Patients' and clinicians' perspectives on item importance, scoring, and clinically meaningful differences for the Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS).

BACKGROUND: The Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS) are patient-reported outcome measures developed to evaluate efficacy in clinical trials and clinical practice. The ESD is a daily electronic diary assessing symptom severity; the EIS is a weekly electronic diary assessing symptom impact. This study explored the importance of symptoms (ESD items) and impacts (EIS domains), perspectives on scoring algorithms, and clinically important difference (CID) thresholds to inform clinical trial score interpretation. METHODS: Endometriosis patients in Germany (n = 8) and the US (n = 17), and expert clinicians (n = 4) in Germany, the US, Spain, and Finland participated in semi-structured qualitative interviews comprising structured tasks. Interview transcripts were analyzed using thematic analysis techniques. RESULTS: Quality and severity of endometriosis-associated pelvic pain varied considerably among patients; some experienced pelvic pain daily, others during menstrual bleeding (dysmenorrhea) only. Patients and clinicians ranked "worst pelvic pain" as the most meaningful pain concept assessed by the ESD, followed by constant and short-term pelvic pain. Preferences for summarizing daily pain scores over the 28-day menstrual cycle depended on individuals' experience of pain: patients experiencing pain daily preferred scores summarizing data for all 28 days; patients primarily experiencing pain during selected days, and their treating clinicians preferred scores based on the most severe pain days. Initial CID exploration for the "worst pelvic pain" 0-10 numerical rating scale (0-10 NRS) revealed that, for most patients, a 2- or 3-point reduction was considered meaningful, depending on baseline severity. Patients and clinicians ranked "emotional well-being" and "limitations in physical activities" as the most important EIS domains. CONCLUSIONS: This study informs the use of the ESD and EIS as clinically relevant measures of endometriosis symptoms and their impact. Findings from the ESD highlight the importance of individual-patient assessment of pain experience and identify "worst pelvic pain" as the most meaningful symptom assessed. Aggregating scores over the 28-day menstrual cycle may inform meaningful endpoints for clinical trials. Diverse EIS concepts (e.g. impact on emotional well-being and physical activities) are meaningful to patients and clinicians, emphasizing the importance of evaluating the impact on both to comprehensively assess treatment efficacy and decisions. TRIAL REGISTRATION: Not applicable. Qualitative, non-interventional study; registration not required.

Patterns of missing data in the use of the endometriosis symptom diary.

BACKGROUND: Endometriosis is a common, chronic condition in women of reproductive age that is characterized by the presence of functional endometriotic lesions outside the uterus. The Endometriosis Symptom Diary (ESD) is an electronic patient-reported outcome (ePRO) instrument that assesses women's experience of endometriosis symptoms, with pain scored using a 0-10 numeric rating scale. This study investigated patterns of data missing from the ESD in the VALEPRO study. METHODS: Post hoc analyses of missing data were conducted. RESULTS: Of 272 participants using the ESD, 26.5% had no missing diary entries, 46.7% had > 0-5% of entries missing, 13.2% had > 5-10% of entries missing and 13.6% had > 10% of entries missing over the entire study period. The duration of missing episodes (defined as ≥1 consecutive days with missing diary entries) was generally short; most (81.4%) were 1 day. The difference in mean worst pain scores between missing and complete episodes per participant was - 0.1, suggesting that missing episodes were not related to severity of pain. Entries were significantly more likely to be missing on Fridays (18.5%) and Saturdays (22.9%) compared with other days of the week (p < 0.0001). Participants in the USA had significantly more long missing episodes than those in Germany (proportions of missing episodes longer than 1 day, 22.6 and 10.5%, respectively; p < 0.0001). The proportions of women with ≥1 missing entry were 50.0, 70.2 and 79.8% for women with elementary education, secondary education, and a college or university education, respectively. The proportions of women with ≥1 missing entry were similar for those with and without children (72.2 and 74.3%, respectively). CONCLUSIONS: Most participants were highly compliant with entering data in the ESD and the amount of missing data was low. Entries were significantly more likely to be missing on Fridays and Saturdays compared with other days of the week, and participants in the USA had significantly more long missing episodes than participants in Germany. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01643122 , registered 4 July 2012.

Design of OASIS 1 and 2: phase 3 clinical trials assessing the efficacy and safety of elinzanetant for the treatment of vasomotor symptoms associated with menopause.

OBJECTIVE: Elinzanetant is a selective neurokinin-1,3 receptor antagonist in development for the treatment of vasomotor symptoms (VMS) associated with menopause. The pivotal, double-blind, randomized, placebo-controlled phase 3 studies Overall Assessment of efficacy and Safety of elinzanetant In patients with vasomotor Symptoms (OASIS) 1 and 2 will assess the efficacy and safety of elinzanetant in women with VMS. METHODS: The OASIS 1 and 2 pivotal studies are designed in accordance with regulatory guidance. Postmenopausal women with moderate/severe VMS are randomized to receive 120 mg elinzanetant or placebo once daily for 12 weeks, followed by a 14-week active treatment extension. Primary endpoints are the mean change in frequency and severity of moderate/severe VMS from baseline to weeks 4 and 12. Key secondary endpoints will assess the onset of action and effects on sleep disturbance and menopause-related quality of life. Primary and key secondary endpoints will be analyzed using a mixed model with repeated measures. Feedback from postmenopausal women with VMS was used during protocol development. RESULTS: Women confirmed the relevance of endpoints that assess the impact of VMS, sleep disturbance, and mood changes, and the need for new nonhormone treatments. Educational materials around study design, conduct and expected assessments and procedures were developed based on questions and concerns raised by women. CONCLUSIONS: The OASIS 1 and 2 pivotal phase 3 studies will enable assessment of the efficacy and safety of elinzanetant as a treatment for VMS, together with its effect on sleep disturbances, depressive symptoms, and menopause-related quality of life. Feedback from postmenopausal women with VMS was used to maximize patient centricity in the trials.

The Severity of Chronic Cough Diary (SCCD): development and content validation of a novel patient-reported outcome instrument for evaluating the symptom experience of chronic cough.

BACKGROUND: Refractory chronic cough (RCC), a cough lasting longer than 8 weeks with an unexplained underlying etiology and unresponsive to conventional treatment, can have substantial effects on patients' quality of life. For assessment of the efficacy of antitussive medication in clinical trials in RCC, patient-reported outcome (PRO) instruments should be fit for purpose with appropriate content validity. Here we describe the qualitative testing of a newly developed PRO instrument: the Severity of Chronic Cough Diary (SCCD). METHODS: The SCCD was developed to assess patients' symptom experience of cough in patients with RCC. A preliminary version was tested and refined based on an iterative process in a qualitative study. In total, three rounds of interviews were conducted with adult participants diagnosed with RCC in the USA (n = 19) and UK (n = 10). Rounds 1-3 consisted of hybrid concept elicitation (CE) interviews and cognitive interviews (CIs), with Round 3 also including interviews in a subset of participants (n = 5) about the usability of the SCCD as administered on an electronic handheld device. RESULTS: The CE interviews identified concepts important to patients' experiences related to RCC that were broadly in line with the concepts in the preliminary version of the SCCD. Participants provided positive feedback on the draft SCCD across all CI rounds, reporting the instrument to be relevant and straightforward to complete, and containing a comprehensive set of concepts to evaluate their symptom experience of RCC. Participants demonstrated a good understanding of proposed item wording, response options, and the 24-hour recall period, and thought completion of the SCCD on the electronic device was easy. Following revisions based on results from each interview round, the SCCD at the end of this qualitative research study had 14 items assessing the concepts of: cough symptoms (five items), symptoms related to cough (four items), disruption to activities due to cough (three items), and disruption to sleep due to cough (two items). CONCLUSIONS: The results of this study provide qualitative evidence supporting the content validity of the SCCD as a PRO instrument for evaluating outcomes of therapies for RCC in clinical trials.

Rehospitalization in the first 2 years of life in children born preterm.

AIM: Aim of the study is to investigate the frequency of and predictors for rehospitalization within the first 2 years of life among preterm infants. METHODS: All children born before 32 weeks of gestation in Northern Tyrol between January 2003 and July 2008 were prospectively enrolled. Data on rehospitalizations were obtained from hospital admission records. The association between candidate risk factors and readmission was analysed by means of logistic regression analysis. RESULTS: In the first and second years of life, 151 and 93 of 377 children (40.1% and 24.7%), respectively, were readmitted to one of the hospitals in Northern Tyrol. The most common causes of rehospitalization were respiratory disorders, accounting for 42.1% and 47.4% of total readmissions in the first and second years of life. Chronic lung disease (CLD), male sex and smoking in pregnancy were risk conditions relevant to readmission in the first year of life, but only CLD in the second year. CONCLUSION: Infants born before 32 weeks of gestation have a high risk of rehospitalization with respiratory illness significantly contributing to postdischarge morbidity. Neonatal intensive care should aim to further improve respiratory health in preterm infants, and adequate follow-up services must be offered.

Validation of a menstrual pictogram and a daily bleeding diary for assessment of uterine fibroid treatment efficacy in clinical studies.

BACKGROUND: To evaluate the psychometric and measurement properties of two patient-reported outcome instruments, the menstrual pictogram superabsorbent polymer-containing version 3 (MP SAP-c v3) and Uterine Fibroid Daily Bleeding Diary (UF-DBD). Test-retest reliability, criterion, construct validity, responsiveness, missingness and comparability of the MP SAP-c v3 and UF-DBD versus the alkaline hematin (AH) method and a patient global impression of severity (PGI-S) were analyzed in post hoc trial analyses. RESULTS: Analyses were based on data from up to 756 patients. The full range of MP SAP-c v3 and UF-DBD response options were used, with score distributions reflecting the cyclic character of the disease. Test-retest reliability of MP SAP-c v3 and UF-DBD scores was supported by acceptable intraclass correlation coefficients when stability was defined by the AH method and Patient Global Impression of Severity (PGI-S) scores (0.80-0.96 and 0.42-0.94, respectively). MP SAP-c v3 and UF-DBD scores demonstrated strong and moderate-to-strong correlations with menstrual blood loss assessed by the AH method. Scores increased in monotonic fashion, with greater disease severities, defined by the AH method and PGI-S scores; differences between groups were mostly statistically significant (P < 0.05). MP SAP-c v3 and UF-DBD were sensitive to changes in disease severity, defined by the AH method and PGI-S. MP SAP-c v3 and UF-DBD showed a lower frequency of missing patient data versus the AH method, and good agreement with the AH method. CONCLUSIONS: This evidence supports the use of the MP SAP-c v3 and UF-DBD to assess clinical efficacy endpoints in UF phase III studies replacing the AH method.

Development and content validation of two new patient-reported outcome measures for endometriosis: the Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS).

BACKGROUND: Endometriosis is a common, chronic, impactful condition in women of reproductive age. In the absence of established sensitive and specific biomarkers, disease severity is determined by patient-reported symptoms and impacts. This article details the development of two new patient-reported outcome (PRO) measures designed to assess efficacy endpoints in clinical studies: The Endometriosis Symptom Diary (ESD) and the Endometriosis Impact Scale (EIS). METHODS: The ESD and EIS were developed according to best practice and scientific standards (including the Food and Drug Administration (FDA) PRO Guidance) and with extensive input from women with surgically-confirmed endometriosis. Research included: a review of published qualitative literature; concept elicitation interviews in the US, Germany and France (n = 45) to explore the experiences of women with endometriosis and to inform ESD and EIS development; and cognitive interviews in the US and Germany (n = 31) to assess relevance and understanding of the ESD and EIS and usability of administration using an electronic handheld device. The FDA and the European Medicines Agency (EMA) as well as PRO and clinical experts were consulted throughout the process. RESULTS: Pelvic pain was identified as the most frequent, severe and bothersome symptom for women with endometriosis. Pain was reported to be greatest during menstruation (dysmenorrhea) and during or after sexual intercourse (dyspareunia). Pain resulted in significant impairments in physical activities, work/study, social/leisure activities, household activities and sexual functioning. All women highlighted the emotional impact of endometriosis. Descriptions of pain and associated impacts were largely consistent across participants from the US and Europe, with the most notable differences being the words used to describe the location of pain (e.g., 'pelvis' vs. 'abdomen'). Testing during cognitive interviews indicated that the ESD and EIS were well understood and consistently interpreted. Furthermore, all participants found the ePRO devices easy to use and no issues regarding visual presentation, selection of responses or navigation were identified. CONCLUSIONS: Evidence from extensive qualitative research supports the content validity of the ESD and EIS as patient-reported measures of the disease-defining symptoms of endometriosis and the associated impact on women's lives. Future research will seek to establish the measurement properties of the measures.

Comparing the EQ-5D-5L utility index based on value sets of different countries: impact on the interpretation of clinical study results.

OBJECTIVE: To compare the country-specific value sets of the EQ-5D-5L utility index and to evaluate the impact on the interpretation of clinical study results. Six country value sets from Canada, England, Japan, Korea, Netherlands and Uruguay were obtained from literature. In addition, ten crosswalk value sets were downloaded from the EuroQol.org website. RESULTS: For each of the 3125 possible health states the difference between the country with the highest index and the country with the lowest index was calculated. The median difference was 0.417 across the health states. When analyzing multinational clinical studies, country-specific value sets should be used to evaluate treatment effects. Additional country-specific analyses are needed.

Neonatal characteristics and risk of atopic asthma in schoolchildren: results from a large prospective birth-cohort study.

AIM: Asthma is among the most common chronic diseases in childhood and steadily increasing in prevalence. Identification of risk predictors for a hospitalization for atopic asthma in childhood may help design prevention programmes and improve our understanding of disease pathobiology. METHODS: An ongoing birth-cohort study prospectively enrolled all liveborn infants in Tyrol. Between 1994 and 1999 baseline data were collected for 33,808 infants. From 2000 to 2005, all children hospitalized for atopic asthma at an age of 6 years or over (n = 305) were identified in a careful search of hospital databases. Disease status was ascertained from the typical medical history, a thorough examination and proof of atopy. RESULTS: Male sex (relative risk 2.11, 95% CI 1.65-2.70), urban living environment (vs. rural) (1.93, 1.47-2.54), neonatal admission to hospital (1.70, 1.20-2.40), lack of breastfeeding (1.32, 1.02-1.70), postnatal smoking (1.31, 1.00-1.72) and low birth weight (1.45, 0.94-2.23) all emerged as adverse risk predictors for hospitalization for atopic asthma whereas a low risk was found among children living on a farm (0.22, 0.05-0.87) and children with two to three siblings (vs. no or one sibling) (0.71, 0.51-0.97). CONCLUSION: In this study a number of neonatal characteristics and environmental exposures were associated with hospitalization for atopic asthma in childhood, suggesting that early life is crucial for disease determination and lending further indirect support to the hygiene hypothesis.