Confirmatory psychometric evaluations of the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT).

The Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) was developed to assess weight-related physical and psychosocial functioning in the context of clinical trials. Data from two pivotal trials of once-weekly subcutaneous semaglutide for the purpose of weight management (NCT03548935 and NCT03552757) were analysed to confirm the structure, reliability, validity, and responsiveness of the IWQOL-Lite-CT and evaluate the magnitude of meaningful within-patient change in patients with overweight or obesity, with and without type 2 diabetes. Factor analyses and inter-item correlations confirmed the IWQOL-Lite-CT structure and scoring algorithm. Each composite score (physical, physical function, psychosocial, and total) demonstrated excellent internal consistency (Cronbach's alphas ≥ 0.82) and test-retest reliability (intraclass correlation coefficients ≥ 0.85) in both trials. Patterns of cross-sectional and longitudinal construct validity correlations were generally consistent with hypotheses. Each of the IWQOL-Lite-CT composites was able to discriminate between known groups. Effect sizes and paired t tests comparing IWQOL-Lite-CT scores at baseline and Week 68 were statistically significant for all composites in both trials (P < 0.0001), providing strong support for the ability to detect change. Results of anchor-based analyses supported responder thresholds ranging from 13.5 to 16.6 across composite scores. The IWQOL-Lite-CT, a comprehensive assessment of weight-related functioning from the patient perspective, is appropriate for use in clinical trials evaluating the efficacy of new treatments for weight management.

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

Psychometric evaluation of a visual analog scale for the assessment of anxiety.

BACKGROUND: Fast-acting medications for the management of anxiety are important to patients and society. Measuring early onset, however, requires a sensitive and clinically responsive tool. This study evaluates the psychometric properties of a patient-reported Global Anxiety-Visual Analog Scale (GA-VAS). METHODS: Data from a double-blind, randomized, placebo-controlled study of lorazepam and paroxetine in patients with Generalized Anxiety Disorder were analyzed to assess the reliability, validity, responsiveness, and utility of the GA-VAS. The GA-VAS was completed at clinic visits and at home during the first week of treatment. Targeted psychometric analyses--test-retest reliabilities, validity correlations, responsiveness statistics, and minimum important differences--were conducted. RESULTS: The GA-VAS correlates well with other anxiety measures, at Week 4, r=0.60 (p<0.0001) with the Hamilton Rating Scale for Anxiety and r=0.74 (p<0.0001) with the Hospital Anxiety and Depression Scale-Anxiety subscale. In terms of convergent and divergent validity, the GA-VAS correlated -0.54 (p<0.0001), -0.48 (p<0.0001), and -0.68 (p<0.0001) with the SF-36 Emotional Role, Social Function, and Mental Health subscales, respectively, but correlated much lower with the SF-36 physical functioning subscales. Preliminary minimum important difference estimates cluster between 10 and 15 mm. CONCLUSIONS: The GA-VAS is capable of validly and effectively capturing a reduction in anxiety as quickly as 24 hours post-dose.

Development and psychometric evaluation of the Endometriosis Treatment Satisfaction Questionnaire.

PURPOSE: To develop and psychometrically evaluate the Endometriosis Treatment Satisfaction Questionnaire, a patient-reported assessment of satisfaction with endometriosis treatment. METHODS: The Endometriosis Treatment Satisfaction Questionnaire was developed based on the results of five focus groups and three iterative sets of cognitive interviews along with expert opinion and a review of the literature. The psychometric properties were assessed using data collected during a multicenter, randomized, proof-of-concept trial. The development and validation processes followed the guidance recommended by the United States FDA for patient-reported outcome instruments. RESULTS: The Endometriosis Treatment Satisfaction Questionnaire's reliability, validity, and utility as a measure of patient satisfaction with their endometriosis treatment were supported. The results of the item-level analyses showed no evidence of distributional anomalies or response scale biases. The Endometriosis Treatment Satisfaction Questionnaire is unidimensional, has excellent internal consistency reliability, and discriminates well between known groups. Scores correlated well with other patient-reported outcome measures of endometriosis without being redundant. CONCLUSIONS: The Endometriosis Treatment Satisfaction Questionnaire has utility for assessing patient satisfaction with endometriosis treatment and may be useful in clinical trials that are assessing new treatments for endometriosis, especially when deciding between competing treatments or regimens that are found to have similar tolerability and efficacy.

Validation of a new measure of quality of life in obesity trials: Impact of Weight on Quality of Life-Lite Clinical Trials Version.

The Impact of Weight on Quality of Life-Lite (IWQOL-Lite) is widely used in evaluations of weight-loss interventions, including pharmaceutical trials. Because this measure was developed using input from individuals undergoing intensive residential treatment, the IWQOL-Lite may include concepts not relevant to clinical trial populations and may be missing concepts that are relevant to these populations. An alternative version, the IWQOL-Lite Clinical Trials Version (IWQOL-Lite-CT), was developed and validated according to the US Food and Drug Administration's (FDA's) guidance on patient-reported outcomes. Psychometric analyses were conducted to validate the IWQOL-Lite-CT using data from two randomized trials (NCT02453711 and NCT02906930) that included individuals with overweight/obesity, with and without type 2 diabetes. Additional measures included the SF-36, global items, weight and body mass index. The IWQOL-Lite-CT is a 20-item measure with two primary domains (Physical [seven items] and Psychosocial [13 items]). A five-item Physical Function composite and Total score were also supported. Cronbach's alpha and intraclass correlation coefficients exceeded 0.77 at each time point; patterns of construct validity correlations were consistent with hypotheses; and scores demonstrated treatment benefit. The IWQOL-Lite-CT is appropriate for assessing weight-related physical and psychosocial functioning in populations commonly targeted for obesity clinical trials. Qualification from the FDA is being sought for use of the IWQOL-Lite-CT in clinical trials to support product approval and labelling claims.

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

Development and evaluation of the Daily Assessment of Symptoms - Anxiety (DAS-A) scale to evaluate onset of symptom relief in patients with generalized anxiety disorder.

BACKGROUND: Fast-acting anxiolytics are important to patients and society. Measuring early onset, however, requires a sensitive and clinically responsive measure. This study develops and evaluates the psychometric properties of a new patient-reported instrument, the Daily Assessment of Symptoms - Anxiety (DAS-A), designed to detect reduction of anxiety symptoms in patients with Generalized Anxiety Disorder (GAD) during the first week of treatment. METHODS: Clinician interviews and patient focus groups were conducted to identify relevant constructs; discussions focused on early symptom improvement and meaningful changes in GAD symptoms. The draft questionnaire underwent iterative sets of cognitive interviews to inform item reduction and revision. A double-blind, randomized, placebo-controlled study of paroxetine and lorazepam assessed the performance of the new instrument in GAD patients. Analyses evaluated the structure, reliability, validity, and utility of the instrument. RESULTS: There was consistency across focus groups and clinicians in the description of symptoms that improve first. The final item set was easily understood by interview participants. Factor analyses indicated that a unidimensional structure best described the data. Item-level descriptive statistics, Cronbach's alphas, effect sizes, and validity correlations with other scales were favorable. Most importantly, the DAS-A demonstrated separation of lorazepam from placebo within 24h of first dose and correlated with other anxiety measures. CONCLUSIONS: This study resulted in the development of a reliable and valid instrument addressing the DSM-IV dimensions of GAD. The DAS-A is capable of detecting reduction in anxiety symptoms within 24h, making it a desirable measure to include in future trials of fast-acting anxiety medications.

Review and evaluation of patient-centered psychosocial assessments for children with central precocious puberty or early puberty.

The objective of this study was to assess the current use of patient-centered psychosocial assessments for the evaluation of children with central precocious puberty (CPP). Studies evaluating the psychosocial impact of CPP were identified through searches of the PubMed and Cochrane Library databases, ClinicalTrials.gov, a drug prescribing information database, and regulatory websites. Studies were screened using prespecified inclusion and exclusion criteria. Potentially relevant patient-centered outcome assessments (including patient-, parent- or observer-reported measures) used in the identified studies were evaluated in detail for their relevance in CPP. Of the 467 studies identified, 15 met the inclusion criteria. Frequently assessed concepts included depression and anxiety, behavior and behavioral problems, body image and self-esteem and personality type/characteristics. Among the assessments used in the identified studies, the Child Behavior Checklist, Pediatric Quality of Life Inventory (PedsQL), SF-10 for Children and Child Health Questionnaire were comprehensively evaluated. The PedsQL showed promise as a patient-centered outcome measure in CPP. Although there is a lack of validated tools measuring psychosocial health and health-related quality of life in patients with CPP, the PedsQL captures issues seen in this patient population and is relatively easy to administer. Further studies using this and other tools in children with CPP are needed.

Estimating the prevalence and impact of antidepressant-induced sexual dysfunction in 2 European countries: a cross-sectional patient survey.

OBJECTIVE: Sexual dysfunction is a common side effect of antidepressant treatment, but recognition of the problem is variable. The aim of this study was to estimate the prevalence and impact of sexual dysfunction during antidepressant treatment in 2 European countries. METHOD: A cross-sectional survey of 502 adults in France and the United Kingdom. All participants were diagnosed with depression and taking a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), starting within the previous 3 months. Information was gathered about other medications and conditions known to impair sexual functioning, recent changes in sexual functioning, and the impact of any changes. The Medical Outcomes Study 12-Item Short-Form Health Survey and the Arizona Sexual Experience Scale were administered to measure health status and sexual functioning. Data were collected from June to July of 2002. RESULTS: Applying a prevalence estimate algorithm, 26.6% of the French sample and 39.2% of the U.K. sample were classified as having antidepressant-induced sexual dysfunction; 34.2% of men and 32.5% of women were classified with antidepressant-induced sexual dysfunction. There was no clear pattern of antidepressant-induced sexual dysfunction related to specific antidepressants. Patients with antidepressant-induced sexual dysfunction reported that changes in sexual functioning negatively affected their self-esteem, mood, and relationships with sexual partners. 23.8% of the French sample and 25.2% of the U.K. sample reported that they perceived that their partner was dissatisfied with their sex life. CONCLUSION: The prevalence of antidepressant-induced sexual dysfunction in this study is similar to previous estimates reported in the literature. The impact of antidepressant-induced sexual dysfunction is substantial and negatively affects quality of life, self-esteem, mood, and relationships with sexual partners.

The validity and utility of the BPI interference measures for evaluating the impact of osteoarthritic pain.

The psychometric properties of the Brief Pain Inventory (BPI), a widely used measure of pain and its impact on functioning, were assessed using data from two clinical trials of controlled-release oxycodone in osteoarthritis (OA) patients. Specifically, the pain-related functional interference subscale and the sleep item from that subscale were examined. In Study 1 (n = 133), "night awakenings with pain" was positively correlated with the BPI interference score and sleep item and both correlated negatively with "quality of sleep." In Study 2 (n = 107), pain experienced "at night while in bed" correlated higher with sleep interference than with the BPI interference subscale. Intraclass correlations denoted adequate test-retest reliability; moderate-to-large Guyatt's statistics provided evidence of responsiveness. These analyses address a gap in the literature regarding the psychometric properties of the BPI interference measures in noncancer pain patients, confirming their reliability, validity, and responsiveness as potential endpoints in trials of pain medications involving patients with OA.

Uterine fibroids: a review of health-related quality of life assessment.

OBJECTIVE: To summarize the literature describing the impact of uterine fibroids on health-related quality of life (HRQOL), the measures used to assess HRQOL, and related areas for future research. METHODS: A search of three electronic databases (MEDLINE, Embase, and Current Contents) was performed, and 40 papers were identified referencing leiomyoma or uterine fibroids and (health-related) quality of life (HRQOL). Studies including women with benign gynecological conditions other than uterine fibroids were also reviewed. RESULTS: The EQ-5D, SF-36, and related generic measures are used to assess HRQOL in women with diverse gynecological conditions, including uterine fibroids. The UFS-QOL, a condition- specific measure, provides scores on symptom severity and six HRQOL dimensions. All instruments consistently demonstrate that HRQOL is considerably impaired in women with symptomatic uterine fibroids and that appropriate treatment can lead to improved QOL. CONCLUSIONS: The published data on HRQOL associated with uterine fibroids report significantly lower HRQOL scores for women with fibroids than for women without this disorder. Additional research is needed to confirm these findings and provide greater detail describing the specific domains most affected by uterine fibroids. These advances are necessary to effectively compare new treatment modalities vs. standard invasive therapies, such as hysterectomy.

Validation of a pediatric caregiver diary to measure symptoms of postacute respiratory syncytial virus bronchiolitis.

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

Quantitative challenges facing patient-centered outcomes research.

Patient-centered outcomes research collects and analyzes data from patients and other stakeholders to improve health care delivery and outcomes and guide health care decisions. However, there are a number of challenges in conducting quantitative analyses of patient-centered data. This article provides an overview of the analytical challenges and describes approaches to consider to overcome the challenges, as well as directions for future development.

Development of an electronic daily uterine fibroid symptom diary.

BACKGROUND: In some women, uterine fibroids are associated with severe, disabling symptoms. There is a lack of high-quality evidence supporting the effectiveness of most interventions for symptomatic uterine fibroids. In part, this is due to the lack of available disease-specific instruments with comprehensive validation evidence that measure treatment benefit from the patient perspective. OBJECTIVE: The aim of this study was to develop an electronic patient-reported outcomes (PRO) instrument that measures treatment benefit from the patient's perspective that is easily administered and practical for use in clinical trials. Rigorous methods that are consistent with the US FDA's PRO Guidance to Industry were employed. METHODS: The study took place in two phases: a content development phase (eight focus groups; three sets of cognitive interviews) and a prospective non-intervention usability pilot phase. Both phases were conducted in the US. The study population comprised women diagnosed with symptomatic uterine fibroids. A total of 68 women (mean age 40 years) participated in the eight focus groups; 27 women (mean age 41 years) who were not part of the focus groups participated in the cognitive interviews. Fourteen additional women (mean age 39 years) participated in a usability pilot. Efforts were made to recruit a diverse population with respect to race and education. RESULTS: After completing eight focus groups, no new symptom concepts or severity-level measurement ideas were introduced, indicating that concept saturation was achieved. Fourteen draft items were developed during the focus groups for testing in the cognitive interviews. Every symptom represented by the draft items was endorsed by at least two-thirds of the participants in the cognitive interviews. After completing three rounds of cognitive interviews, the Fibroid Symptom Diary© (FSD) contained eight items that assessed bleeding severity, menstrual cramping, and fibroid-related fatigue. An open-field item, tailored to each participant, was also included to assess the most bothersome fibroid-related pain. However, to accommodate electronic administration of the diary this item was replaced, prior to the usability pilot, with three pain-specific items (i.e. abdominal pain, low back pain, and pain during intercourse) that were most commonly expressed during the development phase. The final FSD includes 11 items: five addressing menstrual bleeding or spotting; one each relating to cramping (distinct from other pain), fatigue, and bloating; and three that address other fibroid-related pain. The average time for completing the diary was 1-2 minutes per day. A total of 118 daily diary records were collected from 14 participants (average of nine daily diary completions per participant; range 5-18 days) in the usability pilot. Seven participants completed the diary every day. Most participants experienced the majority of the symptoms included in the FSD. CONCLUSIONS: The FSD captures the concepts most important to women with uterine fibroids and has strong evidence of content validity as required by the FDA PRO Guidance to Industry. Once fully validated, the FSD may replace other measures for assessing changes in symptoms and treatment benefit that are both burdensome to patients and cumbersome to trial sponsors.