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.

Results from a pooled analysis of two European, randomized, placebo-controlled, phase 3 studies of ATX-101 for the pharmacologic reduction of excess submental fat.

BACKGROUND: The injectable adipocytolytic drug ATX-101 is the first nonsurgical treatment for the reduction of submental fat (SMF) to undergo comprehensive clinical evaluation. This study aimed to confirm the efficacy and safety of ATX-101 for SMF reduction through a post hoc pooled analysis of two large phase 3 studies. METHODS: Patients with unwanted SMF were randomized to receive 1 or 2 mg/cm(2) of ATX-101 or a placebo injected into their SMF during a maximum of four treatment sessions spaced approximately 28 days apart, with a 12-week follow-up period. The proportions of patients with reductions in SMF of one point or more on the Clinician-Reported SMF Rating Scale (CR-SMFRS) and the proportions of patients satisfied with the appearance of their face and chin [Subject Self-Rating Scale (SSRS) score ≥4] were reported overall and in subgroups. Other efficacy measures included improvements in the Patient-Reported SMF Rating Scale (PR-SMFRS), calliper measurements of SMF thickness, and assessment of skin laxity [Skin Laxity Rating Scale (SLRS)]. Adverse events and laboratory test results were recorded. RESULTS: Significantly greater proportions of the patients had improvements in clinician-reported measures (≥1-point improvement in CR-SMFRS: 58.8 and 63.8 % of the patients who received ATX-101 1 and 2 mg/cm(2), respectively, and 28.6 % of the placebo recipients; p < 0.001 for both ATX-101 doses vs. placebo) and patient-reported measures (≥1-point improvement in PR-SMFRS: 60.0 and 63.1 % of the patients who received ATX-101 1 and 2 mg/cm(2), respectively, vs. 34.3 % of the placebo recipients; p < 0.001 for both), analyzed alone or in combination, with ATX-101 versus placebo. These improvements correlated moderately with patient satisfaction regarding face and chin appearance (SSRS score ≥4: 60.8 and 65.4 % of the patients who received ATX-101 1 and 2 mg/cm(2), respectively, vs. 29.0 % of the placebo recipients; p < 0.001 for both). In this study, ATX-101 was effective irrespective of gender, age, or body mass index. Reduction in SMF with ATX-101 was confirmed by calliper measurements (p < 0.001 for both doses vs. placebo) and generally did not lead to worsening of skin laxity (SLRS improved or was unchanged: 91.3 and 90.5 % of the patients who received ATX-101 1 and 2 mg/cm(2), respectively, and 91.6 % of the placebo recipients). Adverse events were mostly transient, mild to moderate in intensity, and localized to the treatment area. CONCLUSION: The findings show ATX-101 to be an effective and well-tolerated pharmacologic treatment for SMF reduction.

Riociguat in children with pulmonary arterial hypertension: The PATENT-CHILD study.

Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT-CHILD (NCT02562235), a multicenter, single-arm, 24-week, open-label, Phase 3 study. Patients aged 6-17 years in World Health Organization functional class (WHO-FC) I-III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5-2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty-four patients (mean age 12.8 years), 18 of whom were in WHO-FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study-drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6-minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT-proBNP was -66 ± 585 pg/ml (n = 14). There was no change in WHO-FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.

A Systematic Approach for Post Hoc Subgroup Analyses With Applications in Clinical Case Studies.

BACKGROUND: The analysis of subgroups in clinical trials is essential to assess differences in treatment effects for distinct patient clusters, that is, to detect patients with greater treatment benefit or patients where the treatment seems to be ineffective. METHODS: The software application subscreen (R package) has been developed to analyze the population of clinical trials in minute detail. The aim was to efficiently calculate point estimates (eg, hazard ratios) for multiple subgroups to identify groups that potentially differ from the overall trial result. The approach intentionally avoids inferential statistics such as P values or confidence intervals but intends to encourage discussions enriched with external evidence (eg, from other studies) about the exploratory results, which can be accompanied by further statistical methods in subsequent analyses. The subscreen application was applied to 2 clinical study data sets and used in a simulation study to demonstrate its usefulness. RESULTS: The visualization of numerous combined subgroups illustrates the homogeneity or heterogeneity of potentially all subgroup estimates with the overall result. With this, the application leads to more targeted planning of future trials. CONCLUSION: This described approach supports the current trend and requirements for the investigation of subgroup effects as discussed in the EMA draft guidance for subgroup analyses in confirmatory clinical trials (EMA 2014). The lack of a convenient tool to answer spontaneous questions from different perspectives can hinder an efficient discussion, especially in joint interdisciplinary study teams. With the new application, an easily executed but powerful tool is provided to fill this gap.

Single-agent activity of phosphatidylinositol 3-kinase inhibition with copanlisib in patients with molecularly defined relapsed or refractory diffuse large B-cell lymphoma.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have adverse outcomes. We evaluated the efficacy and safety of the phosphatidylinositol 3-kinase inhibitor copanlisib in patients with relapsed/refractory DLBCL and assessed the relationship between efficacy and DLBCL cell of origin (COO; activated B-cell like [ABC] and germinal center B-cell like [GCB]) and other biomarkers. The primary endpoint was objective response rate (ORR) in DLBCL COO subgroups (ABC, GCB, and unclassifiable) and by CD79B mutational status (NCT02391116). Sixty-seven patients received copanlisib (ABC DLBCL, n = 19; GCB DLBCL, n = 30; unclassifiable, n = 3; missing, n = 15). The ORR was 19.4%; 31.6% and 13.3% in ABC and GCB DLBCL patients, respectively. ORR was 22.2%/20.0% for patients with/without CD79B mutations (wild type, n = 45; mutant, n = 9; missing, n = 13). Overall median progression-free survival and duration of response were 1.8 and 4.3 months, respectively. Adverse events included hypertension (40.3%), diarrhea (37.3%), and hyperglycemia (32.8%). Aberrations were detected in 338 genes, including BCL2 (53.7%) and MLL2 (53.7%). A 16-gene signature separating responders from nonresponders was identified. Copanlisib treatment demonstrated a manageable safety profile in patients with relapsed/refractory DLBCL and a numerically higher response rate in ABC vs. GCB DLBCL patients.

A Systematic Approach for Post Hoc Subgroup Analyses With Applications in Clinical Case Studies.

BACKGROUND: The analysis of subgroups in clinical trials is essential to assess differences in treatment effects for distinct patient clusters, that is, to detect patients with greater treatment benefit or patients where the treatment seems to be ineffective. METHODS: The software application subscreen (R package) has been developed to analyze the population of clinical trials in minute detail. The aim was to efficiently calculate point estimates (eg, hazard ratios) for multiple subgroups to identify groups that potentially differ from the overall trial result. The approach intentionally avoids inferential statistics such as P values or confidence intervals but intends to encourage discussions enriched with external evidence (eg, from other studies) about the exploratory results, which can be accompanied by further statistical methods in subsequent analyses. The subscreen application was applied to 2 clinical study data sets and used in a simulation study to demonstrate its usefulness. RESULTS: The visualization of numerous combined subgroups illustrates the homogeneity or heterogeneity of potentially all subgroup estimates with the overall result. With this, the application leads to more targeted planning of future trials. CONCLUSION: This described approach supports the current trend and requirements for the investigation of subgroup effects as discussed in the EMA draft guidance for subgroup analyses in confirmatory clinical trials (EMA 2014). The lack of a convenient tool to answer spontaneous questions from different perspectives can hinder an efficient discussion, especially in joint interdisciplinary study teams. With the new application, an easily executed but powerful tool is provided to fill this gap.