Changes in hemoglobin and clinical outcomes drive improvements in fatigue, quality of life, and physical function in patients with paroxysmal nocturnal hemoglobinuria: post hoc analyses from the phase III PEGASUS study.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, acquired, hematologic, life-threatening disease characterized by thrombosis, impaired bone marrow function, and complement-mediated hemolysis. The PEGASUS phase III clinical trial demonstrated superiority of pegcetacoplan over eculizumab regarding improvements in hemoglobin levels in patients with suboptimal response to prior eculizumab treatment. The objective of this post hoc analysis was to compare the patient-reported outcome (PRO) response rates observed among PEGASUS participants and the relationships between their PRO scores with clinical and hematological parameters. Data from the 16-week randomized, controlled (1:1 to pegcetacoplan or eculizumab) period of the PEGASUS trial included comparisons of weekly PRO measurements taken using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) scales. A clinically meaningful FACIT-F response was defined as an increase from baseline of ≥5 points. Convergent validity was assessed using conventional threshold correlations between FACIT-F, EORTC QLQ-C30, and laboratory parameters. A clinically meaningful improvement in FACIT-F score was seen in 72.2% of pegcetacoplan-treated patients compared to 22.9% of eculizumab-treated patients. At week 16, the FACIT-F total score correlated with hemoglobin levels (r=0.47, p< 0.0001), absolute reticulocyte count (r=-0.37, p<0.01), and indirect bilirubin levels (r=-0.25, p<0.05). Clinically meaningful improvements in pegcetacoplan-treated patients were also observed for multiple EORTC scales. Fatigue and other self-reported outcomes were correlated with clinically meaningful improvements in clinical and hematological parameters. Clinical trial registration: NCT03500549.

Measuring respiratory symptoms in moderate/severe asthma: evaluation of a respiratory symptom tool, the E-RS®: COPD in asthma populations.

BACKGROUND: Symptom constructs included in the Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease (E-RS®: COPD) tool may be relevant to patients with asthma. The purpose of this study was to evaluate content validity and psychometric performance of the E-RS: COPD in moderate/severe asthma patients. METHODS: Content validity of the E-RS: COPD was evaluated in patients with moderate/severe asthma using concept elicitation and cognitive debriefing interviews. Secondary analyses using data from two clinical trials in patients with moderate/severe asthma evaluated the factor structure of the E-RS: COPD plus two supplementary items (wheeze; shortness of breath with strenuous physical activity) and assessed psychometric properties of the tool, which will be referred to as E-RS®: Asthma when used in asthma populations. RESULTS: Qualitative interviews (N = 25) achieved concept saturation for asthma respiratory symptoms. Concepts in the E-RS: COPD were relevant to patients and instructions were understood. Most patients (19/25; 76%) reported experiencing all concepts in the E-RS: COPD; no patients indicated missing symptoms. Secondary analyses of clinical trial data supported the original factor structure (RS-Total and three symptom-specific subscales). The two supplemental items did not fit with this factor structure and were not retained. RS-Total and subscale score reliability was high (internal consistency [α] > 0.70). Validity was demonstrated through significant (P < 0.0001) relationships with the St George's Respiratory Questionnaire (SGRQ) and Asthma Symptom Severity scale. E-RS: Asthma was responsive to change when evaluated using SGRQ, Patient Global Impression of Change and Asthma Quality of Life Questionnaire as anchors (P < 0.0001). Clinically meaningful change thresholds were also identified (RS-Total: - 2.0 units). CONCLUSIONS: The E-RS: Asthma is reliable and responsive for evaluating respiratory symptoms in patients with moderate/severe asthma.

Psychometric Evaluation of a Novel Instrument Assessing the Impact of Migraine on Physical Functioning: The Migraine Physical Function Impact Diary.

OBJECTIVE: The objective of this study was to evaluate the measurement properties of the Migraine Physical Function Impact Diary (MPFID), a novel patient-reported outcome (PRO) measure for assessing the impact of migraine on physical functioning. METHODS: In a prospective, observational study, adults with episodic migraine (EM) or chronic migraine (CM) used an eDiary to complete the MPFID (assessing daily impacts of migraine on physical function) and a headache diary (capturing migraine days, migraine pain intensity, and migraine interference) each day, and other PRO instruments related to migraine. Item-level evaluation, item response theory (IRT), and exploratory factor analysis (EFA) methods were applied to identify domains, select final MPFID items, and develop scoring procedures. Psychometric properties of the final 13-item MPFID were evaluated using confirmatory factor analysis and tests of reliability (Cronbach's α for internal consistency and intra-class correlation [ICC] for test-retest) and validity (convergent and known-groups). RESULTS: The study enrolled 569 adults with chronic or episodic migraine, mean (SD) age 39.9 (12.0) years and 87.2% female. Item-level analyses based on interim data informed selection of a set of 13 items for the MPFID, through evaluation of floor/ceiling effects, item-to-item correlations, factor loadings, and IRT-based fit/misfit statistics. Two domain scores (EA: Impact on Everyday Activities; PI: Physical Impairment) and a global item score for impact on everyday activities were identified. EA and PI domains exhibited high internal consistency (α = 0.97; α = 0.93) and good test-retest reliability among stable subjects (ICCs = 0.74 and 0.77). Convergent validity was demonstrated by moderate correlations (r = ±0.50-0.68; P < .0001) between MPFID domain scores and number of migraine days, headache days, bed days, and other migraine-related PRO instruments. EA and PI scores differentiated between groups who varied by number of migraine days, migraine interference levels, migraine pain intensity, and median split groups of scores based on other PROs instruments (P < .05). CONCLUSIONS: The MPFID has robust psychometric properties (ie, reliability and validity). Findings supported two distinct domains about the impact of migraine on physical functioning: Impact on Everyday Activities and Physical Impairment. Both domain scores showed evidence of excellent reliability and construct validity in assessing the impacts of migraine on physical functioning.

Psychometric evaluation of a daily gastro-oesophageal reflux disease symptom measure.

OBJECTIVE: The objective of this study was to evaluate the validity of the Heartburn Reflux Dyspepsia Questionnaire (HRDQ), a newly developed measure of gastro-oesophageal reflux disease (GORD) symptoms. Specifically, the HRDQ was developed for patients, who still experience symptoms with proton pump inhibitor (PPI) treatment. MATERIAL AND METHODS: The psychometric properties of HRDQ were evaluated based on data from two clinical trials of patients with GORD with a partial response to PPIs, one from the UK and one from Denmark and Germany. RESULTS: The HRDQ had good internal consistency (Cronbach's alpha range .83-.88) and test-retest reliability (intraclass correlation coefficient range .71-.90). Convergent and discriminant validity were supported by high correlations with ReQuest™ and ability to differentiate between groups based on ReQuest™ cut-off values. Responsiveness of HRDQ was demonstrated by moderate to high correlations with ReQuest™ change scores and time with symptoms. An HRDQ cut-off value of 0.70 for definition of 'bad day' was also evaluated. CONCLUSIONS: Based on existing evidence, the HRDQ is a valid and reliable measure of GORD symptoms that can be used as a study outcome in clinical trials.

Prevalence of gastroprotective agent (GPA) use in adults with arthritis in the United States.

OBJECTIVE: The prevalence of non-steroidal anti-inflammatory drug (NSAID) and concurrent gastroprotective agent (GPA) use in the US is not known. As such, the prevalence of GPA use among arthritis patients taking NSAIDs was examined. METHODS: Men and women aged ≥ 40 with self-reported arthritis and members of a web-based community panel were invited via e-mail to participate in a web survey. Interested panelists consented and completed the survey. Participants using NSAIDs in the last 30 days were eligible. Questions regarding NSAID and GPA use were asked, likewise adherence to GPA (Morisky scale), comorbid conditions, gastrointestinal (GI) history, and other risk factors. Descriptive analyses and logistic regressions were performed to assess associations with GPA use and adherence. RESULTS: Invitations were sent to 7605 adults; 4108 (54%) responded; 2208 completed. Final sample was 1525 (76%) with osteoarthritis (OA), 354 (18%) with rheumatoid arthritis (RA), and 121 (6%) with both OA and RA. Mean age was 62.0; 64% were female; 83% white; 25% worked full-time, and 39% were retired. Mean duration with arthritis was 13.0 years; 47% and 19% experienced arthritis symptoms 'daily' and 'almost always', respectively. Nearly 43% reported using a GPA and 39% of daily NSAID users reported taking a GPA. Fifty-eight participants (2.9%) were classified as low GI risk, 342 (17.1%) were moderate risk, and 1600 (80.0%) were high risk. Variables significantly associated with GPA use included older age; male gender; being white (vs. Hispanic); taking an NSAID at least daily; taking fewer NSAIDs; taking a Cox-2 inhibitor or prescription NSAID; history of GI conditions; prescription antiplatelet use; and having GI symptoms. Similar variables were associated with GPA adherence. CONCLUSION: Less than half of adult men and women in the US taking a daily NSAID used GPAs and only 37% of high-risk participants were taking GPAs.

An electronic diary is shown to be more reliable than a paper diary: results from a randomized crossover study in patients with persistent asthma.

OBJECTIVES: Test-retest reliability of an asthma paper diary versus an electronic diary (e-diary) with an integrated peak flow meter was investigated. The equivalence of the two modes was also evaluated. METHODS: Prospective, randomized crossover study design in adolescents (12-17 years) and adults (≥18 years). Key inclusion criteria were persistent asthma, Asthma Control Test (ACT) scores ≥16, use of inhaled corticosteroid with or without long-acting beta-agonist for ≥12 weeks, nocturnal awakenings <2 times in the past week, and activity limitations <1 per week. Participants were randomized to either paper then e-diary or e-diary then paper, to be completed for 14 days each. RESULTS: Forty-seven participants completed all study visits. Weekly percentage of symptom-free days (SFDs) and rescue-free days (RFDs) were calculated. Intraclass correlation coefficients (ICCs) of Week 1 mean SFD and RFD (test) and Week 2 mean SFD and RFD (retest), respectively, were estimated in three groups defined as stable: (i) minimal changes in asthma symptoms, as measured by the global patient reported symptom change question, (ii) less than 15% change (absolute value) in 1 second FEV(1) at adjacent study visits, and (iii) changes in ACT scores less than three points for each mode. SFD demonstrated acceptable ICC (≥0.70) using all three definitions of asthma stability for both modes. CONCLUSION: Acceptable reproducibility of the percentage of RFD (ICC = 0.78) was only observed for the e-diary using the FEV(1) stability criterion. The ICCs for SFD and RFD were acceptable, 0.84 and 0.70, respectively, suggesting better reliability for the e-diary.

Validation of the urinary sensation scale (USS).

AIM: The purpose of this study was to assess the validity of the Urinary Sensation Scale (USS) in men with overactive bladder and voiding symptoms (OAB-LUTS) and women with overactive bladder (OAB). METHODS: Data from two OAB clinical trials of tolterodine were used. The USS, a 5-point scale, assesses the amount of urinary urgency associated with each urination. Three methods to calculate the USS are: mean urgency (Mean USS); mode urgency (Mode USS); and sum urgency (sum USS). The validity and responsiveness of the scoring methods was assessed using Spearman's correlations, general linear models, and effect sizes. RESULTS: Data from 650 men (Study 1) and 413 women (Study 2) were analyzed. Mean age was 65.2 (men) and 47.8 (women); 70% were Caucasian in both studies. Correlations of USS scores with bladder diary variables were small to moderate and higher among Sum USS than Mean USS (r=0.02-0.64). Correlations among the USS and patient-reported outcomes (PROs) were again small to moderate and higher with Sum USS (r=0.05-0.41). Both the Mean USS and Sum USS significantly discriminated (all P<0.001) among all bladder diary variables (except nocturia and UUI in men) when grouped as improved/not improved as well as by the PROs. Effect sizes for men and women, respectively, were -0.52 and -1.09 for Mean USS and -0.72 and -1.36 for Sum USS. CONCLUSION: The USS is a valid and highly responsive measure of urinary urgency in men with OAB-LUTS and women with OAB.

Development and validation of a composite score based on clinically meaningful events for the opioid-related symptom distress scale.

PURPOSE: To develop and validate a composite score based on clinically meaningful events (CMEs) for the opioid-related symptom distress scale (OR-SDS) that would be appropriate for use in postoperative clinical trials. METHODS: Secondary analysis of data from 2 multi-site Phase III randomized clinical safety trials: a general surgery trial (N = 1,050) and a coronary artery bypass graft surgery trial (N = 1,636). Validating measures include daily opioid consumption and physician and patient global evaluations of study medication. We empirically defined CMEs for each symptom, using factor analysis and an area under the receiver-operating characteristic analysis of the severity and frequency items of the OR-SDS. Construct validity was examined by testing hypotheses of relationships between composite CME scores and opioid consumption and physician and patient evaluations of study medication. RESULTS: Hypotheses supporting the construct validity of the CME-based composite score were confirmed. Significant associations were found between higher numbers of CMEs with greater opioid consumption and lower likelihood of a positive evaluation of the study medication. CONCLUSIONS: The OR-SDS CME-based composite score demonstrates evidence of construct validity and appears appropriate for use in evaluating patients' opioid-related side effect burden in future postoperative clinical trials.