Dennis D. Gagnon

Epoetin Alfa Treatment Results in Clinically Significant Improvements in Quality of Life in Anemic Cancer Patients When Referenced to the General Population

PURPOSE Anemia, highly common among cancer patients, is often an underlying cause of cancer-related fatigue and other quality-of-life (QOL) deficits. Although randomized clinical trials have shown that treatment with epoetin alfa increases hemoglobin levels, reduces fatigue, lessens transfusion requirements, and improves overall QOL, cancer-related anemia and fatigue remain undertreated. This is, in part, because scales and measures of QOL are still relatively unfamiliar to most clinicians and because population-based reference ranges are lacking, thus making clinical trial results difficult to interpret. METHODS To aid in the interpretation of QOL results from clinical trials, we administered the Functional Assessment of Cancer Therapy-Anemia (FACT-An) QOL instrument to a nationally representative sample of 1,400 people using an Internet survey panel in the United States. We then compared the FACT-An data from the Internet survey with the QOL data of a 375-patient randomized, double-blind clinical trial evaluating epoetin alfa versus placebo in anemic cancer patients. RESULTS FACT-An, as administered to the survey population, displayed good psychometric properties and was able to discriminate between respondents with histories of specified illnesses, including anemia and cancer, and those without. Comparison of the population norm and clinical trial data showed that treatment with epoetin alfa resulted in clinically meaningful as well as statistically significant improvements in QOL (P <.01). CONCLUSION Reliable population norm data are now available to aid in the interpretation of clinical trial results where the FACT-An questionnaire is administered. In the clinical trial, treatment with epoetin alfa overcame much of the QOL deficit seen in anemic cancer patients compared with the norm population sample.

Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial.

BACKGROUND Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy. METHODS The COU-AA-301 trial enrolled patients with metastatic castration-resistant prostate cancer in whom one or two lines of chemotherapy (one docetaxel based) had been unsuccessful and who had Eastern Cooperative Oncology Group performance statuses of 2 or less. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form questionnaire at baseline, day 15 of cycle 1, and day 1 of each treatment cycle thereafter until discontinuation. We assessed, with prospectively defined response criteria that incorporated analgesic use, clinically meaningful changes in pain intensity and interference with daily living. We measured time to first occurrence of skeletal-related events, which we defined as pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery, and regularly assessed them throughout the study. Pain palliation was assessed in patients who had clinically significant baseline pain, whereas all other analyses were done in the overall intention-to-treat population. COU-AA-301 is registered with ClinicalTrials.gov, number NCT00638690. FINDINGS Median follow-up was 20·2 months (IQR 18·4-22·1). In patients with clinically significant pain at baseline, abiraterone acetate and prednisone resulted in significantly more palliation (157 of 349 [45·0%] patients vs 47 of 163 [28·8%]; p=0·0005) and faster palliation (median time to palliation 5·6 months [95% CI 3·7-9·2] vs 13·7 months [5·4-not estimable]; p=0·0018) of pain intensity than did prednisone only. Palliation of pain interference (134 of 223 [60·1%] vs 38 of 100 [38·0%], p=0·0002; median time to palliation of pain interference 1·0 months [95% CI 0·9-1·9] vs 3·7 months [2·7-not estimable], p=0·0004) and median duration of palliation of pain intensity (4·2 months [95% CI 3·0-4·9] vs 2·1 months [1·4-3·7]; p=0·0056) were significantly better with abiraterone acetate and prednisone than with prednisone only. In the overall population, median time to occurrence of first skeletal-related event was significantly longer with abiraterone acetate and prednisone than with prednisone only (25·0 months [95% CI 25·0-not estimable] vs 20·3 months [16·9-not estimable]; p=0·0001). INTERPRETATION In patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, abiraterone acetate and prednisone offer significant benefits compared with prednisone alone in terms of pain relief, delayed pain progression, and prevention of skeletal-related events. FUNDING Janssen Research & Development and Janssen Global Services.

Reliability, validity and ability to detect change of the Personal and Social Performance scale in patients with stable schizophrenia

This report describes the measurement properties of the Personal and Social Performance scale (PSP), a clinician-reported measure of severity of personal and social dysfunction, in an outpatient population with stabilized schizophrenia. Pooled data from two similar antipsychotic clinical studies were analyzed (n=411). The PSP showed good test-retest reliability (intraclass correlation coefficient=0.79). The PSP was more highly correlated with the Strauss-Carpenter Level of Function, an instrument measuring a similar construct, than the Positive and Negative Syndrome Scale, an instrument measuring a different construct. There was a statistically significant difference between mean PSP scores in subjects grouped by their severity rating on the Clinical Global Impression-Severity (CGI-S) (mild or less versus at least moderate), indicating the ability to discriminate between known groups. Effect sizes for mean change in the PSP based on 1-category improvement (0.72) or worsening (-0.88) versus no change in the CGI-S were moderate to large, demonstrating the ability to detect change. Estimates of between-group minimum important difference suggest that a 7-point improvement in the PSP may be clinically meaningful in a clinical trial setting. Initial reliability and validity assessments suggest the PSP may be a useful measure of social functioning in patients with stable schizophrenia.

Relationship Between Seizure Frequency and Costs and Quality of Life of Outpatients with Partial Epilepsy in France, Germany, and the United Kingdom

Summary: Purpose: The relationship between seizure frequency and both health care costs and quality of life (QOL) was investigated in a retrospective, cross‐sectional, multicenter study in France, Germany, and the United Kingdom.

The Premature Ejaculation Profile: validation of self-reported outcome measures for research and practice.

To evaluate the reliability and validity of the Premature Ejaculation Profile (PEP), a self‐reported outcome instrument for evaluating domains of PE and its treatment, comprised of four single‐item measures, a profile, and an index score.

Reliability, validity and ability to detect change of the clinician-rated Personal and Social Performance scale in patients with acute symptoms of schizophrenia

ABSTRACT Objective: To describe the measurement properties of the Personal and Social Performance scale (PSP), a clinician-reported measure of severity of personal and social dysfunction, in subjects with acute symptoms of schizophrenia. Methods: Pooled data from three paliperidone extended-release clinical studies (n = 1665) and data from a separate noninterventional, cross-sectional, validation study (n = 299) were analyzed. Results: The PSP showed good interrater (intraclass correlation coefficient [ICC] = 0.87) and test–retest (ICCs > 0.90) reliability. Pearson correlation coefficient for association between baseline PSP and Positive and Negative Syndrome Scale (PANSS) total scores was −0.32 for subjects assessed by the same rater and −0.29 for subjects assessed by different raters, suggesting low overlap in measurement constructs between the PANSS and PSP. Spearman Rank correlation coefficient for association between baseline PSP and Clinical Global Impression-Severity (CGI-S) scores was −0.51 with the same rater and −0.15 with different raters. Hypothesized relationships between the PSP and the PANSS or CGI-S based on levels of disease severity were prospectively defined. These hypotheses were confirmed by analyses showing statistically significant differences between baseline mean PSP scores in subjects grouped by severity rating on the CGI-S (mild or less vs. at least moderate) (p < 0.001) and the PANSS (‘low symptom severity’ vs. ‘high symptom severity’) (p = 0.005). The PSP was sensitive to change based on statistically significant correlations between change in the PSP and change in the CGI-S (p < 0.001) and the PANSS (p < 0.001). Limitations of analyses include pooling data across studies, interrater reliability assessment in the validation study only, post hoc assessment of test–retest reliability in the paliperidone ER studies, different raters for the PSP and PANSS not specified in the paliperidone ER studies, PSP validity assessment based on the PANSS and the CGI-S as comparators rather than another social function instrument. Conclusion: These initial reliability and validity assessments suggest the PSP has promise as a measure of social functioning in patients with acute symptoms of schizophrenia.

Effect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy

BACKGROUND Fatigue is a common, debilitating side-effect of prostate cancer and its treatment. Patient-reported fatigue was evaluated as part of COU-AA-301, a randomized, placebo-controlled, phase III trial of abiraterone acetate and prednisone versus placebo and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel chemotherapy. This is the first phase III study in advanced prostate cancer to evaluate fatigue outcomes using a validated fatigue-specific instrument. PATIENTS AND METHODS The Brief Fatigue Inventory (BFI) questionnaire was used to measure patient-reported fatigue intensity and fatigue interference with activities of daily life. All analyses were conducted using prespecified responder definitions of clinically meaningful changes. RESULTS A total of 797 patients were randomized to abiraterone acetate and prednisone, and 398 were randomized to placebo and prednisone. Compared with prednisone alone, in patients with clinically significant fatigue at baseline, abiraterone acetate and prednisone significantly increased the proportion of patients reporting improvement in fatigue intensity (58.1% versus 40.3%, P = 0.0001), improved fatigue interference (55.0% versus 38.0%, P = 0.0075), and accelerated improvement in fatigue intensity (median 59 days versus 194 days, P = 0.0155). CONCLUSIONS In patients with mCRPC progressing after docetaxel chemotherapy, abiraterone acetate and prednisone yielded clinically meaningful improvements in patient-reported fatigue compared with prednisone alone.

Effect of abiraterone acetate treatment on the quality of life of patients with metastatic castration-resistant prostate cancer after failure of docetaxel chemotherapy

BACKGROUND In a recent randomised, double-blind, phase III clinical trial among 1195 patients with metastatic castration-resistant prostate cancer (mCRPC) who had failed docetaxel chemotherapy, abiraterone acetate was shown to significantly prolong overall survival compared with prednisone alone. Here we report on the impact of abiraterone therapy on the health-related quality of life (HRQoL) observed during this trial, assessed using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. METHODS All analyses were conducted using prespecified criteria for clinically meaningful improvement and deterioration in FACT-P total score as well as subscale scores; all respective thresholds were defined using an accepted methodology. Improvement was assessed only in patients with clinically significant functional status impairment at baseline. RESULTS Significant improvements in the FACT-P total score were observed in 48% of patients receiving abiraterone versus 32% of patients receiving prednisone (p < 0.0001). Also, the median time to deterioration in FACT-P total score was longer (p < 0.0001) in patients receiving abiraterone (59.9 weeks versus 36.1 weeks). Similar differences were observed in all FACT-P subscales, with the exception of the social/family well-being domain. Median time to improvement in the physical well-being domain and the trial outcome index was significantly shorter (p < 0.01) with abiraterone when compared with the prednisone arm. CONCLUSIONS The previously demonstrated survival benefit for abiraterone is accompanied by improvements in patient-reported HRQoL and a significant delay in HRQoL deterioration when compared with prednisone.

Measuring social functioning with the personal and social performance scale in patients with acute symptoms of schizophrenia: interpretation of results of a pooled analysis of three Phase III trials of paliperidone extended-release tablets.

BACKGROUND The safety and efficacy of paliperidone extended-release tablets (paliperidone ER) in patients with acute symptoms of schizophrenia have been described in 3 randomized, double-blind, 6-week, placebo-controlled, fixed-dose, Phase III clinical trials. The validity and reliability of the Personal and Social Performance (PSP) scale, both in patients with acute symptoms of schizophrenia and those with stabilized symptoms, have also been reported. OBJECTIVE The aim of this work was to estimate the treatment benefit of paliperidone ER compared with placebo in terms of improvements in personal and social functioning as measured by the PSP scale in 3 controlled clinical trials. METHODS Data were derived from 3 paliperidone ER multicenter Phase III pivotal studies of patients with acute symptoms of schizophrenia. Each study included a randomized, double-blind, placebo- and active-controlled, parallel-group, 6-week treatment period with an open-label extension of paliperidone ER treatment. Patients were randomized to receive paliperidone ER, olanzapine 10 mg, or placebo once daily. Paliperidone ER doses were 3, 9, and 15 mg/d in 1 study; 6, 9, and 12 mg/d in another; and 6 and 12 mg/d in the third. Collectively, 1306 intent-to-treat patients received placebo or paliperidone ER in these 3 trials. Most (61.7%) were white; 21.6% were black, 8.8% were Asian, and 7.9% were of another race. The mean age ranged from 36.3 to 39.4 years across treatment groups. Multiple analyses were applied to PSP data (for which higher scores indicate better personal and social functioning) from these paliperidone ER studies: between-group minimum important difference (MID) estimates; responder analyses; between-group cumulative frequency comparisons of PSP change from baseline to end point; and number-needed-to-treat (NNT) estimates. RESULTS Standardized differences and effect sizes between paliperidone ER and placebo in PSP mean change from baseline to end point ranged from 0.52 to 0.85 for all paliperidone ER doses. Observed between-group differences (paliperidone ER minus placebo) in PSP mean change from baseline to end point exceeded the between-group MID of 7 points at all paliperidone ER doses. The percentage of patients achieving at least one 10-point category improvement in the PSP was higher with all paliperidone ER doses (range, 49.6%-63.6%) than placebo (33.1%) (P < 0.005). Across the distribution of all possible PSP scores, the percentage of patients achieving any level of change appeared to be greater for paliperidone ER than for placebo at all doses. Derived NNTs for improved personal and social functioning based on paliperidone ER trials ranged from 3.3 to 6.1. The improvement in personal and social functioning achieved by patients receiving paliperidone ER during the double-blind studies was maintained throughout the 52-week, open-label extension studies, as assessed using multiple definitions of response; subjects in the placebo arm during doubleblind treatment appeared to achieve and maintain improved functioning when switched to paliperidone ER for the extension studies. CONCLUSION These results suggest that paliperidone ER had a meaningful treatment benefit with respect to improving personal and social functioning in these patients with acute symptoms of schizophrenia.

Personal and social functioning in schizophrenia: defining a clinically meaningful measure of maintenance in relapse prevention

Abstract Background: Relapse prevention and maintenance of social functioning are important treatment objectives in the long-term management of schizophrenia. However, relatively little is known about measuring maintenance of social functioning to assess treatment benefit in relapse prevention clinical trials or as a tool to predict relapse in clinical practice. This study aims (1) to define a clinically meaningful decrease in the Personal and Social Performance scale (PSP) to assess antipsychotic treatment benefit in terms of maintenance of functioning and (2) to explore the threshold value of PSP decline as a useful tool to predict relapse in clinical practice. Methods: This post hoc analysis of two similar placebo-controlled relapse prevention clinical trials consisted of an exploration of change in PSP that would represent a clinically important decrement to measure treatment benefit in terms of time to PSP decrement (ITT analysis set; Study 1: n = 205) and an assessment of predictive value of PSP decrement and relapse status (ITT analysis set; Study 2: n = 408). Results: A 10-point decrement in PSP score was the threshold value for a clinically meaningful decline in personal and social functioning in a relapse prevention trial (Study 1). A strong association was found with relapse status: 61% of subjects with at least a 10-point decrease in PSP experienced the decrement prior to (between start of double-blind phase and before day of relapse) or on the day of relapse (Study 2). Kaplan–Meier survival analysis of time to at least a 10-point decrement in PSP showed that the proportion of subjects who did not experience at least a 10-point PSP decrease was statistically significantly greater in the paliperidone palmitate group than in the placebo group (p = 0.0014) (Study 2). Conclusions: Findings suggest a 10-point PSP decrement is a clinically relevant measure of maintenance of functioning in patients stabilized with antipsychotic therapy. Paliperidone palmitate demonstrated a statistically significant treatment benefit in terms of maintenance of functioning versus placebo. Furthermore, measuring a clinically relevant PSP decrement may be useful as an early functional indicator of relapse in clinical practice. Limitations: The exploration and validation of the threshold value of change in the PSP was designed and conducted post hoc. Predictive value is limited by the frequency in which PSP assessments were carried out in these trials, underscoring the importance of regular assessment.