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Increased interest in real-world evidence (RWE) for clinical and regulatory decision making and the need to evaluate long-term benefits and risks of pharmaceutical products raise the importance of understanding the use of external controls (ECs) for uncontrolled extensions of randomized controlled trials (RCTs). We searched clinicaltrials.gov from 2009 to 2019 for uncontrolled extensions and assessed the use of ECs in the trial protocol registry and PubMed. We present characteristics of identified uncontrolled extensions, their adoption of ECs, and a qualitative appraisal of published uncontrolled extensions with ECs according to good pharmacoepidemiologic practice. The number of uncontrolled extensions increased slightly across the study period, resulting in a total of 1,115 studies. Most originated from phase III RCTs (62.2%) and specified safety outcomes (61.9% among those with specified outcomes). Most uncontrolled extensions incorporated no control group with only 7 out of 1,115 (0.6%) employing ECs. For those studies with ECs, all involved treatments for rare conditions and assessment of effectiveness. Attempts to balance comparison groups varied from none mentioned to propensity score matching. We noted consistent deficiencies in outcome ascertainment methods and approaches to address attrition bias. The contrast of the large and growing number of uncontrolled extensions with the small number of studies that utilized ECs showed clear opportunities for enhancement in design, measurement, and analysis of uncontrolled extensions to allow causal inferences on long-term treatment effects. As extensions continue to expand within RWE regulatory frameworks, development of guidelines for use of EC with uncontrolled extensions is needed.

Purpose Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long‐term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness. Methods We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps. Results Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences. Conclusion This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.

Purpose Given current efforts to enhance patient-centered care and shared decision-making, the International Society of Pharmacoepidemiology Workgroup on Patient Engagement assessed patient and other stakeholder engagement in pharmacoepidemiology research and provides recommendations for the field. Methods A systematic review used MEDLINE and EMBASE to identify published literature from 2005 to 2016 addressing how stakeholders-patients, caregivers, and others-assisted researchers conducting pharmacoepidemiologic research. Three pairs of Workgroup members screened titles and abstracts to select articles for full-text review and analysis. Two Workgroup members abstracted the following data: research focus, characterization and role of stakeholders, and type(s) of engagement strategy employed. Data were summarized descriptively. Results We identified 5717 references for abstract screening. Of these, 69 met the criteria for full-text screening, and 11 were selected for data abstraction. Of these 11 studies, seven focused on the development of a research agenda and eight had stakeholders react or advise on an aspect of the study. Although patients were the most commonly identified stakeholders, advocacy groups and health care professionals were also frequently identified. Some studies reported the engagement of other stakeholders, including local government or policy experts. Engagement strategies varied, with five studies using more than one strategy. Studies often did not indicate the involvement of stakeholders in developing the study design or with implementation. Conclusions Currently, few pharmacoepidemiology publications mention patient or other stakeholder engagement in the design, analysis, or reporting of research. This suggests that there are opportunities to expand stakeholder engagement and/or increase the transparency of reporting stakeholder engagement.

Objectives: Although the relationship between migraine and cardiovascular disease (CVD) has been studied, several questions remain unanswered. Herein we contrast the rate of diagnosed CVD as well as of risk factors for CVD in individuals with migraine with and without aura (MA and MO) and in controls. Methods: In this case-control study, migraineurs (n = 6,102) and controls (n = 5,243) were representative of the adult US population. Headache diagnosis was formally assigned using a validated mailed questionnaire which also obtained details on treatment, comorbidities, and other variables. CVD events were obtained based on self-reported medical diagnosis. Risk factors for CVD and modified Framingham scores were computed. Results: In unadjusted analyses, migraine overall and MA were associated with myocardial infarction, stroke, and claudication, and MO was associated with myocardial infarction and claudication. Migraineurs were more likely than controls to have a medical diagnosis of diabetes (12.6% vs 9.4%, odds ratio [OR] 1.4, 95% confidence interval [CI] 1.2–1.6), hypertension (33.1% vs 27.5%, OR 1.4, 95% CI 1.3–1.6), and high cholesterol (32.7% vs 25.6%, OR 1.4, 95% CI 1.3–1.5). Risk was highest in MA, but remained elevated in MO. Framingham scores were significantly higher in MO and MA than in controls. After adjustments (gender, age, disability, treatment, CVD risk factors), migraine remained significantly associated with myocardial infarction (OR 2.2, 95% CI 1.7–2.8), stroke (OR 1.5, 95% CI 1.2–2.1), and claudication (OR 2.69, 95% CI 1.98–3.23). Conclusion: Both migraine with and without aura are associated with cardiovascular disease (CVD) and with risk factors for CVD. However, since our sample size is large, the clinical relevance of the differences is yet to be established.

Background The Safety Planning, Evaluation and Reporting Team (SPERT) was formed in 2006 by the Pharmaceutical Research and Manufacturers of America. Purpose SPERT’s goal was to propose a pharmaceutical industry standard for safety planning, data collection, evaluation, and reporting, beginning with planning first-in-human studies and continuing through the planning of the post-product-approval period. Methods SPERT’s recommendations are based on our review of relevant literature and on consensus reached in our discussions. Results An important recommendation is that sponsors create a Program Safety Analysis Plan early in development. We also give recommendations for the planning of repeated, cumulative meta-analyses of the safety data obtained from the studies conducted within the development program. These include clear definitions of adverse events of special interest and standardization of many aspects of data collection and study design. We describe a 3-tier system for signal detection and analysis of adverse events and highlight proposals for reducing "false positive" safety findings. We recommend that sponsors review the aggregated safety data on a regular and ongoing basis throughout the development program, rather than waiting until the time of submission. Limitations We recognize that there may be other valid approaches. Conclusions The proactive approach we advocate has the potential to benefit patients and health care providers by providing more comprehensive safety information at the time of new product marketing and beyond. Clinical Trials 2009; 6: 430—440. http://ctj.sagepub.com

Migraine, especially migraine with aura (MA), is an established risk factor for ischemic lesions of the brain. Recent evidence has also linked migraine to a broader range of ischemic vascular disorders including angina, myocardial infarction, coronary revascularization, claudication, and cardiovascular mortality. The mechanisms which link migraine to ischemic vascular disease remain uncertain and are likely to be complex. Cortical spreading depression, the presumed substrate of aura, may directly predispose to brain lesions and that would explain why MA is consistently demonstrated as a risk factor for cerebral ischemia, while for migraine without aura (MO), the evidence is less consistent. Additionally, individuals with migraine have a higher prevalence of risk factors known to be associated with cardiovascular disease (CVD), including hypertension, diabetes, and hyperlipidemia. The increased prevalence of CVD risk factors is also higher for MA than for MO. Since the evidence linking migraine and CVD is getting robust, neurologists should be aware of this association. Individuals with MO seem to be at little increased risk of CVD. MA is associated with an increased risk of ischemic stroke and likely also for other ischemic CVD events. Accordingly, heightened vigilance is recommended for modifiable cardiovascular risk factors in migraineurs, especially with MA. Ultimately, it will be important to determine whether MA is a modifiable risk factor for CVD and if preventive medications for migraine or antiplatelet therapy might reduce the risk of CVD in patients with MA.

This article deals with the incorporation of patient-reported outcomes (PROs) into clinical trials and focuses on issues associated with the interpretation and reporting of PRO data. The primary focus and context of this information relates to the evidentiary support and reporting for a labeling or advertising claim of a PRO benefit for a new or approved pharmaceutical product. This manuscript focuses on issues associated with assessing clinical significance and common pitfalls to avoid in presenting results related to PROs. Specifically, the questions addressed by this manuscript involve: What are the best methods to assess clinical significance for PROs? How should investigators present PRO data most effectively in a Food and Drug Administration (FDA) application? In labeling or in a scientific publication? Guidelinesfor interpreting clinical significance of PROs and for comprehensively reporting on the methods, measures and results of clinical trials that incorporate PROs are important for clinicians, regulatory agencies, and most of all to patients. Clear specifications for considering a finding on a PRO measure, as clinically meaningful, need to be determined by instrument developers and psychometricians; they need to be reported for all clinical trials involving PRO end points. Clinical trial reports need to be comprehensive, clear, and sufficient to enable any reader to understand the methods, PRO measures, statistical analysis, and results.

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.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.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 2g (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 (r0.5) 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.The FSQ items and specifically the Global Flushing Severity Score (GFSS), are reliable and valid measures to assess niacin-induced flushing.

Background Nighttime problems constitute a significant burden on the quality of life of patients with seasonal allergic rhinitis (SAR). The aim of this study was to evaluate the effectiveness of montelukast on nighttime AR symptoms. Methods In seven multicenter, double-blind, parallel-group trials, nighttime problems were assessed as the nighttime symptoms score (NSS), an average of three individual symptom scores: difficulty going to sleep, nighttime awakening, and nasal congestion on awakening (each rated 0 = none to 3 = severe). Patients (aged 15–82 years) were randomized to receive montelukast, 10 mg (n = 1751), placebo (n = 1557), or the positive control loratadine, 10 mg (n = 1616). Results In a combined analysis, changes from baseline (mean ± SE) in NSS were -0.28 ± 0.01, -0.16 ± 0.01, and —0.24 ± 0.01 for the montelukast, placebo, and loratadine groups, respectively. Difference versus placebo in least-squares mean change from baseline were —0.11 (95% confidence interval, -0.14, -0.08; p ≤ 0.001) for montelukast and -0.09 (-0.12, -0.06; p ≤ 0.001) for loratadine. Strong baseline correlations (R > 0.70; p < 0.001) of NSS and two of its individual symptoms with the sleep domain of the validated Rhinoconjunctivitis Quality of Life Questionnaire support the validity and importance of measuring nighttime morbidity in SAR. Furthermore, a clinically important benefit of montelukast on the nighttime impact of SAR was shown using an analysis anchored on the Patient's Global Evaluation. Conclusion These data underscore the importance of nighttime problems in patients with SAR and the need to treat nighttime symptoms. In these studies, montelukast significantly improved the NSS, a clinically relevant and valid measure in patients with SAR.

Acute respiratory syncytial virus (RSV)-induced bronchiolitis is often associated with continuing respiratory symptoms following hospitalization. To date, there is no validated objective measure to evaluate symptoms of RSV-induced bronchiolitis. We report on the reliability, validity, and responsiveness of the bronchiolitis caregiver diary (BCD) of symptoms and healthcare utilization associated with postacute RSV. The BCD measures four symptoms (daytime cough, wheeze, trouble breathing, and nighttime cough), healthcare utilization, and rescue medication for worsening of lung symptoms. Data from the 4-week treatment period of the reported prospective, placebo-controlled trial of montelukast for treatment of postacute RSV were used to assess reliability (internal consistency and test-retest), construct validity (cross-sectional and longitudinal correlations), discriminant validity (known-groups analyses), and responsiveness. The primary outcome of this study was the percentage of symptom-free days (SFD). The secondary outcome was a composite symptom score (CSS; average of daytime cough, wheezing, and trouble breathing). Cronbach's alpha of 0.85 indicated that the four symptoms were internally consistent, supporting a unidimensional scale structure. Test-retest reliabilities for the percentage of SFD and CSS were above the recommended cut point of 0.70. Cross-sectional and longitudinal correlations were sizeable and statistically significant, demonstrating construct validity. Hypothesized known-group differences were statistically significant in the appropriate direction. Responsiveness analyses indicated moderate effect sizes for percentage of SFD. In conclusion, the BCD provides a valid, reliable, and responsive tool for the assessment of symptoms of postacute RSV-induced bronchiolitis, capable of measuring moderate effect sizes, and demonstrating responsiveness to therapy.

To compare the effects of rizatriptan and patients’ usual migraine medication(s) on health-related quality of life. The study was a non-blinded, parallel-group, extension trial in which patients who had completed a randomised, placebo-controlled trial of the treatment of migraine with rizatriptan at 23 study sites in the United States were randomly assigned in a 4: 1 ratio either to rizatriptan or to standard care. 265 migraineurs, 18 to 65 years of age. Patients received either rizatriptan 10mg or their usual migraine medication(s). The main outcome measures were: (a) migraine-specific quality of life during the 24-hour period of an attack, as determined by the 24-Hour Migraine-Specific Quality-of-Life Questionnaire (24-HrMQoLQ), for attacks in the first month; (b) general health-related quality of life as determined by the eight domain scores and the Mental and Physical Component Scales of the Short Form Health Survey (SF-36) after 2, 6 and 12 months. The 24-HrMQoLQ domains were scored from 3 to 21, and the SF-36 from 0 to 100, higher scores indicating better performance for both instruments. Patients receiving rizatriptan had significantly better scores in all five domains of the 24-HrMQoLQ compared with patients receiving standard care. Mean scores (standard error) for the rizatriptan and usual care groups were, respectively: Work Functioning, 13.9 (0.4), 12.5 (0.8), p = 0.05; Social Functioning, 13.6 (0.4), 11.8 (0.8), p = 0.015; Energy/Vitality, 13.7 (0.5), 11.6 (0.8), p < 0.01; Feelings/Concerns 13.3 (0.4), 10.6 (0.8), p < 0.001; and Migraine Symptoms 14.1 (0.4), 12.1 (0.7), p < 0.01. There was a trend for patients receiving rizatriptan to have higher scores on the Mental Component Scale of the SF-36: mean score (SE) 50.3 (0.6) for rizatriptan, 48.0 (1.1) for usual care, p = 0.068. There was no difference between the treatment groups in the Physical Component Scale: mean score (SE) 48.4 (0.6) for rizatriptan, 49.7 (1.1) for usual care, p = 0.202. Quality of life in the 24-hour period following a migraine attack was better in patients treated with rizatriptan 10mg than in patients treated with their usual migraine medication.

Determinants of patient satisfaction with migraine treatment are not well understood. The objective of this study was to evaluate which treatment outcomes influence patient satisfaction with treatment. Analyses were performed on data from 1506 migraineurs from two clinical trials of rizatriptan for treatment of migraine. Satisfaction with treatment was assessed 2 h after initial treatment and prior to use of rescue therapy. Over 90% of patients who were pain-free at 2 h were at least somewhat satisfied with treatment compared with < 10% of patients with moderate or severe pain. Only 60–70% of patients with mild pain at 2 h experienced some level of satisfaction with treatment. For patients with mild pain at 2 h, results showed subjects who reported severe pain at baseline, absence of associated symptoms at 2 h and pain relief within the first 90 min had at least a 76% probability of being at least somewhat satisfied. This probability decreased with the presence of associated symptoms, slower pain relief and moderate baseline pain intensity. Fast, complete pain relief is one important factor in determining short-term patient satisfaction with treatment.

Migraine symptoms and therapy side effects cause significant functional disability that can result in work and productivity losses. Effective, well-tolerated migraine therapy with rapid onset of relief could decrease work and productivity losses. The Migraine Work and Productivity Loss Questionnaire (MWPLQ) evaluates the impact of migraine and migraine therapy on paid work. Data from a randomized, open-label extension study were collected over 3 months. Migraineurs were randomized to either rizatriptan (5HT1B/1D receptor agonist) or their usual migraine therapy. Data were analyzed from 164 patients who experienced at least one work-related migraine. Internal consistency (Cronbach's α) for the work difficulty domains ranged from 0.80 to 0.95. Work loss and work difficulty were moderately correlated ( r=0.39-0.58) with migraine severity and functional ability. Differences were found favoring rizatriptan for absenteeism (1.3 vs 2.4 h), effectiveness at work (62% vs 49%), and difficulty with work-related tasks ( p < 0.01). The MWPLQ demonstrated favorable measurement characteristics in this study and could be an important research tool for future evaluations of migraine-related work disability.

OBJECTIVE The Pediatric Asthma Diary was developed and validated to assess efficacy of interventions in children with asthma. DESIGN, PATIENTS, AND SETTING Diary validation was performed in a three week, prospective study of 106 children aged 6–14 years with asthma. Children were classified at baseline as either stable (requiring no additional asthma treatment) or new onset/worse (requiring either addition of or increase in anti-inflammatory treatment). RESULTS A daytime symptom scale and “day without asthma” were defined from diary questions. Both measures demonstrated significant validity and responsiveness to anti-inflammatory treatment. The stable group experienced a higher percentage of days without asthma during week 1 compared with the new onset/worse group (39.6% v 11.6%, respectively). The new onset/worse patients experienced significant improvement in days without asthma (24.5%) compared with stable patients (6.4%). CONCLUSIONS The Pediatric Asthma Diary daytime symptom scale and day without asthma are acceptable measures for use in asthma intervention studies of children aged 6–14 years.

Our objectives were to: (1) develop a self-report questionnaire for measuring the impact of migraine headache on work; and (2) qualitatively assess aspects of its performance. Two samples of migraine sufferers provided the data. Sample 1 (n = 18) participated in a structured discussion group designed to elicit examples of migraine's on-the-job impact. Sample 2 (n = 11) completed a mail survey and participated in in-depth phone interviews. Interviews addressed item comprehensibility, consistency of interpretation, the cognitive processes by which certain answers were generated and response burden. The participants were currently employed men and women, at least 18 years of age, who met the International Headache Society (IHS) criteria for migraine headache [1]. Discussion group participants indicated that migraine attacks substantially diminished their job performance. Pain, photophobia, phonophobia, mental impairment and fatigue were perceived as interfering with even routine or relatively simple job tasks. The Migraine Work and Productivity Loss Questionnaire, Version 1.0© (MWPLQ©)* was written. Next, it was assessed in the context of the in-depth interviews. Result indicated that the MWPLQ was comprehended without difficulty, interpreted consistently and easy to complete. Thus, qualitative results provide initial support for the new questionnaire.

A validated migraine-specific questionnaire (24-h Migraine Quality of Life Questionnaire1: 24-h MQoLQ) was used to assess the impact of migraine and migraine therapy on health related quality of life during an acute migraine attack. Male and female migraineurs aged 18-55 years were randomized to placebo ( n = 41), rizatriptan 2.5 mg ( n = 47), 5 mg ( n = 74), or 10 mg ( n = 85) in a triple-blind, placebo-controlled clinical trial. Rizatriptan 5 mg and 10 mg were significantly more efficacious than placebo on pain relief and functional disability. After accounting, for multiple comparisons to placebo, rizatriptan 10 mg showed significantly better responses compared to placebo on three of five domains of 24-h MQoLQ (social functioning, migraine symptoms, and feelings/concerns). The O'Brien's Rank Sum Test statistic showed a statistically significant overall difference on the 24-h MQoLQ between the 10 mg rizatriptan and placebo groups ( p = 0.005) and for the overall close trend ( p 0.001).

This multicenter study compared the effects of lovastatin (40 mg) and pravastatin (40 mg) on quality of life. Men, aged 20 to 65 years old, with primary hypercholesterolemia (types IIa and IIb) were eligible for enrollment if baseline low-density lipoprotein cholesterol met the first National Cholesterol Education Program adult treatment guidelines. Eligible patients were enrolled into a 6-week diet baseline period, followed by a 6-week diet-plus-placebo period. Patients whose low-density lipoprotein cholesterol still met National Cholesterol Education Program guidelines for drug therapy were randomized into the double-blind, active-treatment period to receive either lovastatin 40 mg or pravastatin 40 mg/day for 12 weeks. Clinic visits were scheduled every 4 weeks and included complete serum lipid profiles, monitoring of adverse experiences, and patient completion of health-related quality-of-life questionnaires. The primary end point of the study was the change in quality of life, as measured by the Nottingham Health Profile (part 1) after 12 weeks of treatment. Secondary end points included responses to a general health question from the National Health and Nutrition Examination Survey, sexual function questions from the Medical Outcomes Study, and stress/life event questions from the National Institutes of Health Post-Coronary Artery Bypass Grafting Study. No significant differences between the 2 groups were observed in tolerability, health-related quality-of-life measures, or changes in lipid profiles.

Understand the choice of recall period for PRO measures based on intended use, characteristics of the disease, treatment, and attributes of studies.Current 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).Rationales 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.Shorter 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.

Although randomized controlled trials (RCTs) are the gold standard for assessing efficacy of a drug intervention, because they are conducted in a highly selected group of patients, they do not necessarily reflect normal customary or optimized patient care. Accordingly, information from RCTs must be supplemented by outcomes research and by nonexperimental or quasi-experimental study designs. Herein, we discuss information that supplements the rigorous but sometimes rigid nature of RCTs in an effort to better understand the clinical utility of drug treatment for migraine with patient-centered outcomes in mind. We start by discussing several lessons we learned from RCTs on comparative triptan studies, followed by presenting data on outcomes studies for rizatriptan. We then briefly discuss migraine treatment behavior issues, including early treatment and adherence to treatment.

This article is part of a series of manuscripts dealing with the incorporation of patient-reported outcomes (PROs) into clinical trials. The issues dealt with in this manuscript concern the common pitfalls to avoid in statistical analysis and interpretation of PROs. Specifically, the questions addressed by this manuscript involve the analysis pitfalls with PRO data in clinical trials and how can they be avoided (e.g.,missing data, multiplicity, null results etc.). The manuscript provides key literature for existing resources and proposes new guidelines.

The aim of this study was to validate the nighttime symptoms score (NSS), which incorporates individual scores for difficulty going to sleep and nighttime awakening caused by nasal symptoms and nasal congestion on awakening, as a clinically relevant measure of allergic rhinitis (AR). Fifty-five general season AR (SAR) symptom items were generated by interviews with 14 patients with symptomatic SAR without concomitant asthma for use in an Importance Rating Questionnaire (IRQ). A second group of patients (n = 83) with symptomatic AR without asthma rated the importance of each item on the IRQ. Correlation coefficients were calculated to examine the relationships between the six sleep quality questions on the IRQ and the other AR symptoms and between the symptom questions of the NSS, the Daytime Nasal Symptoms Score (DNSS), and the individual domains of the Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ). The majority (94%) of patients with active AR reported some degree of symptoms relating to sleep quality. The six sleep quality items on the IRQ were selected by 71-84% of patients. The sleep quality items were more highly correlated with each other (r = 0.48-0.85) than with the four items of the DNSS (r = 0.01-0.42). There was a moderate-to-strong correlation of the RQLQ sleep domain with the two sleep questions of the NSS (r = 0.44-0.57). The individual symptom questions of the NSS and the DNSS were only moderately correlated with each other. Sleep quality questions measure aspects of SAR that are not captured by daytime SAR symptoms. The results show that the NSS is a valid and relevant clinical measure of the impact of nighttime sleep disturbance on AR patients.

Nighttime problems constitute a significant burden on the quality of life of patients with seasonal allergic rhinitis (SAR). The aim of this study was to evaluate the effectiveness of montelukast on nighttime AR symptoms.In seven multicenter, double-blind, parallel-group trials, nighttime problems were assessed as the nighttime symptoms score (NSS), an average of three individual symptom scores: difficulty going to sleep, nighttime awakening, and nasal congestion on awakening (each rated 0 = none to 3 = severe). Patients (aged 15-82 years) were randomized to receive montelukast, 10 mg (n = 1751), placebo (n = 1557), or the positive control loratadine, 10 mg (n = 1616).In a combined analysis, changes from baseline (mean +/- SE) in NSS were -0.28 +/- 0.01, -0.16 +/- 0.01, and -0.24 +/- 0.01 for the montelukast, placebo, and loratadine groups, respectively. Difference versus placebo in least-squares mean change from baseline were -0.11 (95% confidence interval, -0.14, -0.08; por = 0.001) for montelukast and -0.09 (-0.12, -0.06; por = 0.001) for loratadine. Strong baseline correlations (R0.70; p0.001) of NSS and two of its individual symptoms with the sleep domain of the validated Rhinoconjunctivitis Quality of Life Questionnaire support the validity and importance of measuring nighttime morbidity in SAR. Furthermore, a clinically important benefit of montelukast on the nighttime impact of SAR was shown using an analysis anchored on the Patient's Global Evaluation.These data underscore the importance of nighttime problems in patients with SAR and the need to treat nighttime symptoms. In these studies, montelukast significantly improved the NSS, a clinically relevant and valid measure in patients with SAR.

Background: Limited clinical data are available on the long-term effects of asthma controller therapy on the utilization of health care resources in pediatric patients with asthma. Objective: The objective of this study was to compare the effects of long-term treatment with montelukast andusual care on health care resource use in children with asthma. Methods: Pediatric patients aged 2 to 5 years with asthma who had completed a 3-month, double-blind, double-dummyclinical trial comparing montelukast 4 mg and placebo were asked to participate in an open-label, controlled extension study comparing montelukast 4 mg and usual care. Usual care was defined as cromolyn or inhaled corticosteroid therapy Health care resource utilization was measured in terms of oral corticosteroid use and numbers of physician visits, emergency department visits, and hospitalizations. Results: Of 618 patients who completed the primary phase of the study, 516 (83.5%) participated in the extension study Data from 506 patients (302 without previous asthma maintenance therapy, 204 with) were included in the analysis. During the extension phase, patients who received montelukast and had not used previous asthma maintenance therapy were followed for a mean of 329.5 days; those who received usual care and Conclusion: In this open-label study, pediatric patients aged 2 to 5 years with mild to moderate persistentasthma receiving long-term therapy with montelukast had similar rates of asthma-related health care resource utilization compared with those receiving usual care with cromolyn or inhaled corticosteroids.

Failure to use asthma controller medications as prescribed is associated with more asthma-related adverse events. Medication utilization may vary with ease of drug administration, efficacy, and tolerability as well as other factors. We hypothesized that in usual-care clinical practice settings, there would be greater adherence to oral controller than to inhaled controller asthma medications.We compared adherence to newly initiated asthma controller therapy among patients initiating monotherapy with leukotriene receptor antagonists (LTRAs), inhaled corticosteroids (ICS), or inhaled long-acting beta-agonists (ILBA) from March 1998 to July 1999. We measured adherence as the sum of drug supply days between first and last fill dates divided by length of drug therapy. Analyses were stratified by the number of short-acting beta-agonists (SBA) prescriptions per year to control for disease severity.Pharmacy claims data from 48,751 subjects (6 to 55 years) were analyzed (mean age 30.4 years; 56% female). Mean adherence to new start monotherapy on LTRA was 67.7%, to ICS was 33.8%, and to ILBA was 40.0%. Adherence to all three controller agents increased with increasing SBA use. The percent of patients persistent to asthma controller monotherapy at both 6 and 9 months was significantly greater among those on LTRA monotherapy than on either ICS or ILBA.In clinical practice settings, patients initiating LTRA monotherapy have about twice the adherence as patients initiating ICS or ILBA monotherapy. Because adherence to treatment is a critical component of treatment response, it is important to consider this factor in the prescription of oral vs. inhaled asthma medications.

We compared measures of treatment effectiveness when inhaled corticosteroids (ICSs) or leukotriene modifiers (LMs) were used as controller monotherapy for asthma. Asthma patients aged 6-55 years initiating ICS or LM monotherapy between July 1998 and June 1999 (index prescription) were identified using a managed care claims database. Asthma-related hospitalizations, emergency department (ED) visits, and use of short-acting beta-agonists and oral corticosteroids (OCSs) were assessed as proxies for treatment effectiveness. Propensity score was used to adjust for baseline differences between treatment cohorts. The change in the annual rate of claims from the preindex to postindex period for each measure was compared across treatment groups. Logistic regression models of the postindex composite events (hospitalization and/or ED) and OCS use were estimated. Nine hundred sixty patients were initiated on LMs (n = 153) and ICSs (n = 807). The mean annual rate of claims for OCSs increased in the ICS group (0.2) but was unchanged in the LM group (adjusted mean difference in change, 0.2; 95% CI, 0.05-0.4; p = 0.01). The mean annual rate of claims for short-acting beta-agonists increased in both the ICS and LM groups by 1.1 and 0.5, respectively (adjusted mean difference in change, 0.6; 95% CI, -0.06. 1.1; p = 0.08). Similar changes in annualized rates of claims for hospitalizations and ED visits were observed between treatment groups. In logistic regression models, greater odds of postindex OCS use was observed among the ICS group (odds ratio for ICS versus LM = 1.7; 95% CI, 1.04-2.8; p = 0.04). No association between treatment groups and postindex hospitalization and/or ED events was observed. In this managed care population, patients treated with ICSs or LMs had similar measures of treatment effectiveness, as measured by asthma-related health care resource use.

This paper reports an analysis of two randomized controlled trials of rizatriptan, in which the 24-h Migraine Quality of Life Questionnaire© was used to assess migraine-specific quality of life in patients receiving acute treatment. The objective of the analysis was to determine which clinical effects of a migraine medication, as measured by traditional clinical trial endpoints, contribute to a better short-term health-related quality of life. The results demonstrate that patients who experience complete pain relief and are able to function at their normal ability within 2 h and experience no headache recurrence have the highest migraine-specific quality of life scores. Patients who were satisfied with medication at 2 h had higher migraine-specific quality of life scores than those who were not satisfied. In conclusion, migraine therapy that provides rapid, complete, and sustained pain relief, with restoration of functional ability, has the most beneficial impact on short-term health-related quality of life for migraineurs.

Introduction Health-related quality-of-life (HRQL) can be defined as the impact of disease and treatment across the physical, psychological, social and somatic domains of functioning and well-being. Health-related quality-of-life measures are included in clinical trials of drug treatment to assess the impact of therapy on the patient's functioning. HRQL guidance could allow for use of this data in drug labeling and promotion. Objectives The aim of our study was to provide recommendations with respect to regulatory issues important to the development of guidelines for HRQL research. Methods The HRQL workshop was planned jointly by members of the Pharmaceutical Research and Manufacturers of America Health Outcomes Committee and the Division of Drug Marketing, Advertising, and Communications of the Food and Drug Administration. The workshop was limited to six regulatory issues related to HRQL research in clinical trials of pharmaceutical therapies. These six issues were: instrument selection and validation, study design, data analysis, HRQL and safety, clinical meaning, and promotional use. Before the meeting, a consensus was reached that HRQL does not measure, nor should it be used to measure, safety. Therefore, five work groups discussed HRQL issues and made recommendations. Results Overall, the workshop recommended that HRQL measures be treated as any other clinical end point. The workshop recognized that research in HRQL methods is ongoing and that any guidance should be flexible to allow for changes in this developing research area. Conclusions HRQL provides a patient perspective on the impact of disease and therapy on patients' daily life and functioning. Including HRQL information in promotion could be beneficial to decision making on the use of therapies. HRQL is a measure of effectiveness, not safety, and should be treated as any other clinical end point.

Objective.—To compare the proportion of patients who prefer rizatriptan orally disintegrating tablet (ODT) 10-mg to sumatriptan 50-mg tablet. Background.—Migraineurs express treatment preference based on a variety of attributes including the speed of pain relief and medication formulation. Rizatriptan ODT is an orally disintegrating formulation of rizatriptan, a selective 5-HT1B/1D receptor agonist. This study was conducted to determine patient preference between rizatriptan ODT 10-mg and sumatriptan 50-mg tablet for the acute treatment of migraine. Methods.—This was a multicenter, randomized, open-label, two-period crossover study conducted in the United States with 524 enrolled patients. Patients treated a single moderate or severe headache in each treatment period. Patients treated one migraine with either rizatriptan ODT 10-mg or sumatriptan 50-mg tablet, then treated a second migraine with the alternate therapy. Patients completed diary assessments at baseline, and 30, 45, 60, 90, and 120 minutes postdose and rated headache severity on a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). At the final study visit following treatment of their second migraine, patients expressed preference for one of the two study medications by completing an interviewer-administered Global Preference Question and then responded to a self-administered series of questions to capture their most important reason for preferring one study medication over the other. Safety measurements were recorded through standard adverse experience reporting. Results.—Three hundred eighty-six patients treated two migraine attacks. For those patients who expressed a preference for either rizatriptan ODT or sumatriptan (n = 374), the percentage of patients who preferred rizatriptan ODT 10-mg (57%, n = 213) was significantly greater than those who preferred sumatriptan 50-mg tablet (43%, n = 161) (P

Accurate assessment of the value of asthma interventions in pediatric clinical trials is an essential step toward the improvement of the treatment of this disorder in children. Conventional pulmonary function measures can be infeasible and unreliable in younger children, particularly for use in multisite studies. As an alternative or supplemental approach, diary questionnaires completed by the patients or their caregivers may provide valuable data regarding the efficacy of asthma interventions in pediatric clinical trials. These questionnaires, however, have routinely not been validated for use in pediatric populations. Two pediatric diary questionnaires (the child-completed Pediatric Asthma Diary [PAD] and the parent/caregiver-completed Pediatric Asthma Caregiver Diary [PACD]) were designed to evaluate asthma symptoms in children aged 6 to 14 years and 2 to 5 years, respectively. The validity of these diary questionnaires was evaluated in 2 separate prospective studies that included children who were divided into 2 asthma groups: stable (requiring no additional asthma medication) and unstable (requiring either an increase in or the addition of asthma medication). Both scales displayed significant discriminant validity, construct validity, and responsiveness to change in asthma therapy. Only the PACD detected differences between groups in nighttime symptoms, such as awakenings caused by asthma. These validity studies suggest that diary questionnaires such as the PAD and PACD can be valuable as an alternative for the evaluation of interventions in pediatric asthma when pulmonary function testing is inappropriate or as an adjunct to such objective measures. (J Allergy Clin Immunol 2001;107:S465-72.)

Objective: To compare self-reported healthcare resource utilisation, paid work loss, unpaid work loss and loss of effectiveness at work due to migraine in a clinic-based adult migraine population. Methods: The Migraine Background Questionnaire© (MBQ) was translated and pilot-tested for use in 25 countries. The questionnaire was then self-administered by patients at a screening visit for 3 phase III clinical trials of rizatriptan [a selective serotonin (5-hydroxytryptamine) 5-HT1B/1Dreceptor agonist] in 23 US and 78 non-US sites. Participants: Persons 18 to 65 years of age with at least a 6-month history of moderate to severe migraines prior to the screening visit were surveyed. Results: A total of 2670 persons (54.7% Europe, 16.5% Latin America, 23.1% North America, 5.5% other countries) completed the MBQ and had responses which could be analysed. On average, each patient reported 2.78 doctor visits, 0.53 emergency room visits and 0.06 hospitalisations related to migraine per year. Patients self-reported being only 46% effective while on the job with migraine symptoms. Extrapolation of patient self-reported work and productivity loss for the last 4 weeks to an annual basis suggested that clinic-based patients with migraine lose 19.5 workday equivalents (8.3 days due to absenteeism, 11.2 days due to reduced workday equivalents) due to migraine per year. In the US, the annual employer cost of this total migraine-related work loss is estimated to be $US3309 (2000 values) per patient with migraine. The levels of self-reported healthcare resources utilised for migraine and work loss were generally consistent across geographic regions. Conclusions: The impact of migraine symptoms on healthcare resource utilisation and work loss was similar across most measures in Europe, Latin America, North America and other countries. Total migraine-related work loss due to absenteeism and reduced workday equivalents accounts for most of the economic burden of migraine, regardless of country, in a clinic-based migraine population.

The objective was to develop a brief questionnaire to assess short-term functioning decrements in adolescents with acute migraine. One hundred twenty-three potential items were generated by literature review and by interviewing adolescent migraineurs and migraine specialists. To reduce the items, 127 adolescents were asked to identify which items affected their daily functioning in the 24 hours following onset of a migraine, and to rate them on a 5-point scale from “not very important” to “extremely important.” Reduction to an 18-item questionnaire was performed by evaluating subject-perceived importance (number of times an item was chosen times mean importance score) in combination with principal components factor analysis. Five domains were identified: (1) activities, (2) social functioning, (3) cognitive functioning, (4) migraine headache symptoms, and (5) emotional functioning. Questions regarding school loss and school performance during a migraine were added to the final questionnaire as a separate outcome measure. The correlation between the five domains as measured by the Spearman correlation coefficient ranged from 0.17 to 0.49 suggesting some, but minimal, overlap. Cronbach alpha for individual domains ranged from .50 to .84. The questionnaire was pilot-tested in 12 adolescent migraineurs to determine ease of administration and comprehension and revised to improve clarity.

The objective of this study was to measure the self-reported effect of acute migraine and its treatment on paid work and productivity loss. Patients self-administered a questionnaire in which the impact of a recent migraine on paid work and productivity activities was assessed. We included the questionnaire in a randomized, double-blind, placebo-controlled, crossover, out-patient study designed to examine the safety and efficacy of rizatriptan (5-HT1B/1D receptor agonist) 10 mg p.o. in patients treating four separate migraine attacks. A total of 407 patients, aged 18–65 years, suffering from moderate to severe migrainous headaches was studied. Patients receiving rizatriptan compared with placebo reported 0.7 fewer hours ( P < 0.01) of paid worked missed due to absenteeism, 0.4 fewer hours ( P < 0.05) of productive time lost on the job, and 1.1 fewer total hours ( P < 0.01) of work loss per migraine attack. Rizatriptan compared with placebo significantly reduced migraine-related work loss associated with absenteeism and decreased effectiveness on the job.

Background: Young children are generally not able to consistently and reliably perform tests of airway function, and normative values are not available. Reliable and valid measures of parental reporting of asthma symptoms and functioning are needed to determine the efficacy of asthma interventions. Objective: A pediatric asthma caregiver diary was developed and validated for use in interventional asthma studies. Methods: A 3-week prospective study of 125 caregiver parents and their children, aged 2 to 5 years, with persistent asthma was conducted. At baseline, children were classified as either stable (no change to anti-inflammatory therapy) or unstable (anti-inflammatory therapy added or increased). Results: A symptom scale and day without asthma symptoms (DWAS) were defined from pediatric asthma caregiver diary questions. The scale and DWAS statistically differentiated between the stable and unstable groups at week 1 and detected change between the 2 groups (P < .01). On average, caregivers reported low symptom scores. However, the frequency of DWAS was only 43% of days in the stable group and 22% in the unstable group. Conclusion: The pediatric asthma caregiver diary scale and DWAS have acceptable measurement characteristics for use in clinical trials of children with asthma symptoms. The DWAS indicates an opportunity for improvement in asthma control in this population. (J Allergy Clin Immunol 2000;106:861-6.)

In this study, the perceptions of asthmatics to change in their disease was associated with observed changes in clinical asthma measures, in order to identify the threshold where changes in clinical asthma measures are perceivable by patients. The study included 281 asthmatic patients, aged 18-63 yrs, in a randomized, placebo-controlled clinical trial of a leukotriene antagonist. Changes were related in: 1) asthma symptom scores; 2) inhaled beta-agonist use; 3) forced expiratory volume in one second (FEV1); and 4) peak expiratory flow (PEF) to a global question that queried overall change in asthma since starting the study drug. Additional analyses examined differences in the group reporting minimal improvement by treatment (active treatment versus placebo), sex and age groups. The average minimal patient perceivable improvement for each measure was: 1) -0.31 points for the symptom score on a scale of 0-6; 2) -0.81 puffs x day(-1) for inhaled beta-agonist use; 3) 0.23 L for FEV1; and 4) 18.79 L x min(-1) for PEF. In general placebo-treated patients and older patients, who reported minimal improvement, experienced less mean improvement from baseline than active-treated patients and younger patients, who reported minimal improvement. Determining the minimal patient perceivable improvement value for a measure may be helpful to interpret changes. However, interpretation should be carried out cautiously when reporting a single value as a clinically important change.

Objectives: To assess the use of asthma drugs by men and women with asthma and to identify sex specific predictors for the use of oral steroids. Design: Cross sectional study. Setting: Six general practicesin East Anglia. Subjects: 103 men and 134 women aged 20-54 with asthma. Main outcome measures: Self reported use of β agonists, inhaled steroids, and oral steroids. Results: No sex difference was found in use of β agonists or inhaled steroids. However a strong association existed between sex and oral steroid use. 40 (30%) women reported using oral steroids compared with nine (9%) men. Women were more than five times (odds ratio=5.5, 95% confidence interval 2.2 to 13.7) more likely to report use of oral steroids than men after asthma symptoms, age, visits to the general practitioner in previous six months, and time since diagnosis of asthma were controlled for. Women who had visited the general practitioner for asthma one or more times in the previous six months were four times (3.9, 1.6 to 9.5) as likely to report use of oral steroids. In addition, more frequent visits to the general practitioner for asthma were related in a dose-response manner to a greater likelihood of using oral steroids among women after asthma symptoms, age, and time since diagnosis were controlled for. This relation was not observed among men. Conclusion: Women used oral steroids more than men. The more frequent consultations with a doctor by women may result in more requests for oral steroids or doctors may preferentially prescribe oral steroids to women.

OBJECTIVE: To determine the effect of lovastatin therapy on health-related quality of life in older persons. DESIGN: A prospective, randomized, double blind clinical trial. SETTING: Four university medical center research clinics. PARTICIPANTS: There were 431 men and women, primarily 65 years of age or older, with low density lipoprotein levels greater than 159 mg/dL and less than 221 mg/dL. Exclusion criteria included a Mini-Mental state score less than 24 or presence of recent cardiovascular events or other serious chronic disease likely to shorten survival. INTERVENTION: All participants were administered the National Cholesterol Education Program step one diet and were then randomized to placebo, 20 mg lovastatin, or 40 mg lovastatin. MEASUREMENTS: Areas of health-related quality of life assessed in the Cholesterol Reduction in Seniors Program (CRISP) included: (1) physical functioning, (2) sleep behavior, (3) social support, (4) depression, (5) cognitive function, and (6) health perception. Three global change questions asked the patients to judge change in general health since starting the study diet or the study medication and change in ability to function or care for self. Although some patients were followed for a total of 12 months, all participants were followed for 6 months, and 6-month data have been used for the primary analysis in this paper. RESULTS: Patients treated with 20 mg of lovastatin had a 17% and 24% reduction in total cholesterol and LDL-cholesterol, respectively. Patients treated with the 40-mg lovastatin dose achieved reductions of 20% for total cholesterol and 28% for LDL-cholesterol. Complaints of possible adverse events were remarkably similar in the two active treatment groups and the placebo group. At 6 months of follow-up there were no statistically significant differences found in mean change scores from baseline between treatment groups on the health-related quality of life measures (physical functioning, sleep, social support, depression, cognitive function scales, health perception) or global questions. CONCLUSIONS: This study demonstrates that lovastatin was extremely well tolerated in an older cohort, both with regard to symptoms and to health-related quality of life.

The objective of this study is to assess nocturnal asthma as a marker for poor control of asthma. Cross-sectional study of asthmatic patients was conducted in six general practices in East Anglia, England. Subjects were 240 asthma patients, between the ages of 20 and 54 years, from the above general practices. A continuous asthma severity score (range 6-26), consisting of the summation of ordinal responses to questions regarding asthma symptoms during the last 6 months, was used for analysis. The crude association between nocturnal asthma and severity score was statistically highly significant. Regression analysis suggests that, after controlling for possible confounding variables, there remains a strong association between nocturnal asthma (NA) and severity, which is modified by self-report of current consultation for "nervous/emotional trouble" (current NT). In the absence of current NT, NA raises the severity score by 5.3 (95% CI 4.5, 6.2), whereas in the presence of current NT, NA raises the severity score by 8.2 (95% CI 4.8, 11.6). NA appears promising as a marker for poorly controlled asthma. Confirmation of the association found in this study by objective measures of severity would strengthen the utility of NA as a marker.

The objective of this study was to develop a questionnaire to assess the short-term quality of life decrements associated with an acute migraine headache attack. A total of 101 potential quality of life items were generated by interviewing migraineurs and migraine specialists and reviewing the literature. To reduce the items, 76 migraineurs (18 years and older) were asked to identify which of the 101 items affected their quality of life in the 24 hours following onset of a migraine and to rate them on a five-point scale from "not very important" to "extremely important." Reduction of the 101 items to a 15-item questionnaire was performed by evaluating the results of subject-perceived importance (number of times an item was chosen x mean importance score) in combination with principal components analysis. Five domains were identified: (1) work functioning, (2) social functioning, (3) energy/vitality, (4) migraine headache symptoms, and (5) feelings and concerns. Each domain has three items and the correlation between the five domains, as measured by the Spearman correlation coefficient, ranged from 0.08 to 0.38 suggesting minimal overlap. The brief migraine quality of life questionnaire was pilot-tested in two groups of 10 migraineurs and revised to improve clarity.

A brief migraine-specific quality of life questionnaire was developed to assess the quality of life decrement associated with an acute migraine attack in the 24-hour period following headache onset. The migraine quality of life questionnaire has 15 questions across five domains (work functioning, social functioning, energy, concerns, and symptoms). A prospective, observational study was conducted to evaluate the characteristics of internal consistency, construct and discriminant validity, and responsiveness of the migraine quality of life questionnaire. One hundred thirty-eight subjects with migraine were recruited. One hundred seven subjects completed a baseline and a 24-hour postmigraine quality of life questionnaire, along with a migraine diary for recording headache severity, activity limitation, associated symptoms, duration of headache, and use of migraine medication. All five migraine quality of life questionnaire domains showed good internal consistency (Cronbach's alpha, 0.74-0.95). The strongest correlations were seen between activity limitation and associated symptoms and the migraine quality of life questionnaire work, social, and energy domains. Significant differences in mean questionnaire scores between subjects were found with frequency of medication use, global change in symptoms, headache duration, and severity. All five domains showed significant responses within subjects from a migraine-free period to an acute migraine period (P < 0.0001). In summary, the migraine quality of life questionnaire showed good internal consistency, construct and discriminant validity, and responsiveness to acute migraine attacks.

To the Editor. —The Air Force Coronary Atherosclerosis Prevention Study (AFCAPS) is an ongoing randomized, double-blind, placebo-controlled primary prevention trial to determine whether treatment with the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitor, lovastatin, will prevent coronary heart disease in persons with mild to moderate elevations of total and low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol levels. A total of 6605 participants without clinical evidence of coronary heart disease are enrolled, including men aged 45 to 73 years and women aged 55 to 73 years. Participants will be followed annually for total coronary heart disease events during a minimum of 5 years. A trial of this size and duration provides an opportunity to evaluate the long-term impact of cholesterol-lowering drug treatment on patient quality of life (QoL). In fact, it may be argued that it is imperative to assess the impact of long-term pharmacologic therapy on QoL in asymptomatic

Objective. —To assess the efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol to decrease low-density lipoprotein cholesterol (LDL-C) levels in children. Design. —Six-center randomized controlled clinical trial. Participants. —Prepubertal boys (n=362) and girls (n=301) aged 8 to 10 years with LDL-C levels greater than or equal to the 80th and less than the 98th percentiles for age and sex were randomized into an intervention group (n=334) and a usual care group (n=329). Intervention. —Behavioral intervention to promote adherence to a diet providing 28% of energy from total fat, less than 8% from saturated fat, up to 9% from polyunsaturated fat, and less than 75 mg/4200 kJ (1000 kcal) per day of cholesterol (not to exceed 150 mg/d). Main Outcome Measures. —The primary efficacy measure was the mean LDL-C level at 3 years. Primary safety measures were mean height and serum ferritin levels at 3 years. Secondary efficacy outcomes were mean LDL-C levels at 1 year and mean total cholesterol levels at 1 and 3 years. Secondary safety outcomes included red blood cell folate values; serum zinc, retinol, and albumin levels; serum high-density lipoprotein cholesterol (HDL-C) values, LDL-C:HDL-C ratio, and total triglyceride levels; sexual maturation; and psychosocial health. Results. —At 3 years, dietary total fat, saturated fat, and cholesterol levels decreased significantly in the intervention group compared with the usual care group (allP .05) or other safety outcomes. Conclusions. —The dietary intervention achieved modest lowering of LDL-C levels over 3 years while maintaining adequate growth, iron stores, nutritional adequacy, and psychological well-being during the critical growth period of adolescence. (JAMA. 1995;273:1429-1435)