Josephine M. Norquist

Effects of Laropiprant on Nicotinic Acid-Induced Flushing in Patients With Dyslipidemia

Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D(2), which leads to poor patient compliance and suboptimal dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin D(2) receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)-induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n = 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n = 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients.

Methods for interpreting change over time in patient-reported outcome measures

PurposeInterpretation guidelines are needed for patient-reported outcome (PRO) measures’ change scores to evaluate efficacy of an intervention and to communicate PRO results to regulators, patients, physicians, and providers. The 2009 Food and Drug Administration (FDA) Guidance for Industry Patient-Reported Outcomes (PRO) Measures: Use in Medical Product Development to Support Labeling Claims (hereafter referred to as the final FDA PRO Guidance) provides some recommendations for the interpretation of change in PRO scores as evidence of treatment efficacy.MethodsThis article reviews the evolution of the methods and the terminology used to describe and aid in the communication of meaningful PRO change score thresholds.ResultsAnchor- and distribution-based methods have played important roles, and the FDA has recently stressed the importance of cross-sectional patient global assessments of concept as anchor-based methods for estimation of the responder definition, which describes an individual-level treatment benefit. The final FDA PRO Guidance proposes the cumulative distribution function (CDF) of responses as a useful method to depict the effect of treatments across the study population.ConclusionsWhile CDFs serve an important role, they should not be a replacement for the careful investigation of a PRO’s relevant responder definition using anchor-based methods and providing stakeholders with a relevant threshold for the interpretation of change over time.

One-year health-related quality of life outcomes in weight loss trial participants: comparison of three measures

BackgroundThe literature on changes in health-related quality of life (HRQOL) in weight loss studies is inconsistent, and few studies use more than one type of measure. The purpose of the current study was to compare one-year changes in HRQOL as a function of weight change using three different measures: a weight-related measure (Impact of Weight on Quality of Life-Lite [IWQOL-Lite)]) and two generic measures (SF-36; EQ-5D).MethodsData were obtained from 926 participants (mean Body Mass Index (BMI) (kg/m2) = 35.4; 84% female; mean age = 49.5 years) in a placebo-controlled randomized trial for weight loss. At baseline and one-year, participants completed all three HRQOL measures. HRQOL was compared across weight change categories (≥ 5% and 0–4.9% gain, 0–4.9%, 5.0–9.9% and ≥ 10% loss), using effect sizes.ResultsThe weight-related measure of HRQOL exhibited greater improvements with one-year weight loss than either of the generic instruments, with effect sizes ranging from 0.24 to 0.62 for 5–9.9% weight reductions and 0.44 to 0.95 for ≥ 10% reductions. IWQOL-Lite Self-Esteem also showed a small improvement with weight gain. Changes in the two generic measures of HRQOL were inconsistent with each other, and in the case of the SF-36, variable across domains. For participants gaining ≥ 5% of weight, the greatest reductions in HRQOL occurred with respect to SF-36 Mental Health, MCS, and Vitality, with effect sizes of -0.82, -0.70, and -0.63 respectively.ConclusionThis study found differences between weight-related and generic measures of health-related quality of life in a one-year weight loss trial, reflecting the potential value of using more than one measure in a trial. Although weight loss was generally associated with improved IWQOL-Lite, physical SF-36 subscale and EQ-5D scores, a small amount of weight gain was associated with a slight improvement on weight-specific HRQOL and almost no change on the EQ-5D, suggesting the need for further research to more fully study these relationships. We believe our findings have relevance for weight loss patients and obesity clinicians/researchers in informing them of likely HRQOL outcomes associated with varying amounts of weight loss or gain.

Serum Urate During Acute Gout

Objective. To study the frequency of normal serum urate (SU) levels during acute gout in the largest studies of acute gout treatment to date. Methods. Data collected from 2 randomized controlled clinical trials assessing the efficacy of etoricoxib or indomethacin for 7 days in acute gout were used to assess SU levels during acute gouty attacks. Efficacy was similar with both agents, so both groups were combined for analysis. Results. A total of 339 patients were enrolled in the 2 studies; 94% were male; mean age was 50.5 years. At baseline, 14% of patients had a “true” normal SU (≤ 6 mg/dl) and 32% had SU ≤ 8 mg/dl during acute gout. Baseline mean SU was 7.1 versus 8.5 mg/dl (p < 0.001) in those taking allopurinol versus nonusers. Patients taking chronic allopurinol were more likely to have lower SU at baseline compared to those not taking chronic allopurinol (p < 0.001) during the acute attack. Conclusion. A normal SU level at presentation does not exclude an acute gouty attack. In the largest studies of acute gout to date, attacks still occurred despite SU levels being below 6.8 mg/dl, the saturation level for urate. This may be attributed to persistence of tophi and an increased body uric acid pool. Additional studies are needed to determine the correlation between SU and the body uric acid pool as well as the relationship to timing of changes during acute gout.

Validation of a questionnaire to assess niacin-induced cutaneous flushing

ABSTRACT Background: Niacin is currently the most effective approved agent for raising high-density lipoprotein cholesterol. However, niacin-induced cutaneous flushing (redness, warmth, tingling and/or itching) significantly limits patient acceptance. To further characterize flushing, a patient-reported Flushing Symptom Questionnaire* (FSQ) was developed and validated. Methods: The FSQ was validated in an 8‑week, randomized, double-blind, placebo-controlled trial of extended-release (ER) niacin and placebo. The primary flushing endpoint of the study was based on the single Global Flushing Severity Score (GFSS), an item within the FSQ, which assesses overall flushing severity on a 0–10 discretized analog scale. Results: A total of 175 patients were randomized to one of four treatment groups (sequences of placebo and ER niacin [given as niacin (NIASPAN) 1 g (N1) and 2 g (N2)]. Test–retest reliability and reproducibility coefficients for the single-item GFSS were all above 0.75. Construct validity was supported by moderate to strong correlations (r > 0.5) with other FSQ items. All FSQ item scores and specifically the GFSS discriminated between treatment groups and demonstrated expected relationships with predefined known groups. The GFSS demonstrated high responsiveness in patients who switched from ER niacin to placebo. The ability of the GFSS and GFBS to discriminate changes in flushing symptoms in patients who increased drug dose was less than expected possibly due to accommodation to the flushing effects of niacin over time; differential drop-out due to flushing; and/or FSQ items not being sensitive enough to detect a change that was present. Conclusions: The FSQ items and specifically the Global Flushing Severity Score (GFSS), are reliable and valid measures to assess niacin-induced flushing.

Choice of recall period for patient-reported outcome (PRO) measures: criteria for consideration

PurposeUnderstand the choice of recall period for PRO measures based on intended use, characteristics of the disease, treatment, and attributes of studies.MethodsCurrent practice and considerations were reviewed within several disease areas (overactive bladder, menopausal hot flashes, niacin-induced flushing, osteoarthritis pain, irritable bowel symptoms, benign prostatic hyperplasia, and alopecia).ResultsRationales were identified for using different recall periods, including event-driven (immediate), daily, up to weekly, and longer than weekly. This work demonstrates that (1) recall depends on what the PRO measure captures, its intended use, and attributes of the disease and study; (2) within the same disease area, recall can vary depending on the concept or phenomenon of interest; (3) recall must consider patient burden and their ability to easily and accurately recall the information requested; and (4) recall must be consistent with the duration of the trial and the scheduled clinic visits.ConclusionsShorter recall periods may underestimate symptom burden when symptoms have diurnal or day-to-day fluctuation and may place undue burden on patients. On the other hand, recall intervals that are too long may either over- or underestimate the health state. Therefore, appropriate criteria should be considered given attributes of the disease when selecting an adequate recall period.

Development and Validation of the Influenza Intensity and Impact Questionnaire (FluiiQ

OBJECTIVE Clinical trials of new agents to reduce the severity and impact of influenza require accurate assessment of the effect of influenza infection. Because there are limited high-quality adult influenza Patient Reported Outcomes (PRO) measures, the aim was to develop and validate a simple but comprehensive questionnaire for epidemiological research and clinical trials. METHODS Construct and item generation was guided by the literature, concept mapping, focus groups, and interviews with individuals with laboratory-confirmed influenza and expert physicians. Items were administered to 311 people with influenza-like illness (ILI) across 25 US sites. Analyses included classic psychometrics, structural equation modeling (SEM), and Rasch analyses. RESULTS Concept mapping generated 149 concepts covering the influenza experience and clustered into symptoms and impact on daily activities, emotions, and others. Items were drafted using simplicity and brevity criteria. Eleven symptoms from the literature underwent review by physicians and patients, and two were removed and one added. The symptoms domain factored into systemic and respiratory symptoms, whereas the impact domains were unidimensional. All domains displayed good internal consistency (Cronbach α ≥ 0.8) except the three-item respiratory domain (α = 0.48). A five-factor SEM indicated excellent fit where systemic, respiratory, and daily activities domains differentiated patients with ILI or confirmed influenza. All scales were responsive over time. CONCLUSIONS Patient and clinician consultations resulted in an influenza PRO measure with high validity and good overall evidence of reliability and responsiveness. The Influenza Intensity and Impact Questionnaire (FluiiQ™) will improve the evaluation of existing and future agents designed to prevent or control influenza infection by increasing the breadth and depth of measurement in this field.

Measuring flushing symptoms with extended‐release niacin using the flushing symptom questionnaire©: results from a randomised placebo‐controlled clinical trial

Introduction:  Niacin is underutilised because of flushing. Lack of a quantitative tool to assess niacin‐induced flushing has precluded the objective evaluation of flushing associated with extended‐release (ER) niacin formulations. We developed the Flushing Symptom Questionnaire© (FSQ), a quantitative tool to assess patient‐reported flushing, and assessed its ability to characterise ER niacin‐induced flushing.

Key Concepts of Migraine Postdrome: A Qualitative Study to Develop a Post‐Migraine Questionnaire

(Headache 2011;51:105‐117)

The association of flushing bother, impact, treatment satisfaction and discontinuation of niacin therapy

Niacin has lipid‐modifying efficacy and cardiovascular benefit, but is underutilised because of niacin‐induced flushing (NIF). This real‐world, prospective, observational study characterised the severity and impact of NIF symptoms among participants who were newly prescribed extended‐release (ER) niacin.