issues. The expansion to unequal allocation of another very useful in multi-center trials technique where partial blocks of supplies are sent to the centers will be offered.

Practical Considerations and Strategies for Executing Adaptive Clinical Trials

There is great potential for clinical trials designed with adaptive features to result in more efficient decision making within a drug development program. However, clinical trials with adaptive features are more complex to implement than traditional designs such as fixed-sample or group sequential. Workarounds and/or inefficiencies in adaptive design (AD) trial execution may result in human and material wastes. Further, they may result in the introduction of operational biases that may potentially negate any gains in designing an AD trial and may even render trial results not interpretable. In this article, we present and share our experience and best practices in AD trial implementation in the areas of resource planning, randomization considerations including the importance of randomization schemes on clinical supply, Interactive Voice Randomization System vendor capability assessment and quality control, clinical supply strategy considerations, enrollment management and patient enrollment modeling and simulation, data quality and interim analysis planning, managing blinding and unblinding, and the use of a data monitoring committee.

A Phase I/III, multicenter, open-label trial of talimogene laherparepvec (T-VEC) in combination with pembrolizumab for the treatment of unresected, stage IIIb-IV melanoma (MASTERKEY-265)

Meeting abstracts T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF, and stimulate antitumor immune responses. OPTiM, a Phase III trial of T-VEC vs GM-CSF in unresectable stage IIIB-IV melanoma, improved the primary endpoint