Impact of osteoarthritis disease severity on treatment patterns and healthcare resource use: analysis of real-world data.

OBJECTIVE: To understand treatment patterns and healthcare resource utilization (HCRU) related to osteoarthritis (OA) disease severity in patients in five European countries. METHOD: Data were drawn from the Adelphi OA Disease Specific Programme™ (2017-18). Physicians classified their patients as having mild, moderate, or severe OA, and provided details on their current prescribed therapy and HCRU, including healthcare professional (HCP) consultations, diagnostics and testing, and hospitalizations. Comparisons between disease severity groups were made using analysis of variance and chi-squared tests. RESULTS: The study included 489 physicians (primary care physicians, rheumatologists, orthopaedic surgeons) reporting on 3596 OA patients: 24% mild, 53% moderate, and 23% severe disease. Both physicians and patients reported decreasing satisfaction with treatment with greater disease severity, despite the number of classes of prescribed drugs and increased use of opioids, which were used in almost half of patients with severe OA. For patients whose treatment was not effective, physicians prescribed the same therapeutic options, which were cycled in subsequent treatment lines, with multiple treatment regimens being commonly used. Patients with greater symptom severity also had more physician consultations, while the numbers of tests/imaging, predominantly X-rays, conducted to diagnose or monitor OA increased significantly with disease severity. The type of HCP involvement in patient management also varied by OA severity. CONCLUSIONS: Across five European countries, the use of both non-pharmacological and pharmacological treatments increases with greater disease severity. Those with more severe disease place a greater demand on healthcare resources, with HCP consultations, tests, and hospital visits increasing with severity.

Time to first and sustained improvement in WOMAC domains among patients with osteoarthritis receiving tanezumab.

Objective: To assess onset of effect in three placebo- or nonsteroidal anti-inflammatory drug (NSAID)-controlled trials of tanezumab in patients with moderate-to-severe osteoarthritis. Methods: Post-hoc nonparametric Kaplan-Meier analyses were used to estimate median time to first improvement and to sustained improvement in Western Ontario and McMaster Universities Osteoarthritis Index domain (Pain, Physical Function, Stiffness) scores across a range of improvement thresholds (0-100%, in 5% increments). Time to first improvement was defined as the first week scores met the pre-specified threshold. Time to sustained improvement was defined as the first week scores met the pre-specified threshold and were sustained (on average) for the remainder of the treatment period. Results: Across all domains, tanezumab-treated patients had shorter median times to first improvement (at most thresholds) and reached higher levels of improvement than placebo-treated patients. No substantial differences were observed between tanezumab doses (2.5 and 5 â€‹mg), or between tanezumab and NSAIDs. Most patients experiencing an event of first improvement went on to experience a sustained event. At low thresholds, sustained improvement occurred simultaneously with, or shortly after, first improvement. At higher thresholds, median time to sustained improvement was longer than median time to first improvement. Conclusions: Following initiation of tanezumab treatment, first improvement of osteoarthritis symptoms of 30% was evident within 2-4 weeks and sustained improvement was evident within 2-8 weeks. Time to improvement of 50% was more variable, with first and sustained events expected within 4-16 and 8-24 weeks, respectively. ClinicalTrialsgov identifiers: NCT02697773; NCT02709486; NCT02528188.

Patient preferences for osteoarthritis pain and chronic low back pain treatments in the United States: a discrete-choice experiment.

OBJECTIVE: To quantify preferences for attributes of potential analgesic treatments for moderate-to-severe pain associated with osteoarthritis (OA) and/or chronic low back pain (CLBP) as relevant to injectable nerve growth factor (NGF)-inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. METHODS: We used a discrete-choice experiment (DCE) to elicit preferences for attributes of OA and CLBP pharmaceutical treatments, and a best-worst scaling (BWS) exercise to further characterize the relative importance of treatment-related side-effect risks. The survey was completed online by 602 US residents with self-reported chronic, moderate-to-severe OA pain and/or CLBP who had tried, had contraindications for, or were unwilling to take currently available pharmaceutical therapies. In the DCE, respondents repeatedly chose between two hypothetical treatments defined by six attributes (symptom control; treatment-related risks of (1) severe joint problems, (2) heart attack, and (3) physical dependence; mode/frequency of administration; and cost). In the BWS exercise, respondents evaluated ten side-effect risks. Random-parameters logit models were estimated; conditional relative attribute importance, maximum acceptable risks, and willingness to pay were calculated. RESULTS: The most important DCE attributes were improving symptom control (scaled conditional relative importance, 10.00) and reducing risk of physical dependence (6.99). The three most important BWS attributes were, in rank order, risks of stroke, physical dependence, and heart attack. Respondents were willing to accept a > 4% treatment-related risk of severe joint problems for even modest symptom improvement. CONCLUSION: A pharmaceutical treatment with a risk of severe joint problems was viewed as an acceptable alternative to other treatments with comparable efficacy but risks associated with NSAIDs or opioids.

Examining the association between pruritus and quality of life in patients with atopic dermatitis treated with crisaborole.

BACKGROUND: Pruritus is a leading cause of reduced health-related quality of life (QoL) in atopic dermatitis (AD). Crisaborole ointment is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. In identical Phase 3 studies (NCT02118766, NCT02118792), crisaborole reduced disease and pruritus severity versus vehicle. OBJECTIVE: Quantify the relationship between pruritus and QoL using data from these studies. METHODS: Patients aged ≥2 years were randomly assigned 2 : 1 to receive crisaborole:vehicle twice daily for 28 days. QoL was measured at baseline and day 29 using the Dermatology Life Quality Index (DLQI; patients aged ≥16 years), the Children's Dermatology Life Quality Index (CDLQI; patients aged 2-15 years) and the Dermatitis Family Impact (DFI; caregivers of patients aged 2-17 years). Pruritus was measured using the Severity of Pruritus Scale (SPS), a 4-point scale from 0 ('no itching') to 3 ('bothersome itching/scratching that disturbs sleep'), and captured morning and evening via electronic diary. Data from crisaborole and vehicle arms were pooled for this analysis. A repeated-measures longitudinal model was used to estimate relationships between pruritus (SPS) and QoL (DLQI, CDLQI and DFI in separate analyses). RESULTS: One thousand five hundred and twenty two patients received crisaborole or vehicle. A linearity assumption for the relationship between SPS and DLQI (n = 294), CDLQI (n = 1200), and DFI (n = 1293) was appropriate. For DLQI, SPS score of 0 was associated with 'no negative effect on patient QoL'; SPS score of 1 was associated with 'small effect on patient QoL'; SPS score of 2 was associated with 'moderate effect on patient QoL'; and SPS score of 3 was associated with 'very large effect on patient QoL'. The pattern of relationships between SPS and CDLQI and DFI was similar. CONCLUSIONS: The relationships between SPS and DLQI, CDLQI and DFI substantiate the significant link between pruritus and patient/caregiver QoL in AD.

Assessment of progression-free survival as a surrogate end-point for overall survival in patients with metastatic renal cell carcinoma.

BACKGROUND: To determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naïve metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-α) in a phase III study. METHODS: The relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan-Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test. RESULTS: In the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P<0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan-Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P<0.0001). CONCLUSIONS: A positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-α. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS.

Enhanced understanding of the relationship between erection and satisfaction in ED treatment: application of a longitudinal mediation model.

To apportion the direct effect and the indirect effect (through erections) that sildenafil (vs placebo) has on individual satisfaction and couple satisfaction over time, longitudinal mediation modeling was applied to outcomes on the Sexual Experience Questionnaire. The model included data from weeks 4 and 10 (double-blind phase) and week 16 (open-label phase) of a controlled study. Data from 167 patients with erectile dysfunction (ED) were available for analysis. Estimation of statistical significance was based on bootstrap simulations, which allowed inferences at and between time points. Percentages (and corresponding 95% confidence intervals) for direct and indirect effects of treatment were calculated using the model. For the individual satisfaction and couple satisfaction domains, direct treatment effects were negligible (not statistically significant) whereas indirect treatment effects via the erection domain represented >90% of the treatment effects (statistically significant). Week 4 vs week 10 percentages of direct and indirect effects were not statistically different, indicating that the mediation effects are longitudinally invariant. As there was no placebo arm in the open-label phase, mediation effects at week 16 were not estimable. In conclusion, erection has a crucial role as a mediator in restoring individual satisfaction and couple satisfaction in men with ED treated with sildenafil.

Psychometric validation of the physician global assessment scale for assessing severity of psoriasis disease activity.

PURPOSE: The Physician Global Assessment (PGA) is a key measure of psoriasis frequently used in clinical trials. A psychometric validation of a three-item (erythema, induration, and scaling) PGA scale was performed using Phase 2 data. METHODS: Confirmatory factor analysis (CFA) tested the PGA measurement model and appropriateness of equal weighting of the items. PGA test-retest reliability was assessed by estimating the intraclass correlation coefficient (ICC). Internal consistency reliability was gauged by calculating Cronbach's coefficient α (CCα). Clinically important difference (CID) was defined using the repeated measures model to estimate the relationship between PGA and Patient Global Assessment (PtGA). Known-group, convergent, and divergent validity for the PGA were also assessed. RESULTS: 197 patients with psoriasis were randomized to tofacitinib 2, 5, 15 mg twice daily, or placebo. CFA demonstrated that the PGA measurement model fitted the data using equal weighting of the PGA items. The PGA scale demonstrated good test-retest reliability (ICC > 0.7) and internal consistency reliability (CCα > 0.8). The CID for PGA was estimated at 0.52 (95 % confidence interval: 0.47, 0.56). A robust monotonic relationship between PGA and Psoriasis Area and Severity Index (PASI) data substantiated known-group validity. Relatively high correlations of PGA with PASI and PtGA data (all correlations >0.5 except at baseline) supported convergent validity; relatively low correlations of PGA with the Pain/Discomfort Assessment and the Ocular Comfort Index supported divergent validity. CONCLUSIONS: The three-item PGA scale has sound psychometric properties with respect to reliability and validity, with equal weighting of the items being appropriate.

Evaluation of the fibromyalgia impact questionnaire at baseline as a predictor for time to pain improvement in two clinical trials of pregabalin.

BACKGROUND: The Fibromyalgia Impact Questionnaire (FIQ) is a patient-reported outcome that evaluates the impact of fibromyalgia (FM) on daily life. This study evaluated the relationships between the functional status of FM patients, measured with the FIQ at baseline, and median time to a clinically relevant pain reduction. METHODS: Data were derived from two randomised, placebo-controlled trials that evaluated pregabalin 300, 450 and 600 mg/day for the treatment of FM. The Kaplan-Meier (nonparametric) method was applied to estimate median times to 'transient' and 'stable' events. The transient event was defined as a ≥ 27.9% improvement on an 11-point daily pain diary scale (0 = no pain, 10 = worst possible pain), and the stable event was defined as the mean of the daily improvements ≥ 27.9% relative to baseline over the subsequent study duration starting on the day of the transient event. A parametric model using time-to-event analysis was developed for evaluating the relationship between baseline FIQ score and the median time to these events. RESULTS: Median time was longer among patients treated with placebo relative to pregabalin for the transient events (11-12 days vs. 5-7 days) and stable events (86 days vs. 13-29 days). A significant association was observed between baseline FIQ scores and median time to transient and stable events (p < 0.001). Median times to events were similar between the studies. For transient pain reduction events, median times ranged from 3.0 to 4.5 days for baseline FIQ scores of 10, and 9.1-9.6 days for FIQ scores of 100; for stable pain reduction events, the median time ranged from 11.0 to 13.0 days and from 27.0 to 28.5 days for baseline FIQ scores of 10 and 100 respectively. CONCLUSIONS: Time to a clinically relevant reduction in pain was significantly associated with FM severity at baseline as measured by the FIQ. Such an analysis can inform patient and physician expectations in clinical practice.

Baseline quality of life as a prognostic survival tool in patients receiving sunitinib for metastatic renal cell carcinoma.

BACKGROUND: In a randomized phase III trial of sunitinib vs interferon-alfa (IFN-α) in metastatic renal cell carcinoma (mRCC), better baseline quality of life (QoL) was predictive of longer survival. Using this dataset, we have developed a novel prognostic tool that establishes a relationship between baseline QoL scores and median survival time. METHODS: Baseline QoL was assessed using the FACT-Kidney Symptom Index-15 item (FKSI-15), its disease-related symptoms (FKSI-DRS) subscale, and the Functional Assessment of Cancer Therapy-General (FACT-G) scale. Weibull models estimated median progression-free survival (mPFS) and overall survival (mOS) as a function of baseline QoL. RESULTS: Longer PFS and OS were associated with higher baseline FKSI-15, FKSI-DRS, and FACT-G scores (P<0.05), and baseline FKSI-15 score was the best predictor of survival. For example, for a baseline FKSI-15 score of 60, the predicted mPFS was 67.9 weeks, and predicted mOS was 240.6 weeks. The magnitude of benefit was greater with sunitinib vs IFN-α for a given baseline QoL score. CONCLUSION: This novel tool indicates that baseline FKSI-15 scores were linked to mPFS and mOS in a clear and interpretable way. The results support evaluation of patient-reported QoL symptoms at baseline as a prognostic indicator of survival in clinical research and practice.

Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: final results and geographical analysis.

BACKGROUND: In a randomised phase III trial, sunitinib significantly improved efficacy over interferon-alpha (IFN-alpha) as first-line therapy for metastatic renal cell carcinoma (mRCC). We report the final health-related quality of life (HRQoL) results. METHODS: Patients (n=750) received oral sunitinib 50 mg per day in 6-week cycles (4 weeks on, 2 weeks off treatment) or subcutaneous IFN-alpha 9 million units three times weekly. Health-related quality of life was assessed with nine end points: the Functional Assessment of Cancer Therapy-General and its four subscales, FACT-Kidney Symptom Index (FKSI-15) and its Disease-Related Symptoms subscale (FKSI-DRS), and EQ-5D questionnaire's EQ-5D Index and visual analogue scale. Data were analysed using mixed-effects model (MM), supplemented with pattern-mixture models (PMM), for the total sample and the US and European Union (EU) subgroups. RESULTS: Patients receiving sunitinib reported better scores in the primary end point, FKSI-DRS, across all patient populations (P<0.05), and in nine, five, and six end points in the total sample, in the US and EU groups respectively (P<0.05). There were no significant differences between the US and EU groups for all end points with the exception of the FKSI item 'I am bothered by side effects of treatment' (P=0.02). In general, MM and PMM results were similar. CONCLUSION: Patients treated with sunitinib in this study had improved HRQoL, compared with patients treated with IFN-alpha. Treatment differences within the US cohort did not differ from those within the EU cohort.

Evaluating the Power of Food Scale in obese subjects and a general sample of individuals: development and measurement properties.

BACKGROUND: The Power of Food Scale (PFS) was developed to assess the psychological impact of today's food-abundant environments. OBJECTIVE: To evaluate the structure of the PFS in diverse populations of obese and nonobese individuals. DESIGN: Data were obtained from obese adults in a clinical trial for a weight management drug (n=1741), and overweight, obese and normal weight adults in a Web-based survey (n=1275). Exploratory and confirmatory factor analyses were used to investigate the PFS structure using the clinical data. The model developed was then tested using the Web-based data. Relationships between PFS domains and body mass index (BMI) were examined. Logistic regression was used in the Web-based survey to evaluate the association between obesity status and PFS scores. RESULTS: Clinical data indicated that the scale was best represented by a 15-item version with three subscale domains and an aggregate domain (average of three domains); this was confirmed with data from the Web-based survey (Comparative Fit Index: 0.95 and 0.94 for the clinical and Web-based studies, respectively). Cronbach's alpha for both data sets was high, ranging from 0.81 to 0.91. The relationships between BMI and each domain were weak (and approximately linear). A full category increase in PFS domain score (range 1-5) increased the odds of being obese 1.6-2.3 times. CONCLUSIONS: The 15-item PFS is best represented by three domains and an aggregate domain. The PFS may provide a useful tool to evaluate the effects of obesity treatments on feelings of being controlled by food in an obesogenic food environment.

Psychometric analysis of the Three-Factor Eating Questionnaire-R21: results from a large diverse sample of obese and non-obese participants.

BACKGROUND: The 21-item Three-Factor Eating Questionnaire (TFEQ-R21) is a scale that measures three domains of eating behavior: cognitive restraint (CR), uncontrolled eating (UE) and emotional eating (EE). OBJECTIVES: To assess the factor structure and reliability of TFEQ-R21 (and if necessary, refine the structure) in diverse populations of obese and non-obese individuals. DESIGN: Data were obtained from obese adults in a United States/Canadian clinical trial (n=1741), and overweight, obese and normal weight adults in a US web-based survey (n=1275). Confirmatory factor analyses were employed to investigate the structure of TFEQ-R21 using baseline data from the clinical trial. The model was refined to obtain adequate fit and internal consistency. The refined model was then tested using the web-based data. Relationships between TFEQ domains and body mass index (BMI) were examined in both populations. RESULTS: Clinical data indicated that TFEQ-R21 needed refinement. Three items were removed from the CR domain, producing the revised version TFEQ-R18V2 (Comparative Fit Index (CFI)=0.91). Testing TFEQ-R18V2 in the web-based sample supported the revised structure (CFI=0.96; Cronbach's coefficient alpha of 0.78-0.94). Associations with BMI were small. In the clinical study, the CR domain showed a significant and negative association with BMI. On the basis of the web-based survey, it was shown that the relationship between BMI and CR is population-dependent (obese versus non-obese, healthy versus diabetics). CONCLUSIONS: In two independent datasets, the TFEQ-R18V2 showed robust factor structure and good reliability. It may provide a useful tool for characterizing UE, CR and EE.