Comorbidity indices for clinical trials: adaptation of two existing indices for use with the FREEDOM trial in women with postmenopausal osteoporosis.

UNLABELLED: Two comorbidity indices were adapted for use in the FREEDOM trial and significantly correlated with the number of medications and impaired health status at baseline. The indices have applications for the analysis of clinical trial data and would allow for the appropriate adjustment of comorbidities when evaluating clinical trial outcomes. INTRODUCTION: The purpose of this study is to adapt two published comorbidity indices for use with the FREEDOM clinical trial evaluating postmenopausal women with osteoporosis. METHODS: FREEDOM enrolled women aged 60-90 years with a bone mineral density T-score <-2.5 at the lumbar spine or total hip and ≥-4.0 at both sites. Comorbidity indices were calculated using methods described by Sangha (Arthritis Rheum 49:156-163, 2003) and Wolfe (J Rheumatol 37:305-315, 2010) following modification. The adapted Sangha index included 12 conditions with a summary score of 0-12; the adapted Wolfe index included 7 conditions with a weighted summary score of 0-8. Higher scores indicated greater comorbidity. A panel of clinicians independently reviewed subjects' medical histories using a systematic process based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms to map specified comorbid conditions. Spearman correlations between the adapted indices and baseline subject characteristics expected to be associated with comorbidities were examined. RESULTS: Of the 7808 subjects in this study, 74 % had ≥1 comorbidities based on the adapted Sangha or Wolfe comorbidity indices. The mean (SD) adapted Sangha and Wolfe comorbidity indices were 1.4 (1.2) and 1.4 (1.3), respectively. Both indices correlated positively with age, body mass index, and the number of medications (r = 0.54 to 0.55) at baseline and inversely correlated with health-related quality of life (r = -0.22 to -0.30) (all P < 0.0001). Further, when either the adapted Sangha or Wolfe index was included as a covariate for assessing mortality over 36 months in the FREEDOM population, the hazard ratio of the comorbidity index indicated that the mortality risk increased by 27 or 28 %, respectively, for each unit increase in the adapted index (both P < 0.0001). CONCLUSIONS: Our work suggests these comorbidity indices may be adapted for use with clinical trial data, thereby allowing for the appropriate adjustment and reporting of covariates in the evaluation of clinical trial outcomes in an osteoporotic population.

Impact of brodalumab treatment on psoriasis symptoms and health-related quality of life: use of a novel patient-reported outcome measure, the Psoriasis Symptom Inventory.

BACKGROUND: Psoriasis symptoms have a significant negative impact on health-related quality of life, impairing physical functioning and well-being. OBJECTIVE: To evaluate the impact of brodalumab, a human anti-interleukin-17R monoclonal antibody, on psoriasis symptom severity as measured by a novel patient-reported outcome measure, the Psoriasis Symptom Inventory, and dermatology-specific health-related quality of life as measured by the Dermatology Life Quality Index (DLQI). METHODS: This was a secondary analysis of a phase II, randomized, double-blind, placebo-controlled clinical study of patients with moderate-to-severe psoriasis (n = 198) treated with brodalumab or placebo. This analysis assessed Psoriasis Symptom Inventory scores and DLQI scores over time. Analyses were conducted on all patients who were randomized and received one or more injections of the study drug according to intention to treat using last observation carried forward to impute missing data. RESULTS: At week 12, subjects in the brodalumab groups had significant improvements in mean Psoriasis Symptom Inventory total scores [8.5 (70 mg), 15.8 (140 mg), 16.2 (210 mg) and 12.7 (280 mg)] compared with placebo (4.8). Mean improvements in DLQI were clinically meaningful (≥ 5.7) in the brodalumab groups (6.2, 9.1, 9.6 and 7.1, respectively) and significantly greater than placebo (3.1). Improvements in Psoriasis Symptom Inventory were observed as early as week 2 and in DLQI by week 4. All eight Psoriasis Symptom Inventory item scores improved significantly among the brodalumab groups by week 12. CONCLUSIONS: Results were from a single randomized clinical trial and may not generalize to broader patient populations. However, treatment with brodalumab provided significant improvement in psoriasis symptoms in patients with moderate-to-severe psoriasis.

United States Value Set for the Functional Assessment of Cancer Therapy-General Eight Dimensions (FACT-8D), a Cancer-Specific Preference-Based Quality of Life Instrument.

OBJECTIVES: To develop a value set reflecting the United States (US) general population's preferences for health states described by the Functional Assessment of Cancer Therapy (FACT) eight-dimensions preference-based multi-attribute utility instrument (FACT-8D), derived from the FACT-General cancer-specific health-related quality-of-life (HRQL) questionnaire. METHODS: A US online panel was quota-sampled to achieve a general population sample representative by sex, age (≥ 18 years), race and ethnicity. A discrete choice experiment (DCE) was used to value health states. The valuation task involved choosing between pairs of health states (choice-sets) described by varying levels of the FACT-8D HRQL dimensions and survival (life-years). The DCE included 100 choice-sets; each respondent was randomly allocated 16 choice-sets. Data were analysed using conditional logit regression parameterized to fit the quality-adjusted life-year framework, weighted for sociodemographic variables that were non-representative of the US general population. Preference weights were calculated as the ratio of HRQL-level coefficients to the survival coefficient. RESULTS: 2562 panel members opted in, 2462 (96%) completed at least one choice-set and 2357 (92%) completed 16 choice-sets. Pain and nausea were associated with the largest utility weights, work and sleep had more moderate utility weights, and sadness, worry and support had the smallest utility weights. Within dimensions, more severe HRQL levels were generally associated with larger weights. A preference-weighting algorithm to estimate US utilities from responses to the FACT-General questionnaire was generated. The worst health state's value was -0.33. CONCLUSIONS: This value set provides US population utilities for health states defined by the FACT-8D for use in evaluating oncology treatments.

Impact of clinical fractures on health-related quality of life is dependent on time of assessment since fracture: results from the FREEDOM trial.

UNLABELLED: In the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, women with incident clinical fractures reported significant declines in health-related quality of life (HRQoL). The largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain. INTRODUCTION: In the FREEDOM trial, denosumab significantly reduced the risk of new vertebral, hip, and nonvertebral fractures. We evaluated the effect of denosumab on HRQoL and the association between incident clinical fractures and HRQoL. METHODS: The FREEDOM trial enrolled 7,868 women aged 60-90 years with a total hip and/or lumbar spine BMD T-score <-2.5 and not <-4.0 at either site. Women were randomized to receive denosumab 60 mg or placebo every 6 months, in addition to daily calcium and vitamin D. HRQoL was assessed with the Osteoporosis Assessment Questionnaire-Short Version (OPAQ-SV) at baseline and every 6 months for 36 months. The OPAQ-SV assesses physical function, emotional status, and back pain. Higher scores indicate better health status. RESULTS: No statistically significant differences in mean change in HRQoL from baseline to end of study were found when comparing treatment groups. Compared with women without any incident fractures during the study, women with incident clinical fractures reported significant declines in physical function (-4.0 vs. -0.5) and emotional status (-5.0 vs. -0.8) at month 36 (P < 0.001 for both). Importantly, time-dependent covariate analyses demonstrated that the largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain. CONCLUSIONS: These findings not only demonstrate that incident clinical fractures impact HRQoL but also contribute new information regarding the impact of these fracture events on HRQoL over time.

Norms-based assessment of patient-reported outcomes associated with adalimumab monotherapy in patients with ankylosing spondylitis.

OBJECTIVES: To compare the impact of ankylosing spondylitis (AS) on health-related quality of life (HRQL) and of adalimumab on initial and sustained improvement in HRQL for patients with active AS versus the general US population. METHODS: Data from the 5-year ATLAS trial were analysed. HRQL burden of AS and treatment impact on HRQL were assessed by comparing health status and utility scores from ATLAS (Short Form 36 Health Survey [SF-36] and Health Utilities Index Mark 3 [HUI3]) with population norms. RESULTS: Baseline scores for all measures were comparable between adalimumab and placebo. All scores for both groups were significantly worse than general population norms (all p<0.0001). Within- and between-group improvements in SF-36 Physical Component Summary and SF-6D scores from baseline to Weeks 12 and 24 were clinically relevant for patients receiving adalimumab. For patients initially randomised to adalimumab, HRQL scores improved from Weeks 25 to 52 and remained relatively stable through 3 years but remained lower than for the general US population at all time points. CONCLUSIONS: Findings demonstrate a significant burden of AS on HRQL. Treatment with adalimumab significantly improved physical functioning and other measures of HRQL compared with placebo. Clinically relevant improvements in HRQL outcomes over 3 years represent a significant benefit of adalimumab. Because of the advanced AS disease, patient health status remained below that of the general population. Treatment earlier in the course of AS may be needed to restore HRQL to the level of the general population.

Validation of the revised Patient Perception of Migraine Questionnaire (PPMQ-R): measuring satisfaction with acute migraine treatment in clinical trials.

This study was aimed to evaluate in clinical trial settings the psychometric properties of the revised Patient Perception of Migraine Questionnaire (PPMQ-R), a satisfaction measure for acute migraine treatment. The PPMQ-R was administered 24 h post dosing in 1304 migraineurs randomized to two identical Phase 3, single-attack trials. Reliability, concurrent and construct validity and known-groups validity were evaluated using Cronbach's alpha, Pearson correlations and analysis of variance, respectively. PPMQ-R scale and Total scores (Efficacy, Functionality and Ease of use) showed very good internal consistency reliability (alpha 0.84-0.99). Efficacy, Functionality and Total PPMQ-R scores showed large, inverse relationships with migraine pain severity, number of migraine symptoms and work ability (r = -0.62 to -0.75; all P < 0.0001). All scales discriminated among migraine pain severity levels (all P < 0.001). The PPMQ-R has sufficient evidence of validity and reliability for measuring patient satisfaction, an important benchmark of quality and effective care.

The content validity of the PSS in patients with plaque psoriasis.

BACKGROUND: The primary objective of this study was to evaluate the content validity of the Psoriasis Symptom Scale (PSS), with a specific focus on understanding of the content of the PRO measure by conducting one-on-one interviews with patients with moderate to severe plaque psoriasis. This was a cross-sectional, qualitative study conducted with 20 patients with plaque psoriasis who participated in in-person, one-on-one interviews. Participants were asked to describe their psoriasis symptoms, completed the PSS, and were cognitively debriefed on its content. Interviews were conducted in two separate rounds. Following Round 1, the study data were examined to determine if modifications to the PSS were required. All interviews were audio-recorded and transcribed. Sociodemographic and clinical data were collected for sample descriptive purposes. RESULTS: The 20 study participants had a mean age of 50.2 ± 12.0 years (range: 25.0-73.0), and 55% were female. Thirty-five percent of the sample reported their psoriasis severity as moderate or severe. The average time since diagnosis of plaque psoriasis was almost 18 years, ranging from less than one to over 38 years. The most frequently reported symptoms and signs during the concept elicitation portion of the interviews included redness (N = 20, 100%), itching (n = 20, 100%), pain (n = 15, 75%), burning (n = 13, 65%), and flaking (n = 11, 55%). Overall, participants provided positive feedback on the PSS and felt that it was comprehensive and relevant to their experience with psoriasis. The item meaning and response options were well-understood for the majority of the items. Findings indicate that for the patient-reported symptom of redness, which is also a sign that can be reported by clinicians, redness or the perception of redness is most accurately captured by patient report. Study results did not support modifications to the instrument and no changes to the PSS were recommended. CONCLUSION: The evidence gained in this study provided support for the content validity of the PSS for use as clinical trial endpoint among patients with plaque psoriasis. This study found that the symptoms included in the PSS are important to and well-understood by patients with plaque psoriasis. The PSS is appropriate for inclusion in future studies designed to measure the effect of treatment on psoriasis-related symptoms.

Calibration of the Dutch-Flemish PROMIS Pain Behavior item bank in patients with chronic pain.

BACKGROUND: The aims of the current study were to calibrate the item parameters of the Dutch-Flemish PROMIS Pain Behavior item bank using a sample of Dutch patients with chronic pain and to evaluate cross-cultural validity between the Dutch-Flemish and the US PROMIS Pain Behavior item banks. Furthermore, reliability and construct validity of the Dutch-Flemish PROMIS Pain Behavior item bank were evaluated. METHODS: The 39 items in the bank were completed by 1042 Dutch patients with chronic pain. To evaluate unidimensionality, a one-factor confirmatory factor analysis (CFA) was performed. A graded response model (GRM) was used to calibrate the items. To evaluate cross-cultural validity, Differential item functioning (DIF) for language (Dutch vs. English) was evaluated. Reliability of the item bank was also examined and construct validity was studied using several legacy instruments, e.g. the Roland Morris Disability Questionnaire. RESULTS: CFA supported the unidimensionality of the Dutch-Flemish PROMIS Pain Behavior item bank (CFI = 0.960, TLI = 0.958), the data also fit the GRM, and demonstrated good coverage across the pain behavior construct (threshold parameters range: -3.42 to 3.54). Analysis showed good cross-cultural validity (only six DIF items), reliability (Cronbach's α = 0.95) and construct validity (all correlations ≥0.53). CONCLUSIONS: The Dutch-Flemish PROMIS Pain Behavior item bank was found to have good cross-cultural validity, reliability and construct validity. The development of the Dutch-Flemish PROMIS Pain Behavior item bank will serve as the basis for Dutch-Flemish PROMIS short forms and computer adaptive testing (CAT).

Medical care and cost outcomes after pentoxifylline treatment for peripheral arterial disease.

We assessed the medical outcomes and costs associated with the pharmacologic treatment of patients with peripheral arterial disease (PAD) in a population-based historical cohort study of patients enrolled in a health maintenance organization. For up to 2 years, we compared 58 patients who used therapeutic amounts of pentoxifylline with a comparison group of 112 patients who received a minimal subefficacious trial of pentoxifylline. Medical records data were used to assess and control for the severity of PAD and other potentially confounding factors. Continuous use of a therapeutic amount of pentoxifylline during an initial 120-day period significantly reduced the incidence of PAD-related invasive therapeutic and diagnostic procedures in the first year of follow-up (adjusted relative risk, 0.35; 95% confidence interval, 0.12 to 0.99). However, there were no significant differences in the risk of a PAD-related hospitalization or cost of PAD-related care between continuous pentoxifylline users and the comparison group. Pentoxifylline therapy may reduce the risk of vascular surgery while not increasing the total cost of PAD care.

The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life.

BACKGROUND: Two types of reflux episodes have been identified: upright or daytime and supine or nocturnal. The population-based prevalence of symptoms of nocturnal gastroesophageal reflux disease (GERD) and the impact of those symptoms on health-related quality of life (HRQL) have not been established. METHODS: A national random-sample telephone survey was conducted to estimate the prevalence of frequent GERD and nocturnal GERD-like symptoms and to assess the relationship between HRQL, GERD, and nocturnal GERD symptoms. Respondents were classified as controls, subjects with symptomatic nonnocturnal GERD, and subjects with symptomatic nocturnal GERD. The HRQL was assessed using the Medical Outcomes Study Short-Form 36 Health Survey (SF-36). RESULTS: The prevalence of frequent GERD was 14%, with an overall prevalence of nocturnal GERD of 10%. Seventy-four percent of those with frequent GERD symptoms reported nocturnal GERD symptoms. Subjects with nonnocturnal GERD had significant decrements on the SF-36 physical and mental component summary scores compared with the US general population. Subjects reporting nocturnal GERD symptoms were significantly more impaired than subjects reporting nonnocturnal GERD symptoms on both the physical component summary (38.94 vs 41. 52; P<.001) and mental component summary (46.78 vs 49.51; P<.001) and all 8 subscales of the SF-36 (P<.001). Subjects with nocturnal GERD demonstrated considerable impairment compared with the US general population and chronic disease populations. Subjects with nocturnal GERD had significantly more pain than those with hypertension and diabetes (P<.001) and similar pain compared with those with angina and congestive heart failure. CONCLUSIONS: Nocturnal symptoms are commonly experienced by individuals who report frequent GERD symptoms. In addition, HRQL is significantly impaired in those persons who report frequent GERD symptoms, and HRQL impairment is exacerbated in those who report nocturnal GERD symptoms.

Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir-zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults with CD4 cell counts between 50 and 350 per cubic millimeter. PISCES (SV14604) Study Group.

BACKGROUND: This double-blind study evaluated treatment with zalcitabine-zidovudine, saquinavir-zidovudine, or saquinavir-zalcitabine-zidovudine on the health-related quality of life of HIV-infected adults with CD4 cell counts between 50 and 350 cells/mm3. METHODS: Nine hundred and ninety-three HIV-infected male or female quality of life substudy patients aged 18 years or older, with CD4 cell counts between 50 and 350 cells/mm3 naïve to antiretroviral therapy or with less than 16 weeks of zidovudine therapy, were randomly assigned to one of three daily regimens: zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (ddC/ZDV); saquinavir 600 mg and zidovudine 200 mg every 8 h (SQV/ZDV); or saquinavir 600 mg, zalcitabine 0.75 mg and zidovudine 200 mg every 8 h (SQV/ddC/ZDV). The health-related quality of life was measured using the Medical Outcome Study HIV (MOS-HIV) Health Survey subscale and physical and mental health summary scores, and a global visual analogue scale (VAS) score. The primary health-related quality of life endpoints were the MOS-HIV physical and mental health summary scores. RESULTS: After 24 weeks of treatment, no statistically significant differences were observed between the three treatment groups on physical health and mental health summary scores (global test P = 0.118). After 48 weeks of treatment, statistically significant differences among the groups were observed for physical health and mental health summary scores (global test P = 0.020); no change in physical health summary scores from the baseline were seen in the triple combination therapy, whereas the ddC/ZDV combination therapy group showed decreases from baseline in physical health summary scores (P = 0.008). Six of the 10 individual MOS-HIV subscale scores and the VAS scores showed results consistent with the physical health summary endpoints after 48 weeks of therapy. No statistically significant differences in baseline to 48 week changes in MOS-HIV subscale or summary scores were seen between the ddC/ZDV and SQV/ZDV groups (P > 0.05). CONCLUSIONS: Patients on triple combination therapy maintained their quality of life over 48 weeks compared with significant decreases in the quality of life for ddC/ZDV combination therapy.

A randomized trial of the effect of ritonavir in maintaining quality of life in advanced HIV disease. Advanced HIV Disease Ritonavir Study Group.

BACKGROUND: The aim of treatment for HIV disease is prolonging survival and improvement in health-related quality of life. Ritonavir is a potent, orally bioavailable HIV protease inhibitor with demonstrated impact on surrogate endpoints, AIDS-defining disease, and mortality. OBJECTIVES: To evaluate the effect of ritonavir combined with reverse transcriptase inhibitor therapy on patient functioning and well-being. METHODS: An international, multicenter randomized placebo-controlled clinical trial of ritonavir was conducted in HIV-infected patients with CD4 cell counts < or = 100 x 10(6)/l. A total of 1090 patients were randomized to ritonavir and continued treatment with as many as two nucleoside agents (n=543) or placebo and continued treatment with as many as two nucleoside agents (n=547). Health-related quality of life was measured at baseline and after 3 and 6 months of treatment using the Medical Outcomes Study HIV Health Survey (MOS-HIV) and HIV-related symptoms scale. MOS-HIV contains 10 subscales and two summary scores (physical health and mental health). RESULTS: The two treatment groups were comparable on baseline CD4 cell counts, demographic characteristics, and MOS-HIV and HIV symptom subscale scores. After 3 months, statistically significant differences (P < 0.03) favoring the ritonavir-treated patients were seen on the physical health summary, mental health summary, and general health perceptions, social function, mental health, and energy/fatigue subscales. After 6 months of ritonavir therapy, significant differences were observed on physical health and mental health summary scores (P < 0.001), and on measures of general health perceptions, physical function, role function, social function, cognitive function, mental health, health distress, energy/fatigue, and overall ratings of quality of life (P < 0.01). Ritonavir-treated patients reported fewer fever symptoms and neurologic symptoms than the placebo group after 6 months of treatment (P < 0.005). CONCLUSIONS: Ritonavir therapy, combined with other antiretroviral treatments, significantly contributes to maintenance of functioning and well-being over at least 6 months in patients with advanced HIV disease.

Recombinant human erythropoietin and health-related quality of life of AIDS patients with anemia.

To evaluate the effect of recombinant human erythropoietin on anemia and health-related quality of life in patients with acquired immunodeficiency syndrome (AIDS), we initiated an observational study with an open-label multicenter treatment protocol that involved multiple academic and community physicians in the United States. Our subjects comprised 251 anemic (i.e., hematocrit < 30%) patients with a clinical diagnosis of AIDS using 1987 CDC criteria, age > or = 12 years, and serum erythropoietin level < or = 500 IU/L. The initial dosage of recombinant human erythropoietin was 4,000 units subcutaneously for 6 days each week. Based on the patient's response to therapy, the dosage was increased sequentially to 8,000 units subcutaneously for 6 days per week. Our measurements included changes in mean hematocrit and health-related quality of life. The interview included measures of energy/fatigue; physical, social, role and cognitive function; depression; health perceptions; and life satisfaction. Adverse experiences were also documented to assess safety. Changes in mean hematocrit level from a baseline of 27.9% to 33.6% at week 12 (p < .0001) and 34.5% at week 24 (p < .0001) were observed in patients treated with recombinant human erythropoietin. Adverse experiences, not clearly associated with AIDS, were reported by 10% of patients. Increases in energy (p < .05) were observed after 12 and 24 weeks of drug therapy, and increases in health perceptions were seen after 24 weeks (p < .05). No statistically significant increases or decreases were observed on measures of physical functioning, cognitive functioning, depression, social functioning, or home management activities over the 24-week follow-up. Anemia correctors (defined as hematocrit > or = 38%) showed greater improvement in energy, health perceptions, home management, and role function than noncorrectors. Study dropouts and those who died had significantly worse scores for health-related quality of life at baseline compared to study completers. Thus, the AIDS patients with anemia and serum erythropoietin levels < or = 500 IU/L treated with recombinant human erythropoietin showed increased mean hematocrit and improved health perceptions and energy levels. The drug therapy was associated with increased feelings of energy, but it was not associated with other changes in health status and well-being in the AIDS patients completing the study. These observations need to be confirmed in randomized clinical trials.

Quality of life outcomes of saquinavir, zalcitabine and combination saquinavir plus zalcitabine therapy for adults with advanced HIV infection with CD4 counts between 50 and 300 cells/mm3.

BACKGROUND: Benefits in patient health-related quality of life (HRQL) have not yet been demonstrated for combination antiretroviral therapy with protease inhibitors and nucleoside analogues. This double-blind study evaluated zalcitabine or saquinavir monotherapy and combination saquinavir plus zalcitabine therapy on HROL of human immunodeficiency virus (HIV)-infected adults. METHODS: 940 HIV-infected patients (CD4 counts 50-300 cells/mm3) who had discontinued zidovudine therapy (for intolerance or treatment failure) were randomized to one of three regimens: zalcitabine 0.75 mg every 8 h; saquinavir 600 mg every 8 h; or combination zalcitabine 0.75 mg plus saquinavir 600 mg every 8 hours. HRQL was measured at baseline, 24 and 48 weeks using the Medical Outcome Study HIV Health Survey (MOS-HIV). The primary endpoints were the physical and mental health summary scores (PHS; MHS) of the MOS-HIV as well as a global visual analogue scale (VAS) score. RESULTS: After 24 weeks, the zalcitabine-treated patients demonstrated significantly greater decreases in PHS scores (-4.4 +/- 0.6; saquinavir: -1.3 +/- 0.6; zalcitabine plus saquinavir: -1.7 +/- 0.6; P < 0.0001) and MHS scores (-2.2 +/- 0.5; saquinavir: -1.0 +/- 0.5; zalcitabine plus saquinavir: -0.5 +/- 0.5; P = 0.032) compared to saquinavir and zalcitabine plus saquinavir treated patients. No differences were observed on the VAS (P = 0.172). Nine of 10 MOS-HIV subscales demonstrated results consistent with the primary endpoints. After 48 weeks, a statistically significant difference between the saquinavir-treated groups and the zalcitabine monotherapy group was observed for PHS scores (zalcitabine: -5.8 +/- 0.6; saquinavir: -4.1 +/- 0.6; zalcitabine plus saquinavir: -3.5 +/- 0.6; P = 0.014). CONCLUSIONS: Saquinavir monotherapy and combination saquinavir plus zalcitabine demonstrated a benefit in HRQL relative to zalcitabine monotherapy in patients with prior zidovudine therapy. The HRQL findings are concordant with improved survival and reduced clinical progression of HIV infection found in this study.

Methodological and statistical issues of quality of life (QoL) and economic evaluation in cancer clinical trials: report of a workshop.

In recent years, quality of life (QoL) and economic evaluations have become increasingly important as additional outcome measures in cancer clinical trials. However, both fields of research are relatively new and in need of finding solutions to a substantial number of specific methodological problems. This paper reports on the proceedings of a symposium aimed at summarising and discussing some of the most contentious methodological and statistical issues in QoL and economic evaluations. In addition, possible solutions are indicated and the most pertinent areas of research are identified. Issues specific to QoL evaluations that are addressed include clinically meaningful changes in QoL scores; how to analyse QoL data and to handle missing and censored data and integration of length of life and QoL outcomes. Issues specific to economic evaluations are the advantages and disadvantages of various outcome measures; statistical methods to analyse economic data and choice of decision criteria and analytical perspective. How to perform QoL and economic evaluations in large and simple trials and whether the gap between QoL and utility measures can be bridged are also discussed.

Olanzapine versus placebo and haloperidol: quality of life and efficacy results of the North American double-blind trial.

This double-blind study evaluated the impact of treatment with olanzapine compared with haloperidol, and placebo on improvements in symptomatology and quality of life in patients with a DSM-III-R diagnosis of schizophrenia. A total of 335 patients was randomized to five treatment groups; olanzapine 5 +/- 2.5 mg/day, olanzapine 10 +/- 2.5 mg/day, olanzapine 15 +/- 2.5 mg/day, haloperidol 15 +/- 5 mg/day, and placebo. Patients responding to treatment during the 6-week acute phase were eligible to enter a 46-week extension. Efficacy measures included the brief psychiatric rating scale total, scale for assessment of negative symptoms summary, and clinical global impressions severity scores. Quality of life was evaluated using the quality of life scale. Data analyzed after 24 weeks of therapy showed that olanzapine was significantly superior to placebo in reducing clinical severity and significantly superior to haloperidol in reducing negative symptoms in patients responding to acute treatment. Furthermore, improvement in quality of life was observed in olanzapine-treated responders.

The impact of gastroesophageal reflux disease on health-related quality of life.

BACKGROUND: Gastroesophageal reflux disease (GERD) affects health-related quality of life. METHODS: We enrolled 533 adults with a history of heartburn symptoms for at least 6 months of moderate to severe heartburn in 4 of the 7 days before study entry. Patients were treated with ranitidine 150 mg twice a day for 6 weeks and Gelusil antacid tablets as needed. We measured physician-rated symptoms and the Medical Outcomes Study short-form 36 (SF-36) Health Survey at baseline and after 6 weeks of treatment. Baseline results were compared with normative data for the US population and for patients with selected chronic diseases. Treatment response was defined as no episode of moderate to severe heartburn for 7 days. Statistical significance was set at P <0.001. RESULTS: GERD patients reported significantly worse scores on all 8 SF-36 scales, physical function and well-being, and emotional well-being compared with the general population. Patients with GERD reported worse emotional well-being than patients with diabetes or hypertension. Treatment responders demonstrated significantly less pain and better physical function, social function, vitality, and emotional well-being compared with nonresponders. CONCLUSIONS: Patients with GERD experience decrements in health-related quality of life compared with the general population. The impact of GERD is most striking on measures of pain, mental health, and social function. Successful treatment for GERD results in improvements in health-related quality of life.

Development and validation of a disease-specific treatment satisfaction questionnaire for gastro-oesophageal reflux disease.

BACKGROUND: Currently, no disease-specific, patient-based, treatment satisfaction instruments related to gastro-oesophageal reflux disease exist. AIM: To develop and validate a treatment satisfaction questionnaire for gastro-oesophageal reflux disease (TSQ-G). METHODS: A new questionnaire was developed from patient focus groups, clinician input and literature review. A validation study was conducted in treated gastro-oesophageal reflux disease patients. Ancillary measures included the Medical Outcomes Study Short Form-36, Quality of Life in Reflux and Dyspepsia, Gastrointestinal Symptom Rating Scale, Socially Desirable Response Scale, Patient Satisfaction Questionnaire-18 and physician and patient measures of symptoms and satisfaction. Statistical analyses included exploratory factor analysis, Cronbach's alpha, intra-class correlations, analyses of variance and t-tests. RESULTS: A total of 198 gastro-oesophageal reflux disease patients participated in the study, with a mean age of 50.7 years, 68% female and 84% Caucasian. The physician-rated severity of gastro-oesophageal reflux disease was mild (32%), moderate (50%) and severe (18%); 83% were on proton pump inhibitors. The final TSQ-G consisted of 28 items with seven sub-scales; Cronbach's alpha ranged from 0.58 to 0.94. Correlations with the expected sub-scales of the ancillary measures were moderate to strong. The TSQ-G sub-scales discriminated significantly between levels of physician-rated disease severity, symptom days and patient and physician ratings of satisfaction. CONCLUSIONS: The TSQ-G has excellent reliability and construct validity and appears to be a useful tool for the evaluation of treatment satisfaction in gastro-oesophageal reflux disease patients.

Complete resolution of heartburn symptoms and health-related quality of life in patients with gastro-oesophageal reflux disease.

BACKGROUND: Medical treatments for gastro-oesophageal reflux disease (GERD) vary in their ability to completely resolve heartburn and other symptoms. Although GERD reduces health-related quality of life (HRQL) little is known about the relationship between resolution of heartburn symptoms with medical therapy and HRQL. We evaluated the association between complete resolution of heartburn symptoms and functioning and well-being in three samples of patients with GERD. METHODS: We analysed baseline and follow-up assessments of heartburn symptoms and HRQL scores from three clinical trials (total n=1351) comparing omeprazole and ranitidine for acute symptomatic treatment of GERD. Heartburn symptoms were measured using patient diaries and/or patient self-report. HRQL was assessed using the Psychological General Well-Being Index (PGWB) in all three clinical trials and the SF-36 Health Survey in two clinical trials. Resolution of heartburn symptoms was defined as no heartburn reported during the assessment period. RESULTS: We observed statistically significant differences favouring patients with no heartburn symptoms on the PGWB total score (P=0.018 to P < 0.0001) and anxiety (P=0.002 to P < 0.0001), general health (P=0.05 to P < 0. 0001), positive well-being (P=0.028 to P < 0.0001) and vitality (P=0. 05 to P < 0.0001) sub-scale scores at 4-14 weeks. Patients with no heartburn reported better SF-36 pain (P=0.005 to P < 0.0001) and general health perceptions (P=0.032 to P < 0.0001) compared with patients still experiencing heartburn symptoms at 4-24 weeks. SF-36 physical component summary scores were significantly better in patients with no heartburn symptoms compared with patients with heartburn symptoms at 4-24 weeks (P=0.013 to P=0.009), while mental component summary scores were only significantly different at 24 weeks (P=0.0005) in one of the two studies where the SF-36 was utilized. CONCLUSIONS: Complete resolution of heartburn symptoms was consistently associated with improvement in HRQL; the greatest impact was observed on measures of psychological well-being and physical functioning and well-being. Effective treatment of GERD that completely resolves heartburn results in clinically significant improvement in patient HRQL.